ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Alkenes , Ketones , Catalysis , Hydrogenation , StereoisomerismABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Piperidines/chemical synthesis , Pyridinium Compounds/chemistry , Catalysis , Hydrogenation , Iridium , Models, Chemical , Molecular Structure , Oxidation-Reduction , StereoisomerismABSTRACT
The development of enantioselective carbon-carbon bond couplings catalyzed by nonprecious metals is highly desirable in terms of cost efficiency and sustainability. The first nickel-catalyzed enantioselective Mizoroki-Heck coupling is reported. This transformation is accomplished via mild reaction conditions, leveraging on QuinoxP* as a chiral ligand to afford oxindoles containing quaternary stereocenters. Good reactivity and selectivity are observed in the presence of various functional groups. Computational studies suggest that the oxidative addition assembles an atropisomeric intermediate responsible for the facial selectivity of the insertion step.
ABSTRACT
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.
Subject(s)
Amides/chemistry , Esters/chemical synthesis , Nickel/chemistry , Organometallic Compounds/chemistry , Catalysis , Esters/chemistry , Molecular ConformationABSTRACT
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.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Piperidines/chemical synthesis , Piperidines/pharmacology , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , Catalysis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Hydrogenation , Iridium/chemistry , Molecular Conformation , Palladium/chemistry , Piperidines/chemistry , StereoisomerismABSTRACT
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.
ABSTRACT
An Ir-catalyzed enantioselective hydrogenation of 2-alkyl-pyridines has been developed using ligand MeO-BoQPhos. High levels of enantioselectivities up to 93:7 er were obtained. The resulting enantioenriched piperidines can be readily converted into biologically interesting molecules such as the fused tricyclic structures 5, 6, and 7 in 99:1 er, providing a novel, concise synthetic route to this family of chiral piperidine-containing compounds.
ABSTRACT
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.
ABSTRACT
The direct arylation of pyridine substrates using non-precious catalysts is underdeveloped but highly desirable due to its efficiency to access important motifs while being extremely cost-effective. The first nickel-catalyzed C-3 direct arylation of pyridine derivatives to provide a new approach to valuable 1-azafluorene pharmacophore frameworks was developed. This transformation is accomplished using air-stable nickel catalyst precursors combined with phenanthroline ligands and tolerates a variety of substituents. Computational studies suggest facile oxidative addition via the pyridinium form, deprotonation, and a subsequent carbo-nickelation cyclization. Nickel homolysis/recombination permits isomerization to the stereochemical array needed for the final elimination.
ABSTRACT
A general, scalable, and highly diastereoselective aziridination of N-tert-butanesulfinyl ketimino esters is described. The methodology has been utilized to provide straightforward access to previously unobtainable, biologically relevant α-quaternary amino esters and derivatives starting from readily available precursors.
Subject(s)
Aza Compounds/chemistry , Aziridines/chemical synthesis , Aziridines/chemistry , Catalysis , Esters , Molecular Structure , StereoisomerismABSTRACT
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.
Subject(s)
Amides/chemical synthesis , Lewis Bases/chemistry , Phosphines/chemical synthesis , Phosphinic Acids/chemistry , Amides/chemistry , Chemistry Techniques, Synthetic , Molecular Structure , Phosphines/chemistry , StereoisomerismABSTRACT
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.
Subject(s)
5-Lipoxygenase-Activating Protein Inhibitors/chemical synthesis , Boron Compounds/chemistry , Carbamates/chemistry , 5-Lipoxygenase-Activating Protein Inhibitors/chemistry , Catalysis , Molecular Structure , StereoisomerismABSTRACT
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.