THE TOTAL SYNTHESIS OF INDOLIZOMYCIN

The first total synthesis of racemic indolizomycin (1) has been achieved. Initial investigations provided the functionalized indolizidine, 31, via (i) stereospecific intramolecular vinylsilane/carbinol amide cyclization (15 --> 16), (ii) rhodium(II) acetate mediated diazoacetate insertion into thioamide 17, and (iii) epoxide introduction (25 --> 27 --> 29). Although subsequent attempts to fully elaborate 31 into indolizomycin were unsuccessful, these experiments formed the basis of a revised route which did ultimately produce the natural product. Thus, aza-Robinson annulation of diazo ketone 36 afforded dihydropyridone 38, which underwent vinylogous McCluskey fragmentation to provide azininone 40. The use of the [2-(trimethylsilyl)ethoxy]carbonyl (TEOC) protecting group (cf. 40e) was crucial for successful completion of the synthesis. Elaboration of the trienyl side chain was accomplished through 1O2 ene reaction of methyl enol ether 49 followed by Julia olefination of enal 51 with lithio sulfone 52. Fluoride deprotection of TEOC-amino ketone 57 followed by in situ transannular cyclization gave the highly unstable (+/-)-indolizomycin.