Pyrinap ligands for enantioselective syntheses of amines

Qi Liu,Yuan Yao,Xue Zhang,Shengming Ma,Yinlong Guo,Yuling Li,Haibo Xu

doi:10.1038/s41467-020-20205-0

Abstract

Amines are a class of compounds of essential importance in organic synthesis, pharmaceuticals and agrochemicals. Due to the importance of chirality in many practical applications of amines, enantioselective syntheses of amines are of high current interest. Here, we wish to report the development of (R,Ra)-N-Nap-Pyrinap and (R,Sa)-N-Nap-Pyrinap ligands working with CuBr to catalyze the enantioselective A3-coupling of terminal alkynes, aldehydes, and amines affording optically active propargylic amines, which are platform molecules for the effective derivatization to different chiral amines. With a catalyst loading as low as 0.1 mol% even in gram scale reactions, this protocol is applied to the late stage modification of some drug molecules with highly sensitive functionalities and the asymmetric synthesis of the tubulin polymerization inhibitor (S)-(-)-N-acetylcolchinol in four steps. Mechanistic studies reveal that, unlike reported catalysts, a monomeric copper(I) complex bearing a single chiral ligand is involved in the enantioselectivity-determining step.

Highlights

Amines are a class of compounds of essential importance in organic synthesis, pharmaceuticals and agrochemicals
In this work, inspired by such backbone effect on catalytic activity and previous studies on axially chiral P,N ligands[24,40], we report the development of the ligands phenyl-naphthyl-type ligand N-Ph-Pyrinap L1, N-Nap-Pyrinap L2, and the diphenyltype ligand L3 to address the challenges with respect to the scope of the combination of alkynes, aldehydes, and amines (Fig. 1d)
ADetermined by 1H nuclear magnetic resonance (NMR) analysis with CH2Br2 as the internal standard. bDetermined by chiral HPLC analysis of the isolated product. cThe reaction was carried out at 0 °C. d1.2 equivalents of 2a and 3a were used. eThe reaction was conducted on 0.5 mmol scale. fIsolated yield. gData taken from ref. 32. hData produced in this laboratory using (S,S,Ra)-UCD-PHIM prepared in this laboratory

Summary

Introduction

Amines are a class of compounds of essential importance in organic synthesis, pharmaceuticals and agrochemicals. In this work, inspired by such backbone effect on catalytic activity and previous studies on axially chiral P,N ligands[24,40], we report the development of the ligands phenyl-naphthyl-type ligand N-Ph-Pyrinap L1, N-Nap-Pyrinap L2, and the diphenyltype ligand L3 to address the challenges with respect to the scope of the combination of alkynes, aldehydes, and amines (Fig. 1d)

Results

Conclusion