BRYOSTATIN ANALOGUES, SYNTHETIC METHODS AND USES

Abstract: Biologically active compounds related to the bryostatin family of compounds, having simplified spacer domains and/or improved recognition domains are disclosed, including methods of preparing and utilizing the same.

Description: BYROSTATIN ANALOGUES, SYNTHETIC METHODS AND USES BACKGROUND OF THE INVENTION Cross-reference to Related Applications This is a continuation-in-part of co-pending provisional U S Application Serial No 60/168,181, filed November 30, 1999, incorporated herein by reference Government Interest This invention was made with the support of NIH grant number CA31845 Accordingly, the U S Government may have certain rights in this invention Field of the Invention The present invention concerns biologically active compounds related to the bryostatin family of compounds, and to methods of preparing and utilizing the same Introduction Cancer is a major cause of death in the developed countπes, with more than 500,000 human fatalities occurring annually in the United States Cancers are generally the result of the transfoiTtiation of normal cells into modified cells that proliferate excessively, leading to the formation of abnormal tissues or cell populations In many cancers, cell proliferation is accompanied by dissemination (metastasis) of malignant cells to other parts of the body which spawn new cancerous growths Cancers can significantly impair normal physiological processes, ultimately leading to patient mortality Cancers have been observed for many different tissue and cell types, with cancers of the lung, breast, and colorectal system accounting for about half of all cases Currently, about one-third of cancer patients can be cured by surgical or radiation techniques However, these approaches are most effective with cancerous lesions that have not yet metastasized to other regions of the body Chemotherapeutic techniques currently cure another 17% of cancer patients Combined chemotherapeutic and non-chemotherapeutic protocols can further enhance prospects for full recovery Even for incurable cancer conditions, therapeutic treatments can be useful to achieve remission or at least extend patient longevity Numerous anticancer compounds have been developed over the past several decades (e g , Katzung, 1998, Wilson et al , 1991, Hardman et al , 1996) While these compounds comprise many different classes that act by a variety of mechanisms, one general approach has been to block the proliferation of cancerous cells by interfeπng with cell division For example, anthracyclines, such as doxorubicin and daunorubicin, have been found to intercalate DNA, blocking DNA and RNA synthesis and causing strand scission by interacting with topoisomerase II The taxanes, such as Taxol™ and Taxotere™, disrupt mitosis by promoting tubulin polymerization m microtubule assembly Cis-platin forms interstrand crosslinks in DNA and is effective to kill cells in all stages of the cell cycle As another example, cyclophosphamide and related alkylating agents contain dι-(2-chloroethyl)-amιno groups that bind covalently to cellular components such as DNA The bryostatins (Formula A) are a family of naturally occurring macrocyclic compounds originally isolated from marine bryozoa Currently, there are about 20 known natural bryostatins which share three six-membered rings designated A, B and C, and which differ mainly in the nature of their substituents at C7 (OR A ) and C20 (R B ) (Pettit, 1996) Formula A The bryostatins exhibit potent activity against a broad range of human cancer cell lines and provide significant in vivo life extensions in murine xenograft tumor models (Pettit et al , 1982, Hornung et al , 1992, Schuchter et al , 1991, Mohammad et al , 1998) Doses that are effective in vivo are extremely low, with activities demonstrated for concentrations as low as 1 μg/kg (Schuchter et al , 1991) Among additional therapeutic responses, the bryostatins have been found to promote the normal growth of bone marrow progenitor cells (Scheid, 1994, Kraft, 1996), provide cellular protection against normally lethal doses of ionizing radiation (Szallasi, 1996), and stimulate immune system responses that result in the production of T cells, tumor necrosis factors, interleukins and interferons (Kraft, 1996, Lind, 1993) Bryostatins are also effective in inducing transformation of chronic lymphocytic leukemia cells to a hairy cell type (Alkatib, 1993), increasing the expression of p53 while decreasing the expression of bcl-2 in inducing apoptosis in cancer cells (Maki, 1995, Mohammad, 1995) or at least pre-disposing a cell towards apoptosis, and reversing multidrug resistance (MDR) (Spitaler, 1998) At the molecular level, bryostatins have been shown to competitively inhibit the binding of plant-derived phorbol esters and endogenous diacyl glycerols to protein kinase C (PKC) at nanomolar to picomolar drug concentrations (DeVnes, 1998), and to stimulate comparable kinase activity (Kraft, 1986, Berkow, 1985, Ramsdell, 1986) Unlike the phorbol esters, however, the bryostatins do not act as tumor promoters Thus, the bryostatins appear to operate through a mode of action different from, and complementary to, the modes of action of established anticancer agents; human clinical trials are presently evaluating bryostatin combination therapy with cisplatin or taxol. Various studies have demonstrated good affinity for bryostatins in which R A is hydroxyl, acetyl, pivaloyl, or n-butanoate, and R B is H, acetyl, n-butanoate, or 2,4-unsaturated octanoate, as measured by PKC binding assay (Wender et al., 1988). The double bond between C13 and C30 can be hydrogenated or epoxidized without significant loss of binding affinity. Hydrogenation of the C21-C34 alkene or acetylation of the C26 hydroxyl, on the other hand, can significantly reduce binding affinity. Inversion of the stereoconfiguration at C26 leads to modest loss of activity (approx. 30-fold) and the suggestion that the methyl group may limit rotation of bonds proximate to the methyl group and contribute to the apparent high binding affinity observed for the bryostatins. Elimination of the hydroxyl at C19 (with concomitant omission of the C20 R B group) causes an approximately 100-fold to 200-fold decrease in binding. Likewise, impairing the accessibility of the C26 hydroxymethyl moiety by replacement of the C26 hydroxyl, or by replacing the methyl or hydrogen substituents of C26 with a tert-butyl or similar bulky substituent, has been proposed for diminishing toxicity (Blumberg et al., 1997). Although the bryostatins have been known for some time, their low natural abundance, difficulties in isolation and severely limited availability through total synthesis have impeded efforts to elucidate their mode of action and to advance their clinical development. Recently, synthetic analogues of bryostatin were reported wherein the C4-C14 spacer domain was replaced with simplified spacer segments using a highly efficient esterification-macrotransacetalization (Wender et al., 1998a, 1998b). The reported analogues retained orientation of the C1-, C19-, C26-oxygen recognition domain as determined by NMR spectroscopic comparison with bryostatin and varying degrees of PKC-binding affinity. The one analogue tested for in vitro inhibition in human tumor cell lines was reported to posess significant activity. It has remained, however, desired to provide new, simplified, and more readily accessible synthetic agents based on the bryostatin structure to further elucidate the molecular basis of bryostatin's activity and develop improved and more readily available clinical candidates, especially for anticancer applications. SUMMARY OF THE INVENTION One aspect of the present invention concerns simplified bryostatin analogues, i.e., the compounds represented by Formula I: Formula I wherein: R 20 is H, OH, or O 2 CR'; R 21 is =CR a R b or R 2 ' represents independent moieties R c and R d where: R a and R b are independently H, C0 2 R', CONR c R d or R'; R c and R d are independently H, alkyl, alkenyl or alkynyl, or (CH 2 ) n C0 2 R' where n is 1 , 2 or 3; R 26 is H, OH or R'; each R' being independently selected from the group: alkyl, alkenyl or alkynyl, or aryl, heteroaryl, aralkyl or heteroaralkyl; and L is a straight or branched linear, cyclic or polycyclic moiety, containing a continuous chain of preferably from 6 to 14 chain atoms, which substantially maintains the relative distance between the Cl and C17 atoms and the directionality of the C1C2 and C16C17 bonds of naturally- occurring bryostatin; and the pharmaceutically acceptable salt thereof. In a preferred aspect of the recognition domain in this embodiment R 26 is H or methyl, particularly when R 21 is =C(H)C0 2 R'. Especially preferred are the compounds where R 26 is H. A preferred upper limit on carbon atoms in any of R d , R e and R' is about 20, more preferably about 10 (except as otherwise specifically noted, for example, with reference to the embodiment of the invention where a preferred R 20 substituent has about 9 to 20 carbon atoms). In a preferred aspect of the spacer domain of this embodiment, L contains a terminal carbon atom that, together with the carbon atom corresponding to C17 in the native bryostatin structure, forms a trans olefin. Another aspect of the invention concerns the simplified bryostatin analogues represented by Formulae II - V: Formula II Formula IV wherein: R 3 is H, OH or a protecting group; R 6 is H,H or =0; R 8 is selected from the group: H, OH, R', -(CH 2 ) n O(0)CR' or (CH 2 ) n C0 2 -haloalkyl where n is 0, 1, 2, 3, 4 or 5; R 9 is H or OH; R 20 , R 2 ', R 26 and R'are as defined above with respect to Formula I; p is 1 , 2, 3 or 4; and X is C, O, S or N-R c where R e is COH, C0 2 R' or S0 2 R', and the pharmaceutically acceptable salts thereof. In a preferred aspect, the invention relates to the C26 des-methyl analogue of Formula Ila Formula Ila and to pharmaceutical compositions and methods of treatment therewith. Still another aspect of the invention relates to the C26 des-methyl homologues of the native bryostatins, as illustrated in Formula VI: Formula VI where R Λ and R B correspond to the naturally occurring bryostatin substituents, such as C26 des-methyl Bryostatin 1 , the compound of Formula Via: Formula Via and to pharmaceutical compositions and methods of treatment therewith. Excluded from the scope of the present invention are the analogues of Formula 1998a (where R 3 is H or OH) and the analogue of Formula 1998b: 1998a 1998b In another aspect, the invention relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof admixed with at least one pharmaceutically acceptable excipient. In still another aspect, the invention relates to a method of treating hyperproliferative cellular disorders, particularly cancer in a mammal by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, either alone or in combination with a second agent, preferably a second anti-cancer agent that acts by a distinct mechanism vis-a-vis the mechanism of the compound of Formula I In yet another aspect, the invention relates to methods of treatment for a mammal having an immune-related disease or receiving immunosuppressive therapy, by administering of a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof In another aspect of the invention, there is provided a method for the synthesis of bryostatin analogues, including the steps of estenfication and macrotrasacetyhzation of a protected recognition domain with a protected linker synthon, followed by deprotection Particularly preferred is reduction of a C26 OBn protected predursor to give the corresponding C26 des-methyl bryostatin analogue A related aspect of the invention entails the novel products made by the foregoing process The invention also includes pharmaceutical compositions containing one or more compounds m accordance with the invention In another aspect, the invention includes a method of inhibiting growth, or proliferation, of a cancer cell In the method, a cancer cell is contacted with a bryostatin analogue compound in accordance with the invention in an amount effective to inhibit growth or proliferation of the cell In a broader aspect, the invention includes a method of treating cancer in a mammalian subject, especially humans In the method, a bryostatin analogue compound in accordance with the present invention is administered to the subject in an amount effective to inhibit growth of the cancer in the patient These and other objects and features of the invention will be better understood in light of the following detailed descπption DETAILED DESCRIPTION Definitions As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise As used herein, the terms "alkyl", "alkenyl" and "alkynyl," refer to saturated and unsaturated monovalent moieties in accordance with their standard meanings, including straight-chain, branched- chain and cyclic moieties, optionally containing one or more intervening heteroatoms, such as oxygen, sulfur, and nitrogen in the chain or πng, respectively Exemplary alkyl groups include methyl, ethyl, isopropyl, cyclopropyl, 2-butyl, cyclopentyl, and the like Exemplary alkenyl groups include 2-pentenyl, 2,4-pentadιenyl, 2-octenyl, 2,4,6-octatπenyl, CH 3 -CH 2 -CH 2 -CH=CH-CH=CH-, cyclopentadienyl, and the like Exemplary alkynyl groups include CH 3 C≡CCH 2 -, 4-pentyn-l-yl, and the like Exemplary cyclic moieties include cyclopentyl, cyclohexyl, furanyl, pyranyl, tetrahydrofuranyl, 1,3-dιoxanyl, 1,4- dioxanyl, pyrrohdyl, pipeπdyl, mo hohno, and reduced forms of furanyl, lmidazyl, pyranyl, pyπdyl, and the like "Lower alkyl", "lower alkenyl", and "lower alkynyl" refer to alkyl, alkenyl, and alkynyl groups containing 1 to 4 carbon atoms The term "aryl" denotes an aromatic ring or fused πng structure of carbon atoms with no heteroatoms in the rιng(s) Examples are phenyl, naphthyl, anthracyl, and phenanthryl Preferred examples are phenyl and napthyl The term "heteroaryl" is used herein to denote an aromatic πng or fused ring structure of carbon atoms with one or more non-carbon atoms, such as oxygen, nitrogen, and sulfur, in the ring or in one or more of the rings in fused nng structures Examples are furanyl, pyranyl, thienyl, lmidazyl, pyrrolyl, pyπdyl, pyrazolyl, pyrazinyl, pyπmidinyl, indolyl, quinolyl, isoquinolyl, quinoxalyl, and quinazohnyl Preferred examples are furanyl, lmidazyl, pyranyl, pyrrolyl, and pyπdyl "Aralkyl" and "heteroaralkyl" refer to aryl and heteroaryl moieties, respectively, that are linked to a main structure by an intervening alkyl group, e g , containing one or more methylene groups "Alkoxy", "alkenoxy", and "alkynoxy" refer to an alkyl, alkenyl, or alkynyl moiety, respectively, that is linked to a main structure by an intervening oxygen atom It will be appreciated that the alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, and heteroaralkyl moieties utilized herein can be unsubstituted or substituted with one or more of the same or different substituents, which are typically selected from -X, -R', =0, -OR', -SR', =S, -NR'R', -NR'R'R' + , =NR', -CX 3 , -CN, -OCN, -SCN, -NCO, -NCS, -NO, -N0 2 , =N 2 , -N 3 , -S(0) 2 0 , -S(0) 2 OH, -S(0) 2 R', -C(0)R', -C(0)X, -C(S)R', -C(S)X, -C(0)OR', -C(0)0 , -C(S)OR', -C(0)SR', -C(S)SR', -C(0)NR'R', -C(S)NR'R' and -C(NR)NR'R', where each X is independently a halogen (F, Cl, Br, or I, preferably F or Cl) and each R' is independently hydrogen, alkyl, alkenyl, or alkynyl In one embodiment, R' is lower alkyl, lower alkenyl, or lower alkynyl NR'R' also includes moieties wherein the two R' groups form a ring with the nitrogen atom While practical size limits for the various substituent groups will be apparent to those skilled in the art, generally preferred are the alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, and heteroaralkyl moieties containing up to about 40 carbon atoms, more preferably up to about 20 carbon atoms and most preferably up to about 10 carbon atoms (except as otherwise specifically noted, for example, with reference to the embodiment of the invention where a prefeπed R 20 substituent has about 7 to 20 carbon atoms) As to any of the above groups that contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are steπcally impractical and/or synthetically non-feasible In addition, the compounds of this invention include all stereochemical isomers and mixtures thereof arising from the substitution of these compounds Except as otherwise specifically provided or clear from the context, the term "compounds" of the invention should be construed as including the "pharmaceutically acceptable salts" thereof (which expression has been eliminated in certain instances for the sake of brevity). The term "pharmaceutically acceptable salt" refers to salts which retain the biological effectiveness and properties of the compounds of this invention and which are not biologically or otherwise undesirable. In some cases, the compounds of this invention are capable of forming acid and/or base salts, derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and "Mammal" is intended to have its conventional meaning Examples include humans, mice, rats, guinea pigs, horses, dogs, cats, sheep, cows, etc The term "treatment" or "treating" means any treatment of a disease in a mammal, including • preventing the disease, that is, causing the clinical symptoms of the disease not to develop, • inhibiting the disease, that is, arresting the development of clinical symptoms, and/or • relieving the disease, that is, causing the regression of clinical symptoms The term "effective amount" means a dosage sufficient to provide treatment for the disease state being treated This will vary depending on the patient, the disease and the treatment being effected. Compounds The present invention provides new analogues of bryostatin that can be synthesized conveniently in high yields and which have useful biological activities. The compounds of the invention can be broadly described as having two main regions that are referred to herein as a "recognition domain" (or pharmacophonc region) and a relatively lipophilic "spacer domain" (or linker region) The recognition domain contains structural features that are analogous to those spanning C17 through C26 to Cl , including the C ring formed in part by atoms C19 through C23, and the lactone linkage between Cl and C25 of the native bryostatin macrocycle The spacer domain, on the other hand, joins the atoms corresponding to Cl through C17 of the native bryostatin macrocycle to substantially maintain the relative distance between the Cl and C17 atoms and the directionality of the C1C2 and C16C17 bonds, as illustrated by the arrows and distance "d" in Formula la (in which the substituent groups are as defined with reference to Formula I). Formula la In addition to its function of maintaining the recognition domain in an active conformation, the spacer domain (shown as "L" in Formula la and sometimes also refeπed to as a linker region) provides a moiety that can be readily derivatized according to known synthetic techniques to generate analogues having improved in vivo stability and pharmacological properties (e g , by modulating side effect profiles) while retaining biological activity It has been found in the present invention that the linker region of of the bryostatin family can be varied significantly without eliminating activity Thus, a wide variety of linkers can be used while retaining significant anticancer and PKC-binding activities Preferably, the compounds of the present invention include a linker moiety L, which is a linear, cyclic, or polycychc linker moiety containing a continuous chain of from 6 to 14 chain atoms, one embodiment of which defines the shortest path from C25 via Cl to C17 Thus, L may consist solely of a linear chain of atoms that links C17 via Cl to C25, or alteratively, may contain one or more πng structures which help link C17 via Cl to C25 Preferably, the linker region includes a lactone group (-C(=0)0-), or a lactam group (-C(=0)NH-), which is linked to C25 of the recognition region, by analogy to the Cl lactone moiety that is present in the naturally occurπng bryostatins In addition, it is preferred that the linker include a hydroxyl group analogous to the C3 hydroxyl found in naturally occurnng bryostatins, to permit formation of an intramolecular hydrogen bond between the C3 hydroxyl of the linker and the C19 hydroxyl group of the recognition region (and optionally with the oxygen of the native B ring) In one preferred embodiment, the linker terminates with -CH(OH)CH 2 C(=0)0-, for joining to C25 of the recognition region via an ester (or when cychzed a lactone) linkage In one embodiment of the invention where R 26 is H, the compounds of the invention differ from known bryostatins and bryostatin analogues in that the present compounds contain a primary alcohol moiety at C26, l e , the present analogues lack a methyl group corresponding to the C27 methyl that is ordinarily present in naturally occurring bryostatins Surprisingly, while the C27 methyl moiety was previously believed to limit rotation of the C26 alcohol and contribute to PKC binding affinity, it has been found that this structural modification can significantly increase PKC binding and also increases efficacy against cancer cells Other modifications of R 26 are provided to further modulate these characteπstics, as are the C26 des-methyl homologues of the native bryostatins In another aspect, the present invention provides bryostatins and bryostatin analogues in which R 20 is longer (e g , having 9 to 20 or more carbon atoms) than the corresponding substituents at C20 in the native bryostatins (e g , Bryostatin 3 having an 8-carbon atom moiety) Certain preferred spacer domains employed in the compounds of the invention are illustrated in Formulae II throught V wherein R is H, OH or a protecting group, R 8 is selected from the group H, OH, R', -(CH 2 ) n O(0)CR' or (CH 2 ) n C0 2 -haloalkyl, where n is 0, 1, 2, 3, 4 or 5, R 20 , R 21 , R 26 and R'are as defined above with respect to Formula I, X is C, O, S or N-R e where R e is a group that stabilizes the nitrogen's lone pair of electrons, such as COH, C0 2 R' or S0 2 R', and the pharmaceutically acceptable salts thereof Excluded from the present invention are the analogues of Formula 1998a (where R 3 is H or OH) and the analogue of Formula 1998b 1998a 1998b Nomenclature For simplicity of reference, the compounds of Formulae I-V are named and numbered herein as corresponding to the naturally occurring bryostatin macrocycle, described above with reference to Formula A For example, the C26 des-methyl homologue of native bryostatin 1 (a compound of the present invention) has the structure illustrated in Formula Via Formula Via By way of compaπson, the analogues of the invention in which R 26 is hydrogen, such as those of Formula Ila and Formula IVa Formula Ila Formula IVa are also referred to as "C26 des-methyl", notwithstanding that the structures corresponding to L (in Formula I) or the corresponding spacer domain (in Formulae II-V), or even the recognition domain, contain fewer carbon atoms than native bryostatin such that the "C26" position would be assigned a lower number were these analogues to be named without reference to the native structure Synthetic Reaction Parameters The terms "solvent", "inert organic solvent" or "inert solvent" mean a solvent inert under the conditions of the reaction being described in conjunction therewith [including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloπde (or dichloromethane), diethyl ether, methanol, pyπdine and the like] Unless specified to the contrary, the solvents used in the reactions of the present invention are inert organic solvents The terms "protecting group" or "blocking group" refer to any group which when bound to a functional group such as one or more hydroxyl, thiol, amino or carboxyl groups of the compounds (including intermediates thereof) prevents reactions from occurπng at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl, thiol, amino or carboxyl group The particular removable blocking group employed is not cπtical and preferred removable hydroxyl blocking groups include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl-diphenylsilyl and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product The term "q s " means adding a quantity sufficient to achieve a stated function, e g , to bring a solution to the desired volume (I e , 100%) Unless specified to the contrary, the reactions descnbed herein take place at atmospheπc pressure within a temperature range from about 5°C to 100°C (preferably from 10°C to 50°C, most preferably at "room" or "ambient" temperature, e g , 25°C) Further, unless otherwise specified, the reaction times and conditions are intended to be approximate, e g , taking place at about atmospheric pressure within a temperature range of about 5°C to about 100°C (preferably from about 10°C to about 50°C, most preferably about 25°C) over a period of about 0 5 to about 10 hours (preferably about 1 hour) Parameters given in the Examples are intended to be specific, not approximate Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or puπfication procedure such as, for example, distillation, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures Specific illustrations of suitable separation and isolation procedures can be had by reference to the general description and examples However, other equivalent separation or isolation procedures can, of course, also be used Synthesis of the Compounds of Formula I The compounds of the invention may be produced by any methods available in the art, inducing chemical and biological (e g , recombinant and in vitro enzyme-catalyzed) methods In one embodiment, the present invention provides a convergent synthesis in which subunits primarily corresponding to the recognition and spacer domains are separately prepared and then joined by esteπfication- macrotransacetalization (Wender et al., 1998a, 1998b, 1998c). Additional syntheses of the compounds of Formulae I-VI are described below with reference to the Reaction Schemes. Reaction Scheme 1 illustrates synthesis of precursors for the recognition domain in compounds of the invention. Reaction Scheme 1 104a R = βH 104b R = αH 106 R = OBn 107 R = H 108 R = θCCθ 2 R' Reaction Scheme 2 illustrates the further synthesis of recognition domains for C26 des-methyl compounds of the invention. Reaction Scheme 2 207 Reaction Scheme 3 illustrates synthesis of the protected alcohol precursor to many of the hyl analogues of the invention. Reaction Scheme 3 301 CHjOH 302 CHO Reaction Scheme 4 illustrates the synthesis of linker synthons for preparing the compounds of Formula II. Reaction Scheme 4 407 R = TBSO 408 R = TESO Reaction Scheme 5A illustrates the synthesis of linker synthons for preparing the compounds of Formula III where R is OH. Reaction Scheme 5A 504 Reaction Scheme 5B illustrates the synthesis of linker synthons for preparing the compounds of Formula III where R and/or R are H. Reaction Scheme 5B 505 507 - R° : H 508 - R 8 ■ K Reaction Scheme 5C illustrates the synthesis of linker synthons for preparing the compounds of Formula III where R 6 is =0 with a variety of possible substituents at R 8 . 