Sébastien Lemaire

Stereoselective C-glycosylation reactions with arylzinc reagents.

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.

Cine Substitution with Arylzinc Reagents: Scope and Mechanistic Studies

The unexpected ability of arylzinc reagents bearing electron-donating substituents to react in a Friedel-Crafts fashion (cine) with electrophiles like perpivaloylated glucoside bromide and benzhydryl bromides in competition with organometallic coupling (ipso) is shown. The stereoelectronic factors required to promote the cine reactivity versus the classical ipso, and the mechanism of this alternative pathway, have been investigated. The Wheland intermediate is deprotonated intramolecularly in a 1,2-shift but also in a longer-range shift, leaving in this case the C-Zn untouched. In the latter case, it is possible to take advantage of this result for further functionalization.

α-C-Glycosides via syn Opening of 1,2-Anhydro Sugars with Organozinc Compounds in Toluene/n-Dibutyl Ether

The diastereoselective addition of organozinc species to 1,2-anhydro sugars in toluene/n-dibutyl ether solvent is reported. Compared to the existing methods, the reaction proceeds at 0 °C, and only a slight excess of nucleophile is required to achieve good yields. Scope was assessed with different O-protected glycals along with various nucleophiles (aryl, alkynyl). This methodology was applied to the synthesis of the α-anomer of canagliflozin.

Stereoselective C-glycosylation of furanosyl halides with arylzinc reagents

Abstract Were are reporting a highly diastereoselective, transition-metal-free approach of C-aryl glycosides in the pyranoside and furanoside series by the direct coupling of glycosyl halides with diarylzinc reagents in a toluene/di-n-butyl ether solvent mixture.

Development of Efficient Routes to Access C-Glycosides as SGLT-2 Inhibitors for the Treatment of Type 2 Diabetes

C-Glycosides represent an attractive class of compounds for the medicinal chemist because they are more resistant to enzymatic hydrolysis than O-glycosides and therefore are considered as potential drug candidates. The potential was confirmed by the emergence of a new family of C-glycosides known as the SGLT-2 inhibitors leading to the development of new drugs for the treatment of type 2 diabetes. In this chapter, chemical processes to access new active pharmaceutical ingredients (API) will be described focusing on the key C-glycosylation step.