Asymmetric synthesis of (1R,2S,3R)-3-methylcispentacin and (1S,2S,3R)-3-methyltranspentacin by kinetic resolution of tert-butyl(±)-3-methylcyclopentene-1-carboxylate

摘要

Conjugate addition of lithium dibenzylamide to tert-butyl(±)-3-methylcyclopentent-1-carboxylate occurs with high levels of stereo control, with preferential addition of lithium dibenzylamide to the face of the cyclic α,β-unsaturated acceptor anti-to the 3-methyl substituent. High levels of enantiorecognition are observed between tert-butly (±)-3-methylcyclopentene-1-carboxylate and an excess of lithium (±)-N-benzyl-N-α-methylbenzylamide (10eq.)(E>140) in their mutal kinetic rresolution, while the kinetic resolution, while the kinetic resolution of tert-butyl (±)-3-methylcyclopentene-1-carboxylate with lithium (S)-N-benzyl-Z-α-methylbenzylamide procees to give, at 51% conversion, tert-butyl (1R, 2S,3R,αS)-3-methyl-2-N-benzyl-N-α-methylbenzylaminocycolpentane-1-carboxylate consistent with E>130, and in 39% yield and 99±0.5% de after purification. Subsequent deprotection by hydrogenolysis and ester hydrolysis gives (1R,2S,3R)-3-methylcispentacin in >98% de and 98±1%ee. Selective epimerisation of tert-butyl (1R,2S,3R,αS)-3-methyl-2-N-α-methylbenzylaminocycolpentane-1-carboxylate by treatment with KO'Bu in BuOH gives tert-butyl(1R,2S,3R,αS)-3-methyl-2-N-benzyl-N-α-methylbenzylaminocyclopenane-1-carboxylate in quantitative yield and in >98% de, with subsequent deprotecion by hydrogenolysis and ester hydrolysis giving (21S,2S,3R)-3-methyltranspentacin hydrochloride in >98% de and 97±1%ee.