Chiral donor\u2013acceptor azetines as powerful reactants for synthesis of amino acid derivatives

Kostiantyn O Marichev,Kan Wang,Hadi Arman,Lynée A Massey,Michael P Doyle,Kuiyong Dong,Luca De Angelis,Yongming Deng

doi:10.1038/s41467-019-13326-8

Kostiantyn O Marichev, Kan Wang + Show 6 more

Open Access

https://doi.org/10.1038/s41467-019-13326-8

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Journal: Nature Communications	Publication Date: Nov 22, 2019
Citations: 19	License type: open-access

Affiliation: The University of Texas at San Antonio

Abstract

Coupling reactions of amines and alcohols are of central importance for applications in chemistry and biology. These transformations typically involve the use of a reagent, activated as an electrophile, onto which nucleophile coupling results in the formation of a carbon-nitrogen or a carbon–oxygen bond. Several promising reagents and procedures have been developed to achieve these bond forming processes in high yields with excellent stereocontrol, but few offer direct coupling without the intervention of a catalyst. Herein, we report the synthesis of chiral donor–acceptor azetines by highly enantioselective [3 + 1]-cycloaddition of enoldiazoacetates with aza-ylides and their selective coupling with nitrogen and oxygen nucleophiles via 3-azetidinones to form amino acid derivatives, including those of peptides and natural products. The overall process is general for a broad spectrum of nucleophiles, has a high degree of electronic and steric selectivity, and retains the enantiopurity of the original azetine.

Highlights

Coupling reactions of amines and alcohols are of central importance for applications in chemistry and biology
Irreversible ring opening of the strained 2-azetidinone fourmembered ring, which is one of the key biomolecular events during both the antibiotic action of β-lactams and their inhibition by β-lactamases[1], is a model for nucleophile coupling. Because of their chemically controlled ring opening, 2-azetidinones are widely used for the synthesis of heterocycles, β-amino acids, and their derivatives2–4. 3-Azetidinones, by contrast, are less well established[5] even though they have the potential for analogous nucleophilic carbonyl-carbon cleavage to form amine derivatives (Fig. 1a) if an activating electron-withdrawing group (EWG) is located at the 2-position; but the key to realizing this potential lies in the design of a 3-azetidinone capable of nucleophile coupling
A classic approach to nucleophile coupling is the retro-Claisen reaction of β-ketoesters[6] that would require the construction of 2carboxylate substituted 3-azetidinones, but the basic methods available for their ring-closing formation are the same as those desired for their ring-opening which is favored by ring strain[7,8,9,10]

Summary

Introduction

Coupling reactions of amines and alcohols are of central importance for applications in chemistry and biology. With a corresponding 2-azetine derivative obtained in good yield and high enantioselectivity, desilylation, forming the desired 3-keto-2-carboxylate, could provide the chemical framework for nucleophile coupling that would attach the amino acid framework of the 3-azetidinone to the nucleophile.

Results

Conclusion