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Yonghan Hu,
Derek Cole,
Rajiah Aldrin Denny,
David R Anderson,
Manus Ipek, Yike Ni,
Xiaolun Wang,
Suvit Thaisrivongs,
Timothy Chamberlain,
J Perry Hall,
Julie Liu,
Michael Luong,
Lih-Ling Lin,
Jean-Baptiste Telliez,
Ariamala Gopalsamy
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ABSTRACT: Synthesis, modeling and structure-activity relationship of indazoles as inhibitors of Tpl2 kinase are described. From a high throughput screening effort, we identified an indazole hit compound 5 that has a single digit micromolar Tpl2 activity. Through SAR modifications at the C3 and C5 positions of the indazole, we discovered compound 31 with good potency in LANCE assay and cell-based p-Erk assay.
Bioorganic & medicinal chemistry letters 08/2011; 21(16):4758-61. · 2.65 Impact Factor
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Yike Ni,
Ariamala Gopalsamy,
Derek Cole,
Yonghan Hu,
Rajiah Denny,
Manus Ipek,
Julie Liu,
Julie Lee,
J Perry Hall,
Michael Luong,
Jean-Baptiste Telliez,
Lih-Ling Lin
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ABSTRACT: We report here the synthesis and SAR of a new series of thieno[3,2-d]pyrimidines as potent Tpl2 kinase inhibitors. The proposed binding mode suggests the potential flipped binding mode depending on the substitution. Biacore studies show evidence of binding of these molecules to the protein kinase. The kinome inhibition profile of these molecules suggests good selectivity.
Bioorganic & medicinal chemistry letters 07/2011; 21(19):5952-6. · 2.65 Impact Factor
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ABSTRACT: A unified approach to the pyrrolidine triacid natural products isodomoic acids G and H has been developed. Total syntheses of both natural products were completed, and determination of the correct stereostructure of isodomoic acid G was established by comparing 5'-(R) and 5'-(S) isomers to a sample of authentic material. A nickel-catalyzed cyclization constructs the pyrrolidine ring while simultaneously establishing either the E or Z stereochemistry of an exocyclic tetrasubstituted alkene. Stereoselective assembly of both the E- and Z-alkenes of the natural products is made possible by a predictable strategy that alters the timing of substituent introduction to control alkene stereochemistry.
Journal of the American Chemical Society 11/2009; 131(48):17714-8. · 9.91 Impact Factor
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ABSTRACT: A new nickel-catalyzed procedure for the [4+2+1] cycloaddition of (trimethylsilyl)diazomethane with alkynes tethered to dienes has been developed. A broad range of unsaturated substrates participate in the sequence, and stereoselectivities are generally excellent. Stereochemical studies provided evidence for a mechanism that involves the [3,3] sigmatropic rearrangement of divinylcyclopropanes.
Journal of the American Chemical Society 04/2006; 128(8):2609-14. · 9.91 Impact Factor
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ABSTRACT: The first enantioselective organocatalytic reductive amination reaction has been accomplished. The development of a new chiral phosphoric acid catalyst has provided a convenient strategy for the enantioselective construction of protected primary amines and provided a highly stereoselective method for the reductive amination of heterocyclic amines. A diverse spectrum of ketone and amine substrates can be accommodated in high yield and excellent enantioselectivity. This new protocol realizes a key benefit of reductive amination versus imine reduction, in that ketimines derived from alkyl-alkyl ketones are unstable to isolation, a fundamental limitation that is comprehensively bypassed using this direct organocatalytic reductive amination.
Journal of the American Chemical Society 02/2006; 128(1):84-6. · 9.91 Impact Factor
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ABSTRACT: A new nickel-catalyzed procedure for the [4 + 2 + 1] cycloaddition of trimethylsilyl diazomethane with alkynes tethered to dienes has been developed. A broad range of unsaturated substrates participate in the sequence, and stereoselectivities are generally excellent. Three possible mechanisms are proposed, and each involves the generation of a transient nickel carbene species.
Journal of the American Chemical Society 10/2004; 126(36):11162-3. · 9.91 Impact Factor
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ABSTRACT: [structure: see text] The first total synthesis and stereochemical definition of isodomoic acid G has been achieved. The key nickel-catalyzed coupling of an alkynyl enone with an alkenylzirconium allows formation of the pyrrolidine ring and most of the stereochemical features in a single step. This report provides the first total synthesis application of this new reaction and illustrates its utility in the stereoselective preparation of highly substituted 1,3-dienes.
Organic Letters 11/2003; 5(20):3771-3. · 5.86 Impact Factor
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ABSTRACT: [reaction: see text] 1,3-Dienes were prepared by a variety of nickel-catalyzed couplings and cyclization processes. Intermolecular or partially intramolecular couplings of alkynes, vinylzirconium reagents, and either aldehydes or enones efficiently proceeded to generate a broad range of functionalized dienes.
Organic Letters 06/2002; 4(10):1743-5. · 5.86 Impact Factor
