Ruchir Kant

Palladium-Catalyzed Tandem Intramolecular Oxy/Amino-Palladation/Isocyanide Insertion: Synthesis of α-Benzofuranyl/Indolylacetamides

A novel palladium-catalyzed approach to 2-benzofuranyl/indolylacetamides from 1-(o-hydroxy/aminophenyl)propargylic alcohols and isocyanides is described. The reaction proceeds through a cascade that includes oxy/aminopalladation, isocyanide insertion, and 1,4-hydroxyl migration. No oxidant or ligand is needed to promote the cascade, and the reactions are carried out under mild conditions to afford the products through high functional tolerance.

Palladium‐Catalyzed Regio‐ and Stereoselective Cross‐Addition of Terminal Alkynes to Ynol Ethers and Synthesis of 1,4‐Enyn‐3‐ones

Conjugated enynes, enol ethers, and enynones are versatile building blocks that can be elaborated by a wide variety of synthetic transformations. The selective synthesis of such units is a prerequisite for their effective utilization. The synthesis of conjugated 2-phenoxyenynes through a palladium-catalyzed cross-addition of terminal alkynes to phenylethynyl ethers (hydroalkynylation) is now presented. The reaction is highly regio-, stereo-, and chemoselective, and shows excellent tolerance toward functional groups. The addition further features very mild reaction conditions (room temperature) and an inexpensive catalytic system (without a ligand and with a cheaply available Pd catalyst). The thus synthesized enynyl ethers with allylic hydroxy tethers, which survived the reaction, were shown to be ready precursors for valuable 1-en-4-yn-3-ones.

Peganine hydrochloride dihydrate an orally active antileishmanial agent.

Protozoic infections caused by genus Leishmania pose an enormous public health threat in developing countries, compounded by the toxicity and resistance to current therapies. Under the aegis of our ongoing program on drug discovery and development on antileishmanial agents from plants, we carried out bioassay guided fractionation on Peganum harmala seeds which resulted in the isolation of 1 as an antileishmanial agent. 2D-NMR spectral data and single crystal X-ray crystallography data indicated 1 as peganine hydrochloride in dihydrated form. The compound 1 exhibited in-vitro activity against both extracellular promastigotes as well as intracellular amastigotes residing within murine macrophages in Leishmania donovani. Furthermore, 1 also exhibited in-vivo activity, 79.6 (+/-8.07)% against established VL in hamsters at a dose of 100mg/kgb.wt.

Transition-Metal-Free C-3 Arylation of Quinoline-4-ones with Arylhydrazines.

A transition-metal-free C-3-arylation of quinolin-4-ones in the presence of base has been achieved by using arylhydrazines as aryl radical source and air as oxidant. The reaction proceeds smoothly at room temperature and does not require any prefunctionalization and N-protection of quinoline-4-ones. The utility of this methodology is further demonstrated in synthesis of quinoline-quinolone hybrid as well as 6-aryl-benzofuro[3,2-c]quinoline scaffold.

Metal-Free Three-Component Domino Approach to Phosphonylated Triazolines and Triazoles.

An efficient, three-component domino reaction between aldehydes, amines, and the Bestmann-Ohira reagent is reported that enables a general, mild, and straightforward access to 1,4,5-trisubstituted 1,2,3-triazolines and triazoles. The reaction proceeds through a domino-condensation/1,3-dipolar cycloaddition sequence to afford the triazoline derivatives with excellent diastereoselectivity. Moreover, when both amine and aldehyde employed for this reaction are aromatic, a spontaneous oxidation afforded 1,4,5-trisubstituted triazoles in moderate yields.

Molecular iodine catalysed one-pot synthesis of chromeno[4,3-b]quinolin-6-ones under microwave irradiation

We demonstrate a facile one pot approach for the regioselective synthesis of chromeno[4,3-b]quinolin-6-one derivatives in excellent yields under microwave (MW) irradiation. This transformation presumably proceeds via a three-component tandem annulation of 4-hydroxycoumarin with aromatic aldehydes and aromatic amines, involving a Povarov type reaction.

