Gold(I)-Catalyzed Regioselective Synthesis of Indenylidene Derivatives via 1,5-Acryl Migration.

A novel gold (I)-catalyzed synthetic strategy has been achieved for an efficient construction of indenylidene derivatives from substituted 1,6-diynes. This reaction describes the unique reactivity of gold catalysis in facilitating the intramolecular [3,3]-sigmatropic rearrangement, 5-exo dig cyclization followed by 1,5-migration of acryl group, resulting in the formation of substituted indenylidenes. Various substituted indenylidenes were successfully synthesized with up to 92% yields. In this protocol, two new C-C bonds were sequentially formed atom economically in one pot.

6-Strand to Stable 10/12 Helix Conformational Switch by Incorporating Flexible ß-hGly in the Homooligomers of Camphor Derived ß-Amino Acid: NMR and X-Ray Crystallographic Evidence.

Rational design of unnatural amino acid building blocks capable of stabilizing predictable secondary structures similar to protein fragments is pivotal for foldamer chemistry/catalysis. Here, we introduce novel ß-amino acid building blocks: [1S,2R,4R]exoCDA and [1S,2S,4R]endoCDA, derived from the abundantly available R(+)-camphor, which is traditionally known for its medicinal value. Further, we demonstrate that the homooligomers of exoCDA adopt 6-strand conformation, which switches to a robust 10/12-helix simply by inserting flexible ß-hGly spacer at alternate positions (1 : 1 ß-hGly/exoCDA heterooligomers), as evident by DFT-calculations, solution-state NMR spectroscopy and X-ray crystallography. To the best of our knowledge, this is the first example of crystalline-state structure of left-handed 10/12-mixed helix, that is free from the conventional approach of employing ß-amino acids of either alternate chirality or alternate ß2/ß3 substitutions, to access the 10/12-helix. The results also show that the homooligomers of heterochiral exoCDA don't adopt helical fold, instead exhibit banana-shaped strands, whereas the homodimers of the other diastereomer endoCDA, nucleate 8-membered turns. Furthermore, the homo-exoCDA and hetero-[ß-hGly-exoCDA] oligomers are found to exhibit self-association properties with distinct morphological features. Overall, the results offer new possibilties of constructing discrete stable secondary and tertiary structures based on CDAs, which can accommodate flexible residues with desired side-chain substitutions.

Total Synthesis and Revision of Stereochemistry of a Natural Benzo[g]isochromene Stereodiad Isolated from Rubia philippinensis.

This study presents a total synthesis and revision of the stereochemical configuration of the conformationally flexible natural product benzo[g]isochromene stereodiad alongside its diastereomeric counterparts. The highlights of the synthesis are the TiCl4-mediated diastereoselective aldol reaction, Pd-catalyzed lactonization, and Schmidt glycosidation. Our efforts using total synthesis disclosed herein proved that a previously assigned structure required revision.

N-Substituted piperazine-coupled imidazo[2,1-b]thiazoles as inhibitors of Mycobacterium tuberculosis: Synthesis, evaluation, and docking studies.

An innovative series of N-substituted piperazine-linked imidazothiazole derivatives 7(a-x) were synthesized, and their antitubercular effectiveness was evaluated. A three-step reaction sequence involving the condensation of 1,3-dichloroacetone and thiourea, coupling with substituted piperazines to give the intermediates 5(a-d) and cyclization with substituted α-bromoacetophenones produced the desired imidazothiazole derivatives 7(a-x) in excellent yields. In vitro screening of new derivatives against Mycobacterium tuberculosis H37Rv resulted in 7k (minimum inhibitory concentration [MIC]: 0.78 µg/mL) and 7g and 7h (MIC: 1.56 µg/mL) as potent hit compounds. Further, the docking studies of the promising compounds 7k, 7g, and 7h revealed that the best molecular interactions are with the DprE1 in complex with sulfonyl PBTZ of M. tuberculosis as the target protein (PDB ID: 6G83).

Dual gold-catalyzed regioselective synthesis of benzofulvenes via 5-endo dig cyclization.

An efficient dual gold-catalyzed regioselective synthesis of benzofulvenes has been developed from substituted allyloxy 1,5-diynes via 5-endo dig cyclization. In this intramolecular organic transformation a new C-C bond formation occurs and moderate to very good yields are obtained in one pot.

Radical-mediated sulfonylative/thiolative cyclization of biaryl enones to phenanthrone derivatives.

An approach for the assembly of phenanthrone derivatives bearing all carbon quaternary centres has been developed through visible light-promoted tandem sulfonylation/intramolecular-arylation of biaryl enones with sulfonyl chlorides. A series of sulfonylated 10,10-dialkylphenanthrones were obtained in good yields. In addition, the approach has been extended to thiotrifluoromethyl (SCF3) and thiocyanato (SCN) radicals to obtain the corresponding phenanthrones under oxidative conditions. The synthetic utility was also illustrated by the scalability and further transformations of the product.

