Chiral phosphoric acid-catalyzed stereodivergent synthesis of trisubstituted allenes and computational mechanistic studies

Jiawen Wang,Sujuan Zheng,Subramani Rajkumar,Jinglei Xie,Qian Peng,Xiaoyu Yang,Na Yu

doi:10.1038/s41467-020-19294-8

Jiawen Wang, Sujuan Zheng + Show 5 more

Open Access

https://doi.org/10.1038/s41467-020-19294-8

Copy DOI

Abstract

Chiral molecules with multiple stereocenters are widely present in natural products and pharmaceuticals, whose absolute and relative configurations are both critically important for their physiological activities. In spite of the fact that a series of ingenious strategies have been developed for asymmetric diastereodivergent catalysis, most of these methods are limited to the divergent construction of point chirality. Here we report an enantioselective and diastereodivergent synthesis of trisubstituted allenes by asymmetric additions of oxazolones to activated 1,3-enynes enabled by chiral phosphoric acid (CPA) catalysis, where the divergence of the allenic axial stereogenicity is realized by modifications of CPA catalysts. Density functional theory (DFT) calculations are performed to elucidate the origin of diastereodivergence by the stacking- and stagger-form in the transition state (TS) of allene formation step, as well as to disclose a Münchnone-type activation mode of oxazolones under Brønsted acid catalysis.

Highlights

Chiral molecules with multiple stereocenters are widely present in natural products and pharmaceuticals, whose absolute and relative configurations are both critically important for their physiological activities
We report an enantioselective and diastereodivergent synthesis of trisubstituted allenes via asymmetric conjugate additions of activated 1,3-enynes by oxazolones[57,58,59,60] enabled by chiral phosphoric acid (CPA) catalysis, in which the diastereodivergent construction of the allenic axial chirality is realized by modifications of CPA catalysts (Fig. 1c)
We commenced our study by selecting α-alkynyl-α,β-enone 1a and 2-para-methoxyphenyl (PMP) substituted oxazolone 2a as model substrates under CPA catalysis (Table 1)

Summary

Introduction

Chiral molecules with multiple stereocenters are widely present in natural products and pharmaceuticals, whose absolute and relative configurations are both critically important for their physiological activities. Modulation the sense of diastereoselectivity in an asymmetric catalytic reaction is still challenging, because the diastereochemical preference is largely governed by the inherent structure and stereoelectronic nature of the substrates[32] To address this intrinsic problem, a series of ingenious strategies have been developed for asymmetric diastereodivergent catalysis[33,34,35], such as using distinct catalysts[36,37,38], change of metal cations[39], and ligands[40,41] of the catalysts, change of reaction conditions[42,43], stereodivergent dual catalysis[44,45,46,47,48,49,50] and stepwise control[51,52,53,54]. The origin of the diastereodivergence is well elucidated by DFT calculations, in which a Münchnone-type activation mode of oxazolones under Brønsted acid catalysis is presented

Methods

Results

Conclusion