Design and synthesis of ERα/ERβ selective coumarin and chromene derivatives as potential anti-breast cancer and anti-osteoporotic agents

Several new coumarin and chromene prototype derivatives have been synthesised and evaluated for their ERα and ERβ selective activity. Coumarin prototype compounds 18 & 19 were found to be ERα selective and the most active, exhibiting potential antiproliferative activity against both ER +ve & ER −ve breast cancer cell lines. The surprise finding of the series, however, are the novel prototype III chromenes 45 & 46, with aroyl substitution at the 6th position. Both the compounds have shown potent antiproliferative activity against both the breast cancer cell lines, promote alkaline phosphatase activity, enhance osteoblast mineralization in vitro, significantly decrease ERE–ERα dependent transactivation and induce ERβ activity. This specific upregulation of ERβ isoform activity of compound 45 may be responsible for the antiosteoporotic activity at picomolar concentration. In addition, both the compounds were also devoid of any estrogenic activity, which correlates to their antiestrogenic behaviour in the two breast cancer cell lines. Assessment of selectivity using specific SiRNAs for ERα and ERβ revealed that most of the compounds showed ERα and ERβ-mediated action, except compound 28, which showed selectivity to ERα only. Computational docking analysis of active compounds 18 and 45 was conducted to correlate the interaction with the two receptors and it was found that the docked conformations of the coumarin prototype, compound 18 at ERα and ERβ active sites were more or less superimposable on each other. However, the unique orientation of the aminoalkoxy side chain of novel chromene (prototype III) compound 45 in the ERβ binding cavity may be responsible for its potential biological response.

Tandem C-2 Functionalization–Intramolecular Azide–Alkyne 1,3-Dipolar Cycloaddition Reaction: A Convenient Route to Highly Diversified 9H-Benzo[b]pyrrolo[1,2-g][1,2,3]triazolo[1,5-d][1,4]diazepines

An efficient diversity-oriented synthetic approach to annulated 9H-benzo[b]pyrrolo[1,2-g][1,2,3]triazolo[1,5-d][1,4]diazepines has been developed using a Sc(OTf)3-catalyzed two-component tandem C-2 functionalization-intramolecular azide-alkyne 1,3-dipolar cycloaddition reaction. The reaction shows high substrate tolerance and provides a library of fused heterocycles that may lead to novel biologically active compounds or drug lead molecules.

Silver(I)-Catalyzed Regioselective Construction of Highly Substituted α-Naphthols and Its Application toward Expeditious Synthesis of Lignan Natural Products

A novel route has been developed for regioselective synthesis of highly substituted α-naphthols, binaphthols, and anthracenol through silver(I) catalyzed C(sp(3))-H/C(sp)-H, C(sp(2))-H/C(sp)-H functionalization of β-ketoesters and alkynes, respectively, in a single step using water as a solvent. This protocol exhibited broad substrate scope and paved the way for synthesis of anticancer arylnaphthalene lignan natural products such as diphyllin, taiwanin E, and justicidin A with excellent selectivity.

Organocatalytic Asymmetric Mannich Cyclization of Hydroxylactams with Acetals: Total Syntheses of (−)‐Epilupinine, (−)‐Tashiromine, and (−)‐Trachelanthamidine

An asymmetric, organocatalytic, one-pot Mannich cyclization between a hydroxylactam and acetal is described to provide fused, bicyclic alkaloids bearing a bridgehead N atom. Both aliphatic and aromatic substrates were used in this transformation to furnish chiral pyrrolizidinone, indolizidinone, and quinolizidinone derivatives in up to 89% yield and 97% ee. The total syntheses of (-)-epilupinine, (-)-tashiromine, and (-)-trachelanthamidine also achieved to demonstrate the generality of the process.