2-(1,1-Dicyanomethylene)rhodanine-Functionalized Oligothiophenes: A Structure-Property Investigation of / Photoisomerization Behavior.

A series of oligothiophenes singly and doubly functionalized with dicyanorhodanine (RCN) units have been investigated to understand their / photoisomerization behavior upon structural modulation. Monotopic RCN target molecules (-) were designed to observe the consequences of π-conjugation, solubilizing group substitution, and formylation of the thiophene units. In all cases, the isomer is obtained from synthesis as the thermodynamically stable isomer, whereas the isomer is achieved through selective irradiation (including red light, λ = 628 nm) as a / mixture in solution.

Snapshot of cyclooctyne ring-opening to a tethered alkylidene cyclic polymer catalyst.

Cyclooctyne reacts with the trianionic pincer ligand supported alkylidyne [ BuOCO]WCC(CH)(THF) (1) to yield tungstacyclopropene (3) and tungstacyclopentadiene (4) complexes. The ratio of 3 and 4 in the reaction mixture depends on the stoichiometry of the reaction. The maximum concentration of 3 occurs with one equiv.

Photocatalytic Decarboxylative Alkylation of Cyclic Imine-BF Complexes: A Modular Route to Functionalized Azacycles.

Alkyl radicals generated via an acridine photocatalyzed decarboxylation reaction of feedstock carboxylic acids engage with a range of cyclic imine-BF complexes to provide α-functionalized azacycles in an operationally simple process. A three-component variant of this transformation incorporating [1.1.

Tethered Alkylidenes for REMP from Carbon Disulfide Cleavage.

Reactions between tungsten alkylidyne [BuOCO]W≡CBu(THF) and sulfur containing small molecules are reported. Complex reacts with CS to produce intermediate η bound CS complex [OC(BuC═)W(η-(,)-CS)(THF)] . Heating complex provides a mixture of a monomeric tungsten sulfido complex and a dimeric complex in a 4:1 ratio, respectively.

Dicyanorhodanine-Pyrrole Conjugates for Visible Light-Driven Quantitative Photoswitching in Solution and the Solid State.

Small molecule photoswitches capable of toggling between two distinct molecular states in response to light are versatile tools to monitor biological processes, control photochemistry, and design smart materials. In this work, six novel dicyanorhodanine-based pyrrole-containing photoswitches are reported. The molecular design avails both the and isomers from synthesis, where each can be isolated using chromatographic techniques.

Three-Component ,-Disubstitution of Nitrocoumarins.

The development of a three-component ,-disubstitution of nitrocoumarins is reported. The reaction leverages the electrophilicity of nitrocoumarins, the nucleophilicity of nitronates, and the leaving group ability of nitrite (NO) to yield complex polyfunctionalized biaryls that often display stable axial chirality.

Influence of solvent on cyclic polynorbornene tacticity.

Tacticity is critical to polymer properties. The influence of solvent on tacticity in the catalytic synthesis of cyclic polynorbornene (c-PNB) is reported. In toluene , c-PNB forms; in THF, / c-PNB forms.

Alicyclic-Amine-Derived Imine-BF Complexes: Easy-to-Make Building Blocks for the Synthesis of Valuable α-Functionalized Azacycles.

A new strategy to access α-functionalized alicyclic amines via their corresponding imine-BF complexes is reported. Isolable imine-BF complexes, readily prepared via dehydrohalogenation of N-bromoamines in a base-promoted/18-crown-6 catalyzed process followed by addition of boron trifluoride etherate, undergo reactions with a wide range of organometallic nucleophiles to afford α-functionalized azacycles. Organozinc and organomagnesium nucleophiles add at ambient temperatures, obviating the need for cryogenic conditions.

A case of alkylidyne-imine metathesis.

Reactions between imines and tungsten alkylidyne complexes are studied. The trianionic pincer ligand supported alkylidyne [BuOCO]WCC(CH)(THF) (1) reacts with -(R)-1-phenylmethanimine (PMI-R, R = Me, Ph, Bn, and TMS) yielding [BuOC(H)O]W(ηBuCCPh)N(R) (4-R), products from metathesis reaction. In contrast, the non-pincer alkylidyne (BuO)WCC(CH) does not react with PMI-R imines.

