Epothilone DERA

The flexibility of DERA enzymes makes them a valuable synthetic tool for the quick access to a range of polyoxgenated products, such as the cytotoxic agent epothilone A (Scheme 1.58). ... 

In comparison to other aldolases, DERA has a rather broad substrate range. DERA-catalyzed aldol reactions were used to get an access to key intermediates for epothilones (Fig. 36) [194]. According to retrosynthetic analysis, both fragments of the molecule could be obtained from aldol building blocks, and two out of seven stereocenters were established enzymatically. For the southern part of epothilone A,... 

Fig. 36 DERA mediated access to key synthons in the synthesis of epothilone A...

A particularly successful synthesis of Epothilone A is based on two DERA-cata-lyzed steps. In these two of the seven stereocentres of Epothilone A were established. When a racemic aldehyde was released in situ from its acetal, DERA converted only the R-enantiomer into the stable cyclic hemiacetal. This is a combined kinetic resolution and carbon-carbon bond formation yielding a building block with two chiral centers. Since the alcohol function was oxidized, the optical information obtained from the kinetic resolution was lost. Thus, for the overall yield it would have been better if DERA had displayed no stereoselectivity towards the acceptor (Scheme 5.32). In the DERA-catalyzed synthesis of another part of Epothilone A DERA is again highly stereoselective. Fortunately its preference is for the S-enan-tiomer of the acceptor aldehyde, the enantiomer that has to be submitted to the carbon-carbon bond formation in order to obtain the desired building block, again a stable hemiacetal (Scheme 5.32). Indeed, both DERA-catalyzed reactions yield open chain products that form stable cyclic hemiacetals. This ensures that the equilibria of these aldol reactions are shifted towards the desired products. Further synthetic manipulations converted these intermediates into Epothilone A [55]. 

Scheme 5.32 DERA catalyzes key steps in the synthesis of Epothilone A.

Scheme 5.46. Synthesis of key epothilone fragments using DERA. Conditions (a) 42% yield (b) Br2/H20 (c) 35% (d) (i) Ac20, pyridine, (ii) BF3/Et20 (e) HS(CH2)3SH/BF3/Et20 (/) (i) Swern oxidation, (ii) Wittig reaction (g) (i) Swern oxidation, (ii) Wittig reaction TBS = tert-butyldimethylsilyl TIPS = triisopropylsilyl.

A different aldolase has been over-expressed in E. coli and used by Chi-Huey Wong in his synthesis of epothilones. It is 2-deoxyribose-5-phosphate aldolase (DERA) and the natural reaction is the condensation of acetaldehyde as enol with glyceraldehyde-3-phosphate 164 as electrophilic component to give an aldol product 165 that is trapped as a hemiacetal 166. 

DERA has also been used for the development of new pathways to building blocks in the total synthesis of epothi-lone A (Scheme 28.20). The epothilones are a new class of cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with mbulin, but in early trials, epothilones have better efficacy and milder adverse effects than taxanes. Epothilones were originally... 

SCHEME 28.20. DERA-catalyzed production of important chiral building blocks, A and B, for the total synthesis of epothilone A. 

In the proposed synthesis, DERA defines several of the seven stereocenters of epothilone A. Two stereocenters were obtained in a first building block (A) by combined kinetic resolution of a racemic mixture 45 and C—C bond formation. Two others were determined for a second building block (B) by the reaction of a 5-aldehyde 48 with acetaldehyde 28. 

---