Abstract
Nitrogen-containing scaffolds are ubiquitous in nature and constitute an important class of building blocks in organic synthesis. The asymmetric aza-Michael reaction (aza-MR) alone or in tandem with other organic reaction(s) is an important synthetic tool to form new C–N bond(s) leading to developing new libraries of diverse types of bioactive nitrogen compounds. The synthesis and application of a variety of organocatalysts for accomplishing highly useful organic syntheses without causing environmental pollution in compliance with ‘Green Chemistry” has been a landmark development in the recent past. Application of many of these organocatalysts has been extended to asymmetric aza-MR during the last two decades. The present article overviews the literature published during the last 10 years concerning the asymmetric aza-MR of amines and amides catalysed by organocatalysts. Both types of the organocatalysts, i.e., those acting through non-covalent interactions and those working through covalent bond formation have been applied for the asymmetric aza-MR. Thus, the review includes the examples wherein cinchona alkaloids, squaramides, chiral amines, phase-transfer catalysts and chiral bifunctional thioureas have been used, which activate the substrates through hydrogen bond formation. Most of these reactions are accompanied by high yields and enantiomeric excesses. On the other hand, N-heterocyclic carbenes and chiral pyrrolidine derivatives acting through covalent bond formation such as the iminium ions with the substrates have also been included. Wherever possible, a comparison has been made between the efficacies of various organocatalysts in asymmetric aza-MR.
Highlights
The Michael reaction though discovered about 135 years ago [1,2] continues to attract attention of the chemists owing to its potential of making a vast variety of organic compounds of pharmacological importance accessible
In view of its ability to introduce a nitrogen-containing functionality at the β-position of an activated alkenyl- or alkynyl-substrate, over the years, it has developed as an important synthetic strategy for the preparation of a large variety of β-amino carbonyl and similar motifs which are present in many bioactive natural products [8,9], antibiotics [10,11,12] and chiral auxiliaries [13,14,15]
Five organocatalysts belonging to three categories, namely cinchona alkaloid bases, bifunctional squaramides and thioureas were screened for the enantioselective N-alkylation of isoxazolin-5-ones via a 1,6-aza-Michael addition of isoxazolin-5-ones to p-quinone methides (p-QMs) to give isoxazolin-5-ones 67 bearing a chiral diarylmethyl
Summary
The Michael reaction though discovered about 135 years ago [1,2] continues to attract attention of the chemists owing to its potential of making a vast variety of organic compounds of pharmacological importance accessible. It has an added advantage that a large number of enantiomerically pure organocatalysts can be accessed from the chiral pool Both types of organocatalysts, namely those acting through non-covalent bonding as well as those working by making covalent bonding have been employed for accomplishing asymmetric aza-MRs. There are several review articles available on organocatalytic asymmetric aza-MRs, each highlighting a certain aspect of the reaction. The known stereoselective syntheses of pharmacology-oriented nitrogen containing heterocyclic scaffolds via non-covalent bonding and covalent bonding organocatalytic aza-MRs has been systematized. This classification is especially useful for researchers to understand both the noncovalent and covalent organocatalysis. Nitrogen nucleophiles comprise a large variety of compounds; in order to comply with the requirements of a mini review, additions of amines and amides only will be included
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