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The development of an efficient manufacturing process for sotagliflozin (LX4211), a dual inhibitor of sodium–glucose cotransporter-1/2 (SGLT-1/2) for the treatment of diabetes, is described. Sotagl...

This Letter describes the synthesis of olefins by coupling of electron deficient sulfonylhydrazones with aryl sulfinate salts in the presence of a palladium(II) catalyst under aerobic conditions. This methodology obviates the need for preparation of an organometallic and separate activation of the ketone starting material via a vinyl halide or triflate. The oxidant, reagent stoichiometry, and the electronics of the sulfinate coupling partner are reported.

This paper describes a new reactivity of the Pd-catalyzed coupling of 2-amino-3-bromo-aromatic and heteroaromatic compounds with sulfonylhydrazones (Barluenga reaction).The new catalyst system and modulation of the electronic nature of hydrazone that were needed for successful reaction are described herein.

This contribution describes the total synthesis of a complex macrocyclic integrase inhibitor, a key enzyme involved in the infection process of various immunodeficiency viruses. The key transformation of the synthetic strategy was the selective C–N coupling of a sulfonamide to a heteroaryl bromide in the presence of potentially competing amide and carbamate functionalities. The transformation was accomplished with CuI catalysis using bypiridine as the ligand in the presence of base and enabled a convergent approach to the target molecule.

This paper describes a new convergent approach to the synthesis of an HIV protease inhibitor which was designed to be suitable in long acting formulations. Unique features in the synthesis include an asymmetric hydrogenation as well as enzymatic reduction of a key chloro ketone intermediate, to set the threo stereochemistry in the corresponding epoxide and the diastereoselective coupling of the latter with the zinc enolate of a suitable functionalized amide derivative.

This Letter describes the synthesis of olefins by coupling of electron deficient sulfonylhydrazones with aryl sulfinate salts in the presence of a palladium(II) catalyst under aerobic conditions. This methodology obviates the need for preparation of an organometallic and separate activation of the ketone starting material via a vinyl halide or triflate. The oxidant, reagent stoichiometry, and the electronics of the sulfinate coupling partner are reported.

The synthesis of an anti-infective nucleoside derivative was accomplished through selective hydrogenation using an achiral ligand to establish the stereochemistry of the 2′ stereogenic center. The quaternary 4′ center was introduced through stereoselective epoxidation with dimethyl dioxirane followed by a regioselective, stereospecific epoxide opening with trimethylsilyl azide.

A general, transition-metal-free, highly stereoselective cross-coupling reaction between glycosyl bromides and various arylzinc reagents leading to β-arylated glycosides is reported. The stereoselectivity of the reaction is explained by invoking anchimeric assistance via a bicyclic intermediate. Stereochemical probes confirm the participation of the 2-pivaloyloxy group. Finally, this new method was applied to a short and efficient stereoselective synthesis of Dapagliflozin and Canagliflozin.

The carboxylate anion has been used as a directing group in the aromatic amination of electronically equivalent aryl bromides to afford selective ortho-substituted derivatives (>99:1 selectivity; 60-80% yield) in the case of copper(I) catalysis. The solvent, base and equivalents of base were important factors in the success of this reaction. Complementary selectivity was achieved with palladium catalysis where the para-substituted derivatives were produced selectively (>99% selectivity, 70-80% yield).

Diastereoselective hydrogenation of 2'-deoxy-2'-exo-methyleneuridine was carried out under homogeneous conditions using a low loading of a chiral Rh catalyst. This, coupled with improvements in the synthesis of the substrate, allowed the smooth pilot plant preparation of the title compound on >10 kg scale.

Highly substituted aromatic olefins are obtained by a new, effective, and atom-economical intramolecular cross-coupling reaction of the corresponding electron-rich aromatic sulfonylhydrazones involving a formal extrusion of SO2 and N2.

A novel reactivity of sulfonylhydrazones under Pd catalysis is described, where SO2 and N2 are formally extruded to afford the product of an apparent internal coupling reaction. The reaction is effective with both carbocyclic and heterocyclic aromatic precursors.

It is found that K2CO3/Pd2dba3-mediated treatment of the dichloro acid (I) with boronic acids allows selective formation of 2-arylated derivatives like (III).

The carboxylic acid anion moiety has been used as a tunable directing group in the cross-coupling reaction of 2,6-dichloronicotinic acid and 2,5-dibromo-1,2,4-triazole derivatives producing selectively the 2- or 6-substituted nicotinic acids, while only the 5-substituted triazoles were obtained under a variety of conditions.