402 509 513 Reaction Scheme 6 illusttates the synthesis of linker synthons for preparing the compounds of Formula IV. Reaction Scheme 6 HO 605 606 OTBS OSEM Reaction Scheme 7A illustrates the synthesis of the compounds of Formula II. Reaction Scheme 7A Reaction Scheme 7B illustrates the synthesis of the compounds of Formula III. Reaction Scheme 7B 207 / 303 / 304 R' = OTBS or OBn 705 R" - OH, OTBS or OBn Reaction Scheme 8 illusttates synthesis of the Compounds of Formula IV, particularly where R is methyl, the C26 des-methyl analogues of Formula IV being obtained by like synthesis. Reaction Scheme 8 806 R = OBn 807 R = OH Reaction Scheme 9 illustrates synthesis of the Compounds of Formula V. 903 Reaction Schemes 10 and 11 illustrate the synthesis of compounds of the invention that are further derivatized at the C20 position, as discussed in Examples 4B, 4C and 4D Reaction Scheme 10 a) CH(OMe) 3 , PPTS, MeOH, b) K 2 C0 3 , MeOH, c) heptenoic acid, EfeN, DMAP, Yamaguchi's reagent, CH2CI2 (84% for three steps), d) DDQ, CH2CI2 H2O (85%), e) 48% HF, CH 3 CN/H 2 0 (80% yield), f) Yamaguchi's reagent, EfeN, DMAP (80%), g) HF-Pyπdine, THF (68%), h) Amberlyst 15, CH 2 Cl2 (70%), i) Pd(OH) 2 , EtOAc, H , 1 atm (63% yield) Reaction Scheme 11 44 R = C 13 H 27 46 R = C-J3I I27 48 R = 0-J3M27 45 R = Ph 47 R = Ph 49 R = Ph (a) 2,4,6-trιchlorobenzoylchlorιde, EfeN, DMAP then 44 or 45, CH 2 CI 2 , rt, 90% for R = C 13 H 27 , 89% for R = Ph (b) HF'pyπdine, THF, rt, 83% for R = C 13 H 27 , 80% for R = Ph (c) Pd(OH) 2 , H 2 , EtOAc, 1 atm, 97% for 48, 63% for 49 Starting Materials. Conveniently, compounds of the invention can be prepared from starting materials that are commercially available or may be readily prepared by those skilled in the art using commonly employed synthetic methodology Reaction Scheme 1 illustrates a method for forming a synthon designated herein as 111 which is useful for providing the recognition domain in compounds of the invention, for example as detailed in Example 1 6-(Ter/-butyldιmethylsιlylhydroxy)-5-dιmethylhexane-2,4-dιone (101, Example IB) is stirred with 2 equivalents of LDA (lithium dnsopropylamine) in THF (tetrahydrofuran), followed by addition of 0 9 equivalents of 3R-p-methoxybenzyl-4R-benzylhydroxypentane-l-al (102, Example 1A) to afford diasteπomenc aldol mixture 103 after suitable purification To 103 is then added a catalytic amount of p-methylphenylsulfonic acid (p-TsOH) with stirring at room temperature followed by base quenching to produce pyranone condensation product 104 as a mixture of α and β-isomers at C23 (104a and 104b) The β-isomer (104a) is separated from the α-isomer and is reacted with NaBH 4 in the presence of CeCl 3 *7H 2 0, followed by quenching with aqueous brine to form an allylic alcohol (not shown)that can then be epoxidized with m-chloroperbenzoic acid (mCPBA) in 2 1 CH 2 C1 2 MeOH containing sodium bicarbonate as a buffer to yield a C19-methoxylated C20,C21 s w-diol 105 Selective benzoylation of the C21 equatoπal alcohol with benzoyl chloride to afford C21 monobenzoate (not shown), followed by oxidation of the C20 hydroxyl with Dess-Martin peπodinane ( 1,1,1 -tπacetoxy- 1,1- dιhydro-l,2-benzιodoxol-3(lH)-one) at room temperature affords the corresponding 20-keto-21-benzoate product 106 Treatment of 106 with Sml 2 (2 equiv) yields a ketone 107 selectively deoxygenated at C21 Next, ketone 107 is reacted with LDA and OHCC0 2 CH 3 in THF at -78°C to afford aldol mixture 108. After purification, 108 is reacted with methanesulfonylchloπde in CH 2 C1 2 containing tπethylamine, followed by reaction with DBU (l,8-dιazabιcyclo[5 4 0]undec-7-ene) in THF to effect an aldol condensation and elimination of water, to yield an α,β-unsaturated methyl ester (enone 109) with an E- stereoconfiguration Treatment of enone 109 with NaBH in the presence of CeCl 3 '7H 2 0 produces exclusively the C20 axial alcohol 110 This product can then be esteπfied at C20, with octanoic acid for example, to yield the desired synthon 111 It will be appreciated how the foregoing procedures can be exploited or modified to produce recognition region synthons having different substituents For example, compounds where R 21 contains a C35 ester group having a Z-configuration are produced during formation of intermediate 109 (Example 1C) and can be isolated by chromatography Similarly, other ester groups can be introduced at C35 by replacing the OHCC0 2 CH 3 reactant used to form 108 above with an appropπately substituted compound of the form OHCC0 2 R\ in which R' is other than methyl In addition, as detailed below, other substituents can be introduced in synthon 111 to generate substituent R 20 at C20 by substituting any of a variety of carboxylic acids for the octanoic acid reacted with axial alcohol 110 (as in the last step of Example 1C), including other saturated, unsaturated, aryl, and carboxyhc acids In synthesizing the compounds of the invention where R 20 has been varied, the substituent (e g , a desired C20 ester substituent) can be introduced into a recognition region synthon prior to condensing the recognition region synthon with a linker synthon using the procedures descnbed in Example 4 In Example 4A, the C20 octanoate substituent in synthon 111 can be replaced with an acetyl group by first protecting the base labile aldehyde group using tπmethyl orthorformate to form the dimethyl acetal The C20 octanoate ester can then be cleaved using a basic solution, such as K 2 C0 3 in methanol, to afford the free C20 alcohol, followed by reaction with an activated form of acetic acid, such as acetic anhydride or acetyl chloride, to obtain the C20 acetate product The product can then be deprotected at the C15 aldehyde, C19 oxygen, and C25 oxygen using benzoqumone compound DDQ (to remove the p-methoxybenzyl group and cleave the dimethyl acetal) followed by aqueous HF (demethylation at C19) to afford the corresponding C19 alcohol This product can then be condensed with an appropnately substituted linker synthon to produce a desired bryostatin analogue, such as analogue 702.1, as detailed in Example 4A The protected alcohol precursor to many of the C26-desmethyl bryostatin analogues of the invention (the compounds of Formula I where R 26 is H) can be made as illustrated in Reaction Scheme 2 Dι(benzyl ether) 111 can be hydrogenated over Pearlman's catalyst to produce the corresponding C25,C26 diol 201 Treatment of the diol with lead tefraacetate yields the corresponding C25 aldehyde (not shown), with the release of C26 and C27 Reaction of the aldehyde with Cp 2 Tι(Cl)CH 2 Al(CH 3 ) 2 (Tebbe's reagent) yields C25,C26 olefin 202 Alternatively, sodium peπodate can be used in place of lead tettaacetate Treatment of olefin 202 with HF/pyπdine is effective to remove the silyl protecting group, followed by treatment with Dess-Martin peπodinane (supra) to oxidize the C17 alcohol to an aldehyde group, affording aldehyde 203 The C25,C26 olefin of 203 can be converted to C25,C26 diol 204 by reaction with chiral dihydroxylating reagent (DHQD) 2 AQN in the presence of K 3 Fe(CN) 6 , K 2 C0 3 and K 2 Os0 2 (OH) 4 in /-butanol Product 204 is obtained as a 2 1 (β α) mixture of 25-hydroxy diastereomers The α-diastereomer can be removed later in the synthesis Treatment of 204 with tπethylsilyl chlonde yields protected diol 205, which can be employed in the synthesis of the compounds of Formula V Addition of backbone atoms corresponding to C15 and C16 of the bryostatin backbone to 205 can be accomplished in four steps First, the C17 aldehyde is allylated with allyl diethylborane The reaction is quenched with saturated sodium bicarbonate to yield the desired C17 allyl adduct The C17 hydroxyl group can then be acylated with acetic anhydride in the presence of tπethylamine and 4- dimethylaminopyπdine (DMAP), to afford a diastereomeπc mixture of homoallyhc C17 acetates This product mixture can be oxidized using N-methylmorphohne N-oxide and osmium tetraoxide, followed by neutralization with sodium bicarbonate After extraction, the residue is reacted with lead tettaacetate, followed by addition of DBU to cause elimination of the acetate group, yielding enal 206 The C25 hydroxyl group of 206 can be unmasked in preparation for closure of the macrocycle as follows First, enal 206 is treated with aqueous hydrofluoπc acid to provide a crude diol intermediate in which the C19 methoxy group is converted to a free hydroxyl Next, the diol product is reacted with tert- butyldimethylsilyl chloride (TBSC1) in the presence of lmidazole to produce alcohol 207 containing a C25 hydroxyl group and C26 OTBS group as a 2 1 (β α) mixture of C25 diastereomers Silica gel chromatography can be used to resolve the diastereomers, affording the β diastereomer in 50-60% yield The protected alcohol precursor to many of the C26-methyl bryostatin analogues of the invention (Formula I where R 26 is methyl) can be made as illustrated in Reaction Scheme 3, via methods analogous to the preparations for 205 and 206 Deprotection and acylation of formula 111 may be accomplished, for example, by following the procedures descnbed in Wender et al , (1998a) Linker synthons for the compounds of Formula II (where X is a heteroatom) can be prepared, for example, as illustrated with reference to Reaction Scheme 4, and later described in Examples 2A and 2B These compounds contain two nngs that are analogous to the A and B πngs of bryostatin, but lack the naturally occurring substituents at C7, C8, C9, and C13 The presence of a heteroatom, such as an oxygen, sulfur or nitrogen atom (the lone electron pair of which is stabilized) in place of C14 does not adversely affect activity of the end product, but is required for transacerylization in the later synthetic steps The compounds of formulae 406 and 408 differ in that 402 provides a protecting group precursor for a hydroxyl group attached to C3, whereas 406 does not provide for a hydroxyl at C3 The linker synthons for the compounds of Formula III (in which X is a heteroatom), which contain a B-πng-like structure but lack an A-πng, are prepared, for example, as illustrated with reference to Reaction Schemes 5A through 5C Examples 2C and 2D describe methods for prepaπng synthons 504 and 508 In both examples, R 8 is a tert butyl group attached to C9 However, with reference to the preparation of 505, the /-BuLi reactant can be replaced by R'Li to generate the corresponding linker synthons of 508 where R 8 is R' 504 additionally contains a TMS protecting group for synthesis of the compounds where R 9 is a hydroxyl attached to C9, rather than hydrogen Also, both synthons contain a TBS protecting group for the compounds where R 3 is a hydroxyl group attached to C3 Example 2E describes the corresponding method for making synthon 507, which is unsubstituted at C9 Example 2G describes a method for preparing linker synthons in which C5 is provided as an ester carbonyl In addition, the synthons in this Example contain an R 6 substituent that is preferably a saturated or unsaturated substituent containing 1 to 20 carbon atoms and optionally (1) one or more oxygen atoms and (2) optionally one or more nitrogen atoms In synthon 514 in Example 2G, R 8 is -C(CH 3 ) 2 CH 2 OC(=0)Cι 3 H 27 However, other R 6 substituents can be introduced by suitable modification of the procedure as will be evident to one of ordinary skill in the chemical arts Synthesis of a completely acyclic linker synthon 606 (where neither an A- nor a B-πng-hke structure is present) is descnbed with reference to Reaction Scheme 6 and in Example 2F As illustrated with reference to Reaction Scheme 7A, and further described in Example 3A, an alcohol such as 207, 303 or 304 is reacted with an acid such as 406 or 408 in a two step process to form the desired macrocychc structure After in situ conversion of the acid (408) to a mixed anhydride, the alcohol (207) is added to form ester 701 The ketal portion of 408 is then joined (in a process referred to as macrotranacetylization) to C15 of 701 by adding 70% HF/pyndine hydrofluoric acid to catalyze cleavage of the menthone ketal, cleavage of the TBS ethers at C3 and C26, and formation of a new ketal between the C15 aldehyde group and the linker diol moiety generated by release of the menthone (where X is oxygen), to afford desired analogue of Formula II where X is a heteroatom and R 26 is H (starting with alcohol 207) or methyl (starting with 303 or 304), I e , compound of formula 702 This last reaction is also effective to set the stereocenter at C15 to a thermodynamically prefened configuration The analogous synthesis of compounds of Formula III (where X is a heteroatom), first forming the ether bond between Cl and C25, is lllustratred with reference to Reaction Scheme 7B (where formula 703 corresponds to any of formulae 504, 507, 508 or 513) and further described in Example 3C As illustrated with reference to Reaction Scheme 8, and further described in Example 3B, the compounds of Formula IV (such as formula 807) can be made from pharmacophonc synthon 801 and linker synthon 606 from Example 2F Reaction Scheme 9 illustrates synthesis of the compounds of Formula V, e g , as further described in Example 3D, from synthon 111 and an activated dicarboxyhc acid (succinic anhydπde) to give formula 903 Although the bryostatin analogues produced in Examples 3B, 3C and 3D all contain a C27 methyl group, analogous C26 desmethyl analogues can be readily synthesized using an appropriate C26 desmethyl synthon, such as C26 desmethyl synthon 207 descnbed in Example 1C Compounds of the invention having a naturally occurring bryostatin backbone (e g , including a naturally occuπng linker region), but lacking the C27 methyl group, can also be prepared by adapting synthetic protocols published by Kageyama et al (1990) and Evans et al (1998), which are incorporated herein by reference In brief, the published methods are modified by utilizing synthons in which the C27 methyl group has been omitted, to afford the desired C26-desmethyl analogues As illustrated with reference to Reaction Scheme 10, synthesis of a C20 heptanoate ester 43 is described in Example 4B, using a similar reaction scheme to that employed in Example 4A, except that heptenoic acid in the presence of tπethylamine, DMAP, and Yamaguchi's agent is used in place of acetic anhydride Yamaguchi's reagent is again employed in step f to activate the COOH group of formula 6, followed by removal of the TBS group in step g, hydrolysis of the menthone and transacetyhzation in step h, and saturation of the double bond upon removal of the benzyl group by hydrogenolysis in step i Synthesis of a C20 myπstate ester analogue 48 (14 carbon atom chain) is lllustratred with reference to Reaction Scheme 11 and descnbed in Example 4C Reaction Scheme 11 and Example 4D descnbes synthesis of a bryostatin analogue containing an aryl ester group (benzoate) at C20, by suitable adaptation of the procedure in Example 1C for making compound 207 It will be appreciated how these procedures can be modified to inttoduce other C20 esters by substituting the starting materials necessary to produce the desired products In particular, C26 des-methyl analogues can be made using an appropriate C26 des-methyl synthon, such as 207 noted above The lactam analogues of the invention are obtained by converting the C25 hydroxyl group (e g , of formula 207) to an amine under Mitsonobu conditions, after first protecting the aldehyde (and the C19 hydroxyl group in the corresponding compounds in Reaction Schemes 10 and 11) followed by formation of the macrocycle and de-protection under conditions analogous to those employed for the lactone analogues, as will be apparent to one skilled in the art The C26 des-methyl bryostatin homologues of the invention can be obtained by substituting homologous des-methyl starting materials for the starting materials employed in published bryostatin syntheses (e g , Masamune 1988a, 1988b, Evans et al 1998, Kageyama et al 1990) For example, in the total synthesis of bryostatin 7, Serine is substituted for threomne in a Masamune's C17-C26 southern bryostatin synthesis to yield the corresponding C26 des-methyl sulfone Other synthetic methodology will be apparent to those skilled in the art given the objective of providing such C26 des-methyl bryostatin homologues Preferred Processes and Last Steps A C19,C26 hydroxyl-protected, C26 des-methyl bryostatin recognition domaine precursor and an optionally protected linker synthon are esteπfied, macrottansacetylated and de-protected to give the corresponding C26 des-methyl bryostatin analogue A bryostatin analogue precursor having the C26 hydroxyl substituted by a protecting group (particularly OBn) is reduced to give the corresponding compound of Formula I Serine is substituted for threomne m a Masamune's C17-C26 southern bryostatin synthesis to yield the corresponding C26 des-methyl sulfone, which in turn is employed in synthesis of a C26 desmethyl bryostatin homologue A compound of Formula I-VI is contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salt A pharmaceutically acceptable acid addition salt of Formula I-VI is contacted with a base to form the corresponding compound of Formula I-VI Preferred Compounds The following substituents, compounds and groups of compounds are presently preferred In the compounds of Formulae I-V, especially those of Formulae II-V, it is preferred that R 26 is H Most preferred are the compounds of Formula II where R 26 is H, and of those where X is oxygen Of the compounds where R 26 is H, additionally preferred are those compounds where R 20 is 0 2 CR', especially where R' is alkyl (preferably about C 7 -C 20 alkyl), alkenyl (preferably about C 7 -C 20 alkenyl such as CH 3 -CH 2 -CH 2 -CH=CH-CH=CH-) or aryl (preferably phenyl or naphthyl). Another group of preferred compounds where R 26 is H are those where R 21 is =CR a R b (especially where one of R a or R b is H and the other is C0 2 R', and preferably where R' is C,-Cι 0 alkyl, most preferably lower alkyl such as methyl). The compounds of Formulae I-V, especially II-V, are preferred where R 20 is 0 2 CR' and R' is alkyl (preferably about C 7 -C 20 alkyl), alkenyl (preferably about C 7 -C 20 alkenyl such as CH 3 -CH 2 -CH 2 -CH=CH-CH=CH-) or aryl (preferably phenyl or naphthyl). Particularly preferred are those compounds where R 20 is 0 2 CR' and R 21 is =CR a R b (especially where one of R a or R b is H and the other is C0 2 R', and preferably where R' is C Cι 0 alkyl, most preferably lower alkyl such as methyl). The compounds of Formulae I-V, especially II-V, are preferred where R 21 is =CR a R b (especially where one of R a or R b is H and the other is C0 2 R', and preferably where R' is C Cι 0 alkyl, most preferably lower alkyl such as methyl). Of the compounds according to Formula I, it is preferred that L be a group having from about 6 to about 14 carbon atoms. Of the compounds according to Formulae II or III, it is preferred that X is oxygen. Of the compounds according to Formulae II-IV, it is preferred that R 3 is OH, and especially preferred that X is oxygen in the case of Formulae II and III. Of the compounds according to Formula II, it is preferred that R 20 is 0 2 CR' where R' is alkyl (preferably about C 7 -C 20 alkyl), alkenyl (preferably about C 7 -C 20 alkenyl such as CH 3 -CH 2 -CH 2 -CH=CH-CH=CH-) or aryl (preferably phenyl or naphthyl). Of these, further preferred are the compounds where R 2 ' is =CR a R b (especially where one of R a or R b is H and the other is C0 2 R', and preferably where R' is C Cιo alkyl, most preferably lower alkyl such as methyl). Of the compounds according to Formula III, it is preferred that R 9 is H. It is further preferred that R 8 is -(CH 2 ) n O(0)CR\ particularly where R' is alkyl, R 6 optionally being =0. Further prefeπed are those compounds that combine various of the above-mentioned features. The single isomers highlighted in the reaction schemes and examples are also preferred. Presently, most prefeπed is the compound of Formula II where X is oxygen, R 3 is OH, R 20 is -0-CO-C 7 H, 5 , R 2 ' is =CH-C0 2 Me and R 26 is H. Utility, Testing and Administration General Utility The compounds of the present invention are useful as bryostatin-like therapeutic agents, and in pharmaceutical formulations and methods of treatment employing the same. Other compounds of the invention are useful a precursors in the synthesis of such agents. Importantly, in many cases, the compounds of the present invention can be readily synthesized on a large scale, and thus can be made readily available for commercial purposes as compared to the low yields and environmental problems lnherrent in the isolation of bryostatins from natural sources In one aspect, the compounds of the invention find use as anticancer agents in mammalian subjects For example, representative cancer conditions and cell types against which the compounds of the invention may be useful include melanoma, myeloma, chronic lymphocytic leukemia (CLL), AIDS- related lymphoma, non-Hodgkin's lymphoma, colorectal cancer, renal cancer, prostate cancer, cancers of the head, neck, stomach, esophagus, anus, or cervix, ovarian cancer, breast cancer, peritoneal cancer, and non-small cell lung cancer The compounds appear to operate by a mechanism distinct from the mechanisms of other anticancer compounds, and thus can be used synergistically in combination with other anticancer drugs and therapies to treat cancers via a multimechamstic approach The compounds of the invention exhibit potencies comparable to or better than previous bryostatins against many human cancer types In another aspect, the compounds of the invention can be used to strengthen the immune system of a mammalian subject, wherein a compound of the invention is administered to the subject in an amount effective to increase one or more components of the immune system For example, strengthening of the immune system can be evidenced by increased levels of T cells, antibody-producing cells, rumor necrosis factors, mterleukins, mterferons, and the like Effective dosages may be comparable to those for anticancer uses, and can be optimized with the aid of vaπous immune response assay protocols such as are known in the art (e g , see Kraft, 1996, Lind, 1993, US Patent 5,358,711, all incorporated herein by reference) The compound can be administered prophyllactically, e g , for subjects who are about to undergo anticancer therapies, as well as therapeutically, e g , for subjects suffering from microbial infection, bum victims, subjects with diabetes, anemia, radiation treatment, or anticancer chemotherapy The lmmunostimulatory activity of the compounds of the present invention is unusual among anticancer compounds and provides a dual benefit for anticancer applications First, the lmmunostimulatory activity allows the compounds of the invention to be used in greater doses and for longer periods of time than would be possible for compounds of similar anticancer activity but lacking lmmunostimulatory activity Second, the compounds of the present invention can offset the immunosuppressive effects of other drugs or treatment regimens when used in combination therapies Additional features of the invention can be further understood from the following illustrative examples which are not intended to limit the scope of the invention in any way Testing In practicing vaπous aspects of the present invention, compounds in accordance with the invention can be tested for a biological activity of interest using any assay protocol that is predictive of activity in vivo For example, a variety of convenient assay protocols are available that are generally predictive of anticancer activity in vivo In one approach, anticancer activity of compounds of the invention can be assessed using the protein kinase C assay detailed in Example 5 In this assay, K, values are determined for analogues based on competition with radiolabeled phorbol 12,13-dιbutyrate for binding to a mixture of PKC lsoenzymes PKC enzymes are implicated in a variety of cellular responses which may be involved in the activity of the bryostatins Example 6 descnbes another protein kinase C assay which can be used to assess the binding affinities of compounds of the invention for binding to the C1B domain of PKCδ Although all PKC isozymes are upregulated immediately after administration of bryostatin or tumor promoting phorbol esters followed by an extended down-regulation penod, PKCδ appears to be protected against down regulation by bryostatin 1 Overexpression of PKCδ inhibits tumor cell growth and induces cellular apoptosis, whereas depleting cells of PKCδ can cause tumor promotion Accordingly, this assay provides useful binding data for assessing potential anticancer activity Another useful method for assessing anticancer activities of compounds of the invention involves the multiple-human cancer cell line screening assays run by the National Cancer Institute (e g , Boyd, 1989) This screening panel, which involves approximately 60 different human cancer cell lines, is a useful indicator of in vivo antitumor activity for a broad vanety of tumor types (Grever et al , 1992, Monks et al , 1991), such as leukemia, non-small cell lung, colon, central nervous system (CNS), melanoma, ovanan, renal, prostate, and breast cancers Antitumor activites can be expressed in terms of ED 50 (or GI 50 ), where ED 50 is the molar concentration of compound effective to reduce cell growth by 50% Compounds with lower ED 50 values tend to have greater anticancer activities than compounds with higher ED 50 values Example 7 descπbes a P388 munne lymphocytic leukemia cell assay which measures the ability of compounds of the invention to inhibit cellular growth Upon the confirmation of a compounds potential activity in the above in vitro assays, further evaluation is typically conducted in vivo in laboratory animals, for example, measunng reduction of lung nodule metastases in mice with B16 melanoma (e g , Schuchter et al, 1991) The efficacy of drug combination chemotherapy can be evaluated, for example, using the human B-CLL xenograft model in mice (e g , Mohammad et al, 1996) Ultimately, the safety and efficacy of compounds of the invention are evaluated in human clinical trials Expenments conducted in support of the present invention demonstrate that compounds of the present invention exhibit high potencies in several anticancer assays, as summanzed in the Examples Administration The invention includes a method of inhibiting growth, or proliferation, of a cancer cell, or enhancing the effectiveness of other drugs In the method, a cancer cell is contacted with a bryostatin analogue compound in accordance with the invention in an amount effective to inhibit growth or proliferation of the cell In a broader aspect, the invention includes a method of treating cancer in a mammalian subject, especially humans In the method, a bryostatin analogue compound in accordance with the invention is administered to the subject in an amount effective to inhibit growth of the cancer in the patient Similarly, in the immune modulation methods of the invention, a compound of the invention is aqdministered to a subject in need thereof, in an amount herapeutically effective for bolstering of the immune system predisposed toward apoptosis Compositions and methods of the present invention have particular utility in the area of human and veterinary therapeutics Generally, administered dosages will be effective to deliver picomolar to micromolar concenttations of the therapeutic composition to the target site Typically, nanomolar to micromolar concentration at the target site should be adequate for many applications Appropπate dosages and concenttations will depend on factors such as the particular compound or compounds being administered, the site of intended delivery, and the route of administration, all of which can be deπved empirically according to methods well known in the art Administration of compounds of the invention in an appropnate pharmaceutical form can be carried out by any appropπate mode of administration Thus, administration can be, for example, intravenous, topical, subcutaneous, ttansocular ttanscutaneous, intramuscular, oral, intta-joint, parenteral, peπtoneal, lnttanasal, or by inhalation The formulations may