Abstract:
A method for making epothilones and epothilone analogs is described, as are novel compounds made by the method. Exemplary novel compounds include those according to the formula: 
                         
 
With respect the formula, G is selected from the group consisting of 
                         
 
R 2  substituents independently are selected from the group consisting of H and lower alkyl groups; Z is selected from the group consisting of the halogens and —CN; M is selected from the group consisting of O and NR 3 ; R 3  is selected from the group consisting of H, lower alkyl, R 4 CO, R 4 OCO, and R 4 SO 2 ; R 4  is selected from the group consisting of H, lower alkyl, and aryl; T is selected from the group consisting of CH 2 , CO, HCOH and protected derivatives thereof; W is H or OR; and X and Y independently are selected from the group consisting of O, NH, S, CO, and C. Embodiments of the method provide convenient access to analogs of the epothilones, such as those having alternate stereochemistry and those containing an ester, amide, thioester, or alkyne moieties in the macrocycle.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation-in-part of pending U.S. patent application Ser. No. 09/846,154, filed Apr. 30, 2001 now U.S. Pat. No. 6,596,875, which claims the benefit of the earlier filing date of U.S. patent application Ser. No. 09/499,596, filed Feb. 7, 2000, now abandoned, which claims the benefit of the earlier filing date U.S. Provisional Application No. 60/118,883, filed Feb. 5, 1999. Each of these prior applications is incorporated herein by reference. 
    
    
     ACKNOWLEDGEMENT OF GOVERNMENT SUPPORT 
     The United States government may have certain rights in this technology pursuant to Grant No. GM-50574, awarded by the National Institutes of Health. 
    
    
     FIELD 
     The present disclosure concerns a method for making epothilones and epothilone analogs, and compounds made by the method. 
     BACKGROUND 
     I. Introduction 
     Epothilones A (2) and B (4) were discovered by Höfle and coworkers while examining metabolites of the cellulose-degrading myxobacterium  Sorangium cellulosum  (Myxococcales) as potential antifungal agents. Höfle, G.; Bedorf, N.; Gerth, H.; Reichenbach (GBF), DE-B 4138042, 1993 ( Chem. Abstr.  1993, 120, 52841). Höfle, G.; Bedorf, N.; Steinmeth, H.; Schomburg, D.; Gerth. H.; Reichenbach, H.  Angew. Chem. Int. Ed. Engl.  1996, 35, 1567. 
                        
 
     Although the antifungal spectrum of 2 and 4 proved to be quite narrow, scientists at Merck found that these macrolides are highly cytotoxic. Bollag, D. M.; McQueney, P. A.; Zhu, J.; Hensens, O.; Koupal, L.; Liesch, J.; Goetz, M.; Lazarides, E.; Woods, C. M.  Cancer Res.  1995, 55, 2325. The epothilones had powerful activity against mouse fibroblast and leukemia cells (2 ng mL −1 ) and strong immunosuppressive activity. Gerth, K., et al.,  Antibiot.,  1996, 49, 560-563. By observing the effect of the epothilones on induction of tubulin polymerization to microtubules and noting that 2 and 4 are competitive inhibitors of Taxol with almost identical IC 50  values, it was concluded that epothilones act at the cellular level by a mechanism similar to Taxol. Bollag, D. M.  Exp. Opin. Invest. Drugs  1997, 6, 867; Nicolaou, et al.,  Angew. Chem. Int. Ed. Engl.,  supra. Epothilone B (2) was particularly impressive in these assays, having a 2,000-5,000-fold higher potency than Taxol in multiple-drugresistant cell lines. Bollag, D. M.; et al.,  Cancer Res.  1995, supra. 
     After scientists from Merck reported their findings on the mode of action of epothilones in 1995, interest in these compounds increased. The Merck scientists subjected tens-of-thousands of compounds to biological assays for Taxol-like tubulin-polymerization activity. However, of the compounds assayed, only epothilones A and B proved biologically active. 
     II. Tubulin and Microtubules 
     Tubulin polymerization-depolymerization plays an important role in the cell cycle, particularly during mitosis. Tubulin, a heterodimer protein comprising globular αβ-tubulin subunits is the monomeric building block of microtubules. Microtubules are one of the fundamental structural components of the cytoskeleton in all eukaryotic cells, and help develop and maintain the shape and structure of the cell as needed. Microtubules may operate alone, or in conjunction with other proteins to form more complex structures, such as cilia, centrioles, or flagella. Nicolaou et al., at 2019, supra. 
     Structurally, microtubules are regular, internetworked linear polymers (protofilaments) of highly dynamic assemblies of heterodimers of α and β tubulin. Nicolaou et al., supra. When thirteen of these protofilaments are arranged parallel to a cylindrical axis they selfassemble to form microtubes. These polymers form tubes of approximately 24 nm in diameter and up to several μm in length. Nicolaou et al., supra. 
     Growth and dissolution of microtubules are regulated by bound GTP molecules. During polymerization, GTP molecules hydrolyze to guanosine diphosphate (GDP) and orthophosphate. The half-life of tubulin at 37° C. is nearly a full day, but that of a given microtubule may be only 10 minutes. Consequently, microtubules are in a constant state of flux to respond to the needs of the cell. Microtubule growth is promoted in a dividing or moving cell, but is more controlled in a stable, polarized cell. The regulatory control is exerted by adding (for growth) or hydrolyzing (for shrinkage) GTP on the ends of the microtubule. 
     Microtubules are major components of the cellular apparatus and play a crucial role in mitosis, the process during cell replication in which duplicated genetic material in the form of chromosomes is partitioned equally between two daughter cells. When cells enter mitosis, the cytoskeletal microtubule network (mitotic spindle) is dismantled by melting at the center, and two dipolar, spindle-shaped arrays of microtubules are formed outwardly from the centrosome. Nicolaou et al., at 2020, supra. In vertebrate cells, the centrosome is the primary site of microtubule nucleation (microtubule-organizing center or MTOC). At metaphase, the dynamic action of the microtubules assembles the chromosomes into an equatorial position on the mitotic spindle. At anaphase, the microtubule dynamics change and the chromosomes partition and move to the new spindle poles on the dynamic microtubules, where the new cells are being formed. Nicolaou et al., supra. By this process, the parent cell duplicates its chromosomes, which provides each of the two daughter cells with a complete set of genes. When it is time for a eukaryotic cell to divide, microtubules pull its chromosomes apart and pushes them into the two emerging daughter cells. The rate at which microtubules change their length increases by 20- to 100-fold during mitosis relative to the rate during interphase. These rapid dynamics are sensitive to tubulin-interactive agents that exert their antimitotic action at the metaphase-to-anaphase transition. Kirschner et al.,  Cell,  1986, 45, 329-342. 
     III. Anticancer Drugs that Disrupt Microtubule Dynamics 
     A number of anticancer drugs having diverse molecular structures are cytotoxic because they disrupt microtubule dynamics. Most of these compounds, including known chemotherapeutic agents colchicine, colcemid, podophyllotoxin, vinblastine, and vincristine, interfere with the formation and growth of microtubules and prevent the polymerization of microtubules by diverting tubulin into other aggregates. This inhibits cell proliferation at mitosis. 
     Vinblastine binds to the ends of microtubules. Vinblastine&#39;s potent cytotoxicity appears to be due to a relatively small number of end-binding molecules. Mitchison et al,  Nature,  1984, 312, 237-242. 
     Colchicine first binds to free tubulin to form complexes. These complexes are incorporated into the microtubules at the growth ends in relatively low concentrations, but show profound effects on the microtubule dynamics. Toso R. J.,  Biochemistry,  1993, 32, 1285-1293. 
     Taxol disturbs the polymerization-depolymerization dynamics of microtubules in vitro by binding to the polymeric microtubules and stabilizing them against depolymerization. Cell death is the net result. Epothilones appear to act by the same mechanism and bind to the same general regions as Taxol does. Bollag et al.,  Cancer Res.,  1995, 55, 2325-2333. Epothilones displace Taxol from its receptor, but bind in a slightly different manner to microtubules, as suggested by their action against Taxol-resistant tumor cells, which contain mutated tubulin. Each tubulin molecule of the microtubules contains a Taxol binding site. Taxol and epothilone binding markedly reduce the rate of α/β tubulin dissociation. 
     Merck scientists compared the effects of the epothilones and Taxol on tubulin and microtubules and reported higher potencies for both epothilones A and B as tubulin polymerization agents (epothilone B&gt;epothilone A&gt;Taxol). All three compounds compete for the same binding site within their target protein. The epothilones exhibit similar kinetics in their induction of tubulin polymerization, and gave rise to microscopic pictures of stabilized microtubules and damaged cells that were essentially identical to those obtained with Taxol. Epothilones are superior to Taxol as killers of tumor cells, particularly multiple drug resistant (MDR) cell lines, including a number resistant to Taxol. In some of the cytotoxicity experiments, epothilone B demonstrated a 2,000-5,000-fold higher potency than Taxol, as stated above. Moreover, in vivo experiments, carried out recently at Sloan Kettering in New York involving subcutaneous implantations of tumor tissues in mice, proved the superiority of epothilone B. 
     On treatment with epothilone B, cells appear to be in disarray with their nuclei fragmented in irregular shapes and the tubulin aggregated in distinct wedge-shaped bundles. By interacting with tubulin, the epothilones block nuclear division and kill the cell by initiating apoptosis. 
     Recently, Hamel and co-workers examined the actions of epothilones A and B with additional colon and ovarian carcinoma cell lines and compared them with the action of Taxol. Kowalski R. J., et al.,  J. Biol. Chem.,  1997, 272, 2534-2541. Pgp-overexpressing MDR colon carcinoma lines SW620 and Taxol-resistant ovarian tumor cell line KBV-1 retained susceptibility to the epothilones. With  Potorous tridactylis  kidney epithelial (PtK2) cells, examined by indirect immunofluorescence, epothilone B proved to be the most active, inducing extensive formation of microtubule bundles. Nicolaouet al., at 2022, supra. 
     Epothilone A initiates apoptosis in neuroblastoma cells just as Taxol does. Unlike Taxol, epothilone A is active against a Pgp-expressing MDR neuroblastoma cell line (SK-N SH). And, the efficacy of epothilone was not diminished despite the increase of the Pgp level during administration of the drug. 
     IV. Taxol Side Effects 
     Taxol molecules bind to microtubules, making cell division impossible, which kills the cells as they begin to divide. Since cancer cells divide more frequently than healthy cells, Taxol damages tumors where runaway cell division occurs most profoundly. Other rapidly dividing cells, such as white blood cells and hair cells, also can be attacked. Consequently, patients taking the drug experience side effects. Chemotherapy with Taxol frequently is accompanied by immune system suppression, deadening of sensory nerves, nausea, and hair loss (neutropenia, peripheral neuropathy, and alopecia). 
     Taxol exhibits endotoxin-like properties by activating macrophages, which in turn synthesize proinflammatory cytokines and nitric oxide. Epothilone B, despite its similarities to Taxol in its effects on microtubules, lacked any IFN-γ-treated murine-macrophage stimulatory activity as measured by nitric oxide release, nor did it inhibit nitric oxide production. Epothilone-mediated microtubule stabilization does not trigger endotoxin-signaling pathways, which may translate in clinical advantages for the epothilones over Taxol in terms of reduced side effects. 
     The importance of the epothilones as therapeutic agents recently was discussed on the front page of the Jan. 27, 2000, edition of the  Wall Street Journal.  This article states:
         But Taxol has its drawbacks. Some fast-dividing cancer cells can mutate into forms resistant to the drug. Often, patients with advanced cancer who respond at first to Taxol don&#39;t respond after several cycles of treatment because their cells become resistant, too. Despite conducting dozens of trials over the years, Bristol-Myers has been frustrated in its efforts to expand Taxol&#39;s effectiveness beyond certain breast, ovarian and lung cancers.   That&#39;s why the new drugs, broadly classified as part of a family of chemicals known as the epothilones, hold such promise. In studies not yet published, Bristol-Myers and others have shown that the epothilones disrupt cell division through the same biochemical pathway as Taxol. But for reasons scientists are only beginning to understand, the new drugs are equally effective against cancer cells already resistant to Taxol, as well as cells that develop resistance over time.
 
V. Syntheses of Epothilones
       

     Based on the biological activity of the epothilones and their potential as antineoplastics, it will be apparent that there is a need for an efficient method for making epothilones and epothilone analogs. Four total syntheses of 4, and several incomplete approaches, are known. See, for example: (1) Nicolaou, K. C.; Ninkovic, S.; Sarabia, F.; Vourloumis, D.; He, Y.; Vallberg, H.; Finlay, M. R. V.; Yang, Z.  J. Am. Chem. Soc.  1997, 119, 7974; (2) Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka, T.; Sorensen, E. J.; Danishefsky, S. J.  J. Am. Chem. Soc.  1997, 119, 10073; (3) May, S. A.; Grieco, P.  Chem. Commun.  1998, 1597; (4) Schinzer, D.; Bauer, A.; Schieber, J.  Synlett  1998, 861; (5) Mulzer, J.; Mantoulidis, A.  Tetrahedron Lett.  1996, 37, 9179; (6) Claus, E.; Pahl, A.; Jones, P. G.; Meyer, H. M.; Kalesse, M.  Tetrahedron Lett.  1997, 38, 1359; (7) Gabriel, T.; Wessjohann, L.  Tetrahedron Lett.  1997, 38, 1363; (8) Taylor, R. E.; Haley, J. D.  Tetrahedron Lett.  1997, 38, 2061; (9) Brabander, J. D.; Rosset, S.; Bemardinelli, G.  Synlett  1997, 824; (10) Chakraborty, J. K.; Dutta, S.  Tetrahedron Lett.  1998, 39, 101; (11) Liu, Z.-Y.; Yu, C.-Z.; Yang, J. D.  Synlett  1997, 1383; (12) Liu, Z.-Y.; Yu, C.-Z; Wang, R.-F.; Li, G.  Tetrahedron Lett.  1998, 39, 5261; (13) Mulzer, J.; Mantoulidis, A.; Öhler, E.  Tetrahedron Lett.  1997, 38, 7725; and (13) Bijoy, P.; Avery, M. A.  Tetrahedron Lett.  1998, 39 1209. 
     Methods for making epothilone and epothilone analogs also have been described in the patent literature, including: (1) Schinzer et al., WO 98/08849, entitled “Method for Producing Epothilones, and Intermediate Products Obtained During the Production Process”; and (2) Reichanbach et al., WO 98/22461, entitled “Epothilone C, D, E, and F, Production Process, and Their Use as Cytostatic as well as Phytosanitary Agents.” One disadvantage associated with these prior processes for synthesizing epothilones is the lack of stereoselectivity in the production of the Z trisubstituted bond of the desepoxyepothilone. As a result, a new synthetic approach to epothilones and epothilone analogs is required which addresses this and other problems associated with syntheses of the epothilones known prior to the present disclosure. 
     SUMMARY 
     The present disclosure provides a novel method for making epothilones and epothilone analogs. The method can provide almost complete stereoselectivity with respect to producing the Z trisubstituted double bond of the desepoxyepothilone, and therefore addresses one of the disadvantages associated with methods known prior to the present disclosure. 
     One embodiment of the present disclosure provides compounds having the structure represented by Formula 1. 
                        
 
With respect to Formula 1, G is selected from the group consisting of 
                         
 
R substituents independently are H, lower alkyl, or a protecting group, such as a silyl group; R 1  is an aryl group, such as comprising a benzene derivative, or a heterocyclic aryl group, such as a thiazole derivative. R 2  substituents independently are selected from the group consisting of H and lower alkyl groups; Z is selected from the group consisting of the halogens and —CN; M is selected from the group consisting of O and NR 3 ; R 3  is selected from the group consisting of H, lower alkyl, R 4 CO, R 4 OCO, and R 4 SO 2 ; R 4  is selected from the group consisting of H, lower alkyl, and aryl; T is selected from the group consisting of CH 2 , CO, HCOH and protected derivatives thereof; W is H or OR; and X and Y independently are selected from the group consisting of O, NH, S, CO, and C.
 
     In certain disclosed embodiments X and Y define a carboxylic acid derivative, such as provided by an ester, thioester, or amide bond. One example, without limitation of such an ester bond is formed where X is C═O and Y is O. In other preferred embodiments X and Y mutually comprise a triple bond. 
     In particular preferred embodiments, R 1  is a group according to Formula 2 where X and Y independently are selected from the group consisting of O, N, and S, and R 6  is selected from the group consisting of H and lower alkyl. A particular class of aryl group according to Formula 2 is the thiazole class. 
                        
 
     A method for synthesizing compounds according to Formula 1 is provided. One embodiment of the method comprises providing a compound according to Formula 3. 
                        
 
Compounds according to Formula 3 are subjected to macrolactonization conditions to yield macrocyclic compounds according to Formula 1.
 
     Another embodiment of the method comprises procedures for synthesizing compounds according to Formula 3. One embodiment of such procedures comprises providing a compound according to Formula 4, and a compound according to Formula 5, and coupling the compounds to form a bond between X and Y, thereby yielding a compound 
                        
 
according to Formula 3. In particular embodiments, coupling the compounds comprises reacting compounds having Formulas 4 and 5 by a reaction selected from the group consisting of organometallic reactions, such as transition metal-mediated coupling reactions, and amide bond-forming reactions, esterification reactions, thioesterification reactions, and the like.
 
     One embodiment of the method comprises first providing a compound having Formula 6. 
                        
 
With reference to Formula 6, R is H or a protecting group; R 1  is an aryl group, such as, without limitation, benzene derivatives or the thiazole of epothilone B; R 2 -R 5  substituents independently are selected from the group consisting of H and lower alkyl groups; and R 6 , substituents independently are selected from the group consisting of H and lower alkyl groups. Compounds having Formula 6 are then converted into an epothilone or an epothilone analog. For example, in the synthesis of epothilone B the step of converting the compound can involve first removing the protecting groups, and thereafter forming an epoxide at C12-C13.
 
     In preferred embodiments, R 1  is the thiazole shown below. 
                        
 
Most known epothilones have this thiazole derivative as the aryl group.
 
     Providing compounds having Formula 6 can be accomplished in a number of ways. One embodiment comprises coupling a first compound having Formula 7, 
                        
 
where R is H or a protecting group and X is a functional group or chemical moiety equivalent to a carbanion at a terminal carbon of the first compound, with a second compound having Formula 8. With reference to Formula 8, R 6  substituents independently are selected from the group consisting of H and lower alkyl groups, R is H or a protecting group, and Y is an electrophilic group capable of reacting with and coupling to the terminal carbon of the first compound, for example, Y can be an aldehyde. The precursor compound is then converted into compounds having Formula 6. For example, two compounds, one having Formula 7 and the other Formula 8, can be coupled by a Wittig reaction where X is PPH 3 + and Y is a carbonyl compound, such as an aldehyde.
 
     Compounds having Formula 6 can be provided by a second embodiment of the disclosed method. This second embodiment involves coupling a first compound having Formula 9
                        
 
where R is H or a protecting group and X is a halide, with a second compound including an alkyne and having Formula 10. 
                         
 
With reference to Formula 10, R groups independently are H, a protecting group, or a lower alkyl group. This compound is then converted into a compound having Formula 6. This embodiment can proceed by first forming an enyne precursor compound having Formula 11 where the substituents are as stated above. 
                         
