Cleavage of the Robust Silicon-Fluorine σ-Bond Allows Silicon-Carbon Bond Formation: Synthetic Strategies Toward Ortho-Silyl Aryl Phosphonates.

A straightforward, mild, and transition-metal-free three-component coupling reaction involving arynes, phosphites, and silyl fluorides was developed through Si-F bond activation. Although the Si-F bond is one of the strongest bonds, Si-C bond formation via Si-F bond cleavage with the assistance of bidentate silicon and phosphonium Lewis acids has been successfully achieved. This unprecedented strategy provides a facile approach for synthesizing ortho-silyl-substituted aryl phosphonates.

Synthetic Strategies toward -3-propanoate Substituted Aryl Phosphonates by Three-Component Coupling Reactions of Arynes, Phosphites, and Acrylates.

Mild, metal-free, and operationally simple three-component coupling reactions involving arynes, phosphites, and acrylates have been achieved. The reaction proceeded well with α- or β-substituted acrylates. Additionally, various functional groups were tolerated under these reaction conditions, resulting in diverse -3-propanoate-substituted aryl phosphonates.

Identification of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffolds as potent Lck inhibitors as anti-cancer agents.

Lymphocyte-specific protein tyrosine kinase (Lck) plays vital roles in the T-cell receptor- mediated development, function, and differentiation of T-cells. Given its substantial involvement in T cell signaling, irregularities in the expression and functionality of Lck may lead to various diseases, including cancer. In this study, we found that compound 12a exerted significant inhibitory potency against Lck with an IC value of 10.

Discovery of Orally Bioavailable Phthalazinone Analogues as an ENPP1 Inhibitor for STING-Mediated Cancer Immunotherapy.

A lack of the T cell-inflamed tumor microenvironment limits the efficacy of immune checkpoint inhibitors (ICIs). Activation of stimulator of interferon genes (STING)-mediated innate immunity has emerged as a novel therapeutic approach in cancer therapy. 2',3'-Cyclic GMP-AMP (cGAMP) is a natural STING agonist; however, cGAMP is subjected to endogenous degradation by ecto-nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1).

Implications for Combination Therapy of Selective Monoamine Reuptake Inhibitors on Dopamine Transporters.

Monoamine transporters, including dopamine, norepinephrine, and serotonin transporters (DAT, NET, and SERT, respectively), are important therapeutic targets due to their essential roles in the brain. To overcome the slow action of selective monoamine reuptake inhibitors, dual- or triple-acting inhibitors have been developed. Here, to examine whether combination treatments of selective reuptake inhibitors have synergistic effects, the pharmacological properties of DAT, NET, and SERT were investigated using the selective inhibitors of each transporter, which are vanoxerine, nisoxetine, and fluoxetine, respectively.

Chiroptical Synaptic Heterojunction Phototransistors Based on Self-Assembled Nanohelix of π-Conjugated Molecules for Direct Noise-Reduced Detection of Circularly Polarized Light.

High-performance chiroptical synaptic phototransistors are successfully demonstrated using heterojunctions composed of a self-assembled nanohelix of a π-conjugated molecule and a metal oxide semiconductor. To impart strong chiroptical activity to the device, a diketopyrrolopyrrole-based π-conjugated molecule decorated with chiral glutamic acid is newly synthesized; this molecule is capable of supramolecular self-assembly through noncovalent intermolecular interactions. In particular, nanohelix formed by intertwinded fibers with strong and stable chiroptical activity in a solid-film state are obtained through hydrogen-bonding-driven, gelation-assisted self-assembly.

Three-Component Coupling Reactions Involving Arynes, Phosphites, and Aldehydes toward 3-Mono-Substituted Benzoxaphosphole 1-Oxides.

A mild, efficient, and transition-metal-free three-component coupling reaction involving arynes, phosphites, and aldehydes was established to afford 3-mono-substituted benzoxaphosphole 1-oxides. A range of 3-mono-substituted benzoxaphosphole 1-oxides was obtained from both aryl- and aliphatic-substituted aldehydes in moderate to good yields. Moreover, the synthetic utility of the reaction was demonstrated by a Gram-scale reaction and the transformation of the products into various -containing bicycles.

A Convergent Total Synthesis of (+)-Ineleganolide.

We report the total synthesis of the furanobutenolide-derived diterpenoid (+)-ineleganolide. The synthetic approach relies on a convergent strategy based on the coupling of two enantioenriched fragments, which are derived from (-)-linalool and (+)-norcarvone, respectively. A high-yielding, one-step Michael addition and aldol cascade furnishes a pentacyclic framework as a single diastereomer, thereby overcoming previous challenges in controlling stereochemistry.

