Catalytic Asymmetric Synthesis of Unprotected β2-Amino Acids.

Chendan Zhu,Rajat Maji,Francesca Mandrelli,Benjamin List,Hui Zhou

doi:10.1021/jacs.1c00249

Chendan Zhu, Rajat Maji + Show 3 more

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https://doi.org/10.1021/jacs.1c00249

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Abstract

We report here a scalable, catalytic one-pot approach to enantiopure and unmodified β2-amino acids. A newly developed confined imidodiphosphorimidate (IDPi) catalyzes a broadly applicable reaction of diverse bis-silyl ketene acetals with a silylated aminomethyl ether, followed by hydrolytic workup, to give free β2-amino acids in high yields, purity, and enantioselectivity. Importantly, both aromatic and aliphatic β2-amino acids can be obtained using this method. Mechanistic studies are consistent with the aminomethylation to proceed via silylium-based asymmetric counteranion-directed catalysis (Si-ACDC) and a transition state to explain the enantioselectivity is suggested on the basis of density functional theory calculation.

Highlights

We report here a scalable, catalytic one-pot approach to enantiopure and unmodified β2-amino acids
Encouraged by our recent studies on silylium-based asymmetric counteranion-directed catalysis (Si-ACDC),[46−66] we envisaged to apply this approach to a TMSX*-catalyzed reaction of bisSKAs with a silylated aminomethyl ether, followed by hydrolytic workup and extraction, which should deliver the free, unmodified β2-amino acids and enable a simple catalyst HX* recovery
An initial catalyst exploration revealed that moderately acidic Brønsted acids, such as chiral phosphoric acids (CPAs),[67,68] even upon warming, did not give any of the desired product, while imidodiphosphoric (IDP)[69] acids promoted the reaction at 0 °C to give racemic product

Summary

Introduction

We report here a scalable, catalytic one-pot approach to enantiopure and unmodified β2-amino acids. Encouraged by our recent studies on silylium-based asymmetric counteranion-directed catalysis (Si-ACDC),[46−66] we envisaged to apply this approach to a TMSX*-catalyzed reaction of bisSKAs with a silylated aminomethyl ether, followed by hydrolytic workup and extraction, which should deliver the free, unmodified β2-amino acids and enable a simple catalyst HX* recovery (eq 2, X*− = enaniopure counteranion). Various free β2-amino acids with electronically and sterically diverse substituents were obtained in excellent yields and enantioselectivities.

Results

Conclusion