Organocatalytic Asymmetric Cascade Michael-Acyl Transfer Reaction between 2-Fluoro-1,3-diketones and 2-Hydroxynitrostyrenes.

An organocatalytic asymmetric cascade Michael-acyl transfer reaction of 2-hydroxynitrostyrenes and monofluorinated ß-diketones has been developed employing a cooperative catalytic system. A combination of quinine-derived bifunctional squaramide catalyst and achiral hydrogen bond donor cocatalyst was found to be the most effective for this reaction and provided the fluorinated acyl transfer products in high yields with good diastereo- and excellent enantioselectivities. Synthetic transformations have been demonstrated, including the synthesis of functionalized 2,3-dihydrobenzofurans and 1-pyrroline.

Kinetic Resolution of Electron-Deficient Bromohydrins via Copper(II)-Catalyzed C-C Bond Cleavage.

Herein, we report a nonenzymatic kinetic resolution (KR) of α,ß-unsaturated ketone-derived bromohydrins (up to s = 211) with N-bromosuccinimide (NBS) in the presence of a chiral Cu(II)-Box catalyst via the C-C bond cleavage of the fast reacting enantiomer. A one-pot synthesis-KR approach of the same has also been realized with excellent enantioselectivities (up to 99% ee). Both protocols are found to be effective for a variety of substrates, leading to enantioenriched bromohydrins. The synthetic utility of this process has been demonstrated by exploring a new strategy to convert the resolved enantiomer to an optically active epoxide.

Rapid resistance profiling of SARS-CoV-2 protease inhibitors.

Resistance to nirmatrelvir (Paxlovid) has been shown by multiple groups and may already exist in clinical SARS-CoV-2 isolates. Here a panel of SARS-CoV-2 main protease (Mpro) variants and a robust cell-based assay are used to compare the resistance profiles of nirmatrelvir, ensitrelvir, and FB2001. The results reveal distinct resistance mechanisms ("fingerprints") and indicate that these next-generation drugs have the potential to be effective against nirmatrelvir-resistant variants and vice versa.

Rapid resistance profiling of SARS-CoV-2 protease inhibitors.

Resistance to nirmatrelvir (Paxlovid) has been shown by multiple groups and may already exist in clinical SARS-CoV-2 isolates. Here a panel of SARS-CoV-2 main protease (Mpro) variants and a robust cell-based assay are used to compare the resistance profiles of nirmatrelvir, ensitrelvir, and FB2001. The results reveal distinct resistance mechanisms ("fingerprints") and indicate that these next-generation drugs have the potential to be effective against nirmatrelvir-resistant variants and vice versa.

Organocatalytic Asymmetric Cascade Michael-acyl Transfer Reaction between 2-Fluoro-1,3-diketones and Unsaturated Thiazolones: Access to Fluorinated 4-Acyloxy Thiazoles.

Quinine derived bifunctional urea catalyzed cascade Michael-acyl transfer reaction of 5-alkenyl thiazolones and monofluorinated ß-diketones has been developed. The fluorine containing 4-acyloxy thiazoles were synthesized in high yields and good diastereo-and excellent enantioselectivities. Synthetic transformations, including synthesis of 4-hydroxy thiazoles, have been demonstrated.

Cu(I)-Catalyzed asymmetric exo-selective synthesis of substituted pyrrolidines via a 1,3-dipolar cycloaddition reaction.

An (R)-DM-BINAP/Cu(CH3CN)4BF4 complex catalyzed exo-selective asymmetric 1,3-dipolar cycloaddition (1,3-DCA) reaction of imino esters with α,ß-unsaturated pyrazoleamides has been developed. A series of highly functionalized pyrrolidines with multiple stereogenic centers were obtained with good yields and diastereoselectivities and excellent enantioselectivities (up to 99% ee).

Enantioselective A3-Coupling Reaction Employing Chiral CuI- iPrpyboxdiPh/ N-Boc-(l)-Proline Complex under Cooperative Catalysis: Application in the Synthesis of (Indol-2-yl)methanamines.

An efficient route to enantioenriched propargylamines via a three-component alkynylation reaction using cooperative catalysis with a CuI- iPrpyboxdiPh complex and N-Boc-(l)-proline has been accomplished. A variety of functionalized amines, aldehydes, and 2-ethynyl anilines were reacted smoothly at ambient temperature to furnish a wide range of propargylamines in high yields (up to 94%) and excellent enantioselectivities (up to 98% ee). Synthetic utility of the methodology has been demonstrated by transforming the products into various synthetically useful intermediates. Finally, propargylamines were transformed into biologically important (indol-2-yl)methanamines over two steps in good yields (up to 88%) with an excellent level of enantioselectivities (up to 95%).

A General Catalytic Route to Enantioenriched Isoindolinones and Phthalides: Application in the Synthesis of ( S)-PD 172938.

Chiral Brønsted acid catalyzed enantioselective syntheses of isoindolinones and phthalides have been accomplished via tandem Mannich-lactamization and aldol-lactonization reactions, respectively. A variety of enantioenriched isoindolinones (up to 99% ee) and phthalides (up to 85% ee) containing α-diazoesters were afforded in excellent yields. Furthermore, a concise synthesis of ( S)-PD 172938 has been demonstrated by using this protocol.

A chiral Brønsted acid-catalyzed highly enantioselective Mannich-type reaction of α-diazo esters with in situ generated N-acyl ketimines.

A chiral phosphoric acid-catalyzed asymmetric Mannich-type reaction of α-diazo esters with in situ generated N-acyl ketimines, derived from 3-hydroxyisoindolinones has been demonstrated in this communication. A variety of isoindolinone-based α-amino diazo esters bearing a quaternary stereogenic center were afforded in high yields (up to 99%) with excellent enantioselectivities (up to 99% ee). Furthermore, the synthetic utility of the products has been depicted by the hydrogenation of the diazo moiety of adducts.

(R)-DM-SEGPHOS-Ag(I)-Catalyzed Enantioselective Synthesis of Pyrrolidines and Pyrrolizidines via (1,3)- and Double (1,3)-Dipolar Cycloaddition Reactions.

An efficient diastereo- and enantioselective route to access a wide range of highly substituted pyrrolidine and pyrrolizidine derivatives has been described via (1,3)- and double (1,3)-dipolar cycloaddition reactions catalyzed by the (R)-DM-SEGPHOS-Ag(I) complex. The reactions proceed smoothly at ambient temperature, affording a variety of pyrrolidines and pyrrolizidines in high yields (up to 93%) with up to 99:1 dr and excellent enantioselectivities (up to 98% ee) without any additives. The newly synthesized pyrrolidine and pyrrolizidine derivatives contain four and seven contiguous stereogenic centers, respectively. Moreover, the synthetic utility of enantioenriched products has been demonstrated by transforming them into various synthetically useful advanced intermediates.