Brönsted-Acid-Catalyzed Asymmetric Three-Component Reaction of Amines, Aldehydes, and Pyruvate Derivatives. Enantioselective Synthesis of Highly Functionalized γ-Lactam Derivatives

Abstract

Chiral phosphoric acids are efficient organocatalysts for the asymmetric three-component reaction of amines, aldehydes, and pyruvate derivatives. Simultaneous condensation of amines with both carbonylic compounds followed by a hydrogen bonding activated nucleophilic addition of enamines to imines affords densely functionalized enantioenriched 1,5-dihydro-2H-pyrrol-2-ones. These substrates can be used in subsequent diastereoselective transformations to afford enantiopure γ-lactam derivatives.

A Brønsted Acid-Catalyzed Multicomponent Reaction for the Synthesis of Highly Functionalized γ-Lactam Derivatives

“…Then, we tried to perform the reaction at higher temperature and, although the same results were observed using tetrahydrofurane (THF) or dimethoxyethane (DME) as solvents (Table 1, Entries 2 and 3), the reaction in refluxing methyl tert -butylether (MTBE) proceeded in full conversion in a few hours, affording the expected 3-amino 1,5-dihydro-2 H -pyrrol-2-one 10a together with enol derivative 11a [41], which may result from the hydrolysis of enamine moiety in 10a (Table 1, Entry 4). The use of an excess of ethyl pyruvate in the parent MCR with benzaldehyde and amines proved to be very effective in reducing the reaction times and temperatures [29]; however, remarkably, when three equivalents of acetylene derivative 8 were used, no formation of γ-lactam derivatives 10a or 11a was observed due to the consumption of p -toluidine 3a (R = p -MeC 6 H 4 ) by reaction with the excess of diethyl acetylenedicarboxylate 8 (Table 1, Entry 5).…”

“…Based on this report, some authors later described several modifications of this synthetic procedure, and the uncatalyzed [25] or solvent-free [26] reaction, and the use of recyclable catalysts [27] were reported in the last few years. Interestingly, it was also established that such reaction can be performed under organocatalysis [28] and, taking the advantage of this fact, very recently, we achieved a highly enantioselective version of this reaction using 1,1′-bi-2-naphthol (BINOL)-derived chiral phosphoric acids as catalysts [29].…”

Bifunctional Brønsted Base Catalyzed Mannich Reaction of β‐Alkoxy α‐Keto Amides: Stereocontrolled Entry to Functionalized Amino Diols

“…One problem associated with adducts from aldol and Mannich reactions with α‐keto esters is their high tendency to cyclize and produce isotetronic acids and pyrrolones, respectively, which would result in the loss of one of the stereogenic centers generated during the reaction ,…”

Multicomponent Reactions in the Synthesis of γ-Lactams

“…39 In 2018, the use of ether solvents in this reaction improved the yield and the enantioselectivity of the process through an effect attributed to the participation of the solvent molecules in the transition state. 45 Good to excellent yields and E. Martinez de Marigorta et al…”