β‑Selective <i>C</i>‑Arylation of Silyl Protected 1,6-Anhydroglucose with Arylalanes: The Synthesis of SGLT2 Inhibitors

The stereoselective arylation of hydroxy protected 1,6-anhydro-β-d-glucose with arylalanes to provide β-<i>C</i>-arylglucosides is reported. Modification of triarylalanes, Ar₃Al, with strong Brønsted acids (HX) or AlCl₃ produced more reactive arylating agents, Ar₂AlX, while the incorporation of alkyl dummy ligands into the arylating agents was also viable. Me₃Al and <i>i</i>-Bu₂AlH were found useful in the <i>in situ</i> blocking of the C3-hydroxyl group of 2,4-di-<i>O</i>-TBDPS protected 1,6-anhydroglucose. The utility of the method was demonstrated by the synthesis of the SGLT2 inhibitor, canagliflozin

β‑Selective <i>C</i>‑Arylation of Diisobutylaluminum Hydride Modified 1,6-Anhydroglucose: Synthesis of Canagliflozin without Recourse to Conventional Protecting Groups

The β-selective phenylation of benzyl and boronate protected 1,6-anhydroglucose and the direct phenylation of unprotected 1,6-anhydroglucose (<b>10</b>), pretreated with <i>i</i>-Bu₂AlH, <i>i</i>-Bu₃Al, Et₃Al, Me₃Al, or <i>n</i>-octyl₃Al, with triphenylalane or aryl­(chloro)­alanes is reported. The utility of the unprotected version of the method is demonstrated by the synthesis of the SGLT2 inhibitor, canagliflozin (<b>1a</b>), from commercially available <b>10</b> in one C–C bond-forming step. This approach circumvents the need for conventional protecting groups, and therefore no formal protection and deprotection steps are required