Enhancing Drug Discovery and Development through the Integration of Medicinal Chemistry, Chemical Biology, and Academia-Industry Partnerships: Insights from Roche's Endocannabinoid System Projects.

The endocannabinoid system (ECS) is a critical regulatory network composed of endogenous cannabinoids (eCBs), their synthesizing and degrading enzymes, and associated receptors. It is integral to maintaining homeostasis and orchestrating key functions within the central nervous and immune systems. Given its therapeutic significance, we have launched a series of drug discovery endeavors aimed at ECS targets, including peroxisome proliferator-activated receptors (PPARs), cannabinoid receptors types 1 (CB1R) and 2 (CB2R), and monoacylglycerol lipase (MAGL), addressing a wide array of medical needs.

Construction of Vicinal Quaternary Centers via Ru-Catalyzed Enantiospecific Allylic Substitution with Lithium Ester Enolates.

The installation of vicinal quaternary centers with absolute stereocontrol constitutes a considerable challenge in organic synthesis. Herein, we introduce a novel [Cp*Ru(MeCN)]PF/phenoxythiazoline catalyst system that achieves enantiospecific allylic substitution of tertiary carbonates with α,α-disubstituted lithium ester enolates to give products containing vicinal quaternary centers. Noteworthy features include the direct use of nonstabilized ester enolates, a class of nucleophiles which has rarely been used in transition metal-catalyzed allylic substitution reactions.

Synthesis of Primary Amines via Hydrogen Atom Transfer-Initiated Cyclization/Reduction Cascade of Unsaturated Nitriles.

We report a hydrogen atom transfer-initiated cyclization/reduction cascade for the synthesis of primary amines from δ,ε- and ε,ζ-unsaturated nitriles. The HAT transformation employs Mn(acac) as a catalyst and utilizes air as an oxidant along with NaBH as a dual-purpose reductant toward the olefin and subsequently C═N. Aromatic and aliphatic nitriles incorporating mono-, di-, and trisubstituted olefins are substrates for the reaction.

Patent review of cannabinoid receptor type 2 (CBR) modulators (2016-present).

Introduction: Cannabinoid receptor type 2 (CBR), predominantly expressed in immune tissues, is believed to play a crucial role within the body's protective mechanisms. Its modulation holds immense therapeutic promise for addressing a wide spectrum of dysbiotic conditions, including cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, and autoimmune diseases, as well as lung disorders, cancer, and pain management.

Areas Covered: This review is an account of patents from 2016 up to 2023 which describes novel CBR ligands, therapeutic applications, synthesis, as well as formulations of CBR modulators.

Cobalt-Catalyzed Photo-Semipinacol Rearrangement of Unactivated Allylic Alcohols.

We report a photochemical method for the semipinacol rearrangement of unactivated allylic alcohols. Aliphatic as well as aromatic groups participate as migrating groups, yielding a variety of α,α-disubstituted ketones. The reaction proceeds under mild conditions and is compatible with ethers, esters, halides, nitriles, carbamates, and substituted arenes.

Flipping the GPCR Switch: Structure-Based Development of Selective Cannabinoid Receptor 2 Inverse Agonists.

We report a blueprint for the rational design of G protein coupled receptor (GPCR) ligands with a tailored functional response. The present study discloses the structure-based design of cannabinoid receptor type 2 (CBR) selective inverse agonists ()- and ()-, which were derived from privileged agonist HU-308 by introduction of a phenyl group at the -dimethylheptyl side chain. Epimer ()- exhibits high affinity for CBR with = 39.

Aryl Azocyclopropeniums: Minimalist, Visible-Light Photoswitches.

We report convenient syntheses of aryl azocyclopropeniums and a study of their photochemical properties. Incorporation of the smallest arene leads to pronounced redshift of the π-π* absorbance band, compared to azobenzenes. Photoisomerization under purple or green light irradiation affords - or -isomers in ratios up to 94% or 90% , and the switches proved stable over multiple irradiation cycles.

Photo- and Cobalt-Catalyzed Synthesis of Heterocycles via Cycloisomerization of Unactivated Olefins.

We report a general, intramolecular cycloisomerization of unactivated olefins with pendant nucleophiles. The reaction proceeds under mild conditions and tolerates ethers, esters, protected amines, acetals, pyrazoles, carbamates, and arenes. It is amenable to N-, O-, as well as C-nucleophiles, yielding a number of different heterocycles including, but not limited to, pyrrolidines, piperidines, oxazolidinones, and lactones.

Harnessing PROTAC technology to combat stress hormone receptor activation.

Counteracting the overactivation of glucocorticoid receptors (GR) is an important therapeutic goal in stress-related psychiatry and beyond. The only clinically approved GR antagonist lacks selectivity and induces unwanted side effects. To complement existing tools of small-molecule-based inhibitors, we present a highly potent, catalytically-driven GR degrader, KH-103, based on proteolysis-targeting chimera technology.

A naturally occurring polyacetylene isolated from carrots promotes health and delays signatures of aging.

To ameliorate or even prevent signatures of aging in ultimately humans, we here report the identification of a previously undescribed polyacetylene contained in the root of carrots (Daucus carota), hereafter named isofalcarintriol, which we reveal as potent promoter of longevity in the nematode C. elegans. We assign the absolute configuration of the compound as (3 S,8 R,9 R,E)-heptadeca-10-en-4,6-diyne-3,8,9-triol, and develop a modular asymmetric synthesis route for all E-isofalcarintriol stereoisomers.

Total Synthesis of (+)-Euphorikanin A via an Atropospecific Cascade.

