Interrogation of Enantioselectivity in the Photomediated Ring Contractions of Saturated Heterocycles.

We recently reported a chiral phosphoric acid (CPA) catalyzed enantioselective photomediated ring contraction of piperidines and other saturated heterocycles. By extruding a single heteroatom from a ring, this transformation builds desirable C(sp)-C(sp) bonds in the ring contracted products; however, the origins of enantioselectivity remain poorly understood. In this work, enantioselectivity of the ring contraction has been explored across an expanded structurally diverse substrate scope, revealing a wide range of enantioselectivities (0-99%) using two distinct CPA catalysts.

Alkene Carboxy-Alkylation via CO

Herein, we introduce a new platform for alkene carboxy-alkylation. This reaction is designed around CO addition to alkenes followed by radical polar crossover, which enables alkylation through carbanion attack on carbonyl electrophiles. We discovered that CO adds to alkenes faster than it reduces carbonyl electrophiles and that this reactivity can be exploited by accessing CO via hydrogen atom transfer from formate.

Activation of Hepatocyte Growth Factor/MET Signaling as a Mechanism of Acquired Resistance to a Novel YAP1/TEAD Small Molecule Inhibitor.

Many tumor types harbor alterations in the Hippo pathway, including mesothelioma, where a high percentage of cases are considered YAP1/TEAD dependent. Identification of autopalmitoylation sites in the hydrophobic palmitate pocket of TEADs, which may be necessary for YAP1 protein interactions, has enabled modern drug discovery platforms to generate compounds that allosterically inhibit YAP1/TEAD complex formation and transcriptional activity. We report the discovery and characterization of a novel YAP1/TEAD inhibitor MRK-A from an aryl ether chemical series demonstrating potent and specific inhibition of YAP1/TEAD activity.

Mechanistic Investigation, Wavelength-Dependent Reactivity, and Expanded Reactivity of -Aryl Azacycle Photomediated Ring Contractions.

Under mild blue-light irradiation, α-acylated saturated heterocycles undergo a photomediated one-atom ring contraction that extrudes a heteroatom from the cyclic core. However, for nitrogenous heterocycles, this powerful skeletal edit has been limited to substrates bearing electron-withdrawing substituents on nitrogen. Moreover, the mechanism and wavelength-dependent efficiency of this transformation have remained unclear.

N to N Isotopic Exchange of Nitrogen Heteroaromatics through Skeletal Editing.

The selective modification of nitrogen heteroaromatics enables the development of new chemical tools and accelerates drug discovery. While methods that focus on expanding or contracting the skeletal structures of heteroaromatics are emerging, methods for the direct exchange of single core atoms remain limited. Here, we present a method for N → N isotopic exchange for several aromatic nitrogen heterocycles.

Translating Planar Heterocycles into Three-Dimensional Analogs by Photoinduced Hydrocarboxylation.

The rapid preparation of complex three-dimensional (3D) heterocyclic scaffolds is a key challenge in modern medicinal chemistry. Despite the increased probability of clinical success for small molecule therapeutic candidates with increased 3D complexity, new drug targets remain dominated by flat molecules due to the abundance of coupling reactions available for their construction. In principle, heteroarene hydrofunctionalization reactions offer an opportunity to transform readily accessible planar molecules into more three-dimensionally complex analogs through the introduction of a single molecular vector.

General access to cubanes as benzene bioisosteres.

The replacement of benzene rings with sp-hybridized bioisosteres in drug candidates generally improves pharmacokinetic properties while retaining biological activity. Rigid, strained frameworks such as bicyclo[1.1.

Nickel-Catalyzed Chemoselective Arylation of Amino Alcohols.

A systematic evaluation of competitive bisphosphine/Ni-catalyzed C-N versus C-O cross-couplings involving model compounds enabled development of hitherto unknown chemoselective O- and N-arylation of amino alcohols with (hetero)aryl chloride electrophiles, without recourse to protection group chemistry. Use of the CyPAd-DalPhos pre-catalyst C2 enabled particularly challenging O-arylation chemoselectivity in amino alcohols featuring branched primary and secondary alkylamine groups, while selective N-arylation was observed in substrates featuring less-hindered linear alkylamine and aniline reacting groups. Useful reaction scope in the (hetero)aryl chloride was achieved throughout, and the ability to conduct such transformations using benchtop handling of materials is demonstrated.

