SARCODICTYIN AND ELEUTHEROBIN USEFUL FOR STABILISING MICROTUBULES

Abstract: Sarcodictyin A and B, eleutherobin, and bioactive analogs (A) thereof synthesized using solid phase and solution phase chemistries. The synthetic method employs an attachment of common precursors, e.g., compounds 1880 or 200, on a solid support for generating conjugates 230 and 240, followed by standard chemical manipulations. A combinatorial library of sarcodictyins and eleutherobin analogs is constructed with modified C-8 ester, C-15 ester and C-4 ketal functionalities and is screened for activity with respect to tubulin polymerization and cytotoxic activity against tumor cells, including Taxol-resistant lines. Compounds 600, 610, 630, 660-700, 730, 760, 850, and 920 are identified to be of equal or superior biological activities as compared to their corresponding natural product.

Description: SARCODICTYIN AND ELEUTHEROBIN USEFUL FOR STABILISING MICROTUBULES Technical Field: The present invention relates to sarcodictyin A and B, eleutherobin and their derivatives and methods for their manufacture, respectively. More particularly, the present application relates to analogs of sarcodictyin and eleutherobin and to their synthesis and use, as well as to pharmaceutical compositions comprising these compounds. Government Rights: This invention was made with government support under Grant No. CA 46446 awarded by the National Institutes of Health. The U.S. government has certain rights in the invention. Background: The Sarcodictyins A (7) and B (8) (Scheme 1 ) were discovered by Pietra et al. in the Mediterranean stoloniferan coral Sarcodictyon roseum and first reported in 1987 (D'Ambrosio et al. Helv. Chim. Acta 1987, 70, 2019-2027; D'Ambrosio et al. Helv. Chim. Ada 1988, 71, 964-976). Sarcodictyins C-F were subsequently disclosed by the same group (D'Ambrosio et al. Helv. Chim. Acta 1988, 71, 964-976). Scheme 1 : Molecular structures of TaxolTM (1), epothilones A (2) and B (3), eleutherobin (4), eleuthosides A (5) and B (6) and sarcodictyins A (7) and B (8) (Ac = acetyl, Bz = ben- zoyl). Eleutherobin was isolated from an Eleutherobia species of soft coral (possibly E. albiflora Alcynacea, Alcyoniidea collected from the Indian Ocean near Bennett's Shoal in Western Australia) by Fenical et al. and first reported in 1995 (Fenical et al., US Patent No. 5,473,057, Dec. 5, 1995). Eleuthosides A (5) and B (6) were isolated from an Eleutherobia aurea species of soft coral (collected near the Kwazula-Natal coast of South Africa) and reported by Kashman et al. (Ketzinel et al. J. Nat. Prod. 1996, 59, 873-875). These substances are closely related to eleutherobin (4). Valdivone (6) was first reported by Kennart and Watson (Lin et al. Tetrahedron 1993, 49, 7977-7984). These substances are also related, both structurally and with regards to their biological action, to eleutherobin (4) and to eleuthosides A (5) and B (6) (Scheme 1). All four of the above marine-derived natural products (4-8) share the same mechanism of action with the soil-derived (myxobacteria) epothilones A (2) and B (3) and the forest-residing Taxol® (1) (Scheme 1 ). (Lindel et al. J. Am. Chem. Soc. 1997, 119, 8744-8745; Long et al. Cancer Res. 1998, 58, 1111-1115). This mechanism involves tubulin polymerization and microtubule stabilization. What is needed are synthetic analogs of sarcodictyin A and B, as well as eleutherobin, having enhanced bioactivity, and synthetic methods for producing these natural products and their bioactive analogs. Summary of the Invention: The invention is directed to bioactive analogs of eleutherobin, eleuthosides A and B, and sarcodictyin A and B, and to their synthesis and use for promoting tubuiin assembly and/or stabilizing microtubules. More particularly, an important aspect of the invention is directed to analogs of eleutherobin, eleuthosides A and B, sarcodictyin A and B. Preferred analogs are represented by the following formula [A]: Preferred R- | radicals in the above structure include the radicals -OH and -OAc (Ac = acetyl) or any radical represented by the following structures: Preferred R2 radicals include the following: -OH, -0(0-^6 alkyl), -OCH2CF3, -O-. ' so-propyl, -O-tert-butyl, -O-benzyl, -OCH 2 CH=CH 2 , -OCH 2 CCH, -O(CH 2 )2-OH, -NHMe, -NMe 2 , -NHEt, -NEt 2 , -NH-n-propyl, -N-(propyl) 2 , -NH-/so-propyl, -N-(butyl)2, -NH-benzyl, -N-benzy^, -SH, -SMe, -SEt, -S-n-propyl, -S-/so-propyl, -S-n-butyl, -S-benzyl, and -S-phenyl (Me = methyl, Et = ethyl). Preferred R 3 radicals include the following: -CH OC(O)CH3, -CH2OC(O)-phenyl, -CH 2 OC(O)O-CH 3 , -CH 2 OC(O)NH-phenyl, -CH 2 -OH, -CH(O), -CH 2 -O-tri-isopropylsilyl, -CH 2 O-Ac, -CH 2 -F, -CH 2 N 3 , -CH 2 NAc, -CH 2 NBz, C(O)-O(C r C 6 alkyl), -C(O)-CH 2 CF 3 , -C(O)-CH 2 CHCH2, -C(O)- O-CH 2 CH 2 CI, -C(0)0(CH 2 )2CH 2 CI, -C(O)O(CH 2 ) 2 CH(CH 3 ), -C(O)CH 2 Ph, -C(O)CH 2 -phenyl-OMe, -CH 2 -O-tetrahydropyran, -CH 2 -O-C(O)CHCI 2 , -CH2-O-C(O)-CCI 3 ,-CH2-O-C(O)CHBr 2 , -CH 2 -O-C(O)-CF 3 , -CH 2 -O-C(O)CHPh2, EtC(O)-O-CH 2 -, CH 2 =CHC(O)-O-CH 2 -, HC CC(0)-O-CH 2 -, n-propyl-C(O)-O-CH 2 -, /-PrC(O)-O-CH 2 -, cyclopropyl-C(O)-O-CH 2 -, n-BuC(O)-0-CH 2 -, /-BuC(O)-O-CH 2 -, f-BuC(0)-0-CH 2 -, cyc/o-C 6 H 1 1 C(O)-O-CH 2 -, phenyl-O-CH 2 -, 2-furyl-C(O)-O-CH 2 -, PhCH=CHC(O)-O-CH 2 -, 2-thiophene-C(O)-O-CH 2 -, (C C 6 alkyl)-O-CH 2 -, /-propyl-O-CH 2 -, allyl-O-CH 2 -, benzyl-O-CH 2 -, AcOCH 2 CH 2 -O-CH 2 -, -COOH, -COO-(C r C 6 alkyl), -COO-/-propyl, -COO-f-butyl, -COO-benzyl, -COOCH 2 CH=CH 2 , -COO-CH 2 C CH, -COO-cyc/o-C 6 H- | ! , -CONHBn, -CONH(C r C 6 alkyl), -CONH-propyl, and - COO-C3H17; and a radical selected from the group represented by the following structures: (Me = methyl, Et = ethyl, Ac = acetyl, Bz = Bn = benzyl, i-Pr = iso-propyl, n-Bu = n-butyl, i- Bu = iso-butyl, t-Bu = tert-butyl) Preferred R 4 radicals include the following: -OH, -OAc, 2-CI-AcO-, CCI 3 C(O)O-, 2-Br-AcO-, CF 3 C(O)O-, 2-phenyl-AcO-,(C r C 6 alkyl)-C(O)O-, CH 2 =CHC(O)O-, HC CC(O)O-, /-propyl-C(O)O-, cyc/o-propyl-C(O)O-, -butyl-C(O)O-, f-butyl-C(O)O-, cyclo-CQ ^ C(0)0-, phenyl-O-, 2-furylC(O)O-, PhCH=CHC(O)O-, and 2-thiophene-C(O)O-. Preferred R5 radicals include -OAc and -OH. Preferred RR radicals include -OAc and -OH. Preferred R7 radicals include -H and -methyl. Preferred R3 radicals include -OAc, 2-CI-AcO-, CCI 3 C(O)O-, 2-Br-AcO-, CF 3 C(O)O-, 2-phenyl-AcO-, (C r C 6 alkyl)-C(O)O-, CH 2 =CHC(O)O-, HCCC(O)O-, /-propyl-C(O)O-, cyc/o-propyl-C(O)O-, /-butyl-C(O)O-, f-butyl-C(0)0-, cyc/o-C 6 H 1 - ( C(O)O-, phenyl-O-, 2-furylC(O)O-, PhCH=CHC(O)O-, and 2-thiophene-C(O)O-. However, the following provisos pertain: R 3 cannot be simultaneously -CO -methyl or -CO 2 -ethyl; if R-, is and R 2 is -O-methyl, then R 3 cannot be wherein R4 is -OAc, R5 is hydroxy, Rg is hydroxy, and Ry is hydrogen; then R 3 cannot be wherein R 4 is -OAc, R 5 is hydroxy, Rg is -OAc and Ry is hydrogen; and, then Ro cannot be wherein R 4 and R 5 are -OAc, Rg is -OH, and Ry is hydrogen. Another aspect of the invention is directed to a first advanced intermediate (see especially compound III*, Scheme 2, see below) represented by the following structure: Preferred R-- and R 3 radicals are the same as described above for the analogs of sarcodictyin A and B and eleutherobin above, except that none of the provisos pertain. Another aspect of the invention is directed to a second advanced intermediate (especially compound II*, Scheme 2, se below) represented by the following structure: Preferred R-- and R 3 radicals are the same as described above for the analogs of sarcodictyin A and B eleutherobin above, except that none of the provisos pertain. Another aspect of the invention is directed to a method for cyclizing the above described first advanced intermediate (especially compound III*, Scheme 2, see below) for producing the above described second advanced intermediate (especially compound II*, Scheme 2). The method employs the step of cyclizing the first advance intermediate for producing the second second intermediate. Another aspect of the invention is directed to a method for cyclizing the above described second advanced intermediate (especially compound II*, Scheme 2, see below) for producing a third advanced intermediate (especially compound I, Scheme 2). The third advanced intermediate may be represented by the following structure: Preferred R-- and R 3 radicals are the same as described above for the analogs of sarcodictyin A and B eleutherobin above, except that none of the provisos pertain. The method employs the step of cyclizing the second advanced intermediate for producing the third advanced intermediate. Preferred analogs of eleutherobin, eleuthosides A and B, sarcodictyin A and B may then be produced by substitution of R 2 onto the third advanced intermediate. Detailed Description of the Invention The present invention relates to sarcodictyin A and B, eleutherobin, sarcodictyin analogs, eleutherobin analogs, libraries of both sarcodictyin and eleutherobin analogs, and methods for producing such compounds using solid phase and solution phase chemistries. The invention is directed analogs derived from the total synthesis of sarcodictyins A and B, eleutherobin and eleuthosides A (5) and B (6), the absolute stereochemistry of eleutherobin (4), and the construction of a number of analogs of these compounds. A further embodiment of the invention is directed to solid phase chemistry that provides the generation of a combinatorial sarcodictyin library and its biological evaluation leading to the discovery of analogs possessing higher antitumor potencies than those of the natural products. The gained knowledge provides important information regarding the structure activity relationships within the sarcodictyin-eleutherobin molecular framework and sets the stage for further advances in the field. In this disclosure, the following abbreviations have the following meanings: Me stands for methyl; Et stands for ethyl; i-Pr is isopropyl; n-Pr is n-propyl; t-Bu, tert-Bu or l Bu stands for tert-Butyl; i-Bu is isobutyl; Bz is benzyl; Bn is benzyl; Ph is phenyl; c-Pro is cyclopropyl; c-Bu is cyclobutyl; Ac is acetyl; further abbreviations are self-evident or explained where they are used within this text. Preferably, the invention relates to a compound of formula [A] wherein: R is a radical selected from the group consisting of -O-Me, -O-Et, and -O-CH CF 3 ; and R 3 is is a radical selected from the group consisting of -C(O)-O-Me, -C(O)-O-Et, -C(O)-O-π-propyl, -C(O)-O-n-butyl, -C(O)-(CH 2 ) 3 -CH 2 -Phe, -C(O)-O-CH 2 CH 2 OBn, -C(O)-NHMe, -C(O)-anthracen-9-yl, -C(O)-O- CH 2 CH=CH 2 , -C(O)-O-(CH 2 ) 2 CH 2 CI, and -C(O)-NH-benzyl. More preferably, the invention relates to a compound of the formula [A] wherein Ri is as defined in the preceding pararaph, R 2 is a radical selected from the group consisting of -O-Me, -O-Et, and -O-CH 2 CF 3 ; and R 3 is is a radical selected from the group consisting of -C(O)-O-Me, -C(O)-O-Et, -C(O)-O-n-propyl, -C(O)-O- CH 2 CH=CH 2 , -C(O)-O-(CH 2 ) 2 CH 2 CI, and -C(O)-NH-benzyl. Still more preferably, the invention relates to a compound of the formula [A] wherein Ri is R 2 is -O-methyl or -O-ethyl, and R 3 is -C(O)-methyl, -CH(OMe) 2 or -C(O)-NH-benzyl. More preferably, the invention also relates to the compound of the formula [A] wherein Ri is R 2 is -O-methyl or -O-ethyl, and R 3 is -C(O)-O-methyl, -C(O)-O-ethyl, -C(O)-O-n-propyl, -C(O)-O-n-butyl, -C(O)-O-CH 2 CH 2 -CI, -C(O)-O-(CH 2 ) 3 -CH 2 -phenyl, -C(O)-O-CH 2 CH 2 -O-benzyl, -C(O)-O-CH 2 -CH=CH 2 , CH(OMe) 2 , - C(O)-NH-methyl or -C(O)-O-anthracen-9-ylmethyl. Most preferably, the invention relates to the compounds 600, 730-750 and/or 850 as described in the examples, or to the compounds 600, 610, 630, 660 - 700, 730, 760, 850 and/or 920 as described in the examples. Most preferred are the compounds 600, 610, 670 and/or 680. The compounds of the formula [A], including their salts, if any salt-forming groups are present, may also be obtained in the form of hydrates, or their crystals may, for example, include the solvent used for crystallisation. The invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further jn situ. In the process of the present invention those starting materials are preferably used which result in the compounds of formula I described at the beginning as being especially valuable. Special preference is given to reaction conditions that are analogous to those mentioned in the Examples. Pharmaceutical Preparations The invention relates also to a method of treating warm-blooded animals suffering from a proliferative, especially a tumor disease, especially a disease that is responsive to the inhibition of tubuiin depolymerisation, which method comprises administering, to warmblooded animals requiring such treatment, an amount that is effective in inhibiting tumors of a compound of formula I or of a pharmaceutically acceptable salt thereof, or the use of a compound of the formula I for such treatment. The invention relates also to the use of a compound of formula I or of a pharmaceutically acceptable salt thereof in the inhibition of protein kinase C in warm-blooded animals or in the preparation of pharmaceutical compositions for use in the therapeutic treatment of the human or animal body. Depending on the species, age, individual condition, mode of administration and the particular clinical picture, effective doses, for example daily doses of approximately 0.01 -1000mg, especially 0.1- 500mg, are administered to a warm-blooded animal of approximately 70kg body weight. The invention relates also to pharmaceutical compositions comprising an effective amount, especially an amount effective in the prophylaxis or treatment of one of the above-mentioned disorders, of the active ingredient together with pharmaceutically acceptable carriers that are suitable for topical, enteral, for example oral or rectal, or parenteral administration and that may be inorganic or organic, solid or liquid. There are used for oral administration especially tablets or gelatin capsules that comprise the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerol, and/or lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Tablets may also comprise binders, for example magnesium aluminum silicate, starches, such as corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegrators, for example starches, agar, alginic acid or a salt thereof, such as sodium aiginate, and/or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners. It is also possible to use the pharmacologically active compounds of the present invention in the form of parenterally administrable compositions or in the form of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions which, for example in the case of lyophilized compositions that comprise the active ingredient alone or together with a carrier, for example mannitol, can be made up prior to use. The pharmaceutical compositions may be sterilized and/or may comprise excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical compositions, which may, if desired, comprise other pharmacologically active substances, such as antibiotics, are prepared in a manner known perse, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes, and comprise approximately from 1% to 100%, especially from approximately 1 % to approximately 20%, active ingredient(s). The following examples are to illustrate the invention - they are not thought to limit the scope thereof in any way. Example I. Total Synthesis of Sarcodictyins A and B This example provides the total synthesis of cytotoxic marine natural products possessing tubuiin polymerization and microtubule stabilization properties, sarcodictyins A (7) and B (8). Two related approaches to these target molecules have been developed, both utilizing (+)- carvone (9) as starting material. The first approach involves a stereoselective construction of acetylenic aldehyde 27 (Scheme 4, see below) while the second approach proceeds through a more direct but less selective sequence to the similar intermediate 36 (Scheme 6, see below). Both strategies involve ring closures of the acetylenic aldehyde precursors to 10-membered rings under basic conditions followed by elaboration and selective reduction of the acetylenic linkage to a cis double bond. This promotes bridging to form the required tricyclic skeleton of the sarcodictyins (27→ 37→ 38→ 39→ 4, Scheme 7, see below, and 37→ 44→ 45→ 46→ 47→ 42, Scheme 9, see below) and (36→4→45, Scheme 10, see below). Installation of the (E)-Λ/(6')-methylurocanic acid residue is achieved by esterification with mixed anhydride 52, while the C-3 ester moieties are installed by standard deprotection, oxidation, and esterification procedures. Retrosynthetic Analysis and Strategy: The general structures of sarcodictyins (I*, Scheme 2) are characterized by a rigid tricyclic framework from which a number of appendages branch out. Scheme 2: Retrosynthetic analysis of the core structure of eleutherobin (4), eleuthosides A (5) and B (6) and sarcodictyins A (7) and B (8). Ra-C(O)-O- prefereably has the corresponding meanings of R 3 as defined for formula [A]; Rb-O- preferably has the corresponding meanings of R 2 as defined for formula [A]; and Rc-O- preferably has the corresponding meanings of Ri as defined for formula [A]. (A) = acetylide aldehyde addition; (B) = acetylide- ketone addition; and (C) = Knoevenagel condensation: Prominent amongst these appendages are the carboxylate group at C-3, the hydroxyl group at C-4, and the ester group at C-8 carrying the (E)-Λ/(6)-methylurocanic acid residue. The bridging oxygen involved in the lactol functionality at C-4 allows a strategic disconnection that unravels the [6.2.1 ]-bicyclic structure of I into the 10-membered ring II*. The latter structure is expected to spontaneously collapse back into I* in the synthetic directions. The 5,6-c/s-double bond in II* can be derived from the corresponding acetylene moiety whose disconnection at C4-C5 via a retro acetylide-aldehyde addition leads to open-chain acetylenic aldehyde III*. Two further disconnections, indicated in structure III* through retro ace- tylide-ketone addition and Knoevenagel condensation, furnish intermediate IV* whose structure is highly suggestive of (+)-carvone (9). This retrosynthetic analysis leads to a strategy whose execution results in efficient total synthesis of both sarcodictyins A (7) and B (8). The sequence can be divided in three subsequences: the construction of the key cyclization precursors, the cyciization and formation of the tricyclic framework and the construction of the remaining side-chains. Construction of Cyclization Precursors 27 and 36 The synthetic plan calls for the initial construction of cyclization precursors of general formula (III*, Scheme 2). Consideration of protecting groups and possible routes define structure 27 (Scheme 4, see below) as a subtarget and compound 14 (Scheme 3, see below) as a key intermediate required for its construction. The appeal of (+)-carvone (9) as a starting material for this synthesis is considerably enhanced by the work of Trost et al. J. Am. Chem. Soc. 1991 , 113, 670-672 who described its conversion to compound 13 (Scheme 3). Thus, following a modification of the communicated protocols 13 is prepared as shown in Scheme 3. Scheme 3: Synthesis of key intermediate (14). Reagents and conditions: a) 1.2 equivalents of H 2 O 2 , 0.3 equivalents of NaOH, methanol, 2 h, 0°C; b) H 2 , 0.005 equivalents of PtO 2 , ethanol, 12 h, 25°C, 87% for two steps; c) 1.4 equivalents of LDA, 5.0 equivalents of CH 2 O, THF, -78 to 0°C, 2 h; d) 1.2 equivalents of TBSCI, 4.0 equivalents of triethylamine, CH 2 CI 2 , 12 h, 53% for two steps; e) 1.2 equivalents of L-selectride, THF, -78°C, 2 h, 93%; f) 1.2 equivalents of MsCI , 2.5 equivalents of triethylamine, CH2CI2, 0°C, 0.5 h; g) 5.0 equivalents of Na-naphthalenide, THF, 0°C, 0.5 h, 85% for two steps; h) 40 equivalents of CH 3 C(OEt) 3 , 0.1 equivalents of n-butyric acid, 170°C, 72 h, 74%; i) 1.2 equivalents of DIBAL, CH 2 CI 2 , -78°C, 0.5 h, 97%. LDA = lithium diisopropylamide, TBS = fert-butyl- dimethylsilyl, MsCI = methanesulfonyl chloride, DIBAL = diisobutylaluminum hydride: Epoxidation of (+)-carvone under basic hydrogen peroxide conditions followed by hydroge- nation of this exocyclic double bond gives 10 in 87% overall yield. Treatment of 10 with LDA (for abbreviations see description of schemes) followed by quenching with formaldehyde and silylation of the resulting alcohol furnishes silylether 11 in 53% overall yield. Stereoselective L-Selectride® reduction of the ketone functionality in 11 leads to 12 (93%). Subsequent mesylation followed by reduction with sodium naphthalenide provides allylic alcohol 13 (85% overall). Finally, exposure of 13 to CH 3 C(OEt) 3 and t7-PrCO 2 H furnishes, via Claisen rearrangement, the expected ethyl ester, which is cleanly reduced with DIBAL to produce aldehyde 14 (72% yield, two steps). The stereoselective conversion of 14 to 27 is shown in Scheme 4. Scheme 4: First generation synthesis of acetylene-aldehyde compound 27. Reagents and conditions: a) 1.5 equivalents of (EtO) 2 P(O)CH 2 CO 2 Et, 2.0 equivalents of NaH, THF, 0°C for 1 h, then 25°C for 4 h, 100%; b) 4.0 equivalents of DIBAL, CH 2 CI 2 , -78°C, 2 h, 91%; c) 0.2 equivalents of Ti(O/Pr)4, 0.24 equivalents of diethyl L-tartrate, 2.0 equivalents of t- BuOO , 4 A MS, CH 2 CI 2 , -20°C, 8 h, 91 %; d) 5.0 equivalents of MsCI, 6.0 equivalents of triethylamine, CH 2 CI 2 , -20°C, 1 h; e) 5.0 equivalents of sodium naphthalenide, THF, 0°C, 10 min, 90% for two steps; f) 5.0 equivalents of PMBOC(=NH)CCI 3 , 1.0 equivalent of PPTS, CH 2 CI 2 , 25°C, 48 h, 89% based on ca. 50% conversion; g. 1.1 equivalents of Hg(OAc) 2 , methanol, 25°C, 12 h; then 1.0 equivalent of Li 2 PdCl4, 3.0 equivalents of CuCI 2 , methanol, 55°C, 3 h, 65%; h) 15 equivalents of HCCMgBr(0.5 M in THF), CH2CI2:THF(3:1 ), -78 to 25°C, 12 h; i) 4.0 equivalents of TBAF, THF, 25°C, 1 h, 72% for two steps, ds ratio ca. 7:1 ; j) 1.5 equivalents of Dess-Martin periodinane, 20 equivalents of pyridine, 20 equivalents of NaHCO 3 , CH2CI2, 0 to 25°C, 4 h; k) 30 equivalents of NCCH COOEt, 4.0 equivalents of β- alanine, 95% ethanol, 25°C, 72 h; I) 5.0 equivalents of TMSOTf, 10 equivalents of /Pr 2 NEt, CH 2 CI 2 , -78°C, 10 min, 71 % for three steps; m) 10 equivalents of DIBAL, CH 2 CI 2 , -78°C for 7 h then -40°C for 1 h, 80%; n) 10 equivalents of TIPSOTf, 20 equivalents of ethyl-diiso- propyl-amine, CH 2 CI 2 , -78°C, 1 h, 91 %. TBS = .-Butyldimethylsilyl; DIBAL = diisobutylalu- minum hydride; PMB = p-methoxybenzyl; PPTS = pyridinium p-toluenesulfonate; TMS = tri- methylsilyl; TIPS = triisopropylsilyl; Ms = methanosulfonyl; TBAF = tetra-n-butylammonium fluoride; D-M [O] = Dess-Martin oxidation; Tf = trifluoromethanesulfonate; MS = molecular sieves; THF = tetrahydrofuran: Thus, olef ination of aldehyde 14 with triethylphosphonoacetate proceeds quantitatively in the presence of NaH to afford ethyl ester 15. DIBAL reduction of 15 gives allylic alcohol 16 in 91 % yield and subsequent Sharpless asymmetric epoxidation (diethyl L-tartrate) furnishes epoxide 17 (91 % yield). The transformation of epoxide 17 to allylic alcohol 19 is accomplished via mesylate 18 in 90% overall yield. Protection of 19 as a PMB-ether [PMBOC(=NH)CCI 3 , PPTS, 89% yield based on ca. 50% conversion] followed by sequential treatment with Hg(OAc) 2 and Li 2 PdCl4-CuCI 2 l 3 furnishes methyl ketone 21 (65% yield). Chelation-controlled addition of HCCMgBr (excess) to ketone 21 , followed by desilylation with TBAF gives acetylenic diol 22 as the major diastereoisomer (72% yield, ca. 7:1 de). Attempted oxidation of alcohol 22 to aldehyde 23 with excess Dess-Martin reagent results in the formation of lactone Z (Scheme 5), m.p.5120-121 C (diethyl ether-hexanes) in 60% yield. Scheme 5: Synthesis of Z (the absolute stereochemistry of advanced intermediate 22 is deduced from the X-ray diagram of Z). a) 3.0 equivalents of Dess-Martin periodinane, 20 equivalents of sodium bicarbonate, methylene chloride 0 to 25°C, 12h, 70%: The serendipitous preparation of this crystalline compound allowed the assignment of relative stereochemistry within 22 and subsequent intermediates (by x-ray crystallographic analysis). Controlled oxidation of 22 with 1.5 equivalents of Dess-Martin reagent in the presence of pyridine and NaHCO3 leads to the desired aldehyde 23 in good yield. Aldehyde 23 is subjected to Knoevenagel condensation conditions with ethyl cyanoacetate in the presence of β-alanine leading, after silylation with TMSOTf and /-Pr 2 NEt, to the (E)-α,β-unsaturated cya- noester 25 via 24 (in 71 % overall yield). The geometry of the cyanoester-bearing double bond is confirmed by successful ring closure to intermediate 37 (vide infra, Scheme 7). A highly regioselective reduction of the cyanoester moiety of 25 is effected with DIBAL to afford hydroxy-aldehyde 26 in 80% yield. Finally, protection of the primary alcohol in 26 with TIPSOTf and /-Pr2NEt gives the targeted protected acetylenic aldehyde precursor 27 in 91 % yield. A second, less stereoselective but more direct, route to a cyclization precursor acetylenic aldehyde 36 is also undertaken, as shown in Scheme 6. Scheme 6: Second generation synthesis of acetylene-aldehyde compound 36. Reagents and conditions: a) 2.0 equivalents of CH 2 =CH(OEt), 1.8 equivalents of t-BuLi (1.7 M in THF), THF, -78 to 0°C, 1 h; then cool to -78°C and add 14 in THF; then slowly warm to - 40°C; b) cone. H 2 SO 4 , diethyl ether, 25°C, 2 min, 82% for two steps as a ca. 1.25:1 mixture of diastereoisomers; c) 5.0 equivalents of ethynylmagnesium bromide (0.5 M in THF), THF, -78 to 20 °°C, 14 h, 76%, 29 (43%) plus 7,8-diastereoisomer (33%); d) 29, 2.0 equivalents of TBAF (1.0 M in THF), THF, 0 to 25°C, 1 h, 92%; e) 5.0 equivalents of TESOTf, 10 equivalents of triethylamine, CH 2 CI , 25°C, 2 h, 100%; f) 0.1 equivalents of PPTS, methanol:CH CI 2 , (3:1 ), 25°C, 45 min, 98%; g) 0.05 equivalents of TPAP, 1.5 equivalents of NMO, CH 2 CI 2 , 4 A MS, 1.5 h, 98%; h) 30 equivalents of ethyl cyanoacetate, 4.0 equivalents of β-alanine, 95% ethanol, 72 h, 50°C, 95%; i) 10 equivalents of DIBAL, hexanes, -78°C for 6 h, then -40°C for 1 h, then -10°C for 1 h, 90%; j) 5.0 equivalents of TIPSOTf, 10 equivalents of iPr 2 NEt, CH 2 CI 2 , -78°C, 1 h, 93%. THF = tetrahydrofuran, TBAF = tetra-n-butylammonium fluoride, TESOTf = triethylsilyl trifluoromethanesulfonate, PPTS = pyridinium p-toluenesulfonate, TPAP = tetra-n-propylammonium perruthenate, NMO = 4-methylmorpholine N-oxide, MS = molecular sieves, DIBAL = diisobutylaluminum hydride, TIPSOTf = triisopropylsilyl trifluoromethane sulfonate: Thus, aldehyde 14 (Nicolaou et al. J. Am. Chem. Soc. 1997, 119, 11353-1 1354) is reacted with 1 -ethoxyvinyllithium followed by exposure to acid to afford a 1.25:1 mixture of C8-epi- meric hydroxyketones 28 in 82% overall yield. This mixture is then reacted with excess ethynyl magnesium bromide in a stereoselective manner, affording a chromatographically separable mixture of the two epimeric acetylenic diols, 29 (43% yield) along with it C7,C8- diastereoisomer (33% yield). Removal of the silyl protecting group from 29 is accomplished by exposure to TBAF furnishing, after flash column chromatography, the pure triol 30 (92%). The identity of 30 is proven by comparison to an authentic sample obtained from 22 (whose structure is unambiguously proven by x-ray analysis as discussed above). The conversion of 30 to aldehyde 33 requires a sequence defined by intermediates 31 (persilylation with TESOTf -triethylamine, 100% yield) and 32 (selective desilylation with PPTS in methanol, 98% yield), and oxidation of the latter compound with TPAP-NMO in CH 2 CI (98% yield). The Knoevenagel condensation of 33 with ethyl cyanoacetate proceeds smoothly