Nitro-sulfinate Reductive Coupling to Access (Hetero)aryl Sulfonamides.

A method to assemble (hetero)aryl sulfonamides via the reductive coupling of aryl sulfinates and nitroarenes is reported. Various reducing conditions with sodium bisulfite and with or without tin(II) chloride in DMSO were developed using an ultrasound bath to improve reaction homogeneity and mixing. A range of (hetero)aryl sulfonamides bearing a selection of functional groups were prepared, and the mechanism of the transformation was investigated. These investigations have led us to propose the formation of nitrosoarene intermediates, which were established via an independent molecular coupling strategy.

Fluorophosphonates on-Demand: A General and Simplified Approach toward Fluorophosphonate Synthesis.

Herein, we report a general and simplified synthesis of fluorophosphonates directly from p-nitrophenylphosphonates. This FP on-demand reaction is mediated by a commercially available polymer-supported fluoride reagent that produces a variety (25 examples) of fluorophosphonates in high yields while only requiring reagent filtration for pure fluorophosphonate isolation. This reaction protocol facilitates the rapid profiling of serine hydrolases with diverse and novel sets of activated phosphonates with differential proteome reactivity. Moreover, slight modification of the procedure into a reaction-to-assay format has enabled additional screening efficiency.

2,2,2-Trifluoroethoxy Aromatic Heterocycles: Hydrolytically Stable Alternatives to Heteroaryl Chlorides.

Herein we describe the 2,2,2-trifluoroethoxy group as an alternative leaving group for hydrolytically unstable heteroaryl chlorides. This group provides improved shelf stability by years while maintaining reactivity toward nucleophiles in SNAr reactions. A highlighted trifluoroethyl ether was shown to be tolerant to aqueous Suzuki conditions, permitting sequential Suzuki/SNAr processes inaccessible to the heterocyclic chlorides. The strategic use of trifluoroethyl ethers enables storage of otherwise unstable heterocyclic chlorides and limits costly decomposition.

A Benzyne Insertion Approach to Hetisine-Type Diterpenoid Alkaloids: Synthesis of Cossonidine (Davisine).

The hetisine-type natural products exhibit one of the most complex carbon skeletons within the diterpenoid alkaloid family. The use of network analysis has enabled a synthesis strategy to access alkaloids in this class with hydroxylation on the A-ring. Key transformations include a benzyne acyl-alkylation to construct a key fused 6-7-6 tricycle, a chemoselective nitrile reduction, and sequential C-N bond formations using a reductive cyclization and a photochemical hydroamination to construct an embedded azabicycle. Our strategy should enable access to myriad natural and unnatural products within the hetisine-type.

Mechanism of a No-Metal-Added Heterocycloisomerization of Alkynylcyclopropylhydrazones: Synthesis of Cycloheptane-Fused Aminopyrroles Facilitated by Copper Salts at Trace Loadings.

A mechanistic study of a new heterocycloisomerization reaction that forms annulated aminopyrroles is presented. Density functional theory calculations and kinetic studies suggest the reaction is catalyzed by trace copper salts and that a Z- to E-hydrazone isomerization occurs through an enehydrazine intermediate before the rate-determining cyclization of the hydrazone onto the alkyne group. The aminopyrrole products are obtained in 36-93% isolated yield depending on the nature of the alkynyl substituent. A new automated sampling technique was developed to obtain robust mechanistic data.

An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism.

GPR61 is an orphan GPCR related to biogenic amine receptors. Its association with phenotypes relating to appetite makes it of interest as a druggable target to treat disorders of metabolism and body weight, such as obesity and cachexia. To date, the lack of structural information or a known biological ligand or tool compound has hindered comprehensive efforts to study GPR61 structure and function. Here, we report a structural characterization of GPR61, in both its active-like complex with heterotrimeric G protein and in its inactive state. Moreover, we report the discovery of a potent and selective small-molecule inverse agonist against GPR61 and structural elucidation of its allosteric binding site and mode of action. These findings offer mechanistic insights into an orphan GPCR while providing both a structural framework and tool compound to support further studies of GPR61 function and modulation.

Tungsten-catalyzed heterocycloisomerization approach to 4,5-dihydro-benzo[b]furans and -indoles.

A W(CO)(5)·THF-catalyzed cycloisomerization of bicyclo[4.1.0] substrates to afford mono C4-substituted 4,5-dihydro-benzo[b]furans and -indoles is reported. The title compounds are versatile intermediates that lead to a range of fused bicycles including the cores of various furan-, benzofuran-, and indole-containing natural products. In many cases, the functionalization of the dihydro-benzo[b]furans and -indoles is orthogonal to that of the corresponding benzofurans and indoles and, thus, offers complementary approaches for synthesis.

