Synthesis of carbohydrate modified alpha-galactosylceramide analogs and the discovery of novel reactions involving strained heterocycles

α-Galactosylceramide (KRN7000) was developed by Kirin Brewery Co., Ltd. in Japan. It exhibits potent anti-tumor activity in murine models and has also shown promising potential in the treatment of infectious and autoimmune diseases. The activity of KRN7000 is due to the immune responses induced by the CD1d-mediated natural killer T cell (NKT) activation. SAR studies on KRN7000 led to the development of several interesting analogs with different immunostimulatory properties. There are many analogs synthesized with modifications on the ceramide portion. However, there is limited data on how the modification on the carbohydrate portion of the α-galactosylceramide influences the outcome of different immune responses. Hence, for this study novel α-galactosylceramide analogs were designed by identifying potential areas for modification on carbohydrate portion from the crystal structure of CD1d/α-GalCer/T-cell receptor complex. These analogs are currently being investigated by our collaborators for their ability to stimulate NKT cells. During the synthesis of the marine natural product, laureatin from a 2-methyleneoxetane, novel rearrangement reactions were discovered.