Modified Nazarov reactions and ring expansion chemistry: Useful methodologies for the construction of carbocyclic and heterocyclic compounds.

摘要

The design and development of new chemical transformations is an important area of organic chemistry. Many synthetic chemists are compelled to explore novel methodologies to improve upon or successfully complete an elegant total synthesis. As an example, the Nazarov reaction has been used extensively in strategies towards the synthesis of numerous natural products. The reaction provides a direct route to functionalized five-membered carbocycles through the Lewis or protic acid-mediated 4t electrocyclization of cross-conjugated dienones. The Nazarov reaction has garnered a great deal of attention in recent years with the advent of very useful asymmetric and catalytic variants, as well as "interrupted" Nazarov reactions.;During our examination of the scope of this reaction, a surprising "interrupted" Nazarov variant was observed. A gem-dichiorocyclopropane substrate bearing a tethered phenyl ring was able to participate in an intramolecular trapping process wherein the unsubstituted phenyl moiety captured the intermediate cyclic oxyallyl cation, affording a benzohydrindenone product. Further investigation revealed that electron-poor, neutral, and electron-rich aromatic rings were compatible with this reaction sequence, providing a number of benzohydrindenone products in moderate to good yields. In chapter three, the results of this investigation are described and a new mode of arene trapping is also presented.;In chapter four, the development of a two-step ring expansion sequence for the synthesis of functionalized heterocycles is reported. Ring expansion was found to proceed as a result of tert-butyl propiolate addition into simple and readily available lactones or lactams, providing conjugated ynones that could undergo cyclization in the presence of pyridinium acetate. This methodology provides a straightforward route to the construction of six- and seven-membered oxygen- and nitrogen-containing heterocycles.;Recent advances in Nazarov cyclization chemistry will be reviewed (chapter one) prior to the introduction of gem-dihalocyclopropanes as innovative substrates for the Nazarov reaction. In chapter two, preparation of the requisite 1,1-dihalo-2-(silyloxy)-2-vinylcyclopropanes will be outlined and their reactivity towards treatment with silver tetrafluoroborate will be described. It was found that these conditions induced sequential disrotatory ring opening and 4pi electrocyclization (Nazarov cyclization) to furnish alpha-chlorocyclopentenone products. This strategy was also used in our preliminary investigation into a general approach towards imino Nazarov reactions.