 
Thus, another embodiment of the present method for forming epothilones or epothilone analogs comprises forming the precursor enyne compound having Formula 11 where R 1  is H or a protecting group, or is a thiazole group according to the triene compound having Formula 12 where R groups independently are H, a protecting group, or a lower alkyl group. Compounds having Formulas 11 and/or 12 are then converted into a compound having Formula 13, where 
                         
 
the carbon atom numbers correspond to the numbering system stated for epothilone A. 
                         
 
     With reference to Formula 13, R-R 7  are independently selected from the group consisting of H, lower aliphatic groups, particularly lower alkyl groups, protecting groups, or are bonded to an 0 in an epoxide or N in an aziridine. More particularly, R substituents independently are H, lower alkyl, or a protecting group; R 1  is an aryl group; R 2  is H or lower alkyl; C13 and C12 are carbons bonded together by a single bond or a double bond; R 3  and R 4  independently are H, lower aliphatic groups, or are bonded to 0 in an epoxide or to N in an aziridine; C10 and C9 are carbons in a double bond or triple bond, and, where C10 and C9 are carbons in a double bond, R5 and R6 independently are H, or lower aliphatic; and R7 substituents independently are selected from the group consisting of lower aliphatic groups. The configuration of the double bond between C10 and C9 may be cis or trans, i.e., E or Z. Compounds having Formula 13 are then converted into an epothilone or an epothilone analog. 
     Moreover, a compound having Formula 11 may be converted into a compound having Formula 12, such as by catalytic semi-hydrogenation. Lindlar&#39;s catalyst has proved to be an effective catalyst for conducting this catalytic semi-hydrogenation. 
     The disclosed embodiments of the present method differ from known synthetic pathways in a number of ways, such as by assembling the macrolide from two segments, which first are connected at C9-C10 before macrolactonization. With reference to the first disclosed embodiment of the present method, fragments were constructed around a preformed Z trisubstituted alkene to circumvent stereochemical problems afflicting known synthetic methods. The 9,10 olefin produced by coupling the two segments confers rigidity on the one portion of the epothilone macrocycle that exhibits flexibility, and hence may be expected to affect its tubulin binding properties. Moreover, this alkene provides a chemical moiety from which novel epothilone analogs can be prepared. 
     Epothilones, such as epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, and epothilone F, can be made by the present method. The disclosed method also provides access to novel compounds. These compounds typically have Formula 13
                        
 
where the substituents are as described above. Preferred compounds satisfying Formula 13 include one or more of the following: (1) R being hydrogen; (2) R 1  being the aryl thiazole side chain of the epothilones; (3) R 2  being hydrogen or methyl; (4) R 3 -R 6  being hydrogen or methyl, or R 3  and R 4  and/or R 5  and R 6  being bonded to oxygen in an epoxide; (5) R 7  being lower alkyl, particularly methyl.
 
     Compounds having Formula 13 include several chiral centers, which allows for a plurality of diastereomers. The disclosed method is directed to all such stereoisomers. 
                        
 
However, naturally occurring epothilones have known stereochemistries at each of the chiral centers. As a result, preferred compounds have the same stereochemistries at each chiral center, as do the epothilones. This is illustrated below in Formula 14, which shows the stereochemistries of preferred epothilone analogs at certain chiral centers. With respect to Formula 14, certain centers are represented stereoambiguously; however, the present method provides access to compounds having defined stereochemistry at these positions. Thus, in certain embodiments of the present method, compounds having controlled stereochemistry at positions 4, 9, 10, 12, 13 and 15 can be prepared.
 
     The present disclosure describes novel, biologically active epothilone analogs having the general structure represented by Formula 15. With reference to Formula 15, particular embodiments include compounds wherein R is H or a protecting group; R 1  is an aryl group, such as, without limitation, benzene derivatives, the thiazole derivative of epothilone B; R 2  and R 3  substituents are selected independently from the group consisting of H and lower alkyl groups; and R 4  substituents are selected independently from the group consisting of lower alkyl groups. Group Y at position 9 can comprise a heteroatom, such as an oxygen, nitrogen, or sulfur. In particular embodiments, Y is an oxygen atom, such as in an ester bond with a carbonyl at position 10 of an epothilone analog. Likewise, Y can comprise an NH group in an 
                        
 
amide bond or a sulfur in a thioester linkage. Group X at position 10 can comprise a carbon, such as a methylene, a methine, or a carbon bonded to a heteroatom, such as an oxygen atom. In particular embodiments, group X is a carbonyl, such as a carboxylic acid derivative. For example X can be bonded to Y in an ester, thioester or amide linkage.
 
     The present method provides novel synthetic routes to compounds having the general structure represented by Formula 15. For example, with reference to Formula 16, Y can be a hydroxyl group, and as such, can be oxidized to provide the corresponding carboxylic acid. This compound can then be coupled, for example, with a compound having the structure represented by Formula 17. 
                        
 
     With reference to Formulas 16 and 17, each R group independently can be H or a protecting group, with R 1 -R 4  as defined above. In particular embodiments, groups X and Y independently comprise an oxygen, nitrogen or sulfur, such as in an alkoxy group, an amine, or a sulfhydryl, respectively. 
    
    
     DETAILED DESCRIPTION 
     The process of the present method can be used to make known epothilones A, B, C, D, E and F, as well as analogs of these compounds, including the cryptothilones, which typically are dilactone or lactone-amide-type analogs of the epothilones. The cryptothilones are hybrid structures that include a portion of cryptophycins and a portion of the epothilones.
 
One such novel diene analog 10 has double bonds at positions C9-C10, and C12-C13. The 
                        
 
alkene configurations at C 9 -C10, and C12-C13 can be cis or trans (Z or E), including compounds 11 and 12. 
                         
 
     Using compound 10 and/or 11 to make analogs of epothilones, such as the cryptothilones, provides advantages relative to prior known syntheses, as indicated above. 
     A method for making diene 10 and converting 10 into, for example, epothilone B, as well as other epothilones and epothilone analogs, is described below. 
     I. Epothilone Structures and Epothilone Analogs 
     Formula 1 is a generic structural formula for diene and enyne derivatives of Compound 10, and analogs of the epothilones, such as a bislactone analog. 
                        
 
     Preferred compounds have the stereochemistries shown in Formula 14. 
                        
 
With reference to Formula 14, R is H, lower aliphatic, preferably lower alkyl, or a protecting group; R 1  is an aryl group; C13 and C12 are carbons bonded together by a single or double bond; R 3  and R 4  independently are H, lower alkyl, or are bonded to oxygen in an epoxide or to nitrogen in an aziridine; C10 and C9 are carbons in a single bond, double bond or triple bond, with preferred compounds having C10 and C9 bonded together by a double bond or a triple bond; if C10 and C9 are bonded together by a double bond, the configuration of the double bond may be cis or trans or E or Z; and R 5  and R 6  independently are H, lower aliphatic, preferably lower alkyl, or are bonded to heteroatoms in cyclic structures, such as to oxygen in an epoxide or to nitrogen in an aziridine.
 
     As used herein, “lower” refers to carbon chains having 10 or fewer carbon atoms, typically less than 5 carbon atoms. “Lower aliphatic” includes carbon chains having: (a) sites of unsaturation, e.g., alkenyl and alkynyl structures; (b) non-carbon atoms, particularly heteroatoms, such as oxygen and nitrogen; and (c) all branched-chain derivatives and stereoisomers. 
     The phrase “protecting group” is known to those of ordinary skill in the art of chemical synthesis. “Protecting group” refers generally to a chemical compound that easily and efficiently couples to a functional group, and can be easily and efficiently removed to regenerate the original functional group. By coupling a protecting group to a first functional group of a compound other functional groups can undergo chemical or stereochemical transformation without affecting the chemistry and/or stereochemistry of the first functional group. Many protecting groups are known and most are designed to be coupled to only one or a limited number of functional groups, or are used for particular circumstances, such as reaction conditions. Theodora Greene&#39;s  Protecting Groups in Organic Syntheses,  (Wiley Science, 1984), and later editions, all of which are incorporated herein by reference, discuss protecting groups commonly used in organic syntheses. Examples of protecting groups used to protect hydroxyl functional groups for the syntheses of epothilones and epothilone analogs include the silyl ethers, such as t-butyl dimethyl silyl (TBDMS) ethers, and tetrahydropyranyl (THP) ethers. 
     The term “analog” refers to a molecule that differs in chemical structure from a parent compound, for example a homolog (differing by an increment in the chemical structure, such as a difference in the length of an alkyl chain), a molecular fragment, a structure that differs by one or more functional groups, or an ion differing in ionization state from the parent compound. 
     A “derivative” is a chemical substance structurally related to a parent substance and theoretically derivable from it. 
     “R groups” in generic structural formulas are typically recited as being independent. This means that each R group can be varied, one from another, even when designated with the same R group. Thus each R group can represent the same chemical moiety, some R groups can be the same chemical moiety, or each R group can represent a different chemical moiety. 
     “Aryl” refers to compounds derived from compounds having aromatic properties, such as benzene. “Aryl” as used herein also includes compounds derived from heteroaromatic compounds, such as oxazoles, imidazoles, and thiazoles. 
     Preferred aryl groups have Formula 2
                        
 
where X and Y are independently selected from the group consisting of heteroatoms, particularly oxygen, nitrogen and sulfur, and R 6  is selected from the group consisting of lower alkyl. For the epothilones, and most epothilone analogs, the R 1  aryl group is thiazole 18 shown below. 
                         
 
     C12 and C13 of Formula 13 are carbons bonded together by a single or double bond. Whether C12 and C13 are joined by a single or double bond determines, in part, substituents R 3  and R 4 . For example, if C12 and C13 are coupled by a single bond, then R 3  and R 4  independently are selected from the group consisting of hydrogen and lower alkyl. Moreover, if C12 and C13 are coupled by a single bond then R 3  and R 4  can be bonded to a heteroatom, such as oxygen and nitrogen, in a cyclic structure, such as an epoxide or an aziridine. Epoxide 20 and aziridine 22 are examples of these compounds. 
     Several chiral centers of these structures are represented stereoambiguously to indicate that the various stereoisomers are within the scope of the disclosed method. With respect to the aziridine analogs, such as aziridine 22, R 2  is selected from the group consisting of hydrogen, lower aliphatic, particularly lower alkyl, acyl, and aryl. Preferred compounds have R 2  be hydrogen or lower alkyl. 
                        
 
     C9 and C10 of Formula 13 are carbons bonded together by a single, double or triple bond. Whether C9 and C10 are joined by a single bond, a double bond or a triple bond determines, in part, substituents R 5  and R 6 . For example, if C9 and C10 are coupled by a single bond, then R 5  and R 6  typically are selected from the group consisting of hydrogen and lower aliphatic, preferably lower alkyl. Moreover, if C9 and C10 are coupled by a single bond then R 5  and R 6  also can be bonded to a heteroatom, such as oxygen and nitrogen, in a cyclic structure, such as an epoxide or an aziridine. Epoxide 24 and aziridine 25 provide examples of these compounds. 
                        
 
     Compounds 26-35 provide additional examples of epoxide/aziridine epothilone analogs. 
                        
                         
                         
                         
                         
 
II. Biological Activity
 
     Known epothilones have significant biological activity. Novel epothilone analogs made according to the method also have been shown to have significant biological activity. For example, Tables 1 and 2 provide biological data for certain epothilones and epothilone analogs. The antiproliferative activity of cis 9,10-dehydroepothilone D and trans 9,10-dehydroepothilone D was assessed in vitro using a panel of human cancer cell lines. 
     As illustrated in Table 1, cis 9,10-dehydroepothilone was 20- to 30-fold less potent than natural epothilone D, and 330- to 670-fold less potent than epothilone B. Interestingly, trans 9,10-dehydroepothilone D showed biological activity very similar to that of its cis isomer in spite of an apparent difference in the conformation of these two macrolactones. Thus, the average IC 50  of trans 9,10-dehydroepothilone D for growth inhibition in the cell line panel used in this study was only 1.36-fold higher than that observed for cis 9,10-dehydroepothilone D. As noted for epothilones B and D, cis 9,10-dehydroepothilone D and trans 9,10-dehydroepothilone D retain full anti-proliferative activity against KB-8511 cells, a paclitaxel-resistant cell line overexpressing P-glycoprotein (Table 1). While the tubulin polymerization activity of cis 9,10-dehydroepothilone D and trans 9,10-dehydroepothilone D was lower than of natural epothilone D (56%, 36%, and 88%, respectively) (Table 1), it is conceivable that decreased cellular penetration may contribute to the reduction in antiproliferative potency observed for cis 9,10-dehydroepothilone D and trans 9,10-dehydroepothilone D. The absence of a clear difference in the biological profiles of cis and trans analogs of 9,10-dehydroepothilone D observed here has a parallel in results previously reported for other epothilone analogs. Thus, epothilones incorporating a trans epoxide or trans olefin at C12-C13 have been shown to possess biological activity comparable to their cis isomer. 
     
       
         
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                   
                   
                 IC 50   
                 IC 50   
                   
                   
                   
                   
               
               
                   
                   
                 KB-31 
                 KB-8511 
                 IC 50   
                 IC 50   
                 IC 50   
                 IC 50   
               
               
                   
                 Tubulin 
                 (Epider- 
                 (Epider- 
                 A549 
                 HCT-116 
                 PC3-M 
                 MCF-7 
               
               
                 Compound 
                 Polym. a   
                 moid) b   
                 moid) b,c   
                 (lung) b   
                 (colon) b   
                 (prostate) b   
                 (breast) b   
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 95 
                 0.17 
                 0.16 
                 0.16 
                 0.34 
                 0.32 
                 0.29 
               
               
                 Epothilone B 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 88 
                 1.94 
                 1.00 
                 4.62 
                 4.48 
                 7.40 
                 2.31 
               
               
                 Epothilone D 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 56 
                 59.39 
                 28.54 
                 109.03 
                 101.83 
                 146.47 
                 72.00 
               
               
                 9,10-cis-Dehydroepothilone D 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 36 
                 103.70 
                 70.37 
                 109.27 
                 109.97 
                 146.80 
                 95.03 
               
               
                 trans 9,10-, trans 12,13-Dehydroepothilone D 
               
               
                 Paclitaxel (Taxol) 
                 53 
                 2.67 
                 841.80 
                 5.19 
                 4.88 
                 6.62 
                 3.26 
               
               
                   
               
               
                   a Tubulin polymerization data (induction of porcine tubulin polymerization) are for 5 μM compound concentration relative to the effect of Epothilone B at a concentration of 25 μM, which is defined as 100%.  
               
               
                   b IC 50  values are expressed in nM and represent the mean of three independent experiments:  
               
               
                   c KB8511 is a Pgp-overexpressing sub-line of the KB-31 line.  
               
             
          
         
       
     
     With reference to Table 2, the bislactone epothilone analog was tested as indicated under the conditions used for Table 1. The bislactone was standardized against epothilone B, epothilone D, and paclitaxel in each experiment. The data indicate that although the bislactone is less active than epothilone B and D, the analog retains useful biological activity, particularly against the paclitaxel resistant KB-8511 cells. 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                   
                 Tubulin 
                 IC 50  KB-31 
                 IC 50  KB-8511 
               
               
                 Compound 
                 Polym. 
                 (Epidermoid) 
                 (Epidermoid) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 21.4 
                 25.5 
                 25.2 
               
               
                 Bislactone 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 81.4 
                 0.24 
                 0.15 
               
               
                 Epothilone B 
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 62.3 
                 1.94 
                 1.00 
               
               
                 Epothilone D 
               
               
                 Paclitaxel 
                 38.9 
                 2.9 
                 661 
               
               
                   
               
             
          
         
       
     
     Taken together, these data support the proposition that the C 8 -C 13  region of the epothilone perimeter is relatively tolerant of structural modification and suggest that the interaction of this segment of the molecule with tubulin is less stringently defined. 
     III. Method for Making Epothilones 
     The synthesis of epothilones can be exemplified by a working embodiment of a method for making epothilone B. Epothilone B was synthesized by coupling a first subunit with a second subunit to form a coupled intermediate for forming epothilones. One embodiment of the method comprised coupling a first subunit 36 with a second subunit 38. 
                        
 
     A second embodiment comprised coupling a first allylic halide subunit 40 with a second alkyne subunit 42. With respect to 36, 38, 40, and 42, the R substituents are as described above. 
                        
 
     A first embodiment of a the present method for making epothilones and epothilone analogs comprised making a suitable subunit 36 as illustrated by Scheme 1, i.e., compound 60. 
                        
 
     Synthesis of segment 36, as represented by 60 in Scheme 1, began from (Z)-3-iodo-2-methyl-2-propen-1-ol prepared in geometrically pure form from propargyl alcohol. After protection to provide 44, the iodoalkene was converted to the corresponding cuprate, which underwent clean conjugate addition to (S)-3-acryloyl-4-benzyl-2-oxazolidinone (45, not shown) to yield 46. Hydroxylation of the sodium enolate derived from 46 with Davis oxaziridine gave 48. See, for example, Evans et al.  Angew. Chem. Int. Ed Engl.  1997, 26, 2117. The configuration of 48 was confirmed by oxidative degradation to dimethyl (S)-malate. Protection of alcohol 48 as silyl ether 50, followed by exposure to catalytic potassium thioethoxide in ethanethiol provided 52, along with recovered oxazolidinone (93%). Treatment of thioester 52 with lithium dimethylcuprate furnished ketone 54, which upon Homer-Emmons condensation with phosphonate 53 (shown below) produced diene 56 in excellent yield, accompanied by 5% of its (Z,Z) isomer. 
                        
 
     The tetrahydropyranyl ether protecting group was removed using magnesium bromide. The liberated alcohol was converted to bromide 58. Homologation of 58 to phosphonium bromide 60 using triphenylmethylenephosphorane completed the synthesis of segment 36, as represented by compound 60 in Scheme 1. 
                        
 
     One embodiment of a segment 38, i.e., compound 74, was made as illustrated by Scheme 2. A key construction in one embodiment of a suitable segment 38 involved an aldol condensation of ketone 62 with aldehyde 64. This double stereodifferentiating reaction proceeded in good yield to give anti-Felkin product 66 as the sole stereoisomer. An important contribution to the stereoselectivity of this condensation is made by the p-methoxybenzyl (PMB) ether of 64, since the TBS protected version of this aldehyde resulted only in a 3:2 mixture of 66 and its Felkin diastereomer, respectively. The favorable outcome with 64 is consistent with chelation of the aldehyde carboxyl with both the lithium enolate from 62 and the PMB ether. After protection of 66 as tris ether 68, the terminal olefin was cleaved oxidatively to carboxylic acid 70, which was converted to its methyl ester 72. Hydrogenolysis of the PMB ether and oxidation of the resultant alcohol 74 yielded aldehyde 76. 
     Subunits 60 and 76 were coupled together, followed by macrolactonization, to provide the diene lactone precursor to epothilone B as shown below in Scheme 3. Wittig coupling of the ylide from 58, compound 60, with aldehyde 76 at low temperature afforded triene 78 as a single stereoisomer in excellent yield. Selective removal of the C15 silyl ether of 78 was unsuccessful. But, after saponification to carboxylic acid 80 this deprotection was readily accomplished with tetra-n-butylammonium fluoride. Macrolactonization of seco acid 82 was carried out under Yamaguchi&#39;s conditions and both silyl ethers were cleaved with acid to yield 9,10-dehydrodes-epoxyepothilone B 84. 
     Compounds made in this manner can be converted to epothilones using conventional chemistry. For example, selective hydrogenation of the disubstituted olefin of 84 with diimide gave the known lactone 86. Lactone 86 underwent epoxidation with dimethyldioxirane to produce 4. Epoxidation of lactone 86 to provide epothilone B (4) can be accomplished according to the method of Danishefsky et al.,  Angew. Chem. Int. Ed. Engl.,  1997, 36, 757, which is incorporated herein by reference. Characterization data for both 86 and 4 matched those in the literature and/or of the naturally occurring product. The  1 H NMR spectrum of 4 was in excellent agreement with that provided by Professor Grieco. 
     Schemes 1-3 provide a convergent synthesis of epothilone B (4), which generates all seven of its asymmetric centers in a completely stereoselective fashion. In addition, clean Z configuration at the C12-C13 double bond is incorporated by this pathway. Finally, the Z olefin at C9-C10 provides a chemical moiety from which exploratory structural modifications can be made. 
                        
