Lewis-Acid-Catalyzed (3+2) Annulation of 2-Indolylmethanols with Propargylic Alcohols to Access Cyclopenta[b]indoles.

Herein, a Sc(OTf)3-catalyzed (3+2) annulation of 2-indolylmethanols with propargylic alcohols is reported. The reaction proceeds via a Friedel-Crafts-type allenylation/5-exo-annulation cascade. In the reaction, 2-indolylmethanol is used as a three-carbon synthon, and propargyl alcohol is used as a two-carbon synthon. This method provides a direct and high-yield pathway for synthetically useful cyclopenta[b]indoles. In general, the method features easily accessible substrates with broad scope and generality, the formation of multiple bonds with high efficiency, and easy scale-up.

Formal (3 + 4)-Annulation of Propargylic p-Quinone Methides with 2-Indolylmethanols: Synthesis of Polysubstituted Indole-Fused Oxepines.

A novel Brønsted acid catalyzed 1,8-addition mediated (3 + 4)-annulation of in situ generated propargylic p-quinone methides with 2-indolylmethanols is described. This method provides a convenient and mild approach to structurally interesting and synthetically important polysubstituted indole-fused oxepines in high yields. Moreover, 2-indolylmethanols as four-atom synthons in the (3 + 4)-annulations under Brønsted acid conditions have been explored for the first time.

Dearomatization of 2,3-Disubstituted Indoles via 1,8-Addition of Propargylic (Aza)-para-Quinone Methides.

Dearomatization of indole is a useful strategy to access indolimines: a motif widely exists in biologically active molecules and natural products. Herein, an efficient method for the dearomatization of 2,3-disubstituted indoles to generate diverse indolimines with tetrasubstituted allenes is described. This work accomplishes dearomatization of 2,3-disubstituted indoles through 1,8-addition of (aza)-para-quinone methides, which are generated in situ from propargylic alcohols. A series of synthetically useful indolimines containing quaternary carbon centers and tetrasubstituted allenes can be accessed in good yields (up to 99%). Additionally, the separability of product isomers, diversified product transformations, and easy scale-up of the reaction demonstrate the potential application of this method.

Brønsted Acid-Catalyzed Formal (3+3)-Annulation of Propargylic (Aza)-para-Quinone Methides with 4-Hydroxycoumarins and 1,3-Dicarbonyl Compounds.

Herein, we describe a highly effective 1,8-conjugate-addition-mediated formal (3+3)-annulation of (aza)-para-quinone methides in situ generated from propargylic alcohols with 4-hydroxycoumarins and 1,3-dicarbonyl compounds under the catalysis of a Brønsted acid. This methodology affords efficient and practical access to synthetically important and highly functionalized pyranocoumarins and pyrans in excellent yields under mild conditions. Importantly, these products exhibit impressive inhibitory activity toward α-glucosidase.

Development and validation of ultra-high performance supercritical fluid chromatography method for quantitative determination of six compounds in Guizhi Fuling capsule and tablet samples.

A fast and simple ultra-high performance supercritical fluid chromatography method has been developed for the determination of six analytes, namely (paeonol, coumarin, cinnamic alcohol, cinnamic acid, paeoniflorin, and amygdalin) in Guizhi Fuling capsule and tablet samples. The influence of the key chromatographic parameters for the separation purposes was evaluated. The optimal column was Trefoil CEL1 column. The optimal mobile phase was a gradient mixture of carbon dioxide and methanol at flow rate of 1.0 mL/min. The back pressure of the system was set to 1.38 × 107  Pa and the temperature to 45°C. The six compounds were separated within 11 min by the proposed ultra-high performance supercritical fluid chromatography method with satisfactory resolution. Method validation confirmed that the procedure is accurate with the recovery rates from 87.04 to 104.30%, intraday precision values less than 4.81% and interday precision less than 5.22%, and linear with R2 higher than 0.9967. Therefore, this work provides a simple and novel method for the simultaneous analysis of six compounds in Guizhi Fuling capsule and tablet samples.