take the form of solid, semi -solid, lyophihzed powder, or liquid dosage forms, such as, for example, tablets, pills, capsules, powders, sustained-release formulations, solutions, suspensions, emulsions, suppositones, retention enemas, creams, ointments, lotions, aerosols, and the like In one embodiment, the formulation has a unit dosage form suitable for administration of a precise dose Pharmaceutical compositions of the invention typically include a conventional pharmaceutical earner or excipient and may additionally include other medicinal agents, earners, adjuvants, antioxidants, and the like In one embodiment, the composition may comprise from about 1% to about 75% by weight of one or more compounds of the invention, with the remainder consisting of suitable pharmaceutical excipients For oral administration, such excipients include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, for example Appropnate excipients can be tailored to the particular composition and route of administration by methods well known in the art, e g , (Gennaro, 1990) Additional guidance for formulations and methods of administration can be found in patent references concerning previously known bryostatins, such as U S Patents 4,560,774 and 4,611,066 to Pettit et al , which are incorporated herein by reference Usually, for oral administration, the compositions will take the form of a pill, tablet or capsule Thus the composition will contain, along with active drug, a diluent such as lactose, sucrose, dicalcium phosphate, and or other material, a disintegrant such as starch or derivatives thereof, a lubricant such as magnesium stearate and the like, and a binder such a starch, gum acacia, polyvinylpyπo done, gelatin, cellulose and/or derivatives thereof The compounds of the invention may also be formulated into a suppository compnsing, for example, about 0 5% to about 50% of a compound of the invention, disposed in a polyethylene glycol (PEG) carrier (e g , PEG 1000 [96%] and PEG 4000 [4%]) Liquid compositions can be prepared by dissolving or dispersing compound (e g , from about 0 5% to about 20% of final volume), and optional pharmaceutical adjuvants in a carrier, such as, for example, aqueous saline, aqueous dextrose, glycerol, ethanol and the like, to form a solution or suspension Useful vehicles also include polyoxyethylene sorbitan fatty acid monoesters, such as TWEEN™ 80, and polyethoxylated castor oils, such as Cremophor EL™ available from BASF (Wyandotte, MD), as discussed in PCT Publ No WO 97/23208 (which is incorporated herein by reference), which can be diluted into conventional saline solutions for intravenous administration Such liquid compositions are useful for intravenous administration One such formulation is PET diluent which is a 60/30/10 v/v/v mixture of PEG 400, dehydrated ethanol, and TWEEN™-80 Liquid compositions may also be formulated as retention enemas The compounds of the invention may also be formulated as liposomes using liposome preparation methods known in the art Preferably, the liposomes are formulated either as small unilamellar vesicles or as larger vesicles If desired, the composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, such as, for example, sodium acetate, sorbitan monolaurate, ttiethanolamine oleate, and antioxidants For topical administration, the composition is administered in any suitable format, such as a lotion or a ttansdermal patch For delivery by inhalation, the composition can be delivered as a dry powder (e g , Inhale Therapeutics) or in liquid form via a nebulizer Methods for prepanng such dosage forms are known or will be apparent to those skilled in the art, for example, see Gennaro (1990) The composition to be administered will, in any event, contain a quantity of one or more compounds of the invention in a pharmaceutically effective amount for relief of the condition being treated The compounds of the invention may also be introduced in a conttolled-re lease form, for long-term delivery of drug to a selected site over a penod of several days or weeks In this case, the compound of the invention is incorporated into an implantation device or matrix for delayed or controlled release from the device The compounds can be incorporated in a biodegradable matenal, such as a biodegradable molded article or sponge Exemplary biodegradable materials include matrices of collagen, polylactic acid- polyglycohc acid, and the like In preparing bryostatin compounds in matrix form, the compounds may be mixed with matnx precursor, which is then crosslinked by covalent or non-covalent means to form the desired matnx Alternatively, the compound can be diffused into a preformed matnx Examples of suitable matenals for use as polymenc delivery systems have been descnbed e g , Aprahamian, 1986, Emmanuel, 1987, Fnendenstein, 1982, and Uchida, 1987 Generally, compounds of the invention are administered in a therapeutically effective amount, I e , a dosage sufficient to effect treatment, which may vary depending on the individual and condition being treated Typically, a therapeutically effective daily dose is from 0 1 μg/kg to 100 mg/kg of body weight per day of drug Given the high therapeutic activities of the compounds of the invention, daily dosages of from about 1 μg/kg and about 1 mg/kg of body weight may be adequate, although dosages greater than or less than this range can also be used It will be appreciated that the compounds of the invention may be administered in combination (I e , together in the same formulation or in separate formulations administered by the same or different routes) with any other anti-cancer regimen deemed appropriate for the patient For example, the compounds of the invention may be used in combination with other anticancer drugs such as vincnstine, cisplatin, ara-C, taxanes, edafrexate, L-buthionine sulfoxide, tiazofuπn, gallium nitrate, doxorubicin, etoposide, podophyllotoxins, cyclophosphamide, camptothecins, dolastatin, and auπstatin-PE, for example, and may also be used in combination with radiation therapy In a prefeπed embodiment, the combination therapy entails co-administration of an agent selected from ara-C, taxol, cisplatin and vincnstine EXAMPLES General Techniques Unless noted otherwise, materials were obtained from commercially available sources and used without further punfication Tettahydrofuran (THF) and diethyl ether (Et 2 0) were distilled from sodium benzophenone ketyl under a nitrogen atmosphere Benzene, dichloromethane (CH 2 C1 2 ), acetonitrile (CH 3 CN), tnethylamine (Et 3 N) and pyπdine were distilled from calcium hydride under a nitrogen atmosphere Chloroform (CHC1 3 ), carbon tettachlonde (CC1 4 ) and deuterated NMR solvents were dned over 1/16" bead 4A molecular sieves All operations involving moisture-sensitive materials were conducted in oven- and/or flame- dried glassware under an atmosphere of anhydrous nitrogen Hygroscopic solvents and liquid reagents were ttansfeπed using dry Gastight™ syringes or cannulating needles In cases where πgorous exclusion of dissolved oxygen was required, solvents were degassed via consecutive freeze, pump, thaw cycles or inert gas purge Nuclear magnetic resonance (NMR) spectra were recorded on either a Vaπan UNITY INOVA- 500, XL-400 or Gemιnι-300 magnetic resonance spectrometer Η chemical shifts are given in parts per million (δ) downfield from tetramethylsilane (TMS) using the residual solvent signal (CHC1 3 = δ 7.27, benzene = δ 7.15, acetone = δ 2 04) as internal standard. Proton (Η) NMR information is tabulated in the following format: number of protons, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; sept, septet, m, multiplet), coupling constant(s) (J) in hertz and, in cases where mixtures are present, assignment as the major or minor isomer, if possible. The prefix app is occasionally applied in cases where the true signal multiplicity was unresolved and br indicates the signal in question was broadened. Proton decoupled C NMR spectra are reported in ppm (δ) relative to residual CHC1 3 (δ 77.25) unless noted otherwise. Infrared spectra were recorded on a Perkin-Elmer 1600 senes FTIR using samples prepared as thin films between salt plates High-resolution mass spectra (HRMS) were recorded at the NIH regional mass spectrometty facility at the University of California, San Francisco. Fast Atom Bombardment (FAB) high-resolution mass spectra were recorded at the University of California, Riverside Combustion analyses were performed by Desert Analytics, Tucson, AZ, 85719 and optical rotations were measured on a Jasco DIP-1000 digital polanmeter. Flash chromatography was performed using E Merck silica gel 60 (240-400 mesh) according to the protocol of Still et al (1978) Thin layer chromatography was performed using precoated plates purchased from E Merck (silica gel 60 PF254, 0 25 mm) that were visualized using either a p- amsaldehyde or Ce(IV) stain For binding and cell-inhibition studies, dilutions of bryostatin and bryostatin analogues were performed in glass rather than plastic, to avoid problems associated with adsorption to plastic Example 1 - Exemplary Precursors 1A Protected Diol Aldehyde 102 BnO ,H Al Benzyl bromide (7 0 mL, 57 7 mmol) and freshly prepared Ag 2 0 (11.0 g, 48 1 mmol) were added successively to an Et 2 0 (150 mL) solution of R-(+)-methyl lactate (5 0 g, 48.1 mmol) at rt (room temperature) The resulting suspension was brought to reflux and stiπed for 2 h The reaction was cooled to rt, filtered through a pad of Cehte^M and concentrated in vacuo. Chromatography on silica gel (10% EtOAc/hexanes) afforded 7 5 g (80%) of benzyl ether Al as a colorless oil. Al: R (15% EtOAc/hexanes) = 0.66; IR 2988, 2952, 2874, 1750, 1497, 1454, 1372, 1275, 1207, 1143, 1066, 1025, 739, 698 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 1.44 (3H, d, J = 6.8 Hz, C27), 3.75 (3H, s, CH 3 0), 4.07 (IH, q, J = 6.8 Hz, C26), 4.45 (IH, ά, J = 11.7 Hz, CH 2 Ph), 4.69 (IH, d, J =1 1.7 Hz, CH 2 Ph), 7.28-7.37 (5H, m, Ph); 13 C NMR (75 MHz, CDC1 3 ) δ 18.6, 51.8, 71.9, 73.9, 127.7, 127.8, 128.3, 137.4, 173.6; HRMS Calcd for C„H 14 0 3 (iVT): 194.0943. Found: 194.0942. A3 To a solution of methyl ester Al (6.3 g, 32.3 mmol) in Et 2 0 (150 mL ) was added DIBAL-H (1.0M in hexanes, 38.75 mL) dropwise at -78°C via cannulating needle. After 5 min at -78°C, the reaction was quenched with H 2 0 and gradually warmed to rt. The resultant thick emulsion was filtered through a pad of Celite * M an( j san d, rinsing thoroughly with Et 2 0 and EtOAc. The organic phase was washed with NaHC0 3 (2x), dried over MgS0 4 and concentrated in vacuo to afford crude aldehyde A2 (not shown) as a light yellow liquid. To a solution of SnCl 4 (1.0M in CH 2 C1 2 , 32.3 mmol) in CH 2 C1 2 (120 mL) was slowly added a CH 2 C1 2 solution of aldehyde A2 at -78°C. The mixture was stirred for an additional 10 min before allyltrirnethylsilane (5.65 mL, 35.53 mmol) was added via syringe. The ensuing white suspension was kept at -78°C for 10 min, quenched by addition of H 2 0 and allowed to warm to rt. The aqueous layer was extracted with Et 2 0 and the combined organics were dried over MgS0 4 and concentrated in vacuo. Chromatography on silica gel (10% EtOAc/hexanes) afforded 4.87 g (76%) of desired diastereomer A3 plus 300 mg (5%) of a putative mixture. A3: Ry(15% EtOAc/hexanes) = 0.44; IR (film) 3454, 3066, 3030, 2976, 2871, 1641, 1497, 1554, 1375, 1071 , 1028, 992, 914, 737, 698 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 1.20 (3H, d, J= 6.2 Hz, C27), 2.22 (IH, m, C24), 2.35 (IH, m, C24), 2.56 (IH, br s, OH), 3.45 (IH, m, C25), 4.25 (IH, m, C26), 4.44 (IH, d, J = 11.5 Hz, CH 2 Ph), 4.66 (IH, ά, J = 11.5 Hz, CH 2 Ph), 5.10 (2H, m, CH 2 =CH), 5.87 (IH, m, CH 2 =CH), 7.28-7.35 (5H, m, Ph); 13 C-NMR (75 MHz, CDC1 3 ) δ 15.3, 37.4, 70.9, 74.1, 77.3, 117.03, 127.6, 127.7, 128.3, 134.7, 138.2; HRMS Calcd for Cι 3 H 18 0 2 (M " ): 206.1307. Found: 206.1313. OPMB ^ OBn A4 To a suspension of potassium /ert-butoxide (4.0 g, 35.7 mmol) in 120 mL anhydrous THF was added a solution of alcohol A3 (in 30 mL of THF) slowly over 15 min at 0°C. When complete, the mixture was stirred at rt for 45 min and then warmed to 60°C for an additional 30 min p- Methoxybenzylchlonde (3 56 mL, 26 mmol) was added and the mixture was stiπed at 60°C for 4 h The reaction was cooled to rt and quenched with sat NH 4 C1 The aqueous layer was extracted with Et 2 0 (3x) and the combined organics were dried over MgS0 4 and concentrated in vacuo The crude product was puπfied by flash chromatography (5% EtOAc/hexanes) to provide 6 80 g (88%) of differentially protected diol A4 as a colorless oil A4 R r (15% EtOAc/hexanes) = 0 59, IR (film) 3065, 2935, 2868, 1641, 1613, 1586, 1514, 1464, 1380, 1302, 1248, 1094, 1037, 913, 821, 737 cm ', Η NMR (300 MHz, CDC1 3 ) δ 1 17 (3H, d, J = 6 3 Hz, C27), 2 27 (IH, m, C24), 2 40 (IH, m, C24), 3 44 (IH, ddd, J= 7 7, 4 7, 4 6 Hz, C25), 3 62 (IH, dq, J = 1 1 , 6 3 Hz, C26), 3 78 (3H, s, CH 3 0), 4 51 (IH, d, J = 11 9 Hz, CH 2 Ph), 4 52 (2H, s, CH 2 Ph), 4 60 (IH, d, J = 1 1 9 Hz, CH 2 Ph), 5 04 (2H, m, CH 2 =CH), 5 84 (IH, m, CH=CH 2 ), 6 83 (2H, d, J = 8 7 Hz, Ar), 7 23-7 33 (7H, m, Ar), 13 C-NMR (75 MHz, CDC1 3 ) δ 15 0, 34 4, 55 1, 71 2, 72 1, 75 7, 80 9, 113 6, 116 6, 127 4, 127 6, 127 6, 128 3, 129 4, 130 9, 135 6, 138 9, 159 2, HRMS Calcd for C 21 H 26 0 3 (M + ) 326 1882 Found 326 1876, Anal Calcd for C 2 ιH 26 0 3 C, 77 27, H, 8 03 Found C, 77 22, H, 8 16, [α] D 20 = -8 9° (c 1 43, CH 2 C1 2 ) Formula 102 A4 (3 0 g, 9 2 mmol) was dissolved in 90 mL CH 2 Cl 2 /22 5 mL MeOH and cooled to -78°C Ozone was bubbled through the solution which was carefully monitored for the disappearance of starting matenal by TLC (thin layer chromatography) When the consumption of A4 was judged complete, the system was immediately purged with N 2 for 20 min and treated with solid thiourea (840 mg, 11 04 mmol) The reaction was warmed to rt slowly over 5 hours and stiπed at rt for 6 hours The solvents were removed in vacuo, and the crude mixture was punfied by flash chromatography (20% EtOAc/hexanes) to afford 2 40 g (80%) of aldehyde 102 as a colorless oil 102 Ry (15% EtOAc/hexanes) = 0 31, IR (film) 2868, 2729, 1723, 1612, 1513, 1458, 1384, 1303, 1249, 1 174, 1094, 822, 742 cm ', Η NMR (300 MHz, CDC1 3 ) δ 1 17 (3H, d, / = 6 4 Hz, C27), 2 57 (IH, ddd, J = 16 6, 7 8, 2 4 Hz, C24), 2 67 (IH, ddd, J = 16 6, 4 4, 1 6 Hz, C24), 3 71 (IH, dq, J = 6 4, 4 5 Hz, C26), 3 78 (3H, s, CH 3 0), 4 05 (IH, ddd, J= 7 8, 4 5, 4 4 Hz, C25), 4 45 (IH, d, J=l l 8 Hz, CH 2 Ph), 4 50 (2H, s, CH 2 Ph), 4 58 (IH, d, J = 11 8 Hz, CH 2 Ph), 6 84 (2H, d, J = 8 7 Hz, Ar), 7 20-7 35 (7H, m, Ar), 9 70 (IH, dd, J = 2 4, 1 6 Hz, CHO), l3 C NMR (75 MHz, CDC1 3 ) δ 14 2, 44 1, 55 1, 70 9, 72 0, 74 5, 75 1, 113 8, 127 7, 127 7, 128 4, 129 5, 130 2, 138 4, 159 4, 201 4, HRMS Calcd for C 20 H 24 O 4 (iVF) 328 1675 Found 328 1664, Anal Calcd for C 20 H 24 O 4 C, 73 13, H, 7 37 Found C, 72 81, H, 7 40, [α] D 20 = -9 1° (c 1 06, CH 2 C1 2 ) 1B Diketone 101 TBSO O A6 A mixture of methylisopropyl ketone (53 4 mL, 0 5 mol) and paraformaldehyde (19 5 g, 0 65 mol) in 200 mL CF 3 C0 2 H was stiπed at 60°C for 18 h The reaction mixture was concenttated on a rotary evaporator (warm water bath) with a KOH trap and poured into a cold (5°C) mixture of EtOAc and sat aqueous NaHC0 3 The layers were separated and the organic layer was washed with bπne, dried over MgS0 4 , and concentrated in vacuo Short path distillation gave the tnfluoroacetate ester of 3,3- dιmethyl-4-hydroxy butanone (bp = 53-55°C at 2 mm Hg, 72 4 g) in 68% yield This matenal was dissolved in 400 mL MeOH and treated with 190 mL of 2N NaOH at 0°C After 1 h at 0°C, the reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and sat aqueous NH 4 C1 The organic layer was washed with brine, dried over MgS0 4 , and concentrated to afford 40 1 g (~100%) of 3, 3 -dimethyl -4-hydroxy butanone (A5) as a colorless liquid Crude A5 was taken up in 200 mL anhydrous DMF and treated with /-butyldimethylsilylchloπde (57 3 g, 0 38 mol) and lmidazole (25 9 g, 0 38 mol) at 0°C After stirring at rt for 2 h, the solution was diluted with EtOAc, washed with sat aqueous NaHC0 3 solution and brine, dried over MgS0 and concenttated in vacuo The residue was distilled under reduced pressure to afford silyl ether ketone A6 p = 65°C at 1 5 mm Hg, 55 76 g, 81%) as a colorless oil A6 R r (25% EtOAc/hexanes) = 0 90, IR (film) 2957, 2931, 2858, 1713, 1473, 1362, 1257, 1136, 1097, 838, 777 cm 1 , Η NMR (300 MHZ, CDC1 3 ) δ 0 03 (6H, s), 0 87 (9H, s), 1 09 (6H, s), 2 17 (3H, s), 3 57 (2H, s), 13 C NMR (75 MHz, CDC1 3 ) δ 5 7, 18 1, 21 4, 25 7, 26 1 , 49 6, 70 2, 213 4, HRMS Calcd for C 12 H 26 0 2 Sι (M 4 - CH 3 ) 215 1467 Found 215 1469 A7 To a stiπed solution of dusopropylamine (12 6 mL, 96 mmol) in THF (200 mL) was added n- butyllithium (38 4 mL, 2 5M in hexane, 96 mmol) dropwise at 0°C The mixture was stiπed at 0°C for 30 min, cooled to -78°C, and treated with a solution of ketone A6 (20 0 g, 87 mmol) in THF (50 mL) slowly over 10 min After stirring at -78°C for 40 min, acetaldehyde (5 34 mL, 96 mmol) was added and the mixture was kept at -78°C for 2 h and at -40°C for 1 5 h The reaction was quenched with saturated NH 4 C1 solution (20 mL) and allowed to warm gradually to rt The mixture was extracted with ether and the combined organics were washed with bnne, dried over MgS0 4 and concenttated in vacuo to afford nearly pure aldol A7 (19 g, 80%) as a pale yellow oil. An analytical sample was obtained following chromatography on silica gel. A7: Ry (15% EtOAc/hexanes) = 0.33; IR (film) 2958, 2930, 2858, 1699, 1472, 1392, 1363, 1258, 1101, 838, 777 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 4.16 (IH, m), 3.55 (2H, s), 3.36 (IH, s), 2.74 (IH, dd, J = 18.0, 2.4 Hz), 2.68 (IH, dd, J= 18.0, 9.0 Hz), 1.16 (3H, d, J= 6.3 Hz), 1.08 (3H, s), 1.07 (3H, s), 0.85 (9H, s), 0.01 (6H, s); 13 C NMR (75 MHz, CDC1 3 ) δ -5.7, 18.1, 21.3, 22.3, 25.8, 46.2, 49.7, 63.9, 70.2, 216.8; Anal. Calcd for C 14 H 30 O 3 Si : C, 61.26; H, 11.02. Found: C, 61.01 ; H, 11.28. Formula 101 To a solution of oxalyl chloride (5.3 mL, 60.4 mmol) in CH 2 C1 2 (150 mL) was added dimethyl sulfoxide (8.56 mL, 120.8 mmol) dropwise at -78°C. After 20 min, a solution of crude alcohol A7 (15.0 g, 54.9 mmol) in CH2CI2 (150 mL) was added over 10 min and the mixture was stirred at -78°C for lh. Et 3 N (38 mL, 275 mmol) was added and the mixture was stirred for 20 min, brought to 0°C, quenched with sat. aqueous NH 4 C1 and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2x). The combined organics were washed with brine, dried over MgS0 4 , and concentrated in vacuo. Flash chromatography on silica gel (5 -> 10% EtOAc/hexanes) provided enolic β- diketone 101 (12.0 g, 81%) as a yellow oil. 101: R (15% EtOAc/hexanes) = 0.68; IR (film) 2957, 2930, 1606, 1472, 1362, 1257, 1102, 838, 777 cm "1 ; Η NMR (300 MHZ, CDC1 3 ) δ 0.01 (6H, s), 0.85 (9H, s), 1.10 (6H, s), 2.05 (3H, s), 3.53 (2H, s), 5.62 (IH, s); 13 C NMR (75 MHz, CDC1 3 ) δ -5.5, 18.3, 22.1, 25.5, 25.9, 44.9, 70.0, 98.0, 192.6, 198.5; Anal. Calcd for C 14 H 28 0 3 Si : C, 61.72; H, 10.36. Found: C, 61.08; H, 10.43. lC. Dibenzyl Ether Octanoate 111 Formulae 104a and 104b To a solution of diisopropylamine (3.21 mL, 23 mmol) in 25 mL THF at -60°C was added n- butyllithium (1.6 M in hexanes, 13.83 mL, 22.13 mmol) dropwise. The colorless solution was warmed to 0°C and stiπed for 30 min. A THF solution (35 mL) of diketone 101 (Example IB) (2.98 g, 10.9 mmol) was subsequently added via cannula and the mixture was stiπed for 1 h at 0°C. The reaction was re- cooled to -78°C and treated with a solution of aldehyde 102 (Example 1A) (3.0 g, 9.15 mmol) in 35 mL THF. After 30 min at -78°C, the mixture was quenched with sat. NH 4 C1 and brought to rt. The aqueous layer was extracted with Et 2 0, the combined organics were dried over MgS0 4 and the solvent was removed in vacuo. The crude residue was quickly passed through a column of silica gel (20% EtOAc/hexanes) to provide 5.40 g (98%) of aldol diastereomer mixture 103 as an approximately 1 : 1 mixture of diastereomers. A portion of isolated 103 (2 50 g, 4 2 mmol) was dissolved in 60 mL anhydrous toluene and treated with 4A molecular sieves (1 55g) and p-toluenesulfonic acid (60 mg) The reaction was stiπed at room temperature for 4 5 h, quenched with 2 mL pyridine and concenttated The residue was taken up in Et 2 0, washed with sat NaHC0 3 , dried over MgS0 4 and the solvent was removed in vacuo Flash chromatography (20 -> 25% EtOAc/hexanes) afforded pyrone compounds 104a (1 0 g) and 104b (1 2 g) in 90% overall yield as colorless oils 104b R (30% EtOAc/hexanes) = 0 59, Η NMR (300 MHz, CDC1 3 ) δ 0 05 (6H, s, TBS), 0 85 (9H, s, TBS), 1 05 (3H, s, C18 Me), 1 06 (3H, s, C18 Me), 1 20 (3H, d, J = 5 8 Hz, C27), 1 98 (2H, m, C24), 2 12 (IH, dd, J = 16 7 , 3 6 Hz, C24), 2 28 (IH, dd, J = 16 7, 13 7 Hz, C22), 3 44 (2H, s, C17), 3 54 (IH, m, C25), 3 72 (IH, m, C26), 3 81 (3H, s, CH 3 0), 4 23 (IH, m, C23), 4 40 (IH, d, J =l 1 2 Hz, CH 2 Ph), 447 (IH, d, J= 11 8 Hz, CH 2 Ph), 4 52 (IH, d, J =l l 2 Hz, CH 2 Ph), 4 63 (IH, d, J = 11 8 Hz, CH 2 Ph), 5 39 (IH, s, C20), 6 85 (2H, d, J = 8 7 Hz, Ar), 7 17-7 35 (7H, m, Ar), 13 C NMR (75 MHz, CDC1 3 ) δ -5 5, 14 7, 18 2, 22 4, 25 9, 34 5, 40 9, 42 4, 55 4, 69 6, 71 2, 72 0, 74 3, 76 2, 103 5, 114 1 , 127 9, 128 0, 128 7, 128 8, 129 9, 130 4, 138 8, 159 7, 182 2, 193 7, HRMS Calcd for C 34 H 50 O 6 Sι (iVT) 582 3377 Found 582 3370 104a R r (30% EtOAc/hexanes) = 0 52, IR 2955, 2857, 1667, 1599, 1514, 1397, 1336, 1301, 1249, 1174, 1102, 838 cm ', Η NMR (300 MHz, CDC1 3 ) δ 0 05 (6H, s, TBS), 0 87 (9H, s, TBS), 1 10 (3H, s, C18 Me), 1 14 (3H, s, C18 Me), 1 21 (3H, d, J = 6 3 Hz, C27), 1 71 (IH, m, C24), 2 10 (IH, m, C24), 2 42 (2H, m, C22), 3 48 (IH, d, J = 9 3 Hz, C17), 3 58 (IH, d, J = 9 3 Hz, C17), 3 76 (IH, m, C26), 3 82 (3H, s, CH 3 0), 3 83 (IH, m, C25), 443 (IH, d, J = 10 7 Hz, CH 2 Ph), 4 56 (IH, br m, C23), 4 57 (IH, d, J =l l 8 Hz, CH 2 Ph), 4 63 (IH, d, J = 10 7 Hz, CH 2 Ph), 4 65 (IH, d, J =l l 8 Hz, CH 2 Ph), 5 47 (IH, s, C20), 6 87 (2H, d, J = 8 6 Hz, Ar), 7 20 (2H, d, J= 8 6 Hz, Ar), 7 32-7 38 (5H, m, Ar), 13 C- NMR (75 MHz, CDC1 3 ) δ -5 6, 14 4, 18 1, 22 3, 22 5, 25 7, 35 2, 41 5, 42 3, 55 2, 69 4, 71 1, 72 8, 74 8, 75 9, 76 4, 103 2, 113 8, 127 5, 128 3, 129 3, 130 3, 138 5, 159 2, 181 1, 193 4, HRMS Calcd for C 34 H 50 O 6 Sι (M + ) 582 3377 Found 582 3369, Anal Calcd for C 34 H 50 O 6 Sι C, 70 06, H, 8 65 Found C, 69 95, H, 8 77, [α] D 20 = +43 9° (c 0 70, CH 2 C1 2 ) Formula 105 To a solution of pyrone 104a (680 mg, 2 4 mmol) and CeCl 3 -7H 2 0 (218 mg, 0 59 mmol) in 40 mL methanol was added solid NaBH 4 (89 mg, 2 3 mmol) m a single portion at -20°C The reaction mixture was stirred for 1 h at -20 °C and then quenched with 50 mL brine The mixture was brought to rt, filtered through a pad of Cehte^M and extracted with EtOAc (4x) The combined organics were dπed over Na 2 S0 4 and concentrated in vacuo to afford a crude allylic alcohol This moderately stable oil was earned forward without purification Crude allylic alcohol was dissolved in 45 mL CH 2 Cl 2/ MeOH (2:1) and tteated with solid NaHC0 3 (243 mg, 2.9 mmol). Purified -CPBA (377 mg, 2.20 mmol) was added in a single portion and the reaction mixture was stiπed at rt for 1 h. The mixture was quenched with Et 3 N (15 mL), stirred for 20 min, diluted with 200 mL Et 2 0, and filtered through a pad of CeliteT jhe filtrate was concentrated in vacuo and the residue was purified by flash chromatography (40% EtOAc/hexanes) to give 650 mg (71% from 104a) of syn diol 105 as a colorless oil. 105: Pγ (30% EtOAc/hexanes) = 0.29; IR (film) 3372, 1613, 1514, 1465, 1390, 1302, 1249, 1180, 1150, 1072, 935, 837, 779, 736, 698, 673 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 0.09 (6H, s, TBS), 0.91 (9H, s, TBS), 1.03 (3H, s, C18 Me), 1.07 (3H, s, C18 Me), 1.18 (3H, ά, J= 6.3 Hz, C27), 1.50-1.68 (2H, m, C24/C22), 1.80 (IH, m, C22), 2.57 (IH, app ά, J = 11.2 Hz, C24), 3.28 (3H, s, CH 3 0), 3.39, (IH, d, J= 10.1 Hz, C17), 3.62 (IH, d, J= 11.2 Hz, C17), 3.79 (3H, s, CH 3 0), 3.71-3.94 (5H, m, CH 2 Ph, C23/C25/C26), 4.40 (IH, d, J = 10.7 Hz, CH 2 Ph), 4.56 (IH, d, J = 1 1.8 Hz, CH 2 Ph), 4.62 (IH, d, J = 11.5 Hz, CH 2 Ph), 5.40 (IH, d, J = 2.5 Hz, OH), 6.84 (2H, d, = 8.7 Hz, PMB), 7.18 (2H, d, J = 8.7 Hz, PMB), 7.37-7.26 (5H, m, Bn). Formula 106 A solution of diol 105 (0.81 g, 1.28 mmol) and 4-dimethylaminopyridine (DMAP, 0.55 g, 4.48 mmol) in v 22 mL CH 2 C1 2 was cooled to -10°C and tteated with benzoyl chloride (193 μL, 1.66 mmol) dropwise via syringe. The resulting mixture was stiπed at -10°C for 30 min, quenched with sat NaHC0 3 and diluted with EtOAc (150 mL). The organic layer was washed with H 2 0 and brine, dried over Na 2 S0 4 and concenttated in vacuo to afford a crude mixture of C21 monobenzoate and 4-dimethylaminopyridine as a colorless paste. The crude C21 monobenzoate was taken up in 45 mL CH 2 C1 2 and treated with solid 1,1,1- triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one (Dess-Martin periodinane or DMP, 1.78 g, 4.20 mmol) at rt. The solution was stiπed for 10 h at rt after which a second portion (0.50 g, 1.18 mmol) of DMP was added. The opaque white mixture was stiπed for another 1.5 h and quenched with 30 mL sat. NaHC0 3 /Na 2 S 2 0 3 . The two phase system was vigorously stiπed until the organic layer cleared (-25 min). The layers were separated and the aqueous phase was extracted with CH 2 C1 2 (2x). The combined organics were dried over Na 2 S0 4 and concenttated in vacuo to provide a colorless semi-solid. Flash chromatography on silica gel (25% EtOAc/hexanes) gave 106 (0.85 g - 90% from 105) as a colorless oil. 106: R (15% EtOAc/hexanes) = 0.43; IR (film) 2954, 2933, 1754, 1723, 1610, 1513, 1451, 1267, 1251 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 0.01 (6H, s, TBS), 0.88 (9H, s, TBS), 1.12 (3H, s, C18 Me), 1.14 (3H, s, C18 Me), 1.19 (3H, d, J = 6.3 Hz, C27), 1.64-1.73 (IH, m, C24), 1.82-1.90 (IH, m, C24), 2.13 (IH, app q, J = 12.4 Hz, C22), 2.40 (IH, ddd, J = 12.4, 6.5, 1.6 Hz, C22), 3.54 (3H, s, C19 OCH 3 ), 3.65 (IH, d, J = 9.2 Hz, C17), 3.69 (IH, ά, J = 9.2 Hz, C17) 3.72-3.81 (2H, m), 3.81 (3H, s, ArOCH 3 ), 3.89 (IH, ), 4.49 (IH, ά, J= 10.7 Hz, CH 2 Ar), 4.57 (IH, ά, J= 13.0 Hz, CH 2 Ar), 4.61 (IH, ά, J = 13.0 Hz, CH 2 Ar), 4.62 (IH, d, J = 10.7 Hz, CH 2 Ar), 5.80 (IH, dd, J = 12.9, 6.3 Hz, C21), 6.87 (2H, d, J = 8.3 Hz, Ar), 7.26-7.36 (7H, m, Ar), 7.45 (2H, m, Ar), 7.58 (IH, app t, J = 7.2 Hz, Ar), 8.09 (2H, ά, J= 7.2 Hz, Ar); 13 C-NMR (75 MHz, CDC1 3 ) δ -5.3, 14.7, 18.5, 20.4, 20.6, 26.1, 35.5, 40.4, 45.1, 53.8, 55.5, 65.4, 67.2, 71.4, 73.0, 73.3, 75.1, 103.8, 114.1, 127.9, 128.6, 128.7, 129.7, 129.9, 130.2, 131.0, 133.6, 138.9, 159.6, 165.9, 198.6; HRMS Calcd for C 42 H 58 0 9 Si (M + -MeOH): 702.3588. Found: 702.3563; Anal. Calcd for C 42 H 58 0 9 Si : C, 68.63; H, 7.96. Found: C, 68.28; H, 8.11; [α] D 20 = +22.4° (c 1.53, CH 2 C1 2 ). Formula 107 A solution of benzoate 106 (0.85 g, 1.16 mmol) in 20 mL THF/MeOH (3:1) was titrated with Sml 2 (0.1 M in THF, 25.5 mL, 2.55 mmol) at -78°C until an olive green color persisted. The reaction mixture was quenched with 4 mL sat. NaHC0 3 , warmed to rt and diluted with EtOAc (150 mL). The organic layer was washed with NaHC0 3 , H 2 0 and brine, dried over Na 2 S0 and concenttated in vacuo. Flash chromatography on silica gel (20% EtOAc/hexanes) afforded ketone 107 (675 mg, 95%) as a light yellow oil. 107: R (15% EtOAc/hexanes) = 0.39; IR (film) 2954, 2930, 1723, 1612, 1514, 1464, 1250, 1088 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 0.01 (6H, s, TBS), 0.87 (9H, s, TBS), 0.95 (3H, s, C18 Me), 1.05 (3H, s, C18 Me), 1.19 (3H, ά, J= 6.3 Hz, C27), 1.64 (IH, m, C24), 1.85-1.96 (3H, m, C21 + C24), 2.29 (IH, 5 line m, C22), 2.65 (IH, m, C22), 3.23 (3H, s, C19 OCH 3 ), 3.31 (IH, ά, J = 9.9 Hz, C17), 3.71 (IH, ά, J= 9.9 Hz, C17), 3.78 (3H, s, ArOCH 3 ), 3.79 (IH, m), 3.98 (IH, m), 4.17 (IH, m), 4.43 (IH, d, J = 11.0 Hz, CH 2 Ar), 4.58 (2H, s, CH 2 Ar), 4.60 (IH, ά, J = 11.0 Hz, CH 2 Ar), 6.84 (2H, d, J = 8.7 Hz, PMB), 7.19 (2H, ά, J = 8.7 Hz, PMB), 7.28-7.35 (5H, m, Bn); 13 CNMR (75 MHz, CDC1 3 ) δ -5.5, -5.4, 14.5, 18.6, 19.8, 20.2, 26.0, 29.7, 36.5, 38.2, 46.2, 52.4, 55.4, 68.6, 70.6, 71.3, 72.3, 74.7, 103.6, 114.1, 127.9, 128.7, 129.6, 131.0, 138.9, 159.5, 207.5; HRMS Calcd for C 35 H 54 0 7 Si (M + -MeOH): 582.3377. Found: 582.3372; Anal. Calcd for C 35 H 54 0 7 Si : C, 68.37; H, 8.85. Found: C, 68.04; H, 8.84; [α] D 20 = +21.9° (c 0.72, CH 2 C1 2 ). 