Practical and General Alcohol Deoxygenation Protocol.

Herein, we describe a practical protocol for the removal of alcohol functional groups through reductive cleavage of their benzoate ester analogs. This transformation requires a strong single electron transfer (SET) reductant and a means to accelerate slow fragmentation following substrate reduction. To accomplish this, we developed a photocatalytic system that generates a potent reductant from formate salts alongside Brønsted or Lewis acids that promote fragmentation of the reduced intermediate.

Rapid Access to 2-Substituted Bicyclo[1.1.1]pentanes.

The replacement of aryl rings with saturated carbocyclic structures has garnered significant interest in drug discovery due to the potential for improved pharmacokinetic properties upon substitution. In particular, 1,3-difunctionalized bicyclo[1.1.

Sequential Norrish-Yang Cyclization and C-C Cleavage/Cross-Coupling of a [4.1.0] Fused Saturated Azacycle.

Methods that functionalize the periphery of azacylic scaffolds have garnered increasing interest in recent years. Herein, we investigate the selectivity of a solid-state Norrish-Yang cyclization (NYC) and subsequent C-C cleavage/cross-coupling reaction of a strained cyclopropane-fused azacyclic system. Surprisingly, the NYC primarily furnished a single lactam constitutional and diastereo-isomer.

Photomediated ring contraction of saturated heterocycles.

Saturated heterocycles are found in numerous therapeutics and bioactive natural products and are abundant in many medicinal and agrochemical compound libraries. To access new chemical space and function, many methods for functionalization on the periphery of these structures have been developed. Comparatively fewer methods are known for restructuring their core framework.

Optimization of brain-penetrant picolinamide derived leucine-rich repeat kinase 2 (LRRK2) inhibitors.

The discovery of potent, kinome selective, brain penetrant LRRK2 inhibitors is the focus of extensive research seeking new, disease-modifying treatments for Parkinson's disease (PD). Herein, we describe the discovery and evolution of a picolinamide-derived lead series. Our initial optimization efforts aimed at improving the potency and CLK2 off-target selectivity of compound by modifying the heteroaryl C-H hinge and linker regions.

Achieving C(sp)-C(sp) Coupling with BCP-F Building Blocks via Barluenga Coupling: A Comparative Approach.

We report our efforts toward achieving C(sp)-C(sp) coupling reactions with 2,2-difluorobicyclo[1.1.1]pentane (BCP-F) building blocks.

Non-innocent Radical Ion Intermediates in Photoredox Catalysis: Parallel Reduction Modes Enable Coupling of Diverse Aryl Chlorides.

We describe a photocatalytic system that elicits potent photoreductant activity from conventional photocatalysts by leveraging radical anion intermediates generated . The combination of an isophthalonitrile photocatalyst and sodium formate promotes diverse aryl radical coupling reactions from abundant but difficult to reduce aryl chloride substrates. Mechanistic studies reveal two parallel pathways for substrate reduction both enabled by a key terminal reductant byproduct, carbon dioxide radical anion.

Enantioselective Addition of Pyrazoles to Dienes*.

We report the first enantioselective addition of pyrazoles to 1,3-dienes. Secondary and tertiary allylic pyrazoles can be generated with excellent regioselectivity. Mechanistic studies support a pathway distinct from previous hydroaminations: a Pd -catalyzed ligand-to-ligand hydrogen transfer (LLHT).

The Discovery of Two Novel Classes of 5,5-Bicyclic Nucleoside-Derived PRMT5 Inhibitors for the Treatment of Cancer.

Protein arginine methyltransferase 5 (PRMT5) is a type II arginine methyltransferase that catalyzes the post-translational symmetric dimethylation of protein substrates. PRMT5 plays a critical role in regulating biological processes including transcription, cell cycle progression, RNA splicing, and DNA repair. As such, dysregulation of PRMT5 activity is implicated in the development and progression of multiple cancers and is a target of growing clinical interest.

