Lactamization Lactam ring, rearrangements with

Metabolic activation via cytochromes P-450 to reactive metabolites. A reactive intermediate has been suggested as some inhibitors of cytochromes P-450 decrease the toxicity, and some inducers of the monooxygenases increase toxicity. However, other inducers and inhibitors do not change toxicity, and these treatments also affect the renal concentration of cephaloridine in a manner consistent with the effect on toxicity. As the p-lactam ring is unstable, a chemical rearrangement to produce a reactive intermediate is also possible. 

These bicyclo[4.2.0]octanones also undergo aza-ring expansion to lactams. Beckmann rearrangement of the oxime of a typical bicyclic butanone (1) results in an octahydroisoindolone (2), whereas rearrangement of the methylnitrone (3) with tosyl chloride (4, 510 511 6, 598) proceeds in the opposite direction to give an octahydroindolone (4) as the only product.2... 

Azole approach. The /8-lactam ring in penicillanic acid derivatives can be expanded to a pyrimidine ring. Thus methyl 6/8-phthalimidopenicillanate (506) is transformed by CSI into the corresponding fused pyrimidine (507) with retention of the stereochemistry (78JCS(P1)817). Treatment of penicillanate S-oxides (508) with acyl isocyanates in a similar manner yields fused pyrimidines which subsequently eliminate water from the rearranged sulfoxide (74USP3850933). 

A second partial synthesis of mexicanolide (69) from 7-deacetoxy-7-oxo-khivorin (70) has been reported (see Vol. 1, p. 183). This differed only in the method used to cleave ring B. The oxime (71) underwent a Beckmann rearrangement with thionyl chloride to give the lactam (72) which was converted into the... 

However, when the carbapen-2-am-3-carboxylate 80 was treated with 1.0 mol equiv. of DBU in dimethyl sulfoxide or in dimethylformamide in the presence of a slight excess of methyl iodide at room temperature for 15 min, the rearranged product 81 was obtained in 14% yield (85JOCI996). If sodium hydride was used as base in the latter reaction, the / -lactam ring underwent decomposition. 

MeOC(,H4) has been prepared and found to rearrange to a fused-ring bic bis(Y-lactam) on treatment with methoxidc ion in methanol <96JOC9L56>. 

A practical and general strategy towards such heterocycles from penam precursors was recently disclosed [129, 130] (Scheme 73). Hydroxamic acids 249, formed by cleavage of the P-lactam ring of the penicillinates 248 with hydroxylamine, underwent a smooth Lossen rearrangement in the presence of A/, iV-diethylaminopropyne. The isocyanate intermediates 250 immediately cyclised to give the desired compounds 251 without racemization. 

Several reaction mechanisms were offered to explain the mechanism of anionic ring-opening polymerizations of lactams. One mechanism is based on nucleophilic attacks by the lactam anions at the cyclic carbonyl groups of N-acylated lactams. This leads to formations of intermediate symmetrical mesomeric anions that rearrange with openings of the rings [133, 134] ... 

---