The Catalytic Enantioselective Sommelet–Hauser Rearrangement

Abstract

The Sommelet–Hauser rearrangement of ammonium ylides incorporates a dearomatizing [2,3]-sigmatropic rearrangement of a (hetero)aromatic substituent, followed by tautomerization (rearomatization), to generate (hetero)benzylic amine derivatives. Despite widespread interest in this process, asymmetric variants have previously relied upon stoichiometric chiral auxiliary or chirality transfer strategies to induce stereocontrol. In this manuscript, the organocatalytic enantioselective Sommelet–Hauser rearrangement of ammonium ylides bearing heteroaromatic substituents is demonstrated using a Lewis basic isothiourea catalyst, providing a series of unnatural α-heteroaryl α-amino acid derivatives with high to excellent enantioselectivity (up to 98:2 er). The developed process tolerates cyclic and acyclic ammonium salt precursors with indolyl and benzofuranyl substituents. A range of pronucleophiles was employed that lead to amide, ester, and alcohol products. Computational analysis revealed that a stepwise process (involving initial C–N bond cleavage to generate an ion pair, followed by a barrierless C–C bond formation) is favored over a concerted [2,3]-rearrangement, with distortion-interaction analysis providing insight into the factors that govern the mechanism. Crossover experiments, including the use of isotopologue salt derivatives to minimize chemical differentiation of substrates, showed no scrambling. The totality of accumulated computational and experimental evidence suggests a stepwise rearrangement involving a near-instantaneous second recombination step such that the overall process is indistinguishable from, and effectively, a concerted asynchronous rearrangement.