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Cyclization of Zincated α‐ N ‐Homoallylamino Nitriles: A New Entry to Enantiopure 2,3‐Methanopyrrolidines
Author(s) -
Ouizem Sabrina,
Cheramy Sandrine,
Botuha Candice,
Chemla Fabrice,
Ferreira Franck,
PérezLuna Alejandro
Publication year - 2010
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201001639
Subject(s) - enantiopure drug , stereocenter , lithium diisopropylamide , chemistry , stereoselectivity , transmetalation , stereospecificity , zinc , cycloaddition , stereochemistry , medicinal chemistry , combinatorial chemistry , ion , organic chemistry , enantioselective synthesis , deprotonation , catalysis
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.