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1.
Org Lett ; 26(12): 2349-2353, 2024 Mar 29.
Article in English | MEDLINE | ID: mdl-38489519

ABSTRACT

Enantioselective construction of all-carbon quaternary centers has been achieved via the palladium-catalyzed highly enantioselective allenylation of oxindoles with 2,3-allenylic carbonates to afford a variety of optically active allene products, which contain oxindole units with different functional groups, in high ee. The corresponding synthetic applications have also been demonstrated.

2.
Bioorg Med Chem Lett ; 93: 129429, 2023 09 01.
Article in English | MEDLINE | ID: mdl-37543274

ABSTRACT

Cyclin dependent kinase 7 (CDK7) is an attractive target in tumor indications via regulating both cell cycle and transcription. Here, SHR5428 was discovered as a selective and noncovalent CDK7 inhibitor with highly potent CDK7 enzymatic activity and triple negative breast cancer cellular activity on MDA-MB-468 cell. SHR5428 also displayed favorable pharmacokinetic properties in different preclinical species such as mouse, rat and dog, and showed high selectivity over CDK1, CDK2, CDK4, CDK6, CDK9, CDK12 in CDK family. Furthermore, the computational modeling has shed some light on this mechanism. Additionally the in vivo efficacy study in a breast cancer cell line (HCC70 cell) derived xenograft mouse model proved SHR5428 to be orally efficacious with dose-dependent tumor growth inhibition.


Subject(s)
Cyclin-Dependent Kinase-Activating Kinase , Protein Kinase Inhibitors , Animals , Dogs , Humans , Mice , Rats , Cell Cycle , Cell Cycle Checkpoints , Cell Line, Tumor , Cyclin-Dependent Kinase-Activating Kinase/antagonists & inhibitors , Phosphorylation , Protein Binding , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use
3.
Chem Commun (Camb) ; 55(55): 7938-7941, 2019 Jul 04.
Article in English | MEDLINE | ID: mdl-31219146

ABSTRACT

A straightforward approach to synthesizing substituted 1,3-alkadien-2-yl carboxylic acids starting from readily available propargylic alcohols was developed. Based on mechanistic studies, the reaction was found to proceed via regioselective hydrocarbonylation of the C-C triple bonds of the in situ formed 1,3-enyne intermediates, providing 1,3-alkadien-2-yl carboxylic acids with a very high selectivity.

4.
Chem Commun (Camb) ; 55(31): 4523-4526, 2019 Apr 11.
Article in English | MEDLINE | ID: mdl-30924486

ABSTRACT

A palladium-catalyzed coupling reaction of 2,3-allenylic carbonates with cyclopropanols was developed, affording valuable 1,3-diene products with different functional groups efficiently under mild reaction conditions. Gram scale synthesis was easily conducted with synthetic transformations demonstrated.

5.
Org Lett ; 20(3): 554-557, 2018 02 02.
Article in English | MEDLINE | ID: mdl-29345948

ABSTRACT

The ring opening-coupling reaction of cyclopropanols with propargylic carbonates affording synthetically attractive allenyl ketones has been developed. The mechanism involves the ligand-exchange reaction of in situ formed allenyl palladium methoxide with cyclopropanols followed by carbon-carbon bond cleavage and reductive elimination. The reactions proceeded smoothly under mild reaction conditions with Pd(0)/XPhos catalysis in the absence of any external base and displayed a wide scope and application to a steroidal skeleton. The efficiency of chirality transfer and synthetic utility of the allene products have also been demonstrated.

6.
Angew Chem Int Ed Engl ; 55(32): 9134-66, 2016 08 01.
Article in English | MEDLINE | ID: mdl-27310878

ABSTRACT

Metal carbenes usually possess versatile reactivities that are controlled by the presence of both the metals and the ligands. Diazo compounds are commonly used for the generation of such species through elimination of nitrogen. However, they are often unstable, explosive, and toxic, which limits their applications in large-scale syntheses. Thus, identifying sustainable and safe surrogates for the generation of metal carbenes has attracted great attention. In this Review, we summarize some of the most important breakthroughs in the generation, catalytic reactions, and selectivity control of metal carbenes from non-diazo starting compounds.

