Metal-Free Electrochemical Reduction of Disulfides in an Undivided Cell under Mass Transfer Control.

Electroorganic synthesis is generally considered to be a green alternative to conventional redox reactions. Electrochemical reductions, however, are less advantageous in terms of sustainability, as sacrificial metal anodes are often employed. Divided cell operation avoids contact of the reduction products with the anode and allows for convenient solvent oxidation, enabling metal free greener electrochemical reductions. However, the ion exchange membranes required for divided cell operation on a commercial scale are not amenable to organic solvents, which hinders their applicability. Herein, we demonstrate that electrochemical reduction of oxidatively sensitive compounds can be carried out in an undivided cell without sacrificial metal anodes by controlling the mass transport to a small surface area electrode. The concept is showcased by an electrochemical method for the reductive cleavage of aryl disulfides. Fine tuning of the electrode surface area and current density has enabled the preparation of a wide variety of thiols without formation of any oxidation side products. This strategy is anticipated to encourage further research on greener, metal free electrochemical reductions.

A Practical Method for the Large-Scale Preparation of the P-Chiral Dihydrobenzoazaphosphole Core by Chemical Resolution.

pivZPhos, as an effective ligand in the Cu-catalyzed asymmetric hydrogenation of ketones and aminoboration of alkenes, is prepared efficiently from the corresponding triflate of P-chiral dihydrobenzoazaphosphole 1. However, the previous approach to 1 by chiral separation is time-consuming and costly, preventing its production and further application on a large scale. In this report, a practical method for the large-scale preparation of 1 was developed via chiral chemical resolution with (1S,2S)-diaminocyclohexane as an effective resolution reagent.

Nickel-Catalyzed Cross-Electrophile Reductive Couplings of Neopentyl Bromides with Aryl Bromides.

5-Cyanoimidazole was identified as an inexpensive ligand for nickel-catalyzed cross-electrophile couplings by screening a diverse set of pharmaceutical compound library. A strategic screening approach led to the discovery of this novel ligand, which was successfully applied in the preparation of various alkylated arene products with good to high yields. Furthermore, the properties of this ligand allowed expanding the scope of reductive couplings to challenging substrates, such as sterically hindered neopentyl halides, which are known to generate motifs that are prevalent in biologically active molecules.

Application of a Preformed Pd-BIDIME Precatalyst to Suzuki-Miyaura Cross-Coupling Reaction in Flow.

The application of a Buchwald's third generation palladacycle containing a dihydrobenzooxaphosphole-based ligand (e.g., BIDIME) was reported in the Suzuki cross-coupling reaction. Using flow technology, high yield and reproducible Suzuki cross-coupling reaction for one of our key intermediates was achieved with Pd loadings as low as 0.5 mol %. This continuous flow approach overcomes catalyst deactivation and scale dependence issues that can be a problem in some traditional batch-mode operations and responds to the challenge of improving process greenness.

Sequential C-H Arylation and Enantioselective Hydrogenation Enables Ideal Asymmetric Entry to the Indenopiperidine Core of an 11ß-HSD-1 Inhibitor.

A concise asymmetric synthesis of an 11ß-HSD-1 inhibitor has been achieved using inexpensive starting materials with excellent step-economy at low catalyst loadings. The catalytic enantioselective total synthesis of 1 was accomplished in 7 steps and 38% overall yield aided by the development of an innovative, sequential strategy involving Pd-catalyzed pyridinium C-H arylation and Ir-catalyzed asymmetric hydrogenation of the resulting fused tricyclic indenopyridinium salt highlighted by the use of a unique P,N-ligand (MeO-BoQPhos) with 1000 ppm of [Ir(COD)Cl]2.

Ligand-Accelerated Stereoretentive Suzuki-Miyaura Coupling of Unprotected 3,3'-Dibromo-BINOL.

An efficient synthesis of the enantiomerically pure 3,3'-bis-arylated BINOL derivatives is accomplished through the palladium-catalyzed Suzuki-Miyaura coupling of the unprotected 3,3'-dibromo-BINOL with complete retention of enantiopurity. The active catalyst system Pd(OAc)2/BI-DIME has enabled mild reaction conditions at palladium loads as low as 500 ppm.

Nickel-Catalyzed Esterification of Aliphatic Amides.