Cryptic Isomerization in Diterpene Biosynthesis and the Restoration of an Evolutionarily Defunct P450.

Biosynthetic modifications of the 6/10-bicyclic hydrocarbon skeletons of the eunicellane family of diterpenoids are unknown. We explored the biosynthesis of a bacterial -eunicellane natural product, albireticulone A (), and identified a novel isomerase that catalyzes cryptic isomerization in the biosynthetic pathway. We also assigned functions of two cytochromes P450 that oxidize the eunicellane skeleton, one of which was a naturally evolved non-functional P450 that, when genetically repaired, catalyzes allylic oxidation.

Ring Expansion Alkyne Metathesis Polymerization.

The synthesis, characterization, and preliminary activity of an unprecedented tethered alkylidyne tungsten complex for ring expansion alkyne metathesis polymerization (REAMP) are reported. The tethered alkylidyne is generated rapidly by combining alkylidyne W(CBu)(CHBu)(O-2,6--CH) () with 1 equiv of an yne-ol proligand (). Characterized by NMR studies and nuclear Overhauser effect spectroscopy, complex is a dimer.

Mechanism of a Dually Catalyzed Enantioselective Oxa-Pictet-Spengler Reaction and the Development of a Stereodivergent Variant.

Enantioselective oxa-Pictet-Spengler reactions of tryptophol with aldehydes proceed under weakly acidic conditions utilizing a combination of two catalysts, an indoline HCl salt and a bisthiourea compound. Mechanistic investigations revealed the roles of both catalysts and confirmed the involvement of oxocarbenium ion intermediates, ruling out alternative scenarios. A stereochemical model was derived from density functional theory calculations, which provided the basis for the development of a highly enantioselective stereodivergent variant with racemic tryptophol derivatives.

Axially Chiral Cannabinoids: Design, Synthesis, and Cannabinoid Receptor Affinity.

The resorcinol-terpene phytocannabinoid template is a privileged scaffold for the development of diverse therapeutics targeting the endocannabinoid system. Axially chiral cannabinols (CBNs) are unnatural cannabinols (CBNs) that bear an additional C10 substituent, which twists the cannabinol biaryl framework out of planarity creating an axis of chirality. This unique structural modification is hypothesized to enhance both the physical and biological properties of cannabinoid ligands, thus ushering in the next generation of endocannabinoid system chemical probes and cannabinoid-inspired leads for drug development.

Nuclear Magnetic Resonance Method for Measuring Water Solubility of Organic Compounds.

Water solubility measurements are required in drug discovery, in toxicological or environmental studies, and in developing industrial processes which employ extractions or crystallizations. The gold-standard shake-flask method is tedious and takes at least 24 h. We developed a nuclear magnetic resonance (NMR) method for automation, which has the same accuracy and solubility range as the shake-flask method, but a measurement can be made faster, since the analysis does not require separation of the phases.

iClick synthesis of network metallopolymers.

Described is an approach to preparing the first iClick network metallopolymers with porous properties. Treating digoldazido complex 2-AuN3 with trigoldacetylide 3-AuPPh3 or 3-AuPEt3, trialkyne 3-H, tetragoldacetylide 4-AuPPh3, or tetraalkyne 4-H in CHCl affords five iClick network metallopolymers 5-AuPPh3, 5-AuPEt3, 5-H, 6-AuPPh3, and 6-H. Confirmation of the iClick network metallopolymers comes from FTIR, C solid-state cross-coupling magic angle spinning (CPMAS) NMR spectroscopy, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and nitrogen and CO sorption analysis.

Regioselective α-Cyanation of Unprotected Alicyclic Amines.

Secondary alicyclic amines are converted to α-aminonitriles via addition of TMSCN to their corresponding imines, intermediates that are produced in situ via the oxidation of amine-derived lithium amides with simple ketone oxidants. Amines with an existing α-substituent undergo regioselective α'-cyanation even if the C-H bonds at that site are less activated. Amine α-arylation can be combined with α'-cyanation to generate difunctionalized products in a single operation.

