Cation-Controlled Enantioselective and Diastereoselective Synthesis of Indolines: An Autoinductive Phase-Transfer Initiated 5-endo-trig Process.

Krishna Sharma,David Yeo,Francisca Grande-Carmona,Jamie R Wolstenhulme,Dean J Tantillo,Phillip P Painter,Craig P Johnston,Martin D Smith

doi:10.1021/jacs.5b08834

Abstract

A catalytic enantioselective approach to the synthesis of indolines bearing two asymmetric centers, one of which is all-carbon and quaternary, is described. This reaction proceeds with high levels of diastereoselectivity (>20:1) and high levels of enantioselectivity (up to 99.5:0.5 er) in the presence of CsOH·H2O and a quinine-derived ammonium salt. The reaction most likely proceeds via a delocalized 2-aza-pentadienyl anion that cyclizes either by a suprafacial electrocyclic mechanism, or through a kinetically controlled 5-endo-trig Mannich process. Density functional theory calculations are used to probe these two mechanistic pathways and lead to the conclusion that a nonpericyclic mechanism is most probable. The base-catalyzed interconversion of diastereoisomeric indolines in the presence of certain quaternary ammonium catalysts is observed; this may be rationalized as a cycloreversion-cyclization process. Mechanistic investigations have demonstrated that the reaction is initiated via a Mąkosza-like interfacial process, and kinetic analysis has shown that the reaction possesses a significant induction period consistent with autoinduction. A zwitterionic quinine-derived entity generated by deprotonation of an ammonium salt with the anionic reaction product is identified as a key catalytic species and the role that protonation plays in the enantioselective process outlined. We also propose that the reaction subsequently occurs entirely within the organic phase. Consequently, the reaction may be better described as a phase-transfer-initiated rather than a phase-transfer-catalyzed process; this observation may have implications for mechanistic pathways followed by other phase-transfer-mediated reactions.

Highlights

Asymmetric phase-transfer catalysis is a powerful technique that enables a wide range of transformations under mild conditions, often using inexpensive and environmentally benign reagents.[1]
We have focused on extending the application of phase-transfer catalysis to new reaction manifolds and cascade processes.[3]
We describe an extension of this approach to generate indolines bearing two asymmetric centers, one of which is quaternary and all-carbon and, through density functional theory (DFT) calculations, probe whether or not the reaction is pericyclic (Figure 1)

Summary

■ INTRODUCTION

Asymmetric phase-transfer catalysis is a powerful technique that enables a wide range of transformations under mild conditions, often using inexpensive and environmentally benign reagents.[1] Since its invention, a wide range of asymmetric carbon−carbon bond forming reactions have been disclosed.[2] We have focused on extending the application of phase-transfer catalysis to new reaction manifolds and cascade processes.[3] With this in mind, we conceived an approach to the asymmetric catalysis of electrocyclic reactions based upon using a chiral counterion to achieve π-face selectivity in anionic cyclization manifolds.[4] This ideal led to the development of a method to generate indolines with a single asymmetric center[5] and posed a series of questions: notably, whether the reaction was likely to be pericyclic, and whether the transformation was a general process that would permit the synthesis of stereochemically more complex materials.[6,7] we describe an extension of this approach to generate indolines bearing two asymmetric centers, one of which is quaternary and all-carbon and, through density functional theory (DFT) calculations, probe whether or not the reaction is pericyclic (Figure 1)

■ RESULTS AND DISCUSSION

■ CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES