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General methods have been developed for the synthesis of 7-amino-2-iso-oxacephem-4-carboxylic acid esters 21a,b; 35b. Clayfen [Fe(III) nitrate supported by montmorillonite] was used for the preparation of benzyl 2,3-dioxobutyrate (3). The latter readily reacted with N(1)-unsubstituted β-lactams (9a, 28) to give products formed by addition reaction on the middle carbonyl-C atom. These intermediates furnished the corresponding acetoacetic esters 10, 29 which gave by ring closure the O-mono- and the O,N-diprotected-2-iso-oxacephems (11, 30). Intermolecular carbene insertion was used for the synthesis of tert-butyl 2-(2-oxoazetidin-1-yl)acetoacetates 19a,b whose ring closure led to the tert-butyl 2-iso-oxa-cephem-4-carboxylates 20a,b. The O-protecting tert-butyl group could be removed without decomposition of the 2-isooxacephem moiety to give 2-iso-oxacephem-4-carboxylic acids 2a,b which exhibit antibacterial activity against Grampositive microorganisms.

1-Oxacephem derivatives were synthesized and evaluated as a novel series of chymase inhibitors. Structure-activity relationship studies of 1-oxacephems led to compound 34, which exhibited 6 nM inhibition of human chymase and high selectivity for human chymase compared to other serine enzymes.

1-Oxacephem derivatives were evaluated as a novel series of chymase inhibitors. The structure-activity relationship studies of 1-oxacephems led to compounds 15, which exhibited 27 nM inhibition of human chymase and improvement of stability in human plasma (t 1/2 1.5 h).

A stereocontrolled synthesis of optically active 2-isocephem and 2-iso-oxacephem nuclei is described starting from L-aspartic acid.

Progress in synthetic studies on 1-oxacephems is reviewed. Antibacterial activity of this new class of compounds is also discussed briefly. Earlier syntheses, rather lengthy but quite pioneering, provided us with valuable information of the interesting biological activity of 1-oxacephems. Several improved synthesis have appeared, enabling to prepare a variety of derivatives and examine their antibacterial activity. Thus, syntheses and antibacterial activity of some interesting 1-oxacephems and 7α-methoxy-1-oxacephems, such as, arylmalonamido-, α-acylureidophenylacetamido-, and α-aminothiazolyl-α-methoxyiminoacetamido derivatives with representative 3'-substituents are described. A compound 6059-S 98 discovered in Shionogi Research Laboratories, proved to have excellent antibacterial activity, spectrum, and other pharmacological properties and, therefore, is currently under clinical studies. An industrially feasible synthetic method for its nucleus 88 a as well as 7α-methoxy-1-oxacephem nuclei with a variety of substituents at the 3'-position in general was established after extensive studies.

Acid-catalysed displacement of 7α-methoxy-7β-amino-l-oxacephem (1) with nucleophiles gave the 7α-substituted-7β-amino compounds (5–8), which were converted into the antibiotics (13–16).