Development of methodology for the synthesis of aldehydes, amides and indolizidine alkaloids

Part I. Development of synthetic methodology. The Mitsunobu reaction is a versatile and widely used reaction in organic synthesis for the stereochemical inversion of chiral secondary alcohols. An investigation using polymer-supported triphenylphosphine was pursued showing the advantages of using this reagent. By utilizing polymer-supported triphenylphosphine as a traceless reagent in the Mitsunobu reaction, the typical by-products from this reaction could be easily removed by simple filtration, giving the desired products with minimal purification.; The direct conversion of carboxylic acids to amides has traditionally been carried out via a two-step process involving the conversion of an acid to a more reactive species, such as an acyl halide, with subsequent displacement by a nucleophilic amine. A novel one-flask method was investigated to circumvent this two-step protocol for the conversion of carboxylic acids to amides using the Deoxo-Fluor(TM) reagent [bis(methoxyethyl)amino] sulfur trifluoride. A variety of amides, including Weinreb amides, were successfully prepared using this methodology in good overall yields.; Functional group manipulations continue to play an important role in organic synthesis, and hence the development of new methods to carry out these transformations remains an important part of organic chemistry. The reduction of amides to aldehydes is one such transformation, which has been addressed in our laboratory by utilizing commercially available Cp2Zr(H)Cl (Schwartz reagent). The reaction has been shown to proceed smoothly for tertiary amides in a rapid and high yielding manner. The scope and mechanism of the reaction have been explored.; Part II. Total synthesis studies of tyloindicine F. The tyloindicines F, G, H, and I (Figure 1) are a cytotoxic group of phenanthroindolizidine natural products which were isolated in 1991 by Ali et al. from the aerial parts of Tylophora indica. The tyloindicines F--G are a very promising discovery, which are thought to possess a unique mechanism of action in addition to their extremely potent and selective cytotoxicity profile. Unfortunately, these compounds were isolated only in small quantities ranging from 0.001 to 0.009%. Additionally, the reported structure remains in question. As such, synthetic efforts to explore tyloindicine F were pursued, resulting in the synthesis of 8a-deoxy-tyloindicine F and various tyloindicine analogues.