Silver-Catalyzed Olefination of Aryl Aldehydes Using Propiolates.

Olefination of aldehydes is one of the fundamental reactions in organic synthesis. The commonly used Wittig olefination reaction however uses stoichiometric quantities reagents under basic conditions resulting in stoichiometric amounts of byproducts. Known catalytic alternate to the Wittig reaction requires stoichiometric amounts of silane reducing agents and high temperature. Herein, we report a base-free olefination of aryl aldehydes using propiolates as a surrogate for the Witting reagent under silver catalysis. Trimethyl orthoformate, in the presence of a silver catalyst adds to the alkynoate to form the nucleophilic silver allenolate which reacts with the reactive oxocarbenium ion formed from aldehyde under the reaction conditions. Subsequently decarbonylation occurs to form the olefin. Trans olefin is formed exclusively from simple aryl aldehydes and cinnamaldehydes. Such a silver allenolate is conceptually novel and has not been explored so far.

Dodging the Conventional Reactivity of o-Alkynylanilines under Gold Catalysis for Distal 7-endo-dig Cyclization.

A direct ring-closing strategy involving a less facile 7-endo-dig carbacyclization of o-alkynylaniline derivatives for the synthesis of benzo[b]azepines has been presented. The trivial well-documented 5-endo-dig cyclization in o-alkynylaniline derivatives due to high nucleophilicity of nitrogen has been overcome by using their vinylogous amides under gold catalysis to access a wide array of benzo[b]azepines in an atom economical way with excellent functional group compatibility. Deuterium scrambling experiments and DFT studies favor a mechanism involving stabilizing conformational change of the initially formed seven-membered vinyl gold intermediate through a key cyclopropyl gold carbene intermediate and its subsequent protodeauration mediated by the counter anion.

Activation of o-Propargyl Alcohol Benzaldehydes under Acetalization Conditions for Intramolecular Electrophile Intercepted Meyer-Schuster Rearrangement.

The reactivity of o-propargyl alcohol benzaldehydes has been increased tremendously toward Brønsted acid-catalyzed intramolecular electrophile intercepted Meyer-Schuster (M-S) rearrangement under acetalization conditions using trimethyl orthoformate (TMOF). The in situ formed acetal transfers the methoxy group intramolecularly to generate the M-S intermediate in even less reactive substrates, and the formed oxocarbenium ion makes the carbonyl more electrophilic for an effective intramolecular trapping of the M-S intermediate to furnish the indanone derivatives.

Ag(I)-catalyzed cyclization of o-alkynylacetophenones facilitated through acetal formation: synthesis of C3-naphthyl indole derivatives.

A mild method for an efficient synthesis of C3-naphthyl indoles from o-alkynylacetophenones has been developed. This Ag-catalyzed transformation is assisted by the acetal formed under the reaction condition employing trimethyl orthoformate (TMOF). The role of acetal in promoting the reaction under ambient conditions has been established with control experiments. A range of C3-naphthyl indole derivatives have been synthesized in moderate to very good yields.

Triflic Acid-Catalyzed Synthesis of Indole-Substituted Indane Derivatives via In Situ Formed Acetal-Facilitated Nucleophilic Addition and 4π-Electron-5-Carbon Electrocyclization Sequence.

An efficient protocol for the synthesis of indole-substituted indanes from o-alkenylbenzaldehydes under acetalization conditions has been presented. The cyclization occurs via a nucleophilic addition of indole on the oxacarbenium ion generated from acetal formed under the reaction condition followed by a conrotatory 4π-electrocyclization reaction, which takes care of the exclusive diastereoselectivity observed during the cyclization step. Olefin geometry of o-alkenylbenzaldehyde and the amount of indole play a decisive role in the success of this cyclization process.

Synthesis of Highly Substituted Biaryls by the Construction of a Benzene Ring via In Situ Formed Acetals.

