Synthesis of Immunostimulatory Galactosylceramide Analogs and Platinum(II) Catalyzed Isomerization of 4-Oxaspiro[2.3]hexanes

Glycosphingolipids, in particular a-galactosylceramides have received considerable attention due to their clinically relevant immunostimulatory activity. The prototypical synthetic galactosylceramide KRN7000, has been shown to stimulate NKT cells when bound to and presented by the CD1d protein. 1c This stimulation then leads to the release of different cytokines modulating TH1/TH2 type immune responses. Considerable effort has been made to synthesize analogs of KRN7000 to selectively induce either a TH1 or TH2 type response.;In search of additional analogs of potential therapeutic use, we considered the natural product, Plakoside A, which shares structural features with KRN7000, as well as similarities to a cyclopropanated glycolipid isolated from Sphingomonas witichii. In this thesis, we report synthesis of four different GalCer's, that have structural features from both, Plakoside A and KRN7000. Interestingly, two of these compounds have been found to activate human NKT cells with a TH1 biased profile.;Apart from these four analogs, we also report our attempts to synthesize C-analog of a disaccharide, Gal(alpha1-2)GalCer. A number of approaches were investigated to synthesize alpha-C-anomeric bond, of which only cross-metathesis/oxymercuration strategy was successful. Based on literature precedent on Gal(alpha1-2)GalCer, we anticipate that, the C-analog of Gal(alpha1-2)GalCer can only activate NKT cells in the presence of antigen presenting cells. Since the C-analogue of KRN700 (alpha-C-GalCer) has shown 1000 fold greater activity than KRN7000 and enhanced TH1 response, the disaccharide of alpha-C-GalCer may prove helpful in understanding the role of antigen presenting cells in the NKT cell activation and in the polarization of the immune response.;Another section of the thesis describes a novel Pt(II) catalyzed isomerization reaction of strained heterocyclic compounds, 4-oxaspiro[2.3]hexanes. 4-Oxaspiro[2.3]hexanes undergoes isomerization to 3-methylenetetrahydrofurans in the presence of catalytic amounts of Zeise's dimer. The scope of this transformation and the mechanism has been investigated in this study.