as described above for 33 furnishing (E)-α,β-unsaturated-cyanoester 34 (95% yield) whose DIBAL reduction gives, regioselectively, hydroxyaldehyde 35 (90% yield). Silylation of 35 with TIPSOTf and /-Pr 2 NEt finally leads to the desired acetylenic aldehyde precursor 36 in 93% yield. Cyclization and Formation of Tricyclic Framework: The first approach to sarcodictyins involves key intermediate 27 and has as its initial subtar- get tricyclic compound 42 (Scheme 7). Scheme 7: First generation synthesis of the sarcodictyin tricyclic core structure 42. Reagents and conditions: a) 1.5 equivalents of LiHMDS, THF, 25°C, 10 min; b) 2.5 equivalents of Dess-Martin periodinane, 20 equivalents of NaHCOs, CH 2 CI 2 , 0 to 25°C, 4.5 h, 85% for two steps; c) 1.0 equivalent of PPTS, methanol, 25°C, 30 min, 94%; d) 0.3 equivalents of Lindlar's catalyst, H 2 , toluene, 25°C, 20 min, 75% for 40, plus 15% for 5,6-dihydro analog; e) 1.0 equivalent of PPTS, methanol, 25°C, 10 min, 100%; f) 10 equivalents of Na - liquid NH 3 , -78°C; then add 41 in THF-ethanol, 5 min, 95% yield, ca. 2 :1 mixture of 42 and 5,6- dihydro-analog 43. THF = tetrahydrofuran; LiHMDS = lithium bis(trimethylsilyl)amide; PPTS 41 The ring closure of 27 is effected by the action of LiHMDS in THF at 25 C yielding the expected 10-membered ring alcohol (mixture of two isomers) whose oxidation with Dess- Martin reagent leads to eneynone 37 in 85% overall yield. The TMS group is then removed from 37 by exposure to PPTS in methanol furnishing alcohol 38 in 94% yield. Hydrogenation of eneynone 38 in the presence of Lindlar's catalyst results in the formation of tricyclic system 40 (75% yield), presumably via spontaneous collapse of the initially formed dienone 39. Quantitative conversion of hemiketal 40 to its methoxy derivative 41 is effected by exposure to PPTS in methanol. Removal of the PMB group from 41 for the purposes of side-chain attachment is carried out by Na in liquid NH3 (THF-ethanol) and furnishes the targeted tricyclic system 42 along with its C5-C6 saturated counterpart, compound 43 (95% combined yield, ca. 2:1 ratio). A slightly modified sequence is presented in Scheme 9. Scheme 9: Alternative route to tricyclic core 42. Reagents and conditions: a) 2.0 equivalents of DDQ, CH 2 CI 2 :H 2 O (18:1 ), 25°C, 0.5 h, 80%; b) 1.0 equivalent of PPTS, methanol, 25°C, 1 h, 80%; c) 0.05 equivalents of [Rh(nbd)(dppb)]BF 4 , H 2 , acetone, 25°C, 10 min; d) 0.5 equivalents of PPTS, methanol, 25°C, 10 min, 80% for two steps. DDQ = 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone; PPTS = pyridinium p-toluenesulfonate; nbd = 2,5-norbornadiene, dppb = 1 ,4-bis(diphenylphosphino)butane: Specifically, removal of the PMP-ether from 37 is accomplished after its treatment with DDQ in aqueous CH 2 CI 2 resulting in the formation of hydroxy ynone 44 in 80% yield. Liberation of the propargylic hydroxy moiety is performed by the action of PPTS in methanol furnishing diol 45 in 80% yield. The employment of [Rh(nbd)(dppb)]BF4 as the hydrogenation catalyst proves to be beneficial since tricyclic alcohol 42 is isolated in 80% yield after the formation of the methyl ketal functionality (PPTS, methanol). The significant extent of reduction of the C5-C6 double bond in our first approach, which is observed in the hydrogenation of 38 to 40, prompts the second general approach to the sarcodictyins which involves intermediate 36 (Scheme 10) carrying different protecting groups for easier removal. Its conversion to the key dihydroxy ynone 45 is detailed in Scheme 10. Scheme 10: Second generation synthesis of alkynone 45. Reagents and conditions: a) 2.0 equivalents of LiHMDS, THF, -20°C, 20 min; b) Dess Martin oxidation: 2.0 equivalents of Dess-Martin periodinane, 6.0 equivalents of NaHCO 3 , 6.0 equivalents of pyridine, CH 2 CI 2 , 0°C, 1 h, 89% for two steps; c. 5.0 equivalents of triethylamine-3HF, THF (1 :5), 25°C, 1.5 h, 78%. LiHMDS = lithium bis(trimethylsilyl)amide; THF = tetrahydrofuran: 36 48 49 Thus, treatment of 36 with LiHMDS in THF at -20 C results, as before, in the formation of the 10-membered ring alcohol 48 (mixture of diastereoisomers) which is immediately oxidized with Dess-Martin reagent to eneynone 49 (89% yield for two steps). Selective removal of both TES groups is achieved by exposure to triethylamine- » 3HF (78% yield) furnishing diol 45 and setting the stage for selective hydrogenation and internal cyclization. To this end, the experiments summarized in Scheme 8 and Table 1 are carried out using acetylenic substrates 37 (Scheme 7), 38 (Scheme 7) and 45 (Scheme 10) and a variety of hydrogenation conditions. Scheme 8 and Table 1 : Selective hydrogenation studies for the construction of the sarcodictyin tricyclic core. Reagents and conditions: (A) (= condition in Table 1); a) 1.0 equivalent of PPTS, methanol, 25°C, 30 in, 94%. b) Lindlar's cat. = Pd/CaCO 3 /Pb; PPTS = pyridinium p-toiuenesulfonate; nbd = 2,5-norbomadiene; dppb = 1 ,4-bis(diphenylphosphino)butane. Scheme 8: A- 4 400:: RR == PMB, Rk = H 49 41 : R = PMB, Rk = Me 4 47:: R K == H n,, Rk = H π+ 42: R = H, Rk The exploration leads quickly to the adoption of the rhodium complex [Rh(nbd)(dppb)]BF4 in acetone solution as the catalyst of choice (ca. >10:1 ratio in favor of the desired product 42 which iss obtained in 80% yield). With the solution of the reduction problem at hand, the only remaining task is the construction of the side-chains before the final targets are reached. Construction of the Side Chain and Completion of the Synthesis: The attachment of the C-8 ester functionality, a mixed anhydride protocol is adopted (see Nicolaou et al. Angew. Chem. Int. Ed. Engl. 1997, 36, 2520-2524), see Scheme 1 1. Scheme 11 : Total synthesis of sarcodictyins A (7) and B (8); a) 1.05 equivalents LiOH»H 2 O, THF:H 2 O, 1 :1 , 25°C, 12 h, 100%; b) 1.1 equivalents t-BuC(0)C\, THF, 25°C, 12 h, 75%; c) 2.0 equivalents of 52, 20 equivalents of triethylamine, 1.0 equivalent of 4-DMAP, CH 2 CI , 25°C, 48 h, 83%; d) 2.0 equivalents of TBAF, THF, 25°C, 2 h, 100%; e) 2.0 equivalents of Dess-Martin periodinane, 10 equivalents of NaHCO 3 , CH CI 2 , 25°C, 0.5 h, 100%; f) 6.0 equivalents of NaCIO 2 , 3.0 equivalents of NaH 2 PO4, 50 equivalents of 2-methyl-2-butene, THF, t-BuOH, H O, 2 h; g) excess CH 2 N 2 , diethyl ether, 10 min, 88% for two steps; h) excess CH 3 CH 2 N 2 , diethyl ether, 0.5 h, 89% for two steps; i) 2.0 equivalents of CSA, CH 2 CI 2 :H 2 O (10:1 ), 25°C, 48 h, 80% for 7, 86% for 8. THF = tetrahydrofuran; 4-DMAP = 4- (N,N'-dimethylamino)pyridine; TBAF = tetra-n-butylammonium fluoride; CSA = 10-camphor- sulfonic acid: To this end, ethyl (£)-Λ/(6)-methylurocanate (50, Scheme 11 ; Viguerie et al. Heterocycles 1994, 37, 1561 -1576) is sequentially converted to its sodium salt 51 by the action of NaOH (THF-H20, 100%) and thence to tert-butyl mixed anhydride 52 by treatment with f-BuCOCI in THF (75% yield). Reaction of 42 with 52 in the presence of triethylamine and 4-DMAP results in the formation of ester 53 in 83% yield. For the purposes of completing the side-chain at C-3, a carboxylic acid group is formed at this position as follows: (i) desilylation with TBAF to afford alcohol 54 in 100% yield; (ii) Dess-Martin oxidation to aldehyde 55; and (iii) further oxidation of 55 with NaCIO 2 to furnish 56. Exposure of carboxylic acid to CH 2 N 2 or CH3CH 2 furnishes methoxy-sarcodictyin A (57, 88% overall yield from 54) or methoxy sarcodictyin B (58, 86% overall yield from 54). Finally, sarcodictyins A (7) and B (8) are generated from their respective methoxy derivatives by treatment with CSA in CH 2 CI 2 -H 2 O (80% yield for 7 and 86% for 8). In order to evaluate the importance of the C5-C6 double bond of sarcodictyins for biological activity, C5-C6 dihydrosarcodictyin A (61) is targeted for chemical synthesis. Scheme 12 summarizes an efficient route to 61 from intermediate 45. Scheme 12: Synthesis of C5,C6-dihydro-sarcodictyin A 61. Reagents and conditions: a) 1.0 equivalent of 5% Pd / BaSO , EtOAc, 25°C, 1 h; b) 2.0 equivalents of PPTS, methanol, 25°C, 6 h, 64% for two steps; c) 5.0 equivalents of 52, 20 equivalents of triethylamine, 2.0 equivalents of 4-DMAP, CH 2 CI 2 , 25°C, 48 h, 83%; d) 2.0 equivalents of TBAF, THF, 25°C, 2 h, 100%; e) 2.5 equivalents of Dess-Martin periodinane, 10 equivalents of NaHCOs, CH 2 CI 2 , 25°C, 0.5 h; f) 6.0 equivalents of NaCIO 2 , 3.0 equivalents of NaH PO 4 , 50 equivalents of 2-methyl-2-butene, THF, t-BuOH, H 2 O; g) excess of CH 2 N 2 , diethyl ether, 88% for three steps. PPTS = pyridinium p-toluenesulfonate, 4-DMAP = 4-(Λ/,Λ '-dimethyl- amino)pyridine, TBAF = tetra-n-butylammonium fluoride, D-M [O] = Dess-Martin oxidation: 59 61 60 Thus, hydrogenation of 45 in the presence of 5% Pd/BaSO4 in EtOAc, followed by exposure to PPTS in methanol results in the formation of tricyclic compound 43 (64% overall yield) in which the C5-C6 bond is completely reduced. The construction of the two side- chains proceeds smoothly as described already for compound 42 (Scheme 9) and via compounds 59 and 60 furnishing the desired dihydrosarcodictyin A (61) in excellent overall yield (see Scheme 12). Sarcodictyins A (7) and B (8) and C5-C6 dihydrosarco-dictyin A (61): Two approaches utilize an intramolecular acetylide-aldehyde addition to construct a 10- membered ring, whose elaboration and selective hydrogenation results in the formation of a transient hydroxy-dienone which spontaneously collapses to the tricyclic ring system of sarcodictyins A and B. Appropriate appendage attachments at C-8 and C-15 then lead to completion of the syntheses. The designed strategy allows for a solid phase synthesis, specific analog construction and combinatorial library generation. Solid phase synthesis of sarcodictyins A and B and analogs thereof is described in the following Example II. These studies facilitate the investigation of the chemical biology of sarcodictyins and related compounds. Example II: Solid and Solution Phase Synthesis and Biological Evaluation of Combinatorial Sarcodictyin Libraries: In this example, we disclose (a) the first total synthesis of sarcodictyins A (7) and B (8) by a combination of solution and solid phase methods through the attachment of the common precursors 1880 or 200 on solid support, thus generating conjugates 230 and 240, followed by standard chemical manipulations; (b) the construction of a combinatorial library of sarcodictyins by solution and solid phase chemistry modifying the C-8 ester, C-15 ester and C-4 ketal functionalities, and, therefore, producing analogs of the general structures 330, 370 and 400; (c) the tubuiin polymerization properties of members of the library; and (d) the cytotoxic actions of a selected number of these compounds against a number of tumor cells including Taxol-resistant lines. Several of the synthesized analogs are identified to be of equal or superior biological activities (e.g. 600, 610, 630, 660-700, 730, 760, 850, 920) as compared to the natural products, setting the stage for further developments in the field of cancer chemotherapy. Molecular Diversity Design. Solid Phase Strategy. Inspection of the structure of sarcodictyins A (7) and B (8) reveals the three branches of possible molecular diversification; those emanating from skeletal carbons C-3, C-4 and C-8 (see structure I*, Scheme 2 for numbering). Furthermore, the ready availability of a suitable common intermediate for attachment to a solid support and the potential reactivity of the functional groups at C-3, C-4 and C-8 present an attractive opportunity for the design and construction of a general sarcodictyin library depicted under structure I** (Scheme 13). Scheme 13 illustrates the retrosynthetic analysis of a sarcodictyin library (I). (A) trans- ketalization cleavage; (B) Functional group manipulations; (C) FG chemistry; (D) ester or carbonate formation; (E) Loading. Preferably, R-O- has any of the corresponding meanings of R-, as defined for formula [A]; R'-O- has any of the corresponding meanings of R 2 as defined for formula [A]; and R'" has any of the corresponding meanings of R 3 as defined for formula [A]: IV III LINKER RESIN V Thus, compounds I** are obtained by raπs-ketalization with a variety of alcohols with simultaneous cleavage from the resin II**, whereas the latter structure (II**) can be tailored from III** by various functional group (FG) manipulations at the indicated positions. Structures III**, in turn, could be obtained from IV** by ester or carbamate bond formation. Finally, disconnection of the conjugates IV** unravels possible precursors, sarcodictyin scaffold V**, an appropriate linker VI**, and resin VII** (Scheme 13). Construction of Resins and Substrates for Attachment: In preparation for a solid phase synthesis of sarcodictyins A (7) and B (8) and libraries thereof, the functionalized resins 10, 12 and 14 are designed and constructed as shown in Scheme 14 (Nicolaou et al. Nature (London) 1997, 387, 268-272; Nicolaou et al. J. Am. Chem. Soc. 1998, 120, 5132-5133; Nicolaou et al. Angew. Chem. Int. Ed. Engl. 1997, 36, 2097-2103). Scheme 14: Synthesis of resins 100, 120, and 140 for the loading of the sarcodictyin core on solid phase. Reagents and conditions: a) glutaric anhydride (4.0 equivalents), triethylamine (5.0 equivalents), CH CI , 25°C, 8 h; b) t-BuCOC\ (3.0 equivalents), triethylamine (5.0 equivalents), CH CI , 25°C, 6 h, >90% for two steps; c) 1 ,4-butanediol (4.0 equivalents), NaH (4.0 equivalents), tetrabutylammonium iodide ("n-BuNI") (0.1 equivalents), DMF, 25°C, 15 h, 99%; d) l 2 (4.0 equivalents), Ph 3 P (4.0 equivalents), imidazole (4.0 equivalents), CH 2 CI 2 , 0°C, 4 h, >95%; e) Ph 3 P (10.0 equivalents), 100°C, 15 h, >95%; f) LiHMDS (1.3 equivalents), THF, 25°C, 2 h, >90%. LiHMDS = lithium bis(trimethylsilyl)- amide; THF = tetrahydrofuran; ^ = polystyrene: Thus, hydroxymethyl polystyrene resin (90) is reacted with excess glutaric anhydride in the presence of triethylamine, followed by capping with pivaloyl chloride under the same conditions, to afford resin 100in >90% overall yield. On the other hand, reaction of Merrifield resin (110) with excess of the monosodium alkoxide of 1 ,4-butanediol results in the formation of resin 120 in 99% yield, lodination of the latter (12) with l 2 -Ph 3 P-imidazole then furnishes iodide 130 (>95% yield) which is converted to its phosphonium sait by treatment with Ph 3 P at 100°C (95% yield) and hence to phosphorane 140 (>90% yield) by the action of LiHMDS (for abbreviations see description of Schemes). These resins are then ready for coupling with suitable sarcodictyin scaffolds such as 160, 170, 180 and 200 (Scheme 15). The latter compounds are prepared from the previously synthesized intermediate 47 as shown in Scheme 15. Scheme 15: Synthesis of tethered sarcodictyin cores 160, 170, 180 and 200 from 47. Reagents and conditions: a) PPTS (1.0 equivalent), diol:CH 2 CI 2 (2:1 ), 25°C, 2 h, 91 % for 1 ,2-ethanediol, 94% for 1 ,4-butanediol; b) Acetic anhydride (3.0 equivalents), pyridine (5.0 equivalents), CH CI 2 , 25°C, 1 h, 96%; c) PPTS (1.0 equivalent), 1 ,6-hexanediol (10 equivalents), CH 2 CI 2 , 92%; d) Dess-Martin periodinane (2.0 equivalents), pyridine (5.0 equivalents), NaHCO 3 (10 equivalents), CH 2 CI 2 , 2 h, 96%. PPTS = pyridinium-p-toluene sulfonate: 47 160 : n = 0 b -i 170 : n = 2 200 Thus, coupling of 47 with ethylene glycol or 1 ,4-butane diol in the presence of PPTS results in the formation of compounds 160 (91%) and 170 (94%) respectively. On the other hand, acetylation of 47 furnishes 180 (96%) whose reaction with 1 ,6-hexanediol in the presence of PPTS leads to 190 (92%). Oxidation of 190 with Dess-Martin reagent gives the desired aldehyde 200 in 96% yield. Loading of Sarcodictyin Scaffolds onto the Solid Support. The reaction of sarcodictyin derivatives 160 and 170 with excess functionalized resin 100 in the presence of triethylamine and 4-DMAP leads, unexpectedly, to conjugates 210 and 220 respectively in >95% yield. The surprising fact that derivatives 160 and 170 attach themselves to the resin via their secondary, rather than primary, hydroxyl groups is evident from the resistance of 210 and 220 to undergo cleavage under acidic conditions and the ease by which these scaffolds can be recovered under basic conditions. This leads us to investigate the resins 120 and 140, see Scheme 16. Scheme 16: Loading of sarcodictyin cores to solid supports. Reagents and conditions: a) 100 (5.0 equivalents), triethylamine (10.0 equivalents), 4-DMAP (0.5 equivalents), CH 2 CI 2 , 25°C, 8 h, >95%; then methanol (20 equivalents) b) 120 (10 equivalents), PPTS (1.0 equivalent), 4 A MS, CH 2 CI 2 , 25°C, 48 h, 50%; then cap with MOM-CI (20 equivalents), /Pr 2 NEt (20 equivalents), DMF, 25°C, 24 h; c) 140 (5.0 equivalents), THF, -78 to 25°C, 4 h, >95%; then cap with CH 3 CHO (20 equivalents). 4-DMAP = 4-(dimethylamino)pyridine; PPTS = pyridinium-p-toluene sulfonate, MOM-CI = methoxymethyl chloride; DMF = dimethylformamide; THF = tetrahydrofuran; grey circle = polystyrene: 160: n = 0 210: n = 0 170: n = 2 220: n = 2 200 240 Thus, conjugation of 180 to resin 120 is accomplished in the presence of PPTS to afford 230, but only in 50% yield despite several attempts to drive the reaction to completion with dehydrating agents. In contrast, coupling of aldehyde 200 with resin 140, followed by capping with acetaldehyde, proceeds smoothly to afford conjugate 240 in >95% yield, making this resin a more attractrive starting point for further chemical studies. Solid Phase Synthesis of Sarcodictyins A and B. With resins 230 and 240 in hand, we proceed to investigate their use in the synthesis of a sarcodictyin library. As a prelude to a library construction, and in order to develop the chemistry required for the operation, we first target the naturally occurring sarcodictyins A (7) and B (8). As demonstrated in Scheme 17, both resins perform equally well. Scheme 17: Solid phase synthesis of sarcodictyins A (7) and B (8). a) NaOMe (5.0 equivalents), methanol.THF (1 :3), 25°C, 12 h, >95%; b) 260 (5.0 equivalents), triethylamine (10 equivalents), 4-DMAP (2.0 equivalents), CH 2 CI 2 , 25°C, 48 h, ca. 90%; c) TBAF (10 equivalents), THF, 25°C, 8 h, >95%; d) Dess-Martin periodinane (5.0 equivalents), NaHCO 3 (15 equivalents), pyridine (15 equivalents), CH CI , 25°C, 2 h, 95%; e) NaCIO 2 (12 equivalents), NaH 2 PO (12 equivalents), 2-methyl-2-butene (50 equivalents), THF:f-SuOH:H O (5:5:1 ) 25°C, 48 h, >95%; f) methanol (10 equivalents), DCC (10 equivalents), 4-DMAP (5.0 equivalents), DMF, 25°C, 48 h, ca. 90%; g) CSA (3.0 equivalents), CH 2 CI 2 :H 2 O (2:1), 25°C, 40 h, ca. 75%. Overall yield for sarcodictyin A: ca. 51 % from 240 and ca. 44% from 230. Overall yield of sarcodictyin B: ca. 48% from 240 and ca. 42% from 230. 4-DMAP = 4-(di- methylamino)pyridine; TBAF = tetra-n-butylammonium fluoride; DCC = dicyclohexylcarbodi- imide; THF = tetrahydrofuran; grey circle = polystyrene: 7 8 8 Thus, NaOMe induces deacetylation of 230 or 240 leads smoothly to 250 (>95%) which couples with mixed anhydride 260 in the presence of triethylamine and 4-DMAP to afford conjugate 270 in ca. 90% yield. Desilylation of 270 (>95%), followed by Dess-Martin oxidation (>95%) leads efficiently to aldehyde 280. Further oxidation of 280 with NaCIO 2 (>95%) and esterification of the resulting carboxylic acid with methanol or ethanol in the presence of DCC furnishes, in ca. 90% yield, sarcodictyin A and B conjugates 290 and 300 respectively. Finally, generation of the natural substances (7 and 8) from the corresponding resins is achieved by exposure to CSA in CH CI :H 2 O (2:1 ). The overall yield of sarcodictyin A (7) is ca. 51 % from 240 or 44% from 230 and of sarcodictyin B (8) is 48% from 240 or 42% from 230. The spectroscopic properties of 7 and 8 are identical to those exhibited by authentic samples previously obtained in these laboratories by a solution total synthesis. Construction of a Sarcodictyin Combinatorial Library. The sarcodictyin library shown in Scheme 20 and Table 2, both below, is constructed by a combination of solid phase (Scheme 18) and solution (Scheme 19) methods. For the solid phase chemistry, resin 240 is used because of its excellent profile in terms of formation, efficiency and reactivity performance. Both parallel and combinatorial techniques are applied, the latter utilizing Radiofrequency Encoded Combinatorial (REC) chemistry (Nicolaou et al. Angew. Chem. Int. Ed. Engl. 1995, 34, 2289-2291 ; Moran et al. J. Am. Chem. Soc. 1995, 117, 10787-10788; Nicolaou et al. Angew. Chem. Int. Ed. Engl. 1997, 36, 2097-2103). Scheme 18: Synthesis of a sarcodictyin library on solid phase. Reagents and conditions: a) NaOMe (5.0 equivalents), methanol:THF (1 :3), 25°C, 12 h, >95%; b1) LG-Rm (5.0 equivalents), triethylamine (10 equivalents), 4-DMAP (2.0 equivalents), DMF, 50°C, 48 h, 90-95%; b2) LG-Rm (10 equivalents), DCC (10 equivalents), 4-DMAP (2.0 equivalents), DMF, 50°C, 48 h, 90-95%; c) TBAF (10 equivalents), THF, 25°C, 8 h, >95%; d) LG-Rn (10 equivalents), triethylamine (10 equivalents), 4-DMAP (2.0 equivalents), CH 2 CI 2 , 25°C, 20 h, 70-95%; e) PPTS (3.0 equivalents), methanol, 25°C, 24 h, 60-90%; f) Dess-Martin periodinane (5.0 equivalents), NaHCO 3 (15 equivalents), pyridine (15 equivalents), CH 2 CI 2 , 25°C, 2 h, 95%; g) NaCIO 2 (25 equivalents), KH 2 PO4 (25 equivalents), 2-methyl-2-butene (50 equivalents), THF:.-BuOH:H 2 O (5:5:1 ) 25°C, 48 h, >95%; h) HO-Rp (10 equivalents), DEAD (10 equivalents), Ph 3 P (10 equivalents), THF, 0 to 25°C, 12 h, >95%; i) H 2 N-Rp (10 equivalents), DCC (10 equivalents), 4-DMAP (5 equivalents), DMF, 25°C, 20 h, >95%; j) CSA (3.0 equivalents), HO-Ro, 25°C, 15 h, 60-90%; k. (PhO) 2 PON 3 (10 equivalents), DEAD (10 equivalents), Ph 3 P (10 equivalents), THF, 0 to 25°C, 4 h, >95%; I) Ph 3 P (10 equivalents), H 2 O (30 equivalents), THF, 25°C, 8 h, >95%; m) LG-Rq (10 equivalents), triethylamine (15 equivalents), CH CI 2 , 25°C, 10 h, >90%. LG = leaving group; 4-DMAP = 4-(dimethyl- amino)pyridine; TBAF = tetra-π-butylammonium fluoride; DEAD = diethylazodicarboxylate; DCC = dicyclohexylcarbodiimide; THF = tetrahydrofuran; DMF = dimethylformamide; grey circle = polystyrene: Scheme 18 240 Scheme 18(a) to 18(e) in the following show the details for above-mentioned partial reactions LG-Rm ■ O-Rm : (f) to 18(i) in the following show the details for above-mentioned partial reactions LG-Rn -► O-Rn 18(j) to 18(k) in the following show the details for above-mentioned partial reactions LG-Rq ■ N-Rq In Scheme 18 [including 18(A), 18(B), 18(C) and 18(a) to 18(k)], Ro stands for =H, O-Me, O-Et, O-CH 2 CF 3 and O-n-propyl; O-Rp stands for =-Me, O-Et, O-n-propyl, O-n-butyl, O-CH 2 CF 3 , or for HN-Me, HN-n-propyl, Thus, individual flasks with resin 250 or IRORI Microkans™21 containing resin 250 are utilized to carry out the chemistry summarized in Scheme 18. Thus, 250 (derived by deacety- lation of 240) is reacted with LG-Rn [acid anhydride, acid chloride, carboxylic acid, or isocyanate] under the appropriate coupling conditions to afford a series of esters and cabamates (90-95%) which are deprotected with TBAF, leading to hydroxy esters 310 (>95%). A portion of the reactant (resin or Microkans™, 310) is treated with LG-Rn [acid anhydride, acid chloride or isocyanate] under appropriate coupling conditions to afford, after PPTS-induced cleavage in the presence of HO-Ro (60-90%) a series of sarcodictyins 330 via conjugates 320 (see Scheme 18(A)). A second portion of the reactant 310 is subjected to Dess-Martin oxidation to afford aldehyde resin 340 in >95% yield. Further oxidation of 340 with NaCIO 2 leads to carboxylic acid resin 350 (>95%) which is subjected to coupling reactions with either alcohols [HO-Rp] under Mitsunobu conditions or amines [H 2 N-Rp] under DCC/4-DMAP conditions. The resulting esters or amides (360) are then exposed to acid (CSA) cleavage conditions in HO-Ro, affording sublibrary 370 (60-90%) (see Scheme 18(B)). A third portion of the reactant 31 is converted to azide 380 in >95% yield by the action of (PhO) 2 PON 3 , DEAD and Ph 3 P. Reduction of the azido group in 380 with Ph 3 P-H O gives the corresponding amine (95%) which is coupled with LG-Rq [anhydride or acid chloride] to afford the amide derivatives 390. Compounds 400 are then released from the resins 390 by exposure to PPTS in HO-Ro (60-90%). Each library member is obtained in ca. 1 -5 mg scale and is purified by silica gel chromatography (flash column or thin layer) or HPLC. The rather wide range in yield for the cleavage is attributed to kinetic reasons and/ or instability of the individual products to prolonged exposure to acidic conditions. Due to the low yields obtained for the DCC coupled products on solid phase, a number of sarcodictyin analogs are prepared by conventional solution methods. Specifically, sarcodictyins 420-540 are synthesized as outlined in Scheme 19. Scheme 19: Synthesis of sarcodictyin analogs 480-540 in solution. Reagents and conditions: a) acid Ar-I or Ar-ll or Ar-lll (1.3 equivalents), DCC (2.0 equivalents), 4-DMAP (0.5 equivalents), CH 2 CI 2 , 25°C, 36 h; b) TBAF (2.0 equivalents), THF, 25°C, 1 h, 73% for 420 over two steps, 61 % for 430 over two steps, 79% for 440 over two steps; c) Dess- Martin periodinane (2.5 equivalents), NaHCO 3 (ca. 10 equivalents), CH 2 CI 2) 25°C, 0.5 h, 44% for 450, 40% for 460, 84% for 470; d) NaCIO 2 (6.0 equivalents), NaH 2 PO 4 (3.0 equivalents), 2-methyl-2-butene (50 equivalents), THF:f-SuOH:H 2 O (5:5:1 ), 0°C, 2 h; e) CH 2 N 2 or CH 3 CH 2 N 2 , 0°C, 10 min, 43% for 480 over two steps, 71 % for 490 over two steps, 87% for 500 over two steps; f) acetic anhydride (5.2 equivalents), triethylamine (6.8 equivalents), 4-DMAP (1.6 equivalents), CH 2 CI 2 , 25°C, 2 h, 100%; g) CSA (cat., 10% mol), CH 2 CI 2 :H2O (10:1 ), 25°C, 72 h, 95%; h) DAST (2.0 equivalents), CH 2 CI 2 , -78°C, 3 h, 99%; i) Ph 3 PCHCO 2 Me (1.5 equivalents), benzene, 80°C, 95-98%; j) LiOH (3.0 equivalents), THF:H 2 O (1 :1 ). 