Insights into long-range structural effects on the stereochemistry of aldol condensations: A practical total synthesis of desoxyepothilone F

A processable total synthesis of a potent antitumor agent, desoxyepothilone F (dEpoF, 21-hydroxy-12,13-desoxyepothilone B, 21-hydroxyepothilone D), ha s been accomplished. The route is highly convergent. The new technology has also been applied to a total synthesis of 12,13-desoxyepothilone (dEpoB). The crucial point of departure from previous syntheses of dEpoB and dEpoF i nvolves presentation of the C1-C11 sector for Suzuki coupling with C3 in re duced form. Hitherto, the required S stereochemistry at C3 had been impleme nted via reduction of a keto function after Suzuki coupling. Whereas that c hemistry worked quite well in a synthesis of dEpoB, it was not transferable to a high-yielding synthesis of dEpoF. The reduction of the keto group at C3 via a Noyori protocol after Suzuki coupling had proved to be very diffic ult. In our current approach, two consecutive aldol reactions are used to f ashion the acyl sector. In the first aldol condensation, C6 becomes attache d to C7. Following protection at C7, a two-carbon acetate equivalent is use d to join C2 and C3 with very high asymmetric induction at C3. Only after t his center has been implemented is the Suzuki reaction conducted. This majo r advance allowed us to synthesize dEpoF in a straightforward fashion. Thes e findings found ready application in the total synthesis of dEpoB. Another part of the study involved analysis of the factors associated with aldol c ondensations joining C6 to C7. In the work described herein, the consequenc es of the status of C3 in promoting the C6-C7 aldol coupling are probed in detail. Dramatic stereochemical long-range effects uncovered during the stu dy are described, and a working model to explain these effects has emerged.