Diastereodivergent synthesis of 4-hydroxy-2,3-methanopipecolic acid derivatives as conformationally constrained homoserine analogues

A practical and short procedure for the diastereodivergent synthesis of cyclopropanated 4-hydroxypipecolic acid derivatives with high optical purity is reported. Key steps are the highly enantioselective lipase-catalyzed kinetic resolution and the stereoselective cyclopropanation reaction of 4-hydroxypyridine derivatives. Under the best conditions for the OH-directed cyclopropanation, Charette’s Zn-carbenoid provided cis 4-hydroxy-2,3-methanopipecolic acids with the highest yield (73-86%) and facial selectivity (>99:1). Trans selectivities in Michael-type addition of dimethylsulfoxonium methylide were 1:4 to 1:7 in DMSO and diastereopure trans isomers were obtained by chromatography after OH-deprotection in 57-73% yield. These compounds are new, conformationally constrained homoserine analogues potentially useful as conformational probes and for drug discovery in medicinal chemistry.