Synthetic Strategy for Aryl(alkynyl)phosphinates by a Three-Component Coupling Reaction Involving Arynes, Phosphites, and Alkynes.

An efficient and straightforward method for the synthesis of aryl(alkynyl)phosphinates was developed via a three-component coupling reaction involving arynes, phosphites, and alkynes. An array of aryl(alkynyl)phosphinates were produced from both aryl and aliphatic group-substituted acetylenes. This operationally simple reaction is tolerant to many functional groups, affording various aryl(alkynyl)phosphinates in moderate to good yields.

Identification of novel pyrrolopyrimidine and pyrrolopyridine derivatives as potent ENPP1 inhibitors.

In an effort to discover novel scaffolds of non-nucleotide-derived Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibitors to stimulate the Stimulator of Interferon Genes (STING) pathway, we designed and synthesised pyrrolopyrimidine and pyrrolopyridine derivatives and performed structure-activity relationship (SAR) study. We found possessed high potency (IC = 25.0 nM) against ENPP1, and activated STING pathway in a concentration dependent manner.

Discovery of 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one and 3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one derivatives as novel ENPP1 inhibitors.

Ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) negatively regulates the anti-cancer Stimulator of Interferon Genes (STING) pathway. We discovered that 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one and 3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one derivatives possessed inhibitory activities on ENPP1. A structure-activity relationship (SAR) study led to the identification of 46 and 23 as potent ENPP1 inhibitors.

Identification of highly selective type II kinase inhibitors with chiral peptidomimetic tails.

Identification of highly selective type II kinase inhibitors is described. Two different chiral peptidomimetic scaffolds were introduced on the tail region of non-selective type II kinase inhibitor GNF-7 to enhance the selectivity. Kinome-wide selectivity profiling analysis showed that type II kinase inhibitor potently inhibited Lck kinase with great selectivity (IC of 23.

Synthesis of Benzoxaphosphole 1-Oxide Heterocycles via a Three-Component Coupling Reaction Involving Arynes, Phosphites, and Ketones.

An efficient and transition-metal-free three-component reaction with benzynes formed in situ from 2-(trimethylsilyl)aryl triflate, phosphites, and ketones was developed for the synthesis of benzoxaphosphole 1-oxides. An array of benzoxaphosphole 1-oxides were prepared from both activated and non-activated ketones in moderate to good yields with a broad functional group tolerance. This reaction is useful for preparing organophosphorus compounds encountered in natural products and materials.

A Synthetic Strategy toward Eight-Membered Cyclic Amines by Cycloetherification and Claisen Rearrangement.

Eight-membered nitrogen-containing heterocycles were straightforwardly produced by a nickel-catalyzed cycloetherification and subsequent Claisen rearrangement of secondary and tertiary alcohols. In particular, a one-pot transformation was achieved with tertiary alcohols in moderate to good yields. This operationally simple reaction is tolerant of many functional groups and applicable to the synthesis of various medium-sized ring nitrogen-containing heterocycles.

Enantioselective Allenoate-Claisen Rearrangement Using Chiral Phosphate Catalysts.

Herein we report the first highly enantioselective allenoate-Claisen rearrangement using doubly axially chiral phosphate sodium salts as catalysts. This synthetic method provides access to β-amino acid derivatives with vicinal stereocenters in up to 95% ee. We also investigated the mechanism of enantioinduction by transition state (TS) computations with DFT as well as statistical modeling of the relationship between selectivity and the molecular features of both the catalyst and substrate.

A mild and efficient approach to enantioenriched α-hydroxyethyl α,β-unsaturated δ-lactams.

A straightforward approach toward enantioenriched α-substituted α,β-unsaturated δ-lactams is described. Although a considerable number of approches toward α,β-unsaturated δ-lactams have been reported, there are relatively few examples of enantioenriched α,δ-disubstituted α,β-unsaturated δ-lactams formation. The δ-stereocenter was formed by addition of allylmagnesium bromide to an --butylsulfinyl imine.

Nickel-Catalyzed Intramolecular C-O Bond Formation: Synthesis of Cyclic Enol Ethers.

An efficient and exceptionally mild intramolecular nickel-catalyzed carbon-oxygen bond-forming reaction between vinyl halides and primary, secondary, and tertiary alcohols has been achieved. Zinc powder was found to be an essential additive for obtaining high catalyst turnover and yields. This operationally simple method allows direct access to cyclic vinyl ethers in high yields in a single step.

