Epothilone A, synthesis

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

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

With this preliminary phase of synthetic work accomplished, the more intriguing elements of the anticipated epothilone A synthesis could now begin in earnest. As shown in Scheme 21, the initial merger of fragments 61, 63, and 64 into advanced intermediate 60 proceeded quite smoothly. Treatment of 63 with 2,3 equivalents of LDA in THF at —78°C with warming to —40°C over one hour (to effect both deprotonation of the free acid and formation of the enolate) was followed by the addition of 1.6 equivalents of aldehyde 64, leading to a facile aldol reaction which provided 62 and its C6—C7 syn diastereomer in a 3 2 ratio that favored the desired drawn product. This mixture was carried forward and the acid was esterified directly with the homoallylic thiazole alcohol 61 in the presence of DCC and 4-DM AP to afford, after chromatographic separation, pure 60 (in 52 % yield firom 63) and its alternative syn disposed C6—C7 isomer (in 31 % yield from 63). 

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. 

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. 

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... 

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. 

The synthesis of the promising anti-cancer agent epothilone A 75 and many analogues thereof by means of RCM is comprehensively reviewed in the chapter by K.C. Nicolaou et al., this volume, and will not be duplicated here [35]. 

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 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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