Asymmetric Synthesis of Benzylic Quaternary Carbon Center via an Enzymatic Reaction

Abstract

R)-(+)-((R)-(+)-12) and(.!?)-(-)-1-formyl-1-methyl-7-methoxy-1,2,3,4tetrahydronaphthalene((S)-(-)-12) were synthesized based on enantioselective PLE hydrolysis of diethyl2-(m-methoxypheny1)-2-methylmdonate.From (R)-(+) -1 2, (+)-OMethylaphanorphine (1 6) and (-)-aphanorphine were synthesized.(S)-(+)-1-(N-Acetyl-N-methylaminoethyl)-1-methyl-7methoxytetralin (25) was synthesized from (S)-(-)-12.This !ransformation constitutes a formal synthesis of (-)-eptazocine.Compounds having a benzylic quaternary carbon center such as eprazocine,2a pentawcine2b and aphanorphine2c exhibit potent pharmacological activities, and the constsuction of such centers in a enantioselective manner has been reported from several groups.Elegant asymmetric syntheses of chiral l-hydroxymethyl-l-methyl-7-methoxy-1,2-dihydronaphthdene, a key intermediate for the synthesis of eprazocine and aphanorphine, have been reported by four groups.Takano et d.applied a stereoselective Grignard addition of m-methoxyphenylmagnesium bromide in the presence of wpper(1) bromide to a dienone obtained from cyclopentadiene dimer to give optically active 4-(m-methoxyphenyl)4methylcyclopentenone.3bShibasaki et ol.reported synthesis of the 1, I-disubstituted 1,2-dihydro-and 1,2,3,4 tetrahydronaphthalenes using asymmetric Heck reaction.4Node has synthesized the asymmetric I-methyl-7-methoxytetralin-1-carboxylic acid by the methylation of (R)-binaphthyl ester of 7-methoxytetralin-1-carboxylic acid.5 Meyers has recently reported another route to the chiral 1,l-disubstituted 1,2-dihydro-and 1,2,3,4-tetrahydronaphthalenes, which involve an asymmetric addition to naphthalene derivatives having a chirat oxamline-substituent at the a-position with lithiosilanes and iod~methane.~k a z a n o et ol.synthesized (+)-normetmine by a stereocontrolled alkylation of cbiral pyridinium salts with Grignard reagents and the subsequent Grewe cyclization.7Recently, we have reported the synthesis of (+)-and (-)-eptazocine based on the enantioselective monoacetylation of 2-@-methoxybenzy1)prope-1.3diol with lipase P S .~ Methyl and ?err-butyl esters of c h i d 2-methyl-2-phenyl-3-oxobutanoic acid had been synthesized by an asymmetric Claisen type a~~lation.9Meanwhile, c h i d 2-aryl-2-dkylmalonic monoesters or monoacylated 2-aryl-2-alkylpropane-1.3-diols would be versatile building blocks for the synthesis of biologically active compounds having a benzylic