ABSTRACT
Herein, we report a nine-step synthesis of belzutifan enabled by a novel Rh-catalyzed asymmetric hydrogenation to install the contiguous fluorinated stereocenters with high enantioselectivity. Moreover, the final ketone reduction in the synthesis proceeds with high diastereoselectivity, leading to the expedient assembly of the stereotriad. In contrast to the original 16-step synthesis, this route avoids a lengthy bromination-oxidation sequence and introduces the sulfone functionality via nucleophilic aromatic substitution, obviating the need for transition metal catalysis.
ABSTRACT
An asymmetric cross-coupling of α-N-heterocyclic trifluoroborates with aryl bromides using Ni/photoredox dual catalysis has been developed. This C(sp2)-C(sp3) cross-coupling provides access to pharmaceutically relevant chiral N-benzylic heterocycles in good to excellent enantioselectivity when bioxazolines (BiOX) are used as the chiral ligand. High-throughput experimentation significantly streamlined reaction development by identifying BiOX ligands for further investigation and by allowing for rapid optimization of conditions for new trifluoroborate salts.
Subject(s)
Bromides , Nickel , Stereoisomerism , Molecular Structure , Catalysis , LigandsABSTRACT
Radical addition to dehydroalanine (Dha) represents an appealing, modular strategy to access non-canonical peptide analogues for drug discovery. Prior studies on radical addition to the Dha residue of peptides and proteins have demonstrated outstanding functional group compatibility, but the lack of stereoselectivity has limited the synthetic utility of this approach. Herein, we address this challenge by employing chiral nickel catalysts to control the stereoselectivity of radical addition to Dha on oligopeptides. The conditions accommodate a variety of primary and secondary electrophiles to introduce polyethylene glycol, biotin, halo-tag, and hydrophobic and hydrophilic side chains to the peptide. The reaction features catalyst control to largely override substrate-based control of stereochemical outcome for modification of short peptides. We anticipate that the discovery of chiral nickel complexes that confer catalyst control will allow rapid, late-stage modification of peptides featuring nonnatural sidechains.
Subject(s)
Nickel , Peptides , Nickel/chemistry , Catalysis , Peptides/chemistry , OligopeptidesABSTRACT
Significant catalyst loading reduction and increased reaction robustness have been achieved for a Pd-catalyzed asymmetric intramolecular C-N coupling through comprehensive mechanistic studies. Detailed kinetic, spectroscopic, and crystallographic analyses revealed that the mono-oxidation of the bis-phosphine ligand is critical for a successful transformation. 31P NMR studies provided an understanding of the inefficient activation of the Pd(OAc)2/(R,R)-QuinoxP* pre-catalyst to form the active bis-phosphine mono-oxide-Pd(0) catalyst with competitive formation of a less active (R,R)-QuinoxP*·PdBr2 complex. Based on these detailed mechanistic studies, a new series of bis-phosphine mono-oxides (BPMO)-ligated Pd(ii) pre-catalysts have been rationally developed that allow for reliable and complete catalyst activation which should have general utility in academic and industrial settings.
ABSTRACT
An enantioselective synthesis of the potent anti-HIV nucleoside EFdA is presented. Key features of stereocontrol include construction of the fully substituted 4'-carbon via a biocatalytic desymmetrization of 2-hydroxy-2-((triisopropylsilyl)ethynyl)propane-1,3-diyl diacetate and a Noyori-type asymmetric transfer hydrogenation to control the stereochemistry of the 3'-hydroxyl bearing carbon. The discovery of a selective crystallization of an N-silyl nucleoside intermediate enabled isolation of the desired ß-anomer from the glycosylation step.
Subject(s)
Anti-HIV Agents/chemical synthesis , Deoxyadenosines/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Catalysis , Glycosides/chemistry , Glycosylation , Hydrogenation , Molecular Structure , Oxidation-Reduction , StereoisomerismABSTRACT
A method for the enantioselective synthesis of chiral α-tertiary amines via Rh-catalyzed 1,2-addition of arylboronic acids to cyclic ketimines is described. The products are efficiently accessed in good yields and excellent enantioselectivities using a commercially available chiral ligand. The reaction scope includes vinyl, aryl, and heteroarylboronic acids with yields ranging from 40% to 99% and enantiomeric excesses from 88% to 99%. Conversion of an addition product into an α,α-diaryl-substituted amino acid is also demonstrated.
Subject(s)
Boronic Acids/chemistry , Imines/chemistry , Nitriles/chemistry , Rhodium/chemistry , Amino Acids/chemical synthesis , Amino Acids/chemistry , Catalysis , Combinatorial Chemistry Techniques , Molecular Structure , StereoisomerismABSTRACT
A novel approach to hemiaminal synthesis via palladium-catalyzed C-N coupling with chiral bisphosphine mono-oxides is described. This efficient new method exhibits a broad scope, provides a highly efficient synthesis of HCV drug candidate elbasvir, and has been applied to the synthesis of chiral N,N-acetals.
ABSTRACT
A practical asymmetric synthesis of the complex fused bis-macrocyclic HCV protease inhibitor MK-6325 (1) is described. Through the combination of a high yielding and low catalyst loading ring-closing metathesis (RCM) to forge the 15-membered macrocycle with an intramolecular sp(2)-sp(3) Suzuki-Miyaura cross-coupling to append the 18-membered macrocycle, multikilogram access to the unique and challenging architecture of MK-6325 (1) has been achieved.
