No abstract

Asymmetric allylic alkylation of β-ketoesters with allylic alcohols catalyzed by [Ni(cod)2]/(S)-H8-BINAP was found to be a superior synthetic protocol for constructing quaternary chiral centers at the α-position of β-ketoesters. The reaction proceeded in high yield and with high enantioselectivity using various β-ketoesters and allylic alcohols, without any additional activators. The versatility of this methodology for accessing useful and enantioenriched products was demonstrated.

A highly efficient gold(I)- and platinum(II)-catalyzed process for formal Markownikoff's double hydroamination of alkynes tethered with hydroxyl group has been developed. The method was shown to be applicable to a broad range of 2-aminobenzamides and alkynols leading to the formation of multiply substituted tetrahydroquinazolinones. Interestingly, when Pt(IV)Cl(4) catalyst was employed, cyclic angularly fused compound was obtained.

Pfizer’s drug for the treatment of patients infected with COVID-19, Paxlovid, contains most notably nirmatrelvir, along with ritonavir. Worldwide demand is projected to be in the hundreds of metric tons per year, to be produced by several generic drug manufacturers. Here we show a 7-step, 3-pot synthesis of the antiviral nirmatrelvir, arriving at the targeted drug in 70% overall yield. Critical amide bond-forming steps utilize new green technology that completely avoids traditional peptide coupling reagents, as well as epimerization of stereocenters. Likewise, dehydration of a primary amide to the corresponding nitrile is performed and avoids use of the Burgess reagent and chlorinated solvents. DFT calculations for various conformers of nirmatrelvir predict that two rotamers about the tertiary amide would be present with an unusually high rotational barrier. Direct comparisons with the original literature procedures highlight both the anticipated decrease in cost and environmental footprint associated with this route, potentially expanding the availability of this important drug worldwide.

An efficient method for Markownikoff's hydroamination-hydroarylation of alkynols using PtBr(2) as catalyst has been developed. The platinum-catalyzed reactions of alkynols with amino group containing aromatics were achieved in methanol over a reaction time of 6-24 h and temperature ranging from rt to 80 degrees C. This method works well for a variety of alkynols and aromatic amino compounds to give substituted pyrrolo[1,2-a]quinoxalines and indolo[3,2-c]quinolines in good to excellent yields.