Ni-catalyzed asymmetric hydrogenation of N-aryl imino esters for the efficient synthesis of chiral \u03b1-aryl glycines

Dan Liu,Ilya D Gridnev,Bowen Li,Wanbin Zhang,Jianzhong Chen,Deyue Yan

doi:10.1038/s41467-020-19807-5

Dan Liu, Ilya D Gridnev + Show 4 more

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https://doi.org/10.1038/s41467-020-19807-5

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Abstract

Chiral α-aryl glycines play a key role in the preparation of some bioactive products, however, their catalytic asymmetric synthesis is far from being satisfactory. Herein, we report an efficient nickel-catalyzed asymmetric hydrogenation of N-aryl imino esters, affording chiral α-aryl glycines in high yields and enantioselectivities (up to 98% ee). The hydrogenation can be conducted on a gram scale with a substrate/catalyst ratio of up to 2000. The obtained chiral N-p-methoxyphenyl α-aryl glycine derivatives are not only directly useful chiral secondary amino acid esters but can also be easily deprotected by treatment with cerium ammonium nitrate for further transformations to several widely used molecules including drug intermediates and chiral ligands. Formation of a chiral Ni-H species in hydrogenation is detected by 1H NMR. Computational results indicate that the stereo selection is determined during the approach of the substrate to the catalyst.

Highlights

Chiral α-aryl glycines play a key role in the preparation of some bioactive products, their catalytic asymmetric synthesis is far from being satisfactory
Developed by Knowles, which has received high praise and won the Nobel Prize in Chemistry in 20018. As another category of αamino acids, chiral α-aryl glycines play a key role in synthetic drugs as well as bioactive natural products (Fig. 1a)[9,10,11,12]
Only a few Ni-catalyzed asymmetric hydrogenations of imines have been reported by Zhang[24,43,44] and our group[42], and the imines substrates are all activated by N-sulfonyl groups (Fig. 1c)

Summary

Introduction

Chiral α-aryl glycines play a key role in the preparation of some bioactive products, their catalytic asymmetric synthesis is far from being satisfactory. We report an efficient nickel-catalyzed asymmetric hydrogenation of N-aryl imino esters, affording chiral αaryl glycines in high yields and enantioselectivities (up to 98% ee). A prominent example is the industrial preparation of L-DOPA developed by Knowles, which has received high praise and won the Nobel Prize in Chemistry in 20018 As another category of αamino acids, chiral α-aryl glycines play a key role in synthetic drugs as well as bioactive natural products (Fig. 1a)[9,10,11,12]. Continuing our pursuit of earth-abundant metal-catalyzed asymmetric hydrogenation[38,39,42], we disclose an efficient Ni-catalyzed asymmetric hydrogenation of N-PMP imino esters for the synthesis of useful chiral α-aryl glycines (Fig. 1d)

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Conclusion