Batty, Duncan; (1992) Some studies on acyl radical cyclisations. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis is concerned with the development of acyl radical cyclisations and their applications to organic synthesis. It is divided into five theoretical chapters and an experimental chapter. The first chapter consists of a survey of the literature on acyl radicals and their reactions. The second chapter describes a convenient method for the preparation of phenyl selenoesters, the precursors of choice for acyl radicals, by the reaction of the corresponding carboxylic acid, as its triethylammonium salt, with phenylselenenyl chloride and tributylphosphine. Several examples are presented and the results contrasted with those obtained by alternative methods. 1lie third chapter describes the preparation of two synthons for the 'A' ring of 1α,25-dihydroxyvitamin D3. The first involves a highly efficient 6-exo mode cyclisation of a 6-heptenoyl radical, to give a highly functionalised cyclohexanone in which the exomethylene group is masked as a phenylthiomethyl group. Oxidation and syn elimination of this substance gives the exomethylene cyclohexanone. Attempts at elaboration of the side chain to give a second, known synthon of 1α,25- dihydroxyvitamin D3, the so-called 'Lythgoe Synthon', are described. The methodology developed for the 6-heptenoyl radical cyclisation is extended to a vinyl radical cyclisation. The successful synthesis of the 'Lythgoe Synthon' by this vinyl radical cyclisation is described. The fourth chapter deals with extensive model studies aimed at the determination of substituent patterns necessary for the 1-endo cyclisation of 6-heptenoyl radicals, leading to the formation of cycloheptanones and bicyclo-[5,3,0]-decanones. It is demonstrated that the inefficient 1-endo mode cyclisation of 5-alkoxy-6-heptenoyl radicals occurs by a direct 1-endo mode cyclisation, rather than by a ring expansion or reversible ring closure mechanism and that the influence of the 5-alkoxy residue on the mode of cyclisation is not simply steric. An efficient entry into 4,5-di-O-isopropylidene 6-heptenoyl radicals is described. When the relative configuration is erythro, efficient cyclisation is observed, with preferential 1-endo mode cyclisation, whilst for the r/zreo-isopropylidene the cyclisation is inefficient, with preferential 6-exo mode cyclisation. The introduction of an alkyl substituent into the 7-position of the 4,5-di-O-isopropylidene 6-heptenoyl radical reverses the mode of cyclisation, to give predominantly the 6-exo mode product. The yield of the 1-endo mode product can be increased by using more dilute reaction conditions. The knowledge gained in these studies is applied to a 7,5 double ring closure with the successful formation of a bicyclo-[5,3,0]-decane system. Various spectroscopic, chemical and computational techniques are employed to determine the stereochemistry of the bicycle-[5,3,0]-decanone systems formed. The fifth chapter concerns the development of an acyl radical initiated multiple radical cyclisation/fragmentation sequence aimed at the formation of medium sized rings. It is demonstrated that E-butenyl cyclohexanones can be efficiently prepared by preferential 6-exo mode cyclisation of 6-heptenoyl radicals bearing a cyclopropane ring in the 7-position. Selective ring opening of a cyclopropylmethyl radical bearing a phenyl substituent at the radical centre, to preferentially give the Z-homoallylic radical is described. The attempted cyclisation of 5-melhyl-5-hexenoyl, 6-methyl-6-heptenoyl radicals and an attempted allylic radical cyclisation is also described.

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