109.1 (Formula 109 where R 2 ' is =CH-CO,Me) To a solution of diisopropylamine (150 μL, 1.15 mmol) in THF (1.61 mL) was added n-BuLi (2.5 M in hexanes, 440 μL, 1.10 mmol) dropwise at 0°C. After 5 min at 0°C, a 1.81 mL aliquot (0.5 M LDA, 0.90 mmol) was removed via syringe and slowly added to a solution of ketone 107 (483 mg, 0.79 mmol) in THF (20 mL) at -78°C The solution was stiπed for 10 min, tteated with a stock solution of OHCC0 2 Me (0 5 M in Et 2 0, 4 0 mL, 2 0 mmol), kept at -78°C for 20 mm and quenched with 3 mL sat NH 4 C1 The reaction mixture was brought to rt and diluted with 200 mL EtOAc The organic layer was washed with H 2 0 (2x) and bnne, dried over Na 2 S0 and concenttated in vacuo The crude residue was chromatographed on silica gel (35% EtOAc/hexanes) to afford residual 107 (142 mg) and aldols 108 as a mixture of diastereomers (352 mg, 90% based on recovered 107) The isolated 108 mixture and Et 3 N (418 μL, 3 0 mmol) were dissolved in anhydrous CH 2 C1 2 (15 mL) and cooled to -10°C Methanesulfonylchloπde (116 μL, 1 5 mmol) was added via syringe and the solution was stiπed at -10°C for 30 min 5 mL sat NaHC0 3 was added, the reaction mixture was warmed to rt and diluted with 100 mL EtOAc The organic layer was washed with H 2 0 and brine, dned over Na 2 S0 4 and concentrated in vacuo The residue was immediately dissolved in THF (30 mL) and treated with 1 ,8-dιazabιcyclo[5 4 0]undec-7-ene (DBU, 75 μL, 0 50 mmol) dropwise at rt The resulting bright yellow solution was stiπed at rt for 20 min, treated with sat NH 4 C1 and diluted with 150 mL EtOAc The organic layer was washed with H 2 0 and bnne, dried over Na 2 S0 4 and concentrated in vacuo to afford an orange residue which was chromatographed on silica gel (20% EtOAc/hexanes) to afford exocychc methacrylate (enone) 109.1 (267 mg, 78% from 108) as a yellow oil 109.1 R/ (30% EtOAc/hexanes) = 0 63, IR (film) 2954, 2930, 1724, 1707, 1612, 1514, 1464, 1250, 1088 cm ', Η NMR (300 MHz, CDC1 3 ) δ 0 05 (6H, s, TBS), 0 81 (9H, s, TBS), 0 91 (3H, s, C18 Me), 1 00 (3H, s, C18 Me), 1 19 (3H, d, J = 6 4 Hz, C27), 1 74 (IH, m, C24), 1 94 (IH, m, C24), 2 71 (IH, ddd, J = 17 6, 12 4, 3 1 Hz, C22), 3 19 (3H, s, C19 OCH 3 ), 3 26 (IH, d, J = 10 0 Hz, C17), 3 49 (IH, d, J = 17 6 Hz, C22), 3 68 (IH, d, J = 10 0 Hz, C17), 3 74 (3H, s), 3 77 (3H, s), 3 80 (IH, m), 3 97 (IH, m), 4 19 (IH, m), 4 40 (IH, d, J= 10 9 Hz, CH 2 Ar), 4 53-4 63 (3H, m, CH 2 Ar), 6 64 (IH, d, J = 1 9 Hz, C34), 6 82 (2H, d, J = 8 7 Hz, PMB), 7 14 (2H, d, J = 8 7 Hz, PMB), 7 27-7 36 (5H, m, Bn), 13 C- NMR (75 MHz, CDC1 3 ) δ -5 9, -5 8, 14 1, 18 3, 19 3, 19 8, 25 7, 35 2, 36 0, 46 6, 51 6, 52 1, 55 1, 68 2, 69 5, 71 0, 71 7, 74 2, 76 0, 104 0, 113 8, 122 4, 127 6, 128 4, 129 1, 130 6, 138 6, 147 3, 159 2, 166 4, 196 2, HRMS Calcd for C 38 H 56 0 9 Sι (M + -MeOH) 652 3433 Found 652 3435, Anal Calcd for C 38 H 56 θ 9 Sι C, 66 64, H, 8 24 Found C, 66 87, H, 8 13, [α] D 20 = -55 8° (c 0 78, CH 2 C1 2 ) 111.1 (Formula 111 where R 20 is -O-CO-CiVL, and R 2 ' is =CH-CO,Me) To a solution of enone 109.1 (502 mg, 0 734 mmol) and CeCl 3 -7H 2 0 (137 mg, 0 367 mmol) in methanol (23 mL) was added solid NaBH 4 (56 mg, 1 47 mmol) m a single portion at -30°C Rapid gas evolution subsided after 3 min After an additional 30 min at -30°C, the reaction mixture was poured directly onto a silica gel column and the product quickly eluted with 25% EtOAc/hexanes to afford the coπesponding axial alcohol 110.1 (478 mg) as a colorless oil Octanoic acid (232 mg, 1 61 mmol) and Et 3 N (292 μL, 2 20 mmol) were dissolved in 20 mL toluene and treated with 2,4,6-tπchlorobenzoylchloπde (230 μL, 1 47 mmol) dropwise at rt After 1 h at rt, a toluene solution (7 mL) of freshly prepared 110.1 was added gradually via syringe and stirring was continued for 40 min The reaction mixture was quenched with 10 mL sat NaHC0 3 , diluted with EtOAc and washed successively with sat NH 4 C1 and bnne The organics were dried over Na 2 S0 4 , the solvent was removed in vacuo, and the residue was chromatographed on silica gel (25% EtOAc/hexanes) to provide octanoate 111.1 as a colorless oil (551 mg, 93% from 109.1) 111.1 R (25% Et2θ/hexanes) = 0 33, IR (film) 2928, 2857, 1747, 1722, 1667, 1614, 1514, 1463, 1250, 1155, 1081 , 836 2 cm ', Η NMR (300MHz, CDC1 3 ) δ -0 01 (6H, s, TBS), 0 88 (12H, br s, TBS + octanoate Me), 0 99 (3H, s, C18 Me), 1 03 (3H, s, C18 Me), 1 19 (3H, d, J= 6 3 Hz, C27), 1 20- 1 35 (8H, m), 1 60-1 80 (3H, m), 1 89 (IH, m, C24), 2 31-2 40 (3H, m), 3 26 (3H, s, C19 OCH 3 ), 3 44 (IH, dd, J= 15 6, 1 8 Hz, C22), 3 56 (IH, d, J = 9 3 Hz, C17), 3 60 (IH, d, J = 9 3 Hz, C17), 3 68 (3H, s), 3 78 (IH, m), 3 79 (3H, s), 3 93 (IH, dd, J = 8 4, 4 8 Hz), 4 13 (IH, m), 4 38 (IH, d, J = 10 8 Hz, CH 2 Ar), 4 57 (IH, d, J = 10 8 Hz, CH 2 Ar), 4 60 (2H, s, CH 2 Ar), 5 57 (IH, s, C20), 5 89 (IH, s, C34), 6 83 (2H, d, J = 8 4 Hz, PMB), 7 16 (2H, d, J = 8 4 Hz, PMB), 7 28- 7 38 (5H, m, Bn), 13 C NMR (75 MHz, CDC1 3 ) δ -5 4, 14 1, 14 2, 14 4, 18 4, 20 7, 22 7, 24 8, 26 0, 28 9, 26 0, 28 9, 31 7, 33 2, 34 6, 36 4, 47 1, 51 2, 55 3, 67 6, 68 1, 71 2, 72 2, 74 7, 76 5, 103 1, 114 0, 117 0, 127 8, 128 6, 129 5, 129 9, 130 9, 139 0, 153 1, 159 5, 166 7, 172 2, HRMS Calcd for C 46 H 72 O 10 Sι (M* -MeOH) 780 4632 Found 780 4610, [α] D 20 = -5 1° (c 1 80, CH2CI2) Example 2 - Exemplary Linkers 2A Ketal Acid 406 Formula 402 To a stirred solution of the 1,3 menthone acetal of 1,3,5-pentanetπol 401 (3 33 g, 13 mmol) prepared by the method of Harada et al (1993) in 23 mL of anhydrous CH 2 C1 2 was added 1,1 ,1 - tπacetoxy-l,l-dιhydro-l,2-benzιodoxol-3(lH)-one (Dess-Martin penodmane, 6 60 g, 15 6 mmol) in a single portion The mixture was stiπed at rt for 30 min, poured onto a column of silica gel and the product eluted with 15% EtOAc/hexanes to afford 3 013 g (90%) of pure aldehyde 402 as a colorless oil 402 R (20% EtOAc/hexanes) = 0 50, IR (film) 2952, 2869, 1728, 1456, 1383, 1308, 1265 cm ', Η NMR (300 MHz, CDC1 3 ) δ 9 80 (IH, dd, J = 1 8, 2 5 Hz), 4 36 (IH, dddd, J = 2 9, 4 3, 7 4, 8 2 Hz), 4 13 (1H, ddd, J= 2 7, 11 7, 11 9 Hz), 3 83 (IH, ddd, J = 1 3, 5 2, 11 7 Hz), 2 72 (IH, ddd, J = 1 9, 3 1, 13 5 Hz), 2 56 (IH, ddd, J= 2 5, 8 2, 16 1 Hz), 2 44 (IH, ddd, J= 1 8, 4 3, 16 1 Hz), 2 39 (IH, dsept, J = 1.6, 7.1 Hz), 1.54-1.76 (3H, m), 1.29-1.53 (4H, m), 1.17 (IH, ddd, J= 1.9, 4.1, 12.4 Hz), 0.90 (3H, ά, J = 6.3 Hz), 0.87 (3H, ά, J = 7.0 Hz), 0.85 (3H, ά, J = 7.0 Hz), 0.72 (IH, t, J = 13.2 Hz); 13 C NMR (75 MHz, CDC1 3 ) δ 201.4, 100.9, 63.8, 58.7, 51.1, 49.9, 37.2, 34.8, 31.1, 28.9, 24.2, 23.7, 22.2, 21.7, 18.8; HRMS Calc'd for C 15 H 26 0 3 : 254.1882. Found: 254.1877; [α] D 20 -11.2° (c 1.28, CHC1 3 ). Formulae 403a and 403b To a stirred solution of aldehyde 402 (3.013 g, 11.86 mmol) in 40 mL of anhydrous CH 2 C1 2 was added a solution of (+)-Eu(hfc) 3 (1.42 g, 1.19 mmol) in CH 2 C1 2 (16 mL) at rt. The resultant clear yellow solution was stirred for 5 min before l-methoxy-3-(trimethylsilyloxy)-l,3-butadiene (3.47 mL, 3.07 g, 17.8 mmol) was introduced via syringe. The yellow solution was stiπed at rt for 20 h, treated with 0.5 mL CF 3 C0 2 H and stiπed for an additional 15 min. The solution was quenched with sat. NaHC0 3 , diluted with EtOAc (200 mL), washed with H 2 0 and brine, dried over MgS0 4 and concentrated in vacuo. Purification by flash chromatography (20 -> 25% EtOAc/hexanes) provided anti pyrone 403b (2.53 g, 66%) and syn pyrone 403a (1.30 g, 34%) as colorless solids. 403b: mp = 113-114°C (hexanes); R (15% EtOAc/hexanes) = 0.25; 'H NMR (300 MHz, CDC1 3 ) δ 7.31 (IH, ά, J= 6.0 Hz), 5.40 (IH, d, J= 6.0 Hz), 4.67 (IH, dddd, J= 3.0, 5.8, 9.6, 11.8 Hz), 4.03-4.15 (2H, m), 3.81 (IH, ddd, J= 1.2, 5.2, 11.6 Hz), 2.70 (IH, ddd, J= 1.9, 2.8, 13.5 Hz), 2.42-2.56 (2H, m), 2.38 (IH, dsept, J= 1.6, 6.9 Hz), 1.91 (IH, ddd, J= 2.3, 9.6, 14.3 Hz), 1.28-1.75 (8H, m), 1.18 (IH, ddd, J = 1.9, 3.9, 12.5 Hz), 0.88 (3H, ά, J= 6.6 Hz), 0.87 (3H, ά, J = 7.1 Hz), 0.83 (3H, ά, J = 6.9 Hz), 0.70 (IH, t, J = 12.6 Hz); 13 C NMR (75 MHz, CDC1 3 ) δ 192.7, 162.9, 107.3, 100.7, 75.7, 63.3, 58.9, 51.1, 42.5, 41.7, 37.3, 34.8, 31.7, 29.0, 24.2, 23.6, 22.2, 21.9, 18.9; LRMS (El): 322 (68), 307 (22), 265 (33), 237 (67), 153 (24), 191 (94), 139 (52), 112 (20), 97 (100), 83 (31), 81 (47), 71 (24), 69 (35); HRMS Calcd for C, 9 H 30 O 4 : 322.2144. Found: 322.2142; Anal. Calcd for C 19 H 30 O 4 : C, 70.77; H, 9.38. Found: C, 70.91; H, 9.58; [α] D 20 +42.5° (c 1.59, CH 2 C1 2 ). 403a: R (15% EtOAc/hexanes) = 0.15; IR 2952, 2869, 1682, 1597, 1456, 1405, 1269 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 7.33 (IH, ά, J= 6.0 Hz), 5.40 (IH, dd, J= 0.9, 6.0 Hz), 4.61 (IH, dddd, J = 2.8, 11.6, 12.0 Hz), 4.09 (IH, ddd, J = 2.8, 11.6, 12.0 Hz), 4.00 (IH, dddd, J = 1.0, 4.2, 8.3, 15.5 Hz), 3.81 (IH, ddd, J= 1.4, 5.4, 11.6 Hz), 2.67 (IH, ddd, J = 1.9, 3.2, 13.5 Hz), 2.63 (IH, dd, J = 13.3, 16.8 Hz), 2.47 (IH, ddd, J= 0.9, 4.0, 16.8 Hz), 2.39 (IH, dsept, J= 1.6, 6.9 Hz), 2.02 (IH, ddd, J= 5.6, 8.3, 14.0 Hz), 1.79 (IH, ddd, J= 4.2, 6.9, 14.0 Hz), 1.20-1.75 (7H, m), 1.17 (IH, ddd, J= 1.9, 3.8, 12.6 Hz), 0.89 (3H, ά, J= 6.7 Hz), 0.87 (3 H, d, J= 6.9 Hz), 0.86 (3H, d, J= 6.9 Hz), 0.70 (IH, t, J= 13.5 Hz); 13 C NMR (75 MHz, CDC1 3 ) δ 192.6, 163.3, 107.1, 100.7, 76.4, 63.9, 58.8, 51.1, 41.6, 40.9, 37.3, 34.7, 31.4, 29.3, 24.2, 23.7, 22.2, 21.8, 18.8; LRMS (El): 322 (61), 307 (18), 265 (27), 237 (56), 151 (21), 139 (33), 112 (17), 97 (100), 83 (26), 81 (34), 71 (17), 69 (60); HRMS Calcd for C 19 H 30 O 4 : 322.2144. Found: 322.2146; [α] D 20 -57.8° (c 1.5, CH 2 C1 2 ). Formula 404 To a stiπed solution of pyrone 403a (1.30 g, 4.04 mmol) in 40 mL of anhydrous MeOH was added CeCl 3 -7H 2 0 (904 mg, 2.43 mmol) at rt. After stirring for 10 min, the mixture was cooled to -40°C and NaBH 4 (306 mg, 8.09 mmol) was added in one portion. The mixture was stirred for an additional 15 min before quenching with a 1 : 1 mixture of brine and H 2 0. The aqueous layer was extracted with EtOAc (4x). The combined organics were washed with sat. NaHC0 3 and brine, dried over Na 2 S0 4 and concenttated to afford a clear oil. Purification by flash chromatography (30% EtOAc/hexanes containing 1% Et 3 N) afforded unstable allylic alcohol 404 (1.08 g, 82%) as a single diastereomer. 404: IR (film) 3386, 2951, 2869, 1643, 1456, 1380, 1307, 1268, 1231 cm "1 ; Η NMR (300 MHz, CDCI 3 ) δ 6.35 (IH, br ά, J = 5.4 Hz), 4.75 (IH, ddd, J = 1.9, 1.9, 6.1 Hz), 4.36-4.46 (IH, m), 4.08-4.17 (IH, m), 4.08 (IH, ddd, J = 2.7, 12.4, 12.4 Hz), 3.98 (IH, dddd, = 2.7, 5.2, 7.9, 10.9 Hz), 3.81 (IH, ddd, J = 1.5, 5.2, 11.5 Hz), 2.69 (IH, br ά, J = 13.5 Hz), 2.39 (IH, dsept, J = 1.7, 6.9 Hz), 2.18 (IH, dddd, J= 1.7, 1.9, 6.4, 13.0 Hz), 1.90 (IH, ddd, J= 6.6, 7.7, 14.0 Hz), 1.33-1.74 (9H, m), 1.17 (IH, ddd, J = 1.9, 4.4, 12.3 Hz), 0.90 (3H, d, J = 6.2 Hz), 0.88 (6H, d, J = 6.9 Hz), 0.69 (lH, t, J = 12.7 Hz); 13 C NMR (75 MHz, CDC1 3 ) δ 145.3, 105.5, 100.6, 71.4, 64.3, 63.0, 58.9, 51.2, 41.5, 37.7, 37.4, 34.9, 31.3, 29.2, 24.2, 23.7, 22.2, 21.8, 18.8; [α] D 20 +2.0° (c 0.59, CHC1 3 ). Formula 405 To a solution of 1.08 g (3.32 mmol) of allylic alcohol 404 in 66 mL of ethylvinylether was added mercury(II)trifluoroacetate (142 mg, 0.33 mmol) in a single portion at -10°C. The resulting colorless solution was stiπed for 20 h at 5°C, diluted with Et 2 0, washed with sat. NaHC0 3 and brine, dried over Na 2 S0 , and concentrated in vacuo to give a clear, colorless oil. Rapid flash chromatography (10% EtOAc/hexanes containing 1% Et 3 N) afforded 865 mg (74%) of the coπesponding allyl vinyl ether along with 208 mg (19%) of recovered 404. The vinyl ether was immediately dissolved in 100 mL n-nonane and heated at 145°C for 3.5 h. The solution was cooled to 70-80°C and the solvent was removed by short path distillation at reduced pressure. The remaining residue was purified by flash chromatography (10% EtOAc/hexanes) to provide Claisen product 405 (612 mg, 71%) as a colorless oil. 405: R (30% EtOAc/hexanes) = 0.75; IR (film) 2950, 2869, 1728, 1646, 1456, 1373, 1307, 1267 cm " '; Η NMR (300 MHz, CDC1 3 ) δ 9.78 (IH, t, J = 2.4 Hz), 5.89 (IH, dddd, J = 2.0, 2.0, 4.7, 10.0 Hz), 5.64 (IH, dddd, J = 1.3, 1.3, 2.5, 10.0 Hz), 4.57-4.66 (IH, m), 4.08 (IH, ddd, J = 2.7, 12.1, 12.1 Hz), 3.90-4.01 (IH, m), 3.66-3.82 (2H, m), 2.69 (IH, ddd, J = 1.9, 3.0, 13.4 Hz), 2.55 (2H, dd, J = 2.4, 6.2 Hz), 2.40 (IH, dsept, J= 1.6, 6.9 Hz), 1.12-2.14 (12H, m), 0.89 (3H, ά, J = 6.6 Hz), 0.88 (6H, d, J= 7.1 Hz), 0.68 (IH, t, J= 12.9 Hz); 13 C NMR (75 MHz, CDC1 3 ) δ 201.7, 128.5, 126.3, 100.5, 70.6, 70.5, 64.4, 59.1, 51.2, 48.5, 42.5, 37.4, 34.9, 31.5, 30.7, 29.1, 24.3, 23.7, 22.2, 21.9, 18.9; MS (El) 350 (51), 335 (45), 322 (14), 293 (65), 279 (15), 265 (52), 255 (15), 139 (17), 135 (29), 97 (28), 83 (43), 81 (100), 79 (17), 69 (27), 67 (24); HRMS Calcd for C 21 H 34 0 4 : 350.2457. Found: 350.2466; [α] D 27 0° (CH 2 C1 2 ). Formula 406 To a stirred mixture of trimethylsilyl diethylphosphonoacetate (72 μl, 76.7 mg, 0.286 mmol) in anhydrous THF (1 mL) was added of H-butyllithium (2.5 M in hexanes, 109 μL, 0.272 mmol) dropwise at -78°C. After stirring for 20 min at -78°C and 15 min at rt, the mixture was cooled to -78°C and treated with a THF solution (1 mL) of aldehyde 405 (45 mg, 0.129 mmol). The mixture was allowed to warm to rt over 2 h and stirring was continued for 1 h. The mixture was diluted with 50 mL EtOAc and acidified with 10 mL of a 0.1 N aqueous NaHS0 4 solution. The phases were separated and the aqueous phase was extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over MgS04, and concenttated to give a colorless oil. Rapid filtration through a short pad of silica gel (20% acetone/benzene) gave a crude product which was dissolved in 2 mL methanol. Palladium on activated charcoal (10%, ~ 5 mg) was added and the mixture was stiπed at room temperature for 18 h under balloon pressure of hydrogen gas. Filtration through Celite™ and flash chromatography on silica gel (40% EtOAc/hexanes containing 1% acetic acid) gave 21.8 mg (0.055 mmol, 43%) of ketal carboxylic acid 406 as a clear, colorless oil. Py (40% EtOAc/hexanes + 1% AcOH) = 0.44; IR (film) 3500-2500, 2938, 2868, 1711, 1456, 1377, 1307, 1268, 1158, 1113 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 4.08 (ddd, 1 H, J = 2.6, 12.4, 12.4 Hz), 3.98 (dddd, 1 H, J = 2.4, 6.6, 6.6, 10.7 Hz), 3.81 (ddd, 1 H, J = 1.2, 5.2, 11.5 Hz), 3.38-3.47 (m, 1 H), 3.21 -3.31 (m, 1 H), 2.70 (br ά, 1 H, J = 12.5 Hz), 2.29-2.47 (m, 3 H), 1.62-1.86 (m, 5 H), 1.34-1.62 (m, 11 H), 1.07-1.30 (m, 3 H), 0.78-0.98 (m, 1 H), 0.88 (d, 6 H, J= 7.2 Hz), 0.88 (d, 3 H, J = 7.0 Hz), 0.67 (t, 1 H, J = 12.9 Hz); 13 C NMR (75 MHz, CDC1 3 ) δ 179.1, 100.5, 74.2, 64.6, 59.2, 51.2, 42.9, 37.3, 35.4, 34.9, 33.7, 31.50, 31.46, 31.3, 29.0, 24.2, 23.7, 23.6, 22.2, 21.8, 20.9, 18.8; HRMS Calcd for C 23 H 40 O 5 : 396.2876. Found: 396.2870; [α] 28 D -10.5° (c 1.66, CHC1 3 ). 2B. Ketal Acid 408 Formula 407 To a solution of the aldehyde 405 (Example 2A, 274 mg, 0.778 mmol) in ethyl acetate (5 mL) was added Pd/C (10 mg) and the atmosphere was exchanged to hydrogen, which was applied for 30 min. The mixture was filtered and concentrated to give the coπesponding crude saturated aldehyde, which was directly used in the next step. A stock solution of Ipc2B(allyl) was prepared by first dissolving (-)-Ipc2BOMe (700 mg, 2.22 mmol) in ether (4.15 mL) at 0 °C and adding 1M allyl magnesium bromide (1.78 mL, 1.78 mmol). The mixture was warmed to rt and stiπed for 30 min. In a separate flask, the aldehyde was dissolved in ether (4 mL) and tteated with the stock solution of Ipc2B(allyl) (0.3 M, 3.9 mL, 1.17 mmol) at -78 °C. After stiπing for 2 h at -78 °C, the mixture was treated with hydrogen peroxide (30 %, 2 mL) and sodium hydroxide (15 %, 2 mL) and warmed to rt. After another 2 h, the mixture was partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, and concentrated to give the coπesponding crude homoallylic alcohol, which was directly used in the next step. To a solution of the crude homoallylic alcohol alcohol in methylene chloride (5 mL) at 0°C was added TBSOTf (534 μL, 2.33 mmol) and diisopropyl ethyl amine (676 μL, 3.89 mmol) and stiπed for 30 min. The mixture was directly loaded onto silica gel and purified to give the corresponding alkene (237 mg, 60% in 3 steps). To a solution of the alkene (10 mg, 0.0197 mmol) in tert-butanol (1 mL) at rt was added a solution of KMnθ4 (0.6 mg, 0.0039 mmol) and NaIθ4 (17 mg, 0.0788 mmol) in water (buffered pH 7, 1 mL). After 30 min, the reaction mixture was quenched with sodium thiosulfate. The mixture was partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, and concenttated. Column chromatography afforded TBS ether 407 (6.3 mg, 71 %). 407: Rf = 0.20 (25 % ethyl acetate/ hexane); [α] 25 D = 22.6 ° (c 0.58, CH2CI2); IR (neat) = 2933, 1712, 1457, 1255, 1114 cm "1 ; l U NMR (400 MHz, CDCI3) δ 4.32 (m, 1 H), 4.08 (m, 1 H), 3.93 (m, 1 H), 3.81 (m, 1 H), 3.44 (m, 2 H), 2.69 (d, J =13.2 Hz, 1 H), 2.62 (dd, J = 15.2, 5.2 Hz, 1 H), 2.48 (dd, J = 15.2, 5.2 Hz, 1 H), 2.40 (quint, J = 6.8 Hz, 1 H), 1.85-1.15 (m, 20 H), 0.88 (br s, 18 H), 0.12 (s, 3 H), 0.11 (s, 3 H); 13 C NMR (100 MHz, CDCI3) δ 173.48, 100.44, 73.88, 73.52, 66.15, 64.26, 59.14, 51.24, 43.89, 43.25, 42.48, 37.43, 43.97, 32.13, 31.89, 30.93, 29.23, 25.74, 24.31, 23.77, 23.52, 22.25, 21.89, 19.15, 17.92, -4.77; HRMS: calcd for (C 29 H 54 0 6 Si) = 526.3689; found (M) = 526.3687 Formula 408 To a solution of TBS ether 407 (9.3 mg, 0.0177 mmol) in THF (0.5 mL) at rt was added pyridine (127 μL) and HF-pyridine (51 μL, 1.77 mmol) and stirred for 18 h. The mixture was partitioned between ethyl acetate and water (pH 4). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, concentrated in vacuo and the resulting crude hydroxy acid was used in the next step without further purification. To a solution of crude hydroxy acid in methylene chloride (1.5 mL) at rt was added TESC1 (26 μL, 0.0708 mmol) and TEA (19 μL, 0.142 mmol) and the mixture was stiπed for 4 h. The mixture was treated with water (pH 4, 1 mL) and stiπed for another 10 min. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and then concentrated. The crude product was purified by silica gel chromatography to give the TES acid 408 (7 mg, 75 %- 2 steps). 408: R f = 0.30 (33 % ethyl acetate in hexane); [α] 25 D = 34.0° (c 0.42, CH2CI2); IR (film) = 2951 , 1711, 1457, 1378, 1114, 1005, 976 cm' 1 : ^H NMR (400 MHz, CDCI3) δ 4.33 (m, 1 H), 4.09 (m, 1 H), 3.95 (m, 1 H), 3.81 (m, 1 H), 3.45 (m, 1 H), 2.70 (d, J = 14 Hz, 1 H), 2.64 (dd, J = 15.6, 5.2 Hz, 1 H), 2.51 (dd, J = 15.6, 5.2 Hz, 1 H), 2.40 (m, 1 H), 1.86-1.15 (m, 21 H), 0.98 (t, J = 8.0 Hz, 9 H), 0.89 (m, 9 H), 0.66 (q, J = 8.0 Hz, 6 H); 13 C NMR (100 MHz, CDCI3) δ 173.06, 100.45, 73.94, 73.70, 66.33, 64.28, 59.12, 51.21 , 43.90, 43.23, 42.48, 37.40, 34.96, 32.12, 31.86, 31.00, 29.20, 24.33, 23.77, 23.52, 22.23, 21.89, 19.00, 6.79, 4.73; HRMS: calcd for (C 29 H 54 0 6 Si) = 526.3689; found (M) = 526.3717. 2C. 9-Hydroxy-9-/-Butyl L3 Linker Synthon 504 Formula 501 To a solution of aldehyde 402 (Example 2 A supra, 803 mg, 3.16 mmol) in ether (10 mL) was added a solution of 4-pentenyl magnesium bromide (0.8M in ether, 4.74 mL, 3.79 mmol) at -78°C and the mixture was stirred for 30 min. The reaction was quenched with aq. sat. NH 4 C1 (10 mL) and allowed to warm to rt. The mixture was then extracted with EtOAc (3 x 10 mL) and the combined organics were dried over MgS0 4 , and concentrated in vacuo. The resulting residue was dissolved in CH 2 C1 2 (15 mL) and Dess-Martin Periodinane (2.02 g, 4.74 mmol) was added at rt. After 3 hours, sat. aq. Na 2 S0 3 (10 mL) and sat. aq. NaHC0 3 (10 mL) was added. The mixture was extracted with CHC1 3 (3 x 10 mL), washed with sat. aq. NaHC0 3 (10 mL), dried over MgS0 4 , and concentrated in vacuo. The residue was purified by column chromatography (90% EtOAc/ hexane) to obtain ketone 501 (730 mg, 71.6%) as a colorless oil. 501: IR (film) 2957, 2362, 1716, 1637 cm "1 ; 'H NMR (300 MHz, CDC1 3 ) δ, 0.62-0.92 (11H, m), 1.12-1.70 (9H, m) 2.03 (2H, dd, J = 14.77, 7.63 Hz), 2.24-2.71 (6H, m), 3.79 (IH, ddd, / = 11.53, 5.22, 1.37 Hz), 4.10 (IH, td, J= 11.88, 2.81 Hz), 4.22-4.31 (IH, m), 4.94-5.03 (2H, m), 5.68 (IH, m); 13 C NMR (75 MHz, CDC1 3 ) δ, 18.82, 21.70, 22.13, 22.37, 23.62, 24.18, 28.59, 31.34, 32.95, 34.76, 37.32, 43.73, 49.33, 51.09, 58.81, 65.39, 100.73, 115.21, 138.04, 209.56; HRMS (El) Calc'd. for C 20 H 34 O 3 : 322.2508. Found: 322.2497. [α] D 25 = 5.52° (c 4.79, CH 2 C1 2 ). 502.1 (Formula 502 where R 8 is t-butyl) To a solution of ketone 501 (35 mg, 0.109 mmol) in ether (0.6 mL) was added /-BuLi (1.6 M in pentane, 75 μL, 0.12 mmol) dropwise at -78°C. The mixture was stirred at rt for 30 min. and then quenched with sat. aq. NH 4 CI (2 mL). The mixture was allowed to warm to rt and was then extracted with EtOAc (3 x 5 mL). The combined organics were washed with brine, dried over Na 2 S0 4 , and concentrated in vacuo. Chromatography (10% EtOAc/hexane) afforded a major diastereomer A31a (17.5 mg, 42%) along with a minor diastereomer A31b. (7.4 mg, 18%) as colorless oils (structures not shown). A31a: IR (film): 2956, 1639, 1456 cm "1 ; Η NMR (400 MHz, CDC1 3 ) δ, 0.73 (IH, t, J= 12.88 Hz), 0.89- 0.94 (18H, m), 1,17-1.76 (14H, m), 2.00-2.09 (2H, m), 2.38-242 (IH, m), 2.73 (IH, d, J = 13.73 Hz), 347 (IH, s), 3.79 (IH, dd, J = 11.60, 5.06 Hz), 4.12 (IH, td, J= 11.97, 2.44 Hz), 4.25-4.29 (IH, m), 4.91 (IH, ά, J = 10.17 Hz), 4.98 (IH, ά, J = 17.63 Hz), 5.77-5.84 (IH, m); 13 C NMR (75 MHz, CDC1 3 ) δ 19.07, 22.20, 22.25, 23.15, 23.45, 24.66, 25.43, 25.52, 28.98, 31.80, 34.36, 34.51, 34.60, 36.84, 37.54, 39.29, 39.63, 51.30, 58.92, 67.73, 79.0, 101.26, 114.31, 139.03; HRMS (El) Calc'd. for C^H^O,: 380.3290. Found: 380.3281. [α] D 25 = 5.89° (c 0.85, CDC1 3 ). To a solution of major diastereomer A31a (332 mg, 0.872 mmol) in THF (5 mL) was added KHMDS (0.5M in toluene, 5.24 mL, 2.62 mmol) in an ice bath. TMSC1 (284 mg, 2.62 mmol) was added and the mixture was stirred for 30 minutes. The mixture was quenched with sat. aq. NH 4 C1 (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organics were washed with brine (5 mL), dried over MgS0 4 , and then concentrated in vacuo. Chromatography (5% EtOAc/hexane) providing 502.1 (395 mg, 100%) as a white solid. 502.1: m.p. = 60.0°C; IR (film) 2953, 1642, 1455 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ, 0.132 (6H, s), 0.134 (3H, s), 0.67-1.71 (33H, m), 1.95-1.99 (2H, m), 2.36-2.46 (IH, m), 2.71 (IH, app d, J= 14.3 Hz), 3.74-3.79 (IH, m), 3.88-3.94 (IH, m), 4.07 (IH, td, J = 11.75, 2.96 Hz), 4.95 (IH, ά, J= 10.41 Hz), 5.00 (IH, d, J = 17.33 Hz), 5.74-5.85 (IH, m); 13 C NMR (75 MHz, CDC1 3 ) δ 2.9, 5.3, 18.9, 21.7, 22.2, 23.8, 24.3, 25.3, 26.2, 29.1, 34.2, 34.8, 35.0, 37.6, 39.2, 40.0, 51.3, 59.3, 65.6, 82.9, 100.7, 114.6, 138.7; HRMS (El) Calc'd. for C 27 H 52 0 3 Si: 452.3686. Found: 452.3670; [α] D 26 = -11.33° (c 1.56, CDC1 3 ). 503.1 (Formula 503 where R 8 is f-butyl) To a solution of 502.1 (98 mg, 0.216 mmol) in CH 2 C1 2 (8 mL) and MeOH (0.5 mL) was bubbled 0 3 at -78°C until a blue color persists. Nitrogen gas was then used to purge the system and (EtO) 3 P (54 mg, 0.324 mmol) was subsequently added. The mixture was stiπed for 3 h and then slowly warmed to rt. Sat. aq. Na 2 S0 3 (10 mL) was added and the mixture was extracted with CHC1 3 (3 x 10 mL). The combined organics were then washed with brine (10 mL), dried over MgS0 4 and concentrated in vacuo. Chromatography (0.5% EtOAc/ hexane) afforded 503.1 (63 mg, 64.1%) as a colorless oil. 503.1: IR (film) 2941, 1715, 1454 cm "1 ; Η NMR (400 MHz, CDC1 3 ) δ 0.134 (9H, s), 0.73 (IH, t, J = 13.13 Hz), 0.9-1.81 (32H, m), 2.34-242 (3H, m), 2.72 (IH, ά, J = 12.29 Hz), 3.77 (IH, dd, J = 11.59, 4.58 Hz), 3.92-3.96 (IH, m), 4.08 (IH, td, J= 12.28, 2.01 Hz), 9.77 (IH, s); 13 C NMR (100 MHz, CDC1 3 ) δ, 3.39, 18.98, 19.29, 22.60, 24.23, 24.71, 26.75, 29.76, 34.41, 35.15, 37.77, 38.01, 39.66, 42.95, 45.26, 51.67, 59.64, 65.90, 83.08, 100.99, 202.26; HRMS (El) Calc'd. for C 26 H 50 O 4 Si: 454.3478. Found: 452.3475; [α] D 27 = -6.33° (c 2.9, CH 2 C1 2 ). 504.1 (Formula 504 where R 8 is t-butyl) To (-)-Ipc2BOMe (108.8 mg, 0.34 mmol) (weighed in an inert atmosphere) was added diethyl ether (340 μL). The flask was cooled to -78°C and allylmagnesium bromide (1.0 M, 310 μL, 0.31 mmol) was added. The precipitous mixture was stiπed for 15 min. at -78°C and then slowly warmed to rt and stirred for 1 hour. Diethyl ether (340 mL) was added and then a pre-cooled solution of aldehyde 503.1 (40.1 mg, 0.109 mmol) in diethyl ether (160 μL) was added dropwise. The suspension was stirred for 1 h, then the temperature was slowly raised to rt and 3N NaOH (240 μL), 30% hydrogen peroxide (100 μL) and diethyl ether (400 μL) was added. The biphasic mixture was refluxed for 1 h and then quenched with water (9 mL) and extracted with ethyl acetate (4 x 10 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate and the solvent was removed in vacuo. Chromatography on silica gel (12.5% EtOAc/ hexane) afforded the crude homoallylic alcohol as a yellow oil. To this oil in methylene chloride (500 μL) was added imidazole (19 mg, 0.276 mmol) and TBSC1 (21 mg, 0.138 mmol). The reaction was sealed and stirred for 14 h. The reaction was then quenched with a saturated solution of sodium bicarbonate (2 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organics were washed with brine (5 mL), dried over sodium sulfate, filtered and the solvent was removed in vacuo. Filtration over silica gel (5% EtOAc/hexane) afforded a crude silyl ether A34 as a yellow oil (structure not shown). A34: IR (film) 2956, 1644, 1462 cm "1 ; l H NMR (400 MHz, CDC1 3 ) δ 0.05 (6H, s), 0.05 (9H, s), 0.7-1.70 (42H, m), 2.21 (2H, d, J= 6.48 Hz), 2.38-244 (2H, m), 2.72 (2H, ά, J= 13.36 Hz), 3.71 (IH, t, J= 5.43 Hz), 3.77 (IH, dd, J = 11.53, 3.59 Hz), 3.88-3.93 (IH, m), 4.07 (IH, td, J = 11 91, 3.06 Hz), 5.02 (IH, s), 5.06 (IH, d, J = 3.66 Hz), 5.77-5.88 (IH, m); 13 C NMR (100 MHz, CDC1 3 ) δ - 4.06, 3.39, 19.38, 21.48, 22.23, 22.72, 24.25, 24.78, 26.27, 26.69, 29.52, 34.58, 35.25, 38.06, 38.38, 38.50, 39.68, 42.02, 43.11, 59.68, 51.72, 65.98, 72.08, 83.20, 100.98, 117.06, 135.66; [α] D = -4.18° (c l.O. CDClj). To crude silyl ether A34 in /-butanol (2.3 mL), water (1.4 mL) and pH 7 phosphate buffer (465 μL) was added Na >4 (79 mg, 0.368 mmol) followed by KMn0 4 (2.9 mg, 0.0184 mmol). The purple solution was stirred for 3 h and then water (3 mL) was added. This mixture was then exttacted with ethyl acetate (4 x 5 mL) and the combined organics were washed with brine (5 mL), dried over sodium sulfate and filtered. The solvent was removed in vacuo and chromatography on silica gel (12.5% EtOAc, 0.1% acetic acid/ hexanes) afforded acid 504.1 as well as the β-C3 diastereomeric alcohol. 504.1: IR (film): 3433, 2956, 1712, 1461 cm "1 ; Η NMR (400 MHz, CDC1 3 ) δ 0.08 (3H, s), 0.09 (3H, s), 0.13 (6H, s), 0.70-1.70 (48H, m), 2.35-2.55 (3H, m), 2.72 (IH, ά, J = 12.74 Hz), 3.78 (IH, dd, J = 11.34, 3.97 Hz,), 3.90-3.92 (IH, m), 4.75 (IH, dd, J = 12.45, 11.97 Hz), 4.15 (IH, t, J = 4.89 Hz); 13 C NMR (100 MHz, CDC1 3 ) δ -4.53, -4.10, 3.39, 18.32, 19.39, 21.29, 22.29, 22.66, 24.23, 24.75, 26.12, 26,72, 29.64, 34.49, 35.19, 38.04, 38.38, 38.81, 39.71, 42.11, 43.08, 51.67, 59,65, 65.93, 69.51, 83.10, 101.01, 176.69; [α] D 28 = -8.19° (c 2.70, CDC1 3 ). 