Title

New reactions involving strained heterocycles and syntheses of glycosphingolipids analogues of KRN7000

Date of Completion

January 2011

Keywords

Chemistry, Organic

Degree

Ph.D.

Abstract

2-Methyleneoxetanes combine very interesting structural features that make them highly reactive intermediates. In this thesis, we describe a facile and highly stereoselective double isomerization of 2-methyleneoxetanes leading to α,β-unsaturated methylketones. We propose that oxetes (oxetenes) are the species formed before electrocyclic ring opening. Although there are a number of literature precedents on isomerization of exo-methylene cyclic systems, this was the first example with 2-methyleneoxetanes.^ Also, as part of our focus to explore the reactivity of 2-methyleneoxetane derivatives, cleavage of 2-azido-2-(hydroxymethyl)oxetanes catalyzed by ruthenium tetroxide was investigated. Interestingly, the catalyst allowed these strained compounds to undergo cleavage providing nitriles. This was the first example for cleavage of β-azidoalcohols mediated by ruthenium tetroxide. ^ Glycosphilgolipids (GSLs) are known to be involved with the immune system regulation and are recognized as potential targets to treat diseases such as cancer, malaria and autoimmune disorders. α-GalCer, a synthetic GSL, has shown to strongly stimulate immune responses, however it did not progress in clinical trials. Here we present the syntheses of three GSLs analogues of α-GalCer and plakoside A and one GSL analogue of α-GalCer and a GSL from Sphingomonas wittchii. Biological results showed that two of these targets have a Th1 bias profile and that they activate human iNKT cells, not observed with the Th1 prototype GSL, C-glycoside. ^