Photocatalytic Asymmetric Acyl Radical Truce Smiles Rearrangement for the Synthesis of Enantioenriched α-Aryl Amides.

The radical Truce-Smiles rearrangement is a straightforward strategy for incorporating aryl groups into organic molecules for which asymmetric processes remains rare. By employing a readily available and non-expensive chiral auxiliary, we developed a highly efficient asymmetric photocatalytic acyl and alkyl radical Truce-Smiles rearrangement of α-substituted acrylamides using tetrabutylammonium decatungstate (TBADT) as a hydrogen atom-transfer photocatalyst, along with aldehydes or C-H containing precursors. The rearranged products exhibited excellent diastereoselectivities (7:1 to >98:2 d.r.) and chiral auxiliary was easily removed. Mechanistic studies allowed understanding the transformation in which density functional theory (DFT) calculations provided insights into the stereochemistry-determining step.

A Domino Dearomative ipso-Annulation/Desymmetrization Approach: Stereoselective Access to Tricyclic Alkaloid Skeletons.

Herein, we reveal an unprecedented domino annulation of N-benzyl-acrylamides with 1,3-dicarbonyls for the assembly of fused tricyclic alkaloid frameworks incorporating a spirocycle via an alkylation/dearomative ipso-annulation/Michael addition (desymmetrization) sequence. This conversion involves three carbon-carbon bond formations, generating four chiral carbons, including three quaternary carbon centers, in a single diastereomer in one pot under identical reaction conditions. The synthetic potential of this atom-economic method is illustrated by modifications of the functional groups present in the products obtained.

Carbonylative cyclization of biaryl enones with aldehydes and oxamic acids.

An oxidative radical-promoted carbonylative cyclization strategy for the synthesis of phenanthren-9-(10H)-one frameworks from biaryl enones using aldehydes as the carbonyl radical sources is disclosed. The reaction proceeds through a sequential addition of a carbonyl radical to the olefin followed by cyclization with an aryl ring. The method is further extended to carbamoyl radicals generated from oxamic acids to access the corresponding phenanthrenones with amide functionalities.

One-Pot Synthesis of N-Fused Benzimidazo-ß-carbolines through Sequential Propargylation/aza-Cycloisomerization Approach.

The first sequential acid-catalyzed propargylation/base-mediated aza-cycloisomerization between indolyl-benzimidazoles and propargylic alcohols is described. This protocol enables the one-pot construction of N-fused benzimidazo-ß-carbolines in good yields. The synthetic utility of this approach is demonstrated by the assembly of an aza-helicene and also by a gram-scale reaction.

Dearomative ipso-Cyclization to Spiropseudoindoxyls: An Extendable Approach To Access Indolo[3,2-c]quinolinones and Isocryptolepine.

A metal-free oxidative intramolecular dearomative spirocyclization of indole-3-formyl-2-carboxamides has been developed for the first time, affording spiropseudoindoxyls in good yields. This domino process proceeds through sequential oxidation, decarboxylation and ipso-arylation. The unique feature of this approach includes the compatibility of N-protected-indole-2-carboxamides. Further, a hitherto unknown rearrangement of spiropseudoindoxyls to indoloquinolones has been achieved. The synthetic utility of this strategy has also been showcased by the construction of a natural alkaloid, isocryptolepine.

Seleno/Thio-functionalized ipso-Annulation of N-Propiolyl-2-arylbenzimidazole to Construct Azaspiro[5,5]undecatrienones.

Till date, the ipso-cyclization of propiolamides is limited to provide azaspiro[4,5]decatrienones. Herein, we present the first example of ipso-carbocyclization, leading to azaspiro[5,5]-undecatrienones from N-propiolyl-2-arylbenzimidazoles, involving both the radical-based and electrophilic reactions. This report establishes an access to a wide range of chalcogenated (SCN/SCF3/SePh) benzimidazo-fused azaspiro[5,5]undecatrienones in good yields.

ipso-Cyclization of unactivated biaryl ynones leading to thio-functionalized spirocyclic enones.

Ceric ammonium nitrate (CAN)-promoted oxidative ipso-cyclization of unactivated biaryl ynones with S-centered radicals (SCN/SCF3) to access spiro[5,5]trienones has been established. This approach displayed excellent regioselectivity towards spirocyclization and tolerated a variety of functional groups. Dearomatization of hitherto unknown aryl/heteroaryl groups is also disclosed. DMSO is employed as a low-toxicity, inexpensive solvent as well as a source of oxygen.

Aminative annulation of cyano-enynyl esters leading to functionalized cyclopentenones.

A base-mediated unexpected aminative carbo-cyclization of cyano-enynyl esters, generated from Morita-Baylis-Hillman (MBH) acetates of propiolaldehydes, with secondary-amines is described. This metal-free reaction allows the synthesis of a unique cyclopentenone bearing an exocyclic double bond (cyano-olefin) with high E-selectivity in good yields. The synthetic potential of this annulation was further exemplified by the derivatization of bioactive molecules, a scale-up synthesis and synthetic transformations of the obtained cyclopentenone.

