טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentRuhman Igor
SubjectMethods for Glycosidation of Biologically Active Compounds
DepartmentDepartment of Chemistry
Supervisor Mr. Arie Gutman


Abstract

As demonstrated in the literature, much of the analgesic effect attributed to morphine is due not to morphine itself, but rather to one of its main metabolites, morphine 6--D-glucuronide (M6G). Furthermore, is has been shown that morphine’s other main metabolite, morphine 3--D-glucuronide (M3G), antagonizes the analgesic effect of morphine. This potential pharmaceutical importance of M6G as a powerful analgesic and replacement to morphine prompted several researchers to explore ways for its selective synthesis.

During our research we developed two new simple methods for the stereoselective synthesis of both isomers of M6G and related compounds.


 The first method is based on glycosylation of selectively protected morphinanes with protected alkylthioglycosides in the presence of thiophilic promoters.

The second method uses ZnBr2 as catalyst and the selectivity of this reaction may be controlled by amount of ZnBr2 added. Both processes provide high stereoselectivity and good yields. The syntheses avoid expensive reagents, cleanly produce the desired product without tedious purification and can be easily scaled up for M6G 3a preparation in pharmaceutically sufficient quantities without losses in stereoselectivity.

A detailed NMR analyses unambiguously proved the anomeric configuration of the new compounds. The developed HPLC method may be used for detection of trace quantities of a-isomer 3b in the pharmaceutical grade morphine 6-β-D-glucuronide 3a. The devised convenient synthetic methods will allow significant quantities of heretofore-unknown a-isomers of morphine’s metabolites M6aG 3b, DHM6aG 17b, C6aG 9b, N6aG 10b and M3,6a-diG 4b to be obtained and will also facilitate the testing of its biological activity.

Additionally, the series of new 3-glycoside dihydromorphinanes 58a,b, 16a,b and 59 were synthesized for biological tests and identified by NMR, IR and HRMS experiments. We hope that the proposed methods will be useful for synthesis and testing of the biological activity of the new morphinane glycosides.