Total Synthesis Of A Novel Marine Derived α-Galactoglycosphingolipid Clarhamnoside And Study On The Syntheses Of Several Analogues Of KRN7000

It is well-established that sponges of the genus Agelas and Axinella produceα-galactoglycosphingolipids (α-GalGSLs), unique glycosphingolipids with anα-galactose as the first sugar of the carbohydrate chain, unlike the ubiquitousβ-glycosidic bond from nearly all known higher animals and plants.α-GalGSLs are potent ligands of the MHC class I-like CD1d protein, which is present on the surface of the antigen presenting cells (APCs), and are capable of activating in vitro and in vivo a specialized population of T cells, named natural killer T cells (NKT cells), that play an important role in regulating innate and adaptive immunity during infection, tumor growth, and autoimmune diseases. Besides its biological activities, spongalα-GalGSLs appear to be a quite peculiar class of molecules in terms of the structure of their carbohydrate moieties. Since it is costly to isolate these GSLs from natural sources, and also not possible to obtain homogeneous material, a great deal of effort has been placed on the efficient synthesis ofα-GalGSLs.In this dissertation: (i) the first total synthesis of a novelα-galactoglycosphingolipid clarhamnoside has been achieved through a straightforward strategy; (ii) several analogues of KRN7000 and plakosides were designed and synthesized for the future evaluation in immunoregulatory activity.I. Total synthesis of a novel marine derivedα-galactoglycosphingolipid clarhamnoside. Clarhamnoside, a novelα-GalGSL, which was recently identified by the Mangoni group from new specimens of A. clathrodes, bears quite a unique structure containingα-L-Rhap-(1→3)-β-D-GalpNAc-(1→6)-α-D-Galp-(1→2)-α-D-Galp. It is one of the few naturalα-GalGSLs glycosylated at the inner galactose 2-OH and the onlyα-Gal- GSL with an L-rhamnose unit in the sugar head. In addition, the sequential two 1,2-cis-α-D-galactopyranosidic linkages [Galα-(1"→2')-Galα-(1'→1)-Cer] are also an extraordinary and rare feature in nature. A straightforward strategy was described to complete the synthetic work. (1) An efficient and practical route to azidophytosphingosines from D-galactose is described for use as glycosyl acceptors in the preparation of glycolipids; (2) Thiogalactoside with a benzylidene group at C4 and C6 was the first time applied as glycosyl donor in the stereoselective preparation ofα-GalGSLs instead of the corresponding trichloroacetimidate; (3) So thiolgalactosyl donor with a benzylidene group at C4 and C6 and non-participating PMB groups at C2, has been successfully used to achieveα-stereocontrolled synthesis of 2'-OH ?freeα-galactosyl lipids; (4) The terminal saccharide trifluoroacetimidate was synthesized and employed as the donor for the glycosylation, and was proved to be efficient in fragment coupling for aβ-glycosidic bond; (5) Synthetic procedure in a model compound was successfully translated to thre real target.II. Design and syntheses of analogues of KRN7000 and plakosides for the future evaluation in immunoregulatory activity.KRN7000, a potent analogue of the natural agelasphins isolated from the marine sponge Agelas mauritianus, is an important cerebroside exhibiting immunostimulatory activity. Plakosides are prenylated galactosphingosine isolated form the marine sponge Plakortis simplex and is strongly immunosuppressive without cytotoxicity. There are three major differences between the structures of KRN7000 and plakosides: configuration of the glycosidic bond, prenyl group on the galactose 2-position, and ceramide. As part of our effort to understand possible reasons that why the immunostimulatory activity in RKN7000 shift to immunosuppressive activity in plakoside, we designed and synthesized series of analogues of KRN7000 and plakosides in this dissertation. There are 12 target compounds were designed (TM1-TM12), and 7 of them were synthesized (TM3-TM9, TM12).