Synthesis of Naphthopyrans via Formal (3+3)-Annulation of Propargylic (Aza)-para-Quinone Methides with Naphthols.

Herein, we report an efficient Brønsted acid-catalyzed formal (3+3)-annulation of (aza)-para-quinone methides generated in situ from propargylic alcohols with naphthol derivatives, which involves a 1,8-conjugate addition/6-endo annulation process. This protocol provides an effective method for preparing important functionalized pyranocoumarins under mild conditions.

Aligning retention time shifts in HPLC three-dimensional spectra by icoshift approach combined with data arrangement methods and the release of a graphical user interface.

High-performance liquid chromatography coupled with photodiode array detection has been extensively applied in many fields and the peaks among the analyzed samples can be shifted due to the variations of instrumental and experimental conditions. In multivariate analysis, retention time alignment is an important pretreatment step. Hence, the shifted peaks in high-performance liquid chromatography coupled with photodiode array detection three-dimensional spectra should be aligned for further analysis. Being motivated by this purpose, the interval correlated shifting method combined with the proposed data arrangement methods are recommended and employed on high-performance liquid chromatography coupled with photodiode array detection data as a demonstration. We validate the alignment performance of the proposed method through comparison the consistency of the retention time before and after alignment. The obtained results demonstrated that the proposed method is capable of successful aligning the employed data. Additionally, the interval correlated shifting method combined with the data arrangement modes is implemented in an easy-to-use graphical user interface environment and so can be operated easily by users not familiar with programming languages.

Total Synthesis of Lycopodium Alkaloids Palhinine A and Palhinine D.

The first total syntheses of Lycopodium alkaloids palhinine A, palhinine D, and their C3-epimers have been divergently achieved through the use of a connective transform to access a pivotal hexacyclic isoxazolidine precursor. A microwave-assisted regio- and stereoselective intramolecular nitrone-alkene cycloaddition was tactically orchestrated as a key step to install the crucial 10-oxa-1-azabicyclo[5.2.1]decane moiety embedded in the conformationally rigid isotwistane framework, demonstrating the feasibility of constructing the highly strained medium-sized ring by introduction of an oxygen bridging linker to relieve the transannular strain in the polycyclic scaffold. Subsequent N-O bond cleavage provided the synthetically challenging nine-membered azonane ring system bearing the requisite C3 hydroxyl group. Late-stage transformations featuring a chemo- and stereoselective reduction of the pentacyclic ß-diketone secured the availability of our target molecules.

Cinchona Alkaloid Catalyzed Enantioselective [4 + 2] Annulation of Allenic Esters and in Situ Generated ortho-Quinone Methides: Asymmetric Synthesis of Functionalized Chromans.

A novel enantioselective [4 + 2] annulation of the allenoates having a unique positive ortho-effect with in situ generated ortho-quinone methides has been developed under the catalysis of Cinchona alkaloid. This chiral amine-catalyzed reaction provides an alternative route to asymmetric catalytic construction of synthetically interesting, highly functionalized chiral chromans in good to excellent enantioselectivities (up to 97% ee).

Spirocyclopropanation Reaction of para-Quinone Methides with Sulfonium Salts: The Synthesis of Spirocyclopropanyl para-Dienones.

A novel DBU-mediated stereoselective spirocyclopropanation of para-quinone methides with sulfonium salts has been developed on the basis of the mode involving a 1,6-conjugate addition/intramolecular dearomatizing cyclization cascade. This reaction provides a mild and effective method for the assembly of synthetically and structurally interesting spirocyclopropanyl para-dienones. The feasibility for the enantioselective access to such functionalized para-dienones has also been explored by using the axially chiral sulfonium salt. Importantly, the regioselective ring openings of the related spirocyclopropanyl para-dienones have been achieved divergently.

Diastereoselective and Enantioselective Synthesis of Unsymmetric ß,ß-Diaryl-α-Amino Acid Esters via Organocatalytic 1,6-Conjugate Addition of para-Quinone Methides.