                         
 
     Scheme 4 illustrates a second embodiment of a method for making epothilones and epothilone analogs. With reference to Scheme 4, compound 76 was made as illustrated above in Scheme 2, and as discussed in more detail in Example 16. Aldehyde 76 was reacted with dimethyl diazophosphonate [J. C. Gilbert et al.,  J. Org. Chem.  1982, 47, 1837] in THF at −78° C. to provide alkyne 88 in approximately 80% yield. The copper (I) derivative of alkyne 88 was produced and was found to couple with allylic halide 58. This reaction was extensively investigated, and was found to proceed to product 90 best when the conditions for the reaction were as shown in Table 3, using about 5% CuI, Et 3 N, Et 2 O-DMF, and about 2.0 equivalents of 88. Conditions investigated for this coupling are summarized below in Table 3. 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 Equivalents 
                   
                   
                   
               
               
                 of 88 
                 Coupled With 
                 Reagents/Conditions 
                 Product Yield 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1.1 
                 Allylic Bromide 58 
                 5% CuI, TBAB, K 2 CO 3 , DMF 
                 8 
               
               
                 1.1 
                 Allylic Bromide 58 
                 20% CuI, ALIQUOT 336, 
                 11 
               
               
                   
                   
                 K 2 CO 3 , DMF 
               
               
                 1.1 
                 Allylic Bromide 58 
                 50% CuI, Pyrrolidine, DMF 
                 0 
               
               
                 1.1 
                 Allylic mesylate 58B 
                 (a) Ms 2 O, Et 3 N, DMF 
                 34 
               
               
                   
                   
                 (b) 10% CuI, Na 2 CO 3 , TBAB, 
               
               
                   
                   
                 DMF 
               
               
                 1.1 
                 Allylic mesylate 58B 
                 (a) Ms 2 O, Et 3 N, CH 2 Cl 2   
                 42 
               
               
                   
                   
                 (b) 20% CuI, Na 2 CO 3 , TBAB, 
               
               
                   
                   
                 DMF 
               
               
                 1.1 
                 Allylic Chloride 58A 
                 5% CuI, Et 3 N, Et 2 O-DMF 
                 24 
               
               
                 2.0 
                 Allylic Chloride 58A 
                 5% CuI, Et 3 N, Et 2 O-DMF 
                 60 
               
               
                   
               
             
          
         
       
     
     Product 90 was semi-hydrogenated over Lindlar&#39;s catalyst [Pd/CaCO 3 , Pd(OAc) 2 ]. This reaction was found to proceed best when hexanes was used as the solvent. The hydrogenated product was then saponified using NaOH and isopropyl alcohol at 45° C. to provide the corresponding seco acid 80 in approximately 66% yield. The C15 TBS ether 80 was then deprotected using TBAF and THF by warming the reaction from 0° C. to 25° C., with a yield of about 89%. The selectivity of this reaction is attributed to sterically favorable transilyation involving the carboxylate anion. The resultant silyl ester is hydrolyzed during aqueous work-up. Macrolactonization was then performed under Yamaguchi conditions. Yamaguchi et al.,  Bull Chem. Soc. Jpn.  1970, 52, 1989. The remaining TBS ether protecting groups were then removed using trifluoroacetic acid (TFA) in dichloromethane at 0° C. to provide compound 84. Compound 84 was then converted to 4 as discussed with respect to Scheme 3 and Examples 21, 22 and 23. 
     Schemes 5, 6, and 7 illustrate an embodiment of a synthesis via Stille coupling that yields epothilone derivatives containing a trans (or E) double bond between C9 and C10 (See Formula 13). 
     With reference to Scheme 5, compound 92 was esterified with 2-(trimethylsilyl)ethanol using Mitsunobu conditions to provide 94. Hydrogenolysis removed the p-methoxybenzyl ether from 94, and oxidation of alcohol 95 afforded an aldehyde, which was reacted with Bestmann&#39;s reagent (Müller et al.  Synlett.  1996, 521) to give terminal alkyne 96. Hydrostannylation of the latter in the presence of a palladium dichloride catalyst furnished vinylstannane 98 
     With reference to Scheme 6, compound 48, which was prepared from compound 46 of Scheme 1, was protected as TES ether 49 by reaction with triethylsilyl triflate. The latter was advanced to alcohol 104 by a four-step sequence analogous to that used for converting 48 to 56 (see Scheme 1) and including a final step of removing the tetrahydropyranyl ether protecting group with magnesium bromide. For Stille coupling purposes, the allylic chloride 106 (prepared by chloride displacement of the corresponding mesylate prepared from compound 104) was found to be more effective than the corresponding bromide (Scheme 1). 
     Coupling of 98 with 106 (Scheme 7) in the presence of catalytic dipalladium tris(dibenzylideneacetone)chloroform complex and triphenylarsine (Farina and Krishnan,  J. Am. Chem. Soc.  1991, 113, 9585) proceeded in high yield and gave the 9E,12E,16E-heptadecanoate 108. Exposure of 108 to tetra-n-butylammonium fluoride cleaved both the (trimethylsilyl)ethyl ester and the triethylsilyl ether but left tert-butyldimethylsilyl ethers at C3 and C7 intact. The resulting seco acid 110 underwent facile macrolactonization to 112 under Yamaguchi conditions. Subsequent removal of the remaining pair of TBS ethers with trifluoroacetic acid furnished trans 9,10, trans 12,13-dehydroepothilone D (114). 
                        
                         
                         
                         
 
     Scheme 8 illustrates an embodiment of the method that provides a conformationally constrained epothilone analog, 9,10-didehydroepothilone D (124). Compound 124 was synthesized, its conformation studied, and its tubulin polymerization and antiproliferative activity assayed by White et al.  Org. Lett.  2002, 4, 995-997, which is incorporated herein by reference. 
     With reference to Scheme 8, allylic chloride 106 (Scheme 6) was coupled with alkyne 116 in the presence of cuprous iodide to afford dienyne 118. This dienyne was treated with TBAF to effect selective deprotection of the TES and TMSE blocking groups, yielding compound 120. The resulting hydroxy acid, 120, was lactonized under Yamaguchi conditions to furnish 122, and removal of the remaining silyl ethers using trifluoroacetic acid gave 9,10-didehydroepothilone D (124). 
     Scheme 9 illustrates the synthesis of a bislactone analog, 134, of the epothilones. Bislactone 134 was assayed for tubulin polymerization activity as well as antiproliferative action relative to paclitaxel and epothilones B and D. The biological data are recorded in Table 2. 
     As depicted in Scheme 9, allylic alcohol 104 was coupled to acid 81 via a Mitsunobu reaction to afford compound 126. The resultant ester compound was selectively deprotected to yield hydroxy acid 130, which underwent lactonization under Yamaguchi conditions to afford the bislactone 132. Cleavage of the remaining silyl ethers gave target compound 134. 
     Compounds 126 and 128 are used to synthesize the corresponding lactam and thiolactone epothilone analogs, respectively. The lactam and thiolactone can be prepared in analogous fashion to the bislactone 132. Amine 126 is readily available by the present method from compound 57. For example, compound 57 has been converted to the corresponding allylic halide 106 (Scheme 6). Such an allylic halide can be converted to amine 126 via the corresponding allylic azide (not shown) as is known to those of ordinary skill in the art. Similarly, compound 128 can be prepared from compound 106 via displacement of the allylic halide using thioacetic acid, and followed by removal of the acetyl moiety to provide compound 128. 
                        
                         
 