2D. 9-/-Butyl 14 Linker Synthon 508 508.1 (Formula 508 where R 8 is t-butvu To (-)-Ipc2BOMe (108.8 mg, 0.34 mmol) (weighed in an inert atmosphere) was added diethyl ether (340 μL). The flask was cooled to -78°C and allylmagnesium bromide (1.0 M, 310 μL, 0.31 mmol) was added. The precipitous mixture was stirred for 15 min. at -78°C and then slowly warmed to rt and stiπed for 1 hour. Diethyl ether (340 mL) was added and then a pre-cooled solution of an aldehyde 506(0.109 mmol) (structure not shown) prepared as described for compound 10 in Wender et al. (1998c) in diethyl ether (160 μL) was added dropwise. The suspension was stirred for 1 h, then the temperature was slowly raised to rt and 3N NaOH (240 μL), 30% hydrogen peroxide (100 μL) and diethyl ether (400 μL) was added. The biphasic mixture was refluxed for 1 h and then quenched with water (9 mL) and extracted with ethyl acetate (4 x 10 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate and the solvent was removed in vacuo. Chromatography on silica gel (12.5% EtOAc/ hexane) afforded the crude homoallylic alcohol as a yellow oil. To this oil in methylene chloride (500 μL) was added imidazole (19 mg, 0.276 mmol) and TBSC1 (21 mg, 0.138 mmol). The reaction was sealed and stirred for 14 h. The reaction was then quenched with a saturated solution of sodium bicarbonate (2 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organics were washed with brine (5 mL), dried over sodium sulfate, filtered and the solvent was removed in vacuo. Filtration over silica gel (5% EtOAc/ hexane) afforded a crude silyl ether as a yellow oil. To this oil in /-butanol (2.3 mL), water (1.4 mL) and ρH7 phosphate buffer (465 μL) was added NaI04 (79 mg, 0.368 mmol) followed by KMn0 (2.9 mg, 0.0184 mmol). The purple solution was stirred for 3 h and then water (3 mL) was added. This mixture was then exttacted with ethyl acetate (4 x 5 mL) and the combined organics were washed with brine (5 mL), dried over sodium sulfate and filtered. The solvent was removed in vacuo and chromatography on silica gel (12.5% EtOAc, 0.1% acetic acid/ hexanes) afforded acid 508.1 (34 mg, 56%) as a colorless oil. 508.1: R/ (15% ethyl acetate/ hexanes) = 0.17; IR (film) 2700-3300, 2954, 2869, 1713, 1107, 837, 776 cm "1 ; l U NMR (300 MHz, CDCI3) δ 0.08 (6H, s), 0.69 (IH, t, J = 13.1 Hz), 0.76-0.90 (27H, m), 1.17-1.25 (3H, m), 1.39-1.61 (6H, m), 1.70- 1.82 (3H, m), 2.40 (IH, dsept, J= 7.2, .9 Hz), 2.58 (IH, dd, J= 13.1, 5. 6 Hz), 2.68 (IH, br d, J= 12.6 Hz), 2.91 (IH, t, J = 4.8 Hz), 3.41 (IH, dd, J = 5.9, 2.3Hz), 3.63-3.77 (2H, m), 3.82 (IH, dd, J = 11.7, 4.2 Hz), 4.066 (IH, td, J = 12.0, 2.7 Hz), 4.23-4.29 (IH, m), 9.20-940 (IH, br s); 13 C NMR (100 MHz, C6D6) δ -5.1, -4.8, 17.8, 18.9, 21.9, 22.1, 23.7, 24.3, 25.6, 26.0, 29.1, 31.8, 34.9, 35.7, 37.3, 38.7, 41.8, 51.3, 59.2, 66.6, 66.9, 67.2, 84.5, 174.7; HRMS (FAB) Calc'd. for C3θH58θ6Si: 542.4002, Found: 5424005; [α]D 22 = - 5.88° (C 1.67, CH2CI2). 2E. Linker Synthon 507 To (-)-Ipc2BOMe (108.8 mg, 0.34 mmol) (weighed in an inert atmosphere) was added diethyl ether (340 μL). The flask was cooled to -78°C and allylmagnesium bromide (1.0 M, 310 μL, 0.31 mmol) was added. The precipitous mixture was stiπed for 15 min. at -78°C and then slowly warmed to rt and stiπed for 1 hour. Diethyl ether (340 mL) was added and then a pre-cooled solution of an aldehyde 506 (0.109 mmol) (structure not shown) prepared as described for compound 9 in Wender et al. (1998c) in diethyl ether (160 μL) was added dropwise. The suspension was stirred for 1 h, then the temperature was slowly raised to rt and 3N NaOH (240 μL), 30% hydrogen peroxide (100 μL) and diethyl ether (400 μL) was added. The biphasic mixture was refluxed for 1 h and then quenched with water (9 mL) and extracted with ethyl acetate (4 x 10 mL). The combined organics were washed with brine (10 mL), dried over sodium sulfate and the solvent was removed in vacuo. Chromatography on silica gel (12.5% EtOAc/hexane) afforded the crude homoallylic alcohol A40 (structure not shown) as a yellow oil. Rf (35% ethyl acetate/hexanes) = 0.65; IR (film) 3455, 2950, 2868, 1456, 1373, 1308, 1265, 1110, 997 cm " , ] H NMR (300 MHz, CDCI3) δ 0.68 (IH, t, J = 13.5 Hz), 0.83-0.92 (10H, m), 1.39-1.52 (5H, m), 1.57-1.72 (3H, m), 1.71 (IH, d, J = 4.9 Hz), 2.24 (IH, t, J = 4.9 Hz), 2.35-2.42 (2H, m), 2.70 (3H, br ά, J = 12.4 Hz), 346-3.60 (3H, m), 3.62-3.70 (IH, m), 3.77-3.95 (3H, m), 4.11 (IH, dd, 7 = 11.9, 2.7 Hz), 5.07 (2H, dd, J = 9.5, 1.9 Hz), 5.70-5.91 (IH, m); 13 C NMR (100 MHz, CDC1 3 ) δ 13.9, 16.4, 17.5, 21.1, 22.0, 23.1, 29.1, 30.7, 31.1, 31.8, 33.7, 37.3, 46.1, 51.1, 56.9, 64.7, 65.0, 66.8, 113.3, 129.3; [α] D 20 = 2.5° To A40 in methylene chloride (500 μL) was added lmidazole (19 mg, 0.276 mmol) and TBSC1 (21 mg, 0.138 mmol) The reaction was sealed and stirred for 14 h. The reaction was then quenched with a saturated solution of sodium bicarbonate (2 mL) and extracted with ethyl acetate (3 x 5 mL) The combined organics were washed with brine (5 mL), dried over sodium sulfate, filtered and the solvent was removed in vacuo. Filtration over silica gel (5% EtOAc/ hexane) afforded a crude silyl ether A41 (structure not shown) as a yellow oil. R " (35% ethyl acetate/ hexanes) = 0.65; IR (film): 2953, 2864, 1641, 1472, 1372, 1255, 1108, 830 cm -1 ; ! H NMR (300 MHz, CDCI3) δ 0.05 (3H, s), 0.05 (3H, s), 0.67 (IH, t, J = 13 5 Hz), 0 81-0.96 (18H, 'm), 1 11-1.20 (IH, m), 1.35-147 (4H, m), 1.52-1.71 (5H, m), 2.22 (IH, br s), 2.35-2 42 (2H, m), 2.70 (3H, br d, J = 12.2 Hz), 3.38-3.54 (4H, m), 3.78-3.97 (3H, m), 4 10 (IH, dd, J = 11.9, 2.8 Hz), 5.05 (2H, dd, J = 9.4, 1.8 Hz), 5 69-5.91 (IH, m); 13 C NMR (100 MHz, CDC1 3 ) δ -9.5, -9.1, 13.3, 14.1, 17.1, 17 5, 18.9, 19.5, 21.1, 24.1 , 27 0, 30.2, 31.8, 32.0, 32 6, 37 5, 46.4, 54.4, 59 5, 61.9, 62.8, 64.1, 95.6, 112.0, 130.0, [α] D 20 = 16.2° (c 1.0, CH 2 C1 2 ). To A41 in /-butanol (2.3 mL), water (1 4 mL) and pH 7 phosphate buffer (465 μL) was added NaI04 (79 mg, 0 368 mmol) followed by KMn0 4 (2 9 mg, 0.0184 mmol). The purple solution was stirred for 3 h and then water (3 mL) was added This mixture was then extracted with ethyl acetate (4 x 5 mL) and the combined organics were washed with bnne (5 mL), dπed over sodium sulfate and filtered. The solvent was removed in vacuo and chromatography on silica gel (12.5% EtOAc, 0.1% acetic acid/ hexanes) afforded acid 507. IR (film)' 2700-3300, 2952, 2866, 1738, 1471, 1373, 1307, 1146, 1103, 837, cm "1 , ! H NMR (300 MHz, CDCI3) δ 0.06 (3H, s), 0.07 (3H, s), 0.67 (IH, app t, J= 13.1 Hz), 0 81-0.89 (19H, m), 1.14-1.20 (IH, m), 1.35-147 (5H, m), 1.50-1.82 (4H, m), 2 34-2.41 (IH, m), 245-2.53 (2H, m), 2 69 (3H, br d, J = 13 7 Hz), 3.44-3.51 (4H, m), 3.80 (IH, dd, J = 11.5, 3 9 Hz), 3.87-3.95 (IH, m), 4 02-4.09 (IH, m), 4.22-4.29 (IH, m); 13 C NMR (100 MHz, CDC1 3 ) δ -9 6, 13.1, 14.1, 17.1, 17 5, 18.9, 19 5, 20 9, 24.2, 26 9, 30 1 , 32.0, 32 3, 32 6, 37 1, 46.4, 54.3, 59 6, 61 9, 62.1 , 95.7, 171 5; HRMS (FAB) Calc'd. for C26H50θ6Sr 486.3379, Found: 486.3377, [α] D 20 = 9.4° (c 1 3, CH 2 C1 2 ). 2F. Ether Diester Linker Synthon 606 The following procedure, refeπed to as the "general isolation procedure", was used to purify various reaction products below. The reaction mixture is quenched by dropwise addition of saturated aqueous ammonium chloride, and the resultant mixture is allowed to partition between solvent and brine or water. The aqueous layer is extracted with 1 to 3 portions of ethyl acetate. The combined organic extracts are dπed over sodium sulfate and concentrated in vacuo. Formula 602 To a solution of 3-(p-methoxybenzyloxy)propyl allyl ether 601 (1.0 g, 4.3 mmol) in THF (10 mL) was added 9-BBN (20.6 mL of 0.5 M solution in THF, 10.3 mmol), and the mixture was stiπed for 2 h at rt. Hydrogen peroxide (30 %, 10 mL) and sodium hydroxide (15 %, 10 mL) were added and the mixture was stirred for 3 h. The general isolation procedure afforded crude product which was purified further by silica gel chromatography to give the expected purified alcohol A51 (870 mg, 75 %) (structure not shown). Rf = 0.25 (50 % ethyl acetate in hexane); IR (neat) = 3423, 2934, 2864, 1612, 1513, 1248, 1098 cm "1 ; ! H NMR (300 MHz, CDCI3) δ 7.25 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 4.43 (s, 2 H), 3.80 (s, 3 H), 3.75 (q, J = 5.7 Hz, 2 H), 3.60 (t, J = 5.7 Hz, 2 H), 3.52 (m, 4 H), 2.46 (br t, 1 H), 1.84 (m, 4 H); 13 C NMR (75 MHz, CDCI3) δ 129.36, 113.83, 72.63, 70.34, 68.33, 66.89, 62.20, 55.23, 31.88, 29.96. To a solution of DMSO (1.38 mL, 19.5 mmol) in methylene chloride (5 mL) at -78°C was added oxalyl chloride (850 :L, 9.74 mmol) dropwise. After 5 min, alcohol A51 from the preceding step (870 mg, 6.49 mmol) in methylene chloride (2 mL) was added and the mixture was stirred for another 20 min. TEA (triethylamine, 4.31 mL, 32.5 mmol) was added. After 10 min, the mixture was warmed to rt. The standard isolation procedure afforded the expected aldehyde 602 (760 mg, 89 %). Rf = 0.40 (33 % ethyl acetate in hexane); IR (neat) = 2863, 1724, 1612, 1513, 1248, 1098 cm "1 ; l U NMR (300 MHz, CDCI3) δ 9.75 (s, 1 H), 7.25 (d, J = 9.0 Hz, 2 H), 6.87 (d, J = 9.0 Hz, 2 H), 4.42 (s, 2 H), 3.80 (s, 3 H), 3.74 (t, J = 6.0 Hz, 2 H), 3.51 (m, 4 H), 2.62 (m, 2 H), 1.84 (quint, J = 6.3 Hz, 2 H); 13 C NMR (75 MHz, CDCI3) δ 201.49, 159.26, 130.65, 129.31, 113.78, 72.57, 68.08, 66.69, 64.40, 55.19, 43.75, 29.86. Formula 603 (-)-Ipc2BOMe (1.91 g, 6.04 mmol) in ether (4 mL) was treated with allylmagnesium bromide (4.83 mL, 4.83 mmol) at rt. After 30 min, the mixture was cooled to -78 °C. The aldehyde 602 (370 mg, 2.76 mmol) in ether (1.5 mL) was added and stirred for 2h at -78 °C. 15% NaOH (1.5 mL) and 30% hydrogen peroxide (1.5 mL) were added and the mixture was warmed to rt. After 2 h, the mixture was diluted with ethyl acetate and washed with brine. Column chromatography yielded the expected alcohol A53 (383 mg, 80 %) (structure not shown). Alcohol A53 (150 mg, 0.852 mmol) in methylene chloride (4 mL) was tteated with TBSC1 (168 mg, 1.11 mmol) and imidazole (116 mg, 1.7 mmol) at rt. After overnight, the reaction was worked up by the standard procedure. Column chromatography afforded expected TBS alkene ether 603 (195 mg, 79 %). 603: Rf = 0.50 (10 % ethyl acetate in hexane); [α] 25 D = 13.6 ° (c 1.08, CH2Cl2); IR (neat) = 2952, 2856, 1717, 1613, 1513, 1471, 1362, 1248, 1110 cm" 1 ; 1H NMR (400 MHz, CDCI3) δ 7.26 (d, J = 8.4 Hz, 2 H), 6.88 (d, J = 8.4 Hz, 2 H), 5.81 (m, 1 H), 5.04 (m, 2 H), 4.43 (s, 2 H), 3.86 (s, 3 H), 3.49 (m, 7 H), 2.23 (m, 2 H), 1.87 (m, 2 H), 1.69 (m, 2 H), 0.89 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H); 13 C NMR (100 MHz, CDCI3) δ 159.09, 134.96, 130.60, 116.93, 113.71, 72.59, 68.91, 67.80, 67.48, 67.18, 55.23, 42.28, 36.62, 30.16, 25.85, 18.08, -4.39, -4.76 Formula 605 Alkene ether 603 (195 mg, 0.672 mmol) in /ert-butanol-water (pH 7) (1: 1, 4 mL) was treated with KMnθ4 (11 mg, 0.0672 mmol) and sodium periodate (548 mg, 2.56 mmol) in water (0.5 mL). After 30 min, the reaction was quenched with sodium thiosulfate. The mixture was diluted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concenttated to give a crude acid 604. The crude acid in methylene chloride (3 mL) was treated with SEMC1 (2- (trimethylsilyl)ethoxymethyl chloride, 301 :L, 1.7 mmol) and TEA (452 :L, 3.4 mmol) at rt and stiπed for 2 h. The reaction was worked up by the standard procedure to afford the expected SEM ester 605. SEM ester 605 in wet methylene chloride (3 mL) was tteated with DDQ (291 mg, 1.28 mmol). After 1 h, the mixture was directly purified by silica gel chromatography to give the alcohol product 606 (86 mg, 29 % for 3 steps). 606: Rf = 0.25 (25 % ethyl acetate in hexane); [α] 25 D = 0.4 ° (c 0.82, CH2CI2); IR (neat) = 3458, 2955, 1741, 1472, 1378, 1250, 1116 cπr 1 ; J H NMR (400 MHz, CDCI3) δ 5.25 (q, J = 2.8 Hz, 2 H), 4.25 (quint, J = 6.4 Hz, 2 H), 3.71 (m, 4 H), 3.52 (m, 4 H), 2.50 (d, J = 6.0 Hz, 2 H), 2.44 (br, 1 H), 1.79 (m, 4 H), 0.94 (t, J = 8.4 Hz, 2 H), 0.85 (s, 9 H), 0.05 (s, 3 H), 0.03 (s, 3 H), 0.00 (s, 9 H); 13 C NMR (100 MHz, CDCI3) δ 171.04, 88.97, 69.88, 67.88, 67.25, 66.45, 61.81, 42.84, 37.12, 32.02, 25.71, 17.97, 17.91, -1.48, -4.81, -4.86 2G. C5 Ester-Open C7 Linker Synthon 513 509a 509b To menthone aldehyde 402 (400 mg, 1.56 mmol) from Example 2A in DMF (12 mL) was added prenyl bromide (396 mg, 1.56 mmol) followed by indium powder (359 mg, 3.13 mmol) at rt. After 30 min., the reaction was diluted with EtOAc (20 mL) and saturated aqueous ammonium chloride (15 mL). The layers were separated and the aqueous layer was re-extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (15 mL) and dried over sodium sulfate. The solvent was removed in vacuo and chromatography (7 5% EtOAc/pentane) to afford 509a (105 mg, 21%) and 509b (321 mg, 63%) Undesired isomer 509a can be recycled by the following procedure To 509a (320 8mg, 0 98 mmol) in methylene chloride (3 mL) was added Dess-Martin Penodmane (707 mg, 1 67 mmol) and stiπed for 1 h at room temperature The reaction was diluted with methylene chloπde (3 mL), saturated sodium bicarbonate (3 mL) and sodium thiosulfate (3 mL) and stirred for 1 h The layers were separated and the aqueous layer was re -exttacted with EtOAc (4 x 5 mL) The combined organics were dried over sodium sulfate and the solvent was removed in vacuo The crude ketone was dissolved in MeOH (17 3 mL) and CeCl 3 «7H 2 0 (1 83 g, 4 9 mmol) was added and stiπed for 5 min The solution was cooled to - 50°C and NaBH 4 (74 5 mg, 19 6mmol) was added The reaction was stiπed for 30 min and then poured into a separatory funnel containing EtOAc (30 mL), water (18 mL) and brine (30 mL) The layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 mL) The combined organics were dried over sodium sulfate and the solvent was removed in vacuo Chromatography (7 5%-20% EtOAc/pentane) provided 509b (177 mg, 53%) and 509a (56 mg, 18%) 509a R f (7 5%EtOAc/ pentane) = 0 186, IR (film) 3496 8, 2953 9, 2869 6, 1458 0, 1374 4, 1308 3, 1266 5, 1157 8, 1130 7, 1102 0, 977 6, 912 2 cm ', Η-NMR (300 MHz, CDC1 3 ) δ 0 68 (IH, t, J = 12 9Hz), 0 85-0 89 (9H, m), 0 98 (3H, s), 0 99 (3H, s), 1 14-1 76 (10H, m), 2 38 (IH, sept, J = 6 9Hz), 2 73 (IH, br ά, J = 13 5Hz), 3 59 (IH, br d, J = 9 9Hz), 3 78 (IH, dd, J = 11 7, 5 4Hz), 4 02 (1H, d, J = 11 4 ), 4 11 (IH, d, J = 13 2 ), 5 00- 5 09 (2H, m), 5 81 (IH, dd, J= 17 6, 11 0Hz), 13 C-NMR (75 MHz, CDC1 3 ) δ 18 8, 21 7, 22 0, 22 4, 23 1 , 23 8, 24 3, 29 1, 31 9, 34 9, 37 4, 38 5, 41 2, 51 2, 59 1, 64 5, 73 5, 100 4, 113 2, 145 4, HRMS calc'd for C 20 H 36 O 3 324 2664, found 324 2664, [α] 24 0 d +19 36° (c 8 16, CH 2 C1 2 ) 509b R f (7 5%EtOAc/ pentane) = 0 37, IR (film) 3520 4, 2953 6, 2870 2, 1455 8, 1375 6, 1309 4, 1266 0, 1130 3, 1090 0, 973 3, 914 4 cm Η-NMR (300 MHz, CDC1 3 ) δ 0 73 (IH, t, J= 13Hz), 0 83-0 92 (9H, m), 1 00 (3H, s), 1 01 (3H, s), 1 18-1 77 (10H, m), 2 39 (IH, sept, J= 7Hz), 2 73 (IH, br d, J= 13 5Hz), 3 53 (IH, ά, J = 9 9Hz), 3 57(1H, s), 3 79 (IH, dd, J = 11 7, 4 8Hz), 4 00-4 15 (2H, m), 4 96-5 02 (2H, m), 5 87 (IH, dd, J= 17 1, 11 1Hz), 13 C-NMR (75 MHz, CDC1 3 ) δ 18 9, 21 9, 22 2, 22 3, 23 3, 23 8, 24 2, 28 9, 31 8, 34 6, 37 3, 38 0, 41 1, 50 9, 58 8, 70 3, 78 9, 101 0, 111 9, 145 7, HRMS calc'd for C 20 H 36 O 3 324 2664, found 324 2665, [α] 25 ' d -1 94° (c 9 75, CH 2 C1 2 ) Formula 510 To a solution of 509b (282 mg, 0 87 mmol) in MeOH (3 3 mL) and methylene chloπde (13 mL) at -78°C was bubbled ozone for 5 mm or until a blue color persisted The solution was then purged with nittogen for 5 min NaBH 4 (138mg, 3 65mmol) was then added and stiπed for 1 h at -78°C, and 2 h at 0°C Saturated ammonium chloride (15 mL) and water (5 mL) were then poured into the reaction and the layers were separated The aqueous layer was extracted with methylene chlonde (4 x 5mL) The combined organics were dried over sodium sulfate and the solvent was removed in vacuo, yielding crude diol 510 R f (20%EtOAc/pentane) = 0 195, IR (film) 3452 3, 2954 1, 2871 3, 1455 5, 1383 4, 1308 9, 1266 9, 1131 4, 1047 2, 972 6 cm ', Η-NMR (300 MHz, CDC1 3 ) δ 0 74 (IH, t, J = 13Hz), 0 85-0 89 (12H, m), 0 92 (3H, d, J= 6 6Hz), 1 12-1 25 (2H, m), 1 39-1 78 (7H, m), 2 39 (IH, sept, J= 6 9Hz), 2 73 (IH, br ά, J= 13 5Hz), 3 48 (3H, m), 3 70-3 73 (IH, m), 3 80 (IH, dd, J = 11 4, 5 1Hz), 4 084 15 (3H, m), 13 C-NMR (75 MHz, CDC1 3 ) δ 18 8, 19 0, 22 2, 22 3, 22 5, 23 7, 24 2, 29 0, 31 8, 34 5, 37 3, 37 6, 38 0, 50 9, 58 8, 70 6, 72 0, 80 5, 101 0, HRMS calc'd for Cι 9 H 36 0 4 328 2614, found 328 2619, [α] 260 d -0 78° (c 5 48, CH 2 Cl 2 ) Formula 511 To crude diol 510 was added pyridine (316 μL, 3 91 mmol) and chloroacetic anhydπde (229 mg, 1 3 mmol) at -78°C and stiπed for 2 hr Saturated aqueous sodium bicarbonate (10 mL) was added and the layers were separated The aqueous layer was extracted with methylene chloride (3 x 5 mL) The combined organics were dried over sodium sulfate and the solvent was removed in vacuo Chromatography (10%-20%-30% EtOAc/ pentane) provided residual starting mateπal A61 (89 8 mg, 31%) and chloroacetate ester 511 (152 5 mg, 44%) 511 R f (20% EtOAc/pentane) = 0 56, IR (film) 3515 2, 29544, 2871 9, 1738 5, 1455 8, 1371 6, 1308 7, 1132 8, 972 7 cm 1 , Η-NMR (300 MHz, CDC1 3 ) δ 0 75 (IH, t, J = 13 2Hz), 0 87 (3H, d, J = 2 7Hz), 0 89 (3H, d, J= 3Hz), 0 92-0 93 (10H, m), 1 19-1 26 (2H, m), 1 39-1 79 (7H, m), 2 40 (IH, qmn, J= 6 9Hz), 2 74 (IH, br d, J= 13 2Hz), 3 65-3 66 (2H, m), 3 81 (IH, dd, J= 11 6, 4 7Hz), 4 00-4 17 (4H, m), 4 07 (2H, s), 13 C-NMR (75 MHz, CDC1 3 ) δ 18 9, 19 3, 21 4, 22 2, 22 3, 23 8, 24 2, 29 0, 31 8, 34 5, 37 3, 374, 38 2, 40 9, 50 9, 58 8, 70 5, 71 6, 76 1, 101 0, 167 3, HRMS calc'd for C 21 H 37 C10 5 404 2330, found 4042329, [α] 2 3 d +4 95° (c 3 43, CH 2 C1 2 ) Formula 512 To acid 28 (structure not shown) prepared as descnbed in Theisen et al (1998) (hydrogen (3R, I 'R) -l-(l '-napthyl)ethyl 3-[(/er/-butyldιmethylsιlyl)oxy] pentanedioate, 309 mg, 0 744 mmol) in toluene (6 mL) was added tnethylamme (263 μL, 1 98 mmol) followed by the Yamaguchi reagent (124 μL, 0 79 mmol) and stiπed for 2 hr at room temperature DMAP (303 mg, 2 50 mmol) was then added followed by 511 (190 mg, 0469 mmol) and the mixture was stirred for 45 min The reaction was then diluted with EtOAc (5 mL) and saturated aqueous sodium bicarbonate (10 mL) was added The layers were separated and the aqueous layer was exttacted with EtOAc (3 x 5 mL) The combined organics were washed with saturated aqueous ammonium chlonde (10 mL), the layers were separated and the aqueous layer was extracted with EtOAc (2 x 5 mL) The combined organics were dried over sodium sulfate and the solvent was removed in vacuo Chromatography (5%-10% EtOAc/pentane) provided 512 (311 9 mg, 83%) R f (10%EtOAc/pentane) = 0 46, IR (film) 2953 8, 2868 2, 1738 1, 1471 9, 1373 6, 1307 9, 1258 5, 1160 3, 1108 7, 1069 3, 977 5, 837 0, 777 9 cm ', Η-NMR (500 MHz, CDC1 3 ) δ 0 04 (3H, s), 0 12 (3H, s), 0 61 (IH, t, J = 13 2Hz), 0 79 (9H, s), 0 82-0 92 (9H, m), 0 94 (3H, s), 0 95 (3H, s), 1 12-1 15 (IH, m), 1 35-1 47 (IH, m), 1 56-1 65 (4H, m), 1 69 (3H, d, J = 6 5Hz), 1 72-1 79 (IH, m), 2 37 (IH, quin, J = 6 9Hz), 2 56-2 63 (4H, m), 2 68 (IH, dd, J = 15 3, 5 3Hz), 3 64-3 68 (IH, m), 3 76 (IH, dd, J= 11 8, 4 8Hz), 3 86 (IH, d, J= 11Hz), 3 97 (IH, td, J = 12 6, 1 8Hz), 4 01 (IH, d, J= 11Hz), 4 05 (2H, s), 4 51 (IH, quin, J = 6Hz), 4 98 (IH, dd, J = 9 5, 1 0Hz), 6 64 (IH, q, J = 6 5Hz), 7 42-7 53 (3H, m), 7 57 (IH, d, J = 7 0Hz), 7 78 (IH, d, J = 8 0Hz), 7 85 (IH, d, J = 8 5Hz), 8 06 (IH, ά, J = 8 5Hz) ), 13 C-NMR (125 MHz, CDC1 3 ) δ -5 1, -4 8, 14 2, 17 8, 19 0, 20 3, 21 4, 21 7, 21 8, 22 3, 23 7, 24 3, 25 6, 28 8, 31 0, 34 9, 37 2, 37 3, 38 1, 40 7, 41 8, 42 1, 51 1, 58 9, 65 6, 65 7, 69 7, 70 9, 73 0, 100 5, 123 1, 123 2, 125 3, 125 6, 126 2, 128 4, 128 8, 130 1, 133 8, 137 3, 167 1, 170 1, 170 4, HRMS calc'd for GwH^ClO., Si (+lNa) 825 4149, found 825 4141 , [α] 25 5 d -2 17° (c 8 42, CH 2 C1 2 ) Formula 513 To 512 (156 mg, 0 194 mmol) in EtOAc (4 4 mL) at room temperature was added Pd(OH)JC (75 mg) The black slurry was stiπed and the flask was evacuated and refilled with hydrogen (5 times) After 5 5 h under 1 atm of hydrogen, the reaction was poured directly onto a silica column pre-packed with pentane and eluted (20%EtOAc + l%AcOH/ pentane) to provide 119 mg of linker synthon 513 in 95% yield 513 R f (20%EtOAc + l%AcOH/ pentane) = 0 27, IR (film) 2800 0-3422 4, 2954 1, 2866 6, 1738 3, 1714 1, 1473 1, 1375 8, 1308 0, 1258 4, 1159 6, 1107 3, 977 0, 837 3, 778 8 cm ', Η-NMR (300 MHz, CDC1 3 ) δ 0 08 (3H, s), 0 09 (3H, s), 0 66 (IH, t, J = 13 0Hz), 0 85-0 92 (19H, m), 0 95 (3H, s), 0 97 (3H, s), 1 06-1 25 (IH, m), 1 33-1 50 (4H, m), 1 58-1 81 (4H, m), 2 37 (IH, dsept, J = 6 6, 1 2Hz), 2 53 (IH, dd, J = 15 3, 6 9Hz), 2 58-2 60 (3H, m), 2 66 (IH, dd, J = 15 0, 4 8Hz), 3 64-3 68 (IH, m), 3 79 (IH, dd, J = 11 7, 4 2Hz), 3 86 (IH, d, J = 1 1 1Hz), 3 98-4 03 (IH, m), 4 00 (IH, d, J = 11 1Hz), 4 06 (2H, s), 4 49 (IH, quin, J= 5 9Hz), 4 98 (IH, dd, J = 9 6, 1 8Hz) ), 13 C-NMR (75 MHz, CDC1 3 ) δ - 5 1, -4 8, 17 9, 19 0, 20 3, 21 4, 21 7, 22 3, 23 7, 24 3, 25 7, 28 8, 31 1 , 34 9, 37 3, 37 4, 38 2, 40 7, 41 9, 42 0, 51 1, 58 9, 65 7, 65 7, 70 9, 73 3, 100 6, 167 2, 170 2, 176 4, HRMS calc'd for C 32 H„C10 9 Si (+lNa) 671 3348, found 671 3358, [α] 274 d -20 46° (c 7 46, CH 2 C1 2 ) Example 3 - Exemplary Bryostatin Analogues 3A Formula II - C26 Des-Methyl Bryostatin Analogue (702) 201.1 (Formula 201 where R 20 is -O-CO-C,!^ and R 21 is =CH-CQ 7 Me) To di-benzyl ether 111.1 (Example 1C, 503 mg, 0.169 mmol) in EtOAc (12.3 mL) at room temperature is added Pd(OH) 2 /C (82 mg). The black slurry was stiπed vigorously and the flask was evacuated and refilled 4 times with hydrogen (1 atm). After 1 h, the reaction was poured directly onto a sihca column and eluted (50% EtOAc/ pentane to 100% EtOAc) to provide 201.1 (240 2 mg, 65%) as a colorless oil. 201.1: R (50% EtOAc/pentane) = 0 36, IR (film) = 3424, 2955, 2930, 2857, 1748, 1722, 1156, 1081, 837, 776 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 0.00 (6H, s), 0.84-0.93 (12H, m), 0.96 (3H, s), 0.98 (3H, s), 1.20 (3H, d, J= 6.0 Hz), 1.15-1.38 (10H, m), 1.62 (IH, t, J = 7 1 Hz), 1.71 (IH, t, J= 5.7 Hz), 2.25-245 (2H, m), 2.54 (IH, s), 2 89 (IH, d, J = 4.2 Hz), 3.34-348 (IH, m), 3 36 (3H, s), 3.52 (2H, dd, J = 15 9, 9.6 Hz), 3.58-3 76 (3H, m), 3.67 (3H, s), 4 14-4.26 (IH, m), 5.55 (IH, s), 5 89 (IH, s), 13 C NMR (75 MHz, CDC1 3 ) δ -5.5, 14 0, 18.4, 19.4, 20.7, 22 5, 24.6, 25.9, 28 8, 29.0, 31.6, 32.4, 34.4, 39.0, 46.6, 51 1, 51 3, 67.5, 684, 70 9, 71.9, 72.3, 103 1, 116.9, 1524, 166 5, 171.8; [α 3 9 D = -2.24° (c = 6.53, CH 2 C1 2 ). To diol 201.1 (26.8 mg, 0.045 mmol) in benzene (1.2 mL) under nittogen at 0°C was added tnethylamine (30 μL, 0.227 mmol) followed by lead tettaacetate (50 mg, 0.113 mmol). The resultmg suspension was stirred at 0°C for 20 min. and was then quenched with an aqueous solution of saturated ammonium chloride (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried over sodium sulfate, the solution was decanted and then the solvent was removed in vacuo to provide the crude aldehyde (structure not shown) which was taken immediately to the next step. To the crude aldehyde (34 mg, 0.061 mmol) in THF (1.4 mL) under nitrogen at 0°C was added a 0.5M solution of the Tebbe reagent in toluene (122 μL, 0.061 mmol) dropwise. The reddish-black slurry was stirred at 0°C for 15 min. and was then quenched with a saturated aqueous solution of sodium bicarbonate (5 mL). The biphasic mixture was exttacted with ethyl acetate (3 x 5 mL). The combined organic layers were dried over sodium sulfate, the solution was decanted and then the solvent was removed in vacuo. Chromatography (5% EtOAc/ pentane) provides olefin 202.1 (19 mg, 56% - 2 steps) as a colorless oil. 202.1: R (10% EtOAc/pentane) = 0.62; IR (film) = 2955, 2930, 2857, 1747, 1722, 1667, 1155, 1082, 837, 775 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 0.01 (6H, s), 0.80-0.90 (12H, m), 0.96 (3H, s), 1.00 (3H, s), 1.20-1.38 (10H, m), 1.56-1.72 (IH, m), 2.24-246 (4H, m), 343 (IH, d, J = 15.9 Hz), 3.30 (3H, s), 3.54 (2H, dd, J= 18.9, 9.3 Hz), 3.68 (3H, s), 3.87-3.91 (IH, m), 5.09-5.16 (2H, m), 5.53 (IH, s), 5.80- 5.98 (IH, m), 5.88 (IH, s); 13 C NMR (75 MHz, CDC1 3 ) δ -5.4, 14.0, 18.4, 20.5, 20.6, 22.6, 24.7, 25.9, 28.9, 29.0, 31.6, 32.1, 34.5, 40.0, 47.0, 51.1, 67.3, 71.0, 72.1, 103.0, 116.6, 117.7, 133.8, 153.1, 166.6, 171.9; [α] 22' ° D = -7.91° (c = 1.91, CH 2 C1 2 ). 203.1 (Formula 203 where R 20 is -0-CO-C7H,. and R 21 is =CH-CQ 7 Me) To a solution of silyl ether 202.1 (101.7 mg, 0.1833 mmol) and pyridine (267 μL, 3.30 mmol) in THF (1.53 mL) in a polypropylene vial was added 70% HF/pyridine complex (104.8 μL, 3.67 mmol) at room temperature. The solution was stiπed for 18 hours and was then quenched with a saturated aqueous solution of sodium bicarbonate (5 mL). The biphasic mixture was exttacted with ethyl acetate (4 x 5 mL). The combined organic layers were dried over sodium sulfate, the solution was decanted, and the solvent was removed in vacuo to afford the coπesponding de-silylated alcohol (structure not shown) as a pale yellow oil which was used immediately in the next step. The crude alcohol was dissolved in CH 2 C1 2 (2 mL) and tteated with a single portion of 1,1 ,1- triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one (Dess-Martin periodinane, 117 mg, 0.275 mmol) at room temperature. The mixture was stiπed for 45 min and quenched with saturated aqueous NaHC0 3 /Na 2 S 2 0 3 (2 mL). The two phase system was vigorously stiπed until the organic layer has cleared (90 min). The layers were then separated and the aqueous phase was exttacted with CH 2 C1 2 (4 x 5 mL). The combined organic layers were dried over sodium sulfate, the solution was decanted and then the solvent was removed in vacuo. Chromatography on silica gel (7.5% EtOAc/hexanes) provides aldehyde 203.1 (43.7 mg, 54% - 2 steps) as a colorless oil. 203.1: Py (15% EtOAc/pentane) = 0.58; IR (film) = 2930, 2857, 1750, 1723, 1668, 1160, 1048 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 0.86 (3H, t, J= 6.3 Hz, octanoate Me), 1.00 (3H, s, C18 Me), 1.16 (3H, s, C18 Me), 1.18-1.31 (10H, m), 146-1.60 (2H, m), 2.18 (2H, t, J = 7.4 Hz), 2.43 (2H, t, J = 6.6 Hz), 3.39 (3H, s), 3.66 (IH, d, J = 18.9 Hz), 3.69 (3H, s), 3.74-3.84 (IH, m), 5.13-5.20 (2H, m), 5.85- 6.00 (IH, m), 5.96 (IH, s), 9.71 (IH, s); 13 C NMR (75 MHz, CDC1 3 ) δ 14.1, 16.3, 19.1, 22.6, 24.3, 28.9, 30.4, 31.6, 38.9, 40.0, 51.2, 51.4, 54.0, 71.5, 71.9, 102.2, 118.2, 119.8, 133.4, 150.3, 1664, 171.7, 202.4; [α] 23'6 D = -6.07° (c = 2.23, CH 2 C1 2 ). 