Structure-Functional Selectivity Relationship Studies on A-86929 Analogs and Small Aryl Fragments toward the Discovery of Biased Dopamine D1 Receptor Agonists.

Dopamine regulates normal functions such as movement, reinforcement learning, and cognition, and its dysfunction has been implicated in multiple psychiatric and neurological disorders. Dopamine acts through D1- (D1R and D5R) and D2-class (D2R, D3R, and D4R) receptors and activates both G protein- and β-arrestin-dependent signaling pathways. Current dopamine receptor-based therapies are used to ameliorate motor deficits in Parkinson's disease or as antipsychotic medications for schizophrenia.

Diastereoselective Indole-Dearomative Cope Rearrangements by Compounding Minor Driving Forces.

Reported herein is the discovery of a diastereoselective indole-dearomative Cope rearrangement. A suite of minor driving forces promote dearomatization: (i) steric congestion in the starting material, (ii) alkylidene malononitrile and stilbene conjugation events in the product, and (iii) an unexpected intramolecular π-π* stack on the product side of the equilibrium. The key substrates are rapidly assembled from simple starting materials, resulting in many successful examples.

Isolation of an Elusive Phosphametallacyclobutadiene and Its Role in Reversible Carbon-Carbon Bond Cleavage.

The reactivity of phosphaalkynes, the isolobal and isoelectronic congeners to alkynes, with metal alkylidyne complexes is explored in this work. Treating the tungsten alkylidyne [ BuOCO]W≡C Bu(THF) (1) with phosphaalkyne (10) results in the formation of [O C( BuC=)W{η -(P,C)-P≡C-Ad}(THF)] (13- Bu ) and [O C(AdC=)W{η -(P,C)-P≡C- Bu}(THF)] (13-Ad ); derived from the formal reductive migratory insertion of the alkylidyne moiety into a W-C bond. Analogous to alkyne metathesis, a stable phosphametallacyclobutadiene complex [ BuOCO]W[κ -C( Bu)PC(Ad)] (14) forms upon loss of THF from the coordination sphere of either 13- Bu or 13-Ad .

Anticancer Agents Derived from Cyclic Thiosulfonates: Structure-Reactivity and Structure-Activity Relationships.

Reported are structure-property-function relationships associated with a class of cyclic thiosulfonate molecules-disulfide-bond disrupting agents (DDAs)-with the ability to downregulate the Epidermal Growth Factor Receptor (HER) family in parallel and selectively induce apoptosis of EGFR+ or HER2+ breast cancer cells. Recent findings have revealed that the DDA mechanism of action involves covalent binding to the thiol(ate) from the active site cysteine residue of members of the protein disulfide isomerase (PDI) family. Reported is how structural modifications to the pharmacophore can alter the anticancer activity of cyclic thiosulfonates by tuning the dynamics of thiol-thiosulfonate exchange reactions, and the studies reveal a correlation between the biological potency and thiol-reactivity.

1,2,4-Trifunctionalized Cyclohexane Synthesis via a Diastereoselective Reductive Cope Rearrangement and Functional Group Interconversion Strategy.

Polyfunctionalized cyclohexanes are privileged scaffolds in drug discovery. Reported herein is a method for synthesizing 1,2,4-trifunctionalized cyclohexanes via diastereoselective reductive Cope rearrangement. The scaffolds obtained can be derivatized by orthogonal functional group interconversion to cyclohexanes bearing a 1-amide, 2-branched arylallyl, and variable 4-functional group.

SPAAC iClick: progress towards a bioorthogonal reaction in-corporating metal ions.

Combining strain-promoted azide-alkyne cycloaddition (SPAAC) and inorganic click (iClick) reactivity provides access to metal 1,2,3-triazolates. Experimental and computational insights demonstrate that iClick reactivity of the tested metal azides (LM-N, M = Au, W, Re, Ru and Pt) depends on the accessibility of the azide functionality rather than electronic effects imparted by the metal. SPAAC iClick reactivity with cyclooctyne is observed when the azide functionality is sterically unencumbered, [Au(N)(PPh)] (Au-N3), [W(η-allyl)(N)(bpy)(CO)] (W-N3), and [Re(N)(bpy)(CO)] [bpy = 2,2'-bipyridine] (Re-N3).