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Abstract

The introduction of substituents other than nitrogen into the 6-position of penicillins and the 7-position of cephalosporins is reviewed and particular attention given to the applications of diazo compounds for these reactions.

Diazotization of a model α-aminoamide has been explored and an efficient synthesis of 6-diazopenicillanate esters has been developed.

Cyclopropanation reactions of benzhydryl 6-diazopenicillanate have been carried out with styrene and with cyclohexene. With thiophene, in addition to the expected cyclopropanation product a further adduct was obtained which provides a unique example of carbenoid ring expansion to a 2H-thiopyran. The stereochemistries of the carbenoid adducts have been
established by means of 1H n.O.e. difference spectroscopy.

Reactions of benzhydryl 6-diazopenicillanate with various alcohols have been shown to give rise to mixtures of 6-alkoxypenicillanates and alkoxythiazepines. The latter, and possibly the former, are formed via oxonium ylide intermediates. A different set of oxonium ylides are responsible for alkoxythiazepine formation in the reactions of the diazo compound with orthoesters. With anisole, spiro-cycloheptatrienyl adducts were obtained by Buchner ring expansion. The position of the methoxyl group in the adducts was determined by n.0.e. difference spectroscopy.

Addition of benzhydryl 6-diazopenicillanate to furan gives rise to products containing a conjugated dienal side chain at C-6, in quantitative yield. The potential of this method for the synthesis of 6-alkylated penicillanate derivatives has been explored and is exemplified by a variety of reduction, oxidation, and carbonyl group condensation reactions. Studies of the NaBH4 reduction of the dienals has led to the discovery of a unique, selective, pH-dependent 1,6-reduction. This afforded 6-(alk-l-enyl) penicillanates which provide the first examples of isosteric replacement of the side chain NHCO group in penicillins by a trans C=C bond.

Deprotection of all of the significant new penicillanate esters described in this thesis has been accomplished. None of the compounds showed antibacterial activity.

The applications of preparative HPLC to the purification of steroid esters, of a cephalosporin, and of some of the penicillin derivatives synthesised in this work, are described.

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

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