25°C, 100%. DCC = dicyclohexylcarbodiimide; 4-DMAP = 4-(dimethylami- no)- pyridine; TBAF = tetra-n-butylammonium fluoride; THF = tetrahydrofuran; CSA = camphorsulfonic acid; DAST = diethylaminosulfur trifluoride *) J. Am. Chem. Soc. 34, 8661- 73 (1998): 420 : Ar-I 450 : Ar = 2-pyrldyl 430: Ar-ll 460 : Ar = 2-rnethyl-thiazol-4-yl 440: Ar-I 11 ° 470: Ar = 2-methyl-oxazol-4-yl a HO d e b 410 450, 490, 500 480 : Ar = 2-pyridyl , R = Me 490 : Ar = 2-methyl-thiazol-4-yl, R = Me 500 : Ar = 2-methyl-oxazol-4-yl , R = Et 520 540 Thus, a number of ester side chains are introduced at C-8 and the appendage at C-4 is modified to include CH 2 OH, CH OAc and CH 2 F. Thus, DCC/4-DMAP assisted coupling of 410 with carboxylic acids Ar-I, Ar-ll and Ar-lll (derived from the corresponding known pyridine, thiazole (Nicolaou et al. J. Am. Chem. Soc. 1997, 119, 7960-7973; Nicolaou et al. J. Am. Chem. Soc. 1997, 119, 7974-7991) and oxazole (Kende et al. Tetrahedron Lett. 1995, 36, 4741-4744) aldehydes by a Wittig olefination-saponification sequence in excellent yields) gives, after TBAF removal of the silicon protecting group, esters 420 (73%), 430 (61 %) and 440 (79%) respectively. Dess-Martin oxidation of these hydroxy esters leads to aldehydes 450 (44%), 460 (40%) and 470 (84%) respectively. Further oxidation of 450, 460 and 470 with NaCIO 2 and treatment of the resulting carboxylic acids with CH 2 N 2 or CH 3 CH 2 N 2 leads to the formation of sarcodictyins 480 (43%), 490 (71 %) and 500 (87%) respectively. The fluorosarcodictyin 52 (K.C. Nicolaou et al., Angew. Chem. Int. Ed. 1998, 37, 1418-1421 ) is generated from the previously synthesized compound 51 (K.C. Nicolaou et al. Angew. Chem. Int. Ed. 1998, 37, 1418-142) by the action of DAST (99%), whereas acetates 53 (K.C. Nicolaou et al. Angew. Chem. Int. Ed. 1998, 37, 1418-1421 ) and 54 are prepared from 51 by sequential treatment with acetic anhydride/triethylamine/4-DMAP and CSA in CH 2 CI 2 :H 2 O as indicated in Scheme 19. Biological Evaluation of Sarcodictyins. The synthesized sarcodictyin library (shown in Scheme 20) is screened for induction of tubuiin polymerization using the filtration colorimetric assay and 100 μM compound at 37 g C (results are listed in Table 3; Bollag et al. Cancer Res. 1995, 55, 2325-2333). Scheme 20 and Table 2: Various structures and tubuiin polymerization properties of sarcodictyin analogs. Scheme 20: 6) These investigations are then followed by cytotoxicity studies with ovarian cancer cells (1 A9) including two taxol-resistant lines (1 A9PTX10 and 1A9PTX22; Giannakakou et al. J. Biol. Chem. 1995, 272, 17118-17125). Experiments showing IC50 values less than 2000nM in any of the tested cell lines are tabulated in Table 3. Table 3 tabulates cytotoxicity data of sarcodictyins with the following tubuiin polymerization and cytotoxicity properties of sarcodictyins: (a) The tubuiin polymerization measurements are performed at 37°C except for adjustments in drug concentration (100 μM) and incubation time (90 min). (b) The cytotoxicity experiments are carried out as previously described (see Giannakakou et al. J. Biol. Chem. 1995, 272, 17118-17125; Nicolaou et al. Angew. Chem. Int. Ed. Engl. 1997, 36, 2097-2103). The data reveal a number of important structure activity relationships (SARs). Thus, preferred compounds 600, 730-750 and 850 exhibit superior tubuiin polymerization properties to those of either sarcodictyins A (7) or B (8). In the cytotoxicity studies compounds 600, 610, 630, 660-700, 730, 760, 850 and 920 that are especially preferred exhibit potencies comparable or higher that those of the natural substances (7 and 8). Particularly striking are the cytotoxicities of the more preferred compounds 600, 610, 670, 680, and in a borader sense also 730, 760, 850 and 920 against the taxol resistant tumor cell lines. Interestingly, the tubuiin polymerization potencies of some of these compounds are not always in line with their cytotoxicity effects (e.g. compounds 610 and 700). These observations suggest an additional mechanism of action for these compounds such as DNA alky- lation. The importance of the C-8 ester side chain becomes apparent by a number of substitutions. Thus, replacing the natural urocanic acid side chain with acetate (compound 1070, Scheme 20, Table 2) or phenyl carbamate (compound 1010 results in high loss of activity. Likewise, substitution of the heterocycle with a phenyl group while maintaining the α,β-unsaturated portion of the ester side chain leads to only negligible biological activity (compound 990). Even the more subtle substitution of the imidazole-derived natural substituent for a pyridine (compound 480, Scheme 20, Tables 2 and 3), thiazole (compound 490) or an oxazole (compound 500) moieties leads to considerable loss of activity, thereby suggesting a role for both nitrogen atoms of the natural products in their mechanism of action. In contrast, modifications at the C-4 ketal center appear more tolerable for biological activity. Thus, replacement of the OH group of the natural products with an OMe moiety results in enhanced biological activity against the taxol-resistant cell lines (compounds 600 and 610), whereas substitution with O-πPr or OCH CF 3 results in an overall decrease of cytotoxicity (compounds 740 and 840). The C-15 reduced compound and derivatives thereof (e.g. compounds 510-530 and 550- 590, Scheme 20, Tables 2 and 3) fail to exhibit strong tubuiin polymerization or cytotoxicity properties, which is rather intriguing, given the potent biological actions of eleutherobin (4) whose C-15 position is reduced and glycosylated. Interestingly, the C-15 dimethyl acetal (compound 730) displays biological activities comparable to those of the natural products (7 and 8), thus, demonstrating that ester functionality is not a requirement for activity. Modification of the alcohol component of the C-2 ester group results in significant modulation of the biological actions of these compounds as compared to the natural products. Thus, substitution of the methyl (compound 600) with an ethyl (compound 610), n-propyl (compound 680) or allyl group (compound 700) results in enhancement of the biological activity. A reversal of the trend is noted with bulkier substituents, such as n-butyl (compound 630) or isopentyl (compound 710). Interestingly, however, the bulky moieties of anthracenyl (compound 920), benzyloxyethyl (compound 690) and 4-butylphenyl (compound 660) exhibit cytotoxicity comparable to, or better than, the natural products (even though their tubuiin polymerization potencies are modest). Scheme 21 summarizes the SARs so far obtained within the sarcodictyin family of compounds. Scheme 21 : Stucture activity relationships (SARs) of sarcodictyins. a) Replacement of side chain with acetate, phenyl carbamate or cinnamoyl ester is not tolerated, b) Replacement of the substituted imidazole heterocycle by a pyridine, thiazole or oxazole leads to reduced activity, c) Methyl and ethyl ketals are well tolerated, whereas propyl or trifluoroethyl ketals are not. d) Esters are more active than the corresponding amides; substitution of the ester group is well tolerated; reduction of the ester to the alcohol and derivatives therof are not tolerated (except for the eleutherobin 4). a. Side chain is crucial for activity d. Esters are prefered over amides; reduction of the ester to the alcohol is not tolerated In this example, we illustrate the development of solid phase chemistry for the chemical synthesis of the naturally occurring sarcodictyins A (7) and B (8) and its application to the construction of a sarcodictyin combinatorial library. This library is complemented with compounds synthesized by solution methods and is subjected to biological evaluation with regard to tubuiin polymerization and cytotoxicity. The results are useful both in terms of new synthetic methodology development and structure activity relationships in this new structural class of compounds. Furthermore, the chemistry described herein demonstrates the use of REC chemistry (Nicolaou et al. Angew. Chem. Int. Ed. Engl. 1995, 34, 2289-2291 ; Moran et al. J. Am. Chem. Soc. 1995, 117, 10787-10788; Nicolaou et al. Angew. Chem. Int. Ed. Engl. 1997, 36, 2097-2103) in chemical biology studies and sets the stage for further developments in the field of cancer chemotherapy. Example III. Synthesis of Eleutherobin and Eleuthosides A and B: This example describes the total synthesis of the cytotoxic marine natural products eleutherobin (4) and eleuthosides A (5) and B (6). The strategy involves glycosidation of the (+)- carvone-derived intermediate 35 with the arabinose-derived trichloroacetimidate 900 (Scheme 23, see below) followed by base-induced ring closure and elaboration to afford the dihydroxy eneynone 1900. Selective hydrogenation of 1900 leads to the generation and intramolecular collapse of dienone 2000 furnishing 2100 and thence 22 with the required structural framework of the target molecules. Finally, esterification with mixed anhydride 2400 followed by deprotection gives eleutherobin (4) which serves as a precursor to eleuthosides A (5) and B (6). The α-glycoside anomer of eleutherobin, compound 2700 (Scheme 25, see below), is also synthesized by application of the developed chemistry, demonstrating the flexibility of the sequence in generating designed analogs for biological screening. Retrosynthetic Analysis and Strategy With the exception of the D-arabinopyranose moiety, the structural features of eleutherobin (4) and the eleuthosides A (5) and B (6) are similar to those of the sarcodictyins (7,8). The strategy for their total synthesis is devised from a similar retrosynthetic analysis with appropriate provisions for the introduction of the carbohydrate unit. Scheme 2 (see above) outlines the retrosynthetic analysis for the core structure of eleutherobin (4) and the eleuthosides (5,6). Thus removal of the (£)-Λ/(6)-methylurocanic acid residue from the target structure (I * ) and dismantling of the oxygen bridge of the central bicyclic core leads to the 10- membered ring dihydroxy dienone II * , whose origin can be traced to the open-chain acetylenic aldehyde III * . As shown in Scheme 23 (see below), further carbon-carbon bond disconnections and retro-glycosidation lead to hydroxy acetylene 35, whose relationship to (+)- carvone is evident. It is comforting to know that, although the (-t-)-enantiomer of carvone is chosen as the initial starting material, the (-)-enantiomer is also available in case the absolute stereochemistry of the natural substances requires it. The trichloroacetimidate 900 required for the projected total synthesis is traced to D-arabinose tetraacetate 1000. The execution of the total synthesis of eleutherobin (4) and eleuthosides A (5) and B (6) is carried out as described below. Total Synthesis of Eleutherobin (4) The construction of the (-t-)-carvone-derived hydroxyaldehyde fragment 35 (Scheme 23, see below) has been described in the preceding example. We will, therefore, begin here with the synthesis of the requisite fragment, trichloroacetimidate 900 (Scheme 22). Scheme 22: Construction of glycoside donor 900. Reagents and conditions: a) 1.1 equivalents of NaH, DMF, 0°C, 30 min; then 1.2 equivalents of PMB-CI, 2 h, 93%; b) 0.1 equivalents of TsOH « H 2 O, ethylene glycol-methanol (1 :10), 25°C, 6 h, 84%; (c) 4.0 equivalents of TBS-OTf, 10 equivalents of triethylamine, CH 2 CI 2 , 0°C, 2 h, 97%; (d) 3.4 equivalents of NBS, 11 equivalents of pyridine, acetone-H 2 O (93:7), 80% (ca. 2:1 ratio of anomers); (e) 0.1 equivalents of NaH, 5.0 equivalents of CI 3 CCN, CH 2 CI 2 , 25°C, 3.5 h, 93%. Ts = p-toluene- sulfonyl, TBSOTf = te/t-butyldimethylsilyl trifluoromethanesulfonate, NBS = Λ/-bromosuccin- imide, PMB = p-methoxybenzyl: 1000: : aarraabbiinnoossee a α I tetraacetate l —→*. S R = = ϋ PM a „B 500: R = H (ca. 2:1) 1 o P I 1300: R = H 900: R = C(NH)CCI 3 ^ J C ° L 1400: R = TBS Thus, arabinosetetraacetate (1000) is efficiently converted to thioglycoside 1100 by a sequence recently reported from these laboratories (Nicolaou et al. Angew. Chem. Int. Ed. Engl. 1997, 36, 2520-2524). The hydroxyl group of 1100 is then protected as a PMB ether by the action of PMB-CI in the presence of NaH (93% yield) and the acetonide group of the resulting compound 1200 is removed by treatment with TsOH in ethylene glycohmethanol (1 :10), furnishing diol 1300 in 84% yield. Both hydroxyl groups in 1300 are then silylated (TBSOTf-triethylamine, 97% yield of 1400) and the anomeric position is freed by the action of NBS-pyridine in aqueous acetone, affording lactol 1500 (80% yield, ca. 2:1 mixture of anomers). Finally, treatment of 1500 with NaH, followed by addition of CI 3 CCN gives the desired trichloroacetimidate 900 in 93% yield as the major isomer (greater than 95% purity). Purification of this sensitive intermediate is achieved by flash chromatography with a short column (silica, 10% diethyl ether in hexane containing 1 % triethylamine). The next task is to define suitable conditions for the stereospecif ic glycosidation of hydroxyaldehyde 35 with the arabinose-derived carbohydrate donor 900. To this end, the study in Scheme 24 and Table 4 is carried out: Scheme 24 and Table 4: Key intermediate conditions towards the total synthesis of eleutherobin (4). Studies for the attachment of the sugar moiety.a) concentration of starting material is 0.1 M, TMSOTf (2 - 5%), 1.5 equivalents of imidate; b) concentration of starting material is 0.07 M, TMSOTf (2 - 5%), 2.5 equivalents of imidate; c) The ratio of the two anomers is determined by NMR. TES = triethylsilyl, PMB = p-methoxybenzyl, TBS = f-butyldi- methylsilyl, NIS = /V-iodosuccinimide: Table 4: Ke intermediate conditions towards the total s nthesis of eleutherobin (4) Indeed, it is possible to reverse the stereoselectivity of the formed glycoside bond by varying the experimental conditions. Thus, while reaction of 35 with 900 in hexane in the presence of TMSOTf as a catalyst at -78°C gives a ca. 8:1 ratio of giycosides in favor of the α- anomer 2600 (75% combined yield), the use of dioxane: toluene (2:1 ) as solvent at 0°C leads to a ca. 8:1 ratio of products in favor of the desired β-anomer 2500 (75% yield after flash chromatography purification). Flash chromatography produces pure 2500 ready for the next step. Reaction of the pure β-anomer 2500 with LiHMDS in THF at -30°C causes smooth cyclization via acetylide formation and intramolecular attack on the aldehyde group affording an intermediate secondary alcohol (mixture of diastereomers) which is immediately oxidized with Dess-Martin reagent to dienone 1600 (Scheme 23; Chen et al. Angew. Chem. Int. Ed. 1998, 37, 789-792). Scheme 23: Total Synthesis of eleutherobin (4). Reagents and conditions: a) 900, TMSOTf see Fig. 25; b) 2.0 equivalents of LiHMDS, THF, -30°C, 20 min; c) 2.0 equivalents of Dess-Martin periodinane, 10 equivalents of NaHCO3, 10 equivalents of pyridine, CH 2 CI 2 , 0°C, 15 min, 93% for two steps; d) 2.2 equivalents of DDQ, CH 2 CI 2 :H 2 O (20:1 ), 25°C, 91 %; e) 12 equivalents of acetic anhydride, 16 equivalents of triethylamine, 0.5 equivalents of 4- DMAP, CH 2 CI 2 , 25°C, 1 h, 95%; f) triethylamine » 3HF: THF (1 :7), 25°C, 3 h, 81 %; g) H 2 , 50 mol% Lindlar's catalyst, PhCH 3 , 25°C, 20 min; h) 0.2 equivalents of PPTS, methanol, 25°C, 20 min, 76% for two steps; i) 10 equivalents of 2400, 15 equivalents of triethylamine, 2.0 equivalents of 4-DMAP, CH 2 CI 2 , 25°C, 18 h, 97%; j) 17 equivalents of TBAF, 4.0 equivalents of AcOH, THF, 25°C, 2.5 h, 96%. TMSOTf = trimethylsilyl trifluoromethane sulfonate, LiHMDS = lithium hexamethyl- disiiazane, DDQ = 2,3-dichloro-5,6-dicyano- 1 ,4-benzoqui- none, 4-DMAP = 4-dimethyl-aminopyridine, Lindlar's catalyst = Pd/CaCO 3 /Pb, PPTS = pyridinium p-toluene sulfonate, TBAF = tetra-n-butylammonium fluoride: Now is the time point to install the acetate group at the C-2 position of the pyranose ring. Selective removal of the PMB group from 1600 with DDQ leads to the formation of the corresponding hydroxy compound 1700 (Scheme 23) in 91% yield. Standard acetylation then leads to acetate 1800 (95% yield). Both TES groups are then removed from 1800 without damage of the TBS group by the discriminating action of Et 3 N 3 HF in THF at 25°C furnishing diol 1900. The next objective in the synthesis is the generation of the key dienone 2000, the fleeting intermediate being expected to readily collapse in favor of its bridged isomer 2100 (Scheme 23). Indeed, upon selective hydrogenation of the acetylene moiety (Lindlar cat., H 2 , tolue- ne, 25°C), compound 1900 gives rise to the expected lactol 2100, whose conversion to the methoxy ketal 2200 proves straightforward (methanol, PPTS, 76% yield from 1900). The attachment of the (£)-Λ/(6)-methylurocanic acid residue onto the main framework of the target molecule is accomplished by reaction of alcohol 2200 with mixed anhydride 2400 (Yang et al. Angew. Chem. Int. Ed. Engl. 1997, 36, 166-168; Nicolaou et al. Angew. Chem. Int. Ed. Engl. 1997, 36, 525-526) in the presence of triethylamine and 4-DMAP in CH 2 CI 2 at 25°C, leading to esterified product 2300 (97% yield). Finally, exposure of 2300 to TBAF- AcOH in THF results in the cleavage of the TBS group and the liberation of eleutherobin (4) in 96% yield. Synthetic eleutherobin (4) exhibits identical physical data to those reported for the natural substance. Furthermore, the sign of its rotation [α]r> -67 (c = 0.2, methanol) is the same as that reported for the natural eleutherobin, establishing the absolute stereochemistry of the latter as that corresponding to (+)-carvone and structure 4. The α-glycoside analog 2700 of eleutherobin (Scheme 25) is synthesized from the α-ano- mer 2600 (Scheme 24) by following the same route as for 4 (shown in Scheme 23). Scheme 25: Synthesis of the α-anomer of eleutherobin (2700), that is, the conversion of 2600 to 2700. Reaction conditions as in Scheme 23: The yields for the steps involved in this construction are similar to those for the eleutherobin sequence. Total Synthesis of Eleuthosides The eleuthosides A (5) and B (6) are synthesized from eleutherobin (4) as indicated in Scheme 26. Scheme 26: Synthesis of eleuthosides A (5) and B (6) (Scheme 26 (A)) and derivatives 3100 and 3200 (Scheme 26 (B)). Reagents and conditions: a) 1.1 equivalents of acetic anhydride, 3.0 equivalents of triethylamine, 0.2 equivalents of 4-DMAP, 0°C, 1 h, 16% of 2800 along with 73% of the mixture of 2900 and 3000 (2.2:1 by NMR); b) 2.0 equivalents of CSA, CH 2 CI 2 : H2O (10:1 ), 25°C, 48 h, 80% of the mixture of 5 and 6 (based on 87% conversion of the starting material); c) 4.0 equivalents of TBAF, THF, 25°C, 6 h, 4 (22%), 3100 (60%) and 3200 (8%). 4-DMAP = 4-dimethylaminopyridine, CSA = 10-camphorsulfonic acid: - Scheme 26(B) Thus exposure of 4 to 1.1 equivalents of acetic anhydride in the presence of excess triethylamine and 0.2 equivalents of 4-DMAP in CH 2 CI 2 at 0°C results in the formation of triacetate 2800 (12% yield) and diacetates 2900 and 3000 (75% yield as a ca. 1 :2 mixture in favor of 2900 by 1 H-NMR), plus some unreacted starting material (13%). The inseparable mixture of diacetates (2900 and 3000) is exposed to CSA in moist CH CI 2 , furnishing a mixture of eleuthosides A and B (5+6) (Scheme 26(A)). This mixture can not be separated by conventional chromatographic methods and is characterized as such, matching, in all respects, the data reported for the natural eleuthosides A (5) and B (6). Exposure of bis-TBS ether 2300 (or 4) with TBAF in THF at 25°C causes slow migration of the acetate group from the 2-posi- tion to the 4-hydroxyl group, leading to the isomeric eluetherobin 3100 (60% yield) as well as deacylation leading to deacetoxyeleutherobin 3200 (8% yield) (Scheme 26 B)). The structure of 3100 is established by NMR spectroscopic methods (1 H 1 D- and 2D-COSY) and comparisons with 4 and 2300. Thus, in summary, example III teaches a strategy similar to that described for the sarcodictyins A and B in examples I and II; by incorporating the arabinose pyranoside moiety into the molecule prior to ring closure, the total synthesis of the marine natural products eleutherobin (4) and eleuthosides A (5) and B (6) has been accomplished. In addition, the chemical synthesis of the isomeric eleutherobin (2700) in which the giycosidic bond is oriented in the α-position as well as the eleuthoside analogs 2800-3200 is described. The reported chemistry allows access not only to the rare naturally occurring substances, but also to designed analogs and combinatorial libraries for biological screening purposes. Combined with their appealing mechanism of tubuiin polymerization and microtubule stabilization, the described technology makes the eleutherobins and eleuthosides an attractive proposition as a new class of potential anticancer agents. It should be noted that the compounds as described in Schemes 27 - 33 are synthesized according to the the same conditions as described for the compounds shown in Scheme 20 and Table 2. While a preferred form of the invention has been shown in the drawings and described, since variations in the preferred form will be apparent to those skilled in the art, the invention should not be construed as limited to the specific form shown and described, but instead is as set forth in the claims. EXPERIMENTAL DETAILS General Techniques. All reactions are carried out under an argon atmosphere with dry, freshly distilled solvents under anhydrous conditions, unless otherwise noted. Tetrahydrofuran (THF), toluene and ethyl ether (ether) are distilled from sodium-benzophenone, and methylene chloride (CH 2 CI 2 ), from calcium hydride. Anhydrous solvents are also obtained by passing them through commercially available alumina column. Yields refer to chromato- graphically and spectroscopically H NMR) homogeneous materials, unless otherwise stated. Reagents are purchased at highest commercial quality and used without further purification, unless otherwise stated. Reactions are monitored by thin layer chromatography carried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as visualizing agent and 7% ethanoiic phosphomolybdic acid or p-anisaldehyde solution and heat as developing agents. E. Merck silica gel (60, particle size 0.040-0.063 mm) is used for flash column chromatography. Preparative thin-layer chromatography (PTLC) separations are carried out on 0.25, 0.50 or 1 mm E. Merck silica gel plates (60F-254). NMR spectra are recorded on Bruker DRX-600, AMX-500 or AMX-400 instruments and calibrated using residual undeuterated solvent as an internal reference. The following abbreviations are used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, sept = septet, m = multiplet, br = broad. IR spectra are recorded on a Perkin-Elmer 1600 series FT-IR spectrometer. Optical rotations are recorded on a Perkin-Elmer 241 polarimeter. High resolution mass spectra (HRMS) are recorded on a VG ZAB-ZSE mass spectrometer under fast atom bombardment (FAB) conditions with NBA as the matrix. Melting points (mp) are uncorrected and are recorded on a Thomas Hoover Unimelt capillary melting point apparatus. Synthesis of epoxide 10 from S-(+)-carvone as illustrated in Scheme 3. A solution of 4 N NaOH (48 ml, 192.0 mmol, 0.3 equivalents) is slowly added to a solution of S-(+)-carvone (100.0 g, 665 mmol, 1.0 equivalent) in methanol (1000 ml) at 0°C, followed by the dropwise addition of 35% hydrogen peroxide solution (70.0 ml, 792.6 mmol, 1.2 equivalents) over 3 h. After the reaction is complete as established by TLC analysis, it is quenched by the slow addition of saturated Na 2 SO 3 solution (200 ml) and extracted with CH 2 CI 2 (3 x 300 ml). The organic extracts are dried over Na 2 SO 4 and concentrated to afford the carvone epoxide product which is used without further purification. A solution of this epoxide (101.8 g, 612.4 mmol, 1.0 equivalent) and PtO 2 (0.72 g, 3.18 mmol, 0.095 equivalents) in Ethanol (500 ml) is stirred under a hydrogen atmosphere (1 atm) at 25°C for 12 h. The reaction mixture is then filtered through a Celite® (diatomeous earth, Celite Corp.) pad eluting with diethyl ether and concentrated. The crude product is purified by flash chromatography (silica gel, 5% EtOAc in hexane) to afford epoxide 10 (97.8 g, 87%, two steps) as a colorless oil. Rf= 0.40 (silica gel, EtOAc-hexane, 1 :10); FT-IR (neat) vmax 2959, 2873, 1708, 1466, 1438, 1369, 1111 , 884 and 814 cm -1 . Synthesis of 11 through a formaldehyde aldol reaction as illustrated in Scheme 3. To a solution of diisopropylamine (14.06 ml, 107.26 mmol, 1.2 equivalents) in THF (400 ml) at -78°C, a solution of 1.6 M π-BuLi in hexanes (67.1 ml, 107.3 mmol, 1.2 equivalents) is added. The reaction is then allowed to warm-up to 0°C and stirred for 30 min after which a solution of ketone 10 (15.0 g, 89.2 mmol, 1.0 equivalent) in THF (100 ml) is added dropwise via cannula at -78°C over 1.5 h and stirring continued for 30 min thereafter. A solution of formaldehyde, prepared by cracking paraformaldehyde (33.0 g, 1.10 mol, 12.2 equivalents) at 140°C and bubbling the resulting gas through THF (500 ml) at -78°C for 45 min, is added to the enolate solution via cannula over 1 h at -78°C. The reaction mixture is then allowed to warm to 0°C, quenched by addition of saturated NH CI solution (100 ml), and extracted with diethyl ether (3 x 300 ml). The combined organic extracts are dried over Na 2 SO and concentrated. The crude product is filtered through a short pad of silica and eluted with 10% EtOAc in hexane to afford the corresponding alcohol (ca. 10.9 g, ca. 63%). To a solution of this alcohol (10.9 g, 55.0 mmol, 1.0 equivalent), triethylamine (46 ml, 330 mmol, 6.0 equivalents), and 4-DMAP (328 mg, 2.68 mmol, 0.05 equivalents) in CH 2 CI 2 (200 ml) at 0°C is added TBSCI (9.9 g, 66.0 mmol, 1.2 equivalents). The reaction mixture is stirred at 25°C for 12 h and, after the end of the reaction is established by TLC analysis, quenched via addition of methanol (10 ml) and water (100 ml). The organic layer is separated, dried over Na 2 SO 4 and concentrated. The crude product is purified by flash chromatography (silica gel, 3% EtOAc in hexane) to afford silyl ether 11 (8.21 g, 53%, two steps). Rf= 0.70 (silica gel, EtOAc-hexane, 1 :10); FT-IR (neat) vmax 2958, 2931 , 2856, 1705, 1471 , 1254, 1109, 882, 835, 777 cm- 1 . Synthesis of 12 through enantioselective reduction of ketone 11 as illustrated in Scheme 3. To a solution of ketone 11 (19.2 g, 61.4 mmol) in THF (300 ml) at -78°C, 1.0 M L-Selectride in THF (73.7 ml, 73.7 mmol, 1.2 equivalents) via cannula is added over 1.5 h. The reaction mixture is stirred at the same temperature for an additional 30 min and, after the complete consumption of the starting ketone is established by TLC, quenched by addition of saturated NH 4 CI solution (100 ml) and allowed to warm to 0°C. Excess 35% hydrogen peroxide (8.0 ml, 79.8 mmol, 1.3 equivalents) solution is then added and the mixture is stirred at 0°C for 1 h. The reaction mixture is extracted with EtOAc (3 x 200 ml) and the organic extracts are dried over Na 2 SO 4 and concentrated. The crude product is purified by flash chromato- graphy (silica gel, 5% EtOAc in hexane) to afford the secondary alcohol 12 (18.0 g, 93%) as a light yellow colored oil. Rf= 0.32 (silica gel, EtOAc-hexane, 1 :10); FT-IR (neat) 3553, 3506, 2955, 2882, 1471 , 1436, 1388, 1266, 1255, 1092, 1068, 1006, 960, 905, 836, 776 cm "1 . Synthesis of allylic alcohol 13 via the corresponding mesylate as illustrated in Scheme 3. To a solution of alcohol 12 (29.0 g, 92.2 mmol, 1.0 equivalent) and triethylamine (33.8 ml, 243.0 mmol, 2.6 equivalents) in CH 2 CI 2 (250 ml) at 0°C is added methanesulfonyl chloride (8.2 ml, 106.3 mmol, 1.15 equivalents) dropwise over 1 h. The reaction mixture is stirred at 0°C for 2 h (the progress of the reaction is monitored by TLC), quenched by addition of brine, and extracted with EtOAc (3 x 300 ml). The combined organic extracts are dried over Na 2 SO and concentrated. The product is filtered through a short pad of silica gel eluting with diethyl ether to afford the expected mesylate which is immediately used for the next step without further purification. To a solution of NaC 10 H 8 , prepared by the addition of Na- metal (12.3 g, 535.6 mmol, 5.8 equivalents) to naphthalene (80.3 g, 627.1 mmol, 6.8 equivalents) in THF (1800 ml) and allowing the mixture to stirr for 2 h, is added a solution of the mesylate in THF (300 ml) dropwise via cannula at 0°C. The reaction mixture is stirred for 30 min (TLC monitoring), quenched by addition of saturated NH 4 CI solution (200 ml), treated with brine and extracted with EtOAc (3 x 300 ml). The organic extracts are dried over Na 2 SO and concentrated. The crude product is purified by flash chromatography (silica gel, 10% Et 2 O in hexane followed by 10% EtOAc in hexane) to afford allylic alcohol 13 (24.2 g, 85%, two steps) as a colorless oil. Rf= 0.53 (silica gel, EtOAc-hexane, 1 :3); FT-IR (neat) vmax 3351 , 2956, 2931 , 2857, 1468, 1254, 1095, 1058, 837, 776 cm "1 . Synthesis of key-intermediate aldehyde 14 as illustrated in Scheme 3. A mixture of alcohol 13 (1.61 g, 5.42 mmol, 1.0 equivalent), triethyl orthoacetate (39.6 ml, 216.8 mmol, 40.0 equivalents), and proprionic acid (0.04 ml, 0.542 mmol, 0.1 equivalents) is heated at 170°C for 72 h. The excess triethyl orthoacetate is removed by vacuum distillation (25 mm Hg), and the remaining residue is purified by flash chromatography (silica gel, 3% EtOAc in hexane) to produce the expected ethyl ester (1.50 g, 74%) which is used for the next step without further purification. A 1.0 M CH 2 CI 2 solution of