Asymmetric Synthesis of β-Lactams by Staudinger Ketene-Imine Cycloaddition Reaction

Abstract

[2 + 2] Cycloaddition reactions between ketenes, bearing amino‐, oxy‐, or halo‐ groups, and imines are recognized as being amongst the most important and direct routes to β‐lactams. Alkyl‐substituted ketenes also furnished the corresponding β‐lactams upon reaction with activated imines (iminoesters). In general, ketenes are generated from the appropriate acid chloride and a tertiary amine. The major or sole product of the cycloaddition is usually the cis‐β‐lactam, although a few exceptions showing trans selectivity are known. In this way β‐lactams with a widely varying substitution pattern at the C‐3 and C‐4 positions of the ring are constructed stereoselectively. The diastereoselection of the cycloaddition process can be controlled with variable success from chiral groups attached to either the ketene or the imine component, or alternatively to both. This method, in turn, has proved to be valuable for the synthesis of precursors of important β‐lactam antibiotics, and new successful applications can be expected in the near future.

Asymmetric Synthesis and Antimicrobial Activity of Some New Mono and Bicyclic β-Lactams

“…Among the various methods for constructing this pharmaceutically important four-membered ring, the ketene-imine cycloaddition, also known as the Staudinger reaction [2] has provided useful and economical entries to β-lactams, mainly due to the ready availability of both Schiff bases and ketenes [3]. The asymmetric syntheses of α-amino β-lactams can be divided into five categories: a) asymmetric induction from the imine component; b) asymmetric induction from the ketene component; c) double stereodifferentiating cycloadditions; d) carbacephem intermediates and e) 2-oxaisocephems and 2-isocephems [1]. The asymmetric induction in the reaction of achiral ketenes with chiral imines has been effected from imines derived from chiral aldehydes and achiral amines and also from imines derived from chiral amines and achiral aldehydes.…”

“…The crude alcohol 8 was chromatographed on silica gel. Elution with chloroform-ethyl acetate (9:1) afforded 8 as an oil in 60% yield; 1 …”

“…The residue was purified by column chromatography on silica gel. Elution with chloroform gave 9 as an oil in 60% yield; 1 [5.4.0]undec-7-ene (1.53 g, 10.00 mmol) was added to mesylate β-lactam 9 (2.02 g, 5.00 mmol) in THF-DMF 9:1 (20 mL). The mixture was refluxed for four hours and then the solvent was evaporated.…”

“…The β-lactam skeleton is the key structural element of the most widely used class of antimicrobial agents, the β-lactam antibiotics [1]. Among the various methods for constructing this pharmaceutically important four-membered ring, the ketene-imine cycloaddition, also known as the Staudinger reaction [2] has provided useful and economical entries to β-lactams, mainly due to the ready availability of both Schiff bases and ketenes [3].…”

Intramolecular 1,3-dipolar cycloaddition reaction of novel 2-azetidinone-tethered alkenyl nitrile oxides

“…Tricyclic β-lactam antibiotics, generally referred to as trinems, are a new class of synthetic antibacterial agents featuring good resistance to β-lactamases and dehydropeptidases. 2 Besides, the ever-growing new applications of 2-enantiomers from the corresponding imine of (R)-2,3-O-isopropylideneglyceraldehyde, through a Staudinger reaction with the appropriate alkoxyacetyl chloride in the presence of Et 3 N. 13 Transesterification of 3-acetoxy-2-azetidinone (+)-2d with sodium methoxide in methanol gave alcohol (+)-3, which by treatment with allyl bromide under basic conditions gave the 2-azetidinone (+)-4. Standard acetonide hydrolysis of compounds 2a-c and (+)-4 followed by oxidative cleavage of the resulting diols smoothly provided 4-oxoazetidine-2-carbaldehydes 1a-d ( Figure 1).…”