Pyrrolidines and piperidines bearing chiral tertiary alcohols by nickel-catalyzed enantioselective reductive cyclization of N-alkynones

Guodu Liu,Wenjun Tang,Xiaodong Xu,Ting Wu,Kaidi Li,Ming Nie,Xingye Mu,Wenzhen Fu

doi:10.1038/s42004-018-0092-1

Abstract

Pyrrolidines and piperidines are important building blocks in organic synthesis. Numerous methods exist for constructing substituted pyrrolidines and piperidines. However, efficient syntheses of pyrrolidines and piperidines bearing chiral tertiary alcohols are limited. Here we report an efficient enantioselective nickel-catalyzed intramolecular reductive cyclization of N-alkynones. A P-chiral bisphosphorus ligand DI-BIDIME is designed and applied in the synthesis of tertiary allylic siloxanes bearing pyrrolidine and piperidine rings in high yields and excellent enantioselectivities, with triethylsilane as reducing reagent. The highest turn over number achieved is 1000 (0.1 mol% catalyst loading) with > 99:1 er. This reaction provides a practical way to synthesize pyrrolidine and piperidine derivatives with chiral tertiary alcohols from easily accessible starting materials under mild conditions. The products can be scaled up and transformed to various useful chiral intermediates. The P-chiral bisphosphorus ligand developed in this study represents one of the few ligands for highly enantioselective cyclization of alkynones.

Highlights

Pyrrolidines and piperidines are important building blocks in organic synthesis
Based on our previous experience on ligand design, we proposed this objective could be achieved by the development of our privileged ligand BIDIME31–34
Our design in DI-BIDIME are in two strategies: (1) DIBIDIME is free of H7, avoiding the potential C–H functionalization at H7 position[35,36,37] and making the adjacent C–O bond more hindered and resistant to cleave in the presence of a nickel metal[38,39]; (2) both phosphorus atoms in DIBIDIME should function independently with a reduced ligand entropy by half

Summary

Introduction

Pyrrolidines and piperidines are important building blocks in organic synthesis. Numerous methods exist for constructing substituted pyrrolidines and piperidines. Efficient syntheses of pyrrolidines and piperidines bearing chiral tertiary alcohols are limited. A P-chiral bisphosphorus ligand DI-BIDIME is designed and applied in the synthesis of tertiary allylic siloxanes bearing pyrrolidine and piperidine rings in high yields and excellent enantioselectivities, with triethylsilane as reducing reagent. The highest turn over number achieved is 1000 (0.1 mol% catalyst loading) with > 99:1 er This reaction provides a practical way to synthesize pyrrolidine and piperidine derivatives with chiral tertiary alcohols from accessible starting materials under mild conditions. Transition metal-catalyzed coupling of alkynals/alkynones has become a powerful method for efficient construction of allylic alcohol derivatives in current organic chemistry[1,2,3]. We report an efficient regiospecific and enantioselective nickel-catalyzed intramolecular reductive cyclization of N-alkynones with up to 1000 TON (0.1 mol% catalyst loading) and > 99:1 er under mild conditions

Methods

Results

Conclusion