Dicarboxylates of 3‐Methylidene‐β‐lactams: Addition Reactions to the Exocyclic Double Bond, Formation of Spiro‐β‐lactams, and Reductive Ring Opening by Hydrazines

Abstract

Dedicated to Prof. Dr. Dr. h.c. mult. Horst Bohme, Marburg, on the occasion of his 85th birthday (1 6.V11.93) 0-, S-, and N-Nucleophiles are added to the exocyclic double bond of the title compounds 1. The addition of 0-or S-nucleophiles yields stable products (Scheme I ) , while addition of N-nucleophiles results in thermally labile compounds (Scheme 2). The reaction is studied by spectroscopic methods. From hydrazine adducts, a spiro[azetidine-3,3'-pyrazolidine] 7 is obtained, and the addition products of methyl-and benzylhydrazine rearrange to pyrazo~-4-cdrboxylates 6. Furthermore, the exocyclic double bond is used for the formation of spiro-p-lactams either by cyclopropane formation or by Diels-Alder reactions (Scheme 4 ) . The steric course of all reactions is studied, and it is shown that all reactions with the double bond occur from the side opposite to the bulkier substituent at C(4) of the p-lactam ring.Introduction. -Since the discovery of p-lactam antibiotics with an exocyclic double bond at C(7) like asparenomycins [I], the interest in other similar structures, e.g. monocyclic p-lactams with this structural component has grown [2]. Nucleophiles, e.g. amines [3] or thiols [4], are added to the double bond of unsubstituted 3-methylidene-P-lactams and do not open the lactam ring. Therefore, it seems to be of special interest to study the behaviour of substituted analogues. Principially, two types of substitution may be differentiated: 1) alkyl or aryl groups connected to the double bond directing a nucleophilic attack to the exocyclic C ( a ) atom or 2) electron-withdrawing groups at this position directing the attack towards C(3) of the p-lactam ring. In preceding papers 151, we described the synthesis of compounds 1 from 3-silylated /I-lactams and mesoxalic esters as model compounds of the second type of substitution. Now we wish to present some reactions at the double bond of 1 which show the synthetic possibilities and might allow a look into their mode of action when used in biological systems. These results should give some hints onto the hitherto unknown mechanism of the action of methylidene-P-lactams as 8-lactamase inhibitors.

Synthesis and reactivity of spiro-fused β-lactams

“…In related research, the carbon-carbon double bond of 3-methylidene-2-azetidinones has been subjected to epoxidation, cyclopropanation, Diels-Alder reaction and 1,3-cycloadditions, producing a variety of spiroazetidinones. 61,62 The study of the steric course indicated that reactions with the double bond occurred from the side opposite to the bulkier substituent at C4 of the starting 2-azetidinones. Epoxidation of the electron-poor, carbon-carbon double bond at …”

“…61,62 Cyclopropanation of 120 in THF with the ylide derived from trimethylsulfoxonium iodide 124 in DMF formed 2-azetidinones 125, spiro-fused to a cyclopropane ring (Scheme 42). In the DielsAlder reaction of 120 with Danishefsky's diene 126, a single product 127 was obtained in 95%…”