C─C Cleavage Approach to C─H Functionalization of Saturated Aza-Cycles.

Saturated cyclic amines (aza-cycles) are ubiquitous structural motifs found in pharmaceuticals, agrochemicals, and bioactive natural products. Given their importance, methods that directly functionalize aza-cycles are in high demand. Herein, we disclose a fundamentally different approach to functionalizing cyclic amines which relies on C─C cleavage and attendant cross-coupling.

Synthesis of Bridged Bicyclic Amines by Intramolecular Amination of Remote C-H Bonds: Synergistic Activation by Light and Heat.

The construction of complex aza-cycles is of interest to drug discovery due to the prevalence of nitrogen-containing heterocycles in pharmaceutical agents. Herein we report an intramolecular C-H amination approach to afford value-added and complexity-enriched bridged bicyclic amines. Guided by density functional theory and nuclear magnetic resonance investigations, we determined the unique roles of light and heat activation in the bicyclization mechanism.

C-H/C-C Functionalization Approach to N-Fused Heterocycles from Saturated Azacycles.

Herein we report the synthesis of substituted indolizidines and related N-fused bicycles from simple saturated cyclic amines through sequential C-H and C-C bond functionalizations. Inspired by the Norrish-Yang Type II reaction, C-H functionalization of azacycles is achieved by forming α-hydroxy-β-lactams from precursor α-ketoamide derivatives under mild, visible light conditions. Selective cleavage of the distal C(sp)-C(sp) bond in α-hydroxy-β-lactams using a Rh-complex leads to α-acyl intermediates which undergo sequential Rh-catalyzed decarbonylation, 1,4-addition to an electrophile, and aldol cyclization, to afford N-fused bicycles including indolizidines.

Monophosphine Ligands Promote Pd-Catalyzed C-S Cross-Coupling Reactions at Room Temperature with Soluble Bases.

The Pd-catalyzed cross-coupling of thiols with aromatic electrophiles is a reliable method for the synthesis of aryl thioethers, which are important compounds for pharmaceutical and agricultural applications. Since thiols and thiolates strongly bind late transition metals, previous research has focused on catalysts supported by chelating, bisphosphine ligands, which were considered less likely to be displaced during the course of the reaction. We show that by using monophosphine ligands instead, more effective catalysis can be achieved.

Metal- and Acid-Free C-H Formylation of Nitrogen Heterocycles: Using Trioxane as an Aldehyde Equivalent Enabled by an Organic-Soluble Oxidant.

A metal-free, innate, and practical C-H formylation of nitrogen heterocycles using trioxane as a formyl equivalent is reported. This reaction provides a mild and robust method for modifying medicinally relevant heterocycles with an aldehyde handle. The use of an organic soluble oxidant, tetrabutylammonium persulfate, is critical in promoting the desired coupling.

Photoredox Catalysis as a Strategy for CO Incorporation: Direct Access to Carboxylic Acids from a Renewable Feedstock.

Carbon dioxide is an attractive reagent for organic synthesis from the standpoint of global sustainability. Its widespread use, however, is hampered by the fact that it is poorly reactive. New catalysts and technologies that enable C-C bond constructions are thus of high intrinsic value.

Unprotected Indazoles Are Resilient to Ring-Opening Isomerization: A Case Study on Catalytic C-S Couplings in the Presence of Strong Base.

Indazoles represent a privileged scaffold in medicinal chemistry. In the presence of strong base, however, N-protected indazoles are prone to an undesirable ring-opening reaction to liberate o-aminobenzonitriles. By employing unprotected indazoles with a free N-H bond, isomerization is averted because the heterocycle is deprotonated in situ.

Thiourea-catalyzed enantioselective addition of indoles to pyrones: alkaloid cores with quaternary carbons.

We report the development of a catalytic method for the enantioselective addition of indoles to pyrone-derived electrophiles. Arylpyrrolidino-derived thioureas catalyze the addition with high stereoselectivity in the presence of catalytic quantities of an achiral Brønsted acid. The indole-pyrone adducts feature a quaternary stereocenter and represent an unusual class of indolines bearing structural resemblance to the hybrid natural product pleiocarpamine.