ENANTIOSELECTIVE SYNTHESES OF VINBLASTINE, LEUROSIDINE, VINCOVALINE, AND 20'-EPI-VINCOVALINE

The binary indole-indoline alkaloids vinblastine (1), leurosidine (13), 20'-epi-vincovaline (14a), and vincovaline (14b) were obtained by coupling of vindoline (3) to the tetracyclic intermediates 7a, 7b or 22a, 22b, followed by reduction and cyclization steps (60% overall yield for these reactions). The intermediates were obtained by enantioselective establishment of C20' through a first-step Sharpless oxidation (10a,b) and followed by a subsequent diastereomeric separation (20a,b or 21a,b). Alternatively, enantioselective control of the key secodine-type cyclization in the reaction sequence provided the tetracyclic intermediates 54 and 60 for coupling to vindoline. Selective generation of the natural (1, 13, 14a,b) or unnatural (30, 34, 35a,b) atropisomeric forms of the alkaloids was achieved through alternative closures of ring D'. The natural products were also obtained from the higher energy atropisomers by conformational inversion on heating. For the vinblastine synthesis, the overall yield was 22%.