A Facile Convergent Synthetic Procedure For 3-Deoxydapagliflozin And Study On The Generality Of Structure-Activity Relationships Of Deoxylations Of The Sugar Moiety In SGLT2 Inhibitor

3-Deoxydapagliflzoin I-1 is a highly selective,potent sodium-dependent glucose transporter 2(SGLT2)inhibitor discovered earlier.A facile convergent synthetic procedure for 3-deoxydapagliflzoin 1-1 was developed in 13 steps and in 38%overall yield starting from inexpensive methyl a-D-glucopyranoside 1-2.Regioselective protection of 2-OH and 3-OH in the key intermediate methyl 4,6-O-benzylidene-a-D-glucopyranoside 1-3 was systematically studied;the regioisomers thus obtained were distinguished from each other with nuclear Overhauser effect(NOE)and their ratios and relative polarities were rationally explained.The strategy for deoxygenation of the sterically hindered 3-OH in another key intermediate 4,6-O-benzylidene-2-O-t-butyldiphenylsilyl-a-D-glucopyranoside 1-4 was also systematically studied.The facile synthetic route is characterized by convergence characteristics and inexpensive starting material,also representing an alternative general synthetic approach to phenyl 3-deoxy-C-glucosides.In order to study the generality of the structure-activity relationships(SARs)of 3-deoxylation and 6-deoxylation of the sugar moiety in SGLT2 inhibitors,we synthesize 3-deoxycanagliflozin ?-4,6-deoxyipragliflozin ?-5,6-deoxyempagliflozin?-6 and 3-deoxyempagliflozin ?-7 and evaluate their hSGLT2 and hSGLT1 inhibitory assay in vitro.The deoxylated SGLT2 inhibitors were synthesized from their corresponding aryl halides and 3-/6-deoxylated perbenzylated gluconolactones.In vitro hSGLT2 and hSGLTl inhibitory assay showed that ?-4 and ?-7 almost lost the SGLT2 inhibitory activity,while ?-5 and ?-6 exhibited similar activities to their corresponding parent compounds.It is general that 6-deoxylation of the sugar moiety in SGLT2 inhibitors basically has no effect on the SGLT2 inhibitory activity,whereas the corresponding 3-deoxylation has no universal rules and whether the 3-dexoylated SGLT2 inhibitors still exhibit potent SGLT2 inhibitory activity depends on the structures of the specific SGLT2 inhibitors.