     Trans 9,10-dehydroepothilone 146 can be prepared according to Scheme 10 from aldehyde 76 and compound 140 via a Julia olefination. According to this route, treatment of compound 140 (available from compound 106) with a base, such as butyl lithium, forms the corresponding sulfonyl carbanion. The carbanion then reacts with aldehyde 76 to provide a β-hydroxy sulfone product (not shown). The β-hydroxy sulfone is eliminated under reductive conditions to give 9E, 12Z, 16E-heptadecanoate derivative 142. Selective removal of the triethylsilyl and trimethylsilyl ethyl ester protecting groups from 142, followed by macrolactonization under Yamaguchi conditions, provides compound 144 Removal of the remaining silyl protecting groups affords trans 9,10-dehydroepothilone 146. 
     IV. Examples 
     The following examples are provided to illustrate certain particular features of working embodiments of the disclosed method. The scope of the present invention should not be limited to those features described. 
     Example 1 
     This example describes the synthesis of compound 44 of Scheme 1. To a stirred solution of the alcohol precursor to 44 (1.03 g, 5.20 mmol) in CH 2 Cl 2  (20 mL) was sequentially added DHP (580 mg, 630 μL, 6.91 mmol), followed by PPTS (110 mg, 0.438 mmol). After 1.5 hours, the reaction was quenched with solid NaHCO 3  (5 g), filtered, concentrated in vacuo and purified by chromatography over silica gel, eluting with 30% Et 2 O/petroleum ether, to give 44 (1.42 g, 5.00 mmol, 96%) as a colorless oil: IR (neat) 2940, 1445 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.04 (s, 1H), 4.62 (t, J=3.0 Hz, 1H), 4.26 (d, J=12.1 Hz, 1H), 4.16 (d, J=12.1 Hz, 1H), 3.85-3.95 (m, 1H), 3.5-3.6 (m, 1H), 1.95 (d, J=1.5 Hz, 3H), 1.5-1.9 (m, 6H);  13 C NMR (75 MHz, CDCl 3 ) δ 144.6, 98.4, 75.8, 72.1, 62.5, 30.7, 25.6, 22.2, 19.6; HRMS (CI) calculated for C 9 H 16 O 2  (M + H + ) 283.0195, found 283.0198. 
     Example 2 
     This example describes the synthesis of compound 46. To a stirred solution of t-BuLi (48 mL, 62.4 mmol, 1.3 M in pentane) in Et 2 O (63 mL) at −78° C. was added a solution of 44 (10.27 g, 36.4 mmol) in Et 2 O (75 mL) via syringe pump over 20 minutes. After 20 minutes, the slurry was rapidly transferred to a precooled solution of CuCN (1.58 mg, 17.7 mmol) in THF (122 mL) at −78° C. After 1 hour at −78° C. and 5 minutes at −40° C., the solution was recooled to −78° C., and a precooled solution of 42 (3.40 g, 14.7 mmol) in THF (86 mL) was added via cannula. An additional amount of THF (25 mL) was added to rinse the flask. After 30 minutes, the solution was warmed to 0° C., and after a further 10 minutes the reaction was quenched with saturated aqueous NH 4 Cl (300 mL) and extracted with Et 2 O (3×150 mL). The dried (MgSO 4 ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 15-50% Et 2 O/petroleum ether, to give 46 (5.05 mg, 13.1 mmol, 89%) as a colorless oil: [α]D 23 +46.1 (c 2.58, CHCl 3 ); IR (neat) 1782, 1699 cm −1 ;  1 H NMR (300 MHz, CDCl 3 )δ 7.1-7.4 (m, 5H), 5.40 (t, J=7.1 Hz, 1H), 4.6-4.7 (m, 2H), 4.05-4.2 (m, 4H), 3.8-3.95 (m, 1H), 3.45-3.6 (m, 1H), 3.28 (dd, J=3.2, 13.3 Hz, 1H), 2.9-3.05 (m, 2H), 2.76 (dd, J=9.6, 13.3 Hz, 1H), 2.46 (q, J=7.3 Hz, 2H), 1.5-1.9 (m, 6H), 1.78 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 172.8 , 153.6, 135.5, 133.8, 129.6, 129.1, 127.5, 127.4, 97.8, 97.7, 66.4, 65.5, 65.4, 62.3, 55.3, 38.1, 36.0, 30.8, 25.7, 22.7, 21.9, 19.7; HRMS (FAB) calculated for C 22 H 28 NO 5  (M+H + ) 386.1968, found 386.1965. 
     Example 3 
     This example describes the synthesis of compound 48. To a stirred solution of NaHMDS (7.6 mL, 7.6 mmol, 1 M in THF) in THF (35 mL) at −78° C. was added a solution of the alcohol precursor to 46 (2.482 g, 6.41 mmol) in THF (50 mL) via syringe pump over 30 minutes. An additional amount of THF (5 mL) was added to rinse the syringe. After 20 minutes, a precooled solution of oxaziridine (2.55 g, 9.77 mmol) in THF (8 mL) was quickly added via cannula. After 6 minutes, the reaction was quenched with a solution of CSA (3.54 g, 15.2 mmol) in THF (10 mL). After 2 minutes, saturated aqueous NH 4 Cl (75 mL) was added. The mixture was allowed to warm to room temperature and was concentrated in vacuo to remove THF. The aqueous layer was extracted with Et 2 O (4×100 mL). The dried (MgSO 4 ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 50-70% Et 2 O/petroleum ether, followed by chromatography over silica gel, eluting with 2-4% acetone/CH 2 Cl 2 , followed by trituration in 10% Et 2 O/petroleum ether to give 48 (1.84 g, 4.5 mmol, 71%) as a white foam contaminated with a small amount of the phenyl sulfonamide: [α]D 23 +37.2 (c 4.00, CHCl 3 ); IR (neat) 3476, 1781, 1699 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 7.1-7.4 (m, 5H), 5.40 (m, 1H), 5.05-5.15 (m, 1H), 4.55-4.7 (m, 2H), 4.05-4.3 (m, 4H), 4.02 (dd, J=3.7, 11.7 Hz, 1H), 3.8-3.95 (m, 1H), 3.79 (d, J=8.6 Hz, 1H of a diastereomer), 3.66 (d, J=8.6 Hz, 1H of a diastereomer), 3.45-3.6 (m, 1H), 3.31 (dt, J=3.0, 13.5 Hz, 1H), 2.75-2.9 (m, 1H), 2.45-2.6 (m, 2H), 1.5-1.9 (m, 9H);  13 C NMR (75 MHz, CDCl 3 ) δ 174.6, 174.3, 153.4, 153.3, 136.2, 135.5, 135.11, 135.06, 129.6, 129.2, 127.6, 123.8, 123.1, 98.1, 96.4, 70.5, 70.4, 67.1, 67.0, 65.7, 65.0, 62.4, 61.8, 55.7, 37.7, 32.6, 30.7, 30.5, 25.6, 22.2, 22.1, 19.7, 19.2; HRMS (Cl) calculated for C 22 H 28 NO 6 (M+H + ) 402.1917, found 402.1919. 
     Example 4 
     This example describes the synthesis of compound 50. To a stirred solution of 48 (1.74 g, 4.32 mmol) in CH 2 Cl 2  (22 mL) at −78° C. was added sequentially 2,6-lutidine (1.06 g, 1.15 mL, 9.87 mmol) followed by TBSOTf (2.07 g, 1.8 mL, 7.83 mmol). After 30 minutes, the reaction was quenched with saturated aqueous NH 4 Cl (100 mL) and extracted with Et 2 O (4×100 mL). The dried (MgSO 4 ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 30-50% Et 2 O/petroleum ether, to give 50 (2.06 g, 3.90 mmol, 90%) as a colorless oil: [α]D 23 +32.3 (c 2.96, CHCl 3 ); IR (neat) 1782, 1714 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 7.15-7.4 (m, 5H), 5.35-5.5 (m, 2H), 4.55-4.7 (m, 2H), 4.05-4.2 (m, 2H), 4.0-4.15 (m, 2H), 3.8-3.9 (m, 1H), 3.4-3.5 (m, 1H), 3.36 (d, J=13.1 Hz, 1H), 2.7-2.8 (m, 1H), 2.71 (dt, J=1.6, 10.1 Hz, 1H), 2.45-2.55 (m, 2H), 1.5-1.8 (m, 9H), 0.92 (s, 9H), 0.91 (s, 9H of a diastereomer), 0.11 (s, 3H of a diastereomer), 0.10 (s, 3H of a diastereomer), 0.08 (s, 3H of a diastereomer), 0.07 (s, 3H of a diastereomer);  13 C NMR (75 MHz, CDCl 3 ) δ 173.9, 173.7, 153.3, 135.5, 134.9, 129.6, 129.1, 127.5, 124.0, 97.6, 96.9, 71.1, 66.7, 65.5, 65.2, 62.3, 61.9, 55.8, 37.9, 34.2, 33.7, 30.8, 30.7, 26.0, 25.7, 22.0, 21.9, 19.7, 19.4, 18.5, −4.6, −4.9; HRMS (CI) calculated for C 28 H 44 NO 6 Si (M) 518.2938, found 518.2908. 
     Example 5 
     This example describes the synthesis of compound 52. To a stirred solution of EtSH (713 mg, 850 FL, 11.5 mmol) in THF (45 mL) was added KH (106 mg, 0.93 mmol, 35% in mineral oil). After 30 minutes, the mixture was cooled to 0° C. and a solution of 50 (2.064 g, 3.99 mmol) in THF (15 mL) was added via cannula over 5 minutes. An additional amount of THF (10 mL) was added to rinse the flask. After 50 minutes at room temperature, the reaction was quenched with saturated aqueous NH 4 Cl (50 mL). Air was bubbled through the solution for 2 hours to remove excess EtSH. The solution was extracted with Et 2 O (4×100 mL). The dried (MgSO 4 ) extract was concentrated in vacuo and the residue was crystallized by the addition of 10% Et 2 O/petroleum ether to yield the recovered auxiliary (640 mg, 3.61 mmol, 93%) as a white solid. The decanted solution was purified by chromatography over silica gel, eluting with 10-30% Et 2 O/petroleum ether, to give 52 (1.44 g, 3.50 mmol, 90%) as a colorless oil: [α]D 23  −46.1 (c 3.50, CHCl 3 ); IR (neat) 1684 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) 5.35-5.5 (m, 1H), 4.55 (bs, 1H), 3.9-4.2 (m, 3H), 3.8-3.9 (m, 1H), 3.45-3.6 (m, 1H), 2.75-2.9 (m, 2H), 2.4-2.6 (m, 2H), 1.4-1.9 (m, 6H), 1.21 (t, J=7.5 Hz, 3H), 0.93 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H of a diastereomer), 0.05 (s, 3H of a diastereomer);  13 C NMR (75 MHz, CDCl 3 ) δ 205.1, 205.0, 135.24, 135.16, 97.9, 97.4, 78.6, 65.7, 65.5, 62.3, 62.2, 34.5, 30.8, 25.9, 25.7, 22.6, 22.1, 22.0, 19.7, 19.6, 18.4, 14.8, −4.7, −4.8; HRMS (CI) calculated for C 20 H 37 NO 4 SSi (M+H + ) 401.2182, found 401.2172. 
     Example 6 
     This example describes the synthesis of compound 54. To a stirred solution of CuI (4.85 mg, 25.5 mmol) in Et 2 O (120 mL) at 0° C. was added MeLi (33.1 mL, 23.2 mmol, 1.4 M in Et 2 O). After 15 minutes, the solution was cooled to-50° C. and a solution of 52 (1.78 g, 4.64 mmol) in Et 2 O (90 mL) was added via cannula. An additional amount of Et 2 O (10 mL) was added to rinse the flask. After 30 minutes, the reaction was quenched with saturated aqueous NH 4 Cl (300 mL) and extracted with Et 2 O (4×175 mL). The dried (MgSO 4 ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 15% Et 2 O/petroleum ether, to give 54 (1.36 g, 3.81 mmol, 82%) as a colorless oil: [α]D 23 +14.0 (c 5.00, CHCl 3 ); IR (neat) 1719 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 5.35-5.5 (m, 5H), 4.5-4.55 (m, 1H), 3.9-4.1 (m, 3H), 3.75-3.9 (m, 1H), 3.4-3.5 (m, 1H), 2.3-2.5 (m, 2H), 2.10 (s, 3H), 1.74(s, 3H), 1.4-1.9 (m, 6H), 0.87 (s, 9H), 0.00 (s, 6H);  13 C NMR (75 MHz, CDCl 3 ) δ 211.7, 135.2, 135.1, 123.8, 123.5, 97.7, 97.3, 79.0, 65.5, 65.2, 62.2, 62.1, 33.2, 30.7, 25.8, 25.6, 25.5, 22.0, 19.6, 19.5, 18.2, −4.8, −4.9; HRMS (CI) calculated for C 19 H 37 O 4 Si (M+H + ) 357.2461, found 357.2455. 
     Example 7 
     This example describes the synthesis of compound 56. To a stirred solution of the phosphonate (1.45 g, 5.82 mmol) in THF (10 mL) at −78° C. was added n-BuLi (3.6 mL, 5.76 mmol, 1.6 M in hexanes). After 15 minutes, a solution of 54 (590 mg, 1.66 mmol) in THF (7 mL) was added via cannula. An additional amount of THF (3 mL) was added to rinse the ketone flask. After 30 minutes, the mixture was allowed to warm to room temperature over 1 hour. After an additional 30 minutes, the reaction was quenched with saturated aqueous NH 4 Cl (50 mL) and extracted with Et 2 O (4×75 mL). The dried (MgSO 4 ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 10-20% Et 2 O/petroleum ether, to give sequentially the undesired olefin isomer (40 mg, 0.089 mmol, 5%) as a colorless oil followed by the desired product 54 (690 mg, 1.52 mmol, 92%) as a colorless oil: Minor diastereomer: [α]D 23-59.2  (c 1.26, CHCl 3 ); IR (neat) 2959, 2852, 1022 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.79 (s, 1H), 6.18, (s, 1H), 5.35-5.5 (m, 2H), 4.55-4.65 (m, 1H), 4.05-4.15 (m, 2H), 3.8-3.9 (m, 1H), 3.45-3.6 (m, 1H), 2.68 (s, 3H), 2.4-2.5 (m, 1H), 2.2-2.35 (m, 1H), 1.87 (d, J=0.9 Hz, 3H), 1.76 (s, 3H), 1.4-1.9 (m, 6H), 0.84 (s, 9H), 0.07 (s, 3H), −0.10 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 164.4, 152.9, 143.5, 133.4, 126.7, 126.5, 118.8, 115.2, 97.9, 97.6, 70.8, 70.5, 65.9, 62.4, 62.2, 34.5, 30.9, 26.0, 25.7, 22.1, 19.8, 19.7, 19.4, 18.5, 18.4, −4.7, −4.9. Major diastereomer: [α]D 23 +19.2 (c 3.45, CHCl 3 ); IR (neat) 2959, 1531, 1474 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.91 (s, 1H), 6.45, (s, 1H), 5.35-5.5 (m, 1H), 4.5-4.6 (m, 1H), 3.9-4.2 (m, 3H), 3.8-3.9 (m, 1H), 3.45-3.6 (m, 1H), 2.70 (s, 3H), 2.2-2.4 (m, 2H), 1.99 (d, J=1.0 Hz, 3H), 1.76 (s, 3H) 1.4-1.9 (m, 6H), 0.88 (s, 9H), 0.04 (s, 3H), −0.01 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 164.5, 153.4, 142.5, 142.4, 133.6, 126.2, 126.1, 119.2, 118.9, 115.3, 97.8, 97.5, 79.0, 78.9, 65.8, 65.6, 62.3, 62.2, 35.4, 35.3, 30.1, 26.9, 26.0, 25.7, 22.0, 19.7, 19.4, 18.4, 14.1, −4.5, −4.8; HRMS (CI) calculated for C 24 H 42 NO 3 SSi (M+H + ) 452.2655, found 452.2645. 
     Example 8 
     This example describes the synthesis of the alcohol precursor to compound 58. To a stirred solution of freshly prepared MgBr 2  (27.6 mmol of Mg, 23.8 mmol of BrCH 2 CH 2 Br, 50 mL of Et 2 O) was added 56 (663 mg, 1.26 mmol) in Et 2 O (5 mL) at room temperature followed by saturated aqueous NH 4 Cl (approximately 50 μL). After 3.5 hours, the solution was cooled to 0° C. and carefully quenched with saturated aqueous NH 4 Cl (50 mL). The solution was extracted with Et 2 O (4×70 mL), and the dried (MgSO 4 ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 30-50% Et 2 O/petroleum ether, to give the desired alcohol (459 mg, 1.26 mmol, 99%) as a colorless oil: [α]D 23-16.8  (c 3.40, CHCl 3 ); IR (neat) 3374 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.92 (s, 1H), 6.44, (s, 1H), 5.31 (t, J=7.7 Hz, 1H), 4.14 (d, J=12.2 Hz, 1H), 4.1-4.2 (m, 1H), 4.00 (d, J=12.2 Hz, 1H), 2.71 (s, 3H), 2.4-2.5 (m, 1H), 2.2-2.3 (m, 2H), 2.00 (s, 3H), 1.80 (s, 3H), 0.89 (s, 9H), 0.06 (s, 3H), 0.04 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 164.8, 153.0, 142.4, 137.7, 124.4, 119.0, 115.4, 78.4, 62.0, 35.5, 26.0, 22.2, 19.3, 18.5, 14.3, −4.5, −4.7; HRMS (CI) calculated for C 19 H 34 NO 2 SSi 368.2080. Found 368.2061. 
     Example 9 
     This example describes the synthesis of compound 58. To a stirred solution of the alcohol precursor (620 mg, 1.69 mmol) in CH 2 Cl 2  (5.5 mL) at 0° C. was added Et 3 N (360 FL, 2.58 mmol) followed by Ms 2 O (390 uL, 2.24 mmol). After 10 minutes, Me 2 CO (5.5 mL) was added followed by LiBr (890 mg, 10.3 mmol). After 1.8 hours at room temperature, the mixture was concentrated in vacuo to remove the acetone, diluted with saturated aqueous NH 4 Cl (100 mL), and extracted with Et 2 O (4×200 mL). The dried (MgSO 4 ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 10-20% Et 2 O/petroleum ether, to give 58 (607 mg, 1.44 μmol, 84%) as a colorless oil: [α]D 23 +65.1 (c 2.95, CHCl 3 ); IR (neat) 2949, 2930, 2852, 1479, 844 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.93 (s, 1H), 6.48, (s, 1H), 5.42 (1 dt, J=1.3, 7.6 Hz, H), 4.16 (dd, J=5.4, 7.3 Hz, 1H), 4.06 (d, J=9.5 Hz, 1H), 3.90 (d, J=9.5 Hz, 1H), 2.71 (s, 3H), 2.3-2.5 (m, 2H), 2.01 (d, J=1.1 Hz, 3H), 1.83 (d, J=1.0 Hz, 3H), 0.88 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 164.6, 153.2, 142.1, 133.3, 128.2, 119.2, 115.4, 78.1, 35.7, 32.6, 26.0, 22.2, 19.4, 18.4, 13.1, −4.5, −4.8; HRMS (CI) calculated for C 19 H 33 NO 2 SSiBr (M+H + ) 430.1235, found 430.1244. 
     Example 10 
     This example describes the synthesis of compound 60. To a stirred solution of Ph 3 PMeBr (1.53 g, 4.28 mmol) in THF (16.2 mL) at −78° C. was added n-BuLi (2.7 mL, 4.32 mmol, 1.6 M in hexanes) over a period of 3 minutes. After 35 minutes, a pre-cooled solution of 58 (607 mg, 1.41 mmol) in THF (7 mL) was added dropwise to the ylide over a period of 5 minutes. An additional portion of THF (6 mL) was added to rinse the flask. After 15 minutes, the mixture was allowed to warm to −20° C. After an additional 20 minutes, the reaction was quenched with MeOH, and was concentrated in vacuo. The residue was purified by chromatography over silica gel, eluting with 0-6% MeOH/CH 2 Cl 2 , followed by dilution with CH 2 Cl 2  and an H 2 O wash to remove excess Ph 3 MeBr, to give 60 (890 mg, 1.26 mmol, 89%) as an off-white foam: [α]D 23 +6.4 (c 1.06, CHCl 3 ); IR (neat) 2959, 2930, 2853, 1440;  1 H NMR (300 MHz, CDCl 3 ) δ 7.6-7.9 (1 m, SH), 6.89 (s, 1H), 6.33, (s, 1H), 5.20 (m, 1H), 3.95 (m, 1H), 3.5-3.8 (m, 2H), 2.65 (s, 3H), 2.1-2.3 (m, 2H), 1.88 (s, 3H), 1.83 (s, 3H), 0.78 (s, 9H), −0.07 (s, 3H), −0.09 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 164.7, 153.0, 142.1, 135.6, 133.9, 130.9, 130.7, 124.7, 118.8, 117.5, 115.6, 78.2, 35.9, 26.0, 24.7, 23.7, 22.6, 21.9, 19.4, 18.3, 14.4, −4.6, −4.8; HRMS (CI) calculated for C 38 H 49 NOPSSi (M+H) 626.3042, found 626.3028. 