Herein, we present an interesting method for the construction of a benzene ring using propargylic alcohols and 1,3-dicarbonyls, which involves three new C-C bond formations via cascade alkylation, formylation, annulation, and aromatization to make substituted biaryls. This one-pot Brønsted acid-promoted protocol utilizes the unique reactivity of the acetal formed under the reaction conditions. Alkynyl methyl ketones could be employed instead of 1,3-dicarbonyls as they are converted to 1,3-dicarbonyls by hydration under the reaction conditions.

Brønsted/Lewis Acid-Promoted Site-Selective Intramolecular Cycloisomerizations of Aryl-Fused 1,6-Diyn-3-ones for Diversity-Oriented Synthesis of Benzo-Fused Fluorenes and Fluorenones and Naphthyl Ketones.

Herein, a facile diversity-oriented approach to access functionalized benzo[a]fluorenes, benzo[b]fluorenones, and naphthyl ketones has been demonstrated via site-selective intramolecular cyclization of aryl-fused 1,6-diyn-3-ones. Synthesis of benzo[a]fluorenes and naphthyl ketones has been achieved selectively using TfOH and AgBF4, respectively, via in situ-formed acetals. Aryl-fused 1,6-diyn-3-ones undergo triflic acid-mediated intramolecular cyclization, leading to benzo[b]fluorenone derivatives via a radical intermediate as supported by EPR studies. Kinetic studies of these transformations have also been performed by UV-visible spectroscopic analysis to shed light on the reaction profile.

Synthetic homoserine lactone analogues as antagonists of bacterial quorum sensing.

Quorum sensing (QS) is a density-dependent form of cell-cell communication that triggers the functional coordination of cooperative behaviors such as the production of virulence factors and biofilm formation. Quorum quenching (QQ) refers to all processes involved in the disruption of QS and is regarded as a promising strategy for treating bacterial infections. Herein, four compounds with closely related chemical structures to homoserine γ-lactone were synthesized and fully characterized. The compounds are termed TGK-series compounds. These compounds were subsequently tested in their QS inhibition activity using an E. coli Top 10 QS biosensor strain, a GFP QS reporter, that probes the capacity of bacteria to detect their cognate autoinducer N-(3-oxohexanoyl)-homoserine lactone (3OC6HSL) substrate by means of a single intracellular protein LuxR. All TGK-series compounds were found to significantly inhibit the ability of bacteria to produce GFP but without exerting toxicity when applied at a concentration of 50 µM. In parallel, the interaction of TGK-series compounds with LuxR were studied by molecular docking simulations. These studies revealed that TGK-series compounds bound to the natural substrate N-(3-oxo-octanoyl)-l-homoserine lactone (OOHL) binding site and that the binding ability of the compounds with the TraR protein (a surrogate of LuxR) was even more favorable in comparison with the natural substrate. It was also uncovered that TGK-series compounds form stronger hydrophobic interactions with the TraR protein than 3OC6HSL does, thus providing a rationale for the enhancement of the QQ activity of the synthetic TGK-series compounds. This study will serve to guide future works aimed to design promising novel QS inhibitor candidates on a rational basis.

Annulation of a Highly Functionalized Diazo Building Block with Indoles under Sc(OTf)3/Rh2(OAc)4 Multicatalysis through Michael Addition/Cyclization Sequence.

A highly functionalized and easily accessible six-carbon diazo building block has been developed and utilized as a 1,4-diacceptor for an efficient synthesis of functionalized tetrahydrocarbazoles, carbazoles, and tetrahydropyrido[1,2- a]indoles. The synthesis involves concurrent tandem catalysis by Sc(OTf)3 and Rh2(OAc)4. The role of Sc(OTf)3 is critical as it facilitates both the initial intermolecular Michael reaction of the indole and the subsequent Rh(II)-catalyzed intramolecular annulation. The products, tetrahydrocarbazoles and tetrahydropyridoindoles, are equipped with a ß-ketoester and ester functionalities which can be utilized for further synthetic elaborations.

Amino Groups of Chitosan Are Crucial for Binding to a Family 32 Carbohydrate Binding Module of a Chitosanase from Paenibacillus elgii.

