β-Selective C-Arylation of Silyl Protected 1,6-Anhydroglucose with Arylalanes: The Synthesis of SGLT2 Inhibitors

Abstract

The stereoselective arylation of hydroxy protected 1,6-anhydro-β-d-glucose with arylalanes to provide β-C-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-Bu2AlH were found useful in the in situ blocking of the C3-hydroxyl group of 2,4-di-O-TBDPS protected 1,6-anhydroglucose. The utility of the method was demonstrated by the synthesis of the SGLT2 inhibitor, canagliflozin.

Synthesis of protected glucose derivatives from levoglucosan by development of common carbohydrate protecting group reactions under continuous flow conditions

“…Their range of stabilities under basic and acidic conditions [48], ability to be activated with various promoters such as N -iodosuccinimide (NIS), hypervalent iodine and pentavalent bismuth (V) [49–53], their orthogonal activation over common glycosyl donors [54], and their ability to be preactivated and coupled selectively in the presence of other thioglycosides [55] makes them ideal for building block production and oligosaccharide synthesis. The stereoselective ring opening of functionalized levoglucosan with bis (trimethylsilyl) sulfide, trimethylsilyl azide, and aryl (halo)-alanes under batch conditions has been reported [31–33], although the production of thiol substrates requires 4–6 h in CH 2 Cl 2 [31]. With the use of trimethylsilyl azide, alpha glycosyl azides can be produced in roughly 24 min for click chemistry applications, but this method is not ideal for carbohydrate building block production.…”

“…Increased efforts to produce levoglucosan from biomass have led to significant cost decreases [28–30], thereby making this molecule a more desirable chiral pool material. Past efforts have shown that levoglucosan can be used to produce functionalized glucose analogs in batch production [31–33]. However, these batch production methods do not readily lend themselves to a continuous synthesis process and have not been carried out with the use of green solvents in mind.…”

Nucleophilic Ring‐Opening of 1,6‐Anhydrosugars: Recent Advances and Applications in Organic Synthesis

“…[37] In 2015, the group of Henschke proposed a new approach to this class of compounds based on the β-selective arylation of 1,6-anhydroglucose derivatives with arylalanes prepared from the corresponding aryl lithium or Grignard reagents and AlCl 3 (Scheme 11a). [38,39] As shown in a preliminary screening study, the use of other Lewis acids based on Boron, Gallium, Titanium, Zinc, Indium or Hafnium failed to provide the desired β-aryl C-glucoside product. In the elegant approach designed, the Lewis acid and the aryl nucleophile are combined in a single reagent able to open the 1,6-anhydro sugar via the initial formation of a complex between the arylalanes and the oxygen atom at C-6 (Scheme 11b).…”

“…A bidentate complex bridging the C3-O and C6-O related to Vasella's model involving an intramolecular alkynyl shift (Scheme 8d) is believed to be too conformationally constrained to allow for the requisite alignment of the aryl group with the oxocarbenium ion. [38] Henschke et al synthesized several aryl β-C-glucosides by using aryl(halo)alanes, triarylalanes, aryl(alkyl)haloalanes or aryl(alkyl) alanes. [38] Quite surprisingly, arylation of a tri-O-TBS protected levoglucosan substrate led to significant formation of decomposition products, whereas the corresponding 2,4-di-O-TBDPS analogue provided the desired aryl β-C-glucoside product in good yields despite the presence of a free hydroxyl group at C-3.…”

A concise and practical stereoselective synthesis of ipragliflozin L-proline

“…SGLT-2 inhibitors have the common pharmacophore of β- C -arylglucoside, and the synthesis of β- C -arylglucoside including the usage of arylzinc [12], arylalane [13], and anomeric stannane [14] were applied to prepare dapagliflozin and canagliflozin. However, these approaches might be difficult to scale up because of the involvements of complex synthetic procedures, chromatographic purification or expensive catalysts and ligands.…”