Synthesis of (S)-(−)- and (R)-(+)-O-methylbharatamine using a diastereoselective Pomeranz–Fritsch–Bobbitt methodology

Laterally lithiated (S)-(−)- and (R)-(+)-o-toluamides 6 with a chiral auxiliary derived from (S)- and (R)-phenylalaninol, respectively, were used as the building blocks and chirality inductors in the asymmetric modification of the Pomeranz–Fritsch–Bobbitt synthesis of isoquinoline alkaloids. Their addition to imine 2 proceeded with partial cyclization, giving isoquinolones (+)-7 and (−)-7 along with acyclic products, (−)-8 and (+)-8, respectively. LAH-reduction of (+)-7 and (−)-7, followed by cyclization, afforded both enantiomers of the alkaloid, (S)-(−)- and (R)-(+)-O-methylbharatamine 5, in 32% and 40% overall yield and with 88% and 73% ees, respectively.

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(3S)-N-(2,2-Dimethoxyethyl)-3-(3,4-dimethoxyphenyl)-3,4-dihydro-1-(2H)-isoquinoloneC21H25NO5[α]D = +36.3 (c 0.465, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S)

(S)-N-(2,2-Dimethoxyethyl)-3-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinolineC21H27NO4[α]D = −43.6 (c 0.49, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)