DIBAL (4.6 ml, 4.60 mmol, 1.2 equivalents) is gradually added to a solution of the ethyl ester (1.41 g, 3.83 mmol, 1.0 equivalent) in CH 2 CI 2 (19 ml) at -78°C, and the reaction mixture is stirred for 30 min at that temperature. Quenching is performed by addition of saturated NH CI solution (20 ml) and stirring for 2 h at ambient temperature. The organic layer is separated, dried over Na 2 SO 4 and concentrated. The residue is purified by flash chromatography (silica gel, 5% EtOAc in hexane) to provide aldehyde 14 (1.20 g, 97%) as a colorless oil. Data for ethyl ester: Rf= 0.34 (silica gel, EtOAc-hexane, 1 :30); FT-IR (neat) vmax 2929, 2857, 1738, 1470, 1369, 1255, 1156, 1100, 837, 775 cm '1 . Synthesis of ,β-unsatu rated ester 15 as illustrated in Scheme 4. To a THF (30 ml) suspension of sodium hydride (60% w/w in mineral oil, 542 mg, 13.55 mmol, 2.0 equivalents), gradually a solution of triethyl phosphonoacetate (2.7 ml, 13.55 mmol, 2.0 equivalents) in THF (10 ml) is added via cannula at 0°C. After the addition is complete, the reaction mixture is stirred at 25°C for 30 min before being cooled back down to 0°C. A solution of aldehyde 14 (2.20 g, 6.78 mmol, 1.0 equivalent) in THF (15 ml) is slowly added to the reaction mixture via cannula at 0°C, and the reaction mixture is stirred at the same temperature for 1 h and at 25°C for 4 h. After the end of the reaction is established by TLC, the reaction mixture is quenched by the addition of saturated NH 4 CI solution (50 ml), extracted with diethyl ether (2 x 100 ml), dried over Na 2 SO , and concentrated. The residue is purified by flash chromatography (silica gel, 2% EtOAc in hexane) to furnish the α,β-unsaturated ester 15 (2.67 g, 100%) as a colorless oil. Rf= 0.53 (silica gel, EtOAc- hexane, 1 :10); FT-IR (neat) vmax 2956, 1722, 1651 , 1465, 1367, 1258, 1159, 1078, 841 cm '1 . Synthesis of allylic alcohol 16 from ester 15 as illustrated in Scheme 4. A 1.0 M CH 2 CI 2 solution of DIBAL (12.2 ml, 12.20 mmol, 4.0 equivalents) is gradually added to a solution of α,β-unsaturated ethyl ester 15 (1.20 g, 3.05 mmol, 1.0 equivalent) in CH 2 CI 2 (15 ml) at -78°C, and the reaction is stirred for 2 h at the same temperature. The reaction mixture is quenched by addition of saturated NH CI solution (30 ml), stirred vigorously at ambient temperature for 2 h, extracted with CH 2 CI 2 (3 x 50 ml), dried over Na 2 SO and concentrated. The residue is purified by flash chromatography (silica gel, 10% EtOAc in hexane) to provide allylic alcohol 16 (980 mg, 91%) as a light-yellow oil. Rf= 0.21 (silica gel, EtOAc-hexane, 1 :10); FT-IR (neat) vmax 3326, 2925, 1464, 1385, 1253, 1106, 1005, 836, 774, 668 cm "1 . Synthesis of epoxide 17 from allylic alcohol 16 as illustrated in Scheme 4. To a suspension of diethyl L-tartrate (0.28 ml, 1.50 mmol, 0.2 equivalents) and powdered 4 A Molecular Sieve (MS) (6.8 g) in CH 2 CI 2 (90 ml) is added titanium(IV) isopropoxide (0.40 ml, 1.25 mmol, 0.2 equivalents) at -20°C followed by a 5.0 M CH 2 CI 2 solution of tert-butyl hydroperoxide (2.7 ml, 13.5 mmol, 2.0 equivalents). After the mixture is stirred for 40 min at the same temperature, a solution of allylic alcohol 16 (2.38 g, 6.75 mmol, 1.0 equivalent) in CH 2 CI 2 (5 ml) is added dropwise via cannula. The reaction mixture is stirred for 8 h at the same temperature, further diluted with CH 2 CI 2 (150 ml) and quenched by addition of a saturated NaHCO 3 solution (100 ml). The mixture is then filtered through a Celite® pad eluting with CH 2 CI 2 and the organic phase is separated, washed with water and brine, dried over Na 2 SO 4 and concentrated. The residue is purified by flash chromatography (silica gel, 10% EtOAc in hexane) to furnish epoxy alcohol 17 (2.25 g, 91%) as a colorless oil. Rf= 0.47 (silica gel, EtOAc-hexane, 1 :3); FT-IR (neat) vmax 3442, 2927, 1465, 1387, 1253, 1104, 838, 775, 668 cm "1 . Synthesis of allylic alcohol 19 through the corresponding mesylate as illustrated in Scheme 4. To a solution of epoxy alcohol 17 (1.05 g, 2.82 mmol, 1.0 equivalent) and triethylamine (2.40 ml, 16.9 mmol, 6.0 equivalents) in CH 2 CI 2 (28 ml) is added dropwise methanesulfonyl chloride (1.4 ml, 18.08 mmol, 4.9 equivalents) at -20°C. After 1 h (TLC monitoring), the reaction mixture is quenched by addition of saturated NH 4 CI solution (20 ml), extracted with CH 2 CI 2 (2 x 50 ml), dried over Na 2 SO 4 and concentrated. The residue is filtered through a short silica gel pad eluting with CH 2 CI 2 , concentrated and used immediately for the next step without further purification. A solution of the mesylate in THF (28 ml) is added via cannula to a 0.3 M THF solution of sodium naphthalenide (4.7 ml, 14.1 mmol, 5.0 equivalents), generated in the same way described for the synthesis of allylic alcohol 13, at 0°C. After 10 min, the reaction mixture is quenched by addition of saturated NH CI solution (50 ml), extracted with diethyl ether (2 x 50 ml), washed with brine, dried over Na 2 SO and concentrated. The residue is purified by flash chromatography (silica gel, 5% EtOAc in hexane) to produce allylic alcohol 19 (895 mg, 90%) as a colorless oil. Rf= 0.34 (silica gel, EtOAc-hexane, 1 :10); FT-IR (neat) vmax 3420, 2955, 1464, 1387, 1254, 1073, 837, 775 cm "1 . Synthesis of PMB-ether 20 as illustrated in Scheme 4. To a solution of allylic alcohol 19 (445 mg, 1.57 mmol, 1.0 equivalent) and p-methoybenzyl- 2,2,2-trichloroacetimidate (2.22 g, 7.85 mmol, 5.0 equivalents) in CH 2 CI 2 (8 ml) is added pyridinium p-toluenesulfonate (395 mg, 0.31 mmol, 0.2 equivalents) at 25°C. The reaction mixture is stirred for 48 h at the same temperature, and after the end of the reaction is established by TLC, quenched by addition of saturated NaHCO 3 solution (10 ml). The organic phase is separated and the aqueous layer is extracted with CH 2 CI 2 (2 x 10 ml). The combined organic extracts are dried over Na SO and concentrated. The residue is purified by flash chromatography (silica gel, EtOAc-pentane, 1 :99) to produce PMB-ether 20 (240 mg, 89% based on 50% conversion) as a light yellow oil. Rf= 0.61 (silica gel, EtOAc-hexane, 1 :3); FT-IR (neat) vmax 2954, 1614, 1514, 1464, 1250, 1080, 837, 775 cm "1 . Synthesis of methyl ketone 21 as illustrated in Scheme 4. A solution of PMB-ether 20 (135 mg, 0.285 mmol, 1.0 equivalent) and mercuric acetate (100 mg, 3.4 mmol, 1.2 equivalents) in methanol (2 ml) is stirred at 25°C for 12 h. The reaction mixture is then transferred to a solution of LiCI (24.1 mg, 0.568 mmol, 2.0 equivalents), PdCI 2 (50.5 mg, 0.285 mmol, 1.0 equivalent) and CuCI 2 (0.115 mg, 0.855 mmol, 3.0 equivalents) in methanol (1 ml) via cannula and is further stirred at 55°C for another 3 h. Saturated NaHCO 3 (5 ml) is added, and the product is extracted with diethyl ether (20 x 3 ml). The organic extracts are dried over Na 2 SO 4 and concentrated. The crude product is purified by flash chromatography (silica gel, 6% EtOAc in hexane) to furnish methyl ketone 21 (90.5 mg, 65%) as a colorless oil. Rf= 0.34 (silica gel, EtOAc-hexane, 1 :15); FT-IR (neat) vmax 2956, 1714, 1514, 1249, 1081 , 836 cm "1 . Synthesis of propargylic alcohol 22 as illustrated in Scheme 4. To a stirring solution of methyl ketone 21 (180 mg, 0.369 mmol, 1.0 equivalent) in CH 2 CI 2 :THF (3:1 , 20 ml) at -78°C is added ethynylmagnesium bromide (0.5 M in THF, 11.8 ml, 5.40 mmol, 14.6 equivalents) via syringe over 15 min. The reaction is stirred for 6 h at that temperature after which it is allowed to warm to 25°C. The reaction mixture is quenched with saturated NH 4 CI solution (10 ml). The aqueous layer is separated and extracted with diethyl ether (3 x 20 ml), and the combined organic phase is dried over Na 2 SO 4 and concentrated. The residue is taken up in THF (2 ml) and treated with 1.0 M THF solution of TBAF (1.47 ml, 1.47 mmol, 4.0 equivalents) at 25°C. After 2 h (TLC monitoring), the reaction is quenched with water and extracted with ethyl acetate (3 x 20 ml). The combined organic phase is dried over Na 2 SO 4 and concentrated. The residue is purified by flash chromatography (silica gel, 50% EtOAc in hexane) to afford diol 22 (106 mg, 72%, two steps) as a colorless oil. Rf= 0.24 (silica gel, EtOAc-hexane, 1 :1 ); FT-IR (neat) vmax 3305, 2958, 1614, 1514, 1248, 1090, 1035, 820 cm "1 . Synthesis of cyano ester 25 through an oxidation-Knoevenagel condensation- protection sequence as illustrated in Scheme 4. A mixture of NaHCO 3 (504 mg, 5.99 mmol, 20.0 equivalents), pyridine (0.485 ml, 5.99 mmol, 20.0 equivalents), Dess-Martin periodinane (191 mg, 0.449 mmol, 1.5 equivalents), and diol 22 (0.120 g, 0.300 mmol, 1.0 equivalent) is stirred at 25°C for 4 h. To the reaction is then added saturated NaHCO 3 solution (15 ml), and the product is extracted with diethyl ether (3 x 25 ml). The combined organic layers are dried over Na 2 SO 4 , filtered through Celite® eluting with diethyl ether and concentrated to afford aldehyde 23 that is used for the next step without further purification. To a solution of aldehyde 23 in 95% ethanol (1.8 ml) is added ethyl cyanoacetate (0.963 ml, 9.00 mmol, 30 equivalents) and β- alanine (107 mg, 1.20 mmol, 4.0 equivalents). After 72 h at 25°C, the reaction mixture is filtered through a pad of silica gel eluting with diethyl ether and concentrated to afford α,β- unsaturated cyano ester 24, which is used for the next step without further purification. The residue of 24 is dissolved in CH 2 CI 2 , and Λ/,/V-diisopropylethylamine (0.522 ml, 2.99 mmol, 10 equivalents) is added. The reaction is cooled to -78°C and TMSOTf (0.288 ml, 1.49 mmol, 5.0 equivalents) is added over 15 min. After 2 h, the reaction is quenched with excess methanol (1.0 ml) and concentrated. The resulting residue is purified by flash chromatography (silica gel, 6% EtOAc, hexane) to afford 25 (0.12 g, 71 %, three steps). Rf= 0.27 (silica gel, EtOAc-hexane, 1 :3); FT-IR (neat) vmax 2959, 2231 , 1730, 1614, 1513, 1248, 1078, 1022, 842 cm "1 . Synthesis of ,β-unsaturated aldehyde 27 as illustrated in Scheme 4. To a solution of cyano ester 25 (280 mg, 0.497 mmol, 1.0 equivalent) in hexanes (25 ml) at -78°C is added dropwise a 1.0 M THF solution of DIBAL (5.0 ml, 5.0 mmol, 10.0 equivalents). After 7 h at -78°C and 1 h at -40°C, EtOAc (5 ml) is added and the reaction mixture is warmed to 25°C. Addition of water (30 ml) and stirring for 1 h at ambient temperature completes the workup procedure. The reaction mixture is extracted with diethyl ether (3 x 50 ml), dried over Na 2 SO and concentrated. The product is purified by flash chromatography (silica gel, 10% EtOAc in hexane) to afford alcohol 26 (210 mg, 80%). To a solution of 26 (50.0 mg, 0.0949 mmol, 1.0 equivalent) in CH 2 CI 2 (0.95 ml) is added Λ/,Λ/-diisopropyl- ethylamine (0.33 ml, 1.90 mmol, 20.0 equivalents), and the resulting mixture is cooled to -78°C, after which TIPSOTf (0.26 ml, 0.95 mmol, 10.0 equivalents) is added dropwise. After 1 h (TLC monitoring), the reaction mixture is quenched by the addition of methanol (0.2 ml). After 10 min, aqueous saturated NH 4 CI solution (5 ml) is added and the mixture is warmed to 25°C, extracted with diethyl ether (10 ml) and concentrated. The residue is purified by flash chromatography (silica gel, 2% EtOAc in hexane) to furnish TIPS ether 27 (58.8 mg, 91 %) as a coloriess oil. Rf= 0.33 (silica gel, EtOAc-hexane, 1 :10); FT-IR (neat) vmax 3470, 3300, 2957, 2360, 2337, 1672, 1613, 1513, 1418, 1370, 1302, 1250 cm "1 . Synthesis of diastereoisomeric diols 29 as illustrated in Scheme 6. To a solution of ethyl vinyl ether (1.16 g, 16.0 mmol, 2.0 equivalents) in THF (70.0 ml) at -78°C is added 1.7 M f-BuLi in hexanes (8.5 ml, 14.4 mmol, 1.8 equivalents), and the solution is warmed to 0°C. The reaction is followed by the color change from yellow to colorless. The resulting vinyl-anion solution is then cooled to -78°C and a solution of aldehyde 14 (2.60 g, 8.02 mmol, 1.0 equivalent) in THF (25 ml) is added dropwise, after which the reaction mixture is stirred for an additional 30 min at -78°C. The reaction is quenched by addition of saturated NH 4 CI solution (40 ml) and extracted with diethyl ether (3 x 150 ml). The combined organic extracts are dried over MgSO 4 and concentrated. The crude product is then dissolved in diethyl ether and treated with concentrated H SO in a separatory funnel while shaking vigorously. The progress of the hydrolysis is followed by TLC and, upon completion, the diethyl ether solution is washed with water (20 ml) and saturated NaHCO 3 solution (20 ml), dried over MgSO and concentrated. The residue is purified by flash chromatography (silica gel, 10% to 15% diethyl ether in hexane) to produce hydroxy ketones 28 as an inseparable mixture of stereoisomers (ca. 1.25:1 by NMR). To a solution of mixture 28 in THF (78 ml) at -78°C is added ethynyl magnesium bromide (0.5M in THF, 70.8 ml, 35.0 mmol, 4.4 equivalents) and the solution is stirred at -78°C for 6 h, and then is allowed to slowly warm to -10°C. The reaction mixture is quenched by addition of saturated NH 4 CI solution (50 ml) and extracted with diethyl ether (3 x 100 ml). The combined organic extracts are dried over MgSO and concentrated, and the resulting residue is purified by flash chromatography (silica gel, 10% to 25% diethyl ether in hexane) to afford the desired isomer 29 (1.39 g, 44%) along with its C-7, C-8 stereoisomer (1.04 g, 33%). 29: Rf= 0.40 (silica gel, diethyl ether:hexane,1 :3). Synthesis of triol 30 as illustrated in Scheme 6. To a solution of diol 29 (0.63 g, 1.59 mmol, 1.0 equivalent) in THF (16 ml) at 0°C is added TBAF (1.0M in THF, 3.18 ml, 3.18 mmol, 2.0 equivalents), and the reaction mixture is allowed to warm to 25°C over 1 h. After the end of the reaction is established by TLC, the solution is quenched by addition of saturated NH 4 CI (50 ml) and extracted with diethyl ether (3 x 100 ml). The combined organic extracts are concentrated and the residue is purified by filtration through silica gel to furnish triol 30 (0.45 g, 100%) as a light yellow oil. Rf = 0.12 (silica gel, diethyl ether-hexane, 3:1 ); FT-IR (neat) vmax 3385, 2958, 1448, 1368, 1078, 946 cm "1 . Synthesis of trisilyl ether 31 as illustrated in Scheme 6. To a solution of triol 30 (0.45 g, 1.59 mmol, 1.0 equivalent) in CH 2 CI 2 (16 ml) is added triethylamine (2.3 ml, 16.5 mmol, 10.3 equivalents), and the solution is chilled to 0°C. TESOTf (2.10 g, 8.00 mmol, 5.0 equivalents) is then added and the reaction mixture is allowed to warm to 25°C. After the disappearance of the starting triol is established by TLC, the solution is quenched by addition of saturated NH CI (50 ml) and extracted with CH 2 CI 2 (3 x 100 ml). The organic extracts are combined, dried over MgSO and concentrated. The residue is purified by filtration through silica gel (25% diethyl ether in hexane) to produce trisilyl ether 31 (0.99 g, 100%) as a light yellow oil. Rf= 0.62 (silica gel, diethyl ether-hexane, 1 :9); FT-IR (neat) vmax 3308, 2956, 2876, 1459, 1414, 1378, 1239, 1115, 1006 cm "1 . Selective deprotection of the primary hydroxide to produce alcohol 32 as illustrated in Scheme 6. To a solution of trisilyl ether 31 (1.48 g, 2.37 mmol, 1.0 equivalent) in 3:1 methanol/CH 2 CI 2 (20 ml) is added a catalytic amount of PPTS (45 mg, 0.24 mmol, 0.1 equivalents). After its completion (TLC monitoring), the reaction mixture is worked up by addition of saturated NaHCO 3 (50 ml) and extraction with diethyl ether (3 x 150 ml). The combined organic extracts are dried over MgSO 4 and concentrated. The residue is purified by filtration through silica gel eluting with diethyl ether to provide alcohol 32 (1.18 g, 98%) as a coloriess oil. f?t " = 0.12 (silica gel, diethyl etheπhexane, 1 :9); FT-IR (neat) vmax 3490, 3308, 2955, 2876, 1459, 1414, 1378, 1238, 1109, 1072, 1004 cm"1 . Synthesis of aldehyde 33 as illustrated in Scheme 6. To a solution of alcohol 32 (1.24 g, 2.43 mmol, 1.0 equivalent) and powdered activated 4 A MS (0.5 g) in CH 2 CI 2 (16 ml) is added NMO (0.43 g, 3.64 mmol, 1.5 equivalents) and the reaction mixture is stirred for 10 min. TPAP (0.043 g, 0.181 mmol, 0.07 equivalents) is then added and the reaction mixture is stirred at 25°C for 30 min. The heterogeneous solution is then filtered through a short pad of silica gel and washed with CH 2 CI 2 . After concentration, aldehyde 33 (1.20 g, 98%) is obtained as a coloriess oil. Rf = 0.42 (silica gel, diethyl ether- hexane, 1 :9); FT-IR (neat) vmax 3309, 2955, 2876, 1719, 1458, 1414, 1378, 1238, 1073, 1004 cm "1 . Formation of α,β-unsatu rated cyano ester 34 as illustrated in Scheme 6. A solution of aldehyde 33 (1.14 g, 2.25 mmol, 1.0 equivalent), ethyl cyanoacetate (7.63 g, 67.0 mmol, 30 equivalents), and β-alanine (0.080 g, 9.00 mmol, 4.0 equivalents) in ethanol (15 ml) is stirred at 50°C for 72 h. The reaction mixture is then concentrated and purified by filtration through a short pad of silica gel eluting with 10% diethyl ether in hexanes to produce cyano ester 34 (1.28 g, 95%) as a colorless oil. Rf= 0.40 (silica gel, diethyl ether-hexa- ne, 1 :9); FT-IR (neat) vmax 3308, 2958, 2878, 2201 , 1735, 1619, 1461 , 1370, 1249, 1117, 1008 cm "1 . Synthesis of hydroxyaldehyde 35 as illustrated in Scheme 6. To a solution of cyanoester 34 (101 mg, 0.168 mmol, 1.0 equivalent) in hexanes (8.4 ml) at -78°C is added DIBAL (1.0M in toluene, 1.7 ml, 1.70 mmol, 10.0 equivalents). The reaction mixture is stirred for 6 h at -78°C and then slowly warmed to -10°C for 2 h. The solution is then quenched with ethyl acetate (0.2 ml), saturated NH 4 CI (10 ml) solution is added, and the reaction is stirred for 2 h, after which it is filtered through a short Celite® pad eluting with diethyl ether and extracted with ethyl acetate (3 x 10 ml). The combined organic extracts are concentrated and purified by flash chromatography (silica gel, 10% diethyl ether in hexanes) to produce hydroxyaldehyde 35 (79.8 mg, 90%) as a light yellow oil. Rf = 0.42 (silica gel, diethyl ether-hexane, 1 :1); FT-IR (neat) vmax 3447, 3307, 2957, 2877, 1677, 1459, 1414, 1380, 1239, 1117, 1008 cm "1 . Synthesis of trisilyl ether 36 as illustrated in Scheme 6. To a solution of hydroxyaldehyde 35 (930.0 mg, 1.65 mmol, 1.0 equivalent) and /Pr 2 NEt (2.8 ml, 16.07 mmol, 9.7 equivalents) in CH 2 CI 2 (8 ml) at -78°C is added TIPSOTf (2.2 ml, 8.25 mmol, 5.0 equivalents), and the solution is stirred at that temperature for 1 h. The reaction mixture is quenched by addition of methanol (0.5 ml) followed by addition of saturated NH CI (10 ml). The mixture is then extracted with diethyl ether (10 ml), and the organic extracts are combined, dried over Na 2 SO and concentrated. The resulting residue is purified by flash chromatography (silica gel, 2% EtOAc-hexane) to furnish trisilyl ether 36 (1.10 g, 93%) as a light yellow oil. Rf= 0.33 (silica gel, hexane); FT-IR (neat) vmax 3309, 2957, 2872, 2361 , 1675, 1462, 1381 , 1239, 1167, 1117, 1007, 882, 819, 741 cm "1 . Synthesis of alkynone 37 by intramolecular acetylide addition to aldehyde 27 as illustrated in Scheme 7. A solution of LiHMDS (1.0M in THF, 0.037 ml, 0.037 mmol, 1.5 equivalents) is added dropwise to a solution of aldehyde 27 (17.0 mg, 0.025 mmol, 1.0 equivalent) in THF (1.2 ml) at 25°C. After 10 min (TLC monitoring), the reaction mixture is quenched by the addition of aqueous saturated NH 4 CI solution (5 ml), extracted with diethyl ether (2 x 10 ml), dried over Na 2 SO 4 and concentrated. The residue is redissolved in CH 2 CI 2 (1.0 ml), and NaHCO 3 (41.8 mg, 0.497 mmol, 20 equivalents) is added to the solution at 0°C. After 40 min, Dess-Martin periodinane (10.6 mg, 0.025 mmol, 1.0 equivalent) is added to the reaction mixture at the same temperature, and the solution is warmed to 25°C. After stirring for 4 h at ambient temperature, the reaction mixture is diluted with diethyl ether (5 ml) and quenched by the consecutive addition of saturated aqueous NaHCO 3 solution (5 ml) and sodium thiosulfate pentahydrate (Na 2 S 2 θ 3 - » 5H 2 θ, 65 mg, 0.261 mmol, 10.4 equivalents). The resulting solution is extracted with diethyl ether (2 x 10 ml), and the combined organic extracts are dried over Na 2 SO 4 and concentrated. The crude product is purified by flash chromatography (silica gel, 1% EtOAc in hexane) to provide enyneone 37 (14.4 mg, 85%, two steps) as a colorless oil. Rf= 0.46 (silica gel, EtOAc-hexane, 1 :10); FT-IR (neat) vmax 2961 , 2361 , 2197, 1650, 1611 , 1512, 1461 , 1384, 1461 , 1384, 1248, 1175, 1095, 1035, 841 , 760, 685 cm "1 . Synthesis of propargylic alcohol 38 as illustrated in Scheme 7. To a solution of trimethylsilyl ether 37 (3.2 mg, 0.0047 mmol, 1.0 equivalent) in methanol (1 ml) is added, at 25°C, PPTS (1.18 mg, 0.0047 mmol, 1.0 equivalent), and the reaction mixture is allowed to stir at ambient temperature for 30 min. The reaction is quenched by addition of saturated NaHCO 3 solution (1 ml) and extracted with diethyl ether (2 x 10 ml). The combined organic extracts are dried over Na 2 SO and concentrated. The crude product is purified by flash chromatography (silica gel, 15% EtOAc in hexane) to provide alcohol 38 (2.7 mg, 94%) as a colorless oil. Rf= 0.45 (silica gel, EtOAc-hexane, 1 :3). Synthesis of the basic tricyclic core 40 as illustrated in Scheme 7. To a solution of alkynone 38 (6.2 mg, 0.0135 mmol, 1.0 equivalent) in toluene (1 ml) is added 5% Pd on CaSO 4 treated with Pb (Lindlar cat., 14.0 mg, 0.00675 mmol, 0.5 equivalents) at 25°C under argon. This suspension is then stirred under a H 2 atmosphere (1 atm) at the same temperature for 20 min, and the reaction mixture is filtered through Celite® and concentrated. The crude residue is purified by flash chromatography (silica gel, 10% EtOAc-hexanes) to produce hemiketal 40 (6.2 mg, 75%) as a colorless oil, along with its 5,6-dihydro analog (1.5 mg, 15%). Rf= 0.55 (silica gel, EtOAc-hexane, 1 :3); FT-IR (neat) vmax 3418, 2866, 1615, 1515, 1463, 1248, 1017 cm "1 . Synthesis of methyl ketal 41 as illustrated in Scheme 7. To a solution of hemiketal 40 (4.0 mg, 0.0066 mmol, 1.0 equivalent) in methanol (0.5 ml) is added PPTS (1.65 mg, 0.0066 mmol, 1.0 equivalent). After 10 min, the reaction is quenched by addition of saturated NaHCO 3 solution (5 ml). The bi-phasic system is then extracted with CH 2 CI 2) (3 x 10 ml) and the organic extracts are combined, dried over Na 2 SO 4 and concentrated. The product is purified by flash chromatography (silica gel, 5% EtOAc in hexane) to furnish ketal 41 (4.5 mg, 100%) as a light yellow oil. Rf= 0.68 (silica gel, EtOAc- hexane, 1 :3); FT-IR (neat) vmax 2957, 2866, 1614, 1514, 1463, 1250, 1064 cm "1 . Synthesis of alcohol 42 from PMB ether 41 as illustrated in Scheme 7. A solution of ether 41 (5.0 mg, 0.0080 mmol, 1.0 equivalent) in THF (1 ml) and ethanol (2 drops) is added to liquid NH3 (2 ml) at -78°C. Sodium (1.8 mg, 0.078 mmol, 9.8 equivalents) is then added, and the reaction is stirred at -78°C for 20 min. After the end of the deprotection is established by TLC, the reaction is quenched by addition of solid NH 4 CI (50 mg), warmed to ambient temperature to evaporate the NH 3 , extracted with diethyl ether (3 x 10 ml), dried with Na 2 SO , concentrated and purified by flash chromatography (silica gel, 15% EtOAc in hexane) to provide alcohol 42 along with its 5,6-dihydro analog 43 as an inseparable mixture (ca. 2:1 , 3.8 mg, 95%). Synthesis of alcohol 42 from hydroxy alkynone 45 as illustrated in Scheme 9. To a solution of α,β-alkynone 45 (26.8 mg, 0.055 mmol, 1.0 equivalent) in acetone (3 ml) is added [Rh(nbd)(dppb)]BF4 (1.9 mg, 0.0027 mmol, 0.05 equivalents) at 25°C under argon. The reaction flask is then evacuated and treated with hydrogen gas (1 atm). After 10 min, the reaction is quenched by addition of saturated NaHCO 3 (10 ml), extracted with diethyl ether (3 x 10 ml), dried over Na 2 SO 4 , and concentrated to a crude residue. To a solution of this residue in methanol (6 ml) is added PPTS (6.9 mg, 0.027 mmol, 0.5 equivalents) at 25°C. After 10 min, the reaction is quenched by addition of saturated NaHCO 3) (10 ml), extracted with diethyl ether (3 x 20 ml), dried over Na 2 SO 4 and concentrated. The residue is purified by flash chromatography (silica gel, 15% EtOAc in hexane) to produce methyl ketal 42 (22.2 mg, 80%, two steps) as a coloriess oil. Rf= 0.43 (silica gel, EtOAc-hexane, 1 :3); FT-IR (neat) vmax 3456, 2940 2866, 1466, 1366, 1047, 881 cm "1 . Synthesis of 5,6-dihydro analog 43 from hydroxy alkynone 45 as illustrated in Scheme 12. To a solution of ketone 45 (4.5 mg, 0.0092 mmol, 1.0 equivalent) in ethyl acetate (0.5 ml) is added 5% Pd on BaSO 4 (19.6 mg, 0.0092 mmol, 1.0 equivalent). This suspension is stirred under a hydrogen atmosphere (1 atm) at 25°C for 1 h. The reaction mixture is then filtered through Celite® and concentrated by evaporation. To a solution of the crude residue in methanol (0.5 ml) is added PPTS (4.6 mg, 0.018 mmol, 2.0 equivalents), and the mixture is stirred for 6 h at 25°C. A saturated solution of NaHCO 3 (5 ml) is added, and the reaction mixture is extracted with diethyl ether (3 x 10 ml), dried over Na 2 SO 4 and concentrated. The crude residue is purified by flash chromatography (silica gel, 15% EtOAc-hexane) to provide 5,6-dihydro methyl ketal analog 43 (3.0 mg, 64%, two steps). Rf= 0.50 (silica gel, EtOAc- hexane, 1 :3); FT-IR (neat) vmax 3422, 2961 , 2865, 2361 , 1464, 1383, 1122, 1047, 882, 684 cm "1 . Synthesis of bicyclic alcohol 44 as illustrated in Scheme 9. To a solution of PMB-ether 37 (31.0 mg, 0.045 mmol, 1.0 equivalent) in CH 2 CI 2 (4.6 ml) and H 2 O (0.3 ml) is added DDQ (21.0 mg, 0.091 mmol, 2.0 equivalents), and the reaction is stirred at 25°C for 30 min. After the disappearance of starting ether is established by TLC, the reaction mixture is quenched by addition of saturated NaHCO 3 (3 ml), extracted with diethyl ether (3 x 10 ml), and dried over Na 2 SO 4 . The crude residue is purified by flash chromatography (silica gel, EtOAc-hexane, 1 :99) to yield alcohol 44 (20.4 mg, 80%) as a colorless oil. Rf= 0.57 (silica gel, EtOAc-hexane, 1 :10); FT-IR (neat) vmax 3490, 2959, 2866, 2197, 1651 , 1464, 1384, 1252, 1122, 1095, 1021 , 864, 843 cm "1 . Synthesis of alkynone 49 as illustrated in Scheme 10. To a solution of aldehyde 36 (243.0 mg, 0.338 mmol, 1.0 equivalent) in THF (17 ml) is added dropwise a 1.0 M THF solution of LiHMDS (0.68 ml, 0.68 mmol, 2.0 equivalents) at -20°C. The reaction mixture is stirred for 20 min at that temperature, and then it is quenched with saturated NH 4 CI solution (30 ml), extracted with diethyl ether (2 x 50 ml), dried over Na 2 SO 4 and concentrated to a crude residue. A solution of this residue in CH 2 CI 2 (9 ml) is added to a solution of NaHCO 3 (170.0 mg, 2.0 mmol, 5.9 equivalents), pyridine (0.16 ml, 2.0 mmol, 5.9 equivalents) and Dess-Martin reagent (286.0 mg, 0.67 mmol, 2.0 equivalents) in CH 2 CI (9 ml) at 0°C. The reaction is stirred for 1 h at the same temperature and then it is quenched by consecutive addition of saturated NaHCO 3 (20 ml) and Na 2 S 2 O 3 » 5H 2 O (1.17g, 4.7 mmol, 13.9 equivalents). It is stirred for an additional 30 min, extracted with diethyl ether (2 x 50 ml), dried over Na 2 SO 4 and concentrated. This crude residue is then purified by flash chromatography (silica gel, 0.5% EtOAc in hexane) to produce bicyclic alkynone 49 (216 mg, 89%, two steps) as a light yellow oil. Rf= 0.74 (silica gel, EtOAc-hexane, 1 :10); FT-IR (neat) vmax 2957, 2362, 1652, 1460, 1383, 1212, 1114, 1004, 883, 732, 684 cm "1 . Synthesis of diol 45 as illustrated in Scheme 10. To a solution of trisilyl ether 49 (200 mg, 0.28 mmol, 1.0 equivalent) in THF (1 ml) is added triethylamine » 3HF (0.23 ml, 1.40 mmol, 5.0 equivalents) at 25°C. After 1.5 h, the reaction mixture is cooled to 0°C, quenched by addition of NaHCO 3 (10 ml), extracted with diethyl ether (3 x 10 ml), dried over Na 2 SO 4 and concentrated. The