Enantioselective three-component aminomethylation of \u03b1-diazo ketones with alcohols and 1,3,5-triazines

Jiuwei Che,Dong Xing,Shikun Jia,Wenhao Hu,Li Niu

doi:10.1038/s41467-020-15345-2

Jiuwei Che, Dong Xing + Show 3 more

Open Access

https://doi.org/10.1038/s41467-020-15345-2

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Abstract

Enantioselective α-aminomethylation of carbonyl compounds constitutes a powerful protocol for introducing aminomethyl groups to simple organic molecules. However, current strategies rely on nucleophile-based enantioselective activation with inherently activated substrates only, and enantioselective protocol based on the activation of in situ-generated unstable formaldimines remains elusive, probably owing to their unstable nature and the lack of steric environment for efficient stereocontrols. Here, based on a rhodium/chiral phosphoric acid cooperative catalysis, we achieved an enantioselective three-component reaction of α-diazo ketones with alcohols and 1,3,5-triazines. A dual hydrogen bonding between the chiral phosphoric acid catalyst and two distinct active intermediates was proposed to be crucial for the efficient electrophile-based enantiocontrol. A series of chiral β-amino-α-hydroxy ketones including those derived from simple aliphatic alcohols, allylic alcohol, propargyl alcohol, complicated natural alcohols and water could all be prepared in high efficiency and enantioselectivity.

Highlights

Enantioselective α-aminomethylation of carbonyl compounds constitutes a powerful protocol for introducing aminomethyl groups to simple organic molecules
As an important branch of Mannich reaction, the α-aminomethylation of carbonyl compounds constitutes a powerful protocol for introducing aminomethyl groups to simple organic molecules[1,2,3,4,5,6,7,8]
While the activation of stable imines by chiral Brønsted acid catalysts has been extensively investigated in a variety of enantioselective Mannich reactions[25,26,27,28,29,30,31,32,33,34,35,36], this electrophile-based activating protocol has not been applied to aminomethylation reactions with the in situ-generated formaldimines, probably owing to their generally unstable nature and the lack of steric environment on the carbon atom for efficient stereocontrols (Fig. 1a, Eq 2)

Summary

Introduction

Enantioselective α-aminomethylation of carbonyl compounds constitutes a powerful protocol for introducing aminomethyl groups to simple organic molecules. Different types of formaldehyde-derived imines or iminium salts, which are generally unstable and have to be in situ generated from formaldehyde with aromatic amines[10,11], α-aminomethyl ethers[12,13,14,15,16,17], N,O-acetals[18,19,20], or 1,3,5-triaryl-1,3,5-triazines[21,22,23,24], have been successfully applied Within this context, enantioselective version of this transformation has been achieved by catalytic asymmetric activation of the nucleophilic carbonyl compounds with either amine catalysts[10,11,14,16] or chiral Lewis acid[23,24]. By utilizing rhodium/chiral phosphoric acid (CPA) cooperative catalysis, efficient stereocontrol via a crucial dual hydrogen bonding activation[34,49,50] from CPA toward both the oxonium ylide and the imine substrate has been achieved[45,46,48]

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