Desymmetrization of Vicinal Bis(boronic) Esters by Enantioselective Suzuki-Miyaura Cross-Coupling Reaction.

The development of an enantioselective catalytic Suzuki-Miyaura reaction that applies to meso 1,2-diborylcycloalkanes is described. This reaction provides a modular route to enantiomerically enriched substituted carbocycles and heterocycles that retain a synthetically versatile boronic ester. With appropriately constructed substrates, compounds bearing additional stereogenic centers and fully substituted carbon atoms can be generated in a straightforward fashion. Preliminary mechanistic experiments suggest that substrate activation arises from the cooperative effect of vicinal boronic esters during the transmetalation step.

Stereocontrolled Pericyclic and Radical Cycloaddition Reactions of Readily Accessible Chiral Alkenyl Diazaborolidines.

In this paper is described an easily synthesized chiral diazaborolidine that is inexpensive, stable, and provides excellent stereoselection across a number of reaction classes. These versatile compounds possess utility in four different classes of cycloaddition reactions, offering good yield and stereoselectivity. X-ray structure analysis provides insight about the origin of stereocontrol.

Visible-Light-Initiated Manganese Catalysis for C-H Alkylation of Heteroarenes: Applications and Mechanistic Studies.

A visible-light-driven Minisci protocol that employs an inexpensive earth-abundant metal catalyst, decacarbonyldimanganese Mn2 (CO)10 , to generate alkyl radicals from alkyl iodides has been developed. This Minisci protocol is compatible with a wide array of sensitive functional groups, including oxetanes, sugar moieties, azetidines, tert-butyl carbamates (Boc-group), cyclobutanes, and spirocycles. The robustness of this protocol is demonstrated on the late-stage functionalization of complex nitrogen-containing drugs. Photophysical and DFT studies indicate a light-initiated chain reaction mechanism propagated by . Mn(CO)5 . The rate-limiting step is the iodine abstraction from an alkyl iodide by . Mn(CO)5 .

Generation of stereochemically defined tetrasubstituted enolborinates by 1,4-hydroboration of α,ß-unsaturated morpholine carboxamides with (diisopinocampheyl)borane.

On all fours: The title reaction with (Ipc)2 BH provides tetrasubstituted enolborinates which undergo aldol reactions with aldehydes to form products with all-carbon quaternary centers with exceptional diastereo- and enantioselectivity. A change to the substitution pattern of the starting amide leads to either diastereomer of the α-methyl-α-ethyl-ß-hydroxy carboxamide (1 or 2).

Development of the Commercial Manufacturing Process for Nirmatrelvir in 17 Months.

The advancement of nirmatrelvir, the active ingredient in Paxlovid, from discovery to emergency use authorization was achieved in just 17 months, requiring an unprecedented rate of chemical process development.

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.

Discovery of a Series of Pyrimidine Carboxamides as Inhibitors of Vanin-1.

A diaryl ketone series was identified as vanin-1 inhibitors from a high-throughput screening campaign. While this novel scaffold provided valuable probe 2 that was used to build target confidence, concerns over the ketone moiety led to the replacement of this group. The successful replacement of this moiety was achieved with pyrimidine carboxamides derived from cyclic secondary amines that were extensively characterized using biophysical and crystallographic methods as competitive inhibitors of vanin-1. Through optimization of potency and physicochemical and ADME properties, and guided by co-crystal structures with vanin-1, 3 was identified with a suitable profile for advancement into preclinical development.

Diastereoselective Diboration of Cyclic Alkenes: Application to the Synthesis of Aristeromycin.

The Pt-catalyzed diboration of cyclic alkenes is extended to unsaturated heterocycles and bicyclic compounds and can be accomplished in a diastereoselective fashion. The optimal procedures, substrate scope, and diastereoselectivity were investigated, and examples employing both homogeneous and heterogeneous catalysis were examined. Lastly, application to the construction of the nucleoside analog (±)-aristeromycin was conducted.

Construction of Azacycles by Intramolecular Amination of Organoboronates and Organobis(boronates).

Intramolecular amination of organoboronates occurs with a 1,2-metalate shift of an aminoboron "ate" complex to form azetidines, pyrrolidines, and piperidines. Bis(boronates) undergo site-selective amination to form boronate-containing azacycles. Enantiomerically enriched azacycles are formed with high stereospecificity.

User-friendly stereoselective one-pot access to 1,4-diazepane derivatives by a cyclodehydrative three-component reaction with 1,3-dicarbonyls.

A multicomponent reaction of 1,3-dicarbonyls with 1,2-diamines and aromatic aldehydes is described for the direct stereoselective synthesis of 1,4-diazepane derivatives. Various reaction conditions were tested, including an efficient, user-friendly solvent- and catalyst-free procedure.

Metal-free Michael addition initiated multicomponent oxidative cyclodehydration route to polysubstituted pyridines from 1,3-dicarbonyls.

A simple metal-free, step-economic and selective access to pyridines from readily available substrates is reported, involving a flexible 4 A molecular sieves promoted Michael addition initiated domino three-component reaction between a 1,3-dicarbonyl, a Michael acceptor and a synthetic equivalent of ammonia.