residue is purified by flash chromatography (silica gel, 25% EtOAc in hexane) to produce diol 45 (107 mg, 78%) as a colorless oil. Rf= 0.26 (silica gel, EtOAc-hexane, 1 :3); FT-IR (neat) vmax 3411 , 2941 , 2867, 2202, 1650, 1465, 1385, 1207, 1089, 1018, 883, 757, 685 cm "1 . Synthesis of mixed anhydride of the aromatic side chain 52 as illustrated in Scheme 11. To a solution of ethyl ester 50 (750 mg, 4.16 mmol, 1.0 equivalent) in (1 :1) THF:water (32.0 ml) at 25°C is added LiOH » H 2 O (192 mg, 4.57 mmol, 1.1 equivalents) and the resulting reaction mixture is stirred at the same temperature for 12 h. The solvent is removed under reduced pressure, and the solid is azeotroped with benzene (5 ml x 5) and finally dried under high vacuum. The acid salt 51 is used without further purification. To a solution of 51 in THF (40 ml) at 25°C is added pivaloylchloride (0.54 ml, 4.58 mmol, 1.1 equivalents) and the reaction mixture is stirred at the same temperature for 12 h. After completion judged by TLC, the reaction mixture is filtered, and the filtrate is concentrated under redu- ced pressure and dried under high vacuum to give anhydride 52 (698 mg, 75%). The anhydride is stored as a 0.2 M solution in CH 2 CI 2 and used in this form for the esterification. Synthesis of 53 by attachment of the aromatic side chain (Scheme 11). A mixture of alcohol 42 (61.0 mg, 0.120 mmol, 1.0 equivalent), 4-DMAP (14.7 mg, 0.120 mmol, 1.0 equivalent), triethylamine (0.3 ml, 2.15 mmol, 17.9 equivalents) and mixed anhydride 52 (6.0 ml of 0.2 M solution in CH 2 CI 2 , 1.22 mmol, 10.0 equivalents) is stirred at 25°C for 22 h. The reaction mixture is then concentrated and purified by flash chromatography (silica gel, 10:10:1 , EtOAc:CH 2 CI 2 : methanol) to yield ester 53 (75.0 mg, 98%). Rf= 0.42 (silica gel, 10:10:1 , EtOAc:CH 2 CI 2 :methanol); FT-IR (neat) vmax 2940, 2864, 1704, 1639, 1465, 1384, 1269, 1154, 1060, 994 cm "1 . Synthesis of alcohol 54 as illustrated in Scheme 11. To a solution of silyl ether 53 (75.0 mg, 0.117 mmol, 1.0 equivalent) in THF (2 ml) is added 1.0 M TBAF in THF (0.22 ml, 0.22 mmol, 1.9 equivalents) and the reaction is stirred for 1 h at 25°C. After completion (thin layer chromatography monitoring), the reaction mixture is concentrated and purified by flash chromatography (silica gel, 10:10:1 , EtOAc:CH 2 CI 2 :me- thanol) to provide alcohol 54 (50.0 mg, 89%). Rf= 0.23 (silica gel, 10:10:1 , EtOAc:CH 2 CI 2 :methanol); FT-IR (neat) vmax 3380, 2961 , 2361 , 1700, 1636, 1450, 1382, 1269, 1 156, 1036, 731 cm "1 . Synthesis of aldehyde 55 as illustrated in Scheme 11. To a solution of allylic alcohol 54 (50 mg, 0.104 mmol, 1.0 equivalent) in CH 2 CI 2 (2 ml) is added NaHCO 3 (88.0 mg, 0.595 mmol, 10.0 equivalents) and Dess-Martin reagent (84.8 mg, 0.20 mmol, 2.0 equivalents), and the reaction is stirred for 30 min at ambient temperature, after which isopropanol (0.1 ml) is added followed by ethyl acetate (10 ml). The precipitate is filtered off and the filtrate is concentrated and purified by flash chromatography (silica gel, 10:10:1 , EtOAc:CH 2 CI 2 :methanol) to yield aldehyde 55 (49.5 mg, 100%). Rf= 0.43 (silica gel, 10:10:1 , EtOAc:CH 2 CI 2 :methanol). Synthesis of methyl ester 57 with the intermediacy of acid 56 as illustrated in Scheme 11. To a solution of aldehyde 55 (14.0 mg, 0.0291 mmol, 1.0 equivalent) in f-BuOH:H 2 O (5:1 , 1.2 ml total) is added 2.0 M 2-methyl-2-butene in THF (1 ml, 2.0 mmol, 68.7 equivalents), NaH 2 PO 4 (10.5 mg, 0.087 mmol, 2.9 equivalents) and NaCIO 2 (15.7 mg, 0.174 mmol, 6.0 equivalents) at 0°C. The reaction is stirred at the same temperature for 2 h, after which an diethyl ether solution of CH 2 N 2 (excess) is added and the reaction is stirred for an additional 10 min at 25°C. The excess CH 2 N 2 is removed by an argon stream, the reaction is extracted with ethyl acetate (3 x 15 ml), dried over Na 2 SO 4 and concentrated. The crude residue is purified by flash chromatography (silica gel, 10:10:1 EtOAc:CH 2 CI 2 :methanol) to furnish methyl ester 57 (13.1 mg, 88%, two steps). Rf = 0.42 (silica gel, 10:10:1 EtOAc:CH 2 CI 2 :me- thanol); FT-IR (neat) vmax 3410, 2960, 1711 , 1637, 1435, 1384, 1269, 1155, 1048, 732 cm "1 . Completion of the synthesis for sarcodictyin A (7) as illustrated in Scheme 11. To a solution of methyl ester 57 (6.0 mg, 0.0117 mmol, 1.0 equivalent) in 10:1 CH 2 CI 2 :H 2 O (1.1 ml) is added CSA (10 mg, 0.043 mmol, 6.4 equivalents) and the reaction is stirred at 25°C for 16 h, after which triethylamine is added and the reaction mixture is concentrated. The crude mixture is purified by flash chromatography (silica gel, 10:10:1 , EtOAc:CH 2 CI 2 :methanol) to yield sarcodictyin A (7) (4.6 mg, 79%) as a white solid. Rf= 0.32 (silica gel, 10:10:1 , EtOAc:CH 2 CI 2 :methanol); FT-IR (neat) vmax 2958, 2361 , 1711 , 1636, 1244, 1153, 1050 cm "1 . Synthesis of ethyl ester 58 as illustrated in Scheme 11. To a solution of aldehyde 55 (27.8 mg, 0.058 mmol, 1.0 equivalent) in f-BuOH:H 2 O (5:1 , 1.2 ml total) is added 2.0 M 2-methyl-2-butene in THF (1 ml, 2.0 mmol, 34.4 equivalents), NaH 2 PO 4 (20.9 mg, 0.174 mmol, 3.0 equivalents) and NaCIO 2 (31.5 mg, 0.340 mmol, 2.9 equivalents) at 0°C. The reaction is stirred at the same temperature for 2 h, after which an diethyl ether solution of excess CH 3 CHN 2 is added and the reaction is stirred for an additional 10 min at 25°C. The excess CH 3 CHN 2 is removed by an argon stream, the reaction is extracted with diethyl ether (2 x 15 ml), dried over Na 2 SO 4 and concentrated. The crude residue is purified by flash chromatography (silica gel, 10:10:1 EtOAc:CH 2 CI 2 :methanol) to yield ethyl ester 58 (27.0 mg, 89%, two steps). Rf= 0.41 (silica gel, 10:10:1 EtOAc:CH 2 CI 2 :methanol); FT-IR (neat) vmax 2963, 1708, 1636, 1269, 1154, 1048 cm "1 . Completion of the synthesis of sarcodictyin B (8) as illustrated in Scheme 11. To a solution of ethyl ester 58 (3.5 mg, 0.0067 mmol, 1.0 equivalent) in 10:1 CH 2 CI 2 :H 2 O (1.1 ml) is added CSA (10.0 mg, 0.043 mmol, 6.4 equivalents) and the reaction is stirred at 25°C for 24 h, after which triethylamine is added and the reaction mixture is concentrated. The crude mixture is purified by flash chromatography (silica gel, 10:10:1 EtOAc:CH 2 CI 2 :me- thanol) to yield sarcodictyin B (8) (3.0 mg, 86%) as a white solid. Rf= 0.32 (silica gel, 10:10:1 EtOAc:CH 2 CI 2 :methanol); FT-IR (neat) vmax 3348, 2926, 2855, 1708, 1637, 1458, 1383, 1299, 1271 , 1244, 1156, 1051 cm "1 . Synthesis of C5,C6-saturated analog 61 as illustrated in Scheme 12. Analog 61 is synthesized by the same reaction sequence followed for the two natural products (53, 54, 55, 56, 57, 58) from alcohol 43. Rf= 0.32 (silica gel, 10:10:1 , EtOAc:CH 2 CI 2 :methanol); FT-IR (neat) vmax 2959, 1711 , 1638, 1451 , 1247, 1159, 1043 cm "1 . Synthesis of mixed anhydride resin 100 as illustrated in Scheme 14: A suspension of hydroxymethyl polystyrene resin (5.00 g, 4.00 mmol, 1.0 equivalent) in CH 2 CI 2 (50 ml) at 25°C is treated with triethylamine (2.79 ml, 20.0 mmol, 5.0 equivalents) and glutaric anhydride (1.87 g, 16.0 mmol, 4.0 mmol). The reaction mixture is stirred gently (<300 rpm) over 8 h at 25°C after which time it is poured into a fritted funnel, washed with CH CI 2 (50 ml), methanol (50 ml), CH 2 CI 2 (3 x 50 ml), and diethyl ether (2 x 200 ml) and dried to constant weight under high vacuum. The resulting resin is resuspended in CH 2 CI 2 (50 ml) at 25°C and treated with triethylamine (2.79 ml, 20.0 mmol, 5.0 equivalents) followed by pivaloyi chloride (1.44 g, 12.0 mmol, 3.0 equivalents). The reaction mixture is stirred gently over 6 h at 25°C after which time it is poured into a fritted funnel and washed with the following distilled solvents under an argon atmosphere: CH 2 CI 2 (50 ml), diethyl ether (50 ml), CH 2 CI 2 (3 x 50 ml), and diethyl ether (2 x 200 ml) and dried to constant weight under high vacuum (5.60 g). A two-step yield of >90% is determined by titration of the mixed anhydride resin with benzyl alcohol. Thus, in three separate experiments, the mixed anhydride resin (300 mg, 0.207 mmol, 1.0 equivalent) is treated with benzyl alcohol (15.6 mg, 0.145 mmol, 0.7 equivalents), (20.1 mg, 0.186 mmol, 0.9 equivalents) and (24.5 mg, 0.227 mmol, 1.1 equivalents) followed by triethylamine (43.2 ml, 0.310 mmol, 1.5 equivalents) and 4-DMAP (5.0 mg, 0.041 mmol, 0.2 equivalents). TLC analysis of the reaction mixtures reveals complete consumption of the benzyl alcohol for the experiments with 0.7 and 0.9 equivalents of benzyl alcohol establishing the yield as at least 90%. Synthesis of hydroxy resin 120 as illustrated in Scheme 14: To a suspension of NaH (60% in mineral oil, 1.76 g, 44.0 mmol, 4.0 equivalents) in DMF (100 ml) at 0°C is added 1 ,4-butanediol (3.86 ml, 44.0 mmol, 4.0 equivalents) and the reaction mixture is stirred for 1 h at 0°C. Merrifield resin (10.0 g, 11.0 mmol, 1.0 equivalent) is then added to the reaction mixture followed by tetra-n-butylammonium iodide (400 mg, 0.11 mmol, 0.1 equivalents) and the mixture is stirred gently (<300 φm) over 12 h. The resin is poured into a fritted funnel, washed with aqueous HCI (1 N, 200 ml), DMF (2 x 300ml), methanol (200 ml), CH 2 CI 2 (300 ml), methanol (200 ml), CH 2 CI 2 (2 x 300 ml), and diethyl ether (2 x 200 ml) and dried to constant weight under high vacuum (9.98 g, 99% yield). A sample of this resin is suspended in CH 2 CI 2 at 25°C and treated with Fmoc-CI (5.0 equi- valents) and pyridine (5.0 equivalents) for 6 h. The reactive hydroxyl groups are photometrically quantified from the amount of Fmoc chromophore released upon treatment of the Fmoc-resin with 10% triethylamine in CH CI 2 at 25°C for 8 h. Synthesis of iodo resin 130 as illustrated in Scheme 14: A suspension of hydroxy resin 120 (9.00 g, 9.39 mmol, 1.0 equivalent) in CH 2 CI (100 ml) at 0°C is treated sequentially with imidazole (2.55 g, 37.6 mmol, 4.0 equivalents), Ph 3 P (9.85 g, 37.6 mmol, 4.0 equivalents) and iodine (9.55 g, 37.6 mmol, 4.0 equivalents). The reaction mixture is stirred gently at 0°C for 4 h after which time it is poured into a fritted funnel, washed with CH 2 CI 2 (3 x 200 ml), methanol (200 ml), CH 2 CI 2 (2 x 200 ml), and diethyl ether (2 x 200 ml) and dried to constant weight under high vacuum (9.95 g, >95% yield). Subjection of this resin to the Fmoc assay described in the synthesis of 120, indicates complete consumption of the alcohol. Synthesis of phosphorane resin 140 as illustrated in Scheme 14: A mixture of iodide resin 130 (5.00 g, 4.45 mmol, 1.0 equivalent) and Ph 3 P (11.7 g, 44.5 mmol, 10 equivalents) in DMF (30 ml) is gently stirred at 100°C for 15 h after which time it is poured into a fritted funnel, washed with warm (100°C) DMF (3 x 200 ml), CH 2 CI 2 (2 x 200 ml) and diethyl ether (3 x 300 ml) and dried to a constant weight of 6.10 g (>95% yield based on mass gain). A portion of this resin (2.2 g, 1.57 mmol, 1.0 equivalent) is resuspended in THF (15 ml) at 25°C, LiHMDS (1.0 M in THF, 2.04 ml, 2.04 mmol, 1.3 equivalents) is added, and the reaction is allowed to stir for 2 h at ambient temperature after which time the resin adopts a deep red color. The supernatant solvent is removed by cannulation, the resin is washed with THF (3 x 15 ml) and the resulting resin is used for the next step without any additional treatment (>90% yield). The yield is determined as follows. The ylide is quenched with benzaldehyde (5.0 equivalents, 25°C, 6 h) and the resulting resin is subjected to ozonolysis (CH 2 CI 2 , -78°C, 30 min) followed by a reductive workup (Me2S). The quantity of benzaldehyde recovered is quantified by HPLC absorption calibrated with an authentic benzaldehyde sample. Acetate 180 as illustrated in Scheme 15. A solution of hydroxy compound 47 (0.404 g, 0.806 mmol, 1.0 equivalent) in CH 2 CI (10 ml) at 25°C is treated with pyridine (0.322 g, 4.03 mmol, 5.0 equivalents) and acetic anhydride (0.246 g, 2.42 mmol, 3.0 equivalents). The reaction mixture is stirred for 1 h at 25°C after which time TLC analysis indicates complete reaction. The reaction mixture is poured into diethyl ether (150 ml), washed with sat. aq. NaHCO 3 (3 x 100 ml), dried over MgSO 4 , and concentrated. The crude mixture is purified by flash column chromatography (silica gel, EtOAc- hexane, 1 :3) to furnish pure acetate 180 (0.421 g, 96% yield). Rf= 0.20 (silica gel, EtOAc- hexane, 1 :3); [ α] D25 +47.8 (c = 2.32, CHCI 3 ); FT-IR (neat) vmax 2942, 2866, 2363, 2334, 1739, 1720, 1459, 1364, 1239, 1034 cm "1 . Hydroxy ketal 190 as illustrated in Scheme 15. A solution of ketal 180 (0.421 g, 0.774 mmol, 1.0 equivalent) in CH 2 CI2 (5 ml) at 25°C is treated with 1 ,6-hexanediol (0.913 g, 7.74 mmol, 10 equivalents) and PPTS (0.194 g, 0.774 mmol, 1.0 equivalent). The reaction mixture is stirred for 4 h at 25°C after which time TLC analysis indicates complete reaction. The reaction mixture is loaded onto a short silica column and eluted with EtOAc-hexanes (1 :2) to give pure hydroxy ketal 190 (0.450 g, 92% yield). Rf= 0.15 (silica gel, EtOAc-hexanes, 1 :2); [ ] D25 +36.5 (c = 1.0, C6H6); FT-IR (neat) vmax 3427, 2936, 2864, 1742, 1465, 1368, 1238, 1051 , 1032, 880 cm "1 . Aldehyde ketal 200 as illustrated in Scheme 15. To a solution of Dess-Martin periodinane (0.451 g, 1.07 mmol, 1.5 equivalents) in CH 2 CI 2 (10 ml) at 25°C is added pyridine (0.280 g, 3.56 mmol, 5.0 equivalents) and NaHCO 3 (0.598 g, 7.12 mmol, 10 equivalents). The mixture is stirred for 15 min at ambient temperature and then cooled to 0°C. Alcohol 190 (0.450 g, 0.712 mmol, 1.0 equivalent) is added as a solution in CH 2 CI 2 (10 ml). The reaction mixture is removed from the cold bath after 15 min and stirred for an additional 2 h at 25°C after which time TLC analysis indicates complete reaction. The crude mixture is loaded onto a short silica gel column and eluted with EtOAc-hexane (1 :3) to yield pure product 200 (0.430 g, 96% yield). Rf = 0.18 (silica gel, EtOAc-hexane, 1 :3); [α] D25 +29.0 (c = 1.0, C 6 H 6 ); FT-IR (neat) vmax 2940, 2865, 1939, 1458, 1369, 1238, 1032, 996, 880 cm "1 . Attachment of sarcodictyin core 180 on resin 120 by transketalization as illustrated in Scheme 16. To a suspension of resin 120 (0.563 g, 0.54 mmol, 10 equivalents) in CH 2 CI 2 (3 ml) containing flamed-dried 4 A molecular sieves (0.30 g) at 25°C is added a solution of ketal 180 (28 mg, 0.054 mmol, 1.0 equivalent) in CH 2 CI 2 (1 ml) followed by PPTS (13 mg, 0.054 mmol, 1.0 equivalent). The reaction mixture is agitated gently on a wrist shaker at ambient temperature for 48 h and then filtered and washed with anhydrous CH 2 CI 2 (2 x 5 ml). The unreacted starting material in the combined filtrates is purified to recover 14 mg of pure 180 (50% yield based on recovered starting material). The excess alcohol on the resin is caped by resuspending the resin in DMF (3 ml) followed by addition of MOM-CI (88 mg, 0.054 mmol, 20 equivalents) and Pr 2 NEt (126 mg, 1.1 mmol, 20 equivalents) for 24 h at ambient temperature. The resin is filtered in a fritted funnel, washed with CH 2 CI 2 (3 x 50 ml) containing 1% triethylamine, diethyl ether (2 x 50 ml) and dried under high vacuum to a constant weight of 0.56 g (0.039 mmol/g loading of the sarcodictyin core). Attachment of sarcodictyin core 200 on resin 140 by a Wittig reaction as illustrated in Scheme 16. To a suspension of ylide 140 (0.75 mmol, 7.0 equivalents) in THF (2 ml) cooled to -78°C is added a solution of aldehyde 200 (67.6 mg, 0.107 mmol, 1.0 equivalent) in THF (5 ml). The reaction mixture is allowed to warm up slowly to ambient temperature over 2 h and is stirred for an additional 2 h at 25°C, after which time TLC analysis indicates complete consumption of the aldehyde (>95% yield). The excess ylide is quenched by the addition of acetaldehyde (99 mg, 2.25 mmol, 21 equivalents), the resin is collected on a fritted funnel, washed with THF (3 x 50 ml) containing 1 % triethylamine, diethyl ether (2 x 50 ml) and dried under high vacuum to a constant weight of 836 mg (0.128 mmol/g loading of the sarcodictyin core). In a cleavage demonstration experiment, a sample of this resin (225 mg, 28.8 mmol, 1.0 equivalent) is treated with PPTS (14.3 mg, 57.6 mmol, 2.0 equivalents) in methanol (0.5 ml) at 25°C for 30 h to recover, after purification (silica gel, flash column chromatography), 14.2 mg of the corresponding methyl ketal (90% for 2 steps). Hydrolysis of acetate 240 and formation of polymer-bound alcohol 250 as illustrated in Scheme 17. To a suspension of resin 240 (3.12 g, 0.40 mmol, 1.0 equivalent) in THF (20 ml) is added NaOMe (0.5 M in methanol, 4.0 ml, 2.0 mmol, 5.0 equivalents). The reaction mixture is agitated on a wrist shaker for 12 h at ambient temperature. The resin is filtered and washed with methanol containing 1 % triethylamine (100 ml), CH 2 CI 2 containing 1 % triethylamine (100 ml) and diethyl ether (100 ml) and then dried under high vacuum. The completion of the reaction is verified by TLC analysis after cleavage of the product from the resin with PPTS (ca. 3 equivalents) in methanol. NMR analysis of the crude product obtained from the cleavage shows a single compound corresponding to the previously reported product 410 (Scheme 19) thereby establishing a yield of >95%. Although exact procedures for the sequence of reactions leading to sarcodictyins A (7) and B (8) are given only for resin 240, similar procedures are followed for resin 230 and with similar results. Attachment of the urocanic acid side chain and synthesis of resin 270 as illustrated in Scheme 17. A suspension of hydroxy resin 250 (2.0 g, 0.256 mmol, 1.0 equivalent) in DMF (6 ml) is treated with mixed anhydride 260 (0.302 g, 1.28 mmol, 5.0 equivalents) in the presence of Et 3 N (0.357 ml, 2.56 mmol, 10 equivalents) and 4-DMAP (62 mg, 0.512 mmol, 2.0 equi- valents) for 24 h at 50°C. The resin is filtered, washed with CH 2 CI 2 containing 1 % triethylamine (2 x 25 ml), diethyl ether (25 ml), CH 2 CI 2 containing 1% triethylamine (2 x 25 ml) and diethyl ether (3 x 20 ml) and then dried under high vacuum. The completion of the reaction is confirmed by TLC analysis after cleavage of the product from the resin by the action of PPTS (ca. 3 equivalents) and methanol (which also reveals the presence of 5-10% of a less polar by-product presumed to be derived from impurities in reagent 260). NMR analysis of the crude product obtained from the cleavage confirms its identityl 6 and leads to an estimated yield of 90%. Desilylation and oxidation of alcohol 270. Synthesis of solid-supported aldehyde 280 as illustrated in Scheme 17. A suspension of resin 270 (300 mg, 38.4 mmol, 1.0 equivalent) in THF (1.5 ml) is treated with TBAF (1.0 M in THF, 384 mmol, 10 equivalents) for 8 h at 25°C. The resin is filtered, washed with THF containing 1% triethylamine (4 x 10 ml) and diethyl ether (3 x 10 ml) and then dried under high vacuum. The completion of the reaction is established by TLC analysis after cleavage of the product from a sample of resin by the action of PPTS (ca. 3 equivalents) and methanol. NMR analysis of the crude product so obtained confirms its identity and establishes a yield of >95% for the deprotection steps. The resin (250 mg, 32 mmol, 1.0 equivalent) is resuspended in CH 2 CI 2 (1.0 ml) containing pyridine (12.8 mg, 160 mmol, 5.0 equivalents) and treated with a preformed suspension of Dess-Martin periodinane (67.2 mg, 160 mmol, 5.0 equivalents), NaHCO 3 (40.3 mg, 480 mmol, 15 equivalents) and pyridine (25.6 mg, 64 mmol, 10 equivalents) in CH 2 CI 2 (1.5 ml). The mixture is allowed to react for 2 h at ambient temperature. The resin Is then filtered, washed with CH 2 CI 2 (4 x 10 ml), H O (3 x 10 ml), methanol (2 x 5 ml), CH 2 CI 2 (2 x 5 ml), diethyl ether (3 x 5 ml) and dried under high vacuum. The completion of the reaction, the identity of the resulting product and the yield of the reaction (>95%) are established by TLC and NMR analysis after subjecting a sample of the resin to cleavage with CSA (ca. 3 equivalents) and methanol. Oxidation of aldehyde 280 and esterification of the resulting carboxylic acid. Synthesis of polymer-bound sarcodictyins A (290) and B (300) as illustrated in Scheme 17. A mixture of resin 280 (220 mg, 28.2 mmol, 1.0 equivalent), sodium chlorite (63.3 mg, 704 mmol, 25 equivalents), KH 2 PO (83.7 mg, 704 mmol, 25 equivalents) and isobutylene (2 M in THF, 1.40 mmol, 50 equivalents) in THF:f-SuOH:H 2 O (4:4:1 ) is allowed to react for 48 h at ambient temperature. The resulting resin is filtered, washed with water (3 x 10 ml), methanol (2 x 10 ml), 0.5 M PPTS in CH 2 CI 2 (3 x 10 ml), CH 2 CI 2 (2 x 10 ml) and diethyl ether (2 x 10 ml) and then dried under high vacuum. The completion of the reaction is establi- shed by TLC analysis after cleaving the acid products from the resin with CSA (ca. 3 equivalents) in methanol thereby estimating a yield of >95%. The resin is then split into two portions (100 mg each, 12.8 mmol, 1.0 equivalent) and each is treated with a solution of DMF (0.5 ml) containing DCC (26 mg, 128 mmol, 10 equivalents) and 4-DMAP (7.7 mg, 64 mmol, 5.0 equivalents). To the first portion of resin is added methanol (4.0 mg, 128 mmol, 10 equivalents) and to the second portion of resin is added ethanol (5.9 mg, 128 mmol, 10 equivalents). The reaction vessels are agitated on a wrist shaker for 48 h after which time each resin is filtered and washed with CH 2 CI 2 (4 x 5 ml), methanol (2 x 5 ml), CH 2 CI 2 (3 x 5 ml), diethyl ether (3 x 5 ml). The completion of the reaction is established by TLC after cleaving a sample of each ester product from the solid support by the action of CSA (ca. 3 equivalents) and methanol thereby estimating a yield of >90%. Cleavage of polymer-bound sarcodictyins A an B with CSA/H 2 0. Synthesis of sarcodictyins A (7) and B (8)as illustrated in Scheme 17. A suspension of resin 290 (92 mg, 11.7 mmol, 1.0 equivalent) or 300 (90 mg, 11.5 mmol, 1.0 equivalent) in CH 2 CI 2 /H 2 O (2:1 , 2.0 ml) at 25°C is treated with CSA (8 mg, 35.1 mmol, 3.0 equivalents) and stirred vigorously over the course of 40 h. The reaction mixture is then quenched with NaHCO 3 (9.8 mg, 117 mmol, 10 equivalents) filtered and the aqueous layer washed with CH 2 CI 2 (3 x 1 ml). The combined organic layers are dried over MgSO 4 and concentrated, and the product is purified by PTLC (3% methanol in CH 2 CI 2 ) to yield 3.0 mg of natural sarcodictyin A (7) (ca. 75% yield from 290, ca. 51 % overall yield from 240) or 2.6 mg sarcodictyin B (8) (ca. 75% yield from 300, ca. 44% overall yield from 240). Reaction of resin 250 with fr ns-cinnamoyl chloride. Towards the synthesis of cinnamoate ester 310 as illustrated in Scheme 18. To a suspension of resin 250 (600 mg, 0.077 mmol) in DMF (5.0 ml) is added cinnamoyl chloride (128 mg, 0.77 mmol, 10 equivalents), triethylamine (0.215 ml, 1.54 mmol, 20 equivalents) and 4-DMAP (46.5 mg, 0.385 mmol, 5.0 equivalents), and the reaction mixture is heated at 50°C for 12 h. The resin is then filtered, washed with CH 2 CI 2 containing 1% triethylamine (5 x 20 ml and diethyl ether (2 x 100 ml) and then dried under high vacuum. The completion of the reaction is established by TLC analysis after cleavage of the ester from the solid support by PPTS (ca. 3 equivalents) in methanol thereby estimating a yield of >95%. DCC-mediated esterification of resin 250 with thiazole acid side chain Ar-ll. Towards the synthesis of thiazole ester 310 as illustrated in Scheme 18. To a suspension of resin 250 (200 mg, 0.026 mmol) in DMF (3.0 ml) is added thiazole acid side chain Ar-ll (scheme 5 and 6)(48 mg, 0.26 mmol, 10 equivalents), DCC (52 mg, 0.26 mmol, 10 equivalents) and 4-DMAP (6.3 mg, 0.052 mmol, 2.0 equivalents), and the reaction mixture is heated at 50°C for 48 h. The resin is then filtered, washed with CH 2 CI 2 containing 1 % triethylamine (5 x 20 ml) and diethyl ether (2 x 100 ml) and then dried under high vacuum. The completion of the reaction is established by TLC analysis after cleavage of the ester from the solid support by PPTS (ca. 3 equivalents) in methanol treatment thereby estimating a yield of 90-95%. Reaction of alcohol 250 with phenyl isocyanate. Towards the synthesis of phenyl carbamate 310 as illustrated in Scheme 18. To a suspension of resin 250 (500 mg, 0.064 mmol, 1.0 equivalent) in DMF (4.0 ml) is added phenyl isocyanate (77 mg, 0.64 mmol, 10 equivalents) and 4-DMAP (39 mg, 0.32 mmol, 5 equivalents) and the reaction mixture is shaken on a wrist shaker for 10 h. The resin is filtered, washed with CH 2 CI 2 containing 1% triethylamine (3 x 15 ml) and diethyl ether (2 x 15 ml), and then dried under high vacuum. The completion of the reaction is established by TLC analysis of the product obtained from PPTS (ca. 3 equivalents)/ methanol cleavage of the substrate from the resin thereby estimating a yield of >95%. General desilylation procedure. Synthesis of hydroxy resins 310 as illustrated in Scheme 18. A suspension of the silylated resin (1.0 equivalent) in THF is allowed to react with TBAF (10 equivalents, 1.0 M in THF) at 25°C for 6 h. The resin is then filtered, washed with THF containing 1 % triethylamine, CH 2 CI 2 (containing 1 % triethylamine) and diethyl ether and then dried under high vacuum. The completion of the reactions is verified by cleavage of the corresponding alcohol from the resin under the influence of PPTS (ca. 3 equivalents) and methanol thereby estimating a yield of >95%. General procedure for the functionalization of hydroxy resins 310. Synthesis of compounds 320 as illustrated in Scheme 18(A). A suspension of resin 310 (1.0 equivalent) in CH2C12 at 25°C is treated with triethylamine (10 equivalents), 4-DMAP (2.0 equivalents) and acetic anhydride (10 equivalents) or ben- zoyl chloride (10 equivalents) or methyl chloroformate (10 equivalents) or phenylisocyanate (10 equivalents). After 15 h, the resin is filtered, washed with CH 2 CI 2 containing 1% triethylamine and diethyl ether and then dried under high vacuum. The reactions are monitored by TLC analysis of the product obtained after PPTS (ca. 3 equivalents)/ methanol cleavage. The acylation, benzoylation and formation of carbamate are found to proceed smoothly (>95%) whereas the carbonate formation proceeds in 70% yield along with the formation of two less polar unidentified by-products. General procedure for the Dess-Martin oxidation of solid-supported hydroxy resins 310. Synthesis of aldehyde resins 340 as illustrated in Scheme 18(B). To a suspension of hydroxy resin 310 (1.0 equivalent) in CH 2 CI 2 containing pyridine (5.0 equivalents) is added a preformed suspension of Dess-Martin periodinane (5.0 equivalents), NaHCO 3 (15 equivalents) and pyridine (10 equivalents) in CH 2 CI 2 . The mixture is allowed to react for 2 h at ambient temperature. The resin is then filtered, washed with CH 2 CI 2 , H 2 O, methanol, diethyl ether and dried under high vacuum. A yield of >95% is estimated by TLC analysis of the cleavage products obtained by treatment of the resin with CSA (ca. 3 equivalents) and methanol. General procedure for the sodium chlorite oxidation of aldehyde resins 340. Synthesis of carboxylic acids 350 (Scheme 18(B)). A mixture of aldehyde resin 340 (1.0 equivalent), sodium chlorite (25 equivalents), KH 2 PO 4 (25 equivalents) and isobutylene (2 M in THF, 50 equivalents) in THF:f-S(-OH:H2O (4:4:1 ) is allowed to react for 48 h at ambient temperature. The resulting resin is filtered, washed with water, methanol, 0.5 M PPTS in CH 2 CI 2 , CH 2 CI 2 , diethyl ether and dried under high vacuum. The completion of the reaction is verified by TLC analysis after cleaving the acid products from the resin with CSA (ca. 3 equivalents) in methanol thereby estimating a yield of >95%. General procedure for the DCC/4-DMAP-mediated formation of ester or amide sarcodictyin analogs 360. To a suspension of resin 350 as illustrated in Scheme 18(B) (1.0 