Cyclization of Zincated α‐N‐Homoallylamino Nitriles: A New Entry to Enantiopure 2,3‐Methanopyrrolidines

Abstract

Stereoselective cyclization of zincated α-N-homoallylamino nitriles has been developed. Following treatment with lithium diisopropylamide (LDA) and transmetalation with zinc bromide, α-N-(1-phenylethyl)-N-homoallylamino nitriles lead to 2,3-methanopyrrolidines in moderate to good yields (up to 66 %) and excellent selectivities (up to >98:2). With substrates derived from α-branched homoallylic amines, a stereospecific inversion of the homoallylic stereogenic center was observed. To account for this, a mechanistic rationale involving the formation of zincioiminium ions from zincated α-amino nitriles is put forward. 2,3-Methanopyrrolidines should then arise from a sequence involving an aza-Cope rearrangement providing a configurationally stable (2-azoniaallyl)zinc species that then undergoes a [3+2] cycloaddition reaction.

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

“…We initiated our cyclization studies with prototypical ethyl-substituted amino nitrile 2a (Scheme 3, Table 1). As observed in our previous works, 7 full metalation of 2a in . As anticipated, addition of ZnBr 2 (4 equiv) following lithiation led to the formation of methanopyrrolidine 5a in 40% yield but as a trans/cis mixture (88:12) of diastereomers.…”

“…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.…”

“…The 1R,3R,5R configuration of the major enantiomer was assigned by comparison of the HPLC retention times with enantiopure (1R,3R,5R)-6a. 7 Hence, cyclization of 2a occurred with partial loss of the stereochemical integrity of the homoallylic stereocenter. The reaction of other substrates was next considered (Scheme 5, Table 2).…”

“…The 1R,3S,5R configuration was assigned by transformation into 7 (Scheme 4), the configuration of which was determined by comparison of the HPLC retention times with enantiopure (2S,4R)-7 14 obtained from known 8. 7 The 5-phenyl-substituted methanopyrrolidine 5c was obtained from 4c in low 23% yield and only 88:12 dr. Complete diastereoselectivity but low yield (34%) was obtained in the cyclization of 4d having a silyloxymethyl substituent.…”

“…In this context, we recently reported the diastereoselective formation of 2,3-methanopyrrolidines from α-N-(1phenylethyl)-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.…”