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Three positional analogues (4-, 5-, and 7-) of benzothienylglycine and (N-acetylindolinyl)-5-glycine were prepared and coupled to 7-aminodeacetoxycephalosporanic acid (7-ADCA) to give the cephalosporins 17a-c. In addition two isomeric (2,3-b and 3,2-b) thienothiopheneglycines were synthesized and coupled to 7-ADCA to yield cephalosporins 30d and 30e. In vitro testing of these new cephalosporins indicates good activity against Gram-positive bacteria. Against Streptococcus pneumoniae infections compound 25 displayed better mouse protection (both orally and subcutaneously) than cephalexin.

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Acknowledgment is made to the donors of the Petroleum Research Fund, administered by the American Chemical Society, for the support of this research.(11) Thus far, efforts to detect a stabilized ylide intermediate have not been successful; this suggests that ring opening may be the rate limiting step in these reactions.(12) Carboethoxycyclobutyltriphenylphosphonium fluoroborate ( 17) may be prepared from cyclobutyltriphenylphosphonium bromide13 by a procedure analogous to the one used for the synthesis of 2 (17: 63 % yield (mp 162-163°)).

A new cepham metabolite has been isolated from the filtered broth of Cephalosporium acremonium by high performance liquid chromatography (HPLC) and identified as 7ß-(5-Damino-adipamido)-3ß-hydroxy-3a-methyl-cepham-4a-carboxylic acid (I). Pure penicillin N was prepared using HPLC in the analytical mode. When I was added in place of penicillin N as substrate for the cell-free biosynthetic of cephalosporin, no formation of deacetoxycephalosporin C (II) was observed.A synthetic cepham derivative, 7ß-(5-D-aminoadipamido)-3-exomethylene-cepham-4a-carboxylic acid (III) was also tested in the cell-free system as a possible intermediate. The compound III was shown to be an inhibitor of the ring expansion enzyme that converts penicillin N to deacetoxycephalosporin C.We have shown earlier3) that using HPLC one can isolate metabolites directly from the fermentation broth.Modification of appropriate stationary, and liquid phases, employed in the course of that first investigation, led to the isolation1)of new tripeptides from the broth of P. chrysogenum (Fig. 1).When the same system was applied to the present investigation of the broth of C. acremonium (Fig. 2), a new cepham derivative (I) was obtained.Its structure was suggestive of a possible relationship to deacetoxycephalosporin C (DAC, deacetoxy ceph C) (II) and, therefore, we examined its role in biosynthesis of DAC in a cell-free system derived from C. acremonium.KOHSAKA and DEMAIN4) were first to describe a cell-free system from C. acremonium CW-19 that converted penicillin N into a penicillinase-resistant cephalosporinase-sensitive material. YOSHIDA et al.,5) have shown this compound to be II by paper electrophoresis and paper and TLC chromatography.More recently, in another cell-free system derived from C. acremonium mutant M-0198, this finding was further confirmed6) using the same HPLC system we introduced in the examination of the broth of C. acremonium.3) In all these experiments however impure penicillin N was used as the substrate for the cell-free synthesis of DAC. We are able to prepare essentially pure penicillin N for use in the cellfree experiment.The process of the ring expansion from penicillin N to DAC was followed by injection into the HPLC system of aliquots of 50 microliters of the reaction mixture. The UV absorbance profile at 254 nm of authentic DAC was compared to profiles obtained from aliquots of the reaction mixture observed at 0 time, then at 20-minute intervals after addition of penicillin N to a total of 60 minutes. At that