equivalent) in DMF is added DCC (10 equivalents), 4-DMAP (5.0 equivalents), an alcohol or an amine (10 equivalents, amines are used as HCI or PPTS salts) and the reaction mixture is allowed to react for 20 h at ambient temperature. The resin is then filtered, washed with CH 2 CI 2 , methanol and diethyl ether and dried under high vacuum. A yield of >85% is estimated by TLC analysis of the cleavage product obtained by treatment of the resin with CSA (ca. 3 equivalents) and methanol. General procedure for the Ph 3 P/DEAD-mediated formation of ester sarcodictyin analogs 360 as illustrated in Scheme 18(B). A suspension of resin 350 (1.0 equivalent) in THF containing Ph3P (10 equivalents) and an alcohol (10 equivalents) is cooled to 0°C. DEAD (10 equivalents) is then added dropwise and the reaction mixture is allowed to warm up to 25°C. After 12 h, the resin is filtered, washed with CH 2 CI 2 and diethyl ether and dried under high vacuum. The completion of the reaction is established by TLC analysis after cleaving the esters from the resin with CSA (ca. 3 equivalents) in methanol thereby estimating a yield of >90%. General procedure for the formation of azides 380 via a Mitsunobu reaction as illustrated in Scheme 18(C). A suspension of-resin 310 (1.0 equivalent) in THF containing Ph 3 P (10 equivalents) and (PhO) 2 P(O)N 3 (10 equivalents) is cooled to 0°C and treatd with DEAD (10 equivalents, dropwise addition). After completion of the addition, the reaction mixture is allowed to warm up to 25°C. After 4 h, the resin is filtered, washed with CH 2 CI 2 (containing 1 % triethylamine), diethyl ether and dried under high vacuum. The completion of the reaction is established by TLC after cleaving the azide product from the solid support by the action of PPTS (ca. 3 equivalents) and methanol. NMR analysis of the cleavage product reveals >95% yield (see compound 560 for spectroscopic data). General procedure for the Ph β P/^O-mediated reduction of azides 380. Toward the syntheses of amides 390 as illustrated in Scheme 18(C). A suspension of resin 380 (1.0 equivalent) in THF containing Ph 3 P (10 equivalents) and H 2 O (50 equivalents) is heated to 50°C and stirred at that temperature for 8 h. The resin is then filtered, washed with CH 2 CI 2 containing 1 % triethylamine and diethyl ether and dried under high vacuum. The completion of the reaction is established by TLC analysis after cleaving the amine product from the solid support by the action of PPTS (ca. 3 equivalents) and methanol thereby estimating a yield of >95%. General procedure for the synthesis of amides 390 as illustrated in Scheme 18(C). A suspension of the resin-bound amines (1.0 equivalent) in CH 2 CI 2 at 25°C is treated with triethylamine (15 equivalents) and acetic anhydride (10 equivalents) or benzoyi chloride (10 equivalents) for 10 h at ambient temperature. The resin is then filtered, washed with CH 2 CI 2 containing 1% triethylamine, diethyl ether and dried under high vacuum. A yield of >90% is estimated by TLC analysis of the cleavage product obtained by treatment of the resin with PPTS (ca. 3 equivalents) and methanol. General procedure for the cleavage with PPTS/ ROH. Synthesis of sarcodictyin analogs 330 and 400 as illustrated in Scheme 18. A suspension of resins 320 or 390 (1.0 equivalent) in ROH at 25°C is treated with PPTS (3.0 equivalents). After 15 h, the reaction is quenched with solid NaHCO 3 (10 equivalents), filtered and washed with CH 2 CI and methanol. The combined filtrates are concentrated and the product is purified by PTLC (60-90%, see individual compounds in supplementary material for exact overall yields). General procedure for the cleavage with CSA/H 2 0. Synthesis of sarcodictyin analogs 370 as illustrated in Scheme 18(B). A suspension of resins 290 or 300 (1.0 equivalent) in CH 2 CI 2 /H 2 O (2:1 ) at 25°C is treated with CSA (3.0 equivalents). After 40 h, the reaction is quenched with solid NaHCO 3 (10 equivalents) filtered and washed with CH 2 CI 2 . The organic layer of the combined filtrates is collected, dried over MgSO4, concentrated and the product is purified by PTLC (60-90%, see individual compounds in supplementary material for exact overall yields). General procedure for the transketalization with CSA/ ROH. Synthesis of sarcodictyin analogs 370 as illustrated in Scheme 18(C). A suspension of resins 360 in ROH (0.5 ml) at 25°C is treated with CSA (3.0 equivalents). After 15 h, the resin is quenched with NaHCO 3 (10 equivalents), filtered and washed with CH 2 CI 2 and methanol. The combined filtrates are concentrated and the products are purified by PTLC (60-90%, see individual compounds in supplementary material for exact overall yields). Preparation of pyridine carboxylic acid Ar-I as illustrated in Scheme 19: To a solution of 2-pyridinecarboxaldehyde (2.0 g, 18.7 mmol, 1.0 equivalent) in benzene (37 ml) is added Ph 3 PCHCO 2 Me (9.36 g, 28.0 mmol, 1.5 equivalents), and the reaction mixture is heated at reflux temperature for 2 h. After the end of the reaction is established (TLC), the solvent is evaporated under reduced pressure and the crude product is purified by flash column chromatography (silica gel, diethyl ether-hexanes, 1 :1 , Rf= 0.26) furnishing the expected α,β-unsaturated methyl ester (2.9 g, 95% yield). The so prepared methyl ester (1.5 g, 9.2 mmol, 1.0 equivalent) is treated in THF:H 2 O (1 :1 , 30 ml) with LiOH»H 2 O (1.16 g, 27.6 mmol, 3.0 equivalents) at ambient temperature for 3 h after which time the end of the reaction is established (TLC). The reaction mixture is extracted with sat. aq. NaHCO 3 (3 x 20 ml), and the combined aqueous extracts are acidified with 1 M HCI to pH 4 and further extracted with EtOAc (4 x 20 ml). Concentration of the combined organic solutions furnishes, in quantitative yield, essentially pure carboxylic acid Ar-I (1.4 g, 100% yield). Rf = 0.35 (silica gel, EtOAc); mp 141-142 °C (EtOAc); FT-IR (neat) vmax 3434, 3091 , 1700, 1644, 1595, 1568, 1464, 1319, 1224, 1016, 980 cm "1 . Preparation of thiazole carboxylic acid Ar-ll as illustrated in Scheme 19: According to the procedure described for the synthesis of pyridine derivative Ar-I, the corresponding thiazole aldehyde (2.0 g, 16 mmol, 1.0 equivalent) is reacted with Ph 3 PCHCO 2 Me (8.0 g, 24.0 mmol, 1.5 equivalents) in benzene (32 ml) to yield after chromatographic purification (silica gel, diethyl ether-hexanes, 3:1), the expected α,β-unsatura- ted thiazole methyl ester (2.8 g, 97% yield). Rf= 0.42 (silica gel, diethyl ether-hexanes, 3:1); FT-IR (neat) vmax 3095, 3048, 1707, 1631 , 1431 , 1300, 1275, 1170, 1125, 998 cm "1 . The so obtained methyl ester (0.50 g, 2.73 mmol, 1.0 equivalent) is saponified by the action of LiOH « H 2 O (0.33 g, 8.19 mmol, 3.0 equivalents) in THF:H 2 O (1 :1 , 7 ml) as described for pyridine acid Ar-I above, to produce thiazole acid Ar-ll (0.46 g, 100% yield) as a white crystalline solid. Rf= 0.32 (silica gel, EtOAc); mp 172-173 e C (EtOAc); FT-IR (neat) vmax 3413, 2919, 1690, 1672, 1625, 1496, 1414, 1308, 1273, 1196, 1137 cm "1 . Preparation of oxazole carboxylic acid Ar-lll as illustrated in Scheme 19: According to the procedure described for the synthesis of pyridine derivative Ar-I above, the corresponding oxazole aldehyde (0.7 g, 6.3 mmol, 1.0 equivalent) is reacted with Ph 3 PCHCO 2 Me (3.16 g, 9.45 mmol, 1.5 equivalents) in benzene (13 ml) to yield after chromatographic purification (silica gel, EtOAc), the expected α,β-unsaturated oxazole methyl ester (2.7 g, 96%) yield. Rf= 0.61 (silica gel, EtOAc); FT-IR (neat) vmax 3132, 3088, 1716, 1646, 1439, 1388, 1336, 1298, 1209, 1166, 976, 916, 866, 814 cm "1 . This ester (0.3 g, 1.80 mmol, 1.0 equivalent) is saponified by the action of LiOH » H 2 O (0.22 g, 5.4 mmol, 3.0 equivalents) in THF:H 2 O (1 :1 , 15 ml) as described for pyridine carboxylic acid Ar-I, to produce thiazole carboxylic acid Ar-lll (0.28 g, 100%) in quantitative yield as a white crystaline solid. Rf= 0.33 (silica gel, EtOAc); mp 165-166 9 C (EtOAc); FT- IR (neat) vmax 3085, 2938, 2546, 1668, 1636, 1598, 1566, 1429, 1404, 1274, 1219, 1105, 981 , 915, 870, 796, 692, 637 cm "1 . Attachment of the pyridine side chain and desiiylation. Synthesis of compound 420 as illustrated in Scheme 19. To a solution of hydroxy compound 410 (23.0 mg, 0.046 mmol, 1.0 equivalent) in CH 2 CI 2 (2.2 ml) is added 4-DMAP (2.8 mg, 0.023 mmol, 0.5 equivalents), pyridine carboxylic acid Ar-I (10.2 mg, 0.068 mmol, 1.5 equivalents) and DCC (18.8 mg, 0.091 mmol, 2.0 equivalents) at 25°C. The reaction mixture is stirred for 20 h at that temperature and then concentrated. The crude mixture is purified by flash chromatography (silica gel, EtOAc-hexane, 1:4, Rf= 0.28) to furnish the corresponding ester (24.5 mg, 85%). The latter compound is desilylated as follows: A solution of the silylether (24.5 mg, 0.038 mmol, 1.0 equivalent) in THF (1 ml) is treated with TBAF (1.0 M in THF, 77 ml, 2.0 equivalents) and the reaction mixture is stirred for 1 h at 25°C. The solvent is removed under reduced pressure and the crude product is purified by flash chromatography (silica gel, EtOAc-hexane, 1 :1 ) to yield alcohol 420 (16.1 mg, 87%). Rf= 0.10 (silica gel, EtOAc-hexane, 1 :1); [ α] D 5 -13.75 (c = 0.8, CHCI 3 ); FT-IR (neat) vmax 3410, 2961 , 1713, 1647, 1583, 1468, 1434, 1319, 1160, 1034, 986, 786, 752 cm "1 . Attachment of the thiazole side chain and desilylation. Synthesis of compound 430 as illustrated in Scheme 19. According to the procedure described above for compound 420, to a solution of hydroxy compound 410 (15 mg, 0.030 mmol, 1.0 equivalent) in CH 2 CI 2 (1.8 ml) is added 4-DMAP (1.8 mg, 0.015 mmol, 0.5 equivalents), thiazole carboxylic acid Ar-ll (6.5 mg, 0.039 mmol, 1.3 equivalents) and DCC (11.3 mg, 0.055 mmol, 1.7 equivalents) at 25°C to provide, after flash chromatography (silica gel, EtOAc-hexane, 1 :4), the corresponding ester (12 mg, 61 % yield). Desilylation of the latter compound (6.0 mg, 9.1 mmol, 1.0 equivalent) in THF (1 ml) with TBAF (1.0 M in THF, 18 ml, 2.0 equivalents) furnishes after flash chromatography (silica gel, EtOAc-hexane, 1 :2) alcohol 430 (5.5 mg, 100%). Rf= 0.18 (silica gel, EtOAc-hexane, 1 :2); [ α] D25 +19.6 (c = 0.55, CHCI 3 ); FT-IR (neat) vmax 3414, 2961 , 1711 , 1636, 1450, 1270, 1158, 1038 cm "1 . Attachment of the oxazole side chain and desilylation. Synthesis of compound 440 as illustrated in Scheme 19. According to the procedure described for the synthesis of compound 420, alcohol 410 (21 mg, 0.042 mmol, 1.0 equivalent) is treated with 4-DMAP (2.5 mg, 0.020 mmol, 0.5 equivalents), oxazole carboxylic acid Ar-lll (8.4 mg, 0.055 mmol, 1.3 equivalents) and DCC (16.9 mg, 0.082 mmol, 2.0 equivalents) in CH 2 CI 2 (2 ml) to produce, after chromatographic purification (silica gel, EtOAc-hexane, 1 :4, Rf = 0.43) the desired ester (23 mg, 86%). The latter compound (23 mg, 0.036 mmol, 1.0 equivalent) is deprotected by the action of TBAF (1.0 M in THF, 72 ml, 2.0 equivalents) according to the procedure described above for compound 420 to afford, after chromatographic purification (flash column, silica gel, EtOAc-hexane, 1 :1), alcohol 440 (16 mg, 92%). Rf= 0.21 (silica gel, EtOAc-hexane, 1 :1); [ O ]D25 + 8 - 1 ( c = 1.6, CHCI3); FT-IR (neat) vmax 3410, 2961 , 2865, 1712, 1651 , 1451 , 1302, 1258, 1160, 1106, 1035, 988 cm "1 . Oxidation of alcohol 440. Synthesis of aldehyde 470 as illustrated in Scheme 19. To a solution of alcohol 440 (16 mg, 0.033 mmol, 1.0 equivalent) in CH 2 CI 2 (2.0 ml) is added NaHCO 3 (20 mg, 0.238 mmol, ca. 7 equivalents) and Dess-Martin periodinane (25 mg, 0.060 mmol, ca. 2 equivalents) in CH 2 CI 2 (1.5 ml) and the reaction mixture is stirred for 50 min at 25°C after which time isopropanol (excess) is added followed by EtOAc (2.0 ml). The precipitates are filtered off through a short plug of silica and the filtrates are concentrated and purified by flash chromatography (silica gel, EtOAc-hexane, 1 :1 ) to yield the desired aldehyde 470 (13.3 mg, 84%). Rf= 0.56 (silica gel, EtOAc-hexane, 1 :1 ); [ α] D25 +85.0 (c = 1.3, CHCI 3 ); FT-IR (neat) vmax 2962, 1697, 1650, 1450, 1301 , 1256, 1160, 1107 cm "1 . Preparation of sarcodictyin analog 480 as illustrated in Scheme 19: According to the procedure described above for the synthesis of compound 470, alcohol 420 (16.0 mg, 0.033 mmol, 1.0 equivalent) is treated with NaHCO 3 (26.6 mg, 0.334 mmol, ca. 10 equivalents) and Dess-Martin periodinane (35.4 mg, 0.083 mmol, ca. 2.5 equivalents) in CH 2 CI 2 (1.5 ml) to produce, after chromatographic purification (silica gel, EtOAc-hexane, 1 :4, Rf= 0.35), the corresponding aldehyde (7.0 mg, 44%). The so obtained aldehyde 450 (7.0 mg, 0.015 mmol, 1.0 equivalent) is treated with 2-methyl-2-butene (2.0 M in THF, 1.5 ml), NaH 2 PO 4 (5.3 mg, 0.044 mmol, ca. 3 equivalents) and NaCIO 2 (8.0 mg, 0.088 mmol, ca. 6 equivalents) in THF:f-SuOH:H 2 O (5:5:1 , 2.2 mi) at 0°C. The reaction mixture is stirred at 0°C for 2 h after which time a solution of CH 2 N 2 in diethyl ether (excess) is added and stirring is continued for an additional 10 min at 25°C. The excess CH 2 N 2 is removed by a stream of argon and the reaction mixture is extracted with diethyl ether (3 x 8 ml), dried over Na 2 SO , and concentrated. The crude residue is purified by flash chromatography (silica gel, EtOAc-hexane, 1 :4) to afford sarcodictyin analog 480 (3.2 mg, 43% for 2 steps). Rf= 0.56 (silica gel, EtOAc-hexane, 1 :1 ); [ α] D25 -37.14 (c = 0.07, CHCI 3 ). Preparation of sarcodictyin analog 490 as illustrated in Scheme 19. According to the procedure described above for the synthesis of compound 470, to a solution of alcohol 430 (5.0 mg, 0.010 mmol, 1.0 equivalent) in CH 2 CI 2 (1.0 ml) is added NaHCO 3 (6.7 mg, 0.080 mmol, 8.0 equivalents) and Dess-Martin periodinane (8.5 mg, 0.02 mmol, 2.0 equivalents) and the reaction mixture is stirred for 30 min at 25°C to afford after flash chromatography (silica gel, EtOAc-hexane, 1 :4; Rf= 0.45) the corresponding aldehyde 460 (2.0 mg, 40%) which is used directly in the next step. Thus, aldehyde 460 (2.0 mg, 0.004 mmol, 1.0 equivalent) in r-SitOH:H O (5:1 , 0.6 ml) is treated with 2-methyl-2-bute- ne (2.0 M in THF, 0.5 ml, 1.0 mmol), NaH 2 PO 4 (1.4 mg, 0.012 mmol, 3.0 equivalents) and NaCIO 2 (2.2 mg, 0.024 mmol, 6.0 equivalents) at 0°C. The reaction mixture is stirred at 0°C for 2 h after which time a solution of CH 2 N (excess) in diethyl ether is added and stirring is continued for an additional 10 min at 25°C. The excess CH 2 N 2 is removed by a stream of argon and the reaction mixture is extracted with diethyl ether (3 x 5 ml), dried over Na 2 SO 4 , and concentrated. The crude residue is purified by flash chromatography (silica gel, EtOAc- hexane, 1 :4) to yield sarcodictyin analog 490 (1.5 mg, 71% for 2 steps). Rf= 0.45 (silica gel, EtOAc-hexane, 1 :4); [ α] D25 -13.4 (c = 0.10, CHCI 3 ); FT-IR (neat) vmax 2960, 2360, 2337, 1714, 1636, 1436, 1268, 1157 cm "1 . Preparation of sarcodictyin analog 500 as illustrated in Scheme 19. According to the procedure described above for the synthesis of compound 490, aldehyde 470 (8.5 mg, 0.017 mmol, 1.0 equivalent) is treated with 2-methyl-2-butene (2.0 M in THF, 1.0 ml), NaH 2 PO 4 (6.3 mg, 0.053 mmol, ca. 3 equivalents) and NaCIO 2 (9.6 mg, 0.106 mmol, ca. 6 equivalents) in f-SuOH:H 2 O (5:1 , 1.2 ml) to furnish, after diazoethane treatment and chromatographic purification (silica gel, EtOAc-hexane, 1 :2), sarcodictyin analog 500 (8.0 mg, 87% for 2 steps). Rf= 0.35 (silica gel, EtOAc-hexane, 1 :2); [ α] D25 +3.6 (c = 0.8, CHCI 3 ); FT-IR (neat) vmax 2963, 1713, 1650, 1449, 1301 , 1250, 1158, 1049 cm "1 . Preparation of sarcodictyin analog 520 as illustrated in Scheme 19. A solution of alcohol 510 (2.5 mg, 0.0052 mmol, 1.0 equivalent) in CH CI 2 (1.0 ml) at -78°C is treated with DAST [(diethylamino)sulfur trifluoride] (1.3ml, 0.010 mmol, ca. 2 equivalents) and stirred at that temperature for 3 h. The reaction mixture is quenched by the addition of solid NaHCO 3 (30 mg), warmed to 25°C, concentrated and purified by flash chromatography (silica gel, EtOAc:CH 2 CI 2 :methanol, 10:10:1 ) to afford the desired sarcodictyin analog 520 (2.5 mg, 99% yield). Rf= 0.31 (silica gel, EtOAc:CH 2 CI 2 :methanol, 10:10:1 ); [ α] D25 -32.4 (c = 0.25, CHCI 3 ); FT-IR (neat) vmax 2961 , 1762, 1637, 1451 , 1384, 1269, 1156, 1037, 980 cm "1 . Preparation of sarcodictyin analog 530 as illustrated in Scheme 19. To a solution of alcohol 410 (5.0 mg, 0.01 mmol, 1.0 equivalent) in CH 2 CI 2 (1.0 ml) there is added acetic anhydride (5.0 mg, 0.052 mmol, 5.2 equivalents), triethylamine (10 ml, 0.07 mmol, 6.8 equivalents) and 4-DMAP (2.0 mg, 0.016 mmol, 1.6 equivalents) and the reaction mixture is stirred at ambient temperature for 2 h. After completion of the reaction is established (TLC), quenching with saturated NaHCO 3 solution (2 x 2 ml), removal of the solvents under reduced pressure and flash chromatographic purification (silica gel, EtOAc) afforded sarcodictyin analog 530 in quantitative yield (5.2 mg, 100%). Rf= 0.41 (silica gel, EtOAc); [ α] D25 - 16.2 (c = 0.55, CHCI 3 ); FT-IR (neat) vmax 2961 , 1737, 1704, 1638, 1450, 1381 , 1233, 1155, 1039 cm "1 . Preparation of sarcodictyin analog 540 as illustrated in Scheme 19. To a stirring solution of ketal 530 (5.2 mg, 0.01 mmol, 1.0 equivalent) in CH 2 CI 2 :H2O (10:1) at ambient temperature there is added a catalytic amount of CSA (10% mol) and stirring is continued for 72 h. After completion of the reaction is established by TLC (40 h), quenching with solid NaHCO 3 , filtration and chromatographic purification (silica gel, EtOAc), sarcodictyin analog 540 is obtained (5.1 mg, 95% yield). Rf= 0.37 (silica gel, EtOAc); [ OC]D 25 - 28.9 (c = 0.35, CHCIg); FT-IR (neat) vmax 3348, 2962, 1737, 1704, 1638, 1233, 1155 cm "1 . Synthesis of Phenylthioglycoside 1200 as illustrated in Scheme 22. To a solution of NaH (60% in mineral oil, 0.408 g, 10.2 mmol, 1.2 equivalents) in DMF (20 ml) at 0°C is added a solution of 1100 (2.55 g, 8.67 mmol, 1.0 equivalent; Nicolaou et al. Tetrahedron 1997, 53, 8751-8778; Lindle, T. Angew. Chem. Int. Ed. 1998, 110, 806-808) in DMF (30.0 ml), and the reaction mixture is stirred for 30 min at 0°C, after which PMB-CI (1.6 ml, 1 1.0 mmol, 1.1 equivalents) is added. The reaction is then stirred at room temperature for 2 h and quenched by addition of saturated NH 4 CI (10 ml), extracted with diethyl ether (3 x 50 ml), dried over MgSO 4 and concentrated. The crude product is purified by flash chromatography (silica gel, 20% EtOAc in hexanes) to afford acetonide 1200 (3.26 g, 93%). Rf= 0.64 (silica, EtOAc-hexane,1 :2); [ α] D +40.4 (c 1.0, CHCI 3 ); FT-IR (neat) vmax 2986, 2934, 1612, 1514, 1379, 1243, 1074, 833, 745 cm "1 . Synthesis of Phenylthioglycoside Diol 1300 as illustrated in Scheme 22. To a solution of acetonide 1200 (3.26 g, 8.11 mmol, 1.0 equivalent) in methanol (100 ml) is added ethylene glycol (10 ml). The solution is then chilled to 0°C, TsOH » H 2 O (150 mg, 0.80 mmol, 0.1 equivalents) is added and the reaction is warmed to 25°C and stirred for 5 h. After the reaction is complete (TLC analysis), triethylamine (1.0 ml) is added followed by saturated NaHCO 3 solution (30.0 ml). The reaction mixture is then extracted with ethyl acetate (3 x 200 ml), and the combined organic extracts are washed with brine and dried over Na 2 SO 4 . After concentration, the product is purified by flash chromatography (silica gel, EtOAc in hexanes, 3:2) to afford diol 1300 (2.47 g, 84%). Rf= 0.54 (silica gel, EtOAc-hexane, 2:1 ); [ α] D - 25.9 (c 1.0, CHCI 3 ); FT-IR (neat) vmax 3369, 2908, 1613, 1514, 1249, 1079, 822 cm "1 . Synthesis of Phenylthioglycoside bis-TBS Ether 1400 as illustrated in Scheme 22. To a solution of diol 1300 (1.26 g, 3.48 mmol, 1.0 equivalent) in CH 2 CI 2 (25 ml) at 0°C is added triethylamine (4.7 ml, 33.5 mmol, 9.6 equivalents) followed by TBS-OTf (3.1 ml, 13.5 mmol, 3.9 equivalents), and the reaction mixture is stirred at the same temperature for 2 h. After complete (TLC analysis), the reaction is quenched by addition of water (5 mi) and extracted with CH 2 CI 2 (2 x 50 ml). The combined extracts are washed with brine, dried over Na 2 SO 4 and concentrated. The crude residue is purified by flash chromatography (silica gel, diethyl ether in hexanes, 1 :30) to afford silyl ether 1400 (2.00 g, 97%). Rf= 0.60 (silica gel, EtOAc-hexane, 1 :5); [ α] D -40.42 (c 1.0, CHCI 3 ); FT-IR (neat) vmax 2930, 2856, 1612, 1514, 1472, 1253, 1109, 840 cm "1 . Synthesis of Bis-TBS ether Acetal 1500 as illustrated in Scheme 22. To a solution of 1400 (1.66 g, 2.81 mmol) in wet acetone (93% acetone, 7% water) (40ml) at 0°C is added Λ/-bromosuccinimide (3.3 equivalents, 1.65 g, 9.27 mmol) followed by pyridine (11 equivalents, 30.9 mmol, 2.5 ml). The resulting solution is stirred for 4 h at 0°C and quenched by addition of saturated Na 2 SO 3 -solution. The reaction mixture is extracted with diethyl ether (3 x 5 ml), and the organic extracts are washed with brine and dried over Na 2 SO 4 before concentrating. The crude residue is purified by flash chromatography (silica gel, 10% EtOAc in hexanes) to afford 1500 (1.12 g, 80% as a ca. 2:1 mixture of the two anomers). Rf= 0.37, 0.46 (silica gel, diethyl ether-hexane,1 :1 ); FT-IR (neat) 3456, 2930, 2857, 1513, 1469, 1253, 1096, 1034, 836 cm "1 . Synthesis of Trichloroacetimidate 900 as illustrated in Scheme 22. To a solution of the anomeric mixture 1500 (0.218 g, 437 mmol) and CCI 3 CN (0.220 ml, 2.20 mmol, 5.0 equivalents) in CH 2 CI 2 (5.0 ml) at 0°C is added NaH (0.002 g, 41.7 mmol, 0.1 equivalents) and the reaction mixture is stirred at room temperature for 3.5 h (TLC analysis), after which it is concentrated and the residue is purified by flash chromatography (silica gel, 33% EtOAc in hexanes with 2% triethylamine) to produce 900 (0.261 g, 93%). Rf = 0.76 (silica gel, diethyl ether-hexane,1 :3); [ α]p -69.7 (c 1.0, CHCI 3 ); FT-IR (neat) vmax 3348, 2930, 2857, 1670, 1514, 1252, 1113, 1006, 837 cm "1 . Synthesis of enynone 1600 as illustrated in Scheme 23. A solution of LiHDMS (1.0 M in THF, 0.150 ml, 0.150 mmol, 2.0 equivalents) is added dropwise to a solution of 35 (77.5 mg, 0.0742 mmol, 1.0 equivalent) in THF (4.0 ml) at -30°C and the reaction is stirred for 10 min at -30°C. After the reaction is complete as indicated by TLC analysis, saturated NH 4 CI solution (5 ml) is added and the resulting bi-phasic mixture is extracted with diethyl ether (3 x 30 ml). The combined extracts are washed with brine, dried over over Na 2 SO 4 , and concentrated to give a crude residue which is purified by short column chromatography (silica gel, 10% EtOAc in hexanes). The purified mixture of isomers is then used immediately for the next step. To a solution of this mixture in CH 2 CI 2 (4.0 ml) at 0°C is added NaHCO 3 (62.3 mg, 0.742 mmol, 10.0 equivalents) and pyridine (60 ml, 0.742 mmol, 10.0 equivalents), and the resulting solution is chilled to 0°C and stirred for 10 min. Dess Martin reagent (63.0 mg, 0.149 mmol, 2.0 equivalents) is added, and the reaction is stirred for an additional 15 min at 0°C. After the reaction is complete as indicated by TLC analysis, it is quenched by addition of saturated Na 2 S 2 O 3 (2 ml). The mixture is extracted with CH 2 CI 2 (3 x 30 ml), and the combined extracts are dried over Na 2 SO 4 and concentrated to provide a crude residue which is purified by flash chromatography (silica gel, 5% EtOAc in hexanes) to afford 1600 (72.0 mg, 93% for two steps). Rf= 0.80 (silica, diethyl ether-he- xane,1 :3); [ α] D -11.5 (c 0.46, CHCI 3 ); FT-IR (neat) vmax 2954, 2878, 1663, 1512, 1462, 1250, 1 115, 1037, 1004, 834, 777, 741 cm "1 . Synthesis of enynone alcohol 1700 as illustrated in Scheme 22. To a solution of PMB-ether 1600 (202 mg, 0.194 mmol, 1.0 equivalent) in CH 2 CI 2 (7.0 ml) and water (0.35 ml) at 0°C is added DDQ (98.0 mg, 0.432 mmol, 2.3 equivalents) and the resulting solution is allowed to warm to 25°C and stirred for 20 min. Once complete by TLC analysis, the reaction is quenched by addition of saturated Na 2 S 2 O 3 solution (2.0 ml) and saturated NaHCO 3 solution (2.0 ml). The reaction mixture is then extracted with CH 2 CI 2 (3 x 40 ml) and the combined extractes are dried over Na 2 SO 4 and concentrated to afford a crude residue which is purified by flash chromatography (silica gel, 10% EtOAc in hexanes) to provide alcohol 1700 (163 mg, 91 %). Rf= 0.6 (silica gel, EtOAc-hexane, 1 :5); [ α] D = -0.176 (c 1.6, CHCI3); FT-IR (neat) vmax 2955, 2929, 2203, 1663, 1462, 1366, 1252, 1214, 1118, 1076, 1004, 835, 740 cm "1 . Synthesis of enynone Acetate 1800 as illustrated in Scheme 23. To a solution of alcohol 1700 (163 mg, 0.177 mmol, 1.0 equivalent) in CH 2 CI 2 (5.0 ml) at 0°C is added triethylamine (400 ml, 2.86 mmol, 16.1 equivalents), 4-DMAP (10.0 mg, 0.0818 mmol, 0.46 equivalents), and acetic anhydride (0.2 ml, 2.12 mmol, 12.0 equivalents) and the reaction is warmed to 25°C and stirred for 1 h. After completion is established by TLC analysis, the reaction is quenched by addition of saturated NaHCO 3 solution (2.0 ml). The reaction mixture is then extracted with CH 2 CI 2 (3 x 40 ml) and the combined extracts are dried over Na 2 SO 4 and concentrated to give a crude residue which is purified by flash chromatography (silica gel, 10% EtOAc in hexanes) to afford acetate 1800 (162 mg, 95%). Rf= 0.57 (silica, diethyl ether-hexane,1 :5); [ α]p -0.34 (c 1.4, CHCI 3 ); FT-IR (neat) vmax 2956, 1746, 1661 , 1461 , 1371 , 1237, 1119, 1004 cm "1 . Synthesis of enynone diol 1900 as illustrated in Scheme 23. To a solution of silyl ether 1800 (161 mg, 0.167 mmol, 1.0 equivalent) in THF (4.2 ml) at 0°C is added triethylamine » 3HF (0.60 ml, 3.68 mmol, 22.0 equivalents), and the reaction mixture is warmed to 25°C and stirred for 4 h. After completion (TLC analysis), the reaction is quenched by addition of saturated NaHCO 3 solution (2.0 ml) at 0°C. The bi-phasic mixture is then extracted with diethyl ether (3 x 40 ml) and the combined extractes are washed with brine, dried over Na 2 SO 4 and concentrated to produce a crude residue which is purified by flash chromatography (silica gel, 50% EtOAc in hexanes) to afford diol 1900 (100 mg, 81%). Rf= 0.40 (silica gel, diethyl ether-hexane, 3:1); [ α] D -53.5 (c 0.85, CHCI 3 ); FT-IR (neat) vmax 3410, 2929, 2856, 1744, 1652, 1370, 1254, 1123, 1063, 1037, 837, 777 cm "1 . Synthesis of tricyclic Core Compound 2200 as illustrated in Scheme 23. A heterogeneous mixture of eneynone 1900 (103 mg, 0.140 mmol, 1.0 equivalent) and ϋndlar catalyst (148 mg, 0.069 mmol, 0.5 equivalents) is treated with hydrogen (1 atm), and the reaction is stirred at 25°C for 20 min. The reaction mixture is then filtered through a Celite® pad eluting with diethyl ether and concentrated to give a crude residue which is used without further purification. This residue is dissolved in methanol (4.0 ml), PPTS (7.0 mg, 0.028 mmol, 0.2 equivalents) is added, and the reaction mixture is stirred at 25°C for 20 min. Once complete (TLC monitoring), the reaction is quenced by addition of saturated NaHCO 3 solution (2.0 ml). The reaction mixture is then extracted with diethyl ether (3 x 20 ml), and the combined extracts are washed with brine, dried over Na 2 SO and concentrated to provide a crude residue which is purified by flash chromatography (silica gel, 50% EtOAc in hexanes) to afford methylketal 2200 (80.1 mg, 76%) Rf= 0.74 (silica gel, diethyl ether-hexane, 3:1); [α] D -38.61 (c 0.65, CHCI 3 ); FT-IR (neat) vmax 3448, 2929, 2856, 1748, 1254, 1144, 1038, 837, 775 cm "1 . Eleutherobin bis-TBS Ether 2300 as illustrated in Scheme 23. To a solution of alcohol 2200 (64 mg, 0.0871 mmol, 1.0 equivalent) in CH 2 CI 2 (0.4 ml) is added triethylamine (0.177 ml, 1.27 mmol, 15.0 equivalents) and 4-DMAP (21 mg, 0.0017 mmol, 0.02 equivalents). The solution is then chilled to 0°C and a 0.2 M CH 2 CI 2 solution of mixed anhydride 2400 is added (4.2 ml, 0.84 mmol, 9.6 equivalents; as above in example 2). The reaction mixture is then warmed to 25°C and stirred for 18 h. After completion is established (TLC analysis), the reaction is quenched by addition of saturated NaHCO 3 solution and extracted with CH 2 CI 2 (3 x 20 ml). The combined organic extracts are dried over Na 2 SO 4 and concentrated to afford a crude residue which is purified by flash chromatography (silica gel, 67% EtOAc in hexanes) to produce urocanic ester 2300 (73.0 mg, 97%). Rf- 0.35 (silica gel, EtOAc-hexane, 1 :3); [ α] D -61.3 (c 0.6, CHCI 3 ); FT-IR (neat) vmax 2929, 2856, 2362, 2338, 1746, 1707, 1639, 1468, 1367, 1296, 1253, 1150, 1062, 1038, 1001 , 886, 837, 775 cm "1 . Synthesis of eleutherobin (4)as illustrated in Scheme 23. To a solution of disilyl ether 2300 (15.5 mg, 0.017 mmol, 1.0 equivalent) in THF (4.0 ml) at 0°C is added acetic acid (1.0 M in THF, 0.070 ml, 0.070 mmol, 4.1 equivalents) and TBAF (1.0 M in THF, 0.30 ml, 0.30 mmol, 17.6 equivalents). The reaction mixture is warmed to 25°C and stirred for 2.5 h, after which water (1.0 ml) and saturated NaHCO 3 solution (1.0 ml) are added and the mixture is extracted with CH 2 CI 2 (3 x 20 ml). The combined extracts are dried over Na 2 SO 4 and concentrated to provide a crude residue which is purified by flash chromatography (silica gel, 2% methanol in CH 2 CI 2 with 1 % triethylamine) to afford eleutherobin 4 (1 1.0 mg, 96%) Rf= 0.22 (silica gel, methanol:CH 2 CI 2 , 1 :20); [ α] D -67 (c 0.15, methanol); FT-IR (neat) vmax 3388, 2933, 2851 , 1735, 1708, 1637, 1367, 1247, 1162, 1039, 998 cm "1 . Synthesis of β-Glycoside 2500 as illustrated in Scheme 24. A solution of alcohol 7000 (20.0 mg, 0.0355 mmol, 1.0 equivalent) and imidate 9000 (62.1 mg, 0.0966 mmol, 2.7 equivalents) in 2:1 dioxane:toluene (6.0 ml) is chilled to 0°C, TMSOTf (0.05 M in diethyl ether, 40ml, 0.002 mmol, 0.05 equivalents) is added and the reaction mixture is stirred at 0°C for 10 min after which triethylamine (20 ml) is added followed by NaHCO 3 (3 ml). The reaction mixture is then extracted with diethyl ether (3 x 20 ml), and the combined extractes are washed with brine and dried over Na 2 SO 4 and concentrated to give a crude residue which is purified by flash chromatography (silica gel, 3% EtOAc in hexanes) to afford 2500 (27.9 mg, 75%). Rf= 0.56 (silica gel, EtOAc-hexane, 1 :5); [ -27.7 (c 1.0, CHCI 3 ); FT-IR (neat) vmax 2954, 1676, 1612, 1512, 1461 , 1364, 1250, 1114, 1038, 835, 740 cm "1 . Synthesis of -Anomer of Eleutherobin (2700) as illustrated in Scheme 24. The α-anomer of eleutherobin is constructed by following the reaction sequence depicted in Scheme 23 from compound 2600. Rf= 0.1 (silica gel, methanol: CH 2 CI 2 , 1 :20). Bis-Acetoxy Eleutherobin (2800) and Methyl-Ketal Precursors of Eleuthosides A and B (2900+3000) as illustrated in Scheme 26(A). To a solution of natural eleutherobin (4) (10.0 mg, 0.015 mmol, 1.0 equivalent), triethylamine (6.0 ml, 0.043 mmol, 3.0 equivalents) and 4-DMAP (0.40 mg, 0.0033 mmol, 0.2 equivalents) in CH 2 CI 2 (0.60 ml) at 0°C is added acetic anhydride (1.0 M in CH 2 CI 2 , 0.017 ml, 0.017 mmol, 1.1 equivalents), and the reaction mixture is stirred at the same temperature for 1 h. The reaction mixture is then quenched by addition of saturated NaHCO 3 solution (0.50 ml) and extracted with CH 2 CI 2 (5 x 20 ml). The combined organic extracts are dried over Na 2 SO 4 and concentrated to provide a crude residue which is purified by flash chromatography (silica gel, 2% methanol in CH 2 CI 2 ) to afford triacetate 2800 (1.8 mg, 16%) along with an inseperable mixture of eleuthosides 2900 and 3000 (7.8 mg, 73%) as well as recovered 1 (0.5 mg, 5%). 