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Diastereodivergent Synthesis of 4‐Hydroxy‐2,3‐methanopipecolic Acid Derivatives as Conformationally Constrained Homoserine Analogues
Author(s) -
Occhiato Ernesto G.,
Casini Andrea,
Guarna Antonio,
Scarpi Dina
Publication year - 2011
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201100962
Subject(s) - cyclopropanation , chemistry , carbenoid , enantioselective synthesis , kinetic resolution , yield (engineering) , stereoselectivity , stereochemistry , selectivity , biocatalysis , catalysis , organic chemistry , reaction mechanism , rhodium , materials science , metallurgy
Abstract A short, practical 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 OH‐directed cyclopropanation, Charette's Zn‐carbenoid provided cis ‐4‐hydroxy‐2,3‐methanopipecolic acids in the highest yield (73–86 %) and facial selectivity (> 99:1). The 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.