Remarkable β-Selectivity in the Synthesis of β-1-C-Arylglucosides:  Stereoselective Reduction of Acetyl-Protected Methyl 1-C-Arylglucosides without Acetoxy-Group Participation

Abstract

An efficient and practical process to generate beta-C-arylglucoside derivatives was achieved. The process described involves Lewis acid mediated ionic reduction of a peracetylated 1-C-aryl methyl glucoside derived from the addition of an aryl-Li to selectively protected delta-D-gluconolactone. The reduction of the 2-acetoxy-1-C-oxacarbenium ion intermediates proceeds with a high degree of selectivity to give beta-C-arylglucosides without 2-acetoxy group participation. Furthermore, during the reduction process we also identified an unprecedented critical role of water. By changing from the usual benzyl ether protecting groups because of cost and chemical compatibility concerns, the new process is made additionally efficient and highly selective.

Synthesis of empagliflozin, a novel and selective sodium‐glucose co‐transporter‐2 inhibitor, labeled with carbon‐14 and carbon‐13

“…The molecule itself was known since 1835 and is a naturally occurring compound isolated from the bark of pear, apple, cherry, and other fruit trees . This compound was superseded by better and more selective synthetic analogs like canagliflozin,, dapagliflozin, and empagliflozin (Figure ).…”

Synthetic Strategies toward SGLT2 Inhibitors

“…Overall, the diastereoselectivity of Lewis acid-mediated silane reductions of tetra-O-protected glycopyranosides to β- C -glucosides varies from moderate to high. , Studies have shown that the stereoselectivity of the reduction step might be affected by the use of bulky reducing agents such as i -Pr 3 SiH (TIPS-H) or (TMS) 3 SiH, , conformationally restricted substrates, or other factors such as the nature of the Lewis acid ,, and the aglycone …”

Dapagliflozin, A Selective SGLT2 Inhibitor for Treatment of Diabetes

“…The current synthetic route portrayed in Scheme 5.2 was the result of many process improvements over the initial route [25,26]. In the original route benzyl ether protecting groups were employed throughout the synthesis and were removed by hydrogenolysis in the final step.…”

“…To ascertain if only the spatial presentation of the sugar and benzyl moieties of 20 was conducive to high SGLT2 potency, alternative presentations were systematically evaluated [25]. The assumption was that high affinity SGLT2 antagonists required the distal aryl ring to bear a lipophilic substituent properly oriented so that the substituent would extend into a favorable binding pocket.…”