A novel strategy based on phase transfer catalysis for the diastereoselective and enantioselective direct assembly of unsymmetric ß,ß-diaryl-α-amino acid esters via 1,6-conjugate addition of para-quinone methides and glycine derivatives is described. This protocol also provides an alternative route to the synthetically interesting functionalized chiral tetrahydroisoquinoline and its analogues.

Melatonin derivative 6a as a PARP-1 inhibitor for the treatment of Parkinson's disease.

Both continuous oxidative stress and poly (ADP-ribose) polymerase 1 (PARP-1) activation occur in neurodegenerative diseases such as Parkinson's disease. PARP-1 inhibition can reverse mitochondrial damage and has a neuroprotective effect. In a previous study, we synthesized melatonin derivative 6a (MD6a) and reported that it has excellent antioxidant activity and significantly reduces α-synuclein aggregation in Caenorhabditis elegans; however, the underlying mechanism is largely unknown. In the present study, we revealed that MD6a is a potential PARP-1 inhibitor, leading to mammalian targe of rapamycin/heat shock factor 1 signaling downregulation and reducing heat shock protein 4 and 6 expression, thus helping to maintain protein homeostasis and improve mitochondrial function. Together, these findings suggest that MD6a might be a viable candidate for the prevention and treatment of Parkinson's disease.

Acid-Promoted Cyclization of α-Azidobenzyl Ketones through C═N Bond Formation: Synthesis of 6-Substituted Quinoline Derivatives.

An acid-promoted cyclization of α-azidobenzyl ketones has been developed for the synthesis of 6-substituted quinoline derivatives. A variety of synthetically useful 6-OTf or -OMs quinoline derivatives were obtained in moderate to good yields. The reaction proceeds via C═N bond formation without organophosphine, providing convenient access to structurally interesting and synthetically important 6-substituted quinoline derivatives in moderate to good yields. A mechanistic perspective that is different from the traditional intramolecular Schmidt reaction has been proposed.

Bismuth(III)-Catalyzed 1,8-Addition/Cyclization/Rearrangement of Propargylic para-Quinone Methides with 2-Vinylphenol: Synthesis of Indeno[2,1-c]chromenes.

The unique reactivity of in situ generated propargylic para-quinone methides as a new type of five-carbon synthon has been discovered by a novel bismuth(III)-catalyzed tandem annulation reaction. This 1,8-addition/cyclization/rearrangement cyclization cascade reaction is characterized by unusual structural reconstruction of 2-vinylphenol, involving cleavage of the C1'═C2' bond and formation of four new bonds. This method provides a convenient and mild approach to generate synthetically important functionalized indeno[2,1-c]chromenes. The mechanism of the reaction is proposed from several control experiments.

An accurate and reliable analytical strategy for simultaneous determination of target furanocoumarins and flavonoids in cosmetic and pharmaceutical samples by ultra-high performance supercritical fluid chromatography.

Furanocoumarins and flavonoids have various important biological activities and wide application. In the present study, a rapid and reliable supercritical fluid chromatography method was proposed for the separation of 10 target components including 8 furanocoumarins and 2 flavonoids. After detailed condition optimization, the 10 target compounds can be baseline separated on a Trefoil CEL1 (3.0 mm × 150 mm, 2.5 µm) column using gradient elution. A 0.07% (v/v) trifluoroacetic acid in ethanol was determined to be the most proper mobile phase for the separation of target compounds. The column temperature, back pressure, flow rate were set at 36 â„ƒ, 2000 psi, 1.0 mL min-1 to 1.4 mL min-1, respectively. The ten target compounds were analyzed within 24 min using the optimized conditions. Under the optimized conditions, all the target compounds showed good linearity with linear correlation coefficients higher than 0.995, and satisfactory recovery in the range of 83.52-112.92%. All these results showed that the developed ultra-high performance supercritical fluid chromatography method was reliable and effective. Finally, the application of the developed method to cosmetic, Psoraleae fructus and Angelicae dahuricae radix samples were presented. The results highlight the applicability of the ultra-high performance supercritical fluid chromatography method to the analysis of interested compounds in pharmaceutical and cosmetic samples.