     Example 11 
     This example describes the synthesis of compound 66. To a stirred solution of i-Pr 2 NH (390 μL, 2.78 mmol) in THF (0.7 mL) was added n-BuLi (1.73 mL, 2.77 mmol, 1.6 M in hexanes) dropwise at −78° C. After 5 minutes, the solution was warmed to 0° C. for 45 minutes and recooled to −78° C. To the stirring solution of LDA was added a precooled solution of 62 (718 mg, 2.53 mmol) in THF (0.6 mL) dropwise via cannula over 5 minutes. An additional amount of THF (0.4 mL) was used to rinse the flask. After an additional 50 minutes at −78° C., a precooled solution of 64 (484 mg, 2.33 mmol) in THF (0.6 mL) was added dropwise via cannula. An additional amount of THF (0.4 mL) was used to rinse the flask. After 30 minutes, the reaction was quenched with saturated aqueous NH 4 Cl (20 mL) and extracted with Et 2 O (4×25 mL). The dried (MgSO 4 ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 6-10% Et 2 O/petroleum ether, to give 66(694 mg, 1.41 mmol, 61%) as a colorless oil: [α]D 23 −25.1 (c 3.05, CHCl 3 ); IR (neat) 3483, 1695 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 7.25 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz, 2H), 5.65-5.85 (m, 1H), 4.9-5.1 (m, 2H), 4.44 (s, 2H), 3.93 (dd, J=4.5, 6.4 Hz, 1H), 3.80 (s, 3H), 3.55-3.65 (m, 3H), 3.46 (dd, J=6.1, 8.9 Hz, 1H), 3.15-3.25 (m, 1H), 2.05-2.2 (m, 2H), 1.8-1.9 (m, 1H), 1.18 (s, 3H), 1.11 (s, 3H), 1.05 (d, J=6.8 Hz, 3H), 0.94 (d, J=7.9 Hz, 3H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 221.7, 159.3, 136.5, 130.9, 129.4, 116.9, 113.9, 73.2, 73.1, 72.9, 55.4, 54.4, 41.9, 39.8, 36.4, 29.9, 26.3, 23.9, 19.3, 18.4, 14.3, 10.2, −3.3, −3.8; HRMS (CI) calculated for C 28 H 49 O 5 Si (M+H + ) 493.3349, found 493.3350. 
     Example 12 
     This example describes the synthesis of compound 68. To a stirred solution of 66 (61 mg, 0.124 mmol) in CH 2 Cl 2  (0.7 mL) at 0° C. was sequentially added Et 3 N (29 mg, 40 mL, 0.287 mmol) followed by TBSOTf (43.7 mg, 38 μL, 0.165 mmol) at 0° C. After 45 minutes, the reaction was quenched with saturated aqueous NH 4 Cl (20 mL) and extracted with Et 2 O (4×25 mL). The dried (MgSO 4 ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 3-10% Et 2 O/petroleum ether, to give 68(66.5 mg, 0.111 mmol, 89%) as a colorless oil: [α]D 23-16.0  (c 2.92, CHCl 3 ); IR (neat) 1695 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 7.23 (d, J=8.6 Hz, 2 h), 6.86 (d, J=8.6 Hz, 2 h), 5.7-5.9 (m, 1H), 4.99 (d, J=6.4 Hz, 1H), 4.95 (s, 1H), 4.40 (s, 2H), 3.9-4.0 (m, 1H), 3.85 (d, J=7.3 Hz, 1H), 3.80 (s, 3), 3.58 (dd, J=5.7, 9.2 Hz, 1H), 3.27 (qn, J=7.4 Hz, 1H), 3.19 (t, J=7.4 Hz, 1H), 2.0-2.2 (m, 2H), 1.8-1.9 (m, 1H), 1.13 (s, 3H), 1.04 (s, 3H), 1.02 (3H, d, J=7.0 Hz), 0.96 (3H, d, J=6.9 Hz), 0.891 (s, 9H), 0.887 (s, 9H), 0.06 (s, 6H), 0.05 (s, 3H), 0.03 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 219.2, 159.3, 137.1, 131.0, 129.5, 116.5, 113.9, 76.5, 73.1, 71.8, 55.5, 54.2, 46.2, 39.8, 38.9, 26.5, 26.3, 25.3, 18.7, 18.4, 18.0, 17.0, 16.6, −3.0, −3.3, −3.5, −3.8; HRMS (CI) calculated for C 34 H 63 O 5 Si 2  (M+H + ) 607.4214, found 607.4212. 
     Example 13 
     This example describes the synthesis of compound 70. To a stirred solution of 68(722 mg, 1.19 mmol) in THF (9 mL) and H 2 O (8.5 mL) was sequentially added OSO 4  (400 μL, 4% in H 2 0) followed by NaIO 4  (1.065 g, 4.98 mmol). After 18 hours, the reaction was quenched with saturated aqueous Na 2 S 2 O 3  (50 mL). After 30 minutes, saturated aqueous NaCl (100 mL) was added and the mixture was extracted with Et 2 O (4×100 mL). The dried (MgSO 4 ) extract was concentrated in vacuo to give the aldehyde as a colorless oil: [α] D   23 −13.0 (c 4.20, CHCl 3 ); IR (neat) 1725, 1689 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 9.74 (It, J=1.2 Hz, 1H), 7.22 (d, J=8.5 Hz, 2 h), 6.85 (d, J=8.5 Hz, 2H), 4.46 (t, J=5.3 Hz, 1H), 4.39 (s, 2H), 3.82 (d, J=7.9 Hz, 1H), 3.80 (s, 3H), 3.58 (dd, J=6.0, 9.1 Hz, 1H), 3.27 (qn, J=7.4 Hz, 1H), 3.19 (dd, J=6.9, 8.9 Hz, 1H) 2.3-2.5 (m, 2H), 1.6-1.8 (m, 1H), 1.14 (s, 3H), 1.06 (s, 3H), 1.00 (d, J=7.0 Hz, 3H), 0.94 (d, J=7.0 Hz, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.08 (s, 3H), 0.05 (s, 6H), 0.03 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 219.0, 201.5 159.3, 130.9, 129.5, 113.9, 76.8, 73.1, 71.7, 71.6, 55.4, 53.7, 49.7, 46.2, 38.8, 26.4, 26.1, 24.4, 18.7, 18.3, 17.0, 15.7, −3.4, −3.5, −3.9, −4.3; HRMS (CI) calculated for C 33 H 61 O 6 Si 2  (M+H + ) 609.4007, found 607.4005. 
     To a stirred solution of the crude aldehyde (1.19 mmol) prepared above in t-BuOH (16 mL) and H 2 O (15 mL) was sequentially added 2-methyl-2-butene (3 mL) followed by NaH 2 PO 4  (1.06 g, 11.6 mmol) and NaClO 2  (490 mg, 5.4 mmol). After 1 hour, the reaction was quenched with saturated aqueous NaCl (75 mL) and extracted with Et 2 O (4×100 mL). The dried (MgSO 4 ) extract was concentrated in vacuo to give crude 70 as a colorless oil: [α] D   23 −26.8 (c 4.20, CHCl 3 ); IR (neat) 2400-3400, 1722 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 7.23 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 4.40 (s, 2H), 4.3-4.4 (m, 1H), 3.82 (d, J=7.9 Hz, 1H), 3.80 (s, 3H), 3.58 (dd, J=5.8, 9.1 Hz, 1H), 3.32 (qn, J=7.2 Hz, 1H), 3.18 (dd, J=7.2, 8.9 Hz, 1H) 2.46 (dd, J=2.9, 16.4 Hz, 1H), 2.28 (dd, J=6.8, 16.4 Hz, 1H), 1.7-1.85 (m, 1H), 1.15 (s, 3H), 1.07 (s, 3H), 1.02 (d, J=6.9 Hz, 3H), 0.95 (d, J=7.0 Hz, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.08 (s, 3H), 0.05 (s, 6H), 0.04 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 218.7, 178.0, 159.3, 130.9, 129.5, 113.9, 73.8, 73.1, 71.7, 55.5, 53.7, 46.3, 40.4, 38.9, 26.4, 26.4, 26.2, 24.0, 18.7, 18.4, 17.0, 15.8, −3.3, −3.5, −4.1, −4.4; HRMS (CI) calculated for C 33 H 61 O 7 Si 2  625.3966. Found 625.3957. 
     Example 14 
     This example describes the synthesis of compound 72. To a stirred solution of crude 70 (1.19 mmol) in PhH (20 mL) and MeOH (2.5 mL) was added TMSCHN 2  (700 μL, 1.4 mmol, 2 M in hexanes). After 45 minutes, the mixture was concentrated in vacuo and purified by chromatography over silica gel, eluting with 5-10% Et 2 O/petroleum ether, to give 72 (502 mg, 0.797 mmol, 66% over three steps) as a colorless oil: [α] D −27.1 (c 1.03, CHCl 3 ); IR (neat) 1741, 1690 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 7.23 (d, J=8.5 Hz, 2H), 6.86 (d, J=8.5 Hz, 2H), 4.39 (s, 2H), 4.3-4.4 (m, 1H), 3.83 (d, J=7.8 Hz, 1H), 3.80 (s, 3H), 3.66 (s, 3H), 3.58 (dd, J=5.7, 9.1 Hz, 1H), 3.31 (qn, J=7.2 Hz, 1H), 3.18 (dd, J=7.3, 9.1 Hz, 1H), 2.46 (dd, J=3.1, 16.1 Hz, 1H), 2.26 (dd, J=7.0, 16.1 Hz, 1H), 1.7-1.85 (m, 1H), 1.14 (s, 3H), 1.06 (s, 3H), 1.01 (d, J=6.9 Hz, 3H), 0.95 (d, J=6.9 Hz, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.08 (s, 3H), 0.05 (s, 6H), 0.02 (s, 3H);  3 C NMR (75 MHz, CDCl 3 ) δ 218.5, 172.7, 159.3, 131.0, 129.5, 113.9, 74.1, 73.1, 71.8, 55.5, 53.6, 51.8, 46.3, 40.4, 38.9, 26.5, 26.2, 24.0, 18.8, 18.7, 18.4, 17.0, 15.7, −3.3, −3.5, −4.3, −4.4; HRMS (CI) calculated for C 33 H 63 O 7 Si 2  (M+H + ) 639.4112, found 639.4112. 
     Example 15 
     This example describes the synthesis of compound 74. To a stirred solution of 72 (290 mg, 0.455 mmol) in EtOH (7 mL) was added palladium on carbon (101 mg, 10% Pd) and the mixture was placed under an atmosphere of H 2 . After 0.75 hour, the H 2  atmosphere was replaced by Ar and the reaction was filtered through Celite (EtOH rinse). The liquid was concentrated in vacuo and the residue was purified by chromatography over silica gel, eluting with 10-30% Et 2 O/petroleum ether, to give 74 (216 mg, 0.418 mmol, 92%) as a colorless oil: [α] D   23 −13.2 (c 1.07, CHCl 3 ); IR (neat) 3538, 1743, 1694 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 4.40 (dd, J=2.9, 6.9 Hz, 1H), 3.93 (dd, J=2.0, 7.8 Hz, 1H), 3.67 (s, 3H), 3.6-3.7 (m, 1H), 3.5-3.6 (m, 1H), 3.31 (qn, J=7.5 Hz, 1H), 2.43 (dd, J=2.7, 16.3 Hz, 1H), 2.26 (dd, J=6.9, 16.3 Hz, 1H), 1.55-1.65 (m, 1H), 1.22 (s, 3H), 1.13 (s, 3H), 1.09 (d, J=7.0 Hz, 3H), 0.95 (d, J=7.1 Hz, 3H), 0.92 (s, 9H), 0.87 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.01 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 218.4, 172.8, 78.2, 73.6, 64.9, 53.9, 51.9, 47.0, 40.3, 39.8, 29.9, 26.4, 26.2, 24.1, 19.1, 18.6, 18.4, 16.1, −3.4, −3.6, −4.3, −4.4; HRMS (CI) calculated for C 26 H 51 Si 2 O 6  (M + H + ) 517.3381, found 517.3361. 
     Example 16 
     This example describes the synthesis of compound 76. To a stirred solution of 74(700 mg, 1.36 mmol) and powdered molecular sieves (1.5 g) in CH 2 Cl 2  (35 mL) was sequentially added NMO (420 mg, 3.56 mmol) followed by TPAP (137.5 mg, 106 mmol). After 1 hour, the mixture was diluted with 30% Et 2 O/petroleum ether (100 mL) and filtered through silica gel (30% Et 2 O/petroleum ether rinse). The filtrate was concentrated in vacuo to give 76 (698 mg, 1.36 mmol, 99%) as a colorless oil: [α] D   23 −32.1 (c 1.76, CHCl 3 ); IR (neat) 1746, 1690 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 9.73 (d, J=2.1 Hz, 1H), 4.41 (dd, J=3.2, 6.9 Hz, 1H), 4.08 (dd, J=2.1, 8.3 Hz, 1H), 3.67 (s, 3H), 3.25 (qn, J=7.0 Hz, 1H), 2.41 (1Hdd, J=3.3, 16.1 Hz, 1H), 2.2-2.35 (m, 2H), 1.24 (s, 3H), 1.12 (d, J=7.1 Hz, 3H), 1.10 (d, J=6.9 Hz, 3H), 1.09 (s, 3H), 0.89 (s, 9H), 0.87 (s, 9H), 0.11 (s, 3H), 0.090 (s, 3H), 0.085 (s, 3H), 0.01 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 218.0, 204.4, 172.6, 76.5, 73.9, 53.8, 51.9, 51.0, 46.8, 40.4, 29.9, 26.4, 24.0, 19.2, 18.6, 18.4, 15.9, 12.7, −3.4, −3.6, −4.3, −4.4; HRMS (CI) calculated for C 26 H 51 Si 2 O 6  (M+H + ) 515.3225, found 515.3218. 
     Example 17 
     This example describes the synthesis of compound 78. To LHMDS [HMDS (280 μL, 1.31 mmol) in THF (650 μL) at −78° C. was added n-BuLi (820 μL, 1.31 mmol, 1.6 M in hexanes). After 5 minutes, the solution was warmed to 0° C. and added dropwise to a stirred solution of the salt 58 (930 mg, 1.32 mmol) in THF (17 mL) at −78° C. via cannula. After 15 minutes, the solution was warmed to −30° C. After an additional 15 minutes, the solution was re-cooled to −78° C. and added dropwise to a pre-cooled solution of the 76 (520 mg, 1.03 mmol) in THF (0.6 mL) via cannula. The mixture was then allowed to warm slowly to room temperature over a period of 1 hour. After 10 minutes at room temperature, the reaction was quenched with saturated aqueous NH 4 Cl (25 mL) and was concentrated in vacuo to remove THF. The solution was extracted with Et 2 O (4×50 mL), and the dried (MgSO 4 ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 2-10% Et 2 O/petroleum ether, to give 78 (728 mg, 0.84 mmol, 82%) as a colorless oil: [α] D   23 +3.6 (c 1.00, CHCl 3 ); IR (neat) 1743, 1699 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.91 (s, 1H), 6.45 (s, 1H), 5.58 (t, J=9.2 Hz, 1H), 5.2-5.35 (m, 1H), 5.16 (t, J=6.6 Hz, 1H), 4.39 (1H, dd, J=3.1, 6.9 Hz), 4.09 (1H, t, J=6.6 Hz), 3.8-3.9 (m, 1H), 3.6-3.7 (m, 1H); 3.66 (s, 3H), 3.03 (qn, J=6.7 Hz, 1H), 2.70 (s, 3H), 2.65-2.75 (m, 2H), 2.3-2.5 (m, 2H), 2.15-2.35 (m, 3H), 1.99 (s, 3H), 1.64 (s, 3H), 1.19 (s, 3H), 1.06 (s, 3H), 1.03 (d, J=7.1 Hz, 3H), 1.00 (d, J=7.0 Hz, 3H), 0.92 (s, 9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.08 (s, 3H), 0.07 (s, 6H), 0.04 (s, 3H), 0.00 (s, 3H), −0.01 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 218.0, 172.6, 164.5, 153.4, 142.5, 135.5, 131.7, 128.7, 122.2, 119.0, 115.2, 79.1, 76.1, 74.2, 53.5, 51.8, 46.4, 40.4, 37.9, 35.6, 30.9, 26.4, 26.2, 26.0, 24.0, 23.9, 19.4, 19.3, 18.7, 18.4, 14.9, 14.1, −3.3, −3.7, −4.3, −4.4, −4.7; HRMS (CI) calculated for C 46 H 86 O 6 Si 3 SN (M+H + ) 864.5484, found 864.5510. 
     Example 18 
     This example describes the synthesis of compound 80. To a stirred solution of 78 (51 mg, 59 μmol) in i-PrOH (1 mL) was added NaOH (11.5 FL, 62 μmol, 5.4 M in H 2 O), and the mixture was heated at 45° C. in a sealed tube. After 16 hours, the solution was concentrated, diluted with aqueous HCl (20 mL, 0.5 M) and extracted with Et 2 O (4×50 mL). The dried (MgSO 4 ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 5-20% EtOAc/hexanes, to give 80 (33 mg, 34 μmol, 66%) as a colorless oil: IR (neat) 3500-2500, 1713 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.93 (s, 1H), 6.67 (s, 1H), 5.52 (t, J=9.6 Hz, 1H), 5.3-5.4 (m, 1H), 5.23 (t, J=7.4 Hz, 1H), 4.41 (dd, J=3.3, 6.6 Hz, 1H), 3.75-3.85 (m, 1H), 2.9-3.1 (m, 2H), 2.71 (s, 3H), 2.5-2.8 (m, 2H), 2.1-2.6 (m, 4H), 1.9-2.1 (m, 1H), 1.93 (s, 3H), 1.71 (s, 3H), 1.16 (s, 3H), 1.13 (s, 3H), 1.04 (d, J=7.0 Hz, 3H), 9.94 (obscured d, 3H), 0.92 (s, 9H), 0.88 (18H, s), 0.12 (s, 6H), 0.09 (s, 3H), 0.06 (s, 3H), 0.03 (s, 3H), −0.01 (s, 3H); HRMS (CI) calculated for C 45 H 84 O 6 Si 3 SN (M+H + ) 850.5327, found 850.5281. 
     Example 19 
     This example describes the synthesis of compound 82. To a stirred solution of 80(154 mg, 181 μmol) in THF (3.9 mL) at 0° C. was added TBAF (1.1 mL, 1.1 mmol, 1 M in THF). The solution was allowed to warm slowly to room temperature overnight. After 16 hours, the mixture was diluted with EtOAc, washed with saturated aqueous NH 4 Cl (50 mL), and extracted with EtOAc (4×100 mL). The dried (MgSO 4 ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 2-5% MeOH/CH 2 Cl 2 , to give 82 (118.5 mg, 160 μmol, 89%) as a white foam: [α] D   23 −2.6 (c 3.50, CHCl 3 ); IR (neat) 3500-2500, 1709 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.95 (s, 1H), 6.70 (s, 1H), 5.56 (t, J=10.0 Hz, 1H), 5.3-5.45 (m, 1H), 5.24 (t, J=7.3 Hz, 1H), 4.35-4.45 (m, 1H), 4.16 (t, J=6.2 Hz, 1H), 3.75-3.85 (m, 1H), 3.03 (m, 2H), 2.75-2.85 (m, 1H), 2.72 (s, 3H), 2.65-2.75 (m, 1H), 2.2-2.7 (m, 5H), 1.99 (s, 3H), 1.74 (s, 3H), 1.15 (s, 3H), 1.14 (s, 3H), 1.04 (d, J=7.1 Hz, 3H), 0.98 (d, J=6.9 Hz, 3H), 0.92 (s, 9H), 0.87 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 218.1, 176.0, 165.1, 152.4, 141.9, 137.5, 131.6, 127.8, 120.8, 118.8, 115.1, 77.2, 76.0, 73.5, 53.6, 46.3, 40.1, 38.0, 34.1, 30.8, 26.2, 26.0, 23.7, 23.5, 19.0, 18.9, 18.7, 18.5, 18.1, 15.0, 14.6, −3.6, −4.1, −4.2, −4.6; HRMS (CI) calculated for C 39 H 70 O 6 Si 2 SN (M+H + ) 736.4462, found 736.4451. 
     Example 20 