Construction of Octahydro-4H-cyclopenta[b]pyridin-6-one Skeletons using Pot, Atom, and Step Economy (PASE) Synthesis.

Cascade aza-Piancatelli reaction and [3+3]/[4+2] cycloaddition reactions are carried out using the ideality principles of pot, atom, and step economy (PASE) synthesis. The reaction resulted in generation of octahydro-4H-cyclopenta[b]pyridin-6-one scaffolds. Moreover, octahydro-5,7a-epoxycyclopenta[cd]isoindol-4-one frameworks of gracilamine alkaloid and a novel decahydro-1H-dicyclopenta[cd,hi]isoindol-6-one were also realized in good yields with excellent regio- and diastereo-selectivities.

Silver-catalyzed Regioselective Synthesis of N-aryl-1H-pyrazolyl-substituted Benzenesulfonamides from Ynamides and Pyrazoles.

Silver-catalyzed N-aryl-1H-pyrazolyl substituted benzenesulfonamide derivatives were obtained regioselectively from ynamides and pyrazoles. In this intermolecular organic transformation, several substituted benzenesulfonamides were obtained in good to excellent yields by forming a new C-N bond under mild reaction conditions.

Synthesis of Fused Tetracyclic Compounds via Oxidative Annulation: Access to Copper-Catalyzed Indolo[1,2-a]quinolines and to Ruthenium-Catalyzed Isoquinolin-1[2H]-ones.

A facile double oxidative annulation of (en-3-yn-1-yl)phenylbenzamides was developed allowing us to synthetize fused tetracyclic compounds. Under copper catalysis, the reaction proceeds with high efficiency and leads to new indolo[1,2-a]quinolines via a decarbonylative double oxidative annulation. On the other hand, under ruthenium catalysis, new isoquinolin-1[2H]-ones were obtained via a double oxidative annulation.

Fullerene C70 as Photoredox Catalyst for the Synthesis of Pyrrolo[2,1-a]isoquinolines by 1,3-Dipolar Cycloaddition-Aromatization Sequence.

Herein, fullerene (C70 ) is introduced as an effective photoredox catalyst for the construction of a highly functionalised pyrrolo[2,1-a]isoquinoline framework by 1,3-dipolar cycloaddition-aromatisation reaction sequence. The ability of C70 to efficiently harvest visible light, its long-triplet state lifetime, good photostability, and strong singlet oxygen generation potential (Φ▵ ≈1), make it an efficient photoredox catalyst. Upon photoirradiation, C70 promotes the formation of singlet oxygen and superoxide radical by energy transfer (EnT) and single electron transfer (SET) mechanism. The superoxide radical acts as a potential oxidant in the formation of azomethine ylide through the oxidation-deprotonation tandem process. Azomethine ylide further participates in [3+2]-cycloaddition reaction protocol with alkene/alkyne to give the corresponding pyrrolo[2,1-a]isoquinolines. Interestingly, this protocol allows the activation of a wide range of substrates giving access to a diverse library of 48 well-decorated pyrrolo[2,1-a]isoquinolines with good functional group tolerance.

Ir(III)-Catalyzed Dual C-H Activation of 2-Aryl Phthalazinediones and 3-Aryl-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxides for the Construction of Spiro-Fused Cyclic Frameworks.

An Ir(III)-catalyzed double C-H activation strategy has been developed for the synthesis of highly rigid spiro frameworks by means of ortho-functionalization of 2-aryl phthalazinediones and 2,3-diphenylcycloprop-2-en-1-ones using the Ir(III)/AgSbF6 catalytic system. Similarly, 3-aryl-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxides undergo smooth cyclization with 2,3-diphenylcycloprop-2-en-1-ones to afford a diverse range of spiro compounds in good yields with excellent selectivity. Additionally, 2-arylindazoles provide the corresponding chalcone derivatives under similar reaction conditions.

Substrate-directed Synthesis of Isocoumarin and 3-Ylidenephthalide Conjugated Noscapinoids and their Antiproliferative Activities.

A series of new noscapinoids designed; synthesized and assessed whether its 3-ylidenephthalide and isocoumarin conjugates improved cytotoxicity. Cu-catalysed Sonogashira coupling of N-propargyl noscapine with 2-bromobenzoic acids followed by in-situ substrate-directed 5-exo-dig or 6-endo-dig cyclization produced 3-ylidenephthalide 6 a-6 f and isocoumarin 7 a-7 h analogues in very good yields. In comparison to the lead drug, noscapine, all the newly synthesised derivatives exhibited strong cytotoxic potential in vitro with IC50 ranging from 5.4 µM to 39.5 µM across the evaluated panel of cancer cell lines, without harming normal cells (IC50 >300 µM).

