Epothilones total synthesis

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. 

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. 

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

Nicolaou et al. were the first to report the successful use of RCM to prepare the 16-membered macrolactone nucleus of the epothilones and present a strategy for their total synthesis based on this reaction. The approach involved formation of the C12,C13 olefin and is outlined in Scheme 2 [12,13]. 

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]. 

The greater reactivity of terminal olefins compared to their more hindered di-and tri-substituted counterparts became evident in the model studies (Sect. 2.2.1) and in the total synthesis of epothilones A, B and E (Sects. 2.2.2-2.2.4). Suitably positioned disubstituted olefins can, however, participate in RCM reactions employing the molybdenum initiator 1 [19], and this is demonstrated in the total synthesis of epothilone B (5) (Sect. 2.2.3). As expected this transformation proved impossible using the ruthenium complex 3. 

In addition to Evans CuflD-catalyzed and Carreira s Ti-catalyzed asymmetric aldol reactions, there is omit Shibasaki s La-catalyzed protocol1141 A recent total synthesis of one of the more celebrated targets of the nineties, epothilone A, utilizes both an enan-tioseledive Al-catalyzed cyanide addition to an aldehyde (75 —> 77) and a La-catalyzed enantioseled-... 

Scheme 12. Shibasaki utilizes a Al-catalyzed asymmetric CN addition to aldehydes and a La-catalyzed asymmetric aldol in the total synthesis of epothilone A (2000).

D. Sawada, M. Shibasaki Enantioselective Total Synthesis of Epothilone A Using Multifunctional Asymmetric Catalyses , Angew. Chem, Int. Ed Engl 2000,39,209-213. 

Scheme 2.1 Bond construction strategies for total synthesis of epothilone A and B.

Scheme 2.1 outlines the synthetic strategies pursued in our laboratory towards the total synthesis of the epothilones. Although the structural issues addressed above were not insurmountable, several obstacles were encountered during the course of our pursuit. In nearly each instance, the two sectors containing the stereochemical information were prepared independently and then assembled in a late stage merger. 

Scheme 2.6 Late generation synthesis of desoxy epothilone B and epothilone B. The key steps in this total synthesis are a stereospecific aldol reaction, B-alkyl Suzuki coupling, and stereoselective Noyori reaction.

A second key component of our practical total synthesis of epothilone B includes a B-alkyl Suzuki merger, Scheme 2.8, which successfully occurs between the previously described vinyl iodide [34] 66 and tricarbonyl 65. With the coupling step accomplished, the resultant TBS protecting group could be hydrolyzed to afford the requisite C15-hydroxy ester 67. 

In the past few years the total synthesis of a number of quite complex natural products with many different structures have been achieved on solid supports (Fig. 3.3), for example Verrucine A and B (195, 196) [292], Trypostatin B (197) [97] Epothilone A (198) [181] Deglycobleomycin A5 (194) [293] and Oscillamide Y (199)... 

Klar U, Buchmann B, Schwede W, Sknballa W, Hoffmann J, Lichtner RB. (2006) Total Synthesis and Antitnmor Activity of ZK-EPO The first fully synthetic epothilone in clinical development. Angew Chem Int Ed 45 7942-7948. 

Total synthesis of complex (macrocyclic) natural products using fast and flexible strategies and diversity-oriented synthesis of natural product-like macrocycles are important research topics in our laboratory. The following sections describe the total synthesis of epothilone D and epothilone D5 analogues, DOS of cyclopeptide alkaloid analogues, of biaryl ether macrocycles, and of steroid/peptide hybrid macrocycles, respectively. 

Recently, Hofle and Reichenbach also described the isolation of some further components of the epothilone family [93]. One of these was epothilone D5 (Fig. 14), which differs from epothilone D by the presence of an additional unsaturation between C8 and C9. Since this double bond is inherent to our synthesis of epothilone D, we also decided to pursue the total synthesis of epothilone D5 and its diastereomers. 

The bis(isopinocampheyl)borane reagents described in the sections on enantioselective additions have found extensive use in the total synthesis of complex, bioactive natural products. A synthesis of the potent anticancer agent epothilone... 

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