Efficient and highly enantioselective process for the preparation of enantiomerically pure cylopentane-beta-amino acids

摘要

Preparation of enantiomerically pure cyclopentane beta -amino acid compounds of formula (I) comprises (a) reaction of meso-dicarboxylic acid anhydride of formula (II) with an alkenol of formula (III) in the presence of an equimolar amount of a chiral base and in an inert solvent to give an enantiomerically pure ester of formula (IV); (b) conversion of (IV) into the enantiomerically pure acid (IVa) of formula (IV; E = H); (c) conversion to the azide by (1) Curtius rearrangement by reacting (IVa) with an azide of formula (R6O)2P(O)N3 (V) in the presence of a base and in an inert solvent, or (2) activation of carboxyl group of (IVa) and reaction with an alkali azide or trialkylsilylazide; (d) reaction to the isocyanate of formula (VI); (e) reaction with (III) to give the diester of formula (VII); and (f) cleavage of the urethane and ester functions in an inert solvent in the presence of a Pd catalyst and/or a phosphine and a nucleophilic reagent. A, D = H, halo, OH or 1-8C alkyl (optionally mono- or di-substituted by halo, OH, Ph, benzyloxy, COOH, 1-6C alkoxy, 1-6C acyl, 1-6C alkoxycarbonyl or NR7R8); or A and D together form =CR1R2; E = chiral amine base; R1, R2 = H, halo, 1-8C alkyl, 1-8C alkoxy, 1-8C hydroxyacyl, benzyl or Ph; R4, R5 = H, 1-5C alkyl or Ph, (optionally mono- to tri- substituted by halo, CN, OCF3, NO2, CF3, 1-6C alkyl or 1-6C alkoxy); R3 = as for R4, or 5-7 membered heteroaromatic with 3 heteroatoms from S, N and/or O; R6 = Ph or 1-6C alkyl; R7, R8 = H, Ph or 1-6C alkyl. The enantiomer-pure compounds (IV), (IVa) and (VII) are new.