Abstract: The present invention provides methods by which trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine and related cyclopropane compounds are prepared using synthetic strategies that include a biocatalytic cyclopropanation step.

Abstract: The present invention pertains to the use of engineered variants of enzyme CYP102A, also known as P450-BM3, for cyclopropanation of olefins containing electron-withdrawing groups. One exemplary enzyme variant, referred to as BM3-HStar, contains five mutations away from wild-type P450-BM3, and demonstrates high activity towards cyclopropanation of olefinic substrates using ethyldiazoacetate (EDA) and other carbene transfer reagents. Products of these reactions are potential precursors of levomilnacipran derivatives, a class of compounds that have been shown to be selective inhibitors of monoamine transporters. In addition, cyclopropanation reactions with the P450-BM3 enzyme variants of the invention can be conducted in whole cells expressing the enzyme variants and can proceed under aerobic conditions.

Abstract: The present invention relates to a compound according to formula I wherein R1 is selected from the group consisting of hydrogen and fluoro and R2 is selected from C1-C4 alkyl and hydrates or solvates thereof. The invention further relates to intermediates for the preparation of said compounds, to said compounds for use in therapy, to pharmaceutical compositions comprising said compounds, to methods of treating diseases with said compounds, and to the use of said compounds in the manufacture of medicaments.