Cholesteric bonded stationary phases for high-performance liquid chromatography: synthesis, physicochemical characterization, and chromatographic behavior of a phospho-cholesteric bonded support. A new way to mimic drug/membrane interactions?

Among the various methods exploitable to determine the bioavailability of drugs, reversed-phase liquid chromatography (RPLC) appears to be suited to creation of patterns of prediction. In this context a new stationary phase was designed in this work to reproduce, in terms of chemical structure, as accurately as possible, the main elements of cellular membranes; which include phospholipids and cholesterol molecules. An efficient synthetic pathway was developed to prepare ligands that contain a phosphate head, a long alkyl chain chemically bonded to silica, and a cholesteric moiety, in order to mimic both hydrophilic and hydrophobic interactions, and "membrane-like" organization, respectively. The new stationary phase was characterized by Fourier-transform infra red (FTIR) and (1)H-(13)C, (1)H-(31)P, and (1)H-(29)Si cross-polarization magic-angle-spinning nuclear magnetic resonance (CP MAS NMR) spectroscopy. Its chromatographic behavior has been studied by classical classification tests for RPLC columns. Despite its low surface coverage, the material produced exhibits high shape selectivity, possibly due to the organization of the grafted moieties.

Rational approach to highly potent and selective apoptosis signal-regulating kinase 1 (ASK1) inhibitors.

Many diseases are believed to be driven by pathological levels of reactive oxygen species (ROS) and oxidative stress has long been recognized as a driver for inflammatory disorders. Apoptosis signal-regulating kinase 1 (ASK1) has been reported to be activated by intracellular ROS and its inhibition leads to a down regulation of p38-and JNK-dependent signaling. Consequently, ASK1 inhibitors may have the potential to treat clinically important inflammatory pathologies including renal, pulmonary and liver diseases. Analysis of the ASK1 ATP-binding site suggested that Gln756, an amino acid that rarely occurs at the GK+2 position, offered opportunities for achieving kinase selectivity for ASK1 which was applied to the design of a parallel medicinal chemistry library that afforded inhibitors of ASK1 with nanomolar potency and excellent kinome selectivity. A focused optimization strategy utilizing structure-based design resulted in the identification of ASK1 inhibitors with low nanomolar potency in a cellular assay, high selectivity when tested against kinase and broad pharmacology screening panels, and attractive physicochemical properties. The compounds we describe are attractive tool compounds to inform the therapeutic potential of ASK1 inhibition.

Enantio- and Diastereoselective Synthesis of 1,5-syn-(Z)-Amino Alcohols via Imine Double Allylboration: Synthesis of trans-1,2,3,6-Tetrahydropyridines and Total Synthesis of Andrachcine.

A stereoselective synthesis of trans-1,2,3,6-tetrahydropyridines 8 is described. This synthesis proceeds via intramolecular Mistunobu reactions of 1,5-syn-(Z)-amino alcohols 7, which were prepared by a highly diastereo- and enantioselective double-allylboration reaction of aldehyde 5 and silylimine 6. The chiral bifunctional γ-borylallylborane 9E was generated in situ by hydroboration of allene 3 with (diisopinocampheyl)borane 4. This strategy was applied to the total synthesis of andrachcine 1, thus establishing with certainty the absolute and relative configuration of the natural product.

Visible-Light-Driven Photocatalytic Initiation of Radical Thiol-Ene Reactions Using Bismuth Oxide.

A nontoxic and inexpensive photocatalytic initiation of anti-Markovnikov hydrothiolation of olefins using visible light is reported. This method is characterized by low catalyst loading, thereby enabling a mild and selective method for radical initiation in thiol-ene reactions between a wide scope of olefins and thiols.

Access to Highly Substituted 7-Azaindoles from 2-Fluoropyridines via 7-Azaindoline Intermediates.

A versatile synthesis of 7-azaindoles from substituted 2-fluoropyridines is described. C3-metalation and 1,4-addition to nitroolefins provide substituted 2-fluoro-3-(2-nitroethyl)pyridines. A facile oxidative Nef reaction/reductive amination/intramolecular SNAr sequence furnishes 7-azaindolines. Finally, optional regioselective electrophilic C5-substitution (e.g., bromination or nitration) and subsequent in situ oxidation delivers highly functionalized 7-azaindoles in high overall efficiency.

(Diisopinocampheyl)borane-mediated reductive aldol reactions of acrylate esters: enantioselective synthesis of anti-aldols.

The (diisopinocampheyl)borane promoted reductive aldol reaction of acrylate esters 4 is described. Isomerization of the kinetically formed Z(O)-enolborinate 5Z to the thermodynamic E(O)-enolborinate 5E via 1,3-boratropic shifts, followed by treatment with representative achiral aldehydes, leads to anti-α-methyl-ß-hydroxy esters 9 or 10 with excellent diastereo- (up to ≥20:1 dr) and enantioselectivity (up to 87% ee). The results of double asymmetric reactions of 5E with several chiral aldehydes are also presented.