     This example describes the synthesis of the protected alcohol precursor to compound 84. To a stirred solution of 82 (57.2 mg, 78.0 μmol) in THF (1.3 mL) at 0° C. was added Et 3 N (19 FL, 136 μmol) followed by 2,4,6-trichlorobenzoyl chloride (14 μL, 89.5 mmol). After 45 minutes, the mixture was diluted with THF (1 mL) and PhMe (1.7 mL) and was added via syringe pump to a stirring solution of DMAP (16.3 mg, 133 μmol) in PhMe (18 mL) at 75° C. over a period of 3.5 hours. After an additional 1 hour, the solution was cooled, diluted with EtOAc, washed with saturated aqueous NH 4 Cl (50 mL), and extracted with EtOAc (4×100 mL). The dried (MgSO 4 ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 2-10% EtOAc/hexanes, to give the protected alcohol precursor to compound 84 (35.5 mg, 49.5 mmol, 63%) as a colorless oil contaminated with a small amount of an oligomer: IR (neat) 1738, 1709 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.95 (s, 1H), 6.50 (s, 1H), 5.65 (t, J=10.0 Hz, 1H), 5.3-5.45 (m, 2H), 5.11 (t, J=6.3 Hz, 1H), 4.45 (dd, J=2.8, 8.0 Hz, 1H), 3.7-3.8 (m, 1H), 3.19 (dd, J=9.5, 15.7 Hz, 1H), 3.0-3.1 (m, 1H), 2.71 (s, 3H), 2.2-2.7 (m, 6H), 2.09 (s, 3H), 1.74 (s, 3H), 1.13 (s, 3H), 1.11 (s, 3H), 1.07 (d, J=7.1 Hz, 3H), 0.99 (d, J=7.0 Hz, 3H), 0.93 (s, 9H), 0.87 (s, 9H), 0.14 (s, 3H), 0.11 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H);  3 C NMR (75 MHz, CDCl 3 ) δ 216.0, 169.9, 164.9, 152.9, 137.8, 136.5, 130.8, 126.9, 121.1, 118.9, 116.6, 106.3, 78.1, 76.4, 73.1, 54.0, 47.4, 41.2, 39.0, 31.0, 26.4, 26.3, 26.1, 24.5, 21.3, 20.5, 19.7, 19.5, 18.9, 18.3, 15.2, 14.7, −3.4, −3.5, −4.6; HRMS (CI) calculated for C 39 H 68 O 5 Si 2 SN (M+H + ) 718.4357, found 718.4354. 
     Example 21 
     This example describes the synthesis of compound 84. To a stirred solution of the protected alcohol precursor to compound 82 (16.5 mg, 23 mmol) in CH 2 Cl 2  (110 μL) at 0° C. was added TFA (100 μL). After 4.5 hours, the mixture was concentrated in vacuo and purified by chromatography over silica gel, eluting with 20-50% EtOAc/hexanes, to give 84 (9.3 mg, 19 μmol, 83%) as a colorless oil: [α] D   23 −133.0 (c 1.30, CHCl 3 ); IR (neat) 3438, 1738, 1694 cm −1 ;  1 H NMR (400 MHz, CDCl 3 ) δ 6.97 (s, 1H), 6.52 (s, 1H), 5.5-5.7 (m, 2H), 5.35-5.45 (m, 1H), 5.15 (t, J=7.1 Hz, 1H), 4.22 (dd, J=2.5, 9.4 Hz, 1H), 3.7-3.8 (m, 1H), 3.1-3.2 (m, 1H), 3.04 (dd, J=7.7, 15.3 Hz, 1H), 2.85-2.95 (m, 1H), 2.70 (s, 3H), 2.4-2.7 (m, 6H), 2.06 (s, 3H), 1.72 (s, 3H), 1.27 (s, 3H), 1.1-1.2 (obscured d, 3H×2), 1.12 (s, 3H);  13 C NMR (100.5 MHz, CDCl 3 ) δ 220.4, 170.7, 152.2, 138.1, 137.0, 132.3, 128.1, 119.0, 118.9, 115.7, 77.4, 74.1, 73.0, 52.7, 44.2, 39.1, 36.9, 31.4, 30.2, 29.7, 23.9, 21.8, 20.4, 19.0, 17.5, 16.0, 13.3; HRMS (CI) calculated for C 27 H 40 O 5 SN (M+H + ) 490.2627, found 490.2627. 
     Example 22 
     This example describes the synthesis of 86. To a stirred solution of 84 (6.6 mg, 13.5 μmol) in CH 2 Cl 2  (2 mL) at reflux was added portionwise a large excess of KO 2 CN═NCO 2 K followed by AcOH (2 equivalents) until the reaction was complete by TLC (25 hours). The KOAc precipitate was periodically removed during the course of the reaction. The solution was filtered through SiO 2  (Et 2 O rinse), concentrated in vacuo, and purified by chromatography over silica gel, eluting with EtOAc/hexanes/CH 2 Cl 2  (1:4:5-1:1:2), to give 86 (3.4 mg, 6.9 mmol, 52%) as a colorless oil: [α] D   23 −86.7 (c 0.15, CHCl 3 );  1 H NMR (400 MHz, CDCl 3 ) δ 6.95 (s, 1H), 6.58 (s, 1H), 5.22 (d, J=8.8 Hz, 1H), 5.1-5.2 (m, 1H), 4.30 (d, J=11.2 Hz, 1H), 3.7-3.8 (m, 1H), 3.4-3.55 (m, 1H), 3.15 (q, J=4.8 Hz, 1H), 3.0-3.1 (m, 1H), 2.69 (s, 3H), 2.5-2.7 (m, 1H), 2.05-2.5 (m, 4H), 2.06 (s, 3H), 1.8-1.9 (m, 1H), 1.7-1.8 (m, 1H), 1.34 (s, 3H), 1.2-1.3 (m, 4H), 1.19 (d, J=7.0 Hz, 3H), 1.07 (s, 3H), 1.01 (d, J=6.9, 3H);  13 C NMR (100.5 MHz, CDCl 3 ) δ 220.8, 170.6, 165.2, 152.3, 139.4, 138.7, 121.1, 119.5, 115.9, 79.2, 74.4, 72.6, 53.7, 42.0, 39.9, 32.8, 32.0, 31.9, 25.6, 23.1, 19.3, 18.3, 16.1, 16.0, 13.6. 
     Example 23 
     This example describes the synthesis of compound 4. To a stirred solution of 86 (1.5 mg, 3.05 mmol) in CH 2 Cl 2  (400 mL) at −50° C. was added a solution of dimethyl dioxirane until all of the starting material had been consumed as judged by TLC. The solution was concentrated in vacuo and purified by chromatography over silica gel, eluting with 50-60% EtOAc/pentane, to give epothilone B (4) (1.2 mg, 2.4 mmol, 78%) as a colorless oil: [α] D   23 −36.7 (c 0.12, CHCl 3 );  1 H NMR (400 MHz, CDCl 3 ) δ 6.97 (s, 1H), 6.59 (s, 1H), 5.42 (dd, J=2.8, 7.9 Hz, 1H), 4.1-4.3 (m, 2H), 3.77 (bs, 1H), 3.2-3.35 (m, 1H), 2.81 (dd, J=4.5, 7.6 Hz, 1H), 2.69 (s, 3H), 2.66 (bs, 1H), 2.4-2.55 (m, 1H), 2.36 (dd, J=2.3, 13.6 Hz, 1H), 2.1-2.2 (m, 1H), 2.09 (s, 3H), 1.85-2.0 (m, 1H), 1.6-1.7 (m, 1H), 1.35-1.55 (m, 4H), 1.37 (s, 3H), 1.28 (s, 3H), 1.17 (d, J=6.8 Hz, 3H), 1.08 (s, 3H), 1.00 (d, J=7.1 Hz);  13 C NMR (100.5 MHz, CDCl 3 ) δ 220.6, 170.5, 165.1, 151.8, 137.5, 119.7, 116.1, 74.1, 72.9, 61.6, 61.3, 53.1, 42.9, 39.2, 36.4, 32.3, 32.1, 30.8, 29.7, 22.7, 22.3, 21.4, 19.6, 19.1, 17.0, 15.8, 13.6; HRMS (CI) calculated for C 27 H 42 NO 5 S (M+H + ) 492.2784, found 492.2775. 
     Example 24 
     This example describes the synthesis of alkyne 88 as illustrated in Scheme 4. To a stirred solution of potassium tert-butoxide (0.27 mL, 1.0 M THF solution) in THF (0.5 mL) at −78° C. was added a solution of (diazomethyl)phosphonate (40.2 mg, 1.25 mmol) in THF (0.5 mL). After 5 minutes a solution of 76 (110 mg, 0.21 mmol) in THF (0.5 mL) was added dropwise, and the mixture was stirred at −78° C. for 12 hours. The mixture was then warmed to room temperature and was quenched with saturated aqueous NH 4 Cl. The aqueous layer was extracted with 3×5 mL portions of Et 2 O, and the combined organic extracts were dried (MgSO 4 ), concentrated in vacuo, and purified by chromatography (SiO 2 , 5% Et 2 O/hexane) to give 88 (85 mg, 80%) as colorless crystals: [α] D   24 −24.1 (c 1.12, CHCl 3 ); mp 52-54° C.; IR (film) 3310 2951, 2927, 2883, 2854, 1743, 1691, 1472, 1254, 1089, 990, 837, 775 cm −1 ;  1 H NMR (CDCl 3 , 300 MHz) δ 4.45 (1H, dd, J=3.1, 7.5 Hz), 3.76 (1H dd, J=2.1, 6.4 Hz), 3.65 (1H, s), 3.33 (1H, qn, J=7.5) 2.40-2.26 (3H, m), 2.06 (1H, s), 1.24 (3H, s), 1.18 (3H, d, J=6.9 Hz), 1.17 (3H, 3H), 1.07 (3H, d, J=7.0 Hz), 0.92 (9H, s), 0.86 (9H, s), 0.08 (3H, s), 0.07 (3H, s), 0.00 (3H, s);  13 C NMR (CDCl 3 , 75 MHz) δ 218.6, 172.3, 85.6, 75.7, 73.3, 70.8, 53.9, 46.5, 32.1, 26.1, 23.7, 18.7, 18.5, 18.2, 15.8, −3.3, −3.9, −4.5, −4.7; HRMS (CI) calculated for C 27 H 52 Si 2 O 5  (M+H + ) 512.3353, found 512.3342. 
     Example 25 
     This example describes the synthesis of enyne 90 as illustrated in Scheme 4. To a stirred solution of 88 (70.0 mg, 0.135 mmol) in Et 2 O (1.0 mL) and DMF (0.4 mL) at room temperature was added Et 3 N (18.8 μL, 0.135 mmol) and CuI (25.7 mg, 0.135 mmol). After the mixture turned clear (approximately 5 minutes), a solution of 56 (29.1 mg, 0.068 mmol) in Et 2 O (1.0 mL) was added, and the mixture was stirred for 18 hours. The reaction mixture was quenched with saturated aqueous Na 2 S 2 O 3  (5 mL) and was extracted with Et 2 O (3×2 mL). The combined organic extracts were dried (MgSO 4 ), concentrated in vacua, and purified by flash chromatography over silica gel (50-60% CH 2 Cl 2 /hexanes) to give 90 (35.6 mg, 60%) as a colorless oil: [α] D   23 −16.7 (c 1.01); IR (film) 2927, 2857, 2371, 2341, 1743, 1683, 1648, 1482, 1251, 991, 837 cm −1 ;  1 H NMR (CDCl 3 , 300 MHz) δ 6.91(1H, s), 6.46 (1H, s), 5.36 (1H, t, J=4.7 Hz), 4.45 (1H, dd, J=3.1, 6.9), 4.11 (1H, t, J=6.6), 3.76-3.72 (1H, m), 3.74-3.67 (1H, m), 3.67 (3H, s), 3.36-3.31 (1H, qn, J=6.8), 2.71 (3H, s), 2.41-2.25 (7H, m), 2.01 (3H, s), 1.80 (3H, s), 1.24 (3H, s), 1.16 (3H, s), 1.12 (3H, d, J=7.0), 1.05 (3H, d, J=6.8), 0.92 (9H, s), 0.88 (9H, s), 0.87 (9H, s), 0.09 (3H, s), 0.06 (6H, s), 0.04 (3H, s), 0.01 (3H, s), −0.00 (3H, s);  13 C NMR (CDCl 3 , 75 MHz): δ 218.0, 172.4, 164.3, 153.2, 142.5, 132.2, 122.2, 118.6, 118.9, 83.1, 80.2, 78.6, 75.9, 73.5, 53.7, 51.6, 46.3, 40.4, 35.7, 32.6, 29.7, 29.2, 26.1, 26.0, 25.8, 23.8, 21.7, 19.2, 18.9, 18.4, 18.2, 16.2, 15.7, 13.9, −3.3, −3.9, −4.4, −4.6, −4.7, −4.9; HRMS (CI) calculated for C 46 H 34 O 6 Si 3 SN (M+H + ) 862.5327, found 862.5325. 
     Example 26 
     This example describes the synthesis of methyl ester 80 from compound 90 as illustrated in Scheme 4. A suspension of 90 (10 mg, 0.011 mmol) and Lindlar&#39;s catalyst (1.35 mg, 5% Pd) was stirred at room temperature under an atmosphere of H 2  for 28 hours. The suspension was filtered through silica gel (Et 2 O rinse), concentrated in vacuo, and purified by flash chromatography over silica gel (40-60% CH 2 Cl 2 /hexane) to give 80 (6.8 mg, 68%) as a colorless oil: [α] D   24 +3.6 (c 1.00, CHCl 3 ); IR (film) 1743, 1699 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.91 (1H, s), 6.45 (1H, s), 5.58 (1H, t, J=9.2 Hz), 5.2-5.35 (1H, m), 5.16 (1H, t, J=6.6 Hz), 4.39 (1H, dd, J=3.1, 6.9 Hz), 4.09 (1H, t, J=6.6 Hz), 3.8-3.9 (1H, m), 3.6-3.7 (1H, m); 3.66 (3H, s), 3.03 (1H, qn, J=6.7 Hz), 2.70 (3H, s), 2.65-2.75 (2H, m), 2.3-2.5 (2H, m), 2.15-2.35 (3H, m), 1.99 (3H, s), 1.64 (3H, s), 1.19 (3H, s), 1.06 (3H, s), 1.03 (3H, d, J=7.1 Hz), 1.00 (3H, d, J=7.0 Hz), 0.92 (9H, s), 0.88 (9H, s), 0.86 (9H, s), 0.08 (3H, s), 0.07 (6H, s), 0.04 (3H, s), 0.00 (3H, s), −0.01 (3H, s); C NMR (75 MHz, CDCl 3 ) δ 218.0, 172.6, 164.5, 153.4, 142.5, 135.5, 131.7, 128.7, 122.2, 119.0, 115.2, 79.1, 76.1, 74.2, 53.5, 51.8, 46.4, 40.4, 37.9, 35.6, 30.9, 26.4, 26.2, 26.0, 24.0, 23.9, 19.4, 19.3, 18.7, 18.4, 14.9, 14.1, −3.3, −3.7, −4.3, −4.4, −4.7; HRMS (CI) calculated for C 46 H 86 O 6 Si 3 SN (M+H + ) 864.5484, found 864.5510. 
     Example 27 
     This example describes the saponification of methyl ester 90 to form carboxylic acid 80 as illustrated in Scheme 4. To a stirred solution of the methyl ester (51 mg, 59 μmol) in i-PrOH (1 mL) was added NaOH (11.5 μL, 62 μmol, 5.4 M in H 2 O), and the mixture was heated at 45° C. in a scaled tube. After 16 hours, the solution was concentrated, diluted with aqueous HCl (20 mL, 0.5 M) and extracted with Et 2 O (4×50 mL). The dried (MgSO 4 ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 5-20% EtOAc/hexanes, to give acid 80 (33 mg, 34 mmol, 66%) as a colorless oil: IR (neat) 3500-2500, 1713 cm 1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.93 (s, 1H), 6.67 (s, 1H), 5.52 (t, J=9.6 Hz, 1H), 5.3-5.4 (m, 1H), 5.23 (t, J=7.4 Hz, 1H), 4.41 (dd, J=3.3, 6.6 Hz, 1H), 3.75-3.85 (m, 1H), 2.9-3.1 (m, 2H), 2.71 (s, 3H), 2.5-2.8 (m, 2H), 2.1-2.6 (m, 4H), 1.9-2.1 (m, 1H), 1.93 (s, 3H), 1.71 (s, 3H), 1.16 (s, 3H), 1.13 (s, 3H), 1.04 (d, J=7.0 Hz, 3H), 9.94 (obscured d, 3H), 0.92 (s, 9H), 0.88 (18H, s), 0.12 (s, 6H), 0.09 (s, 3H), 0.06 (s, 3H), 0.03 (s, 3H), −0.01 (s, 3H); HRMS (CI) calculated for C 45 H 84 O 6 Si 3 SN (M+H + ) 850.5327, found 850.5281. 
     Example 28 
     This example describes the deprotection of carboxylic acid 80 to form triene 82 as illustrated in Scheme 4. To a stirred solution of carboxylic acid 80 (154 mg, 181 μmol) in THF (3.9 mL) at 0° C. was added TBAF (1.1 mL, 1.1 mmol, 1 M in THF). The solution was allowed to warm slowly to room temperature overnight. After 16 hours, the mixture was diluted with EtOAc, washed with saturated aqueous NH 4 Cl (50 mL), and extracted with EtOAc (4×100 mL). The dried (MgSO 4 ) extract was concentrated in vacuo and purified by chromatography over silica gel, eluting with 2-5% MeOH/CH 2 Cl 2 , to give 82 (118.5 mg, 160 μmol, 89%) as a white foam: [α] D   23 −2.6 (c 3.50, CHCl 3 ); IR (neat) 3500-2500, 1709 cm 1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.95 (s, 1H), 6.70 (s, 1H), 5.56 (t, J=10.0 Hz, 1H), 5.3-5.45 (m, 1H), 5.24 (t, J=7.3 Hz, 1H), 4.35-4.45 (m, 1H), 4.16 (t, J=6.2 Hz, 1H), 3.75-3.85 (m, 1H), 3.03 (m, 2H), 2.75-2.85 (m, 1H), 2.72 (s, 3H), 2.65-2.75 (m, 1H), 2.2-2.7 (m, 5H), 1.99 (s, 3H), 1.74 (s, 3H), 1.15 (s, 3H), 1.14 (s, 3H), 1.04 (d, J=7.1 Hz, 3H), 0.98 (d, J=6.9 Hz, 3H), 0.92 (s, 9H), 0.87 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 218.1, 176.0, 165.1, 152.4, 141.9, 137.5, 131.6, 127.8, 120.8, 118.8, 115.1, 77.2, 76.0, 73.5, 53.6, 46.3, 40.1, 38.0, 34.1, 30.8, 26.2, 26.0, 23.7, 23.5, 19.0, 18.9, 18.7, 18.5, 18.1, 15.0, 14.6, −3.6, −4.1, −4.2, −4.6; HRMS (CI) calculated C 39 H 70 O 6 Si 2 SN (M+H + ) 736.4462, found 736.4451. 
     Example 29 
     This example describes the synthesis of compound 94. To a stirred solution of 92 (195 mg, 0.32 mmol) in THF (1.5 mL) was added 2-(trimethylsilyl)ethanol (69 μL, 0.48 mmol) and triphenylphosphine (56.8 mg, 0.80 mmol). The solution was cooled to 0° C. and diethyl azodicarboxylate was added. After 1.5 hours, the reaction was quenched with saturated aqueous NH 4 Cl, and the solution was extracted with Et 2 O. The extract was concentrated in vacuo, and the residue was purified by chromatography on silica gel, eluting with 5-10% Et 2 O/petroleum ether, to give 94 (175 mg, 75%) as a colorless oil: [α] D   23 −27.0 (c 1.03, CHCl 3 ; IR (neat) 1741, 1690 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 7.23 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 4.39 (s, 2H), 4.3-4.4 (m, 1H), 3.83 (d, J=7.8 Hz, 1H), 3.80 (s, 3H), 3.58 (dd, J=5.7, 9.1 Hz, 1H), 3.31 (dq, J=7.2, 7.2 Hz, 1H), 3.18 (dd, J=7.3, 9.1 Hz, 1H), 2.46 (dd, J=3.1, 16.1 Hz, 1H), 2.26 (dd, J=7.0, 16.1 Hz, 1H), 1.7-1.85 (m, 1H), 1.14 (s, 3H), 1.06 (s, 3H), 1.01 (d, J=6.9 Hz, 3H), 0.95 (d, J=6.9 Hz, 3H), 0.88 (s, 9H,), 0.87 (s, 9H), 0.08 (s, 3H), 0.05 (s, 6H), 0.02 (s, 3H);  13 C NMR (CDCl 3 ) δ 218.5, 172.7, 159.3, 131.0, 129.5, 113.9, 74.1, 73.1, 71.8, 55.5, 53.6, 51.8, 46.3, 40.4, 38.9, 29.9, 26.5, 26.2, 24.0, 18.8, 18.7, 18.4, 17.0, 15.7, −3.3, −3.5, −4.3, −4.4; HRMS (CI) calculated for C 38 H7307Si (M+H + ) 725.4664, found 725.4666. 
     Example 30 
     This example describes the synthesis of compound 95. To a stirred solution of 94 (150 mg, 0.20 mmol) in EtOH (4.0 mL) was added palladium-on-carbon (55 mg, 10% Pd), and the mixture was stirred under an atmosphere of H2. After 1 hours, the H2 atmosphere was replaced by Ar, and the mixture was filtered through Celite (EtOH rinse). The filtrate was concentrated in vacuo, and the residue was purified by chromatography on silica gel, eluting with 10-30% Et 2 O/petroleum ether, to give 95 (108 mg, 89%) as a colorless oil: [α] D   23 −8.47 (c 1.18, CHCl 3 ); IR (neat) 3538, 1743, 1694 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 4.40 (dd, J=2.9, 6.9 Hz, 1H), 4.17-4.11 (m, 2H) 3.93 (dd, J=2.0, 7.8 Hz, 1H), 3.6-3.7 (m, 1H), 3.5-3.6 (m, 1H), 3.31 (dq, J=7.5, 7.5 Hz, 1H), 2.43 (dd, J=2.7, 16.3 Hz, 1H), 2.26 (1H, dd, J=6.9, 16.3 Hz), 1.55-1.65 (1H, m), 1.22 (3H, s), 1.13 (3H, s), 1.09 (d, J=7.0 Hz, 3H), 0.95 (d, J=7.1 Hz, 3H), 0.92 (s, 9H), 0.87 (s, 9H), 0.85 (m, 2H), 0.02 (s, 9H) 0.12 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.01 (s, 3H);  13 C NMR (CDCl 3 ) δ 218.4, 172.8, 78.2, 73.6, 64.9, 60.3, 53.9, 51.9, 47.0, 40.3, 39.8, 29.9, 26.4, 26.2, 24.1, 19.1, 18.6, 18.4, 17.2 16.1, −3.0, −3.4, −3.6, −4.3, −4.4. 
     Example 31 
     This example describes the synthesis of compound 96. To a stirred mixture of 95 (200 mg, 0.33 mmol) and powdered molecular sieves (300 mg) in CH 2 Cl 2  (6.0 mL) was added sequentially N-methylmorpholine-N-oxide (97 mg, 0.83 mmol) followed by tetra-n-propylammonium perruthenate (11.6 mg, 33 μmol). After 1.5 hours, the mixture was filtered through silica (Et 2 O rinse), and the filtrate was concentrated in vacuo to give the crude aldehyde as a colorless oil. 