A total synthesis of the ingenane-derived diterpenoid (+)-euphorikanin A is described. Key to the strategy is a stereocontrolled one-pot sequence consisting of transannular aldol addition reaction, hemiketal formation, and subsequent semipinacol rearrangement that efficiently leads to the complete euphorikanin skeleton. Atroposelective ring-closing olefin metathesis proved critical for the stereospecific cascade, leading to formation of a ()-bicyclo[7.

Iron-Mediated Photochemical Anti-Markovnikov Hydroazidation of Unactivated Olefins.

Unactivated olefins are converted to alkyl azides with bench-stable NaN in the presence of FeCl·6HO under blue-light irradiation. The products are obtained with anti-Markovnikov selectivity, and the reaction can be performed under mild ambient conditions in the presence of air and moisture. The transformation displays broad functional group tolerance, which renders it suitable for functionalization of complex molecules.

Enantioselective Total Syntheses of Cassane Furanoditerpenoids and Their Stimulation of Cellular Respiration in Brown Adipocytes.

We report the first and enantioselective total syntheses of (+)-1-deacetylcaesalmin C, (+)-δ-caesalpin, (+)-norcaesalpinin MC, and (+)-norcaesalpinin P. Salient features of the synthetic strategy are an exo-selective intramolecular Diels-Alder reaction of a furanoquinone monoketal and subsequent chemoselective reduction of the resulting pentacyclic furfuryl ketal, furnishing a keystone intermediate. The latter enables access to the collection of natural products through implementation of stereoselective oxidations.

Synthesis of Neocaesalpin A, AA, and Nominal Neocaesalpin K.

The first total synthesis of heavily oxidized cassane-type diterpenoid neocaesalpin A (1) is disclosed. At the heart of the synthesis lies an intermolecular Diels-Alder reaction that rapidly assembles the target framework from commercial materials. A carefully orchestrated sequence of oxidations secured the desired oxygenation pattern.

Cobalt-Catalyzed Aerobic Aminocyclization of Unsaturated Amides for the Synthesis of Functionalized γ- and δ-Lactams.

We report the cobalt-catalyzed aminocyclization of unsaturated -acyl sulfonamides in the presence of oxygen to provide γ- and δ-lactam aldehydes. Use of an optically active cobalt catalyst resulted in the formation of enantiomerically enriched γ-and δ-lactam alcohols. The γ-lactam aldehydes and alcohols obtained were elaborated into useful building blocks.

Organophotocatalytic carbo-heterofunctionalization of unactivated olefins with pendant nucleophiles.

We report the difunctionalization of unactivated, terminal olefins through intermolecular addition of α-bromoketones, -esters, and -nitriles followed by formation of 4- to 6-membered heterocycles with pendant nucleophiles. The reaction can be conducted with alcohols, acids, and sulfonamides as nucleophiles furnishing products bearing 1,4 functional group relationships that offer various handles for further manipulation. Salient features of the transformations are the use of 0.

Platform Reagents Enable Synthesis of Ligand-Directed Covalent Probes: Study of Cannabinoid Receptor 2 in Live Cells.

Pharmacological modulation of cannabinoid receptor type 2 (CBR) holds promise for the treatment of neuroinflammatory disorders, such as Alzheimer's disease. Despite the importance of CBR, its expression and downstream signaling are insufficiently understood in disease- and tissue-specific contexts. Herein, we report the first ligand-directed covalent (LDC) labeling of CBR enabled by a novel synthetic strategy and application of platform reagents.

Enantioselective Total Synthesis of (+)-Pedrolide.

The first total synthesis of (+)-pedrolide, a tigliane-derived diterpenoid featuring an unprecedented 5-5-6-6-3 carbon skeleton, is reported. Key to the approach is the construction of the bicyclo[2.2.

Role of Noncovalent Interactions in Inducing High Enantioselectivity in an Alcohol Reductive Deoxygenation Reaction Involving a Planar Carbocationic Intermediate.

The involvement of planar carbocation intermediates is generally considered undesirable in asymmetric catalysis due to the difficulty in gaining facial control and their intrinsic stability issues. Recently, suitably designed chiral catalyst(s) have enabled a guided approach of nucleophiles to one of the prochiral faces of carbocations affording high enantiocontrol. Herein, we present the vital mechanistic insights from our comprehensive density functional theory (B3LYP-D3) study on a chiral Ir-phosphoramidite-catalyzed asymmetric reductive deoxygenation of racemic tertiary α-substituted allenylic alcohols.

Intermolecular Organophotocatalytic Cyclopropanation of Unactivated Olefins.

Intermolecular cyclopropanation of mono-, di-, and trisubstituted olefins with α-bromo-β-ketoesters and α-bromomalonates under organophotocatalysis is reported. The reaction displays broad functional group tolerance, including substrates bearing acids, alcohols, halides, ethers, ketones, nitriles, esters, amides, carbamates, silanes, stannanes, boronic esters, as well as arenes, and furnishes highly substituted cyclopropanes. The transformation may be performed in the presence of air and moisture with 0.

Genome-based discovery and total synthesis of janustatins, potent cytotoxins from a plant-associated bacterium.

Host-associated bacteria are increasingly being recognized as underexplored sources of bioactive natural products with unprecedented chemical scaffolds. A recently identified example is the plant-root-associated marine bacterium Gynuella sunshinyii of the chemically underexplored order Oceanospirillales. Its genome contains at least 22 biosynthetic gene clusters, suggesting a rich and mostly uncharacterized specialized metabolism.

Enantioselective Total Synthesis of (+)-Aberrarone.

We disclose the first total synthesis of (+)-aberrarone, a diterpenoid natural product featuring a 5-5-5-6-fused tetracyclic skeleton. Key to the approach is a Au-catalyzed-Sn-mediated Meyer-Schuster-Nazarov-cyclopropanation-aldol cascade, which closes four rings in high yield. The convergent approach furnishes the natural product (+)-aberrarone stereoselectively in 15 steps.