Catalyst- and Additive-Free Methodical Ring Expansion Protocol to Access Benzooxepino-Fused Pyrroles.

An efficient metal-free, additive-free synthetic method was developed to access benzooxepino-fused pyrrole derivatives from alkynyl substituted aziridines. In this organic transformation, two new C-C bonds were formed via initial cleavage of C-C bond of aziridine ring by in situ generated azomethine ylides. Moderate to excellent yields of benzooxepino-fused pyrroles were obtained atom economically in the presence of t-BuOH in one-pot.

Synthesis of Isoquinoline-Derived Diene Esters and Quinolin-2(1H)-ylidene-Substituted 1,5-Diones from Enynones and (Iso) Quinoline N-Oxides.

An efficient synthetic method was developed to access isoquinoline-derived diene esters from enynones and isoquinoline-N-oxides in an atom-economic manner. The isoquinoline-substituted diene esters were obtained in moderate to excellent yields via [3 + 2]-cycloaddition and isoxazole ring opening followed by a [1,5]-sigmatropic rearrangement reaction, which resulted in one C-C and two C-O bond formations. Further, quinolin-2(1H)-ylidene-substituted 1,5-diones were achieved by reaction of enynones with quinoline-N-oxides in very good to high yields.

BF3·OEt2-catalyzed synthesis of 2,2'-spirobi-2H-1-benzopyrans from 2H-chromenes.

A new BF3·OEt2-catalyzed approach was developed for the construction of 2,2'-spirobi-2H-1-benzopyrancarboxylates by reacting ethyl 2-(chloromethyl)-2-hydroxy-2H-chromene-3-carboxylates with salicylaldehydes. The reactions proceeded through the formation of C-C and C-O bonds in one pot. Structure assignment of compound 3c was confirmed by single crystal X-ray analysis.

Gold(I)-Catalyzed Regioselective Cyclization to Access Cyclopropane-Fused Tetrahydrobenzochromenes.

Gold(I)-catalyzed efficient synthetic transformation was achieved to access the tetrahydrobenzo[h]cyclopropa[c]chromenes from allyl-substituted 1,6-diynes. Cyclopropane-fused tetrahydrobenzochromenes were obtained regioselectively in ≤92% yields. In this atom-economic organic transformation, three new C-C bonds were formed sequentially in one pot.

Cationic Gold-Catalyzed Intramolecular Cyclization of Substituted 1,5-Diynes to Access Indenone Derivatives.

An efficient intramolecular cyclization reaction was developed to achieve indenone derivatives. The substituted 1,5-diyenes were converted to the corresponding indenones via a gold-catalyzed organic transformation, and moderate to excellent yields of the title molecules were obtained via formation of two C=O and one C-C bonds under mild reaction conditions in one pot.

Unexpected ring opening of pyrazolines with activated alkynes: synthesis of 1H-pyrazole-4,5-dicarboxylates and chromenopyrazolecarboxylates.

1H-Pyrazole-4,5-dicarboxylates and chromenopyrazole carboxylates were prepared by reacting pyrazolines with activated alkynes under neat conditions without a catalyst. The products were formed via unexpected ring opening of pyrazolines with the elimination of styrene/ethylene. These types of transformations are unknown and the products formed were confirmed using their spectral/analytical data. In addition, the structures of compounds 5e and 5n were confirmed by single-crystal X-ray analysis. Control experiments were conducted to support the proposed reaction mechanism.

Gold (I)-Promoted Intermolecular Cascade Annulation to Access 2-Hydroxybenzocarbazoles via a Meyer-Schuster Rearrangement.

An efficient cascade annulation protocol was established to access substituted 2-hydroxybenzocarbazoles from alkynylcyclohexadienones and substituted 2-aminophenols under gold catalysis. In this transformation a new C-C, two C-N bonds were formed sequentially and moderate to excellent yields of 2-hydroxybenzocarbazole derivatives were obtained selectively via Meyer-Schuster rearrangement in one-pot.

Catalyst- and Additive-Free Approach to Constructing Benzo-oxazine, Benzo-oxazepine, and Benzo-oxazocine: O Atom Transfer and C═O, C-N, and C-O Bond Formation at Room Temperature.

An exclusive synthesis of benzo-oxazine, benzo-oxazepine, and benzo-oxazocine from aryl propanal and 2-(hydroxyamino)phenyl alcohol under metal-free conditions is described. O atom transfer and formation of new C═O, C-N, and C-O bonds occur at room temperature to form six-, seven-, and eight-membered heterocycles under one-pot reaction conditions without using an external oxidant and base. The photophysical properties are studied using ultraviolet-visible absorption and photoluminescence. The mechanistic elucidation is well supported by control experiment and literature precedents.