α(δ')-Michael Addition of Alkyl Amines to Dimethyl (E)-hex-2-en-4-ynedioate: Synthesis of α,β-Dehydroamino Acid Derivatives

Arjun Chavan,Jie-Cheng Deng,Shih-Ching Chuang

doi:10.3390/molecules18032611

Arjun Chavan, Jie-Cheng Deng + Show 1 more

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https://doi.org/10.3390/molecules18032611

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Abstract

The direct nucleophilic addition of alkyl amines to the α(δ')-carbon atom of dimethyl (E)-hex-2-en-4-ynedioate to generate α,β-dehydroamino acid derivatives is reported. Herein, we have studied the reactivity of various primary and secondary alkyl amines in the α-selective nucleophilic conjugate addition to conjugated dimethyl (E)-hex-2-en-4-ynedioate. The reaction with primary alkyl amines gives only the (2E,4E)-stereoisomer, while that with secondary alkyl amines gives the (2E,4E) and (2Z,4E)-stereoisomers of dimethyl (2-alkylamino)-muconic ester.

Highlights

The Michael addition reaction, the regioselective 1,4-addition of nucleophiles to activated olefins, is one of the versatile methods used for C–C, C–N bond formation, and has found wide application in organic synthesis [1,2,3,4,5,6,7,8,9,10]
The theoretical and mechanical aspects of change in regioselectivity of Michael addition reaction were extensively studied by various groups [22,23,24]
In continuation of our interest in studying the reactivity of enyne 2, we have shown the direct nucleophilic addition of alkyl amines to the α(δ')-carbon of enyne 2 to generate the corresponding α,β-dehydroamino acid derivatives, which are important building blocks in protein and peptide chemistry [28,29,30]

Summary

Introduction

The Michael addition reaction, the regioselective 1,4-addition of nucleophiles to activated olefins, is one of the versatile methods used for C–C, C–N bond formation, and has found wide application in organic synthesis [1,2,3,4,5,6,7,8,9,10]. Molecules 2013, 18 to conjugated alkynoates and used it to prepare various α,β-dehydroamino acid derivatives [25] It occurs through the zwitterionic carbenoid species formation by the attack of phosphine on the β-carbon of the allenoate substrates. Our results have shown that the produced stereoisomers are highly dependent on the degrees of substitution of the alkyl amines—primary alkyl amine gives only the (2E,4E)-stereoisomer, while secondary alkyl amines give the (2E,4E) and (2Z,4E)-stereoisomers of dimethyl (2-alkylamino)-muconic ester. All these investigated alkyl amines react with enyne 2 through α(δ')-selective nucleophilic conjugate addition. Reagents and Conditions: (i) 1% DABCO, DCM (0.5 M), 0 °C,

Results and Discussion

General

General Experimental Procedure for Reactions with Primary Alkyl Amines

General Experimental Procedure for Reactions with Secondary Alkyl Amines

Conclusions