We report here the role and mechanism of specificity of a family 32 carbohydrate binding module (CBM32) of a glycoside hydrolase family 8 chitosanase from Paenibacillus elgii (PeCsn). Both the activity and mode of action of PeCsn toward soluble chitosan polymers were not different with/without the CBM32 domain of P. elgii (PeCBM32). The decreased activity of PeCsn without PeCBM32 on chitosan powder suggested that PeCBM32 increases the relative concentration of enzyme on the substrate and thereby enhanced enzymatic activity. PeCBM32 specifically bound to polymeric and oligomeric chitosan and showed very weak binding to chitin and cellulose. In isothermal titration calorimetry, the binding stoichiometry of 2 and 1 for glucosamine monosaccharide (GlcN) and disaccharide (GlcN)2, respectively, was indicative of two binding sites in PeCBM32. A three-dimensional model-guided site-directed mutagenesis and the use of defined disaccharides varying in the pattern of acetylation suggested that the amino groups of chitosan and the polar residues Glu-16 and Glu-38 of PeCBM32 play a crucial role for the observed binding. The specificity of CBM32 has been further elucidated by a generated fusion protein PeCBM32-eGFP that binds to the chitosan exposing endophytic infection structures of Puccinia graminis f. sp. tritici Phylogenetic analysis showed that CBM32s appended to chitosanases are highly conserved across different chitosanase families suggesting their role in chitosan recognition and degradation. We have identified and characterized a chitosan-specific CBM32 useful for in situ staining of chitosans in the fungal cell wall during plant-fungus interaction.

Catalyst free synthesis of α-fluoro-ß-hydroxy ketones/α-fluoro-ynols via electrophilic fluorination of tertiary propargyl alcohols using Selectfluor™ (F-TEDA-BF4).

A facile method for the synthesis of α-fluoro-ß-hydroxy ketones/α-fluoro-ynols from tertiary propargyl alcohols under electrophilic fluorination conditions using F-TEDA-BF4 has been presented. The products bear pharmaceutically important α-fluoro ketone, gem-diaryl and fluorohydrin moieties in the same molecule. Interestingly, this catalyst free protocol results in monofluorination.

The directing group wins over acidity: kinetically controlled regioselective lithiation for functionalization of 2-(2,4-dihalophenyl)-1,3-dithiane derivatives.

Regioselective lithiation followed by functionalization of 2-(2,4-dihalophenyl)-1,3-dithiane derivatives with different electrophiles was achieved in good to excellent yields. When the title compound is treated with n-butyl lithium, lithiation occurs selectively at the aromatic carbon having less acidic proton despite the presence of thermodynamically more acidic 1,3-dithiane proton in the same molecule. Computationally calculated pKa values of the available reactive site protons and the experimental results suggest that the regioselective lithiation in 2-(2,4-dihalophenyl)-1,3-dithiane derivatives is not governed by thermodynamic acidity rather exclusively dictated by the kinetic removal of protons due to cooperative coordination (complex induced proximity effect, CIPE) and inductive effects of the 1,3-dihalo substituents present in the aromatic ring. By employing this regioselective functionalization, diverse 1,2,3,4-tetra-substituted aromatic compounds were prepared with ease.

Gold-catalysed glycosylation reaction using an easily accessible leaving group.

Gold(III)-catalysed glycosylation reaction has been developed by employing a new and easily accessible leaving group synthesized from ethyl cyanoacetate. Several nucleophiles like alcohols, thiols, allyltrimethylsilane, trimethylsilyl azide and triethylsilane have been reacted to make the corresponding glycosides in good yields and with marginal to excellent α-selectivity.

Triflic acid promoted direct α-alkylation of unactivated ketones using benzylic alcohols via in situ formed acetals.

Direct α-alkylation of unactivated ketones using benzylic alcohols as electrophiles has been achieved at room temperature. This reaction takes place via in situ formed acetal using triflic acid and trimethyl orthoformate. It is believed that methyl vinyl ether formed from the in situ generated dimethyl acetal in the presence of triflic acid undergoes alkylation. Diverse ketones could be alkylated with diarylmethanols, cinnamyl alcohols, and phenyl propargyl alcohols having different electrophilicities.