204.1 (Formula 204 where R 20 is -Q-CO-C 7 H,, and R 21 is =CH-CO,Me) A dihydroxylating stock solution was generated by dissolving (DHQD) 2 AQN (3.6 mg, 0.00425 mmol), K 3 Fe(CN) 6 (425 mg, 1.275 mmol), K 2 C0 3 (175 mg, 1.275 mmol) and K 2 0s0 2 (OH) 4 (0.65 mg, 0.00175 mmol) in /-BuOH (2.1 mL) and water (2.1 mL). The resulting solution was stiπed at room temperature for 3 h. 504 μL of this stock solution was added to olefin 203.1 (7.4 mg, 0.017 mmol) pre- dissolved in /-BuOH (200 μL) and water (200 μL) under nittogen at 0°C. The resulting solution was stirred at 0-5°C for 2 days. Water (2 mL) was then added and the biphasic mixture was then extracted with EtOAc (4 x 5 mL). The combined organic layers were dried over sodium sulfate, the solution was decanted and then the solvent was removed in vacuo. Chromatography (90%) EtOAc/ pentane to 100% EtOAc) provides diol 204.1 (5.6 mg, 70%) as an approximately 2.2: 1 (β:α) mixture of diastereomers as a colorless oil. 204.1: R (90% EtOAc/pentane) = 0.36; IR (film) = 3418, 2932, 2860, 1750, 1722, 1668, 1159, 1081, 1052 cm "1 ; Η NMR (400 MHz, CDC1 3 ) δ 0.86 (3H, t, J= 6.8 Hz), 1.01 (3H, s, major), 1.02 (3H, s, minor), 1.15 (3H, s, minor), 1.17 (3H, s, major), 1.20-1.36 (10H, m), 1.47-1.61 (IH, m), 1.70-1.85 (IH, m), 2.10-2.32 (3H, m), 2.55 (IH, br. s, major), 3.09 (IH, br. s, minor), 342-3.80 (4H, m), 3.45 (3H, s, minor), 346 (3H, s, major), 3.69 (3H, s), 3.98-4.20 (2H, m), 5.20 (IH, s, major), 5.25 (IH, s, minor), 5.96 (IH, s), 9.68 (IH, s, minor) 9.68 (IH, s, major); 13 C NMR (100 MHz, CDC1 3 ) δ 14.0, 16.5, 16.7, 19.0, 19.1, 22.5, 24.3, 28.9, 31.3, 31.3, 31.6, 33.9, 38.8, 38.9, 51.3, 51.3, 51.5, 51.6, 53.9, 66.7, 67.2, 68.2, 68.7, 70.3, 71.0, 71.4, 71.7, 102.2, 102.6, 119.6, 119.7, 150.0, 166.3, 171.7, 183.9, 201.8, 202.2. 205.1 (Formula 205 where R 20 is -0-CO-C 7 H,s and R 21 is =CH-CO,Me) To diol 204.1 (28 5 mg, 0.0603 mmol) in methylene chloride (2.45 mL) was added pyridine (141.3 μL, 1.75 mmol) followed by TESCl (176 mL, 1.05 mmol) at room temperature The resulting clear solution was stiπed at room temperature for 15 h Tπethylamine (250 μL) was then added and the solution was directly loaded onto a silica column and eluted (5% EtOAc + 5% tnethylamine/pentane) to afford bis silyl ether 205.1 (42 2 mg, 100%) as an approximately 2.2: 1 (β'α) mixture of diastereomers as a colorless oil. 205.1- R/(5% EtOAc + 5% tnethylamine/pentane) = 0 58; IR (film) = 2955, 2877, 1754, 1724, 1668, 1462, 1231, 1159, 1107, 1007, 743 cm "1 ; Η NMR (400 MHz, CDC1 3 ) δ 044-0.65 (12H, m), 0 86 (3H, t, J = 6 8 Hz), 0.88-0.98 (18H, m), 0 98 (3H, s, major), 1.00 (3H, s, minor), 1.14 (3H, s, major), 1.15 (3H, s, minor), 1.18-1.32 (10H, m), 1 58-1 71 (IH, m), 1.82-2 00 (IH, m), 2.09-2.21 (3H, m), 3 30- 3.71 (3H, m), 3.41 (3H, s, minor), 3 43 (3H, s, major), 3 68 (3H, s, minor), 3.69 (3H, s, major), 3.90-4.10 (2H, m), 5.19 (IH, s, minor), 5.22 (IH, s, major), 5 94 (IH, s, minor), 6 00 (IH, s, major), 9.69 (IH, s, major) 9 70 (IH, s, minor); 13 C NMR (100 MHz, CDC1 3 ) δ 4.3, 4.3, 4.9, 5 2, 6.2, 6.7, 6.8, 6 9, 14 0, 164, 16.5, 18.9, 19.0, 22.5, 24.3, 28.9, 29.7, 31.4, 31 6, 31.8, 33.9, 41 2, 41 5, 51.1, 51.2, 51.4, 51 7, 53.9, 67 3, 67.5, 68 0, 69.3, 69.8, 70 3, 71.1, 71.3, 102 1, 102.3, 119.4, 119.5, 150.2, 150.3, 151.0, 166 2, 166.2, 171.7, 202.5, 202.6. 206.1 (Formula 206 where R 20 is -O-CO-CH^ and R 2 ' is =CH-CO,Me) To a solution of diethylmethoxyborane (361 μL, 2.75 mmol) in Et 2 0 (2.14 mL) was added allylmagnesium bromide (1.0M in Et 2 0, 2.50 mmol, 2 50 mL) dropwise at 0°C. The white precipitous mixture was stirred at 0°C for 60 min. and then allowed to stand for 5 min A 41.6 μL aliquot (0.5 M allyldiethylborane, 0.021 mmol) of this solution was added dropwise to aldehyde 205.1 (7.3 mg, 0 01 mmol) in 0.5 mL Et 2 0 at -10°C. After stirring for 30 min , the reaction was quenched with aqueous saturated NH C1 (5 mL). The biphasic mixture was then exttacted with EtOAc (3 x 5 mL). The combined organic layers were dπed over sodium sulfate, the solution was decanted and then the solvent was removed in vacuo to provide a colorless oil which was taken directly onto the next step. The crude residue was dissolved in CH 2 C1 2 (1 mL) and treated successively with tπethylamine (17 4 μL, 0 125 mmol), 4-dιmethylamιnopyrιdιne (15 3 mg, 0 125 mmol) and Ac 2 0 (6 μL, 0.06 mmol) at room temperature. The solution was stiπed for 17 h and then pipetted directly onto a short column of silica gel and the products eluted with 7 5% EtOAc/hexanes to afford a diastereomenc mixture of homoallylic acetates (7.9 mg, 97% - 2 steps) as a colorless oil. A portion of the isolated homoallylic acetate (5 mg, 0.0064 mmol) was dissolved in THF (253 μL) and H 2 0 (25.3 μL) and tteated with N-methylmorpholine N-oxide (1.6 mg, 0 014 mmol) followed by Osθ4 (4 wt % in H 2 0 - 16 μL, 0 0025 mmol) at room temperature. The homogeneous solution was stiπed for 3 h, and then aqueous saturated sodium bicarbonate (4 mL) and water (1 mL) was added. The biphasic mixture was extracted with EtOAc (5 x 5 mL). The combined organic layers were dned over sodium sulfate, the solution was decanted and then the solvent was removed in vacuo to provide a colorless oil which was taken directly to the next step. The resulting residue was immediately dissolved in benzene (0.4 mL) and tteated with Et 3 N (2 6 μL, 0.025 mmol) at room temperature. Solid Pb(OAc) 4 (4.2 mg, 0.0096 mmol) was quickly added in one portion and the resulting yellow precipitous mixture was stiπed vigorously for 30 min. 1,8- Dιazabιcyclo[5 4 0]undec-7-ene (DBU, 12 μL, 0.08 mmol) was introduced and the reaction mixture was stiπed for another 30 min. The mixture was added directly to a silica column and eluted (10% EtO Ac/Pet ether) to provide unsaturated aldehyde 206.1 (3.4 mg, 73% - 2 steps) as an approximately 2.2- 1 (β.α) mixture of diastereomers as a colorless oil. 206.1: R (10% EtOAc/Pet ether) = 0.42; IR (film) = 2955, 2877, 1748, 1723, 1692, 1461, 1229, 1154, 1105, 1008, 743 cm "1 , Η NMR (400 MHz, CDC1 3 ) δ 0.55-0.68 (12H, m), 0 87 (3H, t, J= 6 8 Hz), 0.92-1 02 (18H, m), 1 15 (3H, s), 1.18 (3H, s), 1.20-1.34 (10H, m), 148-1.60 (2H, m), 1.85-2.03 (IH, m), 2.04-2 23 (2H, m), 2.27-2.39 (IH, m), 3.45-3.68 (2H, m), 3.38 (3H, s, minor), 3 40 (3H, s, major), 3 69 (3H, s, minor), 3.70 (3H, s, major), 3.95-4.05 (IH, m), 4.06^1.17 (IH, m), 5.45 (IH, s, minor), 5.47 (IH, s, major), 5.89 (IH, s), 5.93 (IH, dd, J = 16.1/ 7.8 Hz, major), 5.93 (IH, dd, J = 16.1/ 7.8 Hz, minor), 7.33 (IH, d, J = 16.1 Hz, major), 7 36 (IH, d, J = 16 1 Hz, minor), 9 53 (IH, d, J = 7.8 Hz, major), 9.54 (IH, d, J = 7.8 Hz, minor); 13 C NMR (100 MHz, CDC1 3 ) δ 4.3, 4.4, 4 9, 5 4, 6.7, 6 8, 6 9, 7.0, 14.0, 21 7, 21.8, 22.5, 23.6, 23.8, 24.5, 28.9, 28.9, 31.6, 32.5, 32 8, 34.4, 41.2, 41.6, 47.3, 51.2, 514, 51 5, 67.3, 67.6, 68 9, 69 2, 69.8, 70.3, 71 0, 71.1, 102 4, 102 6, 117.6, 117.7, 126.7, 151.6, 166.2, 167.2, 171.7, 194 6 207.1b (Formula 207 where R 20 is -O-CO-CvH,. and R 2 ' is =CH-CO,Me) Enal 206.1 (22 mg, 0 03 mmol) was dissolved in acetonitrile (2 mL) and water (205 μL) at room temperature 48% aqueous HF (388 μL, 12 1 mmol) was added dropwise and the resulting clear solution was stiπed at room temperature for 75 min and was then quenched with a saturated aqueous solution of sodium bicarbonate (15 mL) and water (3 mL) The mixture was extracted with ethyl acetate (5 x 10 mL). The combined organic layers were dried over sodium sulfate, the solution was decanted and then the solvent was removed in vacuo to provide a crude diol which was taken immediately to the next step. A 0 75 mM silylating solution was generated by the addition of lmidazole (62 mg, 0 91 mmol) and TBSC1 (45.6 mg, 0.3 mmol) to methylene chlonde (3 9 mL) at room temperature under nitrogen. To the crude diol dissolved in methylene chlonde (3.9 mL) and DMF (0.4 mL) was added the above stock solution (1 mL) and stiπed at room temperature for 2 h. The solution was then quenched with an aqueous solution of saturated ammonium chloride (10 mL) and extracted with methylene chlonde (4 x 10 mL). The combined organic layers were further washed with bnne (10 mL) and then dned over sodium sulfate The solution was decanted and then the solvent was removed in vacuo. Chromatography (40% EtOAc/ pentane) provides the silylated C25 β isomer 207.1b (10.4 mg, 574%) along with the silylated C25 α isomer 207.1a (4.6 mg, 25 4%) as colorless oils 207.1b: R/(40% EtOAc/pentane) = 0 38, IR (film) = 3421, 2930, 2857, 1723, 1691, 1257, 1156, 1110, 837, 779 cm "1 ; Η NMR (400 MHz, CDC1 3 ) δ 0.10 (6H, s), 0.87 (3H, t, J= 6.8 Hz), 0.92 (9H, s), 1.14 (3H, s), 1.15 (3H, s), 1 18-1 32 (10H, m), 1 49 (IH, t, J = 7 2 Hz), 1.66-1.74 (IH, m), 1.84-2.00 (IH, m), 1 98-2 15 (3H, m), 3.49 (IH, dd, J = 10.0, 6.0 Hz), 3.66- 3.76 (IH, m), 3.70 (3H, s), 3.82-4.00 (2H, m), 4 07 (IH, t, J= 6.6 Hz), 4 20 (IH, t, J= 10.8 Hz), 5 13 (IH, s), 5.96 (IH, dd, J= 16.0/ 7.7 Hz), 6.03 (IH, s), 7.35 (IH, d, J = 16 0 Hz), 9 57 (IH, ά, J = 1.1 Hz); 13 C NMR (100 MHz, CDC1 3 ) δ -5.3, 14.0, 18.4, 20 0, 22.5, 23.1, 24 4, 25.9, 28.9, 28 9, 31.1, 31.6, 34.5, 39.0, 45.7, 51.3, 67.1, 67.2, 67.9, 72.6, 99.7, 120.7, 127.6, 150.1, 166.1, 171.7, 194.5; [α] 266 D = -27.24° (c = 1.04, CH 2 C1 2 ). 701.1 (Formula 701 where R 20 is -Q-CO-C 7 H ls , R 21 is =CH-CO,Me and R 26 is H To a solution of acid 408 (Example 2B, 11.2 mg, 0.02 mmol) in toluene (0.9 mL) was added 2,4,6- trichlorobenzoyl chloride (3.2 μl, 0.02 mmol) at room temperature and the mixture was stiπed for 45 min. Alcohol 207.1b (10.2 mg, 0.017 mmol) and DMAP (10.4 mg, 0.085 mmol) in toluene (1.4 mL) were added and stirred for 30 min. The mixture was directly loaded onto a silica gel column and eluted (7.5% EtOAc/ pentane) to afford the ester 701.1 (15.2 mg, 79 %). 701.1: R f (15 % ethyl acetate/ pentane) = 0.29; IR (film) = 3492, 2930, 2859, 1725, 1691, 1155, 1112, 837, 777 cm "1 ; l H NMR (400 MHz, CDC1 3 ) δ 0.04 (3H, s), 0.05 (3H, s), 0.07 (6H, s), 0.68 (IH, t, J = 13.2 Hz), 0.60-0.92 (30H, m), 1.10-1.30 (18H, m), 1.34-1.84 (18H, m), 1.85-2.14 (3H, m), 2.34-2.52 (3H, m), 2.68 (IH, ά, J = 12.3 Hz), 3.13 (IH, s), 3.34-3.46 (2H, m), 3.60-3.70 (3H, m), 3.68 (3H, s), 3.76-3.86 (2H, m), 3.86-3.96 (IH, m), 4.06 (IH, dt, = 11.9, 2.1 Hz), 4.24-4.34 (IH, m), 5.11 (IH, s), 5.20-5.32 (IH, m), 5.96 (IH, dd, J = 16.1, 7.8 Hz), 6.00 (IH, s), 7.42 (IH, ά, J= 16.1 Hz), 9.58 (IH, d, J = 7.8 Hz); 13 C NMR (100 MHz, CDC1 3 ) δ -5.3, -5.3, -4.7, -4.6, 14.0, 18.0, 18.3, 19.2, 20.1, 21.9, 22.3, 22.5, 22.9, 23.6, 23.7, 23.8, 24.3, 24.5, 25.8, 28.9, 28.9, 29.2, 30.9, 31.0, 31.6, 31.8, 31.9, 32.0, 34.5, 35.0, 37.4, 37.4, 43.5, 43.8, 44.7, 45.6, 51.2, 51.3, 59.2, 64.4, 64.9, 65.7, 66.3, 71.1, 72.7, 73.4, 73.8, 99.5, 100.4, 120.5, 127.5, 150.5, 166.4, 166.5, 171.7, 172.1, 194.6; [α] M " D = -27.42° (c = 0.87, CH 2 C1 2 ). 702.1 (Formula 702 where R 3 is OH, R 20 is -Q-CO-C 7 Hi<,, R 21 is =CH-CO,Me and R 26 is H) To seco aldehyde 701.1 (15 mg, 0.013 mmol) in THF (3.7 mL) at room temperature in a plastic flask was added 70% HF/ pyridine dropwise. The resulting yellow solution was stirred for 2 hr and was then quenched with a saturated aqueous solution of sodium bicarbonate (12.5 mL) and water (7.5 mL). The biphasic mixture was extracted with ethyl acetate (5 x 15 mL). The combined organic layers were dried over sodium sulfate, the solution was decanted and then the solvent was removed in vacuo. Chromatography (70% EtOAc/ pentane) provides 702.1 (7 mg, 73%) (the corresponding compound of Formula II where X is oxygen) as an amorphous solid. 702.1: R/(80% EtOAc/pentane) = 0.29; IR (film) = 3454, 3332, 2932, 2858, 1723, 1663, 1138, 976 cm "1 ; Η NMR (400 MHz, CDC1 3 ) δ 0.86 (3H, t, J = 6.7 Hz), 1.01 (3H, s), 1.17 (3H, s), 1.18-1.38 (12H, m), 140-1.66 (7H, m), 1.72-1.88 (3H, m), 1.94-2.14 (3H, m), 2.29 (IH, dt, J= 7.5/ 1.7 Hz), 2.52 (IH, d, J= 7.2 Hz), 3.45 (IH, t, J= 11.2 Hz), 3.53 (IH, t, J= 10.6 Hz), 3.61- 3.72 (4H, m), 3.68 (3H, s), 3.88 (3H, t, J= 12.4 Hz), 4.02-4.09 (2H, m), 4.10-4.19 (IH, m), 4.48 (IH, d, J= 11.6 Hz), 5.02 (IH, d, J = 7.6 Hz), 5.10 (IH, s), 5.13 (IH, s), 5.34-5.39 (IH, m), 5.40 (IH, dd, J= 15.0/ 7.6 Hz), 5.97 (IH, d, J = 15 Hz), 5.99 (IH, s); 13 C NMR (100 MHz, CDC1 3 ) δ 14.1, 19.3, 22.5, 23.0, 24.4, 24.7, 28.9, 29.0, 31.0, 31.3, 31.4, 31.6, 32.4, 34.6, 35.9, 39.9, 42.5, 42.9, 45.1, 51.1, 64.5, 65.8, 66.3, 68.6, 71.6, 74.1, 75.8, 76.0, 78.7, 98.9, 102.4, 119.9, 125.7, 142.6, 151.7, 167.0, 172.1, 172.6; [α 4 ° D = -20.02° (c= 0.70, CH 2 C1 2 ). 3B. Formula IV - Bryostatin Analogue Containing Ether Diester Linker (807) 801.1 and 802.1(Formulae 801 and 802 where R 20 is -O-CO-C7H,. and R 21 is =CH-CO,Me) Enal 801.1, prepared as described for compound 13 in Wender et al. (1998a) (22 mg, 0.030 mmol) in a tert-butanol-THF solution of 2-methyl 2-butene (1 :1, 3 mL) was tteated with sodium chlorite (14 mg, 0.152 mmol) and monobasic sodium phosphate (21 mg, 0.152 mmol) in water (0.5 mL). After 1 h, the mixture was diluted with ethyl acetate. The organic layer was dried over sodium sulfate. Column chromatography afforded acid 802.1: Rf = (25 % ethyl acetate in hexane); [α] 25 D = -5.97 ° (c 0.40, CH2CI2); IR (neat) = 2932, 1716, 1644, 1514, 1456, 1374 cm" 1 ; !H NMR (500 MHz, CDCI3) δ 7.59 (d, J = 16.0 Hz, 1 H), 7.38 (m, 5 H), 7. 18 (d, J = 8.5 Hz, 2 H), 6.85 (d, J = 8.5 Hz, 2 H), 5.88 (s, 1 H), 5.24 (d, J = 16.0 Hz, 1 H), 5.51 (s, 1 H), 5.66 (d, j = 11.0 Hz, 1 H), 5.60 (d, j = 11.0 Hz, 2 H), 5.39 (d, j = 11.0 Hz, 1 H), 4.13 (br, 1 H), 3.97 (m, 1 H), 3.85 (m, 1 H), 3.81 (s, 3 H), 3.70 (s, 3 H), 3.49 (d, J = 14.5 Hz, 1 H), 3.26 (s, 3 H), 2.41 (t, J = 14.5 Hz, 1 H), 2.26 (m, 2 H), 2.00 (m, 1 H), 1.76 (m, 1 H), 1.29-1.16 (m, 21 H), 0.88 (t, J = 7.0 Hz, 3 H); 13 C NMR (125 MHz, CDCI3) δ 172.28, 172.05, 166.29, 159.69, 159.10, 152.00, 138.62, 130.51, 129.17, 128.35, 127.61, 127.52, 117.07, 114.72, 113.75, 102.40, 76.19, 74.30, 71.68, 71.11, 70.80, 68.65, 55.23, 51.16, 48.83, 46.87, 36.08, 35.35, 34.13, 32.97, 31.62, 28.89, 24.53, 23.32, 22.50, 22.25, 14.25, 14.07, 803.1 Acid 802.1 (22 mg, 0.030 mmol) in toluene (3 mL) was treated with Yamaguchi's reagent (6 :L, 0.0395 mmol) and TEA (16 :L, 0.122 mmol). After 30 min, alcohol 606 from Example 2F (17 mg, 0.0395 mmol) and DMAP (11 mg, 0.0912 mmol) in toluene (1 mL) was added and stiπed for 1 h. The mixture was directly purified by silica gel column to give ester 803.1 (27 mg, 77% yield): Rf = (25% ethyl acetate in hexane); [α] 25 D = -214 ° (c 0.82, CH2CI2); IR (neat) = 2930, 2858, 1720, 1652, 1612, 1514, 1464, 1383, 1250, 1110 cm" 1 ; l U NMR (500 MHz, CDCI3) δ 7.46 (d, J = 16.0 Hz, 1 H), 7.36 (m, 5 H), 7.18 (d, J = 8.5 Hz, 2 H), 6.85 (d, J = 8.5 Hz, 2 H), 5.87 (s, 1 H), 5.67 (d, J = 16.0 Hz, 1 H), 5.50 (s, 1 H), 5.29 (q, J = 6.0 Hz, 2 H), 4.63 (m, 3 H), 4.39 (d, J = 11.0 Hz, 1 H), 4.29 (t, J = 11.0 Hz, 1 H), 4.20 (m, 2 H), 4.12 (t, J = 11.0 Hz, 1 H), 3.96 (m, 1 H), 3.86-3.66 (m, 7 H), 3.47 (m, 5 H), 3.25 (s, 3 H), 2.53 (d, J = 6.5 Hz, 2 H), 2.39 (br, 1 H), 2.24 (m, 2 H), 1.99-0.85 (m, 26 H), 0.09 (s, 3 H), 0.07 (s, 3 H), 0.04 (s, 9 H); 13 C NMR (125 MHz, CDCI3) δ 172.04, 171.07, 167.24, 166.30, 159.10, 157.02, 152.11, 138.68, 130.56, 129.18, 128.35, 128.17, 127.61, 117.04, 115.34, 113.74, 102.42, 88.96, 76.35, 74.48, 71.74, 71.13, 70.90, 68.59, 67.86, 67.34, 67.02, 66.59, 66.61, 61.52, 55.22, 51.12, 46.70, 42.93, 37.24, 36.17, 34.12, 31.64, 29.18, 28.99, 28.88, 25.75, 24.53, 23.45, 22.54, 22.38, 18.00, 17.95, 14.36, 14.06, - 146, -4.80. 805.1 (Formula 805 where R 20 is -0-CO-C 7 H, s and R 1 is =CH-CO,Me) Ester 803.1 (27 mg, 0 0233 mmol) in wet methylene chloride (2 mL) was tteated with DDQ (11 mg, 0.0466 mmol) and stirred for 1 h. The mixture was directly purified by silica gel to give the expected alcohol silyl ether product of Formula 804. This silyl ether in acetomtnle-water (10:1, 1.5 mL) was treated with aqueous HF (100 :L, 48 %). After 4 h, the mixture was neuttalized with aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dned over sodium sulfate The crude hydroxy acid product 805.1 was used for the next step. To a solution of DCC (13 mg, 0.0623 mmol), DMAP HC1 (10 mg, 0 0623 mmol) and DMAP (11 mg, 0.089 mmol) was added hydroxy acid 805.1 (7 mg, 0.0089 mmol) in methylene chlonde (3 mL) by syringe pump over 10 h. The resultant mixture was loaded directly onto a silica gel column and puπfied to give C26-0-benzyl ether lactone of Formula 806 where R 20 is -0-CO-C 7 H l5 and R 21 is =CH-C0 2 Me (806.1) (3.5 mg, 50 %). 806.1: Rf = (25 % ethyl acetate in hexane); [α] 25 D = 4.74° (c 0.47, CH2CI2); IR (neat) = 3746, 3323, 2926, 2851, 1739, 1718, 1624, 1436, 1159 cm" 1 ; l U NMR (500 MHz, CDCI3) δ 7 39 (br s, 5 H), 6 84 (d, J = 16.0 Hz, 1 H), 6 03 (s, 1 H), 5.80 (d, J = 16.0 Hz, 1 H), 5 41 (br d, J = 12.5 Hz, 1 H), 5 20 (s, 1 H), 5.15 (s, 1 H), 4 64 (q, J = 12.0 Hz, 2 H), 4.47 (q, J = 5 5, 11.5 Hz, 1 H), 4.31 (m, 3 H), 3.99 (t, J = 1 1.0 Hz, 1 H), 3.80-3.43 (m, 8 H), 2.52 (m, 2 H), 2.37-1.07 (m, 22 H), 0.89 (t, J = 6.5 Hz, 3 H). To a solution of benzyl ether 806.1 (1 mg) in methylene dichloride (0.5 mL) was added boron trichloride (excess) at -78°C, and the mixture was warmed to -20°C over 1 h. The reaction mixture was quenched with aqueous sodium bicarbonate. The standard isolation procedure afforded bryostatin analogue 807.1. Rf = (25% ethyl acetate in hexane); [α] 25 D = 4.17° (c = 0.30, CH2CI2); IR (neat) = 3480, 2927, 2856, 2361, 1718, 1281, 1161, 1105 cm" 1 ; l U NMR (500 MHz, PhH) δ 6.82 (d, J = 16.5 Hz, 1 H), 6.03 (s, 1 H), 5.80 (d, J = 16.5 Hz, 1 H), 5.24 (s, 1 H), 5.17 (br s, 2 H), 4.36 (m, 3 H), 4.01 (t, J = 2.5 Hz, 1 H), 3.84 (q, J = 6.5 Hz, 1 H), 3.68 (m, 7 H), 3.46 (t, J = 9.0 Hz, 1 H), 2.57 (m, 2 H), 2.33 (m, 2 H), 2.18 (m, 1 H), 2.11-1.23 (m, 23 H), 0.90 (t, J = 10.0 Hz, 3 H); 13 C NMR (125 MHz, PhH) δ 174.37, 172.11, 171.38, 152.76, 151.21, 121.46, 120.31, 119.94, 99.21, 86.71, 73.84, 73.67, 71.96, 70.03, 68.76, 68.38, 65.14, 51.13, 45.48, 41.06, 35.99, 34.58, 32.91, 31.63, 31.14, 29.00, 28.86, 28.65, 24.68, 23.18, 22.55, 21.13, 19.64, 14.05. 3C. Formula III - Bryostatin Analogue Containing Selected C7 Substituent (7051 704.1 (Formula 704 where R is OH. R' is OBn. R 3 is TBSO, R 5 is =Q, R 7 is t-Bu-Q 7 CMeC R 8 is H, To a methyl hemiacetal prepared as described for compound 14 in Wender et al. (1998a) (30 mg, 0.05 mmol) in acetonitrile (2.8mL) and water (0.3mL) was added 48% aq. HF (480 μL) and stirred at room temp, for 2 hrs. The reaction was then quenched with a saturated solution of sodim bicarbonate (5mL) and extracted with EtOAc (5mL X 4). The combined organics were dried over sodium sulfate and the solvent was removed in vacuo to give expected hemiacetal (a compound according to Formula 303 where R 20 is -0-CO-C 7 H 15 and R 21 is =CH-C0 2 Me). To crude acid 513 from Example 2G (47mg, 0.075mmol) in toluene (2.6 mL) was added triethylamine (27 μL, 0.2 mmol) and trichlorobenzoyl chloride (12.5 μL, 0.08 mmol), and the mixture was stirred for 90 min. To the resulting solution is added a solution containing the crude hemiacetal and DMAP (30.4 mg, 0.25 mmol) in toluene (4 mL). The resulting precipitous mixture was stirred for 2 h and then added directly to a silica column and eluted (15% EtOAc/ pentane to 25% EtOAc/ pentane) to afford seco aldehyde 704.1 (41.7mg, 70%): R f (15%EtOAc/ pentane) = 0.14; IR (film): 3497.9, 2953.6, 2867.5, 1738.2, 1688.9, 1469.9, 1378.0, 1258.1, 1158.4, 1109.2, 982.5, 835.5, 779.2, 734.9 cm "1 ; Η- NMR (500MHz, CDC1 3 ) δ 0.05 (3H, s), 0.08 (3H, s), 0.66 (IH, t, J= 13.0Hz), 0.79-0.88 (21H, m), 0.91- 0.96 (IH, m), 0.95 (3H, s), 0.97 (3H, s), 1.15 (3H, s), 1.17-1.29 (15H, m), 1.36-1.50 (6H, m), 1.59-1.78 (5H, m), 1.87-2.13 (5H, m), 2.38 (IH, dquin, J = 6.8, 1.3Hz), 2.51-2.64 (5H, m), 3.31 (IH, s), 3.60-3.68 (2H, m), 3.68 (3H, s), 3.76-3.80 (IH, m), 3.78 (IH, d, J = 11.0Hz), 3.83-3.93 (IH, m), 3.99-4.07 (IH, m), 4.00 (IH, d, J= 11.0Hz), 4.07 (2H, d, J = 3.0Hz), 443-4.48 (IH, m), 4.56 (IH, d, J = 12.0Hz), 4.63 (IH, d, J = 12.0Hz), 4.96 (IH, dd, J = 9.5, 2.0Hz), 5.12 (IH, s), 5.41-5.44 (IH, m), 5.95 (IH, dd, J = 16.0, 8.0Hz), 6.00 (IH, d, J = 2.0Hz), 7.27-7.35 (5H, m), 7.38 (IH, ά, J = 16.0Hz), 9.49 (IH, ά, J = 8.0Hz); 13 C-NMR (125MHz, CDC1 3 ) δ -5.1, -4.8, 14.0, 15.0, 17.9, 19.0, 19.8, 20.2, 21.6, 21.7, 22.4, 22.5, 22.8, 23.7, 24.3, 24.4, 25.7, 28.8, 28.8, 28.9, 30.9, 31.1, 31.6, 34.5, 34.9, 35.4, 37.2, 37.5, 38.1, 40.7, 41.6, 42.0, 45.7, 51.1, 51.2, 58.9, 65.6, 65.7, 66.1, 70.8, 71.1, 71.4, 72.5, 73.1, 74.8, 99.5, 100.5, 120.7, 127.5, 127.6, 127.8, 128.4, 138.2, 150.3, 166.2, 166.3, 167.3, 170.5, 171.7, 171.8, 194.6; HRMS calc'd for C 65 H, 03 ClO 17 Si (+lNa): 1241.6532; found: 1241.6551; [α] 270 d :-31.67° (c 4.17, CH 2 C1 2 ). 705.1 (Formula 705 where R is OH, R' is OBn, R 3 is OH, R s is =Q, R 8 is t-Bu-O z MeCl, R 9 is H. R 20 is -O-CO-C7H,.. R 2 ' is =CH-CO,Me and R 26 is Me) To 704.1 (38mg, 0.031mmol) in THF (9.5mL) was added freshly dried 4 Angstrom molecular sieve beads (57 beads) and 70% HF/ pyridine (2.3 mL), and the resulting solution was stirred for 45 min. in a plastic flask. The reaction was then poured into a saturated solution of sodium bicarbonate (95 mL) and diluted with EtOAc (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (40mL x 3). The combined organic layers were dried over sodium sulfate and the solvent was removed in vacuo. Silica chromatography (40% to 100% EtOAc/ pentane) afforded 705.1 (134mg, 45%) and a putative diol 705.1a without the 3-hydroxy TBS protecting group (9.0 mg, 30%). To putative diol 705.1a (4.8mg, 4.95 μmol) in THF (0.5mL) was added freshly dried 4A molecular sieve beads (3 beads) and 70% HF/ pyridine (0.1 mL) and the resulting solution was stirred for 40 min. in a plastic flask. The reaction was then poured into a saturated solution of sodium bicarbonate (5 mL) and diluted with EtOAc (30 mL). The layers were separated and the aqueous layer was exttacted with EtOAc (4 mL x 4). The combined organics were dried over sodium sulfate and the solvent was removed in vacuo. Chromatography (30% to 100% EtOAc/ pentane) afforded 705.1 (a compound of Formula III where R 3 is OH, R 5 is =0, R 8 is /-Bu-chloroacetate, R 9 is H, R 20 is -0-CO-C 7 H 15 , R 21 is =CH-C0 2 Me and R 26 is Me). (1.1 mg, effectively adding 7% to above yield = 52%). 705.1: R f (30%EtOAc/ pentane) = 0.23; IR (film): 3391.9, 2929.4, 2856.8, 1731.9, 1664.5, 1434.2, 1375.1, 1249.6, 1160.5, 1133.2, 1098.3, 982.1, 735.8 cm "1 ; Η-NMR (500MHz, CDC1 3 ) δ 0.87 (3H, t, J = 7.0Hz), 0.93 (3H, s), 0.96 (3H, s), 1.03 (3H, s), 1.18 (3H, d, J = 6.0Hz), 1.20 (3H, s), 1.22-1.30 (10H, m), 1.51 (IH, br. ά, J = 12.5Hz), 1.69-1.81 (3H, m), 2.00-2.08 (4H, m), 2.29-2.34 (3H, m), 2.41 (IH, dd, J = 12.5, 4.0Hz), 2.63 (IH, dd, J = 14.3, 2.5Hz), 2.82 (IH, dd, / = 12.5, 4.5Hz), 3.58 (IH, ά, J = 11.0Hz), 3.61- 3.64 (IH, m), 3.67-3.74 (2H, m), 3.68 (3H, s), 3.80 (IH, ά, J = 11.0Hz), 3.82 (IH, t, 7 = 12.0Hz), 3.95- 3.99 (IH, m), 3.97 (IH, d, J= 11.0Hz), 4.05-4.10 (IH, m), 4.08 (2H, s), 4.34 (IH, s), 4.39-444 (IH, m), 4.53 (lH, d, J = 12.0Hz), 4.65 (IH, d, J = 12.0Hz), 5.12 (IH, s), 5.19 (IH, dd, J = 12.0, 3.0Hz), 5.41 (IH, dd, J= 16.0, 7.3Hz), 5.50 (IH, ddd, J= 12.3, 4.0, 3.0Hz), 5.98 (IH, d, J= 2.0Hz), 6.08 (IH, d, J = 16.0Hz), 7.29-7.38 (5H, m); 13 C-NMR (125MHz, CDC1 3 ) δ 14.0, 15.3, 19.4, 20.0, 21.4, 22.5, 23.9, 24.7, 28.8, 29.0, 31.2, 31.6, 32.6, 34.5, 34.6, 37.1, 38.5, 40.8, 42.2, 43.2, 45.0, 51.1, 65.0, 65.8, 66.5, 71.0, 71.1, 71.1, 73.2, 74.0, 75.0, 75.5, 98.7, 101.2, 119.7, 126.9, 127.7, 127.8, 1284, 138.2, 142.7, 151.4, 166.8, 167.2, 170.1, 170.1, 172.1; HRMS calc'd for C 49 H 71 C10 16 (+lNa): 9734350; found: 9734328; [α] 25 ° d :-3.04° (c 1.34, CH 2 C1 2 ). 705.2 (Formula 705 where R is OH, R' is OBn. R 3 is OH. R 5 is =Q. R 8 is t-Bu-OH, R 9 is H. R 20 is -0-CO-C7H,.;, R 21 is =CH-CQ 7 Me and R 26 is Me) To 705.1 (7.4 mg, 7.785 μmol) in THF (0.66 mL) was added thiourea (66 mg, 0.84 mmol) and the resulting slurry was stiπed at room temperature for 3 days. The reaction was then added directly to a silica column and eluted (50% to 58% to 70% EtOAc/ pentane) to afford 705.2 (a compound of Formula III where R 3 is OH, R 5 is =0, R 8 is f-Bu-OH, R 9 is H, R 20 is -0-CO-C 7 H 15) R 21 is =CH-C0 2 Me and R 26 is Me). (6.3 mg, 92%). 705.2: R f (50%EtOAc/ pentane) = 0.18; IR (film): 3423.1, 2926.7, 2856.8, 1726.4, 1659.2, 1376.1 , 1253.2, 1159.3, 1098.3, 980.8, 799.1, 729.7 cm "1 ; Η-NMR (300MHz, CDC1 3 ) δ 0.77 (3H, s), 0.86 (3H, t, J = 10.8Hz), 0.96 (3H, s), 1.03 (3H, s), 1.18 (3H, d, J= 8.1Hz), 1.20 (3H, s), 1.22- 1.34 (10H, m), 1.68-1.82 (3H, m), 2.01-2.12 (3H, m), 2.18-2.33 (3H, m), 2.45 (IH, dd, J= 12.6, 4.5Hz), 2.62-2.67 (2H, m), 2.85 (IH, dd, J = 12.6, 3.6Hz), 3.09-3.21 (2H, m), 3.60-3.88 (5H, m), 3.68 (3H, s), 3.93-4.00 (IH, m), 4.09 (IH, dd, J = 11.1 , 4.5Hz), 4.35 (IH, s), 4.35-4.60 (IH, m), 4.52 (IH, d, J = 12.0Hz), 4.65 (IH, d, J = 12.0Hz), 5.06 (IH, d, J = 9.6Hz), 5.12 (IH, s), 5.18 (IH, ά, J = 7.2Hz), 5.42 (IH, dd, J = 15.9, 7.2Hz), 5.44-5.51 (IH, m), 5.98 (IH, s), 6.08 (IH, d, J = 15.9Hz), 7.35-7.39 (5H, m); 13 C-NMR (125MHz, CDC1 3 ) δ 14.1, 15.3, 18.4, 19.4, 22.4, 22.5, 23.9, 24.7, 28.9, 29.0, 29.7, 31.2, 31.6, 32.7, 34.5, 34.7, 36.8, 39.7, 42.3, 43.2, 45.0, 51.1, 65.0, 65.9, 66.5, 69.0, 71.1, 71.2, 74.0, 75.0, 77.2, 98.7, 101.3, 119.7, 126.9, 127.7, 127.9, 128.4, 138.2, 142.8, 151.5, 166.9, 170.1, 171.8, 172.1; HRMS calc'd for C 47 H 69 0 15 (+lNa): 8974595; found: 8974612; [α] 25 0 d :-9.50° (c 0.47, CH 2 C1 2 ). Formula 705.3 To myristic acid (10 mg, 0.044 mmol) in toluene (2.14 mL) at rt under nittogen is added triethylamine (23.3 μL, 0.175 mmol) followed by 2,4,6-trichlorobenzoylchloride (6.8 μL, 0.044 mmol). The resulting solution was stirred for 45 min.. An aliquot of this solution (63 μL, 0.0013 mmol) was added to a solution of 705.2 (1 mg, 0.00114 mmol) and DMAP (0.7 mg, 0.0059 mmol) in toluene (500 μL). The slightly yellow, cloudy solution is stiπed at rt for 30 min. and then added directly to a silica column and eluted (30% EtOAC/ pentane). The eluted material is then re-chromatographed (30% EtOAC/ pentane). The resulting material was then dissolved in EtOAc (500 μL) and Pearlman's catalyst (2 mg) was added. The resulting suspension was evacuated and re-filled with hydrogen (5 times) while the reaction was stiπed vigorously. After 30 min., the reaction is added directly to a silica column and eluted (EtOAc). This provided C7 myristate analogue 705.3 (360μg, 32%-2 steps) (a compound of Formula III where R 3 is OH, R 5 is =0, R 8 is /-Bu-myristate, R 9 is H, R 20 is -0-CO-C 7 H 15 , R 21 is =CH-C0 2 Me and R 26 is Me). R f (40% EtOAc / pentane) = 0.19. IR (film) 3256.8, 2915.8, 2845.2, 1746.4, 1722.9, 1158.4, 1029.0, 864.4, 793.8 cm '1 . Η-NMR (500MHz, CDC1 3 ) δ 0.86-0.94 (12H, m), 1.05 (3H, s), 1.14-1.38 (38H, m), 1.59-1.63 (2H, m), 1.63-1.88 (3H, m), 2.03-2.07 (3H, m), 2.31-2.42 (4H, m), 247 (IH, dd, J= 12.8, 3.8 Hz), 2.72-2.74 (2H, m), 2.86 (IH, dd, J= 12.5, 5.0 Hz), 3.70 (3H, s), 3.62-3.75 (3H, m), 3.78-3.87 (3H, m), 3.99-4.04 (IH, m), 4.09-4.14 (IH, m), 4.37-4.50 (2H, m), 5.15 (IH, s), 5.16 (IH, d, J= 7.4 Hz), 5.21 (IH, d, J = 12.0 Hz), 5.33-5.34 (IH, m), 5.43 (IH, dd, J= 15.6, 7.4 Hz), 6.01 (IH, s), 6.07 (IH, ά, J = 15.6 Hz). 13 C-NMR (500MHz, CDC1 3 ) δ 14.1 , 19.9, 20.5, 21.1, 22.7, 23.2, 23.9, 24.7, 24.7, 24.9, 26.7, 29.1, 29.3, 29.4, 29.4, 29.7, 30.2, 31.1 , 31.6, 31.9, 33.5, 33.7, 34.3, 34.5, 35.8, 37.2, 38.4, 42.3, 43.3, 45.0, 51.1, 65.0, 65.9, 66.6, 69.4, 70.0, 73.3, 73.5, 74.0, 75.9, 77.2, 98.7, 101.2, 119.8, 126.9, 128.8, 142.7, 151.3, 166.8, 170.4, 170.9, 172.4. HRMS (FAB) calc'd for C 54 H 90 O 16 Na: 1017.6133, found: 1017.6127. [α] 21 1 D = -7.14° (c 0.035, CH 2 C1 2 ). 3D. Formula V - Bryostatin Analogue Containing Diester Linker (903.1) 901.1 (Formula 901 where R 20 is -O-CO^H.s. R 21 is =CH-CO,Me To a solution of silyl ether 111 from Example 1C (1.17 g, 1.44 mmol) and pyridine (2.07 mL, 25.65 mmol) in 12 mL THF in a polypropylene vial was added HF / pyridine complex (0.83 mL, 28.83 mmol) at rt. The solution was stirred for 24 hours and diluted with EtOAc. The organic layer was washed with sat. CuS0 and brine, dried over Na 2 S0 4 and concentrated in vacuo to afford the coπesponding alcohol (not shown) as a pale yellow oil. To the alcohol (24.6 mg, 0.036 mmol) in methylene chloride (0.7 mL) was added DMAP (24.5 mg, 0.201 mmol) followed by succinic anhydride (8.6 mg, 0.086 mmol) at rt. The solution was heated to 42°C for 3 hours and then slowly cooled to rt. Col. chromatography (40% EtOAc + 1% AcOH/hexane) provided crude 901.1 (28.6 mg, 0.0353 mmol). 