Synthesis of (Z)‐Trisubstituted Olefins by Decarboxylative Grob‐Type Fragmentations: Epothilone D,Discodermolide, and Peloruside A

Methyl‐branched (Z)‐trisubstituted olefins are found in many polyketides with interesting biological activity, such as epothilone D ( 1 ), discodermolide ( 3 ), and peloruside A ( 2 ). Despite the employment of numerous different strategies, this motif has often been the weak point in total synthesis. Thus, we present a novel hydroxide‐ induced Grob‐type fragmentation as an easy access to trisubstituted olefins. In our case, β‐mesyloxy δ‐lactones with three stereogenic centers were chosen whose fragmentation underlies a high stereoelectronic control. Major challenges in the syntheses were the installation of quaternary stereocenters, achieved by enzymatic desymmetrization of meso‐diesters and by aluminium‐promoted stereoselective rearrangement of chiral epoxides, respectively. Different aldol strategies were developed for the formation of the fragmentation precursors. Additionally a short survey about nucleophilic additions to aldehydes with quaternary α‐centers is presented.