     To a stirred solution of the crude aldehyde and K 2 CO 3  (91 mg, 0.66 mmol) in MeOH (5.0 mL) was added dimethyl 1-diazo-2-oxopropylphosphonate (74 mg, 0.46 mmol). The solution was stirred for 4 hours at room temperature, diluted with Et 2 O (30 mL), washed with aqueous NaHCO 3  (5%), and extracted with Et 2 O (3×30 mL). The dried (MgSO 4 ) extract was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel, eluting with 2% Et 2 O/hexanes, to give 96 (155 mg, 78%) as a colorless oil: [α] D   23  −25.1 (c 2.50, CHCl 3 ); IR (neat) 2946, 2928, 2848, 1734, 1690, 1468;  1 H NMR (300 MHz, CDCl 3 ) δ 4.45 (dd, J=3.1, 7.5 Hz, 1H), 4.11-4.16 (m, 2H), 3.76 (dd, J=2.1, 6.4 Hz, 1H), 3.35 (dq, J=7.3, 7.3 Hz, 1H), 2.22-2.24 (m, 3H), 2.06 (s, 1H),1.25 (s, 3H), 1.18 (d, J=7.5 Hz, 3H), 1.17 (s, 3H), 1.07 (d, J=6.8 Hz, 3H), 0.95 (obscured m, 2H) 0.92 (s, 9H), 0.86 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H), 0.07 (s, 3H), 0.03 (s, 9H), 0.02 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 218.6, 172.1, 85.6, 75.7, 73.3, 70.8, 62.7, 53.8, 46.5, 40.6, 32.2, 26.1, 26.0, 18.7, 18.5, 18.2, 17.2, 15.9, −1.6, −3.3, −3.9, −4.4, −4.7; HRMS (FAB) calculated for C 51 H 63 O 5 Si 3  (M+H + ) 599.3983, found 599.3982. 
     Example 32 
     This example describes the synthesis of compound 98. To a stirred solution of 96(60.0 mg, 0.10 mmol) and bis(triphenylphosphine)palladium dichloride (1.4 mg, (0.002 mmol) in THF (0.5 mL) at room temperature was added slowly tri-n-butyltin hydride (32.3 μL, 0.12 mmol). After 10 minutes, the solution was concentrated in vacuo, and the residue was purified by chromatography on silica gel, eluting with 5% Et 2 O/hexanes, to give 98 (79 mg, 89%) as a colorless oil: [α] D   23 −9.6 (c 1.35, CHCl 3 ); IR (neat) 2955, 2928, 2856, 1736, 1472 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.12 (dd, J=7.5, 19.3 Hz, 1H), 5.89 (d, J=19.3 Hz, 1H), 4.43 (dd, J=3.2, 6.8 Hz, 1H), 4.15 (m, 2H), 3.85 (dd, J=1.5, 7.9 Hz, 1H), 3.07 (dq, J=7.1, 7.1 Hz, 1H), 2.40 (dd, J=3.2, 16.2 Hz, 1H), 2.23 (dd, J=6.8, 16.2 Hz, 1H), 1.45-1.53 (m, 6H), 1.23-1.37 (m, 12H), 1.19 (s, 3H), 1.09 (s, 3H), 1.03 (d, J=7.0, 3H), 1.03 (d, J=6.9, 3H), 0.93 (s, 9H), 0.87 (s, 9H), 0.85-0.93 (m, 12H), 0.10 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.04 (s, 9H), 0.03 (s, 3H);  13 C NMR (100 MHz, CDCl 3 ) δ 218.8, 172.6, 150.7, 129.1, 74.0, 63.1, 53.9, 47.5, 47.1, 41.0, 29.6, 27.7, 26.6, 26.4, 24.5, 19.2, 18.9, 17.7, 15.9, 14.1, 9.9, −1.1, −2.9, −3.4, −4.0, −4.3. 
     Example 33 
     This example describes the synthesis of compound 102. To a stirred solution of 100 (1.00 g, 2.48 mmol) in CH 2 Cl 2  (25 mL) at −78° C. was added 2,6-lutidine (61 mg, 0.66 mL, 5.72 mmol). After 4 minutes, triethylsilyl triflate (1.19 g, 1.0 mL, 4.5 mmol) was added to the cold solution, and after 30 minutes the reaction was quenched with saturated aqueous NH 4 Cl (60 mL) and extracted with Et 2 O (3×100 mL). The dried (MgSO 4 ) extract was concentrated in vacuo and the residue was purified by chromatography on silica gel, eluting with 30-50% Et 2 O/hexane, to give 102 (1.00 g, 78%) as a colorless oil: [α] D   23 +31.2 (c 1.63, CHCl 3 ); IR (neat) 1782, 1714 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 7.15-7.4 (m, 5H), 5.35-5.5 (m, 2H), 4.55-4.7 (m, 2H), 4.05-4.2 (m, 2H), 4.0-4.15 (m, 2H), 3.8-3.9 (m, 1H of a diastereomer), 3.4-3.5 (m, 1H of a diastereomer), 3.36 (d, J=13.1 Hz, 1H of a diastereomer), 2.7-2.8 (m, 1H of a diastereomer), 2.45-2.55 (m, 2H), 2.46 (q, J=7.3 Hz, 1H), 1.5-1.8 (m, 9H), 0.97 (t, J=7.8 Hz, 9H), 0.62 (q, J=7.6 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 173.9, 173.7, 153.3, 135.5, 134.9, 129.6, 129.1, 127.5, 124.0, 97.6, 96.9, 71.1, 66.7, 65.5, 65.2, 62.3, 61.9, 55.8, 37.9, 34.2, 33.7, 30.8, 30.7, 26.0, 25.7, 22.0, 21.9, 19.7, 19.4, 18.5, 6.7, 5.1; HRMS (CI) calculated for C 28 H 44 NO 6 Si (M+H + ) 518.2938, found 518.2908. 
     Example 34 
     This example describes the synthesis of compound 104. To a stirred solution of ethanethiol (361 mg, 430 μL, 5.82 mmol) in THF (25 mL) at room temperature was added KH (55 mg, 0.48 mmol, 35% in mineral oil). After 30 minutes, the mixture was cooled to 0° C. and a solution of 102 (1.00 g, 1.94 mmol) in THF (10 mL) was added via cannula during 5 minutes. An additional amount of THF (5 mL) was added, and after 1 hour at room temperature the reaction was quenched with saturated aqueous NH 4 Cl (25 mL). Air was passed through the solution for 2 hours to remove excess ethanethiol, and the mixture was extracted with Et 2 O (3×100 mL). The dried (MgSO 4 ) extract was concentrated in vacuo and the residue was taken up in 10% Et 2 O/petroleum ether, from which 4 benzyloxazolidin-2-one crystallized as a colorless solid. The decanted solution was concentrated and the residue was purified by chromatography on silica gel, eluting with 30% Et 2 O/hexane, to give the thioester (730 mg, 97%) as a colorless oil: [α] D   23 −16.8 (c 2.73, CHCl 3 ); IR (neat) 1684 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 5.35-5.5 (m, 1H), 4.55 (bs, 1H), 3.9-4.2 (m, 3H), 3.8-3.9 (m, 1H), 3.45-3.6 (m, 1H), 3.36 (d, J=13.1 Hz, 1H), 2.75-2.9 (m, 2H), 2.4-2.6 (m, 2H), 1.4-1.9 (m, 6H), 1.21 (t, J=7.5 Hz, 3H), 0.97 (t, J=7.8 Hz, 9H), 0.62 (q, J=7.8 Hz, 6H);  13 C NMR (75 MHz, CDCl 3 ) δ 205.1, 205.0, 135.24, 135.16, 97.9, 97.4, 78.6, 65.7, 65.5, 62.3, 62.2, 34.5, 30.8, 25.9, 25.7, 22.6, 22.1, 22.0, 19.7, 19.6, 18.4, 14.8, 6.7, 5.1; HRMS (CI) calculated for C 20 H 37 NO 4 SSi (M+H + ) 401.2182, found 401.2172 
     To a stirred solution of CuI (2.60 g, 13.67 mmol) in Et 2 O (120 mL) at 0° C. was added MeLi (17.8 mL, 24.9 mmol, 1.4M in Et 2 O). The mixture was cooled to −50° C. and a solution of the thioester (960 mg, 2.49 mmol) in Et 2 O (50 mL) was added via cannula. An additional amount of Et 2 O (5 mL) was added to rinse the flask. After 30 minutes, the reaction was quenched with saturated aqueous NH 4 Cl (200 mL), and the mixture was extracted with Et 2 O (3×120 mL). The dried (MgSO 4 ) extract was concentrated in vacuo and the residue was purified by chromatography on silica gel, eluting with 15% Et 2 O/hexane, to give the methyl ketone (548 mg, 62%) as a colorless oil: [α] D   23-11.0  (c 3.26, CHCl 3 ); IR (neat) 1719 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 5.35-5.5 (m, 5H), 4.5-4.55 (m, 1H), 3.9-4.1 (m, 3H), 3.75-3.9 (m, 1H), 3.4-3.5 (m, 1H), 2.3-2.5 (m, 2H), 2.10 (s, 3H) 1.4-1.9 (m, 6H), 0.97 (t, J=7.8 Hz, 9H), 0.62 (q, J=7.8 Hz, 6H);  13 C NMR (75 MHz, CDCl 3 ) δ 211.7, 135.2, 135.1, 123.8, 123.5, 97.7, 97.3, 79.0, 65.5, 65.2, 62.2, 62.1, 33.2, 30.7, 25.8, 25.6, 25.5, 22.0, 19.6, 19.5, 18.2, 6.7, 5.1; HRMS (CI) calculated for C 19 H 37 O 4 Si (M+H + ) 357.2461, found 357.2455. 
     To a stirred solution of 53 (1.26 g, 5.08 mmol) in THF (9 mL) at −78° C. was added n-BuLi (4.7 mL, 5.00 mmol, 1.2 M in hexanes), and after 20 minutes, a solution of the methyl ketone (520 mg, 1.45 mmol) in THF (6 mL) was added via cannula. An additional amount of THF (2 mL) was added to rinse the flask. After 30 minutes, the solution was allowed to warm slowly to room temperature during 1 hour, then was cooled at −78° C. for an additional 30 minutes before the reaction was quenched with saturated aqueous NH 4 Cl (50 mL). The mixture was extracted with Et 2 O (3×65 mL), and the dried (MgSO 4 ) extract was concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with 20% Et 2 O/hexanes, to give the thiazole (627 mg, 96%) as a colorless oil: [α] D   23  −33.9 (c 2.56, CHCl 3 ); IR (neat) 2950, 1512, 1455 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.91 (s, 1H), 6.45, (s, 1H), 5.35-5.5 (m, 1H), 4.5-4.6 (m, 1H), 3.9-4.2 (m, 3H), 3.8-3.9 (m, 1H), 3.45-3.6 (m, 1H), 2.70 (s, 3H), 2.2-2.4 (m, 2H), 1.99 (d, J=1.0 Hz, 3H), 1.4-1.9 (m, 6H), 0.92 (t, J=7.9 Hz, 9H), 0.72 (q, J=7.9 Hz, 6H);  13 C NMR (75 MHz, CDCl 3 ,) δ 164.2, 153.1, 142.5, 142.2, 133.4, 125.6, 125.5, 118.7, 118.6, 114.9, 97.4, 97.2, 78.4, 77.3, 65.4, 65.3, 62.0, 61.9, 35.0, 34.9, 30.6, 25.4, 21.7, 19.4, 19.4, 19.1, 13.8, 6.7, 4.7; HRMS (CI) calculated for C 24 H 42 NO 3 SSi (M+H + ) 452.2655, found 452.2645. 
     To a stirred solution of freshly prepared MgBr 2 (631 mg, 26.2 mmol of Mg, and 2.38 mL, 27.7 mmol, of 1,2-dibromoethane) in Et 2 O (50 mL) at room temperature was added the thiazole (556 mg, 1.20 mmol) in Et 2 O (5 mL) followed by saturated aqueous NH 4 Cl (approximately 50 μL). After 3.5 hours, the mixture was cooled to 0° C. and carefully quenched with saturated aqueous NH 4 Cl (50 mL). The mixture was extracted with Et 2 O (3×100 mL), and the dried (MgSO 4 ) extract was concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with 30% Et 2 O/hexanes, to give 104 (390 mg, 89%) as a colorless oil: [α] D   23-31.0  (c 2.74); IR (neat) 3374 cm 1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.92 (s, 1H), 6.44, (s, 1H), 5.31 (t, J=7.7 Hz, 1H), 4.14 (d, J=12.2 Hz, 1H), 4.1-4.2 (m, 1H), 4.00 (d, J=12.2 Hz, 1H), 2.71 (s, 3H), 2.4-2.5 (m, 1H), 2.2-2.3 (m, 2H), 2.00 (s, 3H), 1.80 (s, 3H), 0.92 (t, J=7.9 Hz, 9H), 0.72 (q, J=7.9 Hz, 6H);  13 C NMR (75 MHz, CDCl 3 ) δ 164.8, 153.0, 142.4, 137.7, 124.4, 119.0, 115.4, 78.4, 62.0, 61.9, 35.5, 29.9, 26.0, 22.2, 19.3, 18.5, 14.3, 6.7, 4.7; HRMS (CI) calculated for C 19 H 34 NO 2 SSi (M+H + ) 368.2080, found 368.2061. 
     Example 35 
     This example describes the synthesis of compound 106. To a stirred solution of 104 (35 mg, 95 μmol) in CH 2 Cl 2  (0.6 mL) at 0° C. was added Et 3 N (23 μL, 161 μmol) followed by methanesulfonic anhydride (21 mg, 119 μmol). After 10 minutes, acetone (0.6 mL) was added followed by LiCl (40 mg, 950 μmol). After 4 hours at room temperature, the solution was concentrated in vacuo to remove acetone, diluted with saturated aqueous NH 4 Cl, and extracted with Et 2 O. The dried (MgSO 4 ) extract was concentrated in vacuo and the residue was purified by chromatography on silica gel, eluting with 10-20% Et 2 O/petroleum ether, to give 106 (36 mg, 97%) as a colorless oil: [α] D   23 +28.1 (c 1.11, CHCl 3 ); IR (neat) 2954, 2875, 1453, 1072 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.94 (s, 1H), 6.49 (s, 1H), 5.41 (dt, J=1.3, 7.5 Hz, 1H), 4.15 (m, 1H), 4.14 (d, J=10.8, 1H), 4.00 (d, J=10.8, 1H), 2.71 (s, 3H), 2.35 (m, 2H), 2.01 (d, J=1.2, 3H), 1.75 (d, J=1.2, 3H), 0.93 (t, J=7.69, 9H), 0.58 (q, J=7.39, 6H);  13 C NMR (75 MHz, CDCl 13 ) δ 164.5, 153.5, 142.3, 133.4, 127.8, 119.4, 115.6, 78.4, 44.2, 35.8, 22.1, 19.6, 14.4, 7.2, 5.2; HRMS (FAB) calculated for C 19 H 33 ClNOSSi (M+H + ) 386.1741, found 386.1737. 
     Example 36 
     This example describes the synthesis of compound 108. A solution of 106 (44 mg, 114 μmol), tris(dibenzylideneactone)dipalladium-chloroform (7.1 mg, 6.8 μmol) and triphenylarsine (8.4 mg, 27 μmol) in THF (0.4 mL) was stirred at room temperature for 10 minutes solution of 98 (107 mg, 120 μmol) in THF (1.0 mL) was added, and the flask was briefly opened to the atmosphere, resealed, and heated to 65° C. After 18 hours, mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel, eluting with 5% Et 2 O/hexanes, to give 108 (82 mg, 76%) as a colorless oil: [α] D   23 −6.2 (c 1.23, CHCl 3 ); IR (neat) 2955, 2856, 1753, 1694, 1471 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.91(s, 1H), 6.47 (s, 1H), 5.52 (dd, J=7.9, 15.6 Hz, 1H), 5.32 (dt, J=6.7, 8.5 Hz, 1H), 5.17 (t, J=7.3, 1H), 4.40 (dd, J=3.1, 6.7 Hz, 1H), 4.15-4.18 (m, 2H), 3.82 (dd, J=1.8, 7.2, 1H), 3.02 (dq, J=7.1, 7.1 Hz, 1H), 2.72 (s, 3H), 2.66 (d, J=6.6 Hz, 2H), 2.20-2.44 (m, 3H), 2.00 (s, 3H), 1.26 (s, 3H), 1.07 (s, 3H), 1.01 (d, J=7.0 Hz, 3H), 1.00 (d, J=6.0 Hz, 3H), 0.93 (t, J=7.8 Hz, 9H), 0.91 (s, 9H), 0.87 (s, 9H), 0.58 (q, J=7.8 Hz, 6H), 0.10 (s, 3H), 0.06 (s, 3H), 0.03 (s, 3H), 0.03 (s, 9H), 0.02 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 218.5, 172.6, 164.7, 153.6, 143.0, 136.0, 133.1, 129.7, 121.9, 119.0, 115.3, 79.0, 76.8, 63.1, 53.8, 46.6, 43.8, 42.8, 40.9, 26.6, 26.4, 19.6, 18.9, 18.6, 17.7, 16.7, 14.4, 7.3, 5.5, −1.1, −3.1, −3.4, −4.0, −4.2; HRMS (FAB) calculated for C 50 H 96 NO 6 SSi 4  (M+H + ) 950.6036, found 950.6065. 
     Example 37 
     This example describes the synthesis of compound 110. To a stirred solution of 108 (20 mg, 21 μmol) and powdered molecular sieves (100 mg) in THF (8.0 mL) at 0° C. was added tetra-n-butylammonium fluoride (16.5 mg, 63 μmol). After 6 hours, the mixture was filtered through glass wool, and aqueous citric acid (pH 5, 8 mL) was added to the filtrate, which was extracted with Et 2 O. The dried (MgSO 4 ) extract was concentrated in vacuo and the residue was purified by flash chromatography on silica gel, eluting with 4% MeOH/CH 2 Cl 2 , to give 110 (12.8 mg, 83%) as a colorless oil: [α] D   23 −22.4 (c 2.15, CHCl 3 ); IR (neat) 3252, 2956, 2929, 2856, 1712 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.96 (s, 1H), 6.58, (s, 1H), 5.54 (dd, J=7.5, 15.2 Hz, 1H), 5.38 (dt, J=6.7, 15.2 Hz, 1H), 5.20 (t, J=7.8 Hz, 1H), 4.40 (dd, J=3.2, 6.4 Hz, 1H), 4.16-4.24 (m, 1H), 3.83-3.86 (m, 1H), 3.02-3.09 (m, 1H), 2.72 (s, 3H), 2.69-2.72 (m, 2H), 2.28-2.55 (m, 5H), 1.98-2.08 (m, 2H), 2.03 (s, 3H), 1.63 (s, 3H), 1.17 (s, 3H), 1.12 (s, 3H), 1.04 (d, J=6.9 Hz, 3H), 0.97 (d, J=6.9 Hz, 3H), 0.92 (s, 9H), 0.89 (s, 9H), 0.11 (s, 3H), 0.07 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H));  13 C NMR (75 MHz, CDCl 3 ) δ 218.8, 175.9, 165.4, 153.0, 142.1, 138.2, 133.3, 129.5, 120.6, 119.4, 115.7, 76.9, 76.7, 73.7, 54.0, 46.8, 43.6, 42.8, 40.4, 34.6, 30.1, 26.6, 26.4, 24.2, 20.1, 19.3, 18.9, 18.6, 16.9, 14.7, −3.1, −3.5, −3.7, −4.2; HRMS (FAB) calculated for C 39 H 70 NO 6 SSi 2  (M+H + ) 736.4462, found 736.4466. 
     Example 38 
     This example describes the synthesis of compound 112. To a stirred solution of 110 (22.0 mg, 30.0 μmol) in THF (0.5 mL) at 0° C. was added Et 3 N (7.6 μL, 54 μmol) followed by 2,4,6-trichlorobenzoyl chloride (5.6 μL, 36 μmol). After 45 minutes, the mixture was diluted with THF (0.4 mL) and toluene (0.7 mL), and was added via syringe pump to a stirred solution of DMAP (6.5 mg, 53 μmol) in toluene (7.2 mL) at 75° C. during 3.5 h. After an additional 1 hour, the solution was allowed to cool to room temperature, diluted with EtOAc, washed with saturated aqueous NH 4 Cl (20 mL), and extracted with EtOAc (4×40 mL). The dried (MgSO 4 ) extract was concentrated in vacuo and the residue was purified by chromatography on silica gel, eluting with 5% EtOAc/hexanes, to give 112 (19.4 mg, 71%) as a colorless oil: [α] D   23  −2.12 (c 1.13, CHCl 3 ); IR (neat) 2929, 2856, 1735, 1700 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.94 (s, 3H), 6.54 (s, 3H), 5.44-5.46 (m, 2H), 5.28 (m, 1H), 5.22 (dd, J=3.3, 9.7, 1H), 4.63 (dd, J=3.2, 8.7, 1H), 3.90 (m, 1H), 3.16 (dq, J=6.8, 6.8 Hz, 1H), 2.71 (s, 3H), 2.20-2.71 (m, 6H), 2.14 (s, 3H), 1.68 (s, 3H), 1.10 (d, J=6.8 Hz, 3H), 1.10 (s, 3H), 1.07 (s, 3H), 1.04 (d, J=7.0, 1H), 0.93 (s, 9H), 0.85 (s, 9H), 0.11 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.88 (s, 3H);  13 C NMR (100 MHz, CDCl 3 ) δ 215.9, 170.7, 165.1, 153.1, 138.7, 137.8, 133.9, 128.3, 120.3, 119.8, 116.8, 80.8, 77.7, 73.3, 55.1, 44.1, 43.1, 42.3, 42.0, 32.8, 26.6, 26.4, 21.2, 19.7, 19.1, 18.9, 18.2, 18.0, 17.2, 15.2, −2.5, −3.4, −3.8, −3.8; HRMS (FAB) calculated for C 39 H 68 NO 5 SSi 2  (M+H + ) 718.4357, found 718.4345. 
