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Abstract

The main aim of the studies undertaken was to introduce carbon substituents at the 6-position of the penicillin nucleus, by means of the reactions of 6-diazopenicillanates with a variety of nucleophiles, including heterocycles. For this reason, the examples of such C-6 substitution already in the literature were reviewed, as well as the reactions of diazocompounds with hetero-cycles .

The syntheses of penicillanic esters as starting materials for the reactions were carried out according to the literature methods, incorporating either the p-nitrobenzyl or pivoyloxymethy1 groups for protection of the acid function.
Reaction of p-nitrobenzyl 6-diazopenicillanate with diborane gave p-nitrobenzyl penicillanate but with tributylborane afforded only the rearranged thiazepine. In the case of the latter, sev-eral attemptswere made to trap, isolate or identify the proposed enol-borinate intermediate, but without success. Extensive H.P.L.C. was employed for rapid analysis of product mixtures.

With furans, 6-diazopenicillanates were shown to undergo cyclo- propanation, ring-opening and ring-expansion reactions, and a new mechanism for formation of the products via ylid intermediates was proposed. Support for this theory was obtained from a variety of control reactions. Although the corresponding reactions of 6- diazopenicillanates with pyrroles proved unsuccessful, novel sub-stituted penicillins were obtained from the reactions with 3,4- dimethylthiophene and N-methylindole. Assignments of the stereo-chemistries of these adducts were made with the aid of n.O.e. difference spectroscopy.

The reaction of p-nitrobenzyl 6-diazopenicillanate with 1-cyclo- hexenyloxytrimethylsilane produced the cyclopropane adduct as required, but the analogous reaction with 1-phenyl, 1-trimethyl-silyloxyethene afforded no substituted penicillins. Cyclopropanes were produced in the reaction of p-nitrobenzyl 6-diazopenicillanate with methyl acrylate. Reaction with allyl acetate gave both allyl-oxy thiazepine and a doubly-substituted penicillanate, the structure of which has still to be confirmed. With tbutylisonitrile, complex- ation between reagent and catalyst was thought to be the reason for lack of reaction with the carbenoid of the penicillin.

H.P.L.C. was applied to the analysis and isolation of substituted penicillins. Product mixtures which were inseparable by preparative T.L.C. were successfully resolved by preparative H.P.L.C., and rapidly-occurring reactions successfully monitored by analytical H.P.L.C.

Publication Type:	Thesis (Doctoral)
Subjects:	Q Science > Q Science (General) Q Science > QD Chemistry
Departments:	School of Science & Technology School of Science & Technology > School of Science & Technology Doctoral Theses

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