902.1 (Formula 902 where R 20 is -Q-CO-C 7 His, R 21 is =CH-CO,Me To crude 901.1 (28.6 mg) in methylene chloride (0.8 mL) and water (9.5 μL) was added DDQ (10.4 mg, 0.046 mmol) at rt. After stirring for 2 hours, the reaction was quenched with a saturated aqueous solution of ammonium chloride and extracted with EtOAc (3 x 5 mL). The combined organics were then dried over sodium sulfate and the solvent was removed in vacuo. Chromatography (40% EtOAc + 1% AcOH/ hexane) provided seco acid 902.1 (21.9 mg, 0.032 mmol, 91% in 2 steps). 903.1 To 902.1 (5 mg, 7.38 μmol) in acetonitrile (0.4 mL) and water (42 μL) at rt was added 48% aqueous HF dropwise (24 μL, 0.738 mmol). The reaction was stiπed for 40 min. and then quenched with a saturated aqueous solution of sodium bicarbonate (5 mL). The layers were separated and then the aqueous layer was exttacted with EtOAc (6 x 5 mL). The combined organics were dried over sodium sulfate and then the solvent was removed in vacuo. The resulting clear oil (not shown) was then used immediately in the next step. To DMAP (9 mg, 0.074 mmol) and DMAPΗC1 (8.2 mg, 0.052 mmol) in methylene chloride (1.4 mL) was added DCC (10.6 mg, 0.052 mmol) at rt. The clear oil from the preceeding step in methylene chloride (2.2 mL) was then added over 3 h. The resulting mixture was stirred at rt for 4 h and then quenched with a saturated aqueous solution of sodium bicarbonate (5 mL). The layers were separated and then the aqueous layer was extracted with EtOAc (3 x 5 mL). The combined organics were then dried over sodium sulfate and the solvent was removed in vacuo. Silica gel chromatography (30% EtOAc/ hexane) provided coπesponding crude macrocycle (not shown) as a colorless oil. The crude macrocycle from the preceeding step was dissolved in ethyl acetate (2.6 mL) and Pd(OH)2/C (2.4 mg, 20% wt. on carbon) was added. The resulting suspension was evacuated and refilled with 1 Atm. hydrogen gas (x5) and was vigorously stirred under a hydrogen atmosphere for 3 hours. The crude mixture was pipetted directly onto a silica gel column and the product was eluted (50% EtOAc/hexane) to afford of bryostatin analogue 903.1 (0.3 mg, 7% - 3 steps) (a compound of Formula V where p is 2, R 20 is -0-CO-C 7 H 15 , R 21 is =CH-C0 2 Me and R 26 is Me) as a white solid. Example 4 Bryostatin Analogues Containing Selected C20 Ester Substituent This example illustrates methods for preparing bryostatin compounds and analogues that contain selected ester substituents at C20. 4A. Acetyl C20 Ester (702.2) 37 To a solution of enal 13, prepared as described for compound 13 in Wender et al. (1998a) (180 mg, 0.03 mmol) in 0.5 mL of MeOH at rt was added pyridinium p-toluenesulfonate (PPTS, 2 mg, catalytic) and trimethylorthoformate (5 drops). The progress of the reaction was monitored by thin layer chromatography (TLC). After 30 min the reaction was quenched with 1.0 mL Et 3 N. The solvent was removed under reduced pressure to afford the expected crude dimethylacetal product (not shown). This product was immediately dissolved in MeOH (0.5 mL) and K 2 C0 3 (3 mg, catalytic). The progress of the reaction was monitored by TLC. After 30 min the reaction was quenched. The solution was quenched with sat. NaHC0 3 , diluted with EtOAc (10 mL), washed with H 2 0, dried over MgS0 and concentrated under reduced pressure to afford the crude C20 free hydroxyl product (not shown). The crude product was immediately dissolved in methylene chloride (0.5 mL) and acetic anhydride (0.3 mL, excess) and DMAP (5 mg, catalytic) was added at rt. The progress of the reaction was monitored by TLC. After 30 min the reaction was quenched. The solution was quenched with sat. NaHC0 3 , diluted with EtOAc (10 mL), washed with H 2 0, dried over MgS0 4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with 20% EtOAc-hexanes as eluant affording 14 mg (82% for four steps) of dimethylacetal 37. R (20% ethyl acetate/hexanes)=0.17; R (25% EtOAc / hexanes) = 0.44; IR 2927, 2859, 1744, 1719, 1687, 1514, 1249, 1156, 1103, 1079, 1037 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 0.85 (6H, m) 1.16-1.30 (10H, m), 1.14 (3H, s), 1.18 (3H, s), 1.75 (IH, m), 1.98- 2.17 (3H, m), 2.32 (IH, m), 3.27 (3H, s), 3.52 (IH, ά, J= 16.5 Hz), 3.68 (3H, s), 3.79 (3H, s), 3.87 (IH, m), 3.95 (IH, m), 4.09 (IH, m), 4.47 (2H, ABq, J= 11.4 Hz), 5.41 (IH, s), 5.88 (IH, s), 5.91 (IH, dd, J = 16.2, 7.7 Hz), 6.83 (2H, ά, J = 8.7 Hz), 7.16 (2H, d, J = 8.7 Hz), 7.27-7.35 (6H, m), 9.44 (IH, d, J = 7.7 Hz, C15); 13 C NMR (75 MHz, CDC1 3 ) δ 14.1, 21.7, 22.6, 24.0, 24.6, 28.9, 29.0, 31.7, 32.6, 34.5, 36.2, 47.5, 51.3, 51.5, 55.4, 69.2, 71.3, 71.8, 74.4, 76.3, 102.7, 114.1, 118.2, 127.1, 127.7, 127.9, 128.7, 129.5, 130.7, 138.9, 151.6, 159.6, 166.6, 167.3, 172.1, 195.0; [α] D 20 = -0.7° (c 1.7, CH 2 C1 2 ). 303.1 (Formula 303 where R 20 is -O-CO-Mc, R 21 is =CH-C0 7 Me) To a solution of dimethylacetal 37 (14 mg, 0.02 mmol) in 0.6 mL 1% aqueous CH 2 C1 2 was added solid 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ, 10 mg, 0.03 mmol) at rt. The mixture was stiπed for 2 h, pipetted directly onto a column of silica gel, and the product eluted with 35% EtOAc / hexanes to provide intermediate alcohol 303.1 (10 mg, 91%) as a colorless oil: Rf (35% EtOAc / hexanes) = 0.22; IR 3528, 2930, 2858, 1745, 1720, 1686, 1458, 1437, 1380 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 0.86 (3H, t, J= 6.9 Hz), 1.13 (3H, s), 1.17 (3H, s), 1.25 (10 H, m), 1.52 (2H, m), 1.71 (2H, m), 2.12 (2H, m), 2.35 (IH, t, J= 14.1 Hz), 2.60 (IH, d, = 3.6 Hz), 3.41 (3H, s, C19 OCH 3 ), 3.45 (IH, m), 3.68 (3H, s), 3.82 (IH, s), 4.24 (IH, m), 4.55 (2H, ABq, J = 11.4 Hz), 5.47 (IH, s), 5.86 (IH, s), 5.91 (IH, dd, J = 15.9, 7.5 Hz), 7.29 (IH, ά, J = 15.9 Hz), 7.34 (5H, s), 9.52 (IH, d, J = 7.5 Hz); 13 C-NMR (75 MHz, CDC1 3 ) δ 13.6, 15.3, 21.6, 224, 23.5, 24.7, 28.6, 28.8, 31.5, 32.8, 34.1 , 39.5, 47.4, 51.1, 51.2, 68.3, 70.9, 71.0, 71.1, 78.8, 102.4, 117.4, 126.8, 127.9, 128.0, 128.5, 138.1, 151.8, 166.4, 167.3, 171.4, 194.5; [α] D 20 = -21.0° (c 1.0, CH 2 C1 2 ). 304.1 (Formula 304 where R 20 is -O-CO-Me. R 2 ' is =CH-C0 7 Me) Alcohol 303.1 (10 mg, 0.02 mmol) was dissolved in 1.1 mL CH 3 CN / H 2 0 (9: 1) and tteated with 48%ι aqueous HF (200 μL, 300 mol % excess) at rt. The resulting mixture was stirred for 1 h, quenched with sat. NaHC0 3 and diluted with 10 mL EtOAc. The aqueous layer was separated and extracted with EtOAc (2 x). The combined organics were dried over Na 2 S0 4 and concentrated in vacuo to afford crude hemiketal enal 304.1 as a colorless oil. The crude product was purified by column chromatography on silica gel with 35% EtOAc-hexanes as eluant affording 8 mg (89%) of hemiketal enal 304.1. R / - (35% EtOAc / hexanes) = 0.15; IR 3528, 2930, 2858, 1745, 1720, 1686, 1458, 1437, 1380 cm "1 ; Η NMR (300 MHz, CDClj) δ 0.86 (3H, t, J = 6.9 Hz, octanoate Me), 1.13 (3H, s, C18 Me), 1.17 (3H, s, C18 Me), 1.25 (10 H, m), 1.52 (2H, m), 1.71 (2H, m), 2.12 (2H, m), 2.35 (IH, t, J= 14.1 Hz), 2.60 (IH, d, J = 3.6 Hz), 3.41 (3H, s, C19 OCH 3 ), 3.45 (IH, m), 3.68 (3H, s, methyl ester), 3.82 (IH, s), 4.24 (IH, m), 4.44 (IH, d, J = 11.1 Hz, CH 2 Ph), 4.69 (IH, ά, J = 11.4 Hz, CH 2 Ph), 5.47 (IH, s, C20), 5.86 (IH, s, C34), 5.91 (IH, dd, J= 15.9, 7.5 Hz, C16), 7.29 (IH, d, J= 15.9 Hz, C17), 7.34 (5H, s, Ph), 9.52 (IH, d, J= 7.5 Hz, C15); 13 C-NMR (75 MHz, CDC1 3 ) δ 13.8, 15.4, 21.7, 22.3, 23.6, 24.3, 28.7, 28.8, 31.4, 32.7, 34.2, 39.5, 47.3, 51.1, 51.2, 68.3, 70.8, 71.0, 71.1, 78.1, 102.3, 117.4, 126.8, 128.0, 128.1, 128.6, 138.1, 151.8, 166.4, 167.1, 171.7, 194.7; [α] D 20 = -19.0° (c 1.4, CH 2 C1 2 ). 701.1 (Formula 701 where R is OH. R' is OBn. R 3 is TBSO. R 20 is -O-CO-Me. R 2 ' is =CH-CO,Me. R 26 is Me and X is oxygen) Carboxylic acid 407 (Example 2B, 15 mg, 0.03 mmol) and Et 3 N (16.5 μL , 0.12 mmol) were dissolved in 300 μL toluene and tteated with 2,4,6-trichlorobenzoylchloride (4.8 μL, 0.03 mmol) dropwise at rt. After 1 h at rt, a toluene solution of freshly prepared 304.1 and 4-dimethylaminopyridine (14 mg, 0.12 mmol) was added gradually and stirring was continued for 40 min. The crude mixture was pipetted directly onto a column of silica gel and the product eluted with 20% EtOAc / hexanes to provide ester 701.1 as a colorless oil (15 mg, 63%). R f (35% EtOAc / hexanes) = 0.71; IR 3487, 2927, 2856, 1723, 1689, 1455, 1379, 1228, 1156, 1113, 1084, 1032, 981 cm "1 ; Η NMR (300 MHz, C 6 D 6 ) δ 0.80 (IH, t, J = 12.7 Hz), 0.93 (3H, t, J = 7.0 Hz), 0.97 (3H, d, J = 6.6 Hz), 1.10-1.36 (24H, m), 1.36-1.85 (21H, m), 1.91- 2.13 (6H, m), 2.39 (IH, t, J = 12.8 Hz), 2.79 (IH, d, J = 13.2 Hz), 2.93 (IH, m), 3.05 (IH, m), 3.29 (3H, s), 3.33 (IH, s), 3.37-348 (2H, m), 3.80 (IH, dd, J=11.4, 5.1 Hz), 3.95-4.05 (2H, m), 4.15 (IH, td, J= 10.8, 0.9 Hz), 4.23 (IH, d, J= 13.5 Hz), 4.40 (IH, ά, J= 12.0 Hz), 4.47 (IH, d, J= 12.0 Hz), 5.57 (IH, s), 5.64 (IH, dd, J= 10.6, 4.6 Hz), 6.05 (IH, dd, J= 16.1, 7.6 Hz), 6.39 (IH, s), 7.10-7.35 (5H, m), 745 (IH, d, J = 16.1 Hz), 9.60 (IH, ά, J = 7.6 Hz); 13 C-NMR (75 MHz, C 6 D 6 ) δ 14.1, 15.1, 19.3, 20.1, 21.3, 22.3, 22.4, 22.7, 23.8, 24.0, 24.6, 24.6, 29.0, 29.0, 29.3, 31.3, 31.6, 31.8, 34.2, 34.5, 35.2, 35.7, 36.2, 37.6, 43.5, 45.7, 51.6, 59.1, 64.9, 66.7, 71.1, 72.0, 72.9, 74.1, 75.3, 77.1, 100.2, 100.6, 121.2, 127.2, 127.3, 127.9, 128.6, 138.9, 151.2, 164.5, 166.3, 171.5, 175.1, 193.4; [α] 20 D -19° (c 1.5, CH 2 C1 2 ). 701.2 (Formula 701 where R is OH. R' is OBn. R 3 is OH. R 20 is -O-CO-Me R 21 is =CH-CO,Me. R 26 is Me and X is oxygen) To ester 701.1 (13 mg, 0.02 mmol) in THF (0.5 mL) was added pyridine (360 μL, 0.45 mmol) followed by 70% HF/ pyridine (144 μL, 500 mol% excess) and stirred for 20 hours. The reaction was then quenched with a saturated solution of sodium bicarbonate. The biphasic mixture was extracted with ethyl acetate (x4) and the combined organics were dried over sodium sulfate. The solvent was removed in vacuo to provide crude C3 hydroxyester 701.2. The crude mixture was pipetted directly onto a column of silica gel and the product eluted with 35% EtOAc / hexanes to provide ester 701.2 as a colorless oil (9 mg, 82%). R f (40% EtOAc / hexanes) = 0.19; IR 3522, 2927, 2857, 1724, 1664, 1230, 1158, 1136, 1107, 979 cm "1 ; Η NMR (400 MHz, C 6 D 6 ) δ 0.84 (3H, t, J = 5.4 Hz), 0.88-0.96 (5H, m), 1.00 (3H, d, J = 4.8 Hz), 1.02-1.55 (27H, m), 1.63-1.81 (2H, m), 1.82-1.94 (2H, m), 2.03 (IH, br t, J = 5.2 Hz), 2.19-2.27 (IH, m), 2.34 (IH, dt, J = 9, 1.5 Hz), 2.94-3.01 (2H, m), 3.22 (IH, s), 3.58 (IH, br d, J= 3.6 Hz), 3.68-3.74 (IH, m), 3.84-3.88 (IH, m), 3.94 (IH, dd, J= 8.6, 3.1 Hz), 4.23 (IH, dd, J= 104, 1.7 Hz), 4.31 (IH, br t, J= 8.1 Hz), 5.36-5.41 (IH, m), 5.50 (IH, s), 5.61 (IH, d, J = 5.4 Hz), 6.00 (IH, dd, J = 12.0, 5.4 Hz), 6.36 (IH, s), 6.53 (IH, ά, J = 12.0 Hz); 13 C NMR (100 MHz, D 6 ) δ 14.2, 19.4, 19.8, 22.4, 22.9, 24.0, 24.5, 25.0, 29.1, 29.2, 30.2, 31.8, 31.9, 32.0, 33.1, 34.6, 34.9, 354, 36.5, 43.6, 45.6, 50.7, 66.1, 66.7, 69.6, 73.2, 74.7, 75.8, 76.3, 77.5, 98.7, 102.6, 120.5, 140.1, 151.2, 151.5, 166.5, 171.5, 174.2[α] 20 D -13.5° (c 0.9, CDC1 3 ). 702.2 (Formula 702 where W is OH, R" u is -O-CO-Me R 2 ' is =CH-CO,Me, R 26 is Me and X is oxygen) To a solution of C3 hydroxyester 701.2 (8 mg, 0.01 mmol) in 2.0 mL CH 2 C1 2 was added 4A molecular sieves and the mixture was aged for 20 min. 45-50 beads of Amberlyst-15 sulfonic acid resin were added and the mixture was stiπed at rt for 2 h. The crude mixture was pipetted directly onto a column of silica gel and the product eluted with 35% EtOAc / hexanes to provide the expected macrocyclic product (not shown) as a colorless oil (5 mg, 83%). Ry (35% EtOAc / hexanes) = 0.21; IR 3522, 2927, 2857, 1724, 1664, 1230, 1158, 1136, 1107, 979 cm "1 ; Η NMR (400 MHz, C 6 D 6 ) δ 0.84 (3H, t, J= 5.4 Hz), 0.88-0.96 (5H, m), 1.00 (3H, d, J= 4.8 Hz), 1.02-1.55 (27H, m), 1.63-1.81 (2H, m), 1.82- 1.94 (2H, m), 2.03 (IH, br t, J= 5.2 Hz), 2.19-2.27 (IH, m), 2.34 (IH, dt, J= 9, 1.5 Hz), 2.94-3.01 (2H, m), 3.22 (IH, s), 3.58 (IH, br d, J= 3.6 Hz), 3.68-3.74 (IH, m), 3.84-3.88 (IH, m), 3.94 (IH, dd, J= 8.6, 3.1 Hz), 4.23 (IH, dd, J= 10.4, 1.7 Hz), 4.31 (IH, br t, J= 8.1 Hz), 5.36-5.41 (IH, m), 5.50 (IH, s), 5.61 (IH, d, r = 54 Hz), 6.00 (IH, dd, J = 12.0, 5.4 Hz), 6.36 (IH, s), 6.53 (IH, d, J = 12.0 Hz); 13 C NMR (100 MHz, C 6 D 6 ) δ 14.2, 19.4, 19.8, 22.4, 22.9, 24.0, 24.5, 25.0, 29.1, 29.2, 30.2, 31.8, 31.9, 32.0, 33.1, 34.6, 34.9, 35.4, 36.5, 43.6, 45.6, 50.7, 66.1, 66.7, 69.6, 73.2, 74.7, 75.8, 76.3, 77.5, 98.7, 102.6, 120.5, 140.1, 151.2, 151.5, 166.5, 171.5, 174.2. The macrocyclic product from the preceeding step was dissolved in 0.5 mL EtOAc and 2.2 mg Pd(OH) 2 (20% wt. on carbon) was added. The resulting suspension was vigorously stiπed under balloon pressure of hydrogen gas for 35 min. The crude mixture was pipetted directly onto a column of silica gel and the product was eluted with 60% EtOAc / hexanes to afford acetate analogue 702.2 (4 mg, 93%) (a compound of Formula II where R 3 is OH, R 20 is -O-CO-Me, R 21 is =CH-C0 2 Me, R 26 is Me and X is oxygen) as a white semi-solid. R (50% EtOAc / hexanes) = 0.16; IR 3522, 2927, 2857, 1724, 1664, 1230 IR (neat) = 3455, 3319, 2929, 2856, 1735, 1380, 1230, 1138, 976 cm "1 ; Η NMR (500 MHz, CDC1 3 ) δ 0.37 (3H, br. s), .77-.92 (14H, m), 1.06 (3H, d, J = 6.4 Hz), 1.07 (IH, t, J = 11.0 Hz), 1.10- 1.28 (5H, m), 1.27 (3H, s), 1.50 (3H, s), 1.57-1.78 (4H, m), 2.03 (2H, t, J = 7.4 Hz), 2.17 (IH, dd, J = 9.9, 0.5 Hz), 2.37 (IH, m), 2.40 (IH, m), 2.85 (IH, t, J= 11.2 Hz), 2.96 (IH, t, J= 10.8 Hz), 3.15 (3H, s), 3.68- 3.75 (3H, m), 3.91 (IH, dd, J = 11.2, 4.0 Hz), 4.12 (IH, t, J = 9.7 Hz), 4.35 (IH, dd, J= 13.9, 2.3 Hz), 4.48 (IH, td, J = 11.0, 2.8 Hz), 4.70 (IH, ά, J = 12.1 Hz), 5.44 (IH, quint, J = 4.8 Hz), 5.54 (IH, ά, J= 7.3 Hz), 5.69 (IH, s), 5.76 (IH, s), 5.85 (IH, dd, J= 16.1, 7.5 Hz), 6.40 (IH, ά, J= 1.8 Hz), 6.50 (IH, d, J= 15.9 Hz); 13 C NMR (125 MHz, CDC1 3 ) δ 14.3, 19.6, 12.0, 22.9, 23.2, 24.9, 25.0, 29.2, 29.2, 31.4, 31.5, 31.9, 32.9, 34.7, 36.3, 39.9, 42.6, 43.2, 45.4, 50.5, 65.2, 66.2, 67.0, 70.4, 74.2, 74.7, 75.3, 75.9, 78.5, 99.7, 103.1, 120.5, 142.5, 152.5, 171.6, 172.5; [α] 25 D = -9.0° (c= 0.36, CDCI3). 4B. Heptanoate C20 Ester (702.3) 308.1 (Formula 308 where R 20a is Heptenoate, and R 21 is =CH-CO,Me) To solution of the enal of Formula 305 (in which R 20 is C 7 H] 5 ), prepared as described for compound 13 in Wender et al. (1998a), (224 mg, 0.04 mmol) in 0.5 mL of MeOH at rt was added PPTS (2 mg, catalytic) and ttimethylorthoformate (1 drop). The progress of the reaction was monitored by TLC. After 30 min the reaction was quenched with 1.0 mL Et 3 N. The solvent was removed under reduced pressure to afford the coπesponding crude dimethylacetal product of Formula 306. This product was immediately dissolved in MeOH (2.0 mL) and K 2 C0 3 (3 mg, catalytic). The progress of the reaction was monitored by TLC. After 30 min the reaction was quenched. The solution was quenched with sat. NaHC0 3 , diluted with EtOAc (10 mL), washed with H 2 0, dried over MgS0 4 and concentrated under reduced pressure to afford the coπesponding crude C20 free hydroxyl product of Formula 307. Heptenoic acid (6 mg, 0.05 mmol) and Et 3 N (21 μL, 0.16 mmol) were dissolved in 600 μL toluene and treated with 2,4,6-trichlorobenzoylchloride (7.0 μL, 0.05 mmol) dropwise at rt. After 1 h at rt, a toluene solution of the freshly prepared C20 free hydroxyl product of Formula 307 and 4- dimethylaminopyridine (DMAP, 20 mg, 0.17 mmol) was added gradually and stirring was continued for 40 min. After 30 min the reaction was quenched. The solution was quenched with sat. NaHC0 3 , diluted with EtOAc (10 mL), washed with H 2 0, dried over MgS0 4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with 20% EtOAc -hexanes as eluant affording 21 mg (84%) of the coπesponding dimethylacetal, C20 heptenoate product of Formula 308.1. Rf(20% ethyl acetate/ hexanes) = 0.22; IR 2927, 2859, 1744, 1719, 1687, 1514, 1249, cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 0.85 (6H, m) 1.16-1.30 (10H, m), 1.14 (3H, s), 1.18 (3H, s), 1.75 (IH, m), 1.98-2.17 (3H, m), 2.32 (IH, m), 3.27 (3H, s), 3.52 (IH, d, J = 16.5 Hz), 3.68 (3H, s), 3.79 (3H, s), 3.87 (IH, m), 3.95 (IH, m), 4.09 (IH, m), 4.42 (2H, ABq, J = 11.0 Hz), 4.59 (IH, ά, J = 11.0 Hz), 4.65 (IH, d, J= 11.8 Hz), 4.98 (IH, s), 5.02 (IH, ά, J= 15.2 Hz), 5.41 (IH, s), 5.88 (IH, s), 5.91 (IH, dd, J= 16.2, 7.7 Hz), 6.83 (2H, d, J = 8.7 Hz), 7.16 (2H, ά, J = 8.7 Hz), 7.27-7.35 (6H, m), 9.44 (IH, ά, J = 1.1 Hz); 13 C NMR (75 MHz, CDC1 3 ) δ 14.1, 21.7, 22.6, 24.0, 24.6, 28.9, 29.0, 31.7, 32.6, 34.5, 36.2, 47.5, 51.3, 51.5, 55.4, 69.2, 71.3, 71.8, 74.4, 76.3, 102.7, 114.1, 118.2, 127.1, 127.7, 127.9, 128.7, 129.5, 130.7, 138.9, 151.6, 159.6, 166.6, 167.3, 172.1, 195.0. To a solution of 308.1 (17 mg, 0.02 mmol) in 0.5 mL 1% aqueous CH 2 C1 2 was added solid 2,3- dichloro-5,6-dicyano-l,4-benzoquinone (DDQ, 8 mg, 0.03 mmol) at rt. The mixture was stiπed for 2 h, pipetted directly onto a column of silica gel, and the product eluted with 35% EtOAc / hexanes to provide the coπesponding intermediate alcohol (11 mg, 85%) as a colorless oil. Ry (50% EtOAc / hexanes) = 0.55; IR 3528, 2930, 2858, 1745, 1720, 1686 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 0.86 (3H, t, J = 6.9 Hz), 1.13 (3H, s), 1.17 (3H, s), 1.25 (10 H, m), 1.52 (2H, m), 1.71 (2H, m), 2.12 (2H, m), 2.35 (IH, t, J = 14.1 Hz), 2.60 (IH, d, J= 3.6 Hz), 3.41 (3H, s), 3.45 (IH, m), 3.68 (3H, s), 3.82 (IH, s), 4.24 (IH, m), 4.54 (2H, ABq, J= 11.2 Hz), 547 (IH, s), 4.98 (IH, s), 5.02 (IH, d, J = 15.2 Hz), 5.86 (IH, s), 5.91 (IH, dd, J = 15.9, 7.5 Hz), 7.29 (IH, d, J = 15.9 Hz), 7.34 (5H, s), 9.52 (IH, d, J = 7.5 Hz); 13 C- NMR (75 MHz, CDC1 3 ) δ 13.8, 15.4, 21.7, 22.4, 23.6, 24.4, 28.8, 28.8, 31.5, 32.8, 34.4, 39.5, 47.4, 51.1, 51.2, 68.3, 70.8, 71.1, 71.2, 78.3, 102.5, 117.3, 127.0, 127.9, 128.0, 128.5, 138.1, 151.7, 166.5, 167.4, 171.8, 194.6. The intermediate alcohol (11 mg, 0.02 mmol) was dissolved in 1.0 mL CH 3 CN / H 2 0 (9: 1) and treated with 48% aqueous HF (200 μL, 300 mol% excess) at rt. The resulting mixture was stiπed for 1 h, quenched with sat. NaHC0 3 and diluted with 10 mL EtOAc. The aqueous layer was separated and extracted with EtOAc (2x). The combined organics were dried over Na 2 S0 4 and concentrated in vacuo to afford the coπesponding crude hemiketal enal of Formula 303a as a colorless oil. The crude product was purified by column chromatography on silica gel with 50% EtOAc-hexanes as eluant affording 8 mg (80%) of the C20 heptenoate hemiketal enal. R (35% EtOAc / hexanes) = 0.05; IR 3528, 2930, 2858, 1745, 1720, 1686, 1458, 1437, 1380 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 0.86 (3H, t, J = 6.9 Hz), 1.13 (3H, s), 1.17 (3H, s), 1.25 (10 H, m), 1.52 (2H, m), 1.71 (2H, m), 2.12 (2H, m), 2.35 (IH, t, J = 14.1 Hz), 2.60 (IH, d, J = 3.6 Hz), 3.41 (3H, s), 3.45 (IH, m), 3.68 (3H, s), 3.82 (IH, s), 4.24 (IH, m), 4.52 (2H, ABq, J = 11.4 Hz), 4.98 (IH, s), 5.02 (IH, ά, J = 15.2 Hz), 547 (IH, s), 5.86 (IH, s), 5.91 (IH, dd, J = 15.9, 7.5 Hz), 7.29 (IH, ά, J = 15.9 Hz), 7.34 (5H, s), 9.52 (IH, d, J = 7.5 Hz); 13 C-NMR (75 MHz, CDC1 3 ) δ 13.9, 15.4, 21.7, 22.4, 23.6, 24.4, 28.8, 28.8, 31.4, 32.7, 34.2, 39.5, 47.4, 51.1, 51.2, 68.3, 70.9, 71.1, 71.1, 78.5, 102.4, 117.4, 126.8, 128.0, 128.0, 128.6, 138.1, 151.8, 166.4, 167.1, 171.8, 194.7. Carboxylic acid 407 (21 mg, 0.04 mmol) and Et 3 N (19 μL , 0.12 mmol) were dissolved in 400 μL toluene and tteated with 2,4,6-trichlorobenzoylchloride (6.0 μL, 0.04 mmol) dropwise at rt. After 1 h at rt, a toluene solution of freshly prepared C20 heptenoate hemiketal enal (16 mg, 0.03 mmol) and 4- dimethylaminopyridine (17 mg, 0.13 mmol) was added gradually and stirring was continued for 40 min. The crude mixture was pipetted directly onto a column of silica gel and the product eluted with 20% EtOAc / hexanes to provide the expected ester (Formula 701 where R is OH, R' is OBn, R 3 is TBSO, R 20 is hepteonate. R 21 is =CH-COτMe and R 26 is methyl) as a colorless oil (24 mg, 80%). IR 3487, 2927, 2856, 1723, 1689, 1455, 1379 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 0.80 (IH, t, J= 12.7 Hz), 0.93 (3H, t, J = 7.0 Hz), 0.97 (3H, d, J = 6.6 Hz), 1.10-1.36 (24H, m), 1.36-1.85 (21H, m), 1.91- 2.13 (6H, m), 2.39 (1H, t, J = 12.8 Hz), 2.79 (IH, ά, J = 13.2 Hz), 2.93 (IH, m), 3.05 (IH, m), 3.29 (3H, s), 3.33 (IH, s), 3.37-348 (2H, m), 3.80 (IH, dd, 7 =11.4, 5.1 Hz), 3.95-4.05 (2H, m), 4.15 (IH, td, 7 = 10.8, 0.9 Hz), 4.23 (IH, d, 7= 13.5 Hz), 4.50 (2H, ABq, 7 = 12.0 Hz), 4.98 (IH, s), 5.00 (IH, d, 7 = 15.2 Hz), 5.57 (IH, s), 5.64 (IH, dd, J= 10.6, 4.6 Hz), 6.05 (IH, dd, 7 = 16.1, 7.6 Hz), 6.39 (IH, s), 7.10-7.35 (5H, m), 7.45 (IH, d, 7 = 16.1 Hz), 9.60 (IH, d, 7= 7.6 Hz); 13 C-NMR (75 MHz, CDC1 3 ) δ 14.1, 15.1, 19.3, 20.1, 21.3, 22.3, 22.4, 22.7, 23.8, 24.0, 24.6, 24.6, 29.0, 29.0, 29.3, 31.3, 31.6, 31.8, 34.2, 34.5, 35.2, 35.7, 36.2, 37.6, 43.5, 45.7, 51.6, 59.1, 64.9, 66.7, 71.1, 72.0, 72.9, 74.1, 75.3, 77.1, 100.2, 100.6, 121.2, 127.2, 127.3, 127.9, 128.6, 138.9, 151.2, 164.5, 166.3, 171.5, 175.1, 193.4; [α] 20 D -19° (c 1.5, CH 2 C1 2 ). To the ester prepared in the preceeding step (21 mg, 0.03 mmol) in THF (0.5 mL) was added pyridine (360 μL, 0.45 mmol) followed by 70% HF/ pyridine (144 μL, 500 mol% excess) and stiπed for 20 hours. The reaction was then quenched with a saturated solution of sodium bicarbonate. The biphasic mixture was extracted with ethyl acetate (x 4) and the combined organics were dried over sodium sulfate. The solvent was removed in vacuo to provide the coπesponding crude C3 hydroxyester. The crude mixture was pipetted directly onto a column of silica gel and the product eluted with 30% EtOAc / hexanes to provide this coπesponding ester (where R 3 is OH) as a colorless oil (13 mg, 68%). Py (30% EtOAc / hexanes) = 0.23; IR 3522, 2927, 2857, 1724, 1664, 1230, 1158, 1136, 1107, 979 cm 1 ; Η NMR (400 MHz, CDC1 3 ) δ 0.84 (3H, t, 7 = 5.4 Hz), 0.88-0.96 (5H, m), 1.00 (3H, d, J = 4.8 Hz), 1.02- 1.55 (27H, m), 1.63-1.81 (2H, m), 1.82-1.94 (2H, m), 2.03 (IH, br t, J= 5.2 Hz), 2.19-2.27 (IH, m), 2.34 (IH, dt, 7 = 9, 1.5 Hz), 2.94-3.01 (2H, m), 3.22 (IH, s), 3.58 (IH, br d, 7 = 3.6 Hz), 3.68-3.74 (IH, m), 3.84-3.88 (IH, m), 3.94 (IH, dd, 7 = 8.6, 3.1 Hz), 4.23 (IH, dd, J= 10.4, 1.7 Hz), 4.31 (IH, br t, 7 = 8.1 Hz), 4.97 (IH, s), 5.02 (IH, d, 7 = 15.2 Hz), 5.36-541 (IH, m), 5.50 (IH, s), 5.61 (IH, d, 7 = 5.4 Hz), 6.00 (IH, dd, 7 = 12.0, 5.4 Hz), 6.36 (IH, s), 6.53 (IH, d, 7 = 12.0 Hz); 13 C NMR (100 MHz, CDC1 3 ) δ 14.2, 19.4, 19.8, 22.4, 22.9, 24.0, 24.5, 25.0, 29.1, 29.2, 30.2, 31.8, 31.9, 32.0, 33.1, 34.6, 34.9, 35.4, 36.5, 43.6, 45.6, 50.7, 66.1, 66.7, 69.6, 73.2, 74.7, 75.8, 76.3, 77.5, 98.7, 102.6, 120.5, 140.1, 151.2, 151.5, 166.5, 171.5, 174.2; [α] 20 D -13.5° (c 0.9, CDC1 3 ). To a solution of the C3 hydroxy ester of the preceeding step (12 mg, 0.01 mmol) in 1.0 mL CH 2 C1 2 was added 4A molecular sieves and the mixture was allowed to stand for 20 min. 45-50 beads of Amberlyst-15 sulfonic acid resin were added and the mixture was stirred at rt for 2 h. The crude mixture was pipetted directly onto a column of silica gel and the product eluted with 35% EtOAc / hexanes to provide the coπesponding heptenoate macrocycle as a colorless oil (7 mg, 70%). R (35% EtOAc / hexanes) = 0.21; IR 3522, 2927, 2857, 1724, 1664, 1230, 1158, 1136, 1107, 979 cm "1 ; Η NMR (400 MHz, CDC1 3 ) δ 0.84 (3H, t, 7= 5.4 Hz), 0.88-0.96 (5H, m), 1.00 (3H, d, J= 4.8 Hz), 1.02-1.55 (27H, m), 1.63-1.81 (2H, m), 1.82-1.94 (2H, m), 2.03 (IH, br t, 7 = 5.2 Hz), 2.19-2.27 (IH, m), 2.34 (IH, dt, 7 = 9, 1.5 Hz), 2.94-3.01 (2H, m), 3.22 (IH, s), 3.58 (IH, br d, J= 3.6 Hz), 3.68-3.74 (IH, m), 3.84-3.88 (IH, m), 3.94 (IH, dd, J= 8.6, 3.1 Hz), 4.23 (IH, dd, J= 104, 1.7 Hz), 4.31 (IH, br t, 7 = 8.1 Hz), 4.99 (IH, s,, 5.03 (IH, d, 7 = 15.2 Hz), 5.36-541 (IH, m), 5.50 (IH, s), 5.61 (IH, d, 7 = 5.4 Hz), 6.00 (IH, dd, 7 = 12.0, 5.4 Hz), 6.36 (IH, s), 6.53 (IH, d, 7 = 12.0 Hz); 13 C NMR (100 MHz, CDC1 3 ) δ 14.2, 19.4, 19.8, 22.4, 22.9, 24.0, 24.5, 25.0, 29.1, 29.2, 30.2, 31.8, 31.9, 32.0, 33.1, 34.6, 34.9, 35.4, 36.5, 43.6, 45.6, 50.7, 66.1, 66.7, 69.6, 73.2, 74.7, 75.8, 76.3, 77.5, 98.7, 102.6, 120.5, 140.1, 151.2, 151.5, 166.5, 171.5, 174.2. The crude macrocycle of the preceeding step (2 mg, 0.01 mmol) was dissolved in 0.5 mL EtOAc and 2.2 mg Pd(OH) 2 (20% wt. on carbon) was added. The resulting suspension was vigorously stiπed under balloon pressure of hydrogen gas for 35 min. The crude mixture was pipetted directly onto a column of silica gel and the product was eluted with 60%> EtOAc / hexanes to afford heptanoate analogue (702.3) (Formula II where R 3 is OH, R 20 is -0-CO-C 6 H 13 , R 21 is =CH-C0 2 Me, R 26 is methyl and X is oxygen) (1 mg, 63%) as a white semi-solid. R/(50% EtOAc / hexanes) = 0.21; Η NMR (300 MHz, CDC1 3 ) δ 0.37 (3H, br. s), .19-.92 (14H, m), 1.06 (3H, d, 7 = 6.4 Hz), 1.07 (IH, t, 7 = 11.0 Hz), 1.10- 1.25 (5H, m), 1.27 (3H, s), 1.50 (3H, s), 1.57-1.78 (4H, m), 2.03 (2H, t, 7 = 7.4 Hz), 2.17 (IH, dd, 7 = 9.9/ 0.5 Hz), 2.37 (IH, m), 2.40 (IH, m), 2.85 (IH, t, 7 = 11.2 Hz), 2.96 (IH, t, 7 = 10.8 Hz), 3.15 (3H, s), 3.68- 3.72 (3H, m), 3.91 (IH, dd, 7 = 11.2, 4.0 Hz), 4.13 (IH, t, 7 = 9.7 Hz), 4.35 (IH, dd, 7 = 13.9, 2.2 Hz), 4.48 (IH, td, 7 = 11.0/ 2.8 Hz), 4.70 (IH, d, 7 = 12.1 Hz), 544 (IH, quint, 7 = 4.8 Hz), 5.54 (IH, d, 7 = 7.3 Hz), 5.69 (IH, s), 5.76 (IH, s), 5.85 (IH, dd, 7 = 16.1, 7.5 Hz), 6.40 (IH, d, 7 = 1.8 Hz), 6.50 (IH, d, 7 = 15.9 Hz); 13 C NMR (125 MHz, CDC1 3 ) δ 14.2, 19.4, 19.8, 22.4, 22.9, 24.0, 24.5, 25.0, 29.1, 29.2, 30.2, 31.8, 31.9, 32.0, 33.1, 34.6, 34.9, 35.4, 36.5, 43.6, 45.6, 50.7, 66.1, 66.7, 69.6, 73.2, 74.7, 75.8, 76.3, 77.5, 98.7, 102.6, 120.5, 140.1, 151.2, 151.5, 166.5, 171.5, 174.2. 