Synthesis of Enantiopure 5-Substituted 2,3-Methanopyrrolidines by Cyclization of Enantiopure α-Branched α-N-Homoallylamino Nitriles

Abstract

The preparation of 5-substituted 2,3-methanopyrrolidines by the stereoselective cyclization of zincated α-amino nitriles derived from enantiopure α-branched homoallylamines has been investigated. The formation of trans adducts in excellent diastereoselectivities (up to >98:2) and good yields (up to 71%) is observed. The absolute configuration and enantiomeric excess are dependent on the nitrogen protecting group.2,3-Methanopyrrolidines {2-azabicyclo[3.1.0]hexane derivatives} are interesting molecules that have attracted interest both for their use as scaffolds in biologically active peptide mimics 1,2 and as synthetic intermediates for nitrogen-containing compounds. 3 In contrast with the preparation of 2,3-methanopyrrolidines in racemic form, 1a,3,4 general synthetic methods for the preparation of enantiopure 2,3-methanopyrrolidines are not common. 1b-e,5-7 Scheme 1In this context, we recently reported the diastereoselective formation of 2,3-methanopyrrolidines from α-N-(1-phenylethyl)-N-homoallylamino nitriles by treatment with LDA and transmetalation with a zinc salt (Scheme 1). 7 In the case of α-branched substrates 1, the stereochemical outcome of the cyclization was governed by the homoallylic stereocenter, and a stereospecific inversion was observed. Unfortunately, difficulties associated both with the control of the stereoselectivity in preparation of substrates 1 and with the removal of the 1-phenyl-ethyl chiral auxiliary made it difficult to use this reaction for a general approach to 2,3-methanopyrrolidines. We reasoned that these drawbacks might be avoided starting from α-N-(benzyl)-N-homoallylamino nitriles 2 derived from readily available enantiopure α-branched homoallylic amines. 8 First, according to our results with adducts 1, cyclization of 2 should provide stereospecifically enantiopure 5-substituted N-benzyl-2,3-methanopyrrolidines. Second, according to a recent report, 9 removal of the benzyl nitrogen protecting group without altering the 2-azabicyclo[3.1.0]hexane framework should be straightforward.We chose to prepare the required substrates by the route depicted in Scheme 2. Diastereomerically pure sulfinamides 3a-d were isolated in good yields (57-92%) from the reaction of the parent enantiopure tertbutanesulfinylimines 10 and allylmagnesium bromide in CH 2 Cl 2 . 11 Acidic removal of the sulfinyl auxiliary followed by reductive amination of benzaldehyde provided efficiently secondary N-benzyl α-branched homoallylic amines 4a-c. In the case of 3d, removal of the auxiliary with HCl also led to desilylation of the protected alcohol. An additional silylation step to reinstall the tert-butyldimethylsilyl group prior to the reductive amination sequence was thus required. Compound 4d was nevertheless obtained from 3d in 50% yield. Finally, α-N-(benzyl)-Nhomoallylamino nitriles 2a-d were obtained in 54-95% yield by alkylation of 4a-d with bromoacetonitrile in DMF in the presence of K 2 CO 3 .Scheme 2 Reagents and conditions: (a) allylmagnesium bromide, CH 2 Cl 2 , -78°C to r.t., 57% (3a), 86% (3b...