Synthesis of alpha-Galactosylceramide Analogs for Th1 Biased iNKT Cell Activation and Novel Reactions with Ketiminium Salts

Natural killer T (NKT) cells are a subset of T cells that recognizes and is activated by glycolipid antigens. Glycolipids, specifically alpha-galactosylceramides, are a primary focus due to their ability to modulate immune responses based on interactions with NKT cells. KRN7000, the first synthetic glycolipid shown to potently activate NKT cells, has been the foundation of structure-activity relationship (SAR) studies, providing insight to how glycolipids interact with components of the immune system to elicit specific responses. A glycolipid can produce a Th1 and/or Th2 response from NKT cells. A primary goal of many researchers is to produce a potent glycolipid, but also one that selectively induces a Th1 response. Various modifications have been made to the structure of KRN7000 to monitor changes in activity. 7DW8-5 is a potent, Th1 biasing glycolipid that emerged from such efforts. Another modification to KRN7000 was replacing galactose with several disaccharide counterparts. Certain disaccharides have been shown to increase Th1 responses in whole cell assays. Therefore, this thesis describes novel analogs of 7DW8-5 that have been developed in an attempt to produce a potent, Th1 biased biological response. Chiral amines are abundant in pharmaceutically interesting compounds including drugs currently on the market. One method of generating chiral amines is through nucleophilic addition into chiral N-sulfinyl imines and other substituted imines. One major flaw in this method is that the synthesis of N-substituted imines is not trivial. Some methods require highly reactive species or form insoluble byproducts that are not viable for large-scale process chemistry set ups. Transimination has been shown to form N-alkyl substituted ketimines from a ketiminium salt and alkyl amine. This thesis presents the first use of transimination to form chiral N-sulfinyl ketimines under optimal conditions. Ketiminium salts were also used to generate a library of N-phosphinyl, -tosyl, and –carbamoyl ketimines under mildly basic conditions with good to excellent yields.