Catalytic Enantioselective [2,3]-Rearrangements of Allylic Ammonium Ylides: A Mechanistic and Computational Study.

Thomas H. West,Alexander C. Brueckner,Guy C. Lloyd-Jones,James E. Taylor,Ryne C. Johnston,Paul Ha-Yeon Cheong,Andrew D. Smith,Daniel M. Walden

doi:10.1021/jacs.6b11851

Abstract

A mechanistic study of the isothiourea-catalyzed enantioselective [2,3]-rearrangement of allylic ammonium ylides is described. Reaction kinetic analyses using 19F NMR and density functional theory computations have elucidated a reaction profile and allowed identification of the catalyst resting state and turnover-rate limiting step. A catalytically relevant catalyst–substrate adduct has been observed, and its constitution elucidated unambiguously by 13C and 15N isotopic labeling. Isotopic entrainment has shown the observed catalyst–substrate adduct to be a genuine intermediate on the productive cycle toward catalysis. The influence of HOBt as an additive upon the reaction, catalyst resting state, and turnover-rate limiting step has been examined. Crossover experiments have probed the reversibility of each of the proposed steps of the catalytic cycle. Computations were also used to elucidate the origins of stereocontrol, with a 1,5-S···O interaction and the catalyst stereodirecting group providing transition structure rigidification and enantioselectivity, while preference for cation−π interactions over C–H···π is responsible for diastereoselectivity.

Highlights

The [2,3]-rearrangement of allylic ammonium ylides is a direct and elegant method toward the synthesis of α-amino acid derivatives containing multiple stereocenters.1 The mechanism of this process, and that of the competitive [1,2]-Stevens rearrangement, has been much discussed and disputed within the literature
Through 13C kinetic isotope effects, crossover experiments, and computation, these studies demonstrate that the origin of competitive [1,2]- and [2,3]rearrangement is the common loose transition state leading to dynamic bond cleavage
Isotopic entrainment has shown 29/IX to be an irreversibly generated intermediate that is productive toward catalysis

Summary

INTRODUCTION

The [2,3]-rearrangement of allylic ammonium ylides is a direct and elegant method toward the synthesis of α-amino acid derivatives containing multiple stereocenters. The mechanism of this process, and that of the competitive [1,2]-Stevens rearrangement, has been much discussed and disputed within the literature. Through 13C kinetic isotope effects, crossover experiments, and computation, these studies demonstrate that the origin of competitive [1,2]- and [2,3]rearrangement is the common loose transition state leading to dynamic bond cleavage.. Through 13C kinetic isotope effects, crossover experiments, and computation, these studies demonstrate that the origin of competitive [1,2]- and [2,3]rearrangement is the common loose transition state leading to dynamic bond cleavage.4 The development of both catalytic and stereoselective variants of the [2,3]-rearrangement of allylic ammonium ylides has been a significant synthetic challenge. Computational reaction coordinate modeling provides deeper insight into the catalytic cycle, and transition state modeling reveals the origins of stereochemical control

RESULTS AND DISCUSSION

Atom Connectivity

CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES