A Chemoenzymatic Approach to Enantiomerically Pure Amines UsingDynamic Kinetic Resolution: Application to the Synthesis of Norsertraline

摘要

Racemization catalyst 5c and the enzyme Candida antarctica lipase Bwere combined in a one-pot dynamickinetic resolution(DKR)of primary amines in which a wide range of amines were transformed to their correspondingamides in up to 95% isolatedyield and>99% ee.The DKR protocolwas applicable with either isopropylacetate or dibenzyl carbonateas the acyl donor.In the latter case,release of the free amine from the carbamateproducts was carried out undervery mild conditions. The racemizationof(S)-1-phenylethylamine with severaldifferent Ru catalysts was also evaluated.Catalyst 5c,of the Shvo type, was able to selectively racemize amines and was also compatible with the reactionconditions used for DKR.A racemizationstudy of three different amineswith varying electronic properties wasalso performed. Competitive racemizationof a 1:1 mixture of the deuterated and non-deuterated amine was carriedout with 5c and a primary kinetic isotopeeffect was observed for all threeamines,providing supportthat the rate-determining step is b-hydrideelimination.The chemoenzymatic DKR protocol was applied to the synthesis of norsertraline(16)by using anovel route starting from readily available1,2,3,4-tetrahydro-1-naphthylamine(1o).