The Synthesis of Substituted Penicillins and Simpler Structural Analogs. Vii. The Cyclization of a Penicilloate Derivative to Methyl Phthalimidopenicillanate

Abstract

Sir :It was first noted by Ruzicka and van Melsen that treatment of bromonorcedrenedicarboxylic acid (bromoNCDA) with base leads to the loss of the elements of hydrobromic acid and carbon dioxide and the formation of an,unsaturated bicyclic monobasic acid, C12H1802.1 On the (incorrect) assumption that bromoNCDA is a bromosuccinic acid2 the reaction is unexceptional and has many precedents. It was eventually recognized however that the C12 acid is not an alp unsaturated acid and that apparently bromide ion and carbon dioxide are lost from the same carbon atom.'J Little further progress was made in the elucidation of the structure of the C12 acid, and the rearrangement which leads to it has remained one of the arcana of cedrene chemistry.* An entirely new light was shed on the reaction when it was demonstrated that NCDA is a glutaric acid derivativeP and the problem of the base decomposition of bromoNCDA was re-examined. It seemed to us likely that the reaction was essentially one of solvolysis of a neopentyl bromide type, undoubtedly facilitated in the present case by the cancellation of the positive charge on the relevant carboxyl group by formation of a carboxylate anion :The correctness of this assumption was proved in the following manner: The monomethyl ester of NCDA, m.p. 13loI2 was converted into the methyl ketone, dinitrophenylhydrazone m.p. 138' , by reaction of the acid chloride with dimethyl cadmium. Perbenzoic acid cleavage, followed by base hydrolysis of the resulting acetate gave the anticipated hydroxy acid ClSHzoOs, which was then heated with phosphorus tribromide. After hydrolysis with water a crystalline acid was obtained which infrared comparison showed to be identical with the C12 acid of Ruzicka and van Melsen.An attractive hypothesis was that the quaternary grouping involved in the rearrangement of bromo-NCDA included the gem dimethyl group of (1) L. Ruzicka and J. The last published investigation of the Ct; acid is by W. Treibs, Bet.. 7 6 , 160 (1943). (6) G. Stork and R. Brealow, THIS J O U R N A L , 76, 3291 (lQ58).cedrene.6 This hypothesis received support from our observation that the characteristic gem dimethyl split peak a t about 7.3 p,7 which is clearly evident in the infrared spectra of practically all the cedrene degradation products which we have examined, is changed to the usual C-methyl band in the rearranged Clz acid. Conclusive proof of the involvement of the gem dimethyl group was obtained by taking advantage of the fact that a rearranged acid in which the original gem dimethyl grouping had changed to two separate methyl groups must show between one and two more Cmethyls than the parent compound. Experimental results were in agreement with predictions : NCDA monomethyl ester showed C-methyl : Calcd. for one C-methyl, 6.4. Found: 5.9y0. The C12 acid showed C-methyl : Calcd. for three C-methyls, 23.2. Found: 22.6%.The rearrangement of bromonorcedrenedicarboxylic acid, which incidentally finds a striking parallel in the transformation of bromocamphoric acid into laurolenic acid...

The biosynthesis of penicillin. 1. The incorporation of some amino acids into penicillin

“…The only other known analogue which still retains the fused fl-lactam-thiazolidine rings of penicillin is a methyl penicillinate (II) synthesized by Sheehan, Henery-Logan & Johnson (1953). The fact that this compound is inactive against penicillin-sensitive bacteria suggests that the penicillin amide group is essential for biological potency.…”

The structure of cephalosporin C

“…The dihydrothiazine ring is a heterocycle that does not appear to have been encountered previously in Nature. The nucleus of the penicillin molecule has been named 6-aminopenicillanic acid (Sheehan, Henery-Logan & Johnson, 1953). We propose the trivial name 7-aminocephalosporanic acid for the nucleus (XXI) of cephalosporin C. Evidence has been obtained that this compound can be produced from cephalosporin C itself (Loder, Newton & Abraham, 1961 1959that 8-(oc-aminoadipoyl)cysteinylvaline, or the corresponding disulphide, is present in the mycelium of Penicillium chrysogenum has raised the possibility that cephalosporin N, or a closely related substance, occupies a special position in the general scheme of penicillin biosynthesis.…”

Synthesis of Some Stable 7-Halo-1,4-thiazepines. Potential Substituted Penam Precursors

“…Although there are reports, of attempts to achieve such a goal by Knunyants and coworkers (6) and also by Leonard and Wilson (7), this synthetic approach has never been thoroughly investigated due mainly to the unavailability 'NRCC Predoctorate Fellow 1965. 'NRCC Predoctorate Fellow 1968-1971 3The terms "penam" and "penicillanic acid" correspond t o the following ring systems and carry n o stereochemical implications, as first suggested by Sheehan et al (21).…”