Enantioselective Assembly of Fully Substituted α-Amino Allenoates Through a Mannich Addition and Stepwise [3,3]-σ Rearrangement Sequence.

Chiral fully-substituted allenes are synthetically significant and pivotal building blocks that can engage in diverse transformations toward a variety of bioactive molecules. The enantioselective assembly of these skeletons using readily available reactants offers significant advantages but remains challenging. Herein, an asymmetric formal Michael-type addition of alkynyl imines with the key alkylgold intermediates derived in situ from N-propargylamides is accomplished under gold-complex and chiral quinine-derived squaramide (QN-SQA) synergetic catalysis.

Gold-Catalyzed Alkyne Oxidative Cyclization/Mannich-Type Addition Cascade Reaction of Ynamides with 1,3,5-Triazinanes.

Herein, a gold-catalyzed alkyne oxidative cyclization/Mannich-type addition cascade reaction of ynamides with 1,3,5-triazinanes in the presence of a Brønsted acid has been presented. A class of functionalized fluorenes bearing a quaternary carbon center was synthesized directly with moderate to excellent yields via in situ formed α-oxo carbenes using quinoline -oxide as the oxidant under mild reaction conditions.

Enantioselective Construction of Quaternary Stereocenters via A Chiral Spiro Phosphoric Acid-Assisted Formal Gold Carbene -Dialkylation Reaction.

Enantioselective construction of all-carbon quaternary stereocenters has attracted much attention over the past few decades. A variety of catalytic asymmetric methods have been disclosed based on the use of presynthesized complex reagents that impart congested steric hindrance to the reaction center, which generally produce the chiral molecules through forming one C-C bond. The use of readily available reagents that could build two C-C bonds on the same carbonic center with the concomitant assembly of quaternary stereocenters remains challenging.

Catalytic [4+2]- and [4+4]-cycloaddition using furan-fused cyclobutanone as a privileged C4 synthon.

Cycloaddition reactions play a pivotal role in synthetic chemistry for the direct assembly of cyclic architectures. However, hurdles remain for extending the C4 synthon to construct diverse heterocycles via programmable [4+n]-cycloaddition. Here we report an atom-economic and modular intermolecular cycloaddition using furan-fused cyclobutanones (FCBs) as a versatile C4 synthon.

Catalytic (4+2) Annulation via Regio- and Enantioselective Interception of in-situ Generated Alkylgold Intermediate.

A regio- and stereoselective stepwise (4+2) annulation of N-propargylamides and α,β-unsaturated imines/ketones has been accomplished with synergetic catalysis by a combination of a gold-complex and a chiral quinine-derived squaramide (QN-SQA), leading to highly functionalized chiral tetrahydropyridines/dihydropyrans in good to high yields with generally excellent enantioselectivity. Mechanistic studies and DFT calculations indicate that the in situ formed alkylgold species is the key intermediate in this transformation, and the amide group served as a traceless directing group in this highly selective transformation. This method complements the enantioselective (4+2) annulation of allene reagents, providing the formal internal C-C π-bond cycloaddition products, which is challenging and remains elusive.

Nav1.7 Modulator Bearing a 3-Hydroxyindole Backbone Holds the Potential to Reverse Neuropathic Pain.

Chronic pain is a growing global health problem affecting at least 10% of the world's population. However, current chronic pain treatments are inadequate. Voltage-gated sodium channels (Navs) play a pivotal role in regulating neuronal excitability and pain signal transmission and thus are main targets for nonopioid painkiller development, especially those preferentially expressed in dorsal root ganglial (DRG) neurons, such as Nav1.

Catalytic Asymmetric Difluoroalkylation Using In Situ Generated Difluoroenol Species as the Privileged Synthon.

A robust and practical difluoroalkylation synthon, α,α-difluoroenol species, which generated in situ from trifluoromethyl diazo compounds and water in the presence of dirhodium complex, is disclosed. As compared to the presynthesized difluoroenoxysilane and in situ formed difluoroenolate under basic conditions, this difluoroenol intermediate displayed versatile reactivity, resulting in dramatically improved enantioselectivity under mild conditions. As demonstrated in catalytic asymmetric aldol reaction and Mannich reactions with ketones or imines in the presence of chiral organocatalysts, quinine-derived urea, and chiral phosphoric acid (CPA), respectively, this relay catalysis strategy provides an effective platform for applying asymmetric fluorination chemistry.