     Example 39 
     This example describes the synthesis of compound 114 To a stirred solution of 112 (14.5 mg, 20 μmol) in CH 2 Cl 2  (125 μL) at 0° C. was added trifluoroacetic acid (112 μL). After 8 hours, the mixture was concentrated in vacuo, and the residue was purified by chromatography on silica gel, eluting with 20-50% EtOAc/hexanes, to give 114 (9.3 mg, 19 μmol, 95%) as a colorless waxy solid: [α] D   23-35.4  (c 0.50, CHCl 3 ); IR (neat) 2971, 2927, 1729, 1691 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.98 (s, 1H), 6.55 (s, 1H), 5.53-5.48 (m, 2H), 5.38 (dd, J=2.8, 9.4 Hz, 1H), 5.23 (m, 1H), 4.23 (dd, J=4.3, 8.2 Hz, 1H), 3.71 (m, 1H), 3.27 (dq, J=5.8, 6.7 Hz, 1H), 2.27-2.77 (m, 6H), 2.72 (s, 3H), 2.11 (s, 3H), 1.69 (s, 3H), 1.26 (s, 3H), 1.17 (d, J=6.8 Hz, 3H), 1.10 (d, J=7.0 Hz, 3H), 1.05 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 219.7, 171.0, 165.2, 152.7, 138.4, 137.8, 132.8, 129.6, 120.4, 120.2, 116.6, 79.2, 77.0, 76.4, 74.6, 72.3, 53.3, 44.7, 42.9, 40.3, 39.5, 32.6, 21.6, 20.0, 19.6, 17.8, 17.1, 15.9, 15.2; HRMS (FAB) calculated for C 27 H 40 NO 3 S (M+H + ) 490.2627, found 490.2634. 
     Example 40 
     This example describes the synthesis of compound 118. To a stirred solution of alkyne 96 (38.0 mg, 0.063 mmol) in Et 2 O (1.0 mL) and DMF (0.2 mL) at room temperature was added Et 3 N (8.8 μL, 0.063 mmol) and CuI (12.0 mg, 0.063 mmol). After the mixture became clear (approximately 5 minutes), a solution of chloride 59 (12.2 mg, 0.315 mmol) in Et 2 O (0.5 mL) was added. The solution was stirred for 18 hours, quenched with saturated aqueous Na 2 S 2 O 3  (5 mL), and extracted with Et 2 O (3×2 mL). The combined extracts were dried (MgSO 4 ) and concentrated in vacuo, and the residue was purified by chromatography on silica gel, eluting with 50-60% CH 2 Cl 2 /hexanes to give dienyne 118 (17.4 mg, 58%) as a colorless oil: [α] D   23 −12.1 (c 1.74); IR (neat) 1737, 1692 cm −1 ;  1 H NMR (CDCl 3 , 300 MHz) δ 6.91(s, 1H), 6.47 (s, 1H), 5.37 (t, J=6.7 Hz, 1H), 4.44 (dd, J=3.2, 6.64 Hz, 1H), 4.20-4.09 (m, 3H), 3.74 (dq, J=2.1, 11.5 Hz, 1H), 3.34 (dddd, J=2.7, 2.7, 7.6, 7.6 Hz, 1H), 2.71 (s, 3H), 2.41-2.25 (m, 5H), 2.02 (s, 3H), 1.68 (s, 3H) 1.25 (s, 3H), 1.16 (s, 3H), 1.13 (d, J=7.1 Hz, 3H), 1.06 (d, J=6.9 Hz, 3H), 0.98 (obscured m, 2H), 0.94 (t, J=8.1, 9H) 0.92 (s, 9H), 0.88 (s, 9H), 0.59 (q, J=7.9, 9H), 0.10 (s, 3H), 0.07 (s, 6H), 0.04 (s, 9H), 0.03 (s, 3H);  13 C NMR (CDCl 3 , 75 MHz) δ 219.2, 172.6, 164.7, 153.6, 142.9, 132.8, 122.4, 119.1, 115.4, 83.5, 80.6, 78.8, 76.4, 73.9, 63.9, 54.1, 41.1, 36.0, 33.0, 30.1, 26.4, 24.1, 19.6, 19.5, 19.4, 19.1, 18.9, 18.7, 18.6, 17.7, 16.1, 14.4, 7.3, 5.22, −1.1, −−2.9, −3.5, −4.0, −4.3; HRMS (FAB) calculated for C 50 H 94 NO 6 SSi 4  (M+H + ) 948.58790, found 948.59258. 
     Example 41 
     This example describes the synthesis of compound 120. To a stirred solution of dienyne 118 (8.0 mg, 8.4 μmol) and powdered molecular sieves (100 mg) in THF (1.5 mL) at 0° C. was added tetra-n-butylammonium fluoride (6.0 mg, 25 μmol). After 1 hour, the mixture was filtered through glass wool, and aqueous citric acid (pH 5, 3.0 mL) was added to the filtrate, which was extracted with Et 2 O. The dried (MgSO 4 ) extract was concentrated in vacuo and the residue was purified by flash chromatography on silica gel, eluting with 4% MeOH/CH 2 Cl 2 , to give 120 (8.2 mg, quantitative) as a colorless oil: [α] D   23 −0.17 (c 0.82, CHCl 3 ); IR (neat) 3338, 2954, 2929, 2856, 1713 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.96 (s, 1H), 6.58, (s, 1H), 5.50 (t, J=6.7 Hz, 1H), 4.46 (dd, J=2.1, 4.7 Hz, 1H), 4.20 (t, J=4.7H), 3.80 (dd, J=1.1, 5.6 Hz, 1H), 3.34 (dddd, J=5.5, 5.5, 5.5, 10.9 Hz, 1H), 2.9 (s, 1H), 2.73 (s, 3H), 2.58-2.25 (m, 5H), 2.05 (s, 3H), 1.72 (s, 3H) 1.24 (s, 3H), 1.20 (s, 3H), 1.15 (d, J=5.4 Hz, 3H), 1.10 (d, J=5.2 Hz, 3H), 0.93 (s, 9H), 0.90 (s, 9H), 0.11 (s, 3H), 0.09 (s, 9H);  13 C NMR (75 MHz, CDCl 3 ) δ 219.1, 175.4, 165.4, 153.0, 142.2, 134.6, 121.2, 119.3, 115.8, 84.1, 80.4, 76.4, 73.6, 54.4, 46.7, 40.4, 34.7, 33.0, 30.1, 29.6, 26.5, 26.4, 23.9, 19.2, 19.2, 18.9, 18.6, 16.9 16.4, 14.9, −2.94, −3.5, −3.6, −4.2; HRMS (FAB) calculated for C 39 H 68 NO 6 SSi 2  (M+H + ) 734.43082, found 734.42877. 
     Example 42 
     This example describes the synthesis of compound 122. To a stirred solution of seco acid 120 (8.8 mg, 12.0 μmol) in THF (0.2 mL) at 0° C. was added Et 3 N (2.9 μL, 21 μmol) followed by 2,4,6-trichlorobenzoyl chloride (2.2 μL, 14 μmol). After 45 minutes, the mixture was diluted with THF (0.16 mL) and toluene (0.26 mL), and was added via syringe pump to a stirred solution of DMAP (2.4 mg, 20 μmol) in toluene (2.8 mL) at 75° C. during 3.5 h. After an additional 1 h, the solution was allowed to cool to room temperature, diluted with EtOAc, washed with saturated aqueous NH 4 Cl (10 mL), and extracted with EtOAc (4×20 mL). The dried (Mg 2 SO 4 ) extract was concentrated in vacuo and the residue was purified by chromatography on silica gel, eluting with 5% EtOAc/hexanes, to give macrolactone 122(4.1 mg, 47%) as a colorless oil: [α] D   23  11.9 (c 0.41, CHCl 3 ); IR (neat) 2925, 2854, 1739, 1702, 1463 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.94 (s, 3H), 6.55 (s, 3H), 5.70 (t, J=6.2, 1H), 5.33 (dd, J=2.6, 11.3 1H), 4.64 (dd, J=2.5, 8.2, 1H), 3.94 (dd, J=2.5, 8.1 1H), 3.26 (dq, J=7.0, 14.9 Hz, 1H), 2.71 (s, 3H), 2.70-2.35 (m, 5H), 2.15 (s, 3H), 1.66 (s, 3H), 1.16 (d, J=7.1 Hz, 3H), 1.14 (s, 3H), 1.14 (s, 3H), 1.13 (obscured d, 1H), 0.91 (s, 9H), 0.86 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H);  13 C NMR (100 MHz, CDCl 3 ) δ 215.7, 170.9, 165.1, 153.1, 139.0, 137.8, 132.9, 121.5, 120.1, 116.7, 85.5, 80.3, 79.8, 77.6, 76.4, 73.3, 55.2, 44.4, 42.5, 33.1, 32.5, 30.1, 29.0, 26.4, 26.4, 19.8, 19.7, 18.7, 18.5, 18.0, 17.4, 15.2, −2.9, −3.3, −3.8, −4.1; HRMS (FAB) calculated for C 39 H 66 NO 5 SSi 2  (M+H + ) 716.42003, found 716.42093. 
     Example 43 
     This example describes the synthesis of compound 124. To a stirred solution of 122 (4.1 mg, 5.7 μmol) in CH 2 Cl 2  (200 μL) at 0° C. was added trifluoroacetic acid (100 mL). After 10 hours, the mixture was concentrated in vacuo, and the residue was purified by chromatography on silica gel, eluting with 20-50% EtOAc/hexanes, to give 124 (2.4 mg, 19 μmol, 86%) as a colorless waxy solid: [α] D   23 −37.9 (c 0.24, CHCl 3 ); IR (neat) 3480, 2925, 1731, 1692 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.98 (s, 1H), 6.56 (s, 1H), 5.49 (t, J=7.9, 1H), 5.38 (dd, J=3.1, 9.9, 1H), 4.43 (dd, J=5.6, 5.6, 1H), 3.60 (dd, J=8.2, 8.2, 1H), 3.26 (dddd, J=6.7, 6.7, 6.8, 15.5 Hz, 1H), 2.71 (s, 3H), 2.65-2.35 (m, 5H), 2.11 (s, 3H), 1.74 (s, 3H), 1.27 (d, J=6.9, 3H), 1.25 (d, J=7.1, 3H) 1.21, (s, 3H), 1.09 (s, 3H);  13 C NMR (100 MHz, CDCl 3 ) δ 218.5, 171.1, 165.3, 152.6, 137.8, 134.5, 121.3, 120.4, 116.8, 82.7, 82.3, 79.2, 77.6, 76.6, 72.1, 53.5, 47.4, 39.8, 32.7, 31.9, 29.5, 22.2, 19.6, 19.4, 18.9, 17.0, 16.8, 15.8; HRMS (FAB) calculated for C 27 H 38 NO 5 S (M+H + ) 488.24676, found 488.24707. 
     Example 44 
     This example describes the synthesis of compound 81. To a stirred solution of the crude aldehyde 79 in t-BuOH (0.88 mL) and H 2 O (0.83 mL) was added 2-methyl-2-butene (0.16 mL) followed sequentially by NaH 2 PO 4  (55.7 mg, 0.46 mmol) and NaClO 2  (27.1 mg, 0.30 mmol). After 1 hour, the reaction was quenched with saturated aqueous NaCl (1.5 mL), and the mixture was extracted with Et 2 O (4×5 mL). The dried (MgSO 4 ) extract was concentrated in vacuo and the residue was purified by chromatography on silica gel, eluting with 20% EtOAc in hexanes to give acid 81 (38 mg 0.061 mmol, 93%) as a colorless oil: [α] D   23  −26.8 (c 1.20, CHCl 3 ); IR (neat) 2400-3400, 1735, 1722 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 4.40 (dd, J=3.6, 6.9 Hz, 1H), 4.15 (m, 3H), 4.03 (dd, J=2.2, 7.9 Hz, 1H), 3.36 (dq, J=7.3, 7.3 Hz, 1H), 2.45 (td, J=2.2, 7.4 Hz, 1H), 2.37 (d, J=3.4 Hz, 1H), 2.26 (dd, J=7.0, 16.1 Hz, 1H), 1.23 (d, J=7.1 Hz, 3H) 1.22 (s, 3H), 1.14 (s, 3H), 1.11 (d, J=6.9 Hz, 3H) 0.98 (m, 3H), 0.93 (s, 9H), 0.87 (s, 9H), 0.15 (s, 3H), 0.14 (s, 3H), 0.10 (s, 3H), 0.04 (s, 9H), 0.02 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 218.2, 177.4, 172.7, 76.6, 73.9, 63.2, 54.2, 46.8, 45.2, 40.9, 30.1, 26.4, 26.4, 24.1, 19.3, 18.7, 18.6, 17.6, 15.9, 15.6, −1.1, −3.2, −3.5, −4.0, −4.2; HRMS (CI) calculated for C 30 H 63 O 7 Si 3  619.38750; found 619.38817. 
     Example 45 
     This example describes the synthesis of compound 124. To a stirred solution of 81 (30.0 mg, 0.048 mmol) in THF (0.25 mL) was added 104 (20.6 mg, 0.073 mmol) and triphenylphosphine (31.4 mg, 0.12 mmol). The solution was cooled to 0° C. and diethyl azodicarboxylate (0.017 mL, 0.11 mmol) was added. After 4 hours, the reaction was quenched with saturated aqueous NH 14 Cl, and the solution was extracted with Et 2 O. The extract was concentrated in vacuo, and the residue was purified by chromatography on silica gel, eluting with 10% Et 2 O/petroleum ether, to give ester 124 (30 mg, 65%) as a colorless oil: [α] D   23 −20.7 (c 1.50, CHCl 3 ); IR (neat) 2954, 1735, 1251 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.92 (s, 1H), 6.46 (s, 1H), 5.42 (t, J=7.3 Hz, 1H), 4.61 (d, J=12.1 Hz, 1H), 4.51 (d, J=12.1 Hz, 1H), 4.41 (dd, J=3.0, 6.6 Hz, 1H), 4.13 (m, 3H), 3.47 (dq, J=7.1, 7.1 Hz, 1H), 2.71 (s, 3H), 2.47-2.13 (m, 5H) 1.99 (s, 3H), 1.75 (s, 3H), 1.24 (s, 3H), 1.15 (d, J=7.1 Hz, 3H), 1.12 (s, 3H), 1.04 (d, J=6.9 Hz, 3H), 0.98 (m, 3H), 0.92 (t, J=7.7, 9H), 0.85 (s, 18H), 0.57 (q, J=7.9 Hz, 6H), 0.09 (s, 3H), 0.07 (s, 3H), 0.04 (s, 3H), 0.03 (s, 9H), 0.02 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 218.2, 173.7, 172.6, 164.9, 153.2, 142.6, 131.9, 127.2, 119.1, 115.5, 78.5, 76.3, 74.2, 63.7, 63.1, 53.9, 45.6, 40.9, 35.5, 26.4, 24.2, 22.1, 17.7, 15.5, 15.1, 14.4, 7.2, 5.2, −1.1, −3.5, −4.0, −4.2; HRMS (CI) calculated for C 49 H 94 O 8 SSi 4  968.57773; found 968.57748. 
     Example 46 
     This example describes the synthesis of compound 130. To a stirred solution of 124 (30 mg, 31 μmol) and powdered molecular sieves (100 mg) in THF (5.0 mL) at 0° C. was added tetra-n-butylammonium fluoride (24.0 mg, 96 μmol). After 2 hours, the mixture was filtered through glass wool, and aqueous citric acid (pH 5, 5 mL) was added to the filtrate, which was extracted with Et 2 O. The dried (MgSO 4 ) extract was concentrated in vacuo and the residue was purified by flash chromatography on silica gel, eluting with 3% MeOH/CH 2 Cl 2 , to give seco acid 130(15.0 mg, 66%) as a colorless oil: [α] D   23 −26.9 (c 0.75, CHCl 3 ); IR (neat) 3107, 2929, 1716, 1422 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.96 (s, 1H), 6.64 (s, 1H), 5.46 (t, J=7.3 Hz, 1H), 4.69 (d, J=11.8 Hz, 1H), 4.47 (d, J=11.8 Hz, 1H), 4.42 (dd, J=3.6, 6.3 Hz, 1H), 4.17 (t, J=6.8 Hz, 1H), 4.09 (dd, J=2.5, 7.7 Hz, 1H), 3.42 (dq, J=7.4, 7.4 Hz, 1H), 2.72 (s, 3H), 2.56-2.19 (m, 5H) 2.00 (s, 3H), 1.80 (s, 3H), 1.23 (s, 3H), 1.17 (s, 3H), 1.16 (d, J=7.1 Hz, 3H), 1.08 (d, J=6.9 Hz, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.10 (s, 3H), 0.10 (s, 3H), 0.08 (s, 3H), 0.05 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 218.4, 175.3, 173.8, 165.6, 152.8, 142.4, 133.5, 126.7, 118.9, 115.6, 76.1, 73.8, 63.8, 54.3, 45.9, 45.7, 40.6, 34.4, 26.4, 24.2, 22.2, 19.4, 19.2, 18.7, 16.1, 15.3, 13.8, −3.6, −3.7, −3.8, −4.2; HRMS (CI) calculated for C 38 H 68 O 8 NSSi 2  754.42042; found 754.42119. 
     Example 47 
     This example describes the synthesis of compound 132. To a stirred solution of 130 (15.0 mg, 20.0 μmol) in THF (0.4 mL) at 0° C. was added Et 3 N (4.9 μL, 35 μmol) followed by 2,4,6-trichlorobenzoyl chloride (3.6 μL, 23 μmol). After 45 minutes, the mixture was diluted with THF (0.3 mL) and toluene (0.4 mL), and was added via syringe pump to a stirred solution of DMAP (4.2 mg, 34 μmol) in toluene (4.6 mL) at 75° C. during 4 hours. After an additional 1 hour, the solution was allowed to cool to room temperature, diluted with EtOAc, washed with saturated aqueous NH 4 Cl (20 mL), and extracted with EtOAc (4×40 mL). The dried (Mg 2 SO 4 ) extract was concentrated in vacuo and the residue was purified by chromatography on silica gel, eluting with 5% EtOAc/hexanes, to give 132 (9.0 mg, 60%) as a colorless oil: [α] D   23 −36.6 (c 0.45, CHCl 3 ); IR (neat) 2927, 1741, 1471 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 6.96 (s, 1H), 6.57 (s, 1H), 5.44 (dd, J=5.7, 11.8 Hz, 1H), 5.34 (dd, J=3.3, 8.8 Hz, 1H) 4.83 (d, J=11.5 Hz, 1H), 4.46 (m, 2H), 4.02 (dd, J=1.6, 8.7 Hz, 1H), 3.34 (dq, J=7.4, 7.4 Hz, 1H), 2.82 (m, 1H), 2.71 (s, 3H), 2.56 (m, 3H), 2.28 (m, 1H) 2.15 (s, 3H), 1.74 (s, 3H), 1.23 (d, J=7.4 Hz, 3H), 1.20 (d, J=7.1 Hz, 3H), 1.16 (s, 3H), 1.09 (s, 3H), 0.90 (s, 9H), 0.85 (s, 9H), 0.15 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.02 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 217.0, 173.4, 170.8, 165.1, 152.8, 136.6, 133.7, 126.7, 121.3, 116.8, 79.2, 76.6, 73.7, 62.6, 54.2, 48.3, 45.6, 41.9, 33.3, 26.5, 25.1, 22.3, 20.4, 19.7, 18.7, 18.6, 17.4, 15.2, −3.4, −3.5, −3.7, −4.2; HRMS (CI) calculated for C 38 H 66 O 7 NSSi 2  736.40986; found 736.40850. 
     Example 48 
     This example describes the synthesis of compound 134. To a stirred solution of 78 (4.5 mg, 6 μmol) in CH 2 Cl 2  (200 μL) at 0° C. was added trifluoroacetic acid (100 μL). After 8 hours, the mixture was concentrated in vacuo, and the residue was purified by chromatography on silica gel, eluting with 20-2% MeOH/CH 2 Cl 2 , to give 79 (3 mg, 6 μmol, 99%) as a colorless oil: [α] D   23  40.0 (c 0.15, CHCl 3 ); IR (neat) 3503, 2924, 1732, 1458 cm −1 ;  1 H NMR (300 MHz, CDCl 3 ) δ 7.00 (s, 1H), 6.60 (s, 1H), 5.45 (dd, J=6.0, 11.0 Hz, 1H), 5.28 (d, J=9.6 Hz, 1H) 5.02 (d, J=11.2 Hz, 1H), 4.21 (d, J=12.3 Hz, 1H), 4.02 (m, 1H), 3.77 (m, 1H), 3.46 (m, 1H), 3.23 (dq, J=6.8, 6.8 Hz, 1H), 2.74 (s, 3H), 2.67 (m, 3H), 2.45 (m, 2H), 2.24 (m, 1H), 2.11 (s, 3H), 1.78 (s, 3H), 1.38 (d, J=7.1 Hz, 3H), 1.31 (s, 3H) 1.27 (d, J=6.8 Hz, 3H), 1.10 (s, 3H);  13 C NMR (75 MHz, CDCl 3 ) δ 218.9, 177.2, 170.9, 165.4, 152.8, 137.9, 133.6, 126.1, 120.7, 116.9, 78.9, 75.6, 73.3, 63.9, 52.7, 47.9, 41.7, 39.0, 32.7, 22.3, 21.9, 21.8, 19.6, 16.8, 16.5, 15.7; HRMS (CI) calculated for C 26 H 38 O 7 NS 508.23690; found 508.23641. 
     The present method has been described in accordance with working embodiments; however, it will be understood that certain modifications may be made thereto without departing from the method. We claim as our invention the disclosed embodiments and all such modifications and equivalents as come within the true spirit and scope of the following claims.