Abstract
The aim of this project was to develop a synthetic strategy for the production of uncommon sugars thevetose (6-deoxy-3-O-methylglucose) and cymarose (2,6-dideoxy-3-O-methylallose or 2,6-dideoxy-3-O-methylaltrose) derivatives, present in the trisaccharide moiety of a pregnane glycoside with appetite-suppressant activity.
A D-thevetose glycosyl donor was prepared from methyl D-glucopyranoside. The first step of the synthesis was the formation of a 4,6-O-benzylidene derivative that was selectively methylated on the 3-hydroxy group by using a copper mediated alkylation process. Treatment with NBS and reductive removal of the resultant bromide produced the required protected thevetose glycoside. This success is a vast improvement compared to the published results of the patent reporting this synthesis.
Attempts to prepare the 2α-iodo derivative by direct nucleophilic substitution of a 2-O-triflate manno-derivative resulted in a most unusual rearrangement reaction. Allal derivatives as starting materials in the preparation of 2α-iodo sugars were also unsuccessful due to steric hindrance provided by the axial 3-methoxy group. Preparation of a cymaroside precursor was achieved by using glucal as a starting material and by the inversion of C-3 in a consecutive oxidation/reduction sequence of the iodo acetate.
Lastly, the preparation of the β-oleandroside derivative of cholesterol was achieved in a model reaction. The sugar oleandrose is a C-3 epimer to cymarose and it can be found in pregnane and cardenolide glycosides.
Professor F.R. van Heerden