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. A new hydroxide‐induced decarboxylative Grob‐type fragmentation for the stereoselective synthesis of methyl‐branched trisubstituted olefins, an important motif in many polyketides with interesting biological activity, such as peloruside A, discodermolide, and epothilone D, is presented. This strategy centers on mesyloxy lactones (see scheme) with three stereogenic centers, one quaternary, which upon treatment with hydroxide fragment extrusion of the leaving group and carbon dioxide to the olefin.