Optically Active Functionalized Building Blocks for Peptidyl Olefin Peptidomimetics

Peptidyl olefins can function as bio-active peptide isosteres or as intermediates in the synthesis of other peptidomimetics. We previously developed a stereoselective chemo-enzymatic approach to optically active C-terminal building blocks for the synthesis of peptidyl olefins. These building units include a sulfone functionality, to enable a Julia-Kocienski reaction with N-terminal aldehydes. Here, we extend this synthetic methodology to building blocks that are functionalized at their side chains with oxygen, nitrogen or halogen. The method features key enzymatic hydrolysis of prochiral diesters to the corresponding hydroxy esters, a step that introduces the optical activity. The ordering of the subsequent chemical reactions, either protection-methanolysis-functionalization or functionalization-methanolysis-protection, determines the absolute stereochemistry of the final building blocks.