•Aza-Friedel-Crafts reaction of indoles to cyclic aryl α-ketimino esters.•A chiral phosphoric acid was used as catalyst for this transformation.•Enantioselective synthesis of indole-containing α,α-disubstituted α-amino esters.A highly enantioselective aza-Friedel-Crafts alkylation of indoles with cyclic aryl α-ketimino esters catalyzed by a chiral phosphoric acid has been developed, the corresponding α,α-disubstituted unnatural α-amino ester derivatives were obtained in moderate to high yields (67–85%) with high enantioselectivities (up to 93% ee) under mild reaction conditions.

A highly enantioselective C2 Friedel–Crafts alkylation reaction of 3-substituted indoles to β,γ-unsaturated α-ketimino esters has been developed. This reaction was efficiently catalyzed by a chiral phosphoric acid catalyst. The corresponding C2-substituted indole derivatives, bearing an α-ketimino ester motif, were obtained in moderate to high yields (up to 93%) and with high enantioselectivities (up to >99% ee).

Figure optionsA series of highly active C-aryl glucoside SGLT2 inhibitors containing a biphenyl motif were designed and synthesized for biological evaluation. Among the compounds tested, compound 16l demonstrated high inhibitory activity against SGLT2 (IC50 = 1.9 nM) with an excellent pharmacokinetic profile. Further study indicated that the in vivo efficacy of compound 16l was comparable to that of dapagliflozin, suggesting that further development would be worthwhile.

A highly enantioselective domino reaction of α,β-unsaturated aldehydes and 4-acetyl-5-oxohexanal catalyzed by a chiral secondary amine catalyst has been developed, providing an efficient synthetic approach for the synthesis of densely functionalized chiral cyclohexene derivatives with high yields (up to 96%) and enantioselectivities (up to 97% ee) under mild conditions.

We previously reported a highly potent DPP-IV inhibitor 6 with low in vivo efficacy. While trying to maintain consistent in vitro and in vivo biological activity, we initiated a pharmacokinetic property-driven optimization to improve the metabolic stability and permeability of inhibitor 6. A simple scaffold replacement of thienopyrimidine with pyrrolopyrimidine (21a) led to significantly improved metabolic stability (4% vs. 65% remaining). Further modification of the pyrrolopyrimidine scaffold to produce compound 21j resulted in much better oral bioavailability than 6. Importantly, compound 21j exhibits greater in vivo efficacy than does 6 and Alogliptin and is worthy of further development.Highlights► Highly potent DPP-IV inhibitors with poor PK properties were optimized. ► Novel pyrrolopyrimidine analogues were synthesized and assayed for DPP-IV inhibition. ► Selected analogues were evaluated for PK properties and in vivo activity. ► Compound 21j exhibits better in vivo efficacy than Alogliptin in mice.

Highly substituted tetrahydroimidazopyrimidine derivatives with three chiral centers have been synthesized for the first time using an organocatalytic asymmetric domino aza-Michael–Mannich reaction of α,β-unsaturated aldehydes and N-arylidene-1H-imidazol-2-amines. This efficient approach furnishes the products in good yields (42–87%) with excellent stereoselectivities (>20:1 dr, up to >99% ee).