4C. Myristate C20 Ester (702.4) To solution of the enal of Formula 305 (in which R 20 is C 7 Hι 5 ) (180 mg, 0.03 mmol), prepared as described for compound 13 in Wender et al. (1998a), in 0.5 mL of MeOH at rt was added PPTS (2 mg, catalytic) and trimethylorthofoimate (5 drops). The progress of the reaction was monitored by TLC. After 30 min the reaction was quenched with 1.0 mL Et 3 N . The solvent was removed under reduced pressure to afford the coπesponding crude dimethylacetal according to Formula 306.. The dimethylacetyl was immediately dissolved in MeOH (0.5 mL) and K 2 C0 3 (3 mg, catalytic). The progress of the reaction was monitored by TLC. After 30 min the reaction was quenched. The solution was quenched with sat. NaHC0 3 , diluted with EtOAc (10 mL), washed with H 2 0, dried over MgS0 4 and concenttated under reduced pressure to afford crude C20 free hydroxyl product of Formula 307, which was reacted with myristic acid in the same manner as the reaction of heptenoic acid in Example 4B. After 30 min the reaction was quenched. The solution was quenched with sat. NaHC0 3 , diluted with EtOAc (10 mL), washed with H 2 0, dried over MgS0 4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with 35% EtOAc -hexanes as eluant affording 14 mg (70% for three steps) of the desired dimethylacetal myristate of Formula 308. Rf(20% ethyl acetate/hexanes) = 0.5; R (35% EtOAc / hexanes) = 0.50; IR 2927, 2859, 1744, 1719, 1687, 1514, 1249, 1156, 1103, 1079, 1037 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 0.85 (6H, m) 1.16-1.30 (10H, m), 1.14 (3H, s), 1.18 (3H, s), 1.75 (IH, m), 1.95-2.17 (3H, m), 2.32 (IH, m), 3.37 (3H, s), 3.52 (IH, d, 7 = 16.5 Hz), 3.68 (3H, s), 3.79 (3H, s), 3.87 (IH, m), 3.95 (IH, m), 4.09 (IH, m), 4.55 (2H, ABq, 7 = 11.0 Hz), 5.41 (IH, s), 5.86 (IH, s), 5.91 (IH, dd, 7 = 16.2, 7.6 Hz), 6.83 (2H, d, 7= 8.7 Hz), 7.16 (2H, d, 7 = 8.7 Hz), 7.30-7.35 (6H, m), 9.43 (IH, d, 7 = 7.6 Hz); 13 C NMR (75 MHz, CDC1 3 ) δ 14.1, 21.7, 22.6, 24.0, 24.6, 28.9, 29.0, 31.7, 32.6, 34.5, 36.2, 47.5, 51.3, 51.5, 55.4, 69.2, 71.3, 71.8, 74.4, 76.3, 102.7, 114.1, 118.2, 127.1, 127.7, 127.9, 128.7, 129.5, 130.7, 138.9, 151.6, 159.6, 166.6, 167.3, 172.1, 195.0. To a solution of the dimethylacetal myristate (11 mg, 0.01 mmol) in 0.6 mL 1% aqueous CH 2 C1 2 was added solid 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ, 4 mg, 0.02 mmol) at rt. The mixture was stirred for 2 h, pipetted directly onto a column of silica gel, and the product eluted with 35% EtOAc / hexanes to provide the coπesponding intermediate alcohol (8 mg, 89%) as a colorless oil: R (35% EtOAc / hexanes) = 0.22; IR 3528, 2930, 2858, 1745, 1720, 1686, 1458, 1437, 1380 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 0.86 (3H, t, 7 = 6.9 Hz), 1.13 (3H, s), 1.17 (3H), 1.25 (10 H, m), 1.52 (2H, m), 1.71 (2H, m), 2.12 (2H, m), 2.35 (IH, t, 7 = 14.1 Hz), 2.60 (IH, d, 7 = 3.6 Hz), 3.41 (3H, s), 3.45 (IH, m), 3.68 (3H, s), 3.82 (IH, s), 4.24 (IH, m), 4.59 (2H, ABq, 7 = 11.4 Hz), 5.47 (IH, s, C20), 5.86 (IH, s), 5.91 (IH, dd, 7 = 15.9, 7.5 Hz), 7.29 (IH, d, 7 = 15.9 Hz), 7.34 (5H, m), 9.52 (IH, d, 7 = 7.5 Hz); 13 C-NMR (75 MHz, CDC1 3 ) δ 13.86, 15.44, 21.70, 22.38, 23.61, 24.39, 28.75, 28.81, 31.45, 32.75, 34.22, 39.50, 47.35, 51.13, 51.23, 68.32, 70.89, 71.06, 71.12, 78.51, 102.36, 117.43, 126.83, 127.97, 127.98, 128.57, 138.11, 151.80, 166.42, 167.11, 171.76, 194.73; [α] D 20 = -21.0° (c 1.0, CH 2 C1 2 ). The intermediate alcohol (7 mg, 0.02 mmol) was dissolved in 1.1 mL CH 3 CN / H 2 0 (9:1) and treated with 48% aqueous HF (200 μl, 300 mol %> excess) at rt. The resulting mixture was stirred for 1 h, quenched with sat. NaHC0 3 and diluted with 10 mL EtOAc. The aqueous layer was separated and extracted with EtOAc (2 x). The combined organics were dried over Na 2 S0 4 and concenttated in vacuo to afford the crude hemi-ketal enal (44 in Reaction Scheme 11 , which provides the compound number references for the remainder of the present example) as a colorless oil. The crude product was purified by column chromatography on silica gel with 35% EtOAc-hexanes as eluant affording 6 mg (86%) of enal 44. R (35% EtOAc / hexanes) = 0.15; IR 3528, 2930, 2858, 1745, 1720, 1686, 1458, 1437, 1380 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 0.87 (3H, t, 7 = 6.9 Hz), 1.13 (3H, s), 1.15 (3H, s), 1.28 (10 H, m), 1.52 (2H, m), 1.71 (2H, m), 2.12 (2H, m), 2.35 (IH, t, 7= 14.1 Hz), 2.60 (IH, d, 7 = 3.6 Hz), 3.41 (3H, s), 3.45 (IH, m), 3.68 (3H, s), 3.82 (IH, s), 4.24 (IH, m), 4.56 (2H, ABq, 7= 11.0 Hz), 5.47 (IH, s), 5.86 (IH, s), 5.91 (IH, dd, 7 = 15.9, 7.4 Hz), 7.28 (IH, d, 7= 15.9 Hz), 7.35 (5H, s), 9.52 (IH, d, 7 = 7.4 Hz); 13 C-NMR (75 MHz, CDC1 3 ) δ 13.9, 14.1, 194, 20.0, 22.7, 23.0, 24.4, 24.6, 29.1, 29.1, 29.4, 29.4, 29.6, 29.7, 31.2, 31.4, 31.9, 32.4, 34.6, 36.0, 40.0, 42.6, 42.9, 45.0, 51.1, 64.5, 66.3, 68.7, 70.4, 73.7, 74.1, 75.8, 76.1, 77.2, 78.7, 94.0, 98.9, 102.4, 119.7, 125.7, 142.8, 151.8, 167.0, 172.1, 172.5, 194.7. Carboxylic acid 6 (6 mg, 0.01 mmol) and Et 3 N (6 μL , 0.04 mmol) were dissolved in 300 μL toluene and treated with 2,4,6-ttichlorobenzoylchloride (2.0 μL, 0.01 mmol) dropwise at rt. After 1 h at rt, a toluene solution of freshly prepared enal 44 and 4-dimethylaminopyridine (5 mg, 0.04 mmol) was added gradually and stiπing was continued for 40 min. The crude mixture was pipetted directly onto a column of silica gel and the product eluted with 20% EtOAc / hexanes to provide ester-enal 46 as a colorless oil (9 mg, 90%). R f (35% EtOAc / hexanes) = 0.71; IR 3487, 2927, 2856, 1723, 1689, 1455, 1379, 1228, 1156, 1113, 1084, 1032, 981 cm 1 ; Η NMR (300 MHz, CDC1 3 ) δ 0.80 (IH, t, 7= 12.7 Hz), 0.93 (3H, t, 7 = 7.0 Hz), 0.98 (3H, d, 7 = 6.6 Hz), 1.10-141 (24H, m), 1.42-1.85 (21H, m), 1.92- 2.13 (6H, m), 2.39 (IH, t, 7 = 12.7 Hz), 2.81 (IH, d, 7= 13.2 Hz), 2.93 (IH, m), 3.05 (IH, m), 3.29 (3H, s), 3.33 (IH, s), 3.37-3.48 (2H, m), 3.80 (IH, dd, 7=11.4, 5.1 Hz), 3.95-4.05 (2H, m), 4.15 (IH, td, 7= 10.8, 0.9 Hz), 4.23 (IH, d, 7= 13.5 Hz), 4.46 (2H, ABq, 7= 11.0 Hz), 5.57 (IH, s), 5.64 (IH, dd, 7= 10.6, 4.6 Hz), 6.05 (IH, dd, 7= 15.9, 7.5 Hz), 6.39 (IH, s), 7.10-7.35 (5H, m), 7.45 (IH, d, 7= 15.9 Hz), 9.60 (IH, d, 7= 7.5 Hz); 13 C-NMR (75 MHz, CDC1 3 ) δ -9.6, -9.4, 9.2, 10.3, 13.2, 14.1, 15.1, 19.3, 20.1, 21.3, 22.3, 22.4, 22.7, 23.8, 24.0, 24.6, 24.6, 29.0, 29.0, 29.3, 31.3, 31.6, 31.8, 34.2, 34.5, 35.2, 35.7, 36.2, 37.6, 43.5, 45.7, 51.6, 59.1, 64.9, 66.7, 71.1, 72.0, 72.9, 74.1, 75.3, 77.1, 100.2, 100.6, 121.2, 127.2, 127.3, 127.9, 128.6, 138.9, 151.2, 164.5, 166.3, 171.5, 175.1, 193.2; [α] 20 D -19° (c 1.5, CH 2 C1 2 ). To ester-enal 46 (8.0 mg, 0.001 mmol) in THF (0.5 mL) was added 70% HF/ pyridine (0.3 mL, 0.3 mmol) and stiπed for 2 hours. The reaction was then quenched with a saturated solution of sodium bicarbonate. The biphasic mixture was exttacted with ethyl acetate (x4) and the combined organics were dried over sodium sulfate. The solvent was removed in vacuo to provide crude macrocycle. The crude mixture was chromatographed on silica gel and the product was eluted with 50%> EtOAc / hexanes to afford 5.0 mg (83%) of the coπesponding macrocycle as an clear oil.: Rf (40% EtOAc / hexanes) = 0.19; IR 3522, 2927, 2857, 1724, 1664, 1230, 1158, 1136, 1107, 979 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 0.84 (3H, t, 7 = 5.4 Hz), 0.88-0.96 (5H, m), 1.00 (3H, d, 7 = 4.8 Hz), 1.02-1.55 (27H, m), 1.63-1.81 (2H, m), 1.82-1.94 (2H, m), 2.03 (IH, br t, 7= 5.2 Hz), 2.19-2.27 (IH, m), 2.34 (IH, dt, 7= 9, 1.5 Hz), 2.94-3.01 (2H, m), 3.22 (IH, s), 3.58 (IH, br ά, J= 3.6 Hz), 3.68-3.74 (IH, m), 3.84-3.88 (IH, m), 3.94 (IH, dd, 7= 8.6, 3.1 Hz), 4.23 (IH, dd, 7= 10.4, 1.7 Hz), 4.31 (IH, br t, 7= 8.1 Hz), 4.56 (2H, ABq, 7 = 11.0 Hz), 5.36-541 (IH, m), 5.50 (IH, s), 5.61 (IH, d, 7= 5.4 Hz), 6.00 (IH, dd, 7= 12.0, 5.4 Hz), 6.36 (IH, s), 6.53 (IH, d, 7 = 12.0 Hz); 13 C NMR (100 MHz, CDC1 3 ) δ δ 14.1, 194, 20.0, 22.7, 23.0, 24.4, 24.6, 29.1, 29.1, 29.4, 29.4, 29.6, 29.7, 31.2, 31.4, 31.9, 32.4, 34.6, 36.0, 40.0, 42.6, 42.9, 45.0, 51.1, 64.5, 66.3, 68.7, 70.4, 73.7, 74.1, 75.8, 76.1, 77.2, 78.7, 94.0, 98.9, 1024, 119.7, 125.7, 142.8, 151.8, 167.0, 172.1, 172.5. To 5.0 mg (0.0005 mmol) of crude macrocycle of the preceeding step in ethyl acetate (1.0 ml) was added a catalytic amount of Pearlman's catalyst. The flask was evacuated and refilled with a 1 atm. hydrogen atmosphere (x4), stiπed under hydrogen for 30 min, and then pipetted directly onto a silica gel column and eluted with 60% ethyl acetate/ hexanes. This process afforded 4.8 mg (99%) of analogue 48 (702.4) (Formula II where R 3 is OH, R 20 is -0-CO-C 13 H 27 , R 21 is =CH-C0 2 Me, R 26 is methyl and X is oxygen) as an amorphous solid. R/(50% EtOAc / hexanes) = 0.16; IR 3522, 2927, 2857, 1724, 1664, 1230 IR (neat) = 3455, 3319, 2929, 2856, 1735, 1380, 1230, 1138, 976 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 0.37 (3H, bs), 0.79-0.92 (14H, m), 1.06 (3H, d, 7 = 64 Hz), 1.07 (IH, t, 7 = 11.0 Hz), 1.10- 1.25 (5H, m), 1.27 (3H, s), 1.50 (3H, s), 1.57-1.78 (4H, m), 2.03 (2H, t, 7 = 7.4 Hz), 2.17 (IH, dd, 7 = 9.9/ 0.5 Hz), 2.37 (IH, m), 2.40 (IH, m), 2.85 (IH, t, 7 = 11.2 Hz), 2.96 (IH, t, 7 = 10.8 Hz), 3.15 (3H, s), 3.68- 3.72 (3H, m), 3.91 (IH, dd, 7 = 11.2, 4.0 Hz), 4.13 (IH, t, 7 = 9.7 Hz), 4.35 (IH, dd, 7 = 13.9/ 2.2 Hz), 4.48 (IH, td, 7 = 11.0, 2.8 Hz), 4.70 (IH, d, 7 = 12.1 Hz), 5.44 (IH, quint., 7 = 4.8 Hz), 5.54 (IH, d, 7 = 7.3 Hz), 5.69 (IH, s), 5.76 (IH, s), 5.85 (IH, dd, 7= 16.1, 7.5 Hz), 6.40 (IH, d, 7 = 1.8 Hz), 6.50 (IH, d, 7 = 15.9 Hz); 13 C NMR (125 MHz, CDC1 3 ) δ 14.1, 194, 20.0, 22.7, 23.0, 24.4, 24.6, 29.1, 29.1, 29.4, 29.4, 29.6, 29.7, 31.2, 31.4, 31.9, 32.4, 34.6, 36.0, 40.0, 42.6, 42.9, 45.0, 51.1 , 64.5, 66.3, 68.7, 70.4, 73.7, 74.1, 75.8, 76.1 , 77.2, 78.7, 94.0, 98.9, 102.4, 119.7, 125.7, 142.8, 151.8, 167.0, 172.1, 172.5. 4D. Benzoate C20 Ester (702.5) Enal 45 was prepared following the procedure for compound 111 in Example 1C except that benzoic acid was substituted for octanoic acid, to form the coπesponding protected benzoate product. Carboxylic acid 6 (6 mg, 0.01 mmol) and Et 3 N (6 μL , 0.04 mmol) were dissolved in 300 μL toluene and treated with 2,4,6-trichlorobenzoylchloride (2 μL, 0.01 mmol) dropwise at rt. After 1 h at rt, a toluene solution of freshly prepared 45 and 4-dimethylaminopyridine (5 mg, 0.01 mmol) was added gradually and stirring was continued for 40 min. The crude mixture was pipetted directly onto a column of silica gel and the product eluted with 20% EtOAc / hexanes to provide the expected ester product as a colorless oil (8 mg, 89%). R f (35% EtOAc / hexanes) = 0.71; IR 3460, 2927, 2856, 1723 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 0.08 3H,s), 0.08 (3H, s), 0.81 (12H, m), 0.82-0.96 (3H, m), 1.06-1.32 (15H, m), 1.59-1.81 (4H, m), 2.20 (IH, t, 7 = 9.3 Hz), 3.33-344 (2H, m), 3.67-3.84 (IH, m), 4.00-4.15 (4H, m), 4.31-4.39 (IH, m), 4.55 (2H, ABq, 7 = 8.5 Hz), 5.41 (IH, s), 5.75 (IH, dd, 7 = 15.5, 3.4 Hz), 6.01 (IH, s), 6.39 (IH, s), 7.28-7.47 (9H, m), 7.84 (IH, d, 7 = 6.9 Hz), 9.17 (IH, d, 7 = 7.3 Hz); 13 C-NMR (75 MHz, CDC1 3 ) δ -9.6, -94, 9.2, 10.3, 13.2, 14.2, 18.5, 22.0, 23.5, 28.4, 28.7, 30.7, 31.5, 33.5, 39.1, 41.5, 41.9, 44.0, 50.1, 63.7, 65.3, 67.8, 69.6, 70.3, 73.8, 74.8, 75.1, 76.2, 77.7, 98.1, 101.3, 118.8, 124.7, 126.7, 127.4, 127.5, 128.9, 132.2, 137.3, 141.8, 150.8, 163.6, 165.9, 170.2. To the ester of the preceeding step (13 mg, 0.02 mmol) in THF (0.5 mL) was added pyridine (360 μL, 0.45 mmol) followed by 70% HF/ pyridine (144 μL, 500 mol%> excess) with stirring for 20 hours. The reaction was then quenched with a saturated solution of sodium bicarbonate. The biphasic mixture was extracted with ethyl acetate (x4) and the combined organics were dried over sodium sulfate. The solvent was removed in vacuo to provide the coπesponding crude C3 hydroxyester. The crude mixture was pipetted directly onto a column of silica gel and the product eluted with 35% EtOAc / hexanes to provide the purified C3 hydroxyester as a colorless oil (9 mg, 82%). Rf (40% EtOAc / hexanes) = 0.19; IR 3522, 2927, 2857, 1724 cm "1 ; Η NMR (300 MHz, CDC1 3 ) 0.81-0.91 (3H, m), 1.08 (3H, s), 1.20-1.59 (9H, m), 1.31 (6H, s), 1.92-2.18 (4H, m), 2.45 (2H, bs), 340-3.58 (2H, m), 3.67 (3H, s), 3.69-3.78 (2H, m), 3.88-3.98 (2H,m) 4.03-4.24 (3H, m), 4.45 (IH, d, 7= 9.2 Hz), 4.65 (2H, ABq, 7 = 8.5 Hz), 5.17 (IH, d, 7= 9.7 Hz), 5.22 (IH, s), 5.40 (IH, s), 5.44 (IH, dd, 7= 15.5, 7.3 Hz), 6.06 (IH, s), 6.08 (IH, d, 7 = 15.5 Hz), 7.27-7.59 (9H, m), 8.05 (IH, d, 7 = 6.9 Hz); 13 C NMR (100 MHz, CDC1 3 ) δ 14.2, 18.5, 22.0, 23.5, 28.4, 28.7, 30.7, 31.5, 33.5, 39.1, 41.5, 41.9, 44.0, 50.1, 63.7, 65.3, 67.8, 69.6, 70.3, 73.8, 74.8, 75.1, 76.2, 77.7, 98.1, 101.3, 118.8, 124.7, 126.7, 127.4, 127.5, 128.9, 132.2, 137.3, 141.8, 150.8, 163.6, 165.9, 170.2; [α] 20 D -11.5 (c 0.9, CDC1 3 ). To 4.0 mg (0.001 mmol) of the crude C3 hydroxyester of the preceeding step in ethyl acetate (1.0 ml) was added a catalytic amount of Pearlman's catalyst. The flask was evacuated and refilled with a 1 atm. hydrogen atmosphere (x4). Stiπed under hydrogen for 30 min. and then pipetted directly onto a silica gel column and eluted with 60% ethyl acetate/ hexanes. HPLC (hexane: methylene chloride: i- propanol, 16:3:1) Isolated 2.2 mg (63%) of analogue 49 (702.5) (Formula II where R 3 is OH, R 20 is -O-CO-Ph, R 21 is =CH-C0 2 Me, R 26 is methyl and X is oxygen)as an amorphous solid. R/(50% EtOAc / hexanes) = 0.16; IR 3522, 2927, 2857, 1724, 1664, 1230 IR (neat) = 3455, 3319, 2929, 2856, 1735, 1380, 1230, 1138, 976 cm "1 ; Η NMR (300 MHz, CDC1 3 ) δ 0.81-0.92 (3H, m), 1.08 (3H, s), 1.20-1.59 (9H, m), 1.32 (6H, s), 1.90-2.18 (4H, m), 2.52-2.56 (2H, m), 340-3.55 (2H, m), 3.67 (3H, s), 3.73-3.79 (2H, m), 3.82-3.95 (2H,m) 4.02-4.22 (2H, m), 4.51 (IH, d, 7 = 9.1 Hz), 5.11 (IH, d, 7 = 8.9 Hz), 5.26 (IH, s), 5.40 (IH, s), 5.42 (IH, dd, 7= 15.5, 3.4 Hz), 6.04 (IH, d, 7 = 15.5 Hz), 6.07 (IH, s), 7.34-7.57 (4H, m), 8.04 (IH, d, 7 = 7.3 Hz); 13 C NMR (125 MHz, CDC1 3 ) δ 13.1, 18.4, 18.9, 21.7, 23.5, 28.7, 30.6, 31.4, 35.0, 39.1, 41.6, 50.1, 63.6, 67.7, 69.2, 72.6, 76.1, 77.7, 93.0, 99.2, 113.0, 124.7, 127.2, 127.5, 128.9, 132.2, 146.3, 148.1, 149.9, 150.6, 171.4, 173.2; [α] 25 D = -7.0° (c= 0.36, CDCI3). Example 5 Protein Kinase C (Isozyme Mix) Assay Protocol The following procedure was used, based on a modification of a previous procedure described by Tanaka et al. (1986). Filters (Whatman GF-B, 21 mm diam.) are soaked for 1 h in a solution containing deionized water (97 mL), and 10% polyethyleneamine (3 mL). A filtering buffer solution containing TRIS (1M, pH 7 4, 10 mL) and water (490 mL) is prepared and cooled on ice An assay buffer solution is prepared by the addition of TRIS (1M, pH 7 4, 1 mL), KC1 (1M, 2 mL), CaCl 2 (0 1M, 30 μL), bovine serum albumin (40 mg), diluted to 20 mL with deionized water and stored on ice Phosphatidyl serine vesicles are prepared by the addition of phosphatidyl senne (10 mg/mL in chloroform, 0 4 mL) to a glass test tube followed by removal of the chloroform under a stream of nittogen (5 min) To this viscous liquid is added a portion of the prepared assay buffer (4 mL) and the resulting mixture is then ttansfeπed to a plastic tube with washing This tube is then sonicated (Branson Sonifier 250, power=6, 40%> duty cycle) four times for 30 sec with a 30 sec rest penod between somcations The resulting solution is stored over ice PKC is prepared by addition of cooled assay buffer (10 mL) to PKC (25 μL) puπfied from rat brain by the method of Mochly-Rosen and Koshland (1986) and then stored on ice Stock solutions of compounds are diluted with absolute ethanol in glass in serial fashion Each plastic assay incubation tube is made to contain prepared phosphatidyl serine vesicles (60 μL), prepared PKC solution (200 μL) and analogue (0-20 μL) plus EtOH (20-0 μL) for a total volume of 20 μL) Lastly, tntiated phorbol 12,13-dιbutyrate (PDBU) (30 nM, 20 μL) is added to each tube The assay is earned out using 7-10 analogue concenttations, each in triplicate Non-specific binding is measured in 1-3 tubes by the substitution of phorbol mynstate acetate (PMA) (1 mM, 5 μL) and EtOH (15 μL) for the analogue / EtOH combination The tubes are incubated at 37°C for 90 min and then put on ice for 5 min Each tube is then filtered separately through a pre-soaked filter disc Each tube is nnsed with cold 20 mM TRIS buffer (500 μL) and the πnseate is added to the filter The filter is subsequently rinsed with cold 20 mM TRIS buffer (5 mL) dropwise The filters are then put in separate scintillation vials and Universol ® scintillation fluid is added (3 mL) The filters are immediately counted in a scintillation counter (Beckman LS 6000SC) Counts per minute are averaged among three tnals at each concenttation The data is then plotted using a least squares fit algoπthm with the Macmtosh version of Kaleidagraph ® (Abelbeck Software) and an IC 50 (defined as the concentration of analogue required to displace half of the specific PDBU binding to PKC) is calculated The IC 50 then allows determination of the K, for the analogue from the equation K, = IC 50 / (1 + [PDBu] / I j of PDBu) The K < , of [H 3 ]-PDBu was determined under identical conditions to be 1 55 nM Example 6 PKCδ-ClB Assay Protocol All aspects of the PKCδ-ClB assay are identical to the PKC isozyme mix assay from Example 5 except the following features: In the PKCδ-ClB assay system, assay buffer is made without CaCl 2 . PKCδ-ClB (200 μg, 34.14 nmol), prepared by the method of Wender et al. (1995) and Irie et al. (1998) is dissolved in deionized water (160 μL) and ZnCl 2 (5 mM, 40 μL) is added. The resulting solution is allowed to stand at 4°C for 10 min. An aliquot (10 μL) of this solution is diluted to 2 mL with deionized water. An aliquot (290 μL) is further diluted to 20 mL with assay buffer and is ready for use. The incubation time is shortened from 90 min. to 30 min. Lastly, during the filtering portion of the assay, the tube is not washed with filtering buffer (0.5 mL). When tested as described above, the C26 desmethyl analogue 702.1 (Example 3 A), had significantly higher activity than the coπesponding C26 methyl-containing analogue (Formula 1998a where R 3 is OH). Similarly, among several analogues having different C20 ester groups, the presence of longer R20 substituents (48) or an aryl substituent (49) also afforded higher activity. The results are shown below in Table 1 (in all compounds tested, R 3 was OH and R 21 was =CH-C0 Me). Table 1 Example 7 P388 Murine Lymphocytic Leukemia Cell Assay Cells from a P388 cell line (CellGate, Inc., Sunnyvale, CA) are grown in RPMI 1640 cell medium containing fetal calf serum (10%), L-glutamine, penicillin, streptomycin and are split twice weekly. All compounds are first diluted with DMSO. Later serial dilutions are done with a phosphate buffer solution (HYQ DPBS modified phosphate buffered saline). All dilutions are done in glass vials and the final DMSO concenttation is always below 0.5%> by volume. Final two-fold dilutions are done in a 96 well plate using cell media so that each well contains 50 μL. All compounds are assayed in quadruplicate over 12 concentrations. Cell concenttation is measured using a hemacytometer and the final cell concentration is adjusted to 1 x 10 cells/mL with cell medium. The resulting solution of cells (50 μL) is then added to each well and the plates are incubated for 5 days in a 37°C, 5% C0 2 , humidified incubator (Sanyo C0 2 incubator). MTT solution (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltettazolium bromide, 10 μL) is then added to each well and the plates are re-incubated under identical conditions for 2 h. To each well is then added acidified isopropanol (150 μL of z ' -PrOH solution containing 0.05 N HCl) and mixed thoroughly. The plates are then scanned at 595 nm and the absorbances are read (Wallac Victor 1420 Multilabel Counter). The resulting data is then analyzed to determine an ED 50 value using the Prism software package (GraphPad). When tested as described above, the C26 desmethyl analogue 702.1 (Example 3 A), had significantly higher activity than the coπesponding C26 methyl-containing analogue. Similarly, among several analogues having different C20 ester groups, the presence of longer R20 substituents (48) or an aryl substituent (49) also afforded higher activity. The results are shown below in Table 2 (in all compounds tested, R 3 was OH and R 21 was =CH-C0 2 Me). Table 2 Example 8 In Vitro Inhibition of Growth in Human Cancer Cell Lines Anticancer data were obtained in vitro for C26 desmethyl bryostatin analogue 702.1 (Example 3A) tested against a spectrum of different NCI human cancer cell-lines associated with various cancer conditions. The results are shown in Table 3. Data obtained with Bryostatin-1 are included for comparison. Growth inhibition (GI50) values are expressed as the log of molar concentration at half- maximum inhibition. As can be seen, the C26 desmethyl compound was at least as potent, on average, as bryostatin-1 for all cell groups tested. Moreover, the C26 desmethyl compound was more active than bryostatin-1 by more than 2 orders of magnitude for several cell lines: K-562 and MOLT-4 (leukemia), NCI-H460 (NSC lung), HCC-2998 (colon), TK-10 (renal), and MDA-MB-435 (breast). These results are significant and surprising since the C27 methyl group attached to C26 was previously believed to be necessary for activity. Table 3 Documents Cited by Reference Alkatib, A., Exp. Hematol. 21 :61-65 (1993). Aprahamian et al., J. Biomed. Mat. Res. 21 :965-977 (1986). Berkow, R.L. et al., Biochem. Biophys. Res. Commun. 131 : 1109-1116 (1985). Blumberg et al., W097/34598 (1997) (coπesponding to U.S. Patent No. 6,060,505). Boyd, M.R., "Status of the NCI preclinical antitumor drug discovery screen" in Cancer: Principles and Practice of Oncology Updates, DeVita et al., eds, pp. 1-12 (1989). DeVries, D.J., et al., Biochem. Pharmacol. 37:4069-4073 (1998). Emmanuel et al., Stain. Tech. 62:401-409 (1987). Evans, D.A.; et al., Angew. Chem. Int. Ed. 37:2354-2359 (1998). Evans, D.A.; et al., Angew. J. Am. Chem. Soc. 121:7540-7552 (1999). Friendenstein et al., Exp. Hematol. 10:217-227 (1982). Gennaro, A.R., Ed., Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990). Grever, M.R., et al. Seminars Oncol. 19:622 (1992). Harada et al. J. Am. Chem. Soc. 115:7665-7674 (1993). Hardman, J.G., et al. (eds), Goodman & Gilmans's The Pharmacological Basis of Therapeutics, Ninth Edition, McGraw-Hill, New York, NY, Chapter 51 (1996). Hornung, R.L., et al., Cancer Res. 52: 101-107 (1992). Irie, K., et al., J. Am. Chem. Soc. 120:9159 (1998). Kageyama, M., et al., J. Am. Chem. Soc. 112:7407-7408 (1990). Katzung, B.G. (Editor), Basic & Clinical Pharmacology, Seventh Ed., Appleton & Lange, Stamford, CT, 1998, Chapter 55. Kraft, A.S., et al., Proc. Natl. Acad. Sci. USA 83:1334-1338 (1986). Kraft, A.S., et al., Cancer Chemother. Pharmacol. 37:271-278 (1996). Lind, D.S., et al., Surgical Oncol.-Oxford 2:273-282 (1993). Maki, A., et al., Anti-Cancer Drugs 6:392-397 (1995). Masamune, S., Pure Appl. Chem 60:1587-1596 (1988a). Masamune, S., Chimica 42:210-21 1 (1988b). Mochly-Rosen, D., and Koshland Jr., D.E., J. Biol. Chem. 262:2291-2297 (1986). Mohammad, R.M., et al., Leukemia Res. 19:667-673 (1995). Mohammad, R.M., et al., Leukemia 10: 130-137 (1996). Mohammad, R.M., et al, Clin. Cancer Res. 4: 1337-1343 (1998). Monks, A., et al., J. Natl. Cancer Inst, 83:757-766 (1991). Pettit, G.R., et al., J. Am. Chem. Soc. 104:6846-6848 (1982). Pettit, G.R. J. Nat. Prod. 59:812-821 (1996), and references cited therein. Ramsdell, J , et al , J Biol Chem 261 7073-7080 (1986) Scheid, C , et al , Cancer Immunol Immunother 39 223-230 (1994) Schuchter, L M , et al , Cancer Res 51 682-687 (1991) Spitaler, M , et al , Biochem Pharmacol 56 861-869 (1998) Still, C , et al , J Org Chem 43 2923 (1978) Szallasi, Z , et al , Cancer Res 56 2105-21 11 (1996), and references cited therein Tanaka, Y , et al , J Biochem 99 257-261 (1986) Theisen, P D , et al J Org Chem 53 2374-2378 (1998) Uchida et al , J Biomed Mat Res 21 1-10 (1987) Wender, P A , et al , Proc Natl Acad Sci U S A 92 239 (1995) Wender, P A , et al , J Am Chem Soc 120 4534-4535 (1998a) Wender, P A , et al , Proc Natl Acad Sci U S A 95 6624-6629 (1998b) Wender, P A , et al , Tetrahedron Letters 39 8625-8628 (1998c) Wilson, J D , et al (Editors), Hamson's Principles of Internal Medicine, Twelfth Ed , 1991, Chapters 300-310 All references cited herein are hereby incorporated by reference Although the invention has been described with respect to specific embodiments and examples, it will be appreciated that various changes and modifications may be made without departing from the spirit of the invention

Claims: WHAT IS CLAIMED IS A compound having the structure represented by Formula I Formula I wherein R U ιs H, OH, or 0 2 CR', R 21 is =CR a R b or R 21 represents independent moieties R c and R d where R a and R b are independently H, C0 2 R' or R', R c and R d are independently H, alkyl, alkenyl or alkynyl containing 1 to 20 carbon atoms, or (CH 2 ) n C0 2 R' where n is 1, 2 or 3, R 26 ιs H, OH or R', each R' being independently selected from the group alkyl, alkenyl or alkynyl containing 1 to 20 carbon atoms, or aryl, heteroaryl, aralkyl or heteroaralkyl containing 2 to 20 carbon atoms, and L is a straight or branched lmear, cyclic or polycychc, relatively lipophilic moiety containing a continuous chain of from 6 to 14 chain atoms, which substantially maintams relative distance of the Cl and C17 atoms and the directionality of the C1C2 and C16C17 bonds of narurally- ocuπmg bryostatin, and or a pharmaceutically acceptable salt thereof, excluding the compounds of formula 1998a where R 3 is H or OH, and the compound of formula 1998b 1998a 1998b The compound or salt of Claim 1 wherein Z is oxygen. 3. The compound or salt of Claim 1 or 2 wherein R is hydrogen 4. The compound or salt of Claim 1 or 2 wherein R is 0 2 CR'. 5. The compound or salt of Claim 4 wherein R 26 is hydrogen. 6. The compound or salt of Claim 4 wherein the R' of said R 20 substituent is selected from: alkyl having from about 7 to 20 carbon atoms, alkenyl having from about 7 to 20 carbon atoms, phenyl and naphthyl. The compound or salt of Claim 1 or 2 wherein R 21 is =C(H)C0 2 R'. The compound or salt of Claim 7 wherein R is hydrogen. 9. The compound or salt of Claim 8 wherein the R' of said R 21 substituent is C Cι 0 alkyl. 10. The compound or salt of Claim 7 wherein R is 0 2 CR' 11. A pharmaceutical composition comprising a compound or salt of Claim 1 and a pharmaceutically acceptable excipient. 12. A compound having the structure represented by any of Formulae II - V: Formula III Formula V Formula IV wherein: R 3 is H or OH; R 6 is H,H or =0; R 8 is selected from the group: H, OH, R', -(CH 2 ) n O(0)CR' or (CH 2 ) n C0 2 -haloalkyl, where n is 0, 1, 2, 3, 4 or 5; R 9 is H or OH; R 20 is H, OH, or 0 2 CR'; R 21 is =CR a R b or R 21 represents independent moieties R c and R d where: R a and R b are independently H, C0 2 R' or R'; R c and R d are independently H, alkyl, alkenyl or alkynyl containing 1 to 20 carbon atoms, or (CH 2 ) n C0 2 R' where n is 1, 2 or 3; R 26 is H, OH or R'; p is 1, 2, 3 or 4; and X is C, O, S or N-R e where R e is COH, C0 2 R' or S0 2 R'; each R' being independently selected from the group: alkyl, alkenyl or alkynyl containing 1 to 20 carbon atoms, or aryl, heteroaryl, aralkyl or heteroaralkyl containing 2 to 20 carbon atoms, or a pharmaceutically acceptable salt thereof, excluding the compounds of formula 1998a where R 3 is H or OH, and the compound of formula 1998b: 1998a 1998b 13. The compound or salt of Claim 12 wherein R 26 is hydrogen. 14. The compound or salt of Claim 12 or 13 being selected from Formula II or Formula III where X is oxygen. 15. The compound or salt of Claim 12 or 13 wherein R 20 is 0 2 CR'. 16. The compound or salt of Claim 12 or 13 wherein R 21 is =C(H)C0 2 R'. 17. The compound or salt of Claim 12 or 13 being selected from Formula II-IV where R 3 is OH. 18. The compound or salt of Claim 14 wherein R 20 is 0 2 CR'. 19. The compound or salt of Claim 18 wherein the R' of said R 20 substituent is selected from: alkyl having from about 7 to 20 carbon atoms, alkenyl having from about 7 to 20 carbon atoms, phenyl and naphthyl. 20. The compound or salt of Claim 18 wherein R 2 ' is =C(H)C0 2 R' . 21. The compound or salt of Claim 14 where R 8 is -(CH 2 ) n O(0)CR\ 22. The compound of Claim 12 represented by Formula Ila: Formula Ila or a pharmaceutically acceptable salt thereof. 23. A pharmaceutical composition comprising a compound or salt of Claim 12 or 22 and a pharmaceutically acceptable excipient. 24. A C26 des-methyl bryostatin homologue having the structure represented by Formula VI: Formula VI where R Λ and R B correspond to the naturally occuπing bryostatin substituents, or a pharmaceutically acceptable salt thereof. 25. The C26 des-methyl bryostatin homologue of Claim 25 having the structure represented by Formula Via: Formula Via. or a pharmaceutically acceptable salt thereof. 26. A method of treatment for a disorder responsive to bryostatin therapy comprising administering to a mammal in need thereof an effective amount of a compound or pharmaceutically acceptable salt of any of Claims 1, 12 or 24 and optionally co-administering a second agent having therapeutic activity via a mechanism distinct from that of bryostatin. 27. A method for the synthesis of a bryostatin analogue or homologue of any of Claims 1, 12 or 24 comprising de-protecting the C26 hydroxyl of the coπesponding precursor.

Inventors: HINKLE KEVIN W, LIPPA BLAISE, PARK CHEOL-MIN, WENDER PAUL A, HINKLE, KEVIN, W., LIPPA, BLAISE, PARK, CHEOL-MIN, WENDER, PAUL, A.
Applicants: UNIV LELAND STANFORD JUNIOR, THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY
Application year: 2000
Main classification: C07D323
IPC codes: A61K31, A61P35, A61P37, C07D265, C07D309, C07D311, C07D319, C07D327, C07D493, C07D497