CAN-Promoted Thiolative ipso-Annulation of Unactivated N-Benzyl Acrylamides: Access to SCN/SCF3/SO2Ar Containing Azaspirocycles.

A variety of acrylamides holding an unactivated N-benzyl group underwent dearomative ipso-cyclization induced by sulfur-centered radicals (SCN/ SCF3/ SO2Ar) in the presence of ceric ammonium nitrate (CAN) as the oxidant to furnish azaspirocycles in good yields. This is the first report on ipso-dearomatization of N-benzyl acrylamides that proceeds without a substituent at the para-position of the aromatic ring. The developed conditions are also found to be suitable for substrates holding substituents such as F, NO2, OMe, OH, and OAc at the para-position. The reaction features water as the source of oxygen, is compatible with a variety of functional groups, and proceeds in a short time.

Structure Activity Relationship Studies around DB18, a Potent and Selective Inhibitor of CLK Kinases.

Three series of our lead CLK1 inhibitor DB18 have been designed, synthetized and tested against CLKs and DYRK1A kinases. Their cytotoxicity was subsequently measured on seven representative cancer cell lines. Guided by docking experiments, we focused on the less constrained part of the scaffold, and showed that drastically different substituents can be tolerated here. This work ended with the discovery of another promising derivative 12g, with IC50 = 0.004 µM in the inhibition of HsCLK1 and IC50 = 3.94 µM for the inhibition of HsDYRK1A. The SAR results are discussed in the light of extensive molecular modeling analyses. Finally, a kinome scan (463 human kinases) confirmed the outstanding selectivity of our lead compound DB18, suggesting that this scaffold is of prominent interest for selective CLK inhibitors. Altogether, these results pave the way for the development of inhibitors with novel selectivities in this family of kinases.

Discovery of potent dual ligands for dopamine D4 and σ1 receptors.

During our work on exploration of molecules with some piperidine-triazole scaffolds, we realized that our compounds display chemical similarity with some σ, as well as dopaminergic receptor ligands. Here we show that this series of molecules has indeed strong affinity both for σ1 and dopamine D4 receptors. Moreover, they appear selective towards σ2, dopamine paralogues D1, D2, D3 and D5 receptors and hERG channel. Extensive molecular dynamics with our lead compound AVRM-13 were carried out on σ1, supporting agonist activity of the ligand. Unexpectedly, several observations suggested the existence of a cation binding domain, a probable regulatory site for calcium.

Synthesis and biological studies of new piperidino-1,2,3-triazole hybrids with 3-aryl isoxazole side chains.

A small library of new piperidine-triazole hybrids with 3-aryl isoxazole side chains has been designed and synthesized. Their cytotoxicity against a panel of seven cancer cell lines has been established. For the most promising compound, an IC50 value of 3.8 µM on PUMA/Bcl-xL interaction in live cancer cells was established through BRET analysis. A rationale was proposed for these results through complete molecular modelling studies.

Novel Machaeriol Analogues as Modulators of Cannabinoid Receptors: Structure-Activity Relationships of (+)-Hexahydrocannabinoids and Their Isoform Selectivities.

Machaeriols are an important class of compounds that structurally resemble tetrahydrocannabinol (Δ9-THC), with the major differences being inverted stereochemistry at the ring junction as [6aR, 10aR] and an additional stereocenter at the C9 position of the A-ring due to saturation. A previous study reported that machaeriols did not show any cannabinoid receptor activity, even though these hexahydrodibenzopyran analogues mimic a privileged (+)-tetrahydrocannabinoid scaffold. To unravel structural requisites for modulation of cannabinoid receptors, a simple late-stage divergent approach was undertaken to functionalize the machaeriol scaffold using the Suzuki coupling reaction. Fourteen hexahydro analogues were synthesized and screened against both cannabinoid receptor isoforms, CB1 and CB2. Interestingly, many of the analogues showed a significant binding affinity for both receptors; however, two analogues, 11H and 11J, were identified as possessing CB2 receptor-selective functional activity in the GTPγS assay; they were found to be micromolar-range agonists, with EC50 values of 5.7 and 16 µM, respectively. Furthermore, molecular dynamics simulations between the CB2 receptor and two novel analogues resulted in unique interaction profiles by tightly occupying the active ligand-binding domain of the CB2 receptor and maintaining stable interactions with the critical residues Phe94, Phe281, and Ser285. For the first time, with the aid of structure-activity relationships of (+)-hexahydrocannabinoids, CB2 selective agonists were identified with late-stage diversification using palladium-mediated C-C bond formation. By simply switching to (R)-citronellal as a chiral precursor, enantiomerically pure (-)-hexahydrocannabinoids with better CB1/CB2 receptor isoform selectivity can be obtained using the current synthetic approach.