Catalytic 4-exo-dig carbocyclization for the construction of furan-fused cyclobutanones and synthetic applications.

Cyclobutanone is a strained motif with broad applications, while direct assembly of the aromatic ring fused cyclobutanones beyond benzocyclobutenone (BCB) skeletons remains challenging. Herein, we report a Rh-catalyzed formal [3+2] annulation of diazo group tethered alkynes involving a 4-exo-dig carbocyclization process, providing a straightforward access to furan-fused cyclobutanones. DFT calculations disclose that, by comparison to the competitive 5-endo-dig process, 4-exo-dig carbocyclization is mainly due to lower angle strain of the key sp-hybridized vinyl cationic transition state in the cyclization step.

Construction of Chiral Quaternary Carbon Centers via Asymmetric Metal Carbene gem-Dialkylation.

The catalytic asymmetric construction of all-carbon quaternary stereocenters has received tremendous interest over the past decades, and numerous efficient protocols have been disclosed based on the formation of one C-C bond between two assembling reactants. However, the use of asymmetric multi-component reactions that build two C-C bonds on the same carbonic center with concomitant assembly of quaternary stereocenters is rare and remains challenging. Herein, we disclose an enantioselective three-component reaction of α-diazo ketones with alkenes and 1,3,5-triazines under dirhodium/chiral phosphoric acid cooperative catalysis, which leads to a practical and atom-economic synthesis of poly-functionalized chiral ketones that bear a α-quaternary stereocenter in generally good to high yields with excellent enantioselectivities.

Synthesis of dihydrofuran-3-one and 9,10-phenanthrenequinone hybrid molecules and biological evaluation against colon cancer cells as selective Akt kinase inhibitors.

A series of dihydrofuran-3-one and 9,10-phenanthrenequinone hybrid compounds were synthetized through a one-pot gold-catalyzed oxidative cyclization and Aldol-type addition cascade reaction of homopropargylic alcohols with 9,10-phenanthrenequinone. The cytotoxicity of newly synthesized compounds was evaluated in CCK8 assay against different human cancer cells, showing significantly antiproliferative activity against tested tumor cell lines with a lowest IC value of 0.92 μM over HCT-116.

Diastereoselective aldol-type interception of phenolic oxonium ylides for the direct assembly of 2,2-disubstituted dihydrobenzofurans.

A Rh(OAc) catalyzed intermolecular aldol-type interception of phenolic oxonium ylides with isatins has been developed, which provides an effective access to 2,2-disubstituted dihydrobenzofuran derivatives containing 3-hydroxyoxindole in high yields and with high diastereoselectivities under mild reaction conditions. The antiproliferation activity of these synthesized dihydrobenzofuran and 3-hydroxyoxindole hybrid products has been tested the CCK8 assay in different cancer cell lines; compounds 3s and 3t exhibit good anticancer potency against human colon cancer cells (HCT116 cells, 3s: IC = 15.99 μM; 3t: IC = 14.

Enantioselective assembly of 3,3-disubstituted succinimides three-component reaction of vinyl diazosuccinimides with alcohols and imines.

An enantioselective three-component reaction of vinyl diazosuccinimdes with alcohols and imines has been realized by a cooperative catalysis of Rh2(OAc)4 and a chiral phosphoric acid, leading to chiral 3,3-disubstituted succinimides in good to high yields with high to excellent enantioselectivity. The generated product with an alkenyl species could be converted to the chiral tricyclic structure under mild conditions.

Gold(I)-catalyzed intramolecular cyclization/intermolecular cycloaddition cascade as a fast track to polycarbocycles and mechanistic insights.