Recent studies have demonstrated that amides can be used in nickel-catalyzed reactions that lead to cleavage of the amide C-N bond, with formation of a C-C or C-heteroatom bond. However, the general scope of these methodologies has been restricted to amides where the carbonyl is directly attached to an arene or heteroarene. We now report the nickel-catalyzed esterification of amides derived from aliphatic carboxylic acids. The transformation requires only a slight excess of the alcohol nucleophile and is tolerant of heterocycles, substrates with epimerizable stereocenters, and sterically congested coupling partners. Moreover, a series of amide competition experiments establish selectivity principles that will aid future synthetic design. These studies overcome a critical limitation of current Ni-catalyzed amide couplings and are expected to further stimulate the use of amides as synthetic building blocks in C-N bond cleavage processes.

Construction of Quaternary Stereocenters by Nickel-Catalyzed Heck Cyclization Reactions.

A nickel-catalyzed Heck cyclization for the construction of quaternary stereocenters is reported. This transformation is demonstrated in the synthesis of 3,3-disubstituted oxindoles, which are prevalent motifs seen in numerous biologically active molecules. The method shows broad scope, proceeds in synthetically useful yields, and provides a rare means to construct stereochemically complex frameworks by nonprecious-metal catalysis.

Development of an asymmetric synthesis of a chiral quaternary FLAP inhibitor.

A practical sequence involving a noncryogenic stereospecific boronate rearrangement followed by a robust formylation with an in situ generated DCM anion has been developed for the asymmetric construction of an all-carbon quaternary stereogenic center of a FLAP inhibitor. The key boronate rearrangement was rendered noncryogenic and robust by using LDA as the base and instituting an in situ trapping of the unstable lithiated benzylic carbamate with the boronic ester. A similar strategy was implemented for the DCM formylation reaction. It was found that the 1,2-boronate rearrangement for the formylation reaction could be temperature-controlled, thus preventing overaddition of the DCM anion and rendering the process reproducible. The robust stereospecific boronate rearrangement and formylation were utilized for the practical asymmetric synthesis of a chiral quaternary FLAP inhibitor.

Efficient asymmetric synthesis of structurally diverse P-stereogenic phosphinamides for catalyst design.

The use of chiral phosphinamides is relatively unexplored because of the lack of a general method for the synthesis. Reported herein is the development of a general, efficient, and highly enantioselective method for the synthesis of structurally diverse P-stereogenic phosphinamides. The method relies on nucleophilic substitution of a chiral phosphinate derived from the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide. These chiral phosphinamides were utilized for the first synthesis of readily tunable P-stereogenic Lewis base organocatalysts, which were used successfully for highly enantioselective catalysis.

A mild dihydrobenzooxaphosphole oxazoline/iridium catalytic system for asymmetric hydrogenation of unfunctionalized dialins.

Air-stable P-chiral dihydrobenzooxaphosphole oxazoline ligands were designed and synthesized. When they were used in the iridium-catalyzed asymmetric hydrogenation of unfunctionalized 1-aryl-3,4-dihydronaphthalenes under one atmosphere pressure of H2 , up to 99:1 e.r. was obtained. High enantioselectivities were also observed in the reduction of the exocyclic imine derivatives of 1-tetralones.

Remarkable enhancement of enantioselectivity in the asymmetric conjugate addition of dimethylzinc to (Z)-nitroalkenes with a catalytic [(MeCN)4Cu]PF6-Hoveyda ligand complex.

An enantioselective copper-catalyzed asymmetric conjugate addition of Me2Zn to (Z)-nitroalkenes led to the formation of all-carbon quaternary stereogenic centers with high stereoselectivity. The key features of the new method are the unprecedented use of [(MeCN)4Cu]PF6 in conjunction with the Hoveyda ligand L1 and the use of (Z)-nitroalkene substrates so that undesired nitroalkene isomerization is minimized and enantioselectivity is enhanced dramatically. We also describe a novel, practical, and highly (Z)-selective nitroalkene synthesis.

General and Scalable Synthesis of 2-Aryl and 2-Alkyl Pyrimidines via an Electronically Tuned SNAr Approach.

An efficient SNAr approach for generating a wide array of 2-aryl and 2-alkyl pyrimidines in good to high yields was developed. This methodology does not require precious metal catalysts and is compatible with aryl, heteroaryl, and alkyl magnesium halides as nucleophiles. This process is scalable and performed at room temperature well below the temperature of the competing decomposition of the activated 2-tert-butyl sulfonyl pyrimidine electrophile.

