Studies directed toward the synthesis of defucogilvocarcin M.

This thesis describes efforts to develop a synthesis of the defucogilvocarcin M carbon skeleton utilizing either an intramolecular or an intermolecular Diels-Alder cycloaddition as the key step. Chapters 1 and 2 provide background information regarding the isolation, biological activity, mechanism of action and previous syntheses of the gilvocarcins. Chapter 3 provides a retrosynthetic analysis of defucogilvocarcin M and describes the intramolecular and the intermolecular Diels-Alder approaches to its synthesis. Chapter 4 gives a brief review of the o-quinodimethane chemistry central to the proposed synthesis. Chapter 5 describes a photochemical synthesis of 1,4-dioxygenated-o-quinodimethanes. The o-QDMs were obtained by irradiation of 2-(methoxymethyl)-benzaldehyde (11) and the 2-(acyloxymethyl)benzaldehydes 14a-c. The intermolecular Diels-Alder reactivity, regioselectivity and stereoselectivity of the photoenols was ascertained by reaction with several dienophiles of varying reactivity. The catalytic effect of LiCl on the cycloaddition of the photoenol derived from 2-(benzoyloxymethyl)benzaldehyde (14b) and methyl acrylate was briefly examined. Marginal effects were also observed with several other dienophiles. 2-(benzoyloxymethyl)benzaldehyde (14b) was found to dimerize to compound 37 when irradiated in the absence of a reactive dienophile, analogous to the known photochemical behavior of o-tolualdehyde. Two model systems, 14d and 14e, designed to test the feasibility of an intramolecular photochemical Diels-Alder cycloaddition were synthesized. Photoenolization of the compounds, however, failed to afford cycloaddition products. Chapter 6 describes the results obtained from a re-evaluation of the photochemistry of 2-methylbenzoyl cyanide (1a). The latter compound as well as a number of other acyl cyanides (1b-e) were found to act as carbonyl heterodienophiles in Diels-Alder reactions with photochemically (1a-c) and thermally (8a,b) generated o-quinodimethanes. Several dimerizations and mixed cycloadditions were studied which led to highly substituted 3,4-dihydro-3-cyano-1H-2-benzopyran-1-ones. Photoenols derived from aroyl cyanides 1a and 1b were found to react with SO$\sb2$ to give 1-Hydroxy-1-cyano-1,3-dihydrobenzo (c) thiophene 2,2-Dioxides 19 and 20. Chapter 7 describes efforts to utilize the acyl cyanide cycloadducts as synthetic intermediates. A versatile isoquinolone synthesis was developed which involved reacting the acyl cyanide cycloadducts 1 and 8 with alkyl amines then cyclizing the amides obtained in aqueous acetic acid. Two cycloadducts (1 and 8) were converted to isocoumarins by dehydrocyanation with KtBuO in THF