Discovery and optimization of adamantane carboxylic acid derivatives as potent diacylglycerol acyltransferase 1 inhibitors for the potential treatment of obesity and diabetes.

We have developed a series of adamantane carboxylic acid derivatives exhibiting potent diacylglycerol acyltransferase 1 (DGAT1) inhibitory activities. Optimization of the series led to the discovery of E-adamantane carboxylic acid compound 43c, which showed excellent in vitro activity with an IC50 value of 5 nM against human and mouse DGAT1, also good druggability as well as microsomal stability and safety profiles such as hERG, CYP and cytotoxicity. Compound 43c significantly reduced plasma triglyceride levels in vivo (in rodents and zebrafish) and also showed bodyweight gain reduction and glucose area under curve (AUC) lowering efficacy in diet-induced obesity (DIO) mice.

Calpain-mediated cleavage of DARPP-32 in Alzheimer's disease.

Toxicity induced by aberrant protein aggregates in Alzheimer's disease (AD) causes synaptic disconnection and concomitant progressive neurodegeneration that eventually impair cognitive function. cAMP-response element-binding protein (CREB) is a transcription factor involved in the molecular switch that converts short-term to long-term memory. Although disturbances in CREB function have been suggested to cause memory deficits in both AD and AD animal models, the mechanism of CREB dysfunction is still unclear.

Stereochemical evaluation of bis(phosphine) copper catalysts for the asymmetric alkylation of 3-bromooxindoles with α-arylated malonate esters.

An improved method for the asymetric alkylation of 3-bromooxindoles with α-arylated malonate esters is described. The asymmetric alkylation demonstrated was achieved up to 70% ee utilizing a copper(II) bis(phosphine) complex.

Catalytic enantioselective construction of quaternary stereocenters: assembly of key building blocks for the synthesis of biologically active molecules.

The ever-present demand for drugs with better efficacy and fewer side effects continually motivates scientists to explore the vast chemical space. Traditionally, medicinal chemists have focused much attention on achiral or so-called "flat" molecules. More recently, attention has shifted toward molecules with stereogenic centers since their three-dimensional structures represent a much larger fraction of the chemical space and have a number of superior properties compared with flat aromatic compounds.

Evolution of a unified, stereodivergent approach to the synthesis of communesin F and perophoramidine.

Expedient synthetic approaches to the highly functionalized polycyclic alkaloids communesin F and perophoramidine are described using a unified approach featuring a key decarboxylative allylic alkylation to access a crucial and highly congested 3,3-disubstituted oxindole. Described are two distinct, stereoselective alkylations that produce structures in divergent diastereomeric series possessing the critical vicinal all-carbon quaternary centers needed for each synthesis. Synthetic studies toward these challenging core structures have revealed a number of unanticipated modes of reactivity inherent to these complex alkaloid scaffolds.

A New Method for the Cleavage of Nitrobenzyl Amides and Ethers.

A mild and efficient - and -nitrobenzyl cleavage protocol was developed. - and -Nitrobenzyl groups were easily removed from a variety of substrates using 20% aqueous NaOH in methanol at 75 °C, presumably via oxidation at the benzylic position by oxygen dissolved in the solution. These easily introducible and removable nitrobenzyl groups can serve as valuable protecting groups for the synthesis of multifunctional, complex molecules.

A diastereodivergent synthetic strategy for the syntheses of communesin F and perophoramidine.

An efficient, unified, and stereodivergent approach toward communesin F and perophoramidine was examined. The C(3) all-carbon quaternary center of an oxindole was smoothly constructed by base-promoted indolone-malonate alkylation chemistry. The complementary relative stereochemistry of the crucial vicinal quaternary centers found in communesin F and perophoramidine was selectively installed by substrate-controlled decarboxylative allylic alkylations.

Convergent and enantioselective total synthesis of (-)-amphidinolide O and (-)-amphidinolide P.

A convergent and enantioselective total synthesis of (-)-amphidinolide O (1) and P (2), 15-membered macrolides with seven chiral centers along with many functional groups, is described. The key reactions include enantioselective Brown allylation, anti- and syn-selective aldol reactions, (E)-selective olefin metathesis, conformation-controlled stereoselective epoxidation, and selective introduction of the exomethylene group. Assignments of the absolute stereochemistries of the natural (+)-amphidinolide O (ent-1) and P (ent-2) are also discussed in detail.