Total synthesis of analogues of the β-lactam antibiotics. Part 2. Isopenam-3-carboxylates and their 2,2-dioxides

Abstract

t-Butyl hydroxy-(2-iodomethyl-4-oxoazetidin-1-yl)acetate (10a), as a 1 : 1 mixture of diastereoisomers, was transformed, by sequential reactions involving thionyl chloride–2,6-lutidine and hydrogen sulphide–triethylamine, into a 1 : 1.7 mixture of t-butyl isopenam-3-exo-carboxylate (3b) and its endo-diasterepisomer (12a). Using a similar reaction sequence, p-nitrobenzyl hydroxy-(2-iodomethyl-4-oxoazetidin-1-yl)acetate (10b), as a 1 : 1 mixture of diastereoisomers, was converted into a 1 : 1.5 mixture of p-nitrobenzyl isopenam-3-exo-carboxylate (3d) and its endo-diastereoisomer (12b). In the presence of 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), the endo-compounds (12a) and (12b) underwent epimerisations to the exo-isomers (3b) and (3d).

Oxidation of the isopenams (3b), (3d), and (12a) with potassium permanganate gave the corresponding isopenam 2,2-dioxides, i.e.(4b), (4c), and (22). Epimerisation of the endo-compound (22) to its exo-diastereoisomer (4b) was effected by DBN.

Hydrogenolyses of the p-nitrobenzyl esters (3d) and (4c), over palladium and in the presence of sodium hydrogen carbonate, gave the sodium salts of isopenam-3-exo-carboxylic acid and 3-exo-carboxyisopenam 2,2-dioxide, i.e.(3a) and (4a), respectively. Although stable in aqueous solution, the sodium salts (3a) and (4a) were inactive as antibacterial agents. The sodium salt (4a), unlike its analogue sulbactam sodium salt (21a), was ineffective as a β-lactamase inhibitor.

When treated with trifluoroacetic acid, the isopenams (3b) and (12a) were converted respectively, into trans-(2-t-butoxycarbpnyl-3-trifluoroacetylthiazolidin-4-yl)acetic acid (13b) and its cis-diastereoisomer (14b). Under similar conditions, the isopenam dioxides (4b) and (22) afforded trans-2-t-butoxycarbonyl-4-methonycarbonylmethyl-3-trifluoroacetylthiazolidine 1,1-dioxide (13e) and its cis-diastereoisomer (14d). Trifluoroacetolysis of sulbactam benzyl ester (21b) gave (2R,4S)-4-benzyloxy-carbonyl-2-methoxycarbonylmethyl-5,5-dimethyl-3-trifluoroacetylthiazolidine 1,1-dioxide (26b).

The aforecited results suggest that 3,4-bond ruptures do not accompany β-lactam cleavages of compounds (3b), (4b), (12a), and (22) and that a 1,5-bond breakage is not associated with rupture of the β-lactam linkage of sulbactam benzyl ester (21b). The failure to observe such fragmentation processes is interpreted in terms of unfavourable stereoelectronic factors. N-Unsubstituted thiazolidine 1,1-dioxides, species with hitherto have never been isolated or detected, are implicated as intermediates in the trifluoroacetolyses of compounds (4b), (21b), and (22).