2800. Rf= 0.44 (silica gel, methanol- CH2CI2,1 :20); [ α] D -67.3 (c 1.2, CHCI 3 ); FT-IR (neat) vmax 2962, 1746, 1740, 1644, 1634, 1372, 1226, 1156, 1068, 759, 668, 617 cm "1 . Synthesis of eleuthosides A and B (5+6) as illustrated in Scheme 26(A). To a solution of 2700 and 2800 mixture (7.8 mg, 0.011 mmol, 1.0 equivalent) in CH 2 CI 2 (2.0 ml) and H 2 O (0.20 ml) at 25°C is added CSA (5.2 mg, 0.022 mmol, 2.0 equivalents) and the reaction is stirred at the same temperature for 48 h. Once complete (TLC monitoring), the reaction is quenched by addition of saturated NaHCO 3 solution (0.50 ml) and extracted with CH 2 CI 2 (5 x 20 ml). The combined organic extracts are dried over Na 2 SO 4 and concentrated to provide a crude residue which is purified by flash chromatography (silica gel, 3% methanol in CH 2 CI 2 ) to afford an inseparable mixture of eleuthoside A (5) and B (6) (5.3 mg, 80%). Data for mixture of 5 and 6: Mixture of 5 and 6 Rf= 0.32 (silica, methanol-CH 2 CI 2 , 1 :20); FT-IR (neat) vmax 3734, 3628, 2962, 2928, 2866, 1734, 1700, 1684, 1652, 1646, 1636, 1558, 1456, 1374, 1252, 1160, 1065, 1037, 986, 884, 874 cm "1 . Synthesis of regioisomeric Eleutherobin (3100) and Deaceto- Eleutherobin (3200) (Scheme 26(B)). To a solution of disilyl ether 2300 (5.4 mg, 6.1 mmol) in THF (350 ml) is added TBAF (1.0 M in THF, 20 ml, 20 mmol, 3.3 equivalents) and the reaction mixture is stirred for 6 h at ambient temperature. After completion (TLC analysis), the crude residue is immediately purified by column chromatography (gradually increasing the eluting solvent from 2 to 10% methanol in CH 2 CI 2 ) to afford eleutherobin 4 (22%), migration product 3100 (60%) and triol 3200 (8%). 3100. Rf= 0.28 (silica, x2, methanol: CH 2 CI 2 ,1 :20); FT-IR (neat) vmax 3355, 2964, 2925, 1704, 1638, 1260, 1070, 800 cm "1 . Selected Data for key compounds as shown in Scheme 20 and Table 2: Compound 550. Isolated yield after preparative TLC purification 2.8 mg (79% overall from 24). Rf = 0.68 (silica gel, EtOAc); [ α]o 5 - 21.5 (c = 0.20, CHCI 3 ); Rf = 0.15 (silica gel, EtOAc-hexane, 1 :3); FT-IR (neat) max 2961 , 1711 , 1637, 1451 , 1271 , 1154, 1068, 1037, 980, 715 cm "1 . Compound 560. Isolated yield after preparative TLC purification 2.4 mg (64% overall from 24). Rf = 0.56 (silica gel, EtOAc-hexane, 4:1 ); [ α] D25 - 43.8 (c = 0.5, CHCI 3 ); FT-IR (neat) vmax 2962, 2104, 1703, 1639, 1450, 1270, 1156 cm "1 . Compound 570. Isolated yield after preparative TLC purification 1.5 mg (41 % overall from 24). Rf = 0.52 (silica gel, EtOAc); FT-IR (neat) vmax 3333, 2961 , 1709, 1639, 1543, 1445, 1315, 1220, 1160, 1048 cm "1 . Compound 580. Isolated yield after preparative TLC purification 3.9 mg (71% overall from 24). Rf = 0.32 (silica gel, 3% methanol in CH 2 CI 2 ). Compound 590. Isolated yield after preparative TLC purification 2.2 mg (59% overall from 24). Compound 620. Isolated yield after preparative TLC purification 2.3 mg (64% overall from 24). Rf = 0.41 (silica gel, EtOAc). Compound 630. Isolated yield after preparative TLC purification 0.7 mg (20% overall from 24). Rf = 0.42 (silica gel, EtOAc). Compound 640. Isolated yield after preparative TLC purification 1.9 mg (55% overall from 24). Rf = 0.43 (silica gel, EtOAc). Compound 650. isolated yield after preparative TLC purification 0.5 mg (14% overall from 24). Rf = 0.43 (silica gel, EtOAc). Compound 660. Isolated yield after preparative TLC purification 1.8 mg (46% overall from 24). Rf = 0.43 (silica gel, EtOAc). Compound 670. Isolated yield after preparative TLC purification 2.0 mg (58% overall from 24). Rf = 0.40 (silica gel, EtOAc). Compound 680. Isolated yield after preparative TLC purification 2.0 mg (61% overall from 24). Rf = 0.44 (silica gel, EtOAc). Compound 690. Isolated yield after preparative TLC purification 2.1 mg (54% overall from 24). Rf = 0.43 (silica gel, EtOAc). Compound 700. Isolated yield after preparative TLC purification 2.3 mg (69% overall from 24). Rf = 0.40 (silica gel, EtOAc). Compound 710. Isolated yield after preparative TLC purification 0.7 mg (42% overall from 24). Rf = 0.62 (silica gel, EtOAc). Compound 730. Isolated yield after preparative TLC purification 2.0 mg (61 % overall from 24). Rf = 0.39 (silica gel, EtOAc). Compound 740. Isolated yield after preparative TLC purification 1.9 mg (56% overall from 24). Rf = 0.38 (silica gel, 3% methanol in CH 2 CI 2 ). Compound 750. Isolated yield after preparative TLC purification 1.6 mg (55% overall from 24). Rf = 0.40 (silica gel, EtOAc). Compound 760. Isolated yield after preparative TLC purification 2.9 mg (62% overall from 24). Rf = 0.40 (silica gel, EtOAc). Compound 770. Isolated yield after preparative TLC purification 1.1 mg (56% overall from 24). Rf = 0.51 (silica gel, EtOAc). Compound 790. Isolated yield after preparative TLC purification 1.3 mg (33% overall from 24). Rf = 0.40 (silica gel, EtOAc). Compound 800. Isolated yield after preparative TLC purification 1.0 mg (26% overall from 24). Rf = 0.38 (silica gel, EtOAc). Compound 810. Isolated yield after preparative TLC purification 1.3 mg (34% overall from 24). Rf = 0.43 (silica gel, EtOAc). Compound 820. Isolated yield after preparative TLC purification 1.1 mg (28% overall from 24). Rf = 0.45 (silica gel, EtOAc). Compound 830. Isolated yield after preparative TLC purification 1.1 mg (28% overall from 24). Rf = 0.43 (silica gel, EtOAc). Compound 840. Isolated yield after preparative TLC purification 1.2 mg (32% overall from 24). Rf = 0.39 (silica gel, EtOAc). Compound 850. Isolated yield after preparative TLC purification 2.2 mg (69% overall from 24) Rf = 0.32 (silica gel, 3% methanol in CH CI 2 ); [ α]Q25 " 1 - 9 ( c = °- 21 - ethanol); FT-IR (neat) max 2960, 1712, 1637, 1435, 1385, 1299, 1269, 1245, 1155, 1050 cm "1 . Compound 860. Isolated yield after preparative TLC purification 2.0 mg (50% overall from 24). Rf = 0.43 (silica gel, EtOAc). Compound 870. Isolated yield after preparative TLC purification 0.8 mg (46% overall from 24). Rf = 0.74 (silica gel, EtOAc). Compound 880. Isolated yield after preparative TLC purification 2.1 mg (54% overall from 24). Rf = 0.42 (silica gel, EtOAc). Compound 890. Isolated yield after preparative TLC purification 1.8 mg (45% overall from 24). Rf = 0.43 (silica gel, EtOAc). Compound 900. Isolated yield after preparative TLC purification 1.3 mg (32% overall from 24). Rf = 0.40 (silica gel, EtOAc). Compound 910. Isolated yield after preparative TLC purification 1.0 mg (25% overall from 24). Rf = 0.42 (silica gel, EtOAc). Compound 920. Isolated yield after preparative TLC purification 1.7 mg (40% overall from 24). Rf = 0.38 (silica gel, EtOAc). Compound 930. Isolated yield after preparative TLC purification 1.0 mg (23% overall from 24). Rf = 0.41 (silica gel, EtOAc). Compound 940. Isolated yield after preparative TLC purification 0.5 mg (17% overall from 24). Rf = 0.74 (silica gel, EtOAc-hexanes, 1 :3). Compound 950. Isolated yield after preparative TLC purification 0.5 mg (20% overall from 24). Rf = 0.11 (silica gel, EtOAc-hexanes, 1 :3). Compound 960. Isolated yield after preparative TLC purification 1.7 mg (62% overall from 24). Rf = 0.46 (silica gel, EtOAc-hexanes, 1 :3). Compound 970. Isolated yield after preparative TLC purification 2.2 mg (68% overall from 24). Rf = 0.31 (silica gel, EtOAc-hexanes, 1 :1 ). Compound 980. Isolated yield after preparative TLC purification 1.6 mg (51 % overall from 24). Rf = 0.28 (silica gel, EtOAc-hexanes, 1 :2); Rf = 0.31 (silica gel, EtOAc-hexanes, 1 :3). Compound 990: Isolated yield after preparative TLC purification 2.2 mg (68% overall from 24). Rf = 0.50 (silica gel, EtOAc-hexanes, 1 :3). Compound 1000. Isolated yield after preparative TLC purification 1.5 mg (40% overall from 24). Rf = 0.38 (silica gel, EtOAc-hexanes, 1 :3). Compound 1010. Isolated yield after preparative TLC purification 0.7 mg (28% overall from 24). Rf = 0.52 (silica gel, EtOAc-hexanes, 1 :1 ). Compound 1020. Isolated yield after preparative TLC purification 0.5 mg (20% overall from 24). Rf = 0.32 (silica gel, EtOAc-hexanes, 1 :1 ). Compound 1030. Isolated yield after preparative TLC purification 1.5 mg (42% overall from 24). Rf = 0.35 (silica gel, EtOAc-hexanes, 1 :1 ). Compound 1040. Isolated yield after preparative TLC purification 0.5 mg (17% overall from 24). Rf = 0.51 (silica gel, EtOAc-hexanes, 1 :1 ). Compound 1050. Isolated yield after preparative TLC purification 1.9 mg (60% overall from 24). Rf = 0.31 (silica gel, EtOAc-hexanes, 1 :1 ). Compound 1060. Isolated yield after preparative TLC purification 2.2 mg (57% overall from 24). Rf = 0.31 (silica gel, EtOAc-hexanes, 1 :1 ). Compound 1070. Isolated yield after preparative TLC purification 1.8 mg (68% overall from 24). Rf = 0.39 (silica gel, EtOAc-hexanes, 1 :4);[ α] D 25 -2.1 (c = 0.10, CHCI 3 ); FT-IR (neat) max 2960, 1739, 1719, 1436, 1370, 1236, 1049 cm "1 . Compound 1080. Isolated yield after preparative TLC purification 2.6 mg (79% overall from 24). Rf = 0.28 (silica gel, EtOAc-hexanes 1 :4). Compound 1090. Isolated yield after preparative TLC purification 1.7 mg (61 % overall from 24). Rf = 0.44 (silica gel, EtOAc-hexanes, 1 :4). Data for α-Anomer of 1600; [ α] D +38.0 (c 0.40, CHCI 3 ); FT-IR (neat) max 2955, 2879, 2205, 1736, 1653, 1613, 1513, 1461 , 1366, 1250, 1094, 1037, 1004, 835, 777, 740 cm "1 . Data for α-Anomer of 1700: [ α] D +36.6 (c 0.80, CHCI 3 ); FT-IR (neat) max 3471 , 2955, 2879, 2206, 1653, 1600, 1461 , 1255, 1159, 1114, 1091 , 1027, 1004, 834, 777, 740 cm "1 . Data for α-Anomer of 1800: [ α] D +56.7 (c 0.76, CHCI 3 ); FT-IR (neat) max 2956, 2878, 2206, 1757, 1659, 1465, 1368, 1231 , 1116, 1004, 836, 778, 740 cm "1 . Data for β-Anomer of 1900: [ α] D +42.8 (c 0.46, CHCI3); FT-IR (neat) max 3440, 2957, 2930, 2856, 2205, 1739, 1652, 1468, 1368, 1254, 1230, 1168, 1091 , 1057, 1037, 836, 778 cm "1 . Data for β-Anomer of 2200: [ α] D +47.1 (c 0.95, CHCI3); FT-IR (neat) max 3472, 2957, 2930, 2856, 1747, 1469, 1366, 1254, 1233, 1096, 1056, 1038, 837, 777 cm "1 . Data for β-Anomer of 23: [ α] D +23.1 (c 1.1 , CHCI 3 ); FT-IR (neat) max 2956, 2929, 2856, 1748, 1705, 1639, 1439, 1468, 1367, 1253, 1154, 1095, 1037, 836, 776 cm "1 . Scheme 27: General synthesis of an eleutherobin core intermediate 15111. PG 1 = protecting group (tri-loweralkylsilyl); R 3 = lower alkyl: 1111 2111 6111 H 13111 PG 1 = TMS, TES, TBS PG 1 = TMS, TES, TBS 2111 : A solution of 3 N NaOH (0.15 equivalents) is slowly added to a solution of S- (+)-carvone (1.0 equivalent, 0.7 M) in methanol at 0°C, and 35% hydrogen peroxide solution (1.3 equivalents) is added dropwise over 3 h. The reaction mixture is quenched by addition of saturated Na 2 SO 3 solution and extracted with CH 2 CI 2 The extracts are dried over Na 2 SO4 and concentrated to afford the epoxide (92%). 3111 : A solution of 2111 (1.0 equivalent, 1.3 M) and PtO 2 (0.5%) in ethanol is treated with H 2 at room temperature for 6 h. The reaction mixture is then filtered through a Celite® pad and concentrated. The crude product is purified by flash chromatagraphy (silica, 5% EtOAc in hexane) to afford 3111 (95%). 4111 : A solution of LDA is generated by addition of 1.6 M BuLi in hexanes (1.1 equivalents) to a solution of diisopropyl amine (1.2 equivalents) in THF at -78°C. The solution is then warmed to 0°C and stirred for 30 min after which a solution of 3111 (1.0 equivalent, 1.0 M) in THF is added dropwise via cannula at -78°C over 1.5 h. The resulting solution is then stirred for 30 min. A solution of formaldehyde is prepared by cracking paraformaldehyde (10.0 equivalents) at 140°C and bubbling the resulting gas through THF at -78°C over 45 min. This formadehye solution is then added to the enolate solution via cannula over 1 h at - 78°C. The reaction is quenched by addition of saturated NH 4 CI solution, allowed to warm to room temperature, and extracted with diethyl ether. The extracts are dried over Na 2 SO4 and concentrated. The crude product is purified by flash chromatography (silica, 10% EtOAc in hexane) to afford 4111 (63%). 5111 : To a solution of 4111 (1.0 equivalent, 0.25 M), triethylamine (6.0 equivalents), and DMAP (0.05 equivalents) in CH 2 CI 2 at 0°C is added f-butyldimethylsilyl chloride (3.0 equivalents). The reaction mixture is stirred at room temperature for 12 h and quenched via addition of water. The organic layer is separated, dried over Na 2 SO4 and concentrated. The crude product is purified by flash chromatography (silica, 3% EtOAc in hexane) to afford 5111 (84%). 6111 : To a solution of 5111 (1.0 equivalent, 0.2 M) in THF at -78°C is added 1.0 M L-Selectride in THF (1.2 equivalents) via cannula over 1.5 h. The reaction mixture is stirred an additional 30 min and quenched by addition of saturated NH4CI solution and allowed to warm to 0°C. Excess 35% hydrogen peroxide solution is then added and the mixture is stirred at 0°C for 1 h. The reaction mixture is extracted with EtOAc, and the extrats are dried over Na 2 SO4 and concentrated. The crude product is purified by flash chromatography (silica, 5% EtOAc in hexane) to afford 6111 (100%). 7111 : To a solution of 6111 (1.0 equivalent, 0.4 M) and triethyl amine (2.5 equivalents) in CH 2 CI 2 at 0°C is added methanesulfonyl chloride (1.2 equivalents) dropwise over 1 h. The reaction mixture is stirred at 0°C for 2 h, quenched by addition of brine, and extracted with EtOAc. The combined extracts are dried over Na 2 SO4 and concentrated. The crude product is purified by flash chromatagraphy (silica, 10% EtOAc in hexane) to afford 7111 (91 %). 8111 : A 0.4 M solution of NaC- j QHe is prepared by addition of Na metal (5.0 equivalents) to napthalene (5.0 equivalents) in THF and allowing the mixture to stir for 2 h. A solution of 7111 (1.0 equivalent, 0.2 M) in THF is then added dropwise via cannula at 0°C. The reaction mixture is stirred for 30 min and quenched by addition of saturated NH4CI solution. The reaction is then poured into brine and extracted with EtOAc. The extracts are dried over Na 2 SO4 and concentrated. The crude product is purified by flash chromatography (silica, 10% EtO 2 in hexane followed by 10% EtOAc in hexane) to afford 8111 (96%). 9111 : A solution of 8111 (1.0 equivalent, 0.1 M), triethyl orthoacetate (40.0 equivalents), and propionic acid (0.1 equivalents) is heated at 170°C for 4 days. The excess tri- ethylorthoacetate is removed by vacuum distillation, and the residue which remains is purified by flash chromatography (silica, 3% EtOAc in hexane) to give the ester 9111 (74%). 10111 : A 1.0 M CH 2 CI 2 solution of diisobutylaluminumnum hydride (1.0 equivalent) is gradually added to a solution of ethyl ester 9111 (1.0 equivalent, 0.2 M) in CH 2 CI 2 at -78°C, and the reaction mixture is stirred for 30 min. The reaction mixture is quenched by addition of saturated NH4CI solution and stirred for 2 h at room temperature. The organic layer is separated, dried over Na 2 SO4, and concentrated. The residue is purified by flash chromatography (silica, 5% EtOAc in hexane) to give the aldehyde 10111 (92%). 11111. To a solution of ethyl vinyl ether (1.0 equivalent, 0.4 M) in THF at -78°C is added 1.7 M tert-Buϋ in hexanes (1.8 equivalents), and the solution is warmed to 0°C as it changes from yellow to colorless. The solution is then cooled to -78°C and a solution of 10111 (1.0 equivalent) in THF is added dropwise after which the reaction mixture is stirred for an additional 30 min at -78°C. The reaction is quenched by addition of saturated NH4CI solution and extracted with diethyl ether. The extracts are dried over MgSO4 and concentrated. The crude product is then dissolved up in diethyl ether and treated with concentrated H 2 SO4 while shaking vigorously. The diethyl ether solution is washed with water and saturated NaHCO 3 solution, dried over MgSO4, and concentrated. The residue is purified by flash chromatography (silica, 10% to 15% diethyl ether in hexane) to give 11111 (98%). 12111. To a solution of 11111 (1.0 equivalent, 0.1 M) in THF at -78°C is added 0.5 M ethynyl magnesium bromide (4.5 equivalents) and the reaction mixture is stirred at -78°C for 12 h while slowly warming to -10°C. The reaction mixture is quenched by addition of saturated NH4CI solution and extracted with diethyl ether. The extracts are dried over MgSO4 and concentrated, and the residue is purified by flash chromatography (silica, 10% to 25% diethyl ether in hexane)the desired 12111 (56%). 13111. To a solution of 12111 (1.0 equivalent, 0.1 M) in THF at 0°C is added 1 M TBAF (2.0 equivalents) and the reaction mixture is allowed to warm to 25°C. The reaction is quenched by addition of saturated NH4CI and extracted with diethyl ether. The extracts are concentrated and the residue is purified by filtration through silica gel to give 13111 (100%). 14111. To a solution of 13111 (1.0 equivalent, 0.1 M) in CH CI 2 is added 2,6- lutidine (6.0 equivalents) and the solution is chilled to 0°C. A portion of trialkylsilyltriflate (e.g. tert-butyldimethylsilyltriflate) (3.0 equivalents) is then added and the reaction mixture is allowed to warm to 25°C. The reaction is quenched by addition of saturated NH4CI and extracted with CH 2 CI 2 The extracts are dried over MgSO4 and concentrated. The residue is purified by filtration through silica (25% diethyl ether in hexane) to give 14111 (100%). 15111. To a solution of 14111 (1.0 equivalent, 0.1 M) in methanol is added a catalytic amount of PPTS (0.1 equivalents). The reaction mixture is worked up by addition of saturated NaHCO 3 and extracted with diethyl ether. The extracts are dried over MgSO4 and concentrated. The residue is purified by filtration through silica gel to give 15111 (98%). Scheme 28: General synthesis of an eleutherobin core 24111. PG = protecting group: 151 1 1 PG 1 = TMS, TES, TBS PG 2 = TES, TBS, TPS, TIPS, Bn, PMB 85% PG 1 = TMS,TES,TBS PG 2 = TE * S, TBS, TPS, TIPS Bn, PMB - Ill - PG 1 = TMS, TES, TBS PG 2 = TES, TBS, TPS, TIPS, PG = H, TES, TBS, TPS, TIPS, Bn, PMB Bn, TMB PG = H, TES, TBS, TPS, TIPS, Bn, PMB PG=H, TES, TBS, TPS, TIPS, Bn, PMB 16111. To a solution of alcohol 15111 (1.0 equivalent, 0.1 M) and activated 4 A molecular sieves in CH 2 CI 2 is added NMO (1.5 equivalents) and the reaction mixture is stirred for 10 min. TPAP (0.05 equivalents) is then added to the reaction mixture, and it is stirred at room temperature. The reaction mixture is then filtered through silica gel and washed with CH 2 CI 2 . After concentration aldehyde 15111 (98%) is obtained. 17111. A solution of aldehyde 16111 (1.0 equivalent, 0.2 M), ethyl cyano acetate (40.0 equivalents), and α-alanine (4.0 equivalents) in ethanol is stirred at 50°C for 72 h. The reaction mixture is then concentrated and purified by filtration through silica gel (10% diethyl ether in hexanes) to give 17111 (95%). 18111. To a solution of cyanoester 17111 (1.0 equivalent, 0.6 M) in hexanes at -78°C is added 1 M DIBAL in toluene (10.0 equivalents). The reaction mixture is stirred for 6 h at -78°C and then slowly warmed to -10°C for 2 h. The reaction mixture is then diluted with ethyl acetate, quenched by addition of saturated NH4CI solution, and extracted with ethyl aceate. The extracts are concentrated and purified by flash chromatography (silica, 10% diethyl ether in hexanes) to give 18111 (67%). 19111 : To a solution of alcohol 18111 (1.0 equivalent, 0.2 M) in CH 2 CI 2 is added base (3.0 equivalents) and trialkylsilylchloride (3.0 equivalents) and the resulting solution is stirred at 25°C. The reaction is quenched by addition of aqueous saturated ammonium chloride solution and concentrated. The residue is purified by flash chromatography (silica, 2% EtOAc in hexane) to give TIPS ether 19111. 20111 : A 1.0 M THF solution of lithium bis(trimethylsilyl)amide (1.5 equivalents) is added dropwise to a solution of aldehyde 19111 (1.0 equivalent, 0.1 M) in THF at 25°C. After 10 min the reaction mixture is quenched by the addition of aqueous saturated ammonium chloride solution, extracted with diethyl ether, dried over Na 2 SO4, and concentrated. 21111 : Compound 20111 is dissolved in CH 2 CI 2 and NaHCO 3 is added to the solution at 0°C. After 10 min Dess-Martin periodinate is added to the reaction mixture at the same temperature, and the the reaction mixture is then warmed to 25°C. After 4 h the reaction mixture is diluted with diethyl ether and aqueous saturated sodium bicarbonate solution is added to the mixture, and then sodium thiosulfate pentahydrate is added. The resulting solution is extracted with diethyl ether, and the extracts are dried over Na 2 SO4 and concentrated. The crude products is purified via flash chromatography (silica, 1 % EtOAc in hexane) to give the protected alcohol of 21111 (85%). 22111 : To a solution of 21111 in THF at 25°C is added triethylamine»3HF (5:1 , THF/reagent giving 0.1 M). After stirring the reaction mixture is concentrated and purified by flash chromatagraphy. 23111 : To a small flask is added Lindlar's catalyst (0.5 equivalents) under argon. A solution of 22111 (1.0 equivalent) in toluene is then added to the the catalyst, and the reaction mixture is treated with with H 2 at room temperature. After 20 min the reaction mixture is filtered through Celite® and concentrated to 23111. 24111 : To a solution of 23111 (1.0 equivalent) in methanol is added PPTS (1 equivalent). The reaction mixture is then concentrated and the residue is purified by flash chromatography (silica, 50% diethyl ether in hexanes with 1 % triethylamine) to give 24111 (77%). Scheme 29: Introduction of side-chains and synthesis of sarcodictyin and analogs wherein Rs is represented by the products formed in Schemes 31 and 32; Rr is represented by the products formed in Scheme 33; Rt comprises a radical from the group of H, Me, Et, n-Pr, /- Pr, n-Bu, t-Bu, Bn, CH 2 CH=CH 2 , CH 2 CCH, c-C 6 Hn , C 8 H 7 , and HO(CH 2 ) 2 ; Rv = THP, Ac, 2-CI-Ac, CCI 3 C(O), 2-Br-Ac, CF 3 C(O), 2-PhAc, EtC(O), CH 2 =CHC(O), HCCC(O), n-PrC(O), /-PrC(O), cyc/o-PrC(O), n-BuC(O), ABuC(O), f-BuC(O), Lev, cyc/o-C 6 Hn C(O), Bz, 2-furylC(O), PhCH=CHC(O), 2-thiopheneC(O), Me, Et, n-Pr, /-Pr, All, Prop, n-Bu, Bn, AcOCH 2 CH 2 ; Rw: H, Me, Et, n-Pr, / ' -Pr, n-Bu, f-Bu, Bn, CH 2 CH=CH 2 , CH 2 CCH, c-CsH-n , C 8 H 17 ( A " = a "y'* Bn = benz y'' Ac = acetyl, Pr = Prop = propyl, Bu = Butyl, Ph = phenyl, Me = methyl, et = ethyl, THP = tetrahydropyranyl). Reaction conditions: a. DCC, 4-DMAP, CH 2 CI 2 , 25 °C. b. mixed anhydride, triethylamine, 4- DMAP, CH 2 CI 2 , 23 °C. c. TBAF, THF, 25 °C; d- NH 3 , THF, ethanol, -78 °C. e. DDQ, CH 2 CI 2 , H 2 O, 25 °C. f. 3,4-dihydro-2H-pyran, CSA, THF, 25 °C. g. Rv-OH, triethylamine, 4-DMAP, CH 2 CI 2 , 25 °C. h. Rv-CI, triethylamine, CH 2 CI 2 , 25 °C. i. Rv-I, NaH, DMF, 25 °C. I. CSA, CHCI 3 , Rt-OH. m. Rr-OC(NH)CCI 3 , TMS-OTf, diethyl ether, 0 °C. n. Dess-Martin periodinane, NaHCO 3 , pyridine, CH 2 CI 2 , 25 °C. o. NaCIO 2 , NaH 2 PO 4 , 2-methyl-2-butene, THF, tert-butanol, H 2 O: IPS, c, d, e m Rr-OC(CH)CCI. 26111 32111 30111 32111 33111 3511 1 34111 32111 : Compound 28111 (1.0 equivalent) is dissolved in CH 2 CI 2 and NaHCO 3 (10 equivalents) is added to the solution at 0°C. After 10 min Dess-Martin periodinane (2.5 equivalents) is added to the reaction mixture at the same temperature, and the the reaction mixture is then warmed to 25°C. After 1 h the reaction mixture is diluted with diethyl ether and aqueous saturated sodium bicarbonate solution is added to the mixture, and then sodium thiosulfate pentahydrate is added. The resulting solution is extracted with diethyl ether, and the extracts are dried over Na 2 SO4 and concentrated. The crude products is purified via flash chromatography (silica, 10/10/1 = EtOAc/CH 2 CI 2 /methanol) to give the aldehyde 32111 (100%) 33111 : To a solution of 32111 (1.0 equivalent) and 2-methyl-2-butene 2.0 M in THF, 70 equivalents) in f-BuOH/H O (5/1 ) is added NaH PO4 ( 3 -° equivalents) and NaCIO 2 (6.0 equivalents) at 0°C. The reaction mixture is stirred for 2 h, then to it is added the solution of CH 2 N 2 (excess) in diethyl ether. The reaction mixture is concentrated and the residue is purified by flash chromatography chromatography (silica, 10/10/1 = EtOAc/CH 2 CI 2 /metha- nol) to give the ester 33111 (71 %). Scheme 30: Futher eleutherobin and sarcodictyin analogs wherein XRx is a radical selected from a group consisting of MeHN, Me N, EtHN, Et 2 N, n-PrHN, n-Pr 2 N, i-PrHN, i-Pr 2 N, n-Bu 2 N, BnHN, Bn 2 N, HS, MeS, EtS, n-PrS, APrS, n-Bu, PhS, and BnS. Conversion of 26111 to 36111 , conversion of 28111 to 37111 , and conversion of 37111 to 38111 and 39111. Reaction conditions: p. CSA, CHCI 3 , Rx-XH. q. Rx-XX-Rx, PPh 3 , THF. r. DAST, CH 2 CI 2 , 0 °C. s. reagent, conditions as in procedure O described below, t. CSA, CHCI 3 , Rt-OH: 28111 37111 37111 39111 Scheme 31 : Synthesis of Ri side-chain acids and anhydrides with regard to Ri in formula [A]. Starting materials: 49111 : see J. Org. Chem. 44, 2250-6 (1979) and J. Org. Chem. 58, 4494-6 (1993); 53111 and 57111 : see J. Org. Chem. 61, 4623-33 (1996). Reaction conditions: u. LiOH, THF, H 2 O, 25 °C. v. Ph 3 =CHCO 2 Me, PhH, 25 °C. w. DIBAL-H, CH 2 CI 2 , 78 °C. x. (CH 3 ) 3 -C(O)CI, THF, 25 °C. y. Ph 3 =CMeCO 2 Me solvent, 25 °C: 45111 47111 48111 42111 : To a solution of 41111 (1.0 equivalent, 0.3 M) in THF is added pivaloylchlo- ride (2.0 equivalents) and triethylamine (2.0 equivalents). The reaction is stirred overnight at room temperature. The solution is then filtered through Celite®, concentrated, and dissolved in CH 2 CI to produce a 0.2 M stock solution. Scheme 32: Further illustration of the synthesis of Ri side-chain acids and anhydrides with regard to formula [A]. Starting materials: 61111 : J. Org. Chem. 61, 4623-33 (1996); 66111 and 73111 : commercially available from Aldrich. Reaction conditions: s. reagent conditions see Procedure O below u. LiOH, THF, H 2 O, 25 °C. v. Ph 3 P=CHCO 2 Me, PhH, 25 °C. w. DIBAL-H, CH 2 CI 2 , -78 °C. z. NaSMe, ethanol. 