Stereoselective total synthesis of natural (+)-streptazolin via a palladium-catalyzed enyne bicyclization approach

The natural Z isomer of (+)-streptazolin (1), isolated from cultures of Streptomyces viridochromogenes, was synthesized in an optically pure form for the first time on the basis of a palladium-catalyzed enyne bicyclization approach in 12 steps and 4.3% overall yield from (3R,4R)-3,4-bis(benzyloxy)succinimide (5). The requisite enyne 13 for palladium-catalyzed bicyclization was prepared from 5 via N-acyliminium ion cyclization of the acetoxy lactam 9, partial reduction of 10 with DIBALH-BuLi, and conversion to the dibromo olefin 12. The best result in the palladium-catalyzed bicyclization was obtained when treated with 30 mol % Pd(OAc)(2) and N,N '-bis(benzylidene)ethylenediamine (BBEDA) as the ligand in benzene at reflux, thus affording a 93:7 mixture of the 1,2,4a,7a,6,7-hexahydro-5H-1-pyrindine (Z)-14 along with its isomerized product (Z)-15 in 84% total yield. The isomerization of the 1,4-diene in (Z)-14 to the 1,3-diene was achieved by treatment with triiron dodecacarbonyl to generate the stable tricarbonyl(eta(4)-1,3-diene)iron complex 16, which was then converted to the glycol 17. Treatment of 17 with sodium methoxide followed by ordinary chromatography on silica gel resulted in isolation of chemically and enantiomerically pure (+)-streptazolin (1).