Synthesis of racemic and enantiopure 3,4-methanonipecotic acid

The synthesis of both racemic and enantiomerically pure (1R,6S)-3,4-methanonipecotic acid, a cyclopropane-containing β-amino acid, which is a valuable building block for drug discovery, is described. The synthetic scheme commences from natural (S)-malic acid and allows for the preparation of the title compound in 12 steps in 28% overall yield. A novel approach to the racemic 3,4-methanonipecotic acid, which relies on a Simmons–Smith cyclopropanation as the key step, was also developed. In this case, the product was obtained in 8 steps and 38% total yield.

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(1S,6R)-3-(tert-Butoxycarbonyl)-3-azabicyclo[4.1.0]heptane-1-carboxylic acidC12H21NO4Ee = 91.5%[α]D22 = −57.2 (c 1.0, CHCl3)Source of chirality: (S)-malic acidAbsolute configuration: (1S,6R)

(1S,6R)-3-Azabicyclo[4.1.0]heptane-1-carboxylic acid hydrochlorideC7H13ClNO2Ee = 91.5%[α]D22 = −38.8 (c 1.0, H2O)Source of chirality: (S)-malic acidAbsolute configuration: (1S,6R)

(1S,6R)-Methyl 2-oxo-3-azabicyclo[4.1.0]heptane-1-carboxylateC8H11NO3Ee = 91.5%[α]D22 = −35.8 (c 1.0, CHCl3)Source of chirality: (S)-malic acidAbsolute configuration: (1S,6R)