Exploration of P1 and P4 modifications of nirmatrelvir: Design, synthesis, biological evaluation, and X-ray structural studies of SARS-CoV-2 Mpro inhibitors.

We report the synthesis, biological evaluation, and X-ray structural studies of a series of SARS-CoV-2 Mpro inhibitors based upon the X-ray crystal structure of nirmatrelvir, an FDA approved drug that targets the main protease of SARS-CoV-2. The studies involved examination of various P4 moieties, P1 five- and six-membered lactam rings to improve potency. In particular, the six-membered P1 lactam ring analogs exhibited high SARS-CoV-2 Mpro inhibitory activity.

Synthesis of lamellarin R, lukianol A, lamellarin O and their analogues.

Three lamellarin alkaloids type III (lamellarin R, lukianol A and lamellarin O) were synthesized using the Barton-Zard reaction as a key step to construct the central pyrrole core. Some of their corresponding 4-benzoyl and 5-phenyl substituted pyrrole analogues were also prepared an initial three-component reaction of glycine methyl ester, benzaldehyde, and chalcone to generate the pyrrolidine scaffold, and followed by DDQ oxidation and -alkylation.

Enantioselective Synthesis of β-Allenoates via Phosphine-Catalyzed and ZnI-Promoted Preparation of Oxazolidines and Propargylamines Using Chiral Amines, 1-Alkynes, and Propiolates.

Diphenylphosphinoethane (DPPE)-catalyzed and ZnI-promoted in situ formation of oxazolidine, alkynyl zinc, and propargylamine intermediates from 1-alkynes, chiral (S)-diphenyl(pyrrolidin-2-yl)methanol, and propiolates gave the corresponding chiral (R)-β-allenoates in 40-72% yield with up to >99% ee. The intermediate propargylamine was isolated in 50% yield and converted to give the β-allenoate 10aa in 68% yield and 96% ee upon reaction with ZnI. The results are discussed considering a mechanism involving oxazolidine and iminium ions formed in situ followed by addition of alkynyl zinc complex to produce the propargylamine that gives the corresponding allenoate via a 1,5-hydrogen shift in the presence of ZnI.

Diastereoselective Synthesis of Tetrasubstituted Propargylamines via Hydroamination and Metalation of 1-Alkynes and Their Enantioselective Conversion to Trisubstituted Chiral Allenes.

Reaction of cyclic secondary amines with 1-alkynes and copper(I) chloride at 110-120 °C gives the corresponding alkynylcopper complex, which adds to the iminium ion intermediate formed in situ by hydroamination of 1-alkynes to give the corresponding propargylamine derivatives in up to 94% yield and 99% regioselectivity. The diastereomerically pure chiral propargylamines were obtained in 23-89% yield using optically active 2-benzyl morpholine and N-methyl camphanyl piperazine. These chiral propargylamines are readily converted to the corresponding trisubstitued chiral allenes in 71-89% yields with up to 99% ee upon reaction with ZnBr2 at 120 °C.