67111 72111 74111 75111 Scheme 33: Synthesis of the R 2 ( in formula [A]) side-chain imidates, and the projected steps after coupling wherein R40 is selected from Ac, 2-CI-Ac, CCI 3 C(O), 2-Br-Ac, CF 3 C(O), 2-PhAc, EtC(O), CH 2 =CHC(O), HCCC(O), n-PrC(O), /-PrC(O), c-PrC(O), n- BuC(O), BuC(O), t-BuC(O), cyc/oC 6 HnC(O), Bz, 2-furylC(O), PhCH=CHC(O), and 2- thiopheneC(O). Reaction conditions: a. NaH, PMB-CI, DMF, 25 °C. b. p-TsOH, (CH 2 OH) 2 , methanol, 25 °C. c. TBS-OTf, triethylamine, CH 2 CI 2 , 25 °C. d. NBS, pyridine, acetone, H 2 O, 0 °C. e. C1 3 CCN, NaH, CH 2 CI 2 , 25 °C. f.: Procedure E (see description), g. Procedure G (see description), h. Procedure H (see description), i. Procedure I (see description), j. Procedure C (see description), k. TBS-CI, imidazole, DMF, 25 °C. I. (R 40 ) 2 O, triethylamine, 4-DMAP, CH CI 2 . m. potassium-tert-butylate, DMSO. n. HgCI , HgO, acetone, H 2 O. *) = after coupling 79111 ;8 7iιι H&° * TBSO r °™S - •4111 85111 87111 97111 77111 : To a solution of NaH (1.2 equivalents, 0.51 M) in DMF is added 76111 (1.0 equivalent, 0.30 M)in DMF at 0°C and the reaction mixture is stirred at 0°C for 30 min after which PMBCI (1.3 equivalents) is added. The reaction is then stirred at room temperature for 2h and then quenched by addition of saturated NH4CI, extracted with diethyl ether, dried over MgSO4, and concentrated. The crude product is purified by flash chromatography (silica, 20% EtOAc in hexanes) to give 77111 (93%). 78111 : To a solution 77111 (1.0 equivalent, 0.07 M) in methanol and ethyleneglycol (methanol:ethyleneglycol = 10:1 ) is added CSA (0.1 equivalents) at room temperature, and the mixture is stirred at room temperature for 2h and then quenched by addition of saturated NaHCO 3 , extracted with ethyl acetate, dried over MgSO4, and concentrated. The crude product is purified by flash chromatography (silica, 60% EtOAc in hexanes) to give 78111 (84%). 79111 : To a solution of 78111 (1.0 equivalent, 0.14 M) and triethylamine (10.0 equivalents) in CH- 2 CI 2 at 0°C is added TBDMSOTf (4 equivalents) and the reaction imixture is stirred at 0°C for 2 h and then quenched by addition of saturated NaHCO 3 , extracted with ethyl acetate, dried over MgSO4, and concentrated. The crude product is purified by flash chromatography (silica, 3% diethyl ether and 1 % triethylamine in hexanes) to give 79111 (93%). 80111 : To a solution of 79111 (1.0 equivalent, 0.07 M) in wet acetone (93% acetone, 7% water) at 0°C is added N-bromosuccinamide (3.3 equivalents) and pyridine (11.0 equivalents). The resulting solution is stirred for 4 h at 0°C and quenched by addition of saturated Na SO 3 solution. The reaction mixture is extracted with diethyl ether, and the extracts are washed with brine and dried over Na 2 SO4 before concentrating. The crude product is purified by flash chromatography (silica, 10% EtOAc in hexanes) to give 80111 (80%). 81111 : To a solution of 80111 (1.0 equivalent, 0.09 M) and CCI 3 CN (5.0 equivalents) in CH 2 CI 2 at 0°C is added NaH (0.1 equivalents) and the reaction is stirred at room temperature for 3.5 h afterwhich it is concentrated and the residue is purified by flash chromatography (silica, 33% EtOAc in hexanes with 2% triethylamine) to give 81111 (93%). 87111 : Synthesised from 82111 as 81111 from 76111. 89111 : To a solution of alcohol 88111 (1.0 equivalent, 0.1 M) in DMF is added imi- dazole (6.0 equivalents) and TBDMSCI (2.4 equivalents). The reaction mixture is then stirred at room temperature, quenched, concentrated, and purified by flash chromatography. 90111 : To a solution of alcohol 89111 (1.0 equivalent, 0.1 M) in CH 2 CI 2 is added triethylamine (3.0 equivalents), 4-DMAP (0.3 equivalents), and anhydride (e.g. acetic anhydride) (2.0 equivalents). The reaction mixture is then stirred at room temperature, quenched, concentrated, and purified by flash chromatography. 91111 : To a solution of 90111 (1.0 equivalent, 0.1 M) in wet acetone (93% acetone, 7% water) at 0°C is added N-bromosuccinamide (3.3 equivalents) and pyridine (11.0 equivalents). The resulting solution is stirred at room temperature, quenched, concentrated and purified by flash chromatography. 92111 : To a solution of 91111 (1.0 equivalent, 0.1 M) and CCI 3 CN (5.0 equivalents) in CH- 2 CI 2 at 0°C is added NaH (0.1 equivalents). The reaction mixture is then stirred at room temperature, concentrated, and purified by flash chromatography. 94111 : To a solution of alcohol 93111 (1.0 equivalent, 0.1 M) in DMF is added imi- dazole (6.0 equivalents) and TBDMSCI (2.4 equivalents). The reaction mixture is then stirred at room temperature, quenched, concentrated, and purified by flash chromatography. 95111 : To a solution of NaH (1.2 equivalents, 0.5 M) in THF is added 94111 (1.0 equivalent, 0.3 M)in THF at 0°C and the reaction mixture is stirred at 0°C for 30 min after which PMBCI (1.3 equivalents) is added.The reaction mixture is then stirred at room temperature, quenched, concentrated, and purified by flash chromatography. 96111 : To a solution of alcohol 95111 (1.0 equivalent, 0.1 M) in DMSO is added potassium f-butoxide (0.3 equivalents). The reaction mixture is then stirred at room temperature, quenched, concentrated, and purified by flash chromatography to give C-1 vinyl ether. To a solution of the resulting vinyl ether (1.0 equivalent, 0.1 M) in THF and water (THF:water = 20:1 ) is added HgCI 2 (0.3 equivalents). The reaction mixture is then stirred at 70°C, quenched, concentrated, and purified by flash chromatography. 97111 : To a solution of 96111 (1.0 equivalent, 0.1 M) and CCI 3 CN (5.0 equivalents) in CH- 2 CI 2 at 0°C is added NaH (0.1 equivalents). The reaction mixture is then stirred at room temperature, concentrated, and purified by flash chromatography. PROCEDURE A ((a) in Scheme 29): To a solution of alcohol (e.g. 24111) (1.0 equivalent) in CH 2 CI 2 is added DCC (1.8 equivalents), 4-DMAP (0.5 equivalents), and side chain precursor containing the carboxylic acid functionality (1.5 equivalents). The reaction mixture is then stirred at room temperature, quenched, concentrated, and purified by flash chromatography. PROCEDURE B ((b) in Scheme 29): To a solution of alcohol (e.g. 24111) (1.0 equivalent) in CH CI 2 is added triethylamine (10.0 equivalents), 4-DMAP (2.0 equivalents), and the mixed anhydride of the side chain (5.0 equivalents). The reaction mixture is then stirred at room temperature, quenched, concentrated, and purified by flash chromatography. PROCEDURE C ((c) in Scheme 29, (j) in Scheme 33): To a solution of diethyl ether (e.g. 27111) (1.0 equivalent) in THF (0.1 M) is added TBAF (4.0 equivalents). The reaction mixture is then stirred at room temperature for 2 h, quenched with H 2 O, extacted with CH 2 CI 2 , concentrated, and purified by flash chromatography. PROCEDURE D((d) in Scheme 29): A solution of 27111 (1.0 equivalent) in THF:ethanol (20:1 , 0.1 M) is added to liquid NH 3 (0.05 M) followed by addition of Na metal (10 equivalents) and the reaction is stirred for 20 min at -78°C. The reaction mixture is then quenched with solid NH4CI, diluted with diethyl ether, filtered and concentrated, and purified by flash chromatography. PROCEDURE E ((e) in Scheme 29, (f) in Scheme 33)): To a solution of 27111 (1.0 equivalent) in CH 2 CI 2 :water (18:1 , 0.01 M) is added DDQ (2.0 equivalents) and the reaction is stirred at room temperature for 30 min. The reaction mixture is then quenched with saturated NaHCO 3 solution, extructed with CH 2 CI 2 , dried over sodium surfate, filtered, concentrated and purified by flash chromatography. PROCEDURE F ((f) in Scheme 29): To a solution of 28111 (1.0 equivalent, 0.1 M) in THF at 25°C is added 3,4-dihydro-2H-pyran (10.0 equivalents) and CSA (1.0 equivalent). The reaction mixture is stirred at room temperature, quenched, concentrated, and purified by flash chromatography. PROCEDURE G ((a) in Scheme 29, Scheme 33): To a solution of alcohol 28111 (1.0 equivalent, 0.1 M) in CH 2 CI 2 is added triethylamine (3.0 equivalents), 4-DMAP (0.3 equivalents), and anhydride (e.g. acetic anhydride) (2.0 equivalents). The reaction mixture is then stirred at room temperature, quenched, concentrated, and purified by flash chromatography. PROCEDURE H ((h) in Scheme 29, Scheme 33): To a solution of 28111 (1.0 equivalent, 0.1 M) in CH 2 CI 2 is added triethylamine (3.0 equivalents) and chloride (e.g. BzCI) (2.0 equivalents). The reaction mixture is stirred at room temperature, quenched, concentrated, and purified by flash chromatography. PROCEDURE I ((i) in Scheme 29, Scheme 33): To a solution of 28111 (1.0 equivalent, 0.1 M) in DMF at 0°C is added NaH (1.3 equivalents) and the reaction mixture is stirred for 30 min. To this mixture is added iodide (e.g. Mel) at 0°C, and the resulting mixture is stirred at room temperature, quenched, concentrated, and purified by flash chromatography. Procedure J ((j) in Scheme 29): To a solution of acid 33111 (1.0 equivalent) in THF (0.1 M) is added the solution of CH 2 N 2 (excess) in diethyl ether. The reaction is monitored by TLC. After disapearance of the starting material the reaction mixture is concentrated and the residue is purified by flash chromatography (silica, 10/10/1 = EtOAc/CH 2 CI 2 /methanol) to give the ester 34111 in high yield. Procedure K (( ) in Scheme 29): To a solution of acid 33111 (1.0 equivalent) in CH 2 CI 2 (0.1 M) is added alcohol R 5 OH (2.0 equivalents), DMAP (0.5 equivalents) and DCC (1.5 equivalents). The reaction is monitored by TLC. After disapearance of the starting material, the reaction mixture is concentrated, washed with water, extracted with CH 2 CI 2 , and concentrated, and the residue is purified by flash chromatography to give the ester 34111 in high yield. Procedure L ((p) in Scheme 30): To a solution of 26111 (1.0 equivalent) in CHCI 3 (0.1 M) at ambient temperature is added alcohol R^OH (2.0 equivalents) followed by a catalytic amount of CSA (0.1 equivalents) and the progress of the reaction is monitored by TLC. After the reaction is completed, saturated NaHCO 3 is added and the organic layer is extracted with diethyl ether, dried with Na 2 SO4, concentrated and purified by flash chromatography to produce acetal 36111 in high yield. Procedure M ((q) in Scheme 30): To a solution of 26111 (1.0 equivalent) in diethyl ether (0.1 M) at -20°C is added BF3 » diethyl ether (1.0 equivalent) followed by thiol RX-SH (1.2 equivalents), and the progress of the reaction is monitored by TLC. After the reaction is completed, saturated NaHCO 3 is added and the organic layer is extracted with diethyl ether, dried with Na 2 SO4, concentrated and purified by flash chromatography to produce thio-acetal 36111 in high yield. Procedure N ((r) in Scheme 30): To a solution of alcohol 28111 (1.0 equivalent) in CH 2 CI 2 (0.1 M) at 0°C is added DAST (1.2 equivalents) and the solution is allowed to warm to room temperature. The progress of the reaction is monitored by TLC. After the reaction is completed, saturated NaHCO 3 is added and the organic layer is extracted with diethyl ether, dried with Na 2 SO4, concentrated and purified by flash chromatography to produce fiuorinated compound 37111 in high yield. Procedure O ((s) in Scheme 30, Scheme 32): To a solution of 28111 (1.0 equivalent, 0.4 M) and triethyl amine (2.5 equivalents) in CH 2 CI 2 at 0°C is added methanesul- fonyl chloride (1.2 equivalents) dropwise over 1 h. The reaction mixture is stirred at 0°C for 2 h, quenched by addition of brine, and extracted with EtOAc. The combined extracts are dried over Na 2 SO4 and concentrated. The crude product is purified by flash chromatagra- phy (silica, 10% EtOAc in hexane) to afford the coresponding mesylate (91%). To a solution of the mesylate (1.0 equivalent) in DMF (0.1 M) at ambient temperature is added pre-dried CsF (1.2 equivalents), and the solution is warmed to 50°C. The progress of the reaction is monitored by TLC. After the reaction is completed, saturated NaHCO 3 is added and the organic layer is extracted with diethyl ether, dried with a 2 SO4, concentrated and purified by flash chromatography to produce fiuorinated compound 37111 in high yield. Procedure P ((u) in Scheme 31 , Scheme 32): To a solution of ester (1.0 equivalent, 0.4 M)) in THF/Water (3:4) is added NaOH (1.1 equivalents), and the reaction mixture is stirred at room temperature for 12 h. The solution is then concentrated down and dried under high vacuum for 12 h to give the acid salt. Procedure Q ((v) in Scheme 31 , Scheme 32): To a solution of aldehyde (1.0 equivalent, 0.2 M) in benzene is added Ph 3 P=CHCO Me (1.5 equivalents), and the reaction mixture is heated to 80°C. Upon completetion the reaction mixture is concentrated and the residue is purified by flash chromatography. Procedure R ((w) in Scheme 31, Scheme 32): To a solution of ester (1.0 equivalent, 0.2 M) in CH CI 2 at -78°C is added 1.0 M DIBAL in CH 2 CI 2 (1.0 equivalent). The reaction is quenched by addition of saturated NH4CI solution, extracted with diethyl ether, concentrated, and purified by flash chromatography.

Claims: What is claimed is: 1. A compound represented by the following structure [A]: wherein: Ri is a radical selected from the group consisting of -OH, OAc, and radicals represented by the following structures: R 2 is a radical selected from the group consisting of -OH, -O(Cι-C β alkyl), -OCH CF 3 , -O-/so-propyl, -O-te/f-butyl, -O-benzyl, -OCH 2 CH=CH 2 , -OCH 2 CCH, -O(CH 2 ) 2 -OH, -NHMe, -NMe 2 , -NHEt, -NEt 2 , -NH-n-propyl, -N-(propyl) 2 , -NH-/so propyl, -N-butyl 2 , -NH-benzyl, -N-benzyl 2 , -SH, -SMe, -SEt, -S-n-propyl, -S-/so- propyl, -S-n-butyl, -S-benzyl, and -S-phenyl; R 3 is a radical selected from the group consisting of -CH 2 OC(O)CH 3 , -CH 2 OC(O)-phenyl, -CH 2 OC(O)O-CH 3 , -CH 2 OC(O)NH-phenyl, -CH 2 -OH, -CH(O), -CH 2 -O-tri-isopropylsilyl, -CH 2 O-Ac, -CH 2 -F, -CH 2 N 3 , -CH 2 NAc, -CH 2 NBz, C(O)-O(C r C 6 alkyl), -C(O)-CH 2 CF 3 , -C(O)-CH 2 CHCH 2 , -C(O)-O-CH 2 CH 2 CI, -C(O)O(CH 2 ) 2 CH 2 CI, -C(O)O(CH 2 ) 2 CH(CH 3 ), -C(O)CH 2 Ph, -C(O)CH 2 -phenyl-OMe, -CH 2 -O-tetrahydropyran, -CH 2 -O-C(O)CHCI 2 , -CH 2 -O-C(O)-CCI 3 ,-CH 2 -O-C(O)CHBr 2 , -CH 2 -O-C(O)-CF 3 , -CH 2 -O-C(O)CHPh 2 , EtC(O)-O-CH 2 -, CH 2 =CHC(O)-O-CH 2 -, HC CC(O)-O-CH 2 -, n-propyl-C(O)-O-CH 2 -, /-PrC(O)-O-CH 2 -, cyclopropyl-C(O)-O-CH 2 -, n-BuC(O)-O-CH 2 -, ABuC(O)-O-CH 2 -, f-BuC(O)-O-CH 2 -, cyc/o-C 6 Hn C(O)-O-CH 2 -, phenyl-O-CH 2 -, 2-furyl-C(O)-O-CH 2 -, PhCH=CHC(O)-O-CH 2 -, 2-thiophene-C(O)-O-CH 2 -, (C r C 6 alkyl)-O-CH 2 -, /-propyl- O-CH 2 -, allyl-O-CH 2 -, benzyl-O-CH 2 -, AcOCH 2 CH 2 -O-CH 2 -, -COOH, -COO-(C r C 6 alkyl), -COO-/-propyl, -COO-f-butyl, -COO-benzyl, -COOCH 2 CH=CH 2 , -COO-CH 2 C CH, -COO-cyc/o-C β Hn , -CONHBn, -CONH(C r C 6 alkyl), -CONH-propyl, and -COO-C3H 7 and a radical selected from the group represented by the following structures: wherein R 4 is a radical selected from the group consisting of -OH, -OAc, 2-CI-AcO-, CCI 3 C(O)O-, 2-Br-AcO-, CF 3 C(O)O-, 2-phenyl-AcO-, (C r C 6 alkyl)-C(O)O-, CH 2 =CHC(O)O-, HC CC(O)O-, propyl-C(O)O-, cyc/o-propyl-C(O)O-, /-butyl-C(O)O-, f-butyl-C(O)O-, c c/o-C 6 Hι ιC(O)O-, phenyl-O-, 2-furyl-C(O)O-, PhCH=CHC(O)O-, and 2-thiophene-C(O)O-; R 5 is a radical selected from the group consisting of -OAc and -OH; R 6 is a radical selected from the group consisting of -OAc and -OH; R7 is a radical selected from the group consisting of -H, and -methyl; RQ is a radical selected from the group consisting of -OAc, 2-CI-AcO-, CCI 3 C(O)O-, 2-Br-AcO-, CF 3 C(O)O-, 2-phenyl-AcO-, (C r C 6 alkyl)-C(O)O-, CH 2 =CHC(O)O-, HC CC(O)O-, -propyl-C(O)O-, cyc/o-propyl-C(O)O-, -butyl-C(O)O-, f-butyl-C(O)O-, cyc/o-C 6 Hn C(O)O-, phenyl-O-,2-furyl-C(O)O-, PhCH=CHC(O)O-, and 2-thiophene- C(O)O- and the following provisos pertain: a. if Ri is and R 2 is -OH, then R 3 cannot be simultaneously -CO 2 -methyl or -CO 2 -ethyl; if Ri is and R 2 is -O-methyl, then R 3 cannot be wherein R 4 is -OAc, R 5 is hydroxy, Rg is hydroxy, and Ry is hydrogen; then R 3 cannot be wherein R 4 is -OAc, R5 is hydroxy, Rg is -OAc and Ry is hydrogen; and, then R 3 cannot be wherein R4 and R5 are -OAc, Rg is -OH, and Ry is hydrogen. 2. A compound as described in claim 1 wherein: R 2 is a radical selected from the group consisting of -O-Me, -O-Et, and -O-CH 2 CF 3 ; and R 3 is is a radical selected from the group consisting of -C(O)-O-Me, -C(O)-O-Et, -C(O)-O-n-propyl, -C(O)-O-n-butyl, -C(O)-(CH 2 ) 3 -CH 2 -Phe, -C(O)-O-CH 2 CH 2 OBn, -C(O)-NHMe, -C(O)-anthracen-9-ylmethyl, -C(O)-O- CH 2 CH=CH 2 , -C(O)-O- (CH 2 ) 2 CH 2 CI, -CH(OMe) 2 and -C(O)-NH-benzyl. 3. A compound acording to claim 2 wherein Ri is as defined, R 2 is a radical selected from the group consisting of -O-Me, -O-Et, and -O-CH CF 3 ; and R 3 is is a radical selected from the group consisting of -C(O)-O-Me, -C(O)-O-Et, -C(O)-O-n-propyl, -C(O)-O- CH 2 CH=CH 2 , -C(O)-O-(CH 2 ) 2 CH 2 CI, and -C(O)-NH-benzyl. 4. An advanced intermediate represented by the following structure: wherein: Ri is a radical selected from the group consisting of -O-paramethoxybenzyl, -O- triethylsilyl, and radicals represented by the following structures: R 3 is a radical selected from the group consisting of -CH 2 OC(O)CH 3 , -CH 2 OC(O)-phenyl, -CH 2 OC(O)O-CH 3 , -CH 2 OC(O)NH-phenyl, -CH 2 -OH, -CH(O), -CH 2 -O-tri-isopropylsilyl, -CH 2 O-Ac, -CH 2 -F, -CH 2 N 3 , -CH 2 NAc, -CH 2 NBz, C(O)-O(C r C 6 alkyl), -C(O)-CH 2 CF 3 , -C(O)-CH 2 CHCH 2 , -C(O)- O-CH 2 CH 2 CI, -C(O)O(CH 2 ) 2 CH 2 CI, -C(O)O(CH 2 ) 2 CH(CH 3 ), -C(O)CH 2 Ph, -C(O)CH 2 -phenyl-OMe, -CH 2 -O-tetrahydropyran, -CH -O-C(O)CHCI 2 , -CH 2 -O-C(O)-CCI 3 ,-CH 2 -O-C(O)CHBr 2 , -CH 2 -O-C(O)-CF 3 , -CH 2 -O-C(O)CHPh 2 , EtC(O)-O-CH 2 -, CH 2 =CHC(O)-O-CH 2 -, HC CC(O)-O-CH 2 -, π-propyl-C(O)-O-CH 2 -, /-PrC(O)-O-CH 2 -, cyclopropyl-C(O)-O-CH 2 -, n-BuC(O)-O-CH 2 -, ABuC(O)-O-CH 2 -, .-BuC(O)-O-CH 2 -, cyc/o-C 6 H 1 1 C(O)-O-CH 2 -, phenyl-O-CH 2 -, 2-furyl-C(O)-O-CH 2 -, PhCH=CHC(O)-O-CH 2 -, 2-thiophene-C(O)-O-CH 2 -, (C r C 6 alkyl)-O-CH 2 -, /-propyl- O-CH 2 -, allyl-O-CH 2 -, benzyl-O-CH 2 -, AcOCH 2 CH 2 -O-CH 2 -, -COOH, -COO-(C r C 6 alkyl), -COO-/-propyl, -COO-f-butyl, -COO-benzyl, -COOCH 2 CH=CH 2 , -COO-CH 2 C CH, -COO-cyc/o-C Hn , -CONHBn, -CONH(C r C 6 alkyl), -CONH-propyl, and -COO-C 3 Hιy and a radical selected from the group represented by the following structur wherein: R4 is a radical selected from the group consisting of -OH, -OAc, 2-CI-AcO-, CCI 3 C(O)O-, 2-Br-AcO-, CF 3 C(O)O-, 2-phenyl-AcO-, (C r C 6 alkyl)-C(O)O-, CH 2 =CHC(O)O-, HC CC(O)O-, /-propyl-C(O)O-, cyc/o-propyl-C(O)O-, /-butyl-C(O)O-, f-butyl-C(O)O-, cyc/o-C 6 Hn C(O)O-, phenyl-O-, 2-furyl-C(O)O-, PhCH=CHC(O)O-, and 2-thiophene-C(O)O-; R 5 is a radical selected from the group consisting of -OAc and -OH; R 6 is a radical selected from the group consisting of -OAc and -OH; R 7 is a radical selected from the group consisting of -H and -methyl; and R 3 is a radical selected from the group consisting of -OAc, 2-CI-AcO-, CCI 3 C(O)O-, 2-Br-AcO-, CF 3 C(O)O-, 2-phenyl-AcO-, (C r C 6 alkyl)-C(O)O-, CH 2 =CHC(O)O-, HC CC(O)O-, /-propyl-C(O)O-, cyc/o-propyl-C(O)O-, /•butyl-C(O)O-, f-butyl-C(O)O-, cyc/o-C 6 Hn C(O)O-, phenyl-O-, 2-furyl-C(O)O-, PhCH=CHC(O)O-, and 2-thiophene-C(O)O-. 5. An advanced intermediate represented by the following structure: wherein R is a radical selected from the group consisting of -O-paramethoxybenzyl, -O- triethylsilyl, and radicals represented by the following structures: R is a radical selected from the group consisting of -CH 2 OC(O)CH 3 , -CH 2 OC(O)-phenyl, -CH 2 OC(O)O-CH 3 , -CH 2 OC(O)NH-phenyl, -CH 2 -OH, -CH(O), -CH 2 -O-tri-isopropylsilyl, -CH 2 O-Ac, -CH 2 -F, -CH 2 N 3 , -CH 2 NAc, -CH 2 NBz, C(O)-O(C r C 6 alkyl), -C(O)-CH 2 CF 3 , -C(O)-CH 2 CHCH 2 , -C(O)- O-CH 2 CH 2 CI, -C(O)O(CH 2 ) 2 CH 2 CI, -C(O)O(CH 2 ) 2 CH(CH 3 ), -C(O)CH 2 Ph, -C(O)CH 2 -phenyl-OMe, -CH 2 -O-tetrahydropyran, -CH 2 -O-C(O)CHCI 2 , -CH 2 -O-C(O)-CCI 3 ,-CH 2 -O-C(O)CHBr 2 , -CH 2 -O-C(O)-CF 3 , -CH 2 -O-C(O)CHPh 2 , EtC(O)-O-CH 2 -, CH 2 =CHC(O)-O-CH 2 -, HC CC(O)-O-CH 2 -, n-propyl-C(O)-O-CH 2 -, /-PrC(O)-O-CH 2 -, cyclopropyl-C(O)-O-CH 2 -, n-BuC(O)-O-CH 2 -, /-BuC(O)-O-CH 2 -, t-BuC(O)-O-CH 2 -, cyc/o-C 6 H 1 1 C(O)-O-CH 2 -, phenyl-O-CH 2 -, 2-furyl-C(O)-O-CH 2 -, PhCH=CHC(O)-O-CH 2 -, 2-thiophene-C(O)-O-CH 2 -, (C r C 6 alkyl)-O-CH 2 -, /-propyl- O-CH 2 -, allyl-O-CH 2 -, benzyl-O-CH 2 -, AcOCH 2 CH 2 -O-CH 2 -, -COOH, -COO-(C C 6 alkyl), -COO-/-propyl, -COO-r-butyl, -COO-benzyl, -COOCH 2 CH=CH 2 , -COO-CH 2 C CH, -COO-cyc/o-C Hn , -CONHBn, -CONH(C r C 6 alkyl), -CONH-propyl, and -COO-C 3 Hιy and a radical selected from the group represented by the following structures: wherein: R4 is a radical selected from the group consisting of -OH, -OAc, 2-CI-AcO-, CCI 3 C(O)O-, 2-Br-AcO-, CF 3 C(O)O-, 2-phenyl-AcO-, (C r C 6 alkyl)-C(O)O-, CH 2 =CHC(O)O-, HC CC(O)O-, /-propyl-C(O)O-, cyc/o-propyl-C(O)O-, /-butyl-C(O)O-, f-butyl-C(O)O-, cyc/o-C 6 Hι ιC(O)O-, phenyl-O-, 2-furyl-C(O)O-, PhCH=CHC(O)O-, and 2-thiophene-C(O)O-; R5 is a radical selected from the group consisting of -OAc and -OH; Rg is a radical selected from the group consisting of -OAc and -OH; Ry is a radical selected from the group consisting of -H and -methyl; and R 3 is a radical selected from the group consisting of -OAc, 2-CI-AcO-, CCI 3 C(O)O-, 2-Br-AcO-, CF 3 C(O)O-, 2-phenyl-AcO-, (C r C 6 alkyl)-C(O)O-, CH 2 =CHC(O)O-, HC CC(O)O-, /-propyl-C(O)O-, cyc/o-propyl-C(O)O-, Abutyl-C(O)O-, t-butyl-C(O)O-, cyc/o-C Hn C OJO-, phenyl-O-, 2-furyl-C(O)O-, PhCH=CHC(O)O-, and 2-thiophene-C(O)O-. 6. A method for cyclizing a first intermediate to a second intermediate, the first intermediate being a compound as described in claim 2, the second intermediate being a compound as described in claim 3, the method comprising the following step: cyclizing the first intermediate for producing the second intermediate. 7. A method for cyclizing a first intermediate to a second intermediate, the first intermediate being a compound described in claim 3, the second intermediate being represented by the following structure: wherein Ri is a radical selected from the group consisting of -O-paramethoxybenzyl, -O- triethylsilyl, and radicals represented by the following structures: R 3 is a radical selected from the group consisting of -CH 2 OC(O)CH 3 , -CH 2 OC(O)-phenyl, -CH 2 OC(O)O-CH 3 , -CH 2 OC(O)NH-phenyl, -CH 2 -OH, -CH(O), -CH 2 -O-tri-isopropylsilyl, -CH 2 O-Ac, -CH 2 -F, -CH 2 N 3 , -CH 2 NAc, -CH 2 NBz, C(O)-O(C r C 6 alkyl). -C(O)-CH 2 CF 3 , -C(O)-CH 2 CHCH 2 , -C(O)- O-CH 2 CH 2 CI, -C(O)O(CH 2 ) 2 CH 2 CI, -C(O)O(CH 2 ) 2 CH(CH 3 ), -C(O)CH 2 Ph, -C(O)CH 2 -phenyl-OMe, -CH 2 -O-tetrahydropyran, -CH 2 -O-C(O)CHCI 2 , -CH 2 -O-C(O)-CCI 3 ,-CH 2 -O-C(O)CHBr 2 , -CH 2 -O-C(O)-CF 3 , -CH 2 -O-C(O)CHPh 2 , EtC(O)-O-CH 2 -, CH 2 =CHC(O)-O-CH 2 -, HC CC(O)-O-CH 2 -, π-propyl-C(O)-O-CH 2 -, /-PrC(O)-O-CH 2 -, cyclopropyl-C(O)-O-CH 2 -, n-BuC(O)-O-CH 2 -, /-BuC(O)-O-CH 2 -, t-BuC(O)-O-CH 2 -, cyc/o-C 6 HnC(O)-O-CH 2 -, phenyl-O-CH 2 -, 2-furyl-C(O)-O-CH 2 -, PhCH=CHC(O)-O-CH 2 -, 2-thiophene-C(O)-O-CH 2 -, (C r C 6 alkyl)-O-CH 2 -, /-propyl- O-CH 2 -, allyl-O-CH 2 -, benzyl-O-CH 2 -, AcOCH 2 CH 2 -O-CH 2 -, -COOH, -COO-(C C 6 alkyl), -COO-/-propyl, -COO-f-butyl, -COO-benzyl, -COOCH 2 CH=CH 2 , -COO-CH 2 C CH, -COO-cyc/o-CgHn , -CONHBn, -CONH(C C 6 alkyl), -CONH-propyl, and -COO-C 3 Hιy and a radical selected from the group represented by the following structures: wherein: R 4 is a radical selected from the group consisting of -OH, -OAc, 2-CI-AcO-, CCI 3 C(O)O-, 2-Br-AcO-, CF 3 C(O)O-, 2-phenyl-AcO-, (C r C 6 alkyl)-C(O)O-, CH 2 =CHC(O)O-, HC CC(O)O-, Apropyl-C(O)O-, cyc/o-propyl-C(O)O-, /-butyl-C(O)O-, f-butyl-C(O)O-, phenyl-O-, 2-furyl-C(O)O-, PhCH=CHC(O)O-, and 2-thiophene-C(O)O-; R5 is a radical selected from the group consisting of -OAc and -OH; Rg is a radical selected from the group consisting of -OAc and -OH; Ry is a radical selected from the group consisting of -H and -methyl; and R 3 is a radical selected from the group consisting of -OAc, 2-CI-AcO-, CCI 3 C(O)O-, 2-Br-AcO-, CF 3 C(O)O-, 2-phenyl-AcO-, (C r C 6 alkyl)-C(O)O-, CH 2 =CHC(O)O-, HC CC(O)O-, /-propyl-C(O)O-, cyc/o-propyl-C(O)O-, /-butyl-C(O)O-, f-butyl-C(O)O-, cyc/o-C 6 Hn C(O)O-, phenyl-O-, 2-furyl-C(O)O-, PhCH=CHC(O)O-, and 2-thiophene-C(O)O-; the method comprising the following step: cyclizing the first intermediate for producing the second intermediate. 8. A method for promoting tubuiin assembly, the method comprising the step of contacting tubuiin with a compound described in claim 1 for promoting tubuiin assembly. 9. A method for stabilizing a plurality of microtubules, the method comprising the step of contacting tubuiin with a compound described in claim 1 for stabilizing the plurality of microtubules. 10. A method for the treatment of a tumor disease, comprising the administration of a compound of the formula [A] according to claim 1 to a patient in need of such treatment in an amount that is sufficient for the treatment of said tumor disease. 11. The use of a compound of the formula [A] according to any one of claims 1 to 3 for the treatment of a tumor disease. 12. A compound of the formula [A] according to any one of claims 1 to 3 for use in the diagnostic or therapeutic treatment of a warm-blooded animal. 13. A pharmaceutical composition comprising a compound of the formula [A] according to any one of claims 1 to 3 and at least one pharmaceutically acceptable carrier.

Inventors: HOSOKAWA SEIJIRO, KIM SANGHEE, LI TIANHU, NICOLAOU KYRIACOS C, OHSHIMA TAKASHI, PFEFFERKORN JEFF, VANDELFT FLORIS, VOURLOUMIS DIONISIOS, WINSSINGER NICOLAS, XU JIN-YOU, HOSOKAWA, SEIJIRO, KIM, SANGHEE, LI, TIANHU, NICOLAOU, KYRIACOS, C., OHSHIMA, TAKASHI, PFEFFERKORN, JEFF, VANDELFT, FLORIS, VOURLOUMIS, DIONISIOS, WINSSINGER, NICOLAS, XU, JIN-YOU
Applicants: NOVARTIS AG, SCRIPPS RESEARCH INST, THE SCRIPPS RESEARCH INSTITUTE
Application year: 1998
Main classification: C07D493
IPC codes: A61K31, A61P35, A61P43, C07D493, C07F7, C07H15