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Herein we report that simple α-chloro thioesters undergo soft enolization and direct aldol addition to aldehydes in the presence of MgBr2·OEt2 and i-Pr2NEt. At −78 °C the reaction proceeds in a kinetically controlled manner giving good diastereoselectivity. Significantly, the transformation is applicable to both enolizable and nonenolizable aldehydes. Moreover, excellent stereoselectivity results when a chiral nonracemic α-hydroxy aldehyde derivative is used. To our knowledge, this is the first report of a kinetically controlled soft enolization-based aldol addition.

A broadly applicable asymmetric synthetic strategy utilizing N-amino cyclic carbamate alkylation that provides access to the various stereochemical permutations of a common structural motif found in many polycyclic polyprenylated acylphloroglucinols is described. The utility of this methodology is demonstrated through the first asymmetric total synthesis of the antiviral agent (+)-clusianone.

Simple thioesters undergo direct aldol addition to aldehydes in the presence of magnesium bromide-diethyl ether and N,N-diisopropylethylamine using untreated, reagent grade dichloromethane under atmospheric conditions. The reactions proceed extremely rapidly and in excellent yield.

[reaction: see text] Simple thioesters undergo direct aldol addition to aldehydes in the presence of MgBr(2).OEt(2) and i-Pr(2)NEt using untreated, reagent-grade CH(2)Cl(2) under atmospheric conditions. The reactions proceed extremely rapidly and in excellent yield.

Thioesters undergo soft enolization and direct Mannich additionto sulfonylimines on treatment with magnesium bromide ethyl etherateand N, N-diisopropylethylamine.The reactions proceed readily with a range of sulfonylimines and,in the case of 2,4,6-triisopropylphenyl thiopropionate, give moderateto good SYN dia-stereoselectivity.

A facile and efficient four-component anti-selective direct aldol addition of thioester enolates has been developed that is fully compatible with enolizable aldehydes and able to be conducted using untreated reagent-grade CH2Cl2 open to the air. The thioester enolates are generated in situ via an acylation/conjugate addition sequence using commercially available PhSLi and acryloyl chloride, thus avoiding prior enolate formation while maintaining complete chemoselectivity. The organosulfur products are convertible into various polyketide-based structures.

Elucidating the key signal transduction pathways essential for both antipsychotic efficacy and side-effect profiles is essential for developing safer and more effective therapies. Recent work has highlighted noncanonical modes of dopamine D 2 receptor (D 2 R) signaling via β-arrestins as being important for the therapeutic actions of both antipsychotic and antimanic agents. We thus sought to create unique D 2 R agonists that display signaling bias via β-arrestin–ergic signaling. Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin–biased D 2 R ligands. These compounds also represent unprecedented β-arrestin–biased ligands for a G i -coupled G protein–coupled receptor (GPCR). Significantly, UNC9975, UNC0006, and UNC9994 are simultaneously antagonists of G i -regulated cAMP production and partial agonists for D 2 R/β-arrestin-2 interactions. Importantly, UNC9975 displayed potent antipsychotic-like activity without inducing motoric side effects in inbred C57BL/6 mice in vivo. Genetic deletion of β-arrestin-2 simultaneously attenuated the antipsychotic actions of UNC9975 and transformed it into a typical antipsychotic drug with a high propensity to induce catalepsy. Similarly, the antipsychotic-like activity displayed by UNC9994, an extremely β-arrestin–biased D 2 R agonist, in wild-type mice was completely abolished in β-arrestin-2 knockout mice. Taken together, our results suggest that β-arrestin signaling and recruitment can be simultaneously a significant contributor to antipsychotic efficacy and protective against motoric side effects. These functionally selective, β-arrestin–biased D 2 R ligands represent valuable chemical probes for further investigations of D 2 R signaling in health and disease.

The title reaction proceeds without competing Darzens addition affording α-chloro-β-hydroxy thioesters in moderate to high yields with moderate to good diastereoselectivity.

Growing evidence suggests that protein lysine methyltransferases (PKMTs) and protein arginine methyltransferases (PRMTs) are associated with the development of various human diseases, including cancer, inflammation, and psychiatric disorders. Given the significant role of these proteins in human disease, efforts to discover selective small-molecule inhibitors of these enzymes are quickly gaining momentum. In this review, we focus on the recent progress in the discovery of selective PKMT and PRMT inhibitors. A future perspective on developing methyltransferase inhibitors is also offered.

An asymmetric Mannich reaction of phenylacetate thioesters and sulfonylimines using cinchona alkaloid-based amino (thio)urea catalysts is reported that employs proximity-assisted soft enolization. This approach to enolization is based on the cooperative action of a carbonyl-activating hydrogen bonding (thio)urea moiety and an amine base contained within a single catalytic entity to facilitate intracomplex deprotonation. Significantly, this allows thioesters over a range of acidity to react efficiently, thereby opening the door to the development of a general mode of enolization-based organocatalysis of monocarboxylic acid derivatives.

[51805-45-9] C9H15O6P·HCl (MW 286.65) InChI = 1S/C9H15O6P.ClH/c10-7(11)1-4-16(5-2-8(12)13)6-3-9(14)15;/h1-6H2,(H,10,11)(H,12,13)(H,14,15);1H InChIKey = PBVAJRFEEOIAGW-UHFFFAOYSA-N (reduction of disulfides, sulfoxides, sulfonyl chlorides, N-oxides, and azides in aqueous media1, 2) Physical Data: mp 175–177 °C, odorless. Solubility: water-soluble (310 g L−1). Form Supplied in: white crystalline solid or aqueous solution (0.5 M, pH 7.0). Anylysis of Reagent Purity: NMR, mp, UV, elemental analysis, and IR. Preparative Methods: commercially available, but can be conveniently made on a large scale by acid hydrolysis of tris(2-cyanoethyl)phosphine in refluxing aqueous HCl followed by cooling to 0 °C, filtration, and recrystallization from water.1 Purification: recrystallization from water.1 Handling, Storage, and Precautions: store at 2–8 °C; −20 °C for long-term storage. Solid TCEP is stable in air for several months. TCEP is also stable in aqueous solution under both acidic and basic conditions, but is neither particularly stable in phosphate buffers, especially at neutral pH, nor in the presence of a metal chelator, such as EGTA. Therefore, if TCEP is to be used in PBS buffers, working solutions should be prepared immediately before use. TCEP·HCl is an irritant to the eyes, skin, respiratory tract, and digestive tract. Minimize dust generation and accumulation; avoid contact with the eyes, skin, and clothing. Avoid ingestion and inhalation.

A facile and efficient four-component anti-selective direct aldol addition of thioester enolates has been developed that is fully compatible with enolizable aldehydes and able to be conducted using untreated reagent-grade CH2Cl2 open to the air. The thioester enolates are generated in situ via an acylation/conjugate addition sequence using commercially available PhSLi and acryloyl chloride, thus avoiding prior enolate formation while maintaining complete chemoselectivity. The organosulfur products are convertible into various polyketide-based structures.