Gold(I)-Catalyzed Regioselective Hydroarylation of Propiolic Acid with Arylboronic Acids.

A gold-catalyzed intermolecular hydroarylation involving arylboronic acid has been disclosed. This carboxylic acid-directed arylation is highly regioselective and occurs at the less electrophilic carbon to afford α-aryl acrylic acids in attractive yields. This protocol offers easy access to NSAID precursors.

Synthesis of tetrahydrochromenes and dihydronaphthofurans via a cascade process of [3 + 3] and [3 + 2] annulation reactions: mechanistic insight for 6-endo-trig and 5-exo-trig cyclisation.

Substituted tetrahydrochromenes and dihydronaphthofurans are easily accessible by the treatment of ß-tetralone with trans-ß-nitro styrene derived Morita-Baylis-Hillman (MBH) acetates through a formal [3 + 3]/[3 + 2] annulation. The reaction proceeds through a cascade Michael/oxa-Michael pathway with moderate to good yields. A DFT study was carried out to account for the formation of the corresponding six and five-membered heterocycles via 6-endo-trig and 5-exo-trig cyclization.

Small-molecule inhibition of APT1 affects Ras localization and signaling.

Cycles of depalmitoylation and repalmitoylation critically control the steady-state localization and function of various peripheral membrane proteins, such as Ras proto-oncogene products. Interference with acylation using small molecules is a strategy to modulate cellular localization--and thereby unregulated signaling--caused by palmitoylated Ras proteins. We present the knowledge-based development and characterization of a potent inhibitor of acyl protein thioesterase 1 (APT1), a bona fide depalmitoylating enzyme that is, so far, poorly characterized in cells. The inhibitor, palmostatin B, perturbs the cellular acylation cycle at the level of depalmitoylation and thereby causes a loss of the precise steady-state localization of palmitoylated Ras. As a consequence, palmostatin B induces partial phenotypic reversion in oncogenic HRasG12V-transformed fibroblasts. We identify APT1 as one of the thioesterases in the acylation cycle and show that this protein is a cellular target of the inhibitor.

TfOH-promoted synthesis of indoles and benzofurans involving cyclative transposition of vinyl ketone.

A metal-free approach to construct indole rings from vinylogous amides derived from o-alkynylanilines involving a cyclization, retro-aza-Michael reaction and amine trapping cascade is reported here. This atom-economical transformation has been extended to synthesize benzofuran derivatives using analogous vinylogous esters derived from o-alkynylphenols. The excellent stereochemical outcome of the double bond geometry in the products makes it attractive.

Synthesis of arylnaphthalene lignan scaffold by gold-catalyzed intramolecular sequential electrophilic addition and benzannulation.

An intramolecular approach to generate compounds containing an arylnaphthalene lignan scaffold in high yields is presented. It involves a sequential intramolecular electrophilic attack of carbonyl on arylalkyne followed by benzannulation catalyzed by gold salt. AuCl(3) in combination with AgSbF(6) works better to effect this transformation. Selected products have been converted into arylnaphthalene lactone natural products such as justicidin E, taiwanin C, and retrojusticidin B.

Beta-lactone probes identify a papain-like peptide ligase in Arabidopsis thaliana.

New activity-based probes are essential for expanding studies on the hundreds of serine and cysteine proteases encoded by the genome of Arabidopsis thaliana. To monitor protease activities in plant extracts, we generated biotinylated peptides containing a beta-lactone reactive group. These probes cause strong labeling in leaf proteomes. Unexpectedly, labeling was detected at the N terminus of PsbP, nonproteolytic protein of photosystem II. Inhibitor studies and reverse genetics led to the discovery that this unusual modification is mediated by a single plant-specific, papain-like protease called RD21. In cellular extracts, RD21 accepts both beta-lactone probes and peptides as donor molecules and ligates them, probably through a thioester intermediate, to unmodified N termini of acceptor proteins.