Subject(s)
Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Catalysis , Hepacivirus/drug effects , Macrocyclic Compounds/chemistry , Molecular Structure , Protease Inhibitors/chemistryABSTRACT
We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in vivo efficacy in rodent inflammatory and neuropathic pain assays.
ABSTRACT
We report the discovery of novel N,N'-disubstituted cinchona alkaloids as efficient phase-transfer catalysts for the assembly of stereogenic quaternary centers. In comparison to traditional cinchona-alkaloid-based phase-transfer catalysts, these new catalysts afford substantial improvements in enantioselectivity and reaction rate for intramolecular spirocyclization reactions with catalyst loadings as low as 0.3â mol% under mild conditions.
Subject(s)
Cinchona Alkaloids/chemistry , Cinchona Alkaloids/chemical synthesis , Catalysis , Molecular Structure , Spiro Compounds , StereoisomerismABSTRACT
A general method for the preparation of α-hydroxyacetophenones is presented. Functionalized arylmagnesium species are transmetalated to the corresponding arylzinc intermediates, which undergo Cu(I)-catalyzed reaction with acetoxyacetyl chloride. Acidic hydrolysis of the acetate group releases the target α-hydroxyacetophenones with minimal production of undesired polymeric degradates that are often observed under alternative conditions.
Subject(s)
Acetophenones/chemistry , Acetophenones/chemical synthesis , Acetates/chemistry , Catalysis , Hydrolysis , Molecular Structure , Organometallic Compounds/chemistry , StereoisomerismABSTRACT
Development of a practical synthesis of MK-7009, a 20-membered [corrected] macrocycle, is described. A variety of ring-closing strategies were evaluated, including ring-closing metathesis, intermolecular palladium-catalyzed cross-couplings, and macrolactamization. Ring closure via macrolactamization was found to give the highest yields under relatively high reaction concentrations. Optimization of the ring formation step and the synthesis of key intermediates en route to MK-7009 are reported.
Subject(s)
Chemistry Techniques, Synthetic/methods , Indoles/chemistry , Indoles/chemical synthesis , Lactams/chemistry , Macrocyclic Compounds/chemistry , Catalysis , Cyclization , Cyclopropanes , Hydrogenation , Isoindoles , Lactams, Macrocyclic , Leucine/analogs & derivatives , Palladium/chemistry , Proline/analogs & derivatives , SulfonamidesABSTRACT
The highly enantioselective catalytic asymmetric addition of aryl and alkenylboronic acids to N-benzylnicotinate salt 1 is described. The dihydropyridine 2 reaction products can be converted to synthetically useful piperidines. Application of the methodology to the preparation of enantioenriched quaternary chiral centers is also discussed.
Subject(s)
Boronic Acids/chemistry , Nicotinic Acids/chemistry , Rhodium/chemistry , Boronic Acids/chemical synthesis , Catalysis , Molecular Structure , Nicotinic Acids/chemical synthesis , Salts/chemical synthesis , Salts/chemistry , StereoisomerismABSTRACT
A general method for the enantioselective hydrogenation of protected allylic amine derivatives is described. This procedure relies on the generation of a cationic ruthenium complex with the axially chiral ligand (-)-TMBTP. The utility is highlighted by the highly enantioselective hydrogenation of a diene substrate that can then be elaborated to prepare Telcagepant, a compound currently in Phase III clinical trials. The scope of the hydrogenation reaction was studied, and a variety of substituted allylic amine derivatives could be hydrogenated with enantiomeric ratios of 92:8 or higher.
Subject(s)
Allyl Compounds/chemistry , Amines/chemistry , Azepines/chemical synthesis , Caprolactam/chemical synthesis , Catalysis , Hydrogenation , Imidazoles/chemical synthesis , Molecular Structure , StereoisomerismABSTRACT
A novel three-step synthesis of the highly functionalized antifungal agent CANCIDAS (caspofungin acetate, 2) is described, starting from the natural product pneumocandin B0 (1). The highlights of the synthesis include a stereoselective formation of a phenylthioaminal, a remarkable chemoselective, high-yielding, one-step borane reduction of a primary amide, and a stereoselective substitution of the phenylthioaminal with ethylenediamine producing 2 in a 45% overall yield.
Subject(s)
Antifungal Agents/chemical synthesis , Glucosyltransferases/antagonists & inhibitors , Peptides, Cyclic/chemistry , Peptides, Cyclic/chemical synthesis , Amides/chemistry , Amines/chemistry , Antifungal Agents/chemistry , Antifungal Agents/isolation & purification , Caspofungin , Chromatography, High Pressure Liquid , Echinocandins , Lipopeptides , Molecular Structure , Peptides, Cyclic/isolation & purification , Sulfhydryl Compounds/chemistryABSTRACT
[reaction: see text] The relative and absolute configuration of the pneumocandin B(0) side chain has been established as (10R,12S)-dimethylmyristoyl by the stereocontrolled synthesis of both antipodes of the side chain acid and their comparison to a sample derived from the natural product.