Synthesis of 2-substituted polyhydroxytetrahydropyrimidines (N-hydroxy cyclic guanidino-sugars): transition-state mimics of enzymatic glycosidic cleavage.
The synthesis of 2'-substituted polyhydroxytetrahydropyrimidines as transition-state mimics of enzymatic glycosidic cleavage has been achieved by using guanylation and cyclization methodologies. The D-galacto type N-hydroxy cyclic guanidino-sugar 21 was synthesized in six steps from amine 7 and thiourea 14 in an overall yield of 59%. To further derivatize compound 21 to incorporate the leaving group moiety, we have synthesized 2-methylsulfanyl compounds 26-29 as key intermediates. The 2-methylsulfanyl group in 29 was displaced with amines, assisted by silver tetrafluoroborate as Lewis acid, to give protected cyclic guanidines 30-32 in moderate yields (60-67%). Removal of the protecting groups in 32 gave the D-galacto-type N-hydroxy cyclic guanidino-sugar 34. The key steps in the synthesis of the 6-deoxy-DL-galacto type N-hydroxy cyclic guanidino-sugars 49, 54, and 64-66 involve cyclization of the appropriate acetal intermediates (45, 50, and 58-60) followed by removal of the protecting groups.
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Department of Chemistry, Scripps Research Institute, La Jolla, California 92037, USA.
Wong
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D018360:Crystallography, X-Ray; D003500:Cyclization; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006027:Glycosides / Q000737:chemistry*; D006147:Guanine / Q000737:chemistry; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D011743:Pyrimidines / Q000138:chemical synthesis*
D006027:Glycosides; D007202:Indicators and Reagents; D011743:Pyrimidines; D006147:Guanine; D006026:Glycoside Hydrolases