Access to enantioenriched compounds bearing challenging tetrasubstituted stereocenters via kinetic resolution of auxiliary adjacent alcohols.

Contemporary asymmetric catalysis faces huge challenges when prochiral substrates bear electronically and sterically unbiased substituents and when substrates show low reactivities. One of the inherent limitations of chiral catalysts and ligands is their incapability in recognizing prochiral substrates bearing similar groups. This has rendered many enantiopure substances bearing several similar substituents inaccessible. Here we report the rationale, scope, and applications of the strategy of kinetic resolution of auxiliary adjacent alcohols (KRA*) that can be used to solve the above troubles. Using this method, a large variety of optically enriched tertiary alcohols, epoxides, esters, ketones, hydroxy ketones, epoxy ketones, ß-ketoesters, and tetrasubstituted methane analogs with two, three, and four spatially and electronically similar groups can be readily obtained (totally 96 examples). At the current stage, the strategy serves as the optimal solution that can complement the inability caused by direct asymmetric catalysis in getting chiral molecules with challenging fully substituted stereocenters.

Stereodivergent Access to Enantioenriched Epoxy Alcohols with Three Stereogenic Centers via Ruthenium-Catalyzed Transfer Hydrogenation.

The resolution technique of stereodivergent reaction on racemic mixtures (stereodivergent RRM) was employed for the first time in ruthenium complex catalyzed transfer hydrogenation of racemic epoxy ketones, providing a new and very simple method that allows access to enantioenriched epoxy alcohols with three stereogenic centers in a one-step fashion. The protocol features simple reaction conditions, practical operation, ability to scale up, and broad group tolerance.

Camphorsulfonic Acid Catalyzed One-Pot Three-Component Reaction for the Synthesis of Fused Quinoline and Benzoquinoline Derivatives.

A simple and an efficient one-pot three-component reaction of arylamines, aromatic aldehydes, and cyclic ketones was described for the synthesis of various fused quinoline, benzoquinoline, and naphthoquinoline derivatives by using camphorsulfonic acid as a catalyst. The exploitation of pregnenolone steroid for benzoquinolines and terephthalaldehyde for bis-benzoquinolines synthesis was achieved with 68-75% yields. The reactivity of arylamines and the mechanistic study for the formation of benzoquinoline was described precisely. The present protocol offers a great potential for atom-economy under mild conditions.

K2CO3 catalyzed regioselective synthesis of thieno[2,3-b]thiochromen-4-one oximes: access to the corresponding amine and nitroso derivatives.

An unprecedented and efficient method for the synthesis of useful thieno[2,3-b]thiochromen-4-one oximes is accomplished via a thio[3 + 2] cyclization reaction of 4-hydroxydithiocoumarins and trans-ß-nitrostyrenes in the presence of 10 mol% K2CO3 in ethanol under reflux conditions. Furthermore, hitherto, these precursors were converted into the corresponding 2-amino thieno[2,3-b]thiochromen-4-one and 2-nitroso thieno[2,3-b]thiochromen-4-one derivatives respectively. The salient features of the present protocol are mild reaction conditions, shorter reaction times, good yields and unexpected formation of C-C and C-S bonds in a regioselective manner.

Insights into the inhibitory mechanism of triazole-based small molecules on phosphatidylinositol-4,5-bisphosphate binding pleckstrin homology domain.

BACKGROUND: Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] is an important regulator of several cellular processes and a precursor for other second messengers which are involved in cell signaling pathways. Signaling proteins preferably interact with PI(4,5)P2 through its pleckstrin homology (PH) domain. Efforts are underway to design small molecule-based antagonist, which can specifically inhibit the PI(4,5)P2/PH-domain interaction to establish an alternate strategy for the development of drug(s) for phosphoinositide signaling pathways. METHODS: Surface plasmon resonance, molecular docking, circular dichroism, competitive Förster resonance energy transfer, isothermal titration calorimetric analyses and liposome pull down assay were used. RESULTS: In this study, we employed 1,2,3-triazol-4-yl methanol containing small molecule (CIPs) as antagonists for PI(4,5)P2/PH-domain interaction and determined their inhibitory effect by using competitive-surface plasmon resonance analysis (IC50 ranges from 53 to 159 nM for PI(4,5)P2/PLCδ1-PH domain binding assay). We also used phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3], phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2], PI(4,5)P2 specific PH-domains to determine binding selectivity of the compounds. Various physicochemical analyses showed that the compounds have weak affect on fluidity of the model membrane but, strongly interact with the phospholipase C δ1 (PLCδ1)-PH domains. The 1,2,3-triazol-4-yl methanol moiety and nitro group of the compounds are essential for their exothermic interaction with the PH-domains. Potent compound can efficiently displace PLCδ1-PH domain from plasma membrane to cytosol in A549 cells. CONCLUSIONS: Overall, our studies demonstrate that these compounds interact with the PIP-binding PH-domains and inhibit their membrane recruitment. GENERAL SIGNIFICANCE: These results suggest specific but differential binding of these compounds to the PLCδ1-PH domain and emphasize the role of their structural differences in binding parameters. These triazole-based compounds could be directly used/further developed as potential inhibitor for PH domain-dependent enzyme activity.