Studies on the synthesis of the streptovaricins: Total synthesis of 24,27-dimethyl dihydrodamavaricin D

A total synthesis of 24,27-dimethyl dihydrodamavaricin D (1) is described. The synthesis features the highly diastereoselective synthesis of ansa chain alpha,beta-unsaturated aldehyde 3 using crotylboronate technology for three of the four key C-C bond forming events. Coupling of 3 with the aryllithium reagent generated from 2 provides enone 22 which is smoothly elaborated to seco acid 26. Macrolactamization of 26 via the Mukaiyama salt protocol provided 27 in good yield, which was smoothly deprotected to give the title compound. Overall, this synthesis proceeds in 38 steps via the longest linear sequence from commercially available methyl (R)-2-methyl-3-hydroxypropionate, with an overall stereoselectivity of 85%. Attempts to convert 1 to damavaricin D via oxidative demethylation have been unsuccessful owing to the unanticipated neighboring group participation of the carboxamide functionality (c.f., 27 --> 28 and 29 --> 30).