Mechanistic insights for the transprotection of tertiary amines with Boc2O via charged carbamates: access to both enantiomers of 2-azanorbornane-3-exo-carboxylic acids

Abstract

Herein we present a new synthesis methodology for the transprotection of the 1-phenylethyl protected tertiary amines to tert-butyloxycarbonyl (Boc) derivatives under exocyclic N–C hydrogenolysis catalyzed by Pd/C. We provide mechanistic insights into the N-dealkylation of hindered tertiary amines under the unrecognized role of tert-butyloxycarbonyl anhydride (Boc₂O) as an additive to effectively promote the exocyclic N–C hydrogenolysis of tertiary amines by disclosing the role of Boc₂O, which was not fully understood and studied until now. NMR and in silico experiments suggest the formation of a transient charged carbamate as the plausible intermediate. This selective transprotection enabled the development of a robust stereoselective methodology for the preparation of both enantiomers of 2-azanorbornane-3-exo-carboxylates by highly asymmetric aza-Diels–Alder reactions using (−)-8-phenylmenthol (8PM) and (+)-8-phenylneomenthol (8PnM) as chiral auxiliaries.