| Carbon-carbon bond formation is an important hallmark of organic synthesis. The importance of this strategic bond construction is evidenced by the multitude of reagents and methodologies which have been developed to accomplish this task. A vast number of naturally occurring compounds contain simple cyclic secondary or tertiary amine moieties within more complex carbon frameworks. Many of these compounds possess some form of biological activity ranging from simple analgesic and anti-inflammatory properties to more robust substances with power to combat serious illnesses, such as some forms of cancer as well as Parkinson's disease. A key feature in any synthetic approach to such compounds is the carbon-carbon bond forming sequences. Several alkaloids were prepared using alpha-(Heteroatom)alkylcuprate reagents to construct the crucial carbon-carbon bond. This methodology provided a framework on which the chemistry of newly developed cuprate reagents could be investigated, while simultaneously allowing rapid construction of the pyrrolizidine and indolizidine core substructures. Generation of the pyrrolidinyl cuprate reagent followed by coupling with vinyl halides provided substituted pyrrolidines which, after deprotection and cyclization, afforded carbon backbones of both the indolizidine and pyrrolizidine systems. Simple functional group manipulation provided a highly divergent synthesis of the alkaloids heliotridane, isoretronecanol, curassanecine, tashiromine and epitashiromine.; To address issues of stereochemistry, an investigation of asymmetric carbon-carbon bond formation was undertaken. The underlying questions centered on the configurational stability of the carbon-copper bond within the cuprate reagent. In addition to the cyclic pyrrolidinyl cuprate reagents which are configurationally stable under certain reaction conditions, stable acyclic, stereogenic reagents could be prepared. These reagents react with a variety of electrophiles ranging from vinyl halides to alpha, beta-unsaturated ketones and propargylic halides and mesylates in modest to excellent chemical yield. Stereocontrol is capricious giving an array of results from modest enantioselectivity to excellent (99% ee). However, the reaction parameters could be adjusted to afford good enantioselectivities in most cases. Additionally, the methodology has been extended to include not only nitrogen systems but the oxygen analogues as well.; In conclusion, scalemic, stereogenic, alpha-(alkoxy)alkyl- and alpha-( N-carbamoyl)cuprates, both cyclic and acyclic have been developed to probe questions of configurational stability and stereocontrol and have been implemented in the synthesis of several pyrrolizidine and indolizidine alkaloids. |
