Synthesis of Epothilone

Epothilones A 8 and B 118 were first isolated in 1987 by Hofle et al. [90] from culture extracts of the myxobacterium S. cdlulosum (Myxococcales). These compounds display potent antiproUferative activity besides activity against a number of multidrug-resistant cancer cell lines. Keck et al. [91] reported the total synthesis of epothilone B 118 by macrolactonization. 

EtjN (f) (Bocj O, DMAP (g) DMDO. 

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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. 

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. 

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... 

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

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... 

Grieco in the total synthesis of (—)-epothilone B 134 used a rhodium-catalyzed hydroboration as a key step in the synthesis of the macrocyclic ring (Figure 15).141 Completion of the synthesis of the C(3)-C(12) fragment was carried out using a rhodium-catalyzed hydroboration as the key step. 

Ring-Closing Metathesis in the Synthesis of Epothilones and Polyether Natural Products... 

Total Synthesis of Epothilones Via Ring-Closing Metathesis. 75... 

Using a similar C12,C 13 disconnection approach, Schinzer et al. also achieved a total synthesis of epothilone A (4) [16]. The key step involved a highly selective aldol reaction between ketone 27 and aldehyde 10 to afford exclusively alcohol 28 with the correct C6,C7 stereochemistry (Scheme 6). Further elaboration led to triene 29, which underwent RCM using ruthenium initiator 3 in dichloromethane at 25°C, to afford macrocyles 30 in high yield (94%). Although no selectivity was observed (Z E=1 1), deprotection and epoxidation of the desired Z-isomer (30a) completed the total synthesis [16]. 

Following the completion of their first synthesis of epothilone A (4) based on a macroaldolisation strategy [17],Danishefsky and coworkers applied a C12,C13... 

With the C12,C13 disconnection producing an effective solution to the synthesis of epothilone A (4), it would seem likely that the metathesis approach could be extended readily to the preparation of epothilone B (5). However, installation of the desired C12 methyl group requires ring-closure of a diene precursor in which one of the olefins is disubstituted. Recently, such reactions have been shown to be problematic for Grubbs initiator 3 but more successful with Schrock s molybdenum initiator 1 [19]. Consistent with these reports, Danishefsky demonstrated that triene 38 would not undergo RCM with 3, whereas 1 was effective in promoting the transformation of 38 into a 1 1 mixture of 39a and 39b in good yield [14b] (Scheme 8). 

With the synthesis of epothilones A and B secured, subsequent studies concentrated on the preparation of analogs of the natural molecules. In addition to providing structure-activity relationships, it was anticipated that these studies would provide a further test for the generality of the RCM process. In this context, a general strategy was developed by Nicolaou et al. [20] to investigate the... 

Scheme 9. Synthesis of epothilone E and side-chain modified epothilones via RCM and Stille coupling, (a) 0.1 equiv of RuCl2(=CHPh)(PCy3)2 (3), CH2C12,0.004 M, 25°C, 20 h, 65% (41a 41b=1.8 l) (b) HF Py, THF,43 (84%) 44 (85%) (c) R13Sn(Aro), Pd(PPh3)4 or Pd(MeCN)2Cl2, 55-90% (d) H202, CH3CN, KHC03, 65%. Aro=aromatic (Nicolaou et al.) [20]...

Scheme 11. Solid-phase synthesis of epothilones. (a) 0.75 equiv of RuCl2(=CHPh)(PCy3)2 (3), CH2C12, 25°C, 48 h, 52% (84a 84b 85a 85b=3 3 l 3) (Nicolaou etal.) [24]...

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