Iodo- and Chalcogenoannulation of Morita-Baylis-Hillman Alcohols of Propiolaldehydes: Entry to Functionalized 2-Pyrones.

An efficient intramolecular annulation of Morita-Baylis-Hillman (MBH) alcohols of propiolaldehydes is developed in the presence of ICl or PhSeSePh/PhSSPh-CuCl2. This cyclization offers access to a wide variety of iodinated or chalcogenated 3-(chloromethyl)-2-pyrones in good yields. The chloromethyl group of the obtained 2-pyrones has been easily converted to introduce other handy functionalities, which allowed for further transformations to synthesize diverse 2-pyrone containing molecules.

One-Pot Arylative Benzannulation of 2-Carbonyl-3-propargyl Indoles with Boronic Acids Leading to Arylated Carbazoles.

Arylative annulation of 2-carbonyl-3-propargyl indoles with boronic acids under sequential palladium/triflic acid catalysis is described. The present strategy to provide di- and triaryl carbazoles in one pot involves benzannulation through difunctionalization of alkynes. The strategy showed a good substrate scope with respect to boronic acids as well as 2-carbonyl-3-propargyl indoles to afford the corresponding carbazoles in decent yields.

Ag-Catalyzed Oxidative ipso-Cyclization via Decarboxylative Acylation/Alkylation: Access to 3-Acyl/Alkyl-spiro[4.5]trienones.

A strategy to functionalized spiro[4.5]trienones, by domino silver-catalyzed decarboxylative acylation or alkylation/ ipso-cyclization of N-arylpropiolamides with α-keto acids/alkyl carboxylic acids, is presented. This transformation offers a wide range of substituted 3-acyl/alkyl-spiro[4.5]trienones in high yields with a broad substrate scope. The approach was further extended to access fused tricyclic frameworks, 6,7-dihydro-3H-pyrrolo[2,1-j]quinoline-3,9(5H)-diones.

Oxa-[3+3] annulation of MBH-carbonates of propiolaldehydes with α-nitro/bromo ketones to access 2H-pyrans.

A novel alkyne-assisted annulation reaction of MBH-carbonates of propiolaldehydes with α-nitro/bromo ketones is reported, providing a facile synthesis of substituted 2H-pyrans in good yields. This reaction divulges the inimitable reactivity of the MBH-carbonates of propiolaldehydes as C3-synthons wherein the alkyne functionality promoted the reaction without participating in the oxa-[3+3] annulation. The obtained products, having alkyne and ester functionalities, allowed further annulations to generate diverse pyrano[3,4-c]pyran-1-ones.

Silver-catalyzed acylative annulation of N-propargylated indoles with α-keto acids: access to acylated pyrrolo[1,2-a]indoles.

This study describes the first carbon centered radical cyclization of N-propargyl indoles involving decarboxylation of α-keto acids in the presence of an Ag-catalyst. The present cascade carbon-carbon bond formation reactions provide C-acylated pyrrolo[1,2-a]indoles in good yields (25 examples). The amount of oxidant has a profound effect on the reaction to convert either the di-acylated products using 8 equiv. of K2S2O8 or mono-acylated products using 2 equiv. of K2S2O8. N-Propargyl pyrroles are also found to be suitable for delivering the corresponding 3H-pyrrolizines.

Metal-free propargylation/aza-annulation approach to substituted ß-carbolines and evaluation of their photophysical properties.

An efficient acid-catalyzed propargylation/aza-annulation sequence was developed under metal-free reaction conditions, thus leading to a one-pot synthesis of a variety of substituted ß-carbolines starting from propargylic alcohols and indole 2-carbonyls. This versatile strategy was further extended to the synthesis of 5-azaindoles and 5-azabenzothiazoles. Optical properties suggested that manipulation of electron donor and acceptor moieties on ß-carbolines has an impact on their ground and excited state electronic behavior. This leads to blue or green emission and should facilitate the development of organic light emitting diodes (OLEDs). Electrochemical and stability studies revealed that 4a-6 shows ease of redox activity and photostability during illumination.

Copper-Catalyzed Intramolecular Chalcogenoamination of Enynyl Azides: Synthesis of 5-Selenyl/Sulfenyl Nicotinates.

A novel methodology for the synthesis of 5-selenyl/sulfenyl nicotinates involving copper-catalyzed organochalcogenyl aza-annulation of enynyl azide with diorganyl-dichalcogenides has been described. This method offers difunctionalization of alkynes via regioselective intramolecular chalcogenoamination in one pot to provide substituted 5-chalcogenyl nicotinates in good to excellent yields. The resulting nicotinates provide access to their oxides, sulfones, and acid derivatives.