Photoaffinity Labeling and Quantitative Chemical Proteomics Identify LXRß as the Functional Target of Enhancers of Astrocytic apoE.

Utilizing a phenotypic screen, we identified chemical matter that increased astrocytic apoE secretion in vitro. We designed a clickable photoaffinity probe based on a pyrrolidine lead compound and carried out probe-based quantitative chemical proteomics in human astrocytoma CCF-STTG1 cells to identify liver x receptor ß (LXRß) as the target. Binding of the small molecule ligand stabilized LXRß, as shown by cellular thermal shift assay (CETSA). In addition, we identified a probe-modified peptide by mass spectrometry and proposed a model where the photoaffinity probe is bound in the ligand-binding pocket of LXRß. Taken together, our findings demonstrated that the lead chemical matter bound directly to LXRß, and our results highlight the power of chemical proteomic approaches to identify the target of a phenotypic screening hit. Additionally, the LXR photoaffinity probe and lead compound described herein may serve as valuable tools to further evaluate the LXR pathway.

Late-Stage Microsomal Oxidation Reduces Drug-Drug Interaction and Identifies Phosphodiesterase 2A Inhibitor PF-06815189.

Late-stage oxidation using liver microsomes was applied to phosphodiesterase 2 inhibitor 1 to reduce its clearance by cytochrome P450 enzymes, introduce renal clearance, and minimize the risk for victim drug-drug interactions. This approach yielded PF-06815189 (2) with improved physicochemical properties and a mixed metabolic profile. This example highlights the importance of C-H diversification methods to drug discovery.

Catalytic asymmetric generation of (Z)-disubstituted allylic alcohols.

A one-pot method for the direct preparation of enantioenriched (Z)-disubstituted allylic alcohols is introduced. Hydroboration of 1-halo-1-alkynes with dicyclohexylborane, reaction with t-BuLi, and transmetalation with dialkylzinc reagents generate (Z)-disubstituted vinylzinc intermediates. In situ reaction of these reagents with aldehydes in the presence of a catalyst derived from (-)-MIB generates (Z)-disubstituted allylic alcohols. It was found that the resulting allylic alcohols were racemic, most likely due to a rapid addition reaction promoted by LiX (X = Br and Cl). To suppress the LiX-promoted reaction, a series of inhibitors were screened. It was found that 20-30 mol % tetraethylethylenediamine inhibited LiCl without inhibiting the chiral zinc-based Lewis acid. In this fashion, (Z)-disubstituted allylic alcohols were obtained with up to 98% ee. The asymmetric (Z)-vinylation could be coupled with tandem diastereoselective epoxidation reactions to provide epoxy alcohols and allylic epoxy alcohols with up to three contiguous stereogenic centers, enabling the rapid construction of complex building blocks with high levels of enantio- and diastereoselectivity.

Leaving group potential of a substituted cyclopentadienyl anion toward oxidative addition.

The facility with which a substituted cyclopentadienyl anion may function as a leaving group for palladium-catalyzed allylation reactions is demonstrated. Reaction of several allylcyclopentadienyl substrates is shown. Nucleophilic displacement of carbon with nitrogen is achieved in the deallylation of allylpenta-p-acetylphenylcyclopentadiene with N-methylbenzylamine.

Direct, stereospecific generation of (Z)-disubstituted allylic alcohols.

A one-pot method to prepare highly functionalized (Z)-disubstituted allylic alcohols is introduced. Hydroboration of a variety of 1-bromo-1-acetylenes with dicyclohexyl borane, reaction with t-BuLi, and transmetalation to zinc generates a (Z)-disubstituted vinylzinc reagent. In situ reaction of this reagent with aldehydes generates (Z)-disubstituted allylic alcohols in high yields (81-97%). Addition to chiral protected alpha- or beta-oxygenated aldehydes proceeds with diastereoselectivities between 6:1 and 18:1. The anti-Felkin product is obtained in most cases.

An improved method for the bromination of metalated haloarenes via lithium, zinc transmetalation: a convenient synthesis of 1,2-dibromoarenes.

A facile protocol for the synthesis of 1,2-dibromoarenes is described. A standard ortho-lithiation/bromination procedure, when applied to bromoarenes, resulted in poor yields of the corresponding 1,2-dibromoarenes (13-62% yield). However, transmetalation of the transient aryllithium intermediate to an arylzinc species with ZnCl2, followed by bromination, resulted in dramatically improved yields of the synthetically useful 1,2-dibromoarenes (68-95% yield).