Abstract
The formal [2+2] cycloaddition of ketenes and imines, also known as Staudinger synthesis, is a facile method for the synthesis of biologically important β-lactam derivatives. In this paper two previously reported stereoselective reactions were investigated with computational methods. Our computations support experimental data that a chiral imine, derived from d-glyceraldehyde reacting with ketenes, yields almost exclusively one out of the possible four diastereomers. The reaction proceeds stepwise, first addition of the imine to the ketene yields an intermediate, then the product is formed in a conrotatory electrocyclization. Results indicate that the electrostatic repulsion of the chiral auxiliary group is the main factor of the stereoselectivity, but solvent and substituent effects are not negligible. Calculations were performed at M06-2X/6-31+G** level of theory combined with IEF-PCM solvation, in common solvents such as toluene, THF, dichloromethane, acetonitrile and water. These results provide useful insight for the development of new chiral auxiliaries and optimizing reaction parameters.
Highlights
The β-lactam antibiotics have been used in modern medicine for over 70 years, even today they are the most widely used antibacterial agents
Our computations support experimental data that a chiral imine, derived from d-glyceraldehyde reacting with ketenes, yields almost exclusively one out of the possible four diastereomers
In recent years several biologically active β-lactam compounds have been discovered with different enzyme inhibition effects, these include inhibition of cholesterol absorption [2], human leukocyte elastase [3], human cytomegalovirus protease [4], prostate specific antigen [5], thrombin [6], and tryptase [7, 8]
Summary
The β-lactam antibiotics have been used in modern medicine for over 70 years, even today they are the most widely used antibacterial agents. In contrast to β-lactam antibiotics, these compounds or their precursors cannot be synthetized by microorganisms. These compounds often have stereoisomers, it is imperative to synthetize selectively the desired isomers. The stereoselective synthesis of the β-lactam moiety is an actively studied area [9,10,11,12,13,14,15]; in this paper we present a theoretical investigation on this subject
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