Total Synthesis of (+)-Peniciketal B.

An efficient synthesis of (+)-peniciketal B has been accomplished in 15 steps from the commercially available materials atraric acid, acryloyl chloride, and (+)-homoallylic alcohol. A convergent synthetic approach that is quite concise for constructing either "hemisphere" of (+)-peniciketal B with a common intermediate is employed that relies on a cascade intermolecular FeCl3-mediated "inner sphere" Michael-type reaction/double cyclization of an α,ß-unsaturated ketone and substituted phenol to build the benzo-fused 2,8-dioxabicyclo[3.3.1]nonane with excellent diastereoselectivity. The generality of the transformation was also demonstrated by the broad scope of substrates that would be potential candidates for natural product synthesis and medicinal chemistry. Benzannulated [6,6]spiroketal was installed by a late-stage acid-catalyzed spiroketalization.

Enantioselective synthesis of α,α-diarylketones by sequential visible light photoactivation and phosphoric acid catalysis.

Chiral ketones and their derivatives are useful synthetic intermediates for the synthesis of biologically active natural products and medicinally relevant molecules. Nevertheless, general and broadly applicable methods for enantioenriched acyclic α,α-disubstituted ketones, especially α,α-diarylketones, remain largely underdeveloped, owing to the easy racemization. Here, we report a visible light photoactivation and phosphoric acid-catalyzed alkyne-carbonyl metathesis/transfer hydrogenation one-pot reaction using arylalkyne, benzoquinone, and Hantzsch ester for the expeditious synthesis of α,α-diarylketones with excellent yields and enantioselectivities. In the reaction, three chemical bonds, including C═O, C─C, and C─H, are formed, providing a de novo synthesis reaction for chiral α,α-diarylketones. Moreover, this protocol provides a convenient and practical method to synthesize or modify complex bioactive molecules, including efficient routes to florylpicoxamid and BRL-15572 analogs. Computational mechanistic studies revealed that C-H/π interactions, π-π interaction, and the substituents of Hantzsch ester all play crucial roles in the stereocontrol of the reaction.

Brønsted acid catalyzed remote C6 functionalization of 2,3-disubstituted indoles with ß,γ-unsaturated α-ketoester.

A metal-free catalytic approach for the remote C6-functionalization of 2,3-disubstituted indoles has been developed. In the presence of catalytic amounts of Brønsted acid, the ß,γ-unsaturated α-ketoesters react with 2,3-disubstituted indoles at the C6 position selectively. Under mild reaction conditions, a range of C6-functionalized indoles were prepared with good yields and excellent regioselectivity. This methodology provides a concise and efficient route for the synthesis of C6-functionalized indole derivatives.

Copper-catalyzed 1,2-Borylacylation of 1,3-Enynes: synthesis of ß-Alkynyl ketones.

A copper catalyzed 1,2-borylacylation of 1,3-enynes with B2pin2 and acid chlorides has been developed. Using readily available 1,3-enynes, B2pin2 and acid chlorides as substrates, a range of highly functionalized α,α-disubstituted ß-alkynyl ketones were readily prepared under mild conditions in moderate to good yields. The borylacylated products can be easily derivatized to give several valuable structures. Notably, treatment of the products with NaBO3·4H2O provided 1,2-allenyl ketones, which is proposed to proceed via a retro-aldol process of the corresponding homopropargyl alcohols.

Studies toward synthesis of the core skeleton of spiroaspertrione A.

Bioassay-guided isolation of spiroaspertrione A from cultures of Aspergillus sp. TJ23 in 2017 demonstrated potent resensitization of oxacillin against methicillin-resistant Staphylococcus aureus by lowering the oxacillin minimal inhibitory concentration up to 32-fold. To construct this unique spiro[bicyclo[3.2.2]nonane-2,1'-cyclohexane] system, a protocol for ceric ammonium nitrate-induced intramolecular cross-coupling of silyl enolate is disclosed.