Three Component Coupling of α-Iminoesters via Umpolung Addition of Organometals: Synthesis of α,α-Disubstituted α-Amino Acids

Abstract

The synthesis of alpha,alpha-disubstituted alpha-amino acids by means of a three component coupling is reported. The coupling occurs through umpolung addition of organometallic reagents to the nitrogen of alpha-iminoesters. The resulting enolate intermediates subsequently react with electrophiles (aldehydes, imines, alpha,beta-unsaturated nitro, alkyl halides, acyl cyanides) to form a quaternary center. Tethering of the electrophile and nucleophile components provides cyclic alpha,alpha-disubstituted alpha-amino acid derivatives.

Synthesis of chiral N-phosphinyl α-imino esters and their application in asymmetric synthesis of α-amino esters by reduction

“…More attractively, the transformation of α-imino esters can provide an easy access to various natural and unnatural α-amino acid esters [6–10]. Up to now, a series of nucleophilic substrates have been reported to react with α-imino esters, such as enamine [11–14], carbamate ammonium ylide [15], 1,3-dipolar cycle [16], boronic acid [17], acetylide [18], proparygylic anion [19] and ketene silyl acetal [20].…”

An umpolung strategy to react catalytic enols with nucleophiles

“…This term was introduced by D. Seebach and E. J. Corey to refer the inversion of reactivity of acyl carbon atoms in their reactions with electrophiles 2 . Analogous methods based on switching the reactivity of amines 3 , imines [4][5][6] , or carbonyl groups [7][8][9][10][11][12][13] have been developed in recent decades. This approach has played a pivotal role in the design of synthetic procedures, allowing access to target molecules that would be difficult to obtain by classical processes.…”

Chemoselective Activation of sp3 vs sp2 C–H Bonds with Pd(II)

“…The resultant azlactone products are masked α-amino acids, with hindered α,α-disubstitution patterns that are difficult to achieve via other means. 30 Notably, selective sp 3 C–H activation is observed in benzylic systems, even though Pd(OAc) 2 typically causes arene C–H activation. Further studies to understand the mechanism and, in particular, the role of an observed azlactone dimer on the sp 3 vs sp 2 C–H activation selectivity are underway.…”