| The development and application of new methods for the stereoselective synthesis of vicinal amino alcohols has been studied. The methods that have been developed involve the thermal intramolecular cyclization of an azidoformate using an amidohalogenation reaction or an acylnitrene aziridination reaction to form a bicyclic aziridine. This aziridine can be opened with a desired nucleophile to provide an oxazolidinone which can be readily hydrolyzed to give the amino alcohol.; In the amidohalogenation reaction, an amidohalide is produced via an intramolecular nitrene addition to an olefin to initially provide an aziridine, which is not isolated. Under the reaction conditions, HCl is generated from the solvent, which then protonates and opens the aziridine, providing the observed product. The reaction proceeds with good stereoselectivity, giving stereoisomeric ratios of 3:1 to 6.7:1 (trans:cis, respectively).; In the acylnitrene aziridination reaction, the aziridine is isolated. Using this reaction, a variety of substituted bicyclic aziridine precursors were synthesized from the corresponding azidoformates. The nucleophilic ring-opening of these aziridines using carbon, oxygen, nitrogen, sulfur, and halogen-containing nucleophiles provided the oxazolidinones in good yield with high regioselectivity. In all cases, nucleophilic attack occurred exclusively at the least-substituted carbon of the aziridine ring.; These methods were applied to the synthesis of the azepine core of ({dollar}-{dollar})-balanol and to the synthesis of ({dollar}-{dollar})-bestatin and analogs. While the synthesis of the azepine core of balanol was not completed, it was learned that the nature of the protecting group(s) on the amide nitrogen was important, as were the conditions of the final cyclization reaction. Attempts to carry out this cyclization did not give the azepine core; but instead, an eight-membered ring adduct was formed. Other attempts to form the azepine ring thermally or by phosphonimine formation were unsuccessful.; Preparation of ({dollar}-{dollar})-bestatin from an isopropylidene acetonide was unsuccessful due to difficulties with isolation and with separation of diastereomers. Bestatin was prepared regio- and stereospecifically from the more stable cyclohexylidene acetonidle. This approach features an intramolecular acylnitrene aziridination reaction and peptide bond formation using TBTU. Bestatin analogs were prepared by aziridine-opening with n-BuLi, n-hexyllithium, TMSCH{dollar}sb2{dollar}Li, and o-OMePhLi. |
