Asymmetric synthesis of quaternary aryl amino acid derivatives via a three-component aryne coupling reaction

Elizabeth P Jones,Anthony G M Barrett,Andrew J P White,Peter Jones

doi:10.3762/bjoc.7.185

Abstract

A method was developed for the synthesis of α-alkyl, α-aryl-bislactim ethers in good to excellent yields and high diastereoselectivities, consisting of a facile one-pot procedure in which the aryl group is introduced by means of a nucleophilic addition to benzyne and the alkyl group by alkylation of a resultant benzylic anion. Hydrolysis of the sterically less hindered adducts gave the corresponding quaternary amino acids with no racemization, whereas hydrolytic ring opening gave the corresponding valine dipeptides from bulkier bislactims.

Highlights

Arynes are exceptionally versatile reactive intermediates in organic synthesis. Are they able to participate in cycloaddition reactions, they readily undergo addition reactions with nucleophiles, and the resultant aryl anions may be protonated or undergo alternative transformations [1,2,3,4,5,6]
We are interested in the use of arynes in multicomponent coupling reactions, in which the resultant aryl carbanion following nucleophilic attack is allowed to react with a further electrophile, providing ortho-disubstituted, functionalized aromatic products in a one-pot procedure [7,8,9]
We have focused on the addition of carbon-based nucleophiles in such systems (Scheme 1) and have applied this methodology to the syntheses of natural products ent-clavilactone B and dehydroaltenuene B [10,11]

Summary

Introduction

Arynes are exceptionally versatile reactive intermediates in organic synthesis. are they able to participate in cycloaddition reactions, they readily undergo addition reactions with nucleophiles, and the resultant aryl anions may be protonated or undergo alternative transformations [1,2,3,4,5,6]. We are interested in the use of arynes in multicomponent coupling reactions, in which the resultant aryl carbanion following nucleophilic attack is allowed to react with a further electrophile, providing ortho-disubstituted, functionalized aromatic products in a one-pot procedure [7,8,9]. We reported the diastereoselective addition of Schöllkopf’s bislactim ether 1 [12] to substituted arynes 2, which, following hydrolysis of the syn-adducts 3, provided α-aryl amino acids 4 with moderate to high enantioselectivities (Scheme 2) [13].

Results

Conclusion