Asymmetric allylic alkynylation catalyzed by guanidine copper(I) complex

Abstract

The main project during my Ph.D. period was devoted to developing the asymmetric allylic alkynylation of racemic chiral substrates in the presence of Cu(I) and chiral guanidinium catalysts. Previously developed guanidine-derived chiral organocatalysts in Prof Tan Choon Hong’s lab were applied into asymmetric transition-metal catalyzed coupling reaction for the first time, showing great efficiency in the stereoconvergent transformation of racemic cyclic allylic bromides. My Ph.D. thesis is divided into three chapters here to better narrate the exploration of asymmetric allylic alkynylation of racemic chiral substrates catalyzed by (guanidine)copper(I) complex. Chapter 1 introduces the unique properties of guanidine-type molecules, including its neutral form (guanidine), cationic form (guanidinium) and anionic form (guanidinate). Through reviewing their coordination chemistry and catalytic applications in metal-catalyzed reactions, the potentiality of our cyclic guanidines as a ligand or guanidinium as a cation directing metallate is highlighted. Inspired by a Cu-catalyzed asymmetric allylic alkynylation under phase-transfer condition reported by Alper, two chirality induction modes are proposed for an unprecedented Cu-catalyzed stereoconvergent transformation. Chapter 2 demonstrates the current development and challenges of Cu-catalyzed AAAs as well as the detailed condition optimization and scope of asymmetric allylic alkynylation of racemic chiral substrates with copper(I)/guanidinium system. Various reaction conditions, including solvents, catalysts, bases, metal sources and leaving groups were evaluated with orthogonal experiments. An array of unsubstituted or substituted cyclic allylic bromides were transformed to corresponding 1,4-enynes in good yields and high enantioselectivity. Further enantio-retentive transformations of enantioenriched1,4-enynes were also discussed. Chapter 3 describes the efforts to figure out the most reasonable mechanism of this reaction. Firstly, the mechanistic principles of Cu-catalyzed AAAs and different types of mechanism-dependent stereoconvergent transformations were discussed. Analytical strategies including X-ray, CSI-MS, and NMR were used to identify the catalytic resting species thus the chirality induction mode could be preliminarily determined. Further experimental and computational studies of this reaction supported that this reaction belongs to a Type II Dynamic Kinetic Asymmetric Transformation.