Development of a Stereoselective Synthesis of Isomers of (+)-Disorazole Z1's Lateral Chain

(+)-Disorazole Z1 (1) bears two lateral chains, each including a chiral quaternary carbon center with an ester moiety and a methyl group surrounded by two chiral secondary alcohols. Herein, we present different routes to synthesize the lateral chain, unveiling details of their development. The strategies, which include two consecutive aldol steps with a lactone intermediate, led to natural 2 and non-natural 3 lateral chain precursors with very good stereoselectivity. The stereochemistry was confirmed by X-ray crystallography. The results show an alternative lactonization procedure as well as the impact of detailed fine adjustments of the transesterification of a δ-lactone ring on retaining a sensitive triethylsilyl protecting group and avoiding relactonization. Furthermore, the influence of polysubstituted lactones on the stereoselectivity of the subsequent aldol reaction is shown. Vicinal hydroxy groups around the chiral quaternary center were protected in a sequence that allows orthogonal deprotection if a lateral chain should be incorporated in a more complicated structure. This work was crucial for our total synthesis of (+)-disorazole Z1 and could also be helpful for syntheses of other chiral acyclic α-quaternary-β,β'-hydroxy esters.