Recent Advances in the Stevens Rearrangement of Ammonium Ylides. Application to the Synthesis of Alkaloid Natural Products

Abstract

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Lewis acid–catalyzed domino generation/[2,3]-sigmatropic rearrangement of ammonium ylides to access chiral azabicycles

“…[2,3]-Sigmatropic rearrangement of ammonium ylides is one of the most efficient approaches for synthesizing complex nitrogenous compounds (1)(2)(3). During this rearrangement, a new stereogenic carbon center can be stereoselectively created by chiral induction of the neighboring chiral ammonium nitrogen atom through a concerted five-membered ring transition state (4)(5)(6).…”

“…The most common method to generate ammonium ylides for rearrangement involves two separate steps: quaternization of a tertiary amine and deprotonation of the resulting quaternary ammonium salt with a strong base (Fig. 1A) (1)(2)(3). However, the harsh reaction conditions usually required for generation and deprotonation of the quaternary ammonium salts and the problems associated with purification of these salts limit the applicability of this type of reaction (7).…”

“…1B). Upon proton transfer, ammonium ylide 3 would be generated from the bicyclic intermediate 2 for subsequent [2,3]-sigmatropic rearrangement. If this multistep process could be accomplished without a strong acid or base, chirality erosion of the potentially racemization-prone precursors or intermediates could be circumvented, and consequently, the chirality information of 1 would be efficiently transferred to product 4 with an N-fused bicyclic skeleton and a bridgehead quaternary center (Fig.…”

“…Therefore, we speculated that an appropriate -Lewis acid would facilitate nucleophilic addition of a tertiary amine to the ynone moiety to form the quaternary ammonium salt without scrambling the chiral center. Second, deprotonation of the quaternary ammonium salts to generate the ammonium ylides often requires a strong base, which can also erode the chirality (1)(2)(3). Regarding this issue, several reactive intermediates have been proposed.…”

“…This indicates that protonation of the carbon-metal bond in C or D would further enhance the acidity of C2─H. Last, owing to the congested nature of the formed bridgehead quaternary stereogenic carbon center, [1,2]-sigmatropic rearrangement of the ammonium ylide (Stevens rearrangement)-which presumably proceeds by a diradical pathway and could result in racemization-may compete with [2,3]-sigmatropic rearrangement (1)(2)(3).…”