Synthesis of (+)- and (-)-milnaciprans and their conformationally restricted analogs

Article abstract of DOI:10.1016/0040-4039(95)02221-X

Reaction of (R)-epichlorohydrin [(R)-5] and phenylacetonitrile (6) in the presence of NaNH₂ in benzene gave a cyclopropane derivative which was isolated as lactone 4 [(1S,2R)-2-oxo-1-phenyl-3-oxabicyclo[3,1,0]hexane] of 96% e.e. in 67% yield, after alkaline hydrolysis of the cyano group. Compound 4 was readily converted to (+)-milnacipran [(+)-1], by which the absolute stereochemistry of (+)-1 was confirmed. (1S,2R)-1-phenyl-2-[(S)-1-aminoethyl]-cyclopropane-N,N-diethylcarboxam ides (2), a conformationally restricted analog of 1, was also synthesized in high enantiomeric purity from 4. Starting from (S)-epichlorohydrin [(S)-5], their corresponding enantiomers, namely (-)-milnacipran [(-)-1] and ent-2, were also synthesized.