Facile Approach to C‐Glucosides by Using a Protecting‐Group‐Free Hiyama Cross‐Coupling Reaction: High‐Yielding Dapagliflozin Synthesis

Abstract

This work represents another step in the effort to use glycals (1,2unsaturated derivatives of carbohydrates) as donor synthons for transition metal-catalyzed arylation reactions. We have employed a novel 1-silyl derivative of d-glucal, which was obtained as ab enchstable solid and could therefore be used conveniently.F or its preparation, we have used at ransient protection with MOP groups, which we developed previously,a nd therefore we could access the key synthon in its unprotected form. Ta king advantage of this, we have carried out ar ange of Hiyama arylation reactions without the need for protection. We have also spectroscopically confirmed the role of the silyl hydride derivative as am asked silanol and its hydrolytic activation, which is ak ey mechanistic step for transmetalation of the glycal moiety to palladium. Moreover,w eh ave used this strategy to develop av ery short synthesis of Dapagliflozin, an important commercial drug.

Palladium‐Catalyzed Reaction of Aryl Iodides and Glycal Enones: Application in the Preparation of Dapagliflozin Analogues

“…Moreover, the NOE spectrum of compounds 13 and 15 showed a clear interaction between the protons H‐1 and H‐5 due to syn‐relationship, which further confirms the stereochemistry of glycoside as β anomer [4b,7] . Moreover, the analytical data of compound 15 is in agreement with the literature report [13] …”

“…[4b,7] Moreover, the analytical data of compound 15 is in agreement with the literature report. [13] Further, we explored the regioselective synthesis of C-2 nitro aryl enones from aryl enones via nitration reaction (Scheme 7). The aryl enones 3 a and 3 e were treated with a mixture of tetrabutylammonium nitrate and trifluoroacetic anhydride in DCM at 40 °C.…”

C–H Glycosylation of Native Carboxylic Acids: Discovery of Antidiabetic SGLT-2 Inhibitors

“…Since β- C -glucosides broadly exist in drug molecules, this method should provide meaningful synthetic applications in medicinal chemistry. When the silyl-protecting groups were changed to benzyl groups, further transformation with DMDO and Superhydride was conducted to afford the desired C -glycosides 11 with highly controlled α-configuration. , Collectively, we have demonstrated that our newly developed method could be applied to generate structurally diverse and functionalized C -glycosides rapidly and efficiently.…”

Palladium-catalyzed Suzuki-Miyaura cross-couplings of stable glycal boronates for robust synthesis of C-1 glycals

“…Aligned with our focus on the precise preparation of glycopeptides and the modification of complex peptides [53][54][55][56] , we intend to leverage the robust palladium-catalyzed Suzuki-Miyaura coupling method for efficient synthesis of glycal amino acids or glycal peptides (Fig. 3), an area with limited exploration and established synthesis methods 32 . Under standard reaction conditions, both fully protected and partially protected phenylalanine derivatives, including Boc-L-Phe(4-Br)-OMe (16a), Boc-L-Phe(4-Br)-OH (16b), and NH 2 -L-Phe(4-Br)-OMe (16c), yielded the corresponding products in 94%, 53%, and 58% yields, respectively.…”

“…Transition-metal-catalyzed cross-coupling reactions have firmly established themselves as indispensable tools in modern organic synthesis. Notable progress has also been made in constructing C1-substituted glycals through transition-metal-catalyzed Stille [24][25][26][27][28][29] , Negishi 30 , Hiyama-Denmark 17,31,32 , and Heck 33,34 cross-coupling reactions. Among them, the environmentally friendly Suzuki-Miyaura cross-coupling reaction stands out as a crucial tool in glycal-based cross-coupling.…”