Efficient asymmetric synthesis of P-chiral phosphine oxides via properly designed and activated benzoxazaphosphinine-2-oxide agents.

A general, efficient, and highly diastereoselective method for the synthesis of structurally and sterically diverse P-chiral phosphine oxides was developed. The method relies on sequential nucleophilic substitution on the versatile chiral phosphinyl transfer agent 1,3,2-benzoxazaphosphinine-2-oxide, which features enhanced and differentiated P-N and P-O bond reactivity toward nucleophiles. The reactivities of both bonds are fine-tuned to allow cleavage to occur even with sterically hindered nucleophiles under mild conditions.

Early Clinical Development of Lufotrelvir as a Potential Therapy for COVID-19.

Lufotrelvir was designed as a first in class 3CL protease inhibitor to treat COVID-19. Development of lufotrelvir was challenged by its relatively poor stability due to its propensity to epimerize and degrade. Key elements of process development included improvement of the supply routes to the indole and lactam fragments, a Claisen addition to homologate the lactam, and a subsequent phosphorylation reaction to prepare the prodrug as well as identification of a DMSO solvated form of lufotrelvir to enable long-term storage. As a new approach to preparing the indole fragment, a Cu-catalyzed C-O coupling using oxalamide ligands was demonstrated. The control of process-related impurities was essential to accommodate the parenteral formulation. Isolation of an MEK solvate followed by the DMSO solvate ensured that all impurities were controlled appropriately.

Enantioselective acylation of silyl ketene acetals through fluoride anion-binding catalysis.

A highly enantioselective acylation of silyl ketene acetals with acyl fluorides has been developed to generate useful α,α-disubstituted butyrolactone products. This transformation is promoted by a new thiourea catalyst and 4-pyrrolidinopyridine and represents the first example of enantioselective thiourea anion-binding catalysis with fluoride.

Catalytic enantioselective addition of diorganozinc reagents to vinyl sulfones.

An efficient method for the catalytic asymmetric conjugate addition of diorganozinc reagents to vinyl sulfones is reported. Using a Binap*Cu complex, enantioselectivities up to 98% ee and high yields can be attained for a variety of substrates. Several dialkylzinc reagents are also compatible with this procedure.

BABIPhos Family of Biaryl Dihydrobenzooxaphosphole Ligands for Asymmetric Hydrogenation.

Novel bidentate phosphine ligands BABIPhos featuring a biaryl bis-dihydrobenzooxaphosphole core are presented. Their synthesis was achieved via Pd-catalyzed reductive homocoupling of dihydrobenzooxaphosphole aryl triflates. An efficient route toward various analogues was also established, giving access to phosphines with different electronic and steric properties. The newly obtained ligands demonstrated high efficiency and selectivity in Rh-catalyzed asymmetric hydrogenation of di- and trisubstituted enamides. This new class of ligands is complementary to previously described bidentate benzooxaphosphole ligands BIBOP.

Enantioselective Synthesis of α-(Hetero)aryl Piperidines through Asymmetric Hydrogenation of Pyridinium Salts and Its Mechanistic Insights.

Enantioselective synthesis of α-aryl and α-heteroaryl piperidines is reported. The key step is an iridium-catalyzed asymmetric hydrogenation of substituted N-benzylpyridinium salts. High levels of enantioselectivity up to 99.3:0.7 er were obtained for a range of α-heteroaryl piperidines. DFT calculations support an outersphere dissociative mechanism for the pyridinium reduction. Notably, initial protonation of the final enamine intermediate determines the stereochemical outcome of the transformation rather than hydride reduction of the resultant iminium intermediate.

Copper-catalyzed asymmetric hydrogenation of 2-substituted ketones via dynamic kinetic resolution.

A new class of tunable heterophosphole dimeric ligands have been designed and synthesized. These ligands have enabled the first examples of Cu-catalyzed hydrogenation of 2-substituted-1-tetralones and related heteroaryl ketones via dynamic kinetic resolution, simultaneously creating two contiguous stereogenic centers with up to >99 : 1 dr and 98 : 2 er. The ligand-Cu complexes were isolated and characterized by single crystal X-ray, and DFT calculations revealed a novel heteroligated dimeric copper hydride transition state.