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.