Total synthesis of (R)-(+)-salsolidine by hydride addition to (R)-N-tert-butanesulfinyl ketimine

(R)-(+)-Salsolidine 1 of high enantiomeric purity was synthesized using the Pomeranz–Fritsch–Bobbitt methodology, in which the reduction (NaBH4, DIBAL-H) of N-tert-butanesulfinyl ketimine, derived from 3,4-dimethoxyacetophenone, was the key step. The synthesis was completed in a sequence of reactions involving the removal of the chiral auxiliary, N-alkylation with 2,2-diethoxyethyl bromide and final cyclization/hydrogenolysis.

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(R)-(+)-N-[1-(3,4-Dimethoxyphenylethylidene)]-2-methylpropanesulfinamideC14H21NO3S[α]D = +22.2 (c 1.12, CHCl3)Source of chirality: N-tert-butanesulfinylamideAbsolute configuration: (R)

(R,R)-(−)-N-[1-(3,4-Dimethoxyphenylethyl)]-2-methylpropanesulfinamideC14H23NO3SDe 96% [by chiral HPLC][α]D = −36.3 (c 0.32, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R,R)

(R)-(+)-1-(3,4-Dimethoxyphenyl)ethylamine hydrochlorideC10H15NO2·HCl[α]D = +5.8 (c 0.86, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

(R)-(+)-N-(2,2-Diethoxyethyl)-1-(3,4-dimethoxyphenyl)ethylamineC16H27NO4[α]D = +28.0 (c 0.66, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)