7.
Chemistry ; 21(50): 18445-53, 2015 Dec 07.
Article in English | MEDLINE | ID: mdl-26517191

ABSTRACT

The gold-catalyzed synthesis of methylidene 2,3-cyclobutane-indoles is documented through a combined experimental/computational investigation. Besides optimizing the racemic synthesis of the tricyclic indole compounds, the enantioselective variant is presented to its full extent. In particular, the scope of the reaction encompasses both aryloxyallenes and allenamides as electrophilic partners providing high yields and excellent stereochemical controls in the desired cycloadducts. The computational (DFT) investigation has fully elucidated the reaction mechanism providing clear evidence for a two-step reaction. Two parallel reaction pathways explain the regioisomeric products obtained under kinetic and thermodynamic conditions. In both cases, the dearomative CC bond-forming event turned out to be the rate-determining step.

8.
Chem Commun (Camb) ; 51(12): 2320-3, 2015 Feb 11.
Article in English | MEDLINE | ID: mdl-25562811

ABSTRACT

The highly enantioselective synthesis of densely functionalized 2,3-indoline-cyclobutanes by means of chiral gold catalysis is presented. Intermolecular formal [2+2]-cycloaddition reactions between substituted indoles and allenamides enabled direct access to methylenecyclobutane-fused indolines, featuring two consecutive quaternary stereogenic centers with excellent stereochemical control (dr > 20 : 1, ee up to 99%).


Subject(s)
Amides/chemistry , Gold/chemistry , Indoles/chemistry , Catalysis , Crystallography, X-Ray , Cycloaddition Reaction , Molecular Conformation , Stereoisomerism
9.
Angew Chem Int Ed Engl ; 53(50): 13854-7, 2014 Dec 08.
Article in English | MEDLINE | ID: mdl-25346494

ABSTRACT

The effective and unprecedented chiral BINOL phosphoric acid catalyzed (1-10 mol%) dearomatization of indoles through electrophilic activation of allenamides (ee up to 94%), is documented. Besides the synthesis of 3,3-disubstituted indolenine cores, a dearomatization/hydrogen transfer cascade sequence is also presented as a new synthetic shortcut toward highly enantiomerically enriched indolines.

10.
Chemistry ; 20(32): 9875-8, 2014 Aug 04.
Article in English | MEDLINE | ID: mdl-25044346

ABSTRACT

A careful interplay between the π electrophilicity of a cationic Au(I) center and the basicity of the corresponding counterion allowed for the chemo- and regioselective inter- as well as intramolecular de-aromatization of 2,3-disubstituted indoles with allenamides. The silver-free bifunctional Lewis acid/Brønsted base complex [{2,4-(tBu)2C6H3O}3PAuTFA] assisted the formation of a range of densely functionalized indolenines under mild conditions.

11.
J Org Chem ; 77(23): 10996-1001, 2012 Dec 07.
Article in English | MEDLINE | ID: mdl-23140505

ABSTRACT

Highly diastereoselective and enantioselective desymmetrization of α-substituted cyclohexadienones via NHC-catalyzed intramolecular Stetter reaction was realized. Amino-indanol derived triazolium salt bearing a C(6)F(5) group was found to be the optimal catalyst precursor in the intramolecular Stetter reaction furnishing tricyclic products bearing multi-stereocenters in up to 96% yield and >99% ee.

12.
Chem Commun (Camb) ; 2012 May 23.
Article in English | MEDLINE | ID: mdl-22618513

ABSTRACT

Enantioselective desymmetrization of cyclohexadienones via a d-camphor-derived triazolium salt catalyzed intramolecular Stetter reaction was realized. With 10 mol% of camphor-derived triazolium salt E and 10 mol% of DIEA, various substituted cyclohexadienones proceeded through an intramolecular Stetter reaction, affording tricyclic products in moderate to good yields and excellent ee.

13.
Org Lett ; 13(15): 4080-3, 2011 Aug 05.
Article in English | MEDLINE | ID: mdl-21732659

ABSTRACT

Enantioselective N-heterocyclic carbene-catalyzed Michael addition reactions to α,ß-unsaturated aldehydes by redox oxidation were realized. With 10 mol % of camphor-derived triazolium salt D, 15 mol % of DBU, 5 mol % of NaBF(4), and 100 mol % of quinone oxidant, the reactions of various dicarbonyl compounds with α,ß-unsaturated aldehydes led to 3,4-dihydro-α-pyrones in good yields and excellent ee's.

14.
Org Biomol Chem ; 9(7): 2072-4, 2011 Apr 07.
Article in English | MEDLINE | ID: mdl-21340086

ABSTRACT

A series of novel chiral triazolium salts has been synthesized from readily available (1R,2R)-DPEN and found to be efficient for the enantioselective intramolecular Stetter reaction. With 10 mol% of the catalyst, the intramolecular Stetter reaction was realized in excellent yields with up to 97% ee.

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