Organocatalytic synthesis of chiral tetrasubstituted allenes from racemic propargylic alcohols

Deyun Qian,Zhenyang Lin,Jianwei Sun,Linlin Wu

doi:10.1038/s41467-017-00251-x

Abstract

Although chiral allene preparation via formal SN2’ nucleophilic substitutions of enantioenriched propargylic derivatives or metal-catalyzed reactions of racemic propargylic derivatives has attracted considerable attention and found applications in many areas of research, direct use of propargylic alcohols instead of propargylic derivatives for catalytic asymmetric allene synthesis is unknown. Here, we show that a highly enantioselective synthesis of tetrasubstituted allenes from racemic propargylic alcohols has been realized by organocatalysis with good efficiency (up to 96% yield and 97% ee). The intermolecular C–C and C–S bond formation was achieved efficiently with simultaneous stereocontrol over the axial chirality. Furthermore, an adjacent quaternary stereocenter could also be constructed. Mechanistically, the reaction may involve efficient stereocontrol on the propargylic cation by its chiral counter anion or 1,8-conjugate addition of para-quinone methides. In sharp contrast to previous central chirality construction, this process employs quinone methides for axial chirality construction.

Highlights

Chiral allene preparation via formal SN2’ nucleophilic substitutions of enantioenriched propargylic derivatives or metal-catalyzed reactions of racemic propargylic derivatives has attracted considerable attention and found applications in many areas of research, direct use of propargylic alcohols instead of propargylic derivatives for catalytic asymmetric allene synthesis is unknown
Dynamic kinetic resolution (DKR) of the crucial allenic metal intermediates plays a key role in achieving both high efficiency and enantioselectivity by catalyst control, thereby representing a pioneering study of this type (Fig. 2b)
This elegant approach is limited to the synthesis of disubstituted allenoates

Summary

Introduction

Chiral allene preparation via formal SN2’ nucleophilic substitutions of enantioenriched propargylic derivatives or metal-catalyzed reactions of racemic propargylic derivatives has attracted considerable attention and found applications in many areas of research, direct use of propargylic alcohols instead of propargylic derivatives for catalytic asymmetric allene synthesis is unknown. Chiral allenes are well-known subunits widely present in natural products, bioactive molecules, ligands, organocatalysts, and functional materials as well as versatile chiral building blocks in organic synthesis[1,2,3,4,5]. Their orthogonal cumulative π-systems often lead to complementary and unique reactivity compared with olefins and alkynes. Direct construction of the axial chirality of allenes from achiral or racemic substrates via asymmetric induction by a chiral catalyst remains substantially challenging, though highly attractive. The challenges lie in simultaneous construction of a non-hydrogen- involved bond and establishment of the axial chirality, in which the catalyst must be effective in controlling both events[8, 16,17,18]

Methods

Results

Conclusion