Metal carbene is an active synthetic intermediate, which has shown versatile applications in synthetic chemistry. Although a variety of catalytic methods have been disclosed for the generation of carbene species from different precursors, there is an increasing demand for the development of efficient and practical approaches for the in-situ formation of metal carbene intermediates with structural diversity and unrevealed reactivity. Herein we report a gold-catalyzed cascade protocol for the assembly of polycarbocyclic frameworks in high yields under mild reaction conditions.

Blue Light-Promoted Formal [4+1]-Annulation of Diazoacetates with -Aminoacetophenones: Synthesis of Polysubstituted Indolines and Computational Study.

A blue light-promoted formal [4+1]-annulation of diazoacetates with -aminoacetophenones has been reported, which provides an environmentally friendly method for the synthesis of polysubstituted indoline derivatives in moderate to good yields with excellent diastereoselectivities. Detailed mechanistic studies through density functional theory calculations reveal that the ()-enol species is the key intermediate in this transformation, and the excellent diastereoselectivity is enabled -bonding in the intramolecular Aldol-type addition.

Desaturation via Redox-Neutral Hydrogen Transfer Process: Synthesis of 2-Allyl Anilines, Mechanism and Applications.

An unprecedented desaturation method via redox-neutral hydrogen transfer process has been disclosed under mild conditions for the selective formation of terminal alkene with alkyl diazo compounds and aza-o-QMs. The control experiments and DFT calculations suggest that the visible light was introduced as a key parameter to enhance the reactivity via a radical process in the formation of closed-shell cyclopropane intermediate, followed by a ring opening and redox-neutral hydrogen transfer process to give the desaturated product. The high regioselectivity in this transformation is enabled by the internal amino species as an ancillary group (AG) in the final olefin formation step.

Gold(I)-Catalyzed Aromatization: Expeditious Synthesis of Polyfunctionalized Naphthalenes.

A gold-catalyzed 6-endo-dig carbocyclization of alkyne with the pendent diazo group is reported. It provides an expeditious approach for the synthesis of multi-functionalized naphthalene derivatives under mild conditions. Mechanistic studies suggest that a vinyl gold carbene is generated as the key intermediate in this cascade transformation that smoothly delivers naphthalene products through an unprecedented stepwise aromatization or an intermolecular aromatic substitution process.

Spectroscopic identification of monomeric methyl metaphosphate.

Monomeric methyl metaphosphate (CHOPO), a highly electrophilic phosphorylating intermediate in chemical oligonucleotide synthesis, has been generated in the gas phase by high-vacuum flash pyrolysis (1000 K) of methyl 2-butenylphosphonate. In addition to the unambiguous characterization using IR spectroscopy in solid N-, Ar-, and Ne-matrices, the formation CHOPO in the photooxidation of the prototypical phosphinidene oxide CHPO by O with O-isotope scrambling has been observed in the solid N-matrix (15 K).

Rhodium-Catalyzed Nitrene/Alkyne Metathesis: An Enantioselective Process for the Synthesis of N-Heterocycles.

A chiral dirhodium-carboxylates-catalyzed asymmetric nitrene/alkyne metathesis (NAM) cascade reaction of alkyne-tethered sulfamates has been developed, which provides a general access to the synthesis of tricyclic N-heterocycles in good yields and excellent enantioselectivity. The chiral dirhodium catalyst not only promotes the nitrene/alkyne metathesis (NAM) to generate the key α-imino metal carbene intermediate but also is responsible for the observed asymmetric induction in the terminating [2,3]-sigmatropic rearrangement of oxonium ylide species.

Copper- or Thermally Induced Divergent Outcomes: Synthesis of 4-Methyl 2H-Chromenes and Spiro-4H-Pyrazoles.

An unprecedented divergent outcome transformation of alkyne tethered N-sulfonyl hydrazones is reported, which provides a direct and effective access to 4-methyl 2H-chromene derivatives and spiro-4H-pyrazoles in the presence of copper catalyst or under thermal conditions, respectively. The notable features of this process include readily available starting materials, an inexpensive copper catalyst, mild reaction conditions, broad substrate scope, diverse transformations and potential applications of these generated products. Mechanistic studies indicate that the 3H-pyrazole, which is generated via direct [3+2] cycloaddition, is the communal key intermediate of these two divergent transformations.