Epothilone synthesis

The synthesis of an epothilone model system via an alternative C9-C10 disconnection was first examined by Danishefsky in 1997. However, extension of this C9-C10 strategy to a fully functionalized epothilone intermediate was not successful, demonstrating the limitations of RCM with the early catalysts A and B [116]. In 2002, Sinha and Sun disclosed the stereoselective total syntheses of epoA (238a) and epoB (238b) by the RCM of epoxy compounds 242 in the presence of catalyst C (Scheme 50) [117]. The reaction furnished an inconsequential mixture of isomers 243 (E/Z 1 1) in high yield. Subsequent selective hydrogenation of the newly formed double bond followed by deprotection led to epothilones A and B. 

Scheme 50 Epothilone synthesis via RCM between C9 and CIO dependence of chemo-selectivity on the size of the C12 substituent in metathesis substrates 244 [117]...

The feasibility of multistep natural product total synthesis via solid-phase methodology, and its application to combinatorial chemistry, was first demonstrated by Nicolaou and coworkers in epothilone synthesis and in the generation of an epothilone library [152]. The traceless release of TBS-protected epoC 361 by RCM of resin-bound precursor 360 (Scheme 69) is an early and most prominent example for the strategy outlined in Fig. 11a. 

For the synthesis of ring-enlarged epothilone analogs by the same principle, see (a) Rivkin A, Njardarson JT, Biswas K, Chou T-C, Danishefsky SJ (2002) J Org Chem 67 7737 (b) Rivkin A, Biswas K, Chou T-C, Danishefsky SJ (2002) Org Lett 4 4081... 

The camphor sultam derivative 21A was used in a synthesis of epothilone. The stereoselectivity of the aldol addition was examined with several different aldehydes. Discuss the factors that lead to the variable stereoselectivity in the three cases shown. 

Some additional examples are given in Scheme 8.6. The electrophiles that have been used successfully include iodine (Entries 2 and 3) and cyanogen chloride (Entry 4). The adducts can undergo conjugate addition (Entry 5), alkylation (Entry 6), or epoxide ring opening (Entries 7 and 8). The latter reaction is an early step of a synthesis of epothilone B. 

Suzuki couplings have been used in the synthesis of complex molecules. For example, coupling of two large fragments of the epothilone A structure was accomplished in this way.229... 

Entries 6 to 11 are examples of nucleophilic ring opening. Each of these entries displays the expected preference for reaction at the less hindered carbon. Entries 8 and 9 involve metal ion catalysis. Entry 11, which involves carbon-carbon bond formation, was part of a synthesis of epothilone A. 

Scheme 13.60. Epothilone A Synthesis by Olefin Metathesis K. C. Nicolaou and Co-... 

The olefin metathesis reaction was also a key feature of the synthesis of epothilone A completed by a group at the Technical University in Braunschweig, Germany (Scheme 13.61). This synthesis employs a series of stereoselective additions to create the correct substituent stereochemistry. Two enantiomerically pure starting materials... 

Samuel Danishefsky s group at the Sloan Kettering Institute for Cancer Research in New York has also been active in the synthesis of the natural epothilones and biologically active analogs. One of their syntheses also used the olefin metathesis reaction (not shown). The synthesis in Scheme 13.62 used an alternative approach to create the macrocycle, as indicated in the retrosynthetic scheme. The stereochemistry at C(6), C(7), and C(8) was established by a TiCl4-mediated cyclocondensation (Step A). The thiazole-containing side chain was created by reaction sequences F and G. The... 

Scheme 13.62. Epothilone A Synthesis by Macroaldol Cyclization S. J. Danishefsky and...

Scheme 13.81. Combinatorial Synthesis of Epothilone Analogs Using Microreactors3...

The epothilone synthesis in Scheme 13.59 (p. 1221) has been used as the basis for a combinatorial approach to epothilone analogs.69 The acyclic precursors were... 

An expedient and fully stereocontrolled synthesis of epothilones A (435, R = H) and B (435, R = Me) has been realized (473, 474). The routes described, involve an extensive study of nitrile oxide cycloadditions, as substitutes for aldol addition reactions, leading to the realization of a highly convergent synthesis, based on the Kanemasa hydroxyl-directed nitrile oxide cycloaddition. 

Storer RI, Takemoto T, Jackson PS, Brown DS, Baxendale IR, Ley SV (2004) Multi-step application of immobilized reagents and scavengers a total synthesis of epothilone C. Chem Eur J 10 2529-2547... 

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