- Au(I)-Catalyzed Domino Cyclization of 1,6-Diynes Incorporated with Indole
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We disclose herein a Au(I)-catalyzed domino cyclization of 1,6-diynes incorporated with indole. This protocol enabled the diastereoselective buildup of indole-fused azabicyclo[3.3.1]nonanes from linear precursors. Density functional theory calculations showed that the reaction proceeded via an unprecedented cascade dearomatization/rearomatization/dearomatization process. Independent gradient model analysis revealed that a noncovalent attractive interaction between the distal alkyne and the Au/proximal complex was responsible for the chemoselectivity of the first spirocyclization step.
- Chen, Guzhou,Liu, Peng-Yu,Zou, Huanhuan,Hu, Jiadong,Fang, Xiaowu,Xu, Dongyang,He, Yu-Peng,Wei, Hongbo,Xie, Weiqing
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supporting information
p. 2279 - 2284
(2021/04/05)
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- Tandem Olefin Isomerization/Cyclization Catalyzed by Complex Nickel Hydride and Br?nsted Acid
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We disclose a nickel/Br?nsted acid-catalyzed tandem process consisting of double bond isomerization of allyl ethers and amines and subsequent intramolecular reaction with nucleophiles. The process is accomplished by [(Me3P)4NiH]N(SO2CF3)2 in the presence of triflic acid. The methodology provides rapid access to tetrahydropyran-fused indoles and other oxacyclic scaffolds under very low catalyst loadings.
- Kathe, Prasad M.,Caciuleanu, Alexandru,Berkefeld, Andreas,Fleischer, Ivana
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p. 15183 - 15196
(2020/11/30)
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- Improved and Flexible Synthetic Access to the Spiroindole Backbone of Cebranopadol
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By changing the dimethylamino to a nitro group, a novel synthetic access to the spirocyclic opioid analgesic cebranopadol was developed that is much more efficient compared with the established route. On the basis of the α-acidity of α-nitrotoluene, the two-fold Michael addition to acrylate gave an acyclic precursor compound, which was easily transformed by Dieckmann condensation and decarboxylation to the cyclohexanone derivative needed for the annulation of the indole ring by an oxa-Pictet-Spengler reaction. As an additional benefit, the reduction of the nitro group furnished an amine, which could be late-stage-diversified to carboxamides, sulfonamides, ureas, and N-alkyl congeners. The transformation of the nitro group at the spirocyclic scaffold to the dimethylamino function of the actual title compound was achieved in one step with zinc/formic acid/formaldehyde in 83% yield.
- Christoffers, Jens,Schmidtmann, Marc,Wachtendorf, Daniel
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supporting information
p. 6420 - 6423
(2020/09/02)
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- Palladium-Catalyzed Asymmetric Allylic Alkylation of 3-Substituted 1 H-Indoles and Tryptophan Derivatives with Vinylcyclopropanes
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Vinylcyclopropanes (VCPs) are known to generate 1,3-dipoles with a palladium catalyst that initially serve as nucleophiles to undergo [3 + 2] cycloadditions with electron-deficient olefins. In this report, we reverse this reactivity and drive the 1,3-dipoles to serve as electrophiles by employing 3-alkylated indoles as nucleophiles. This represents the first use of VCPs for the completely atom-economic functionalization of 3-substituted 1H-indoles and tryptophan derivatives via a Pd-catalyzed asymmetric allylic alkylation (Pd-AAA). Excellent yields and high chemo-, regio-, and enantioselectivities have been realized, providing various indolenine and indoline products. The method is amenable to gram scale and works efficiently with tryptophan derivatives that contain a diketopiperazine or diketomorpholine ring, allowing us to synthesize mollenine A in a rapid and ligand-controlled fashion. The obtained indolenine products bear an imine, an internal olefin, and a malonate motif, giving multiple sites with diverse reactivities for product diversification. Complicated polycyclic skeletons can be conveniently constructed by leveraging this unique juxtaposition of functional groups.
- Trost, Barry M.,Bai, Wen-Ju,Hohn, Christoph,Bai, Yu,Cregg, James J.
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supporting information
p. 6710 - 6717
(2018/05/24)
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- A Cooperative Hydrogen Bond Donor–Br?nsted Acid System for the Enantioselective Synthesis of Tetrahydropyrans
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Carbocations stabilized by adjacent oxygen atoms are useful reactive intermediates involved in fundamental chemical transformations. These oxocarbenium ions typically lack sufficient electron density to engage established chiral Br?nsted or Lewis acid catalysts, presenting a major challenge to their widespread application in asymmetric catalysis. Leading methods for selectivity operate primarily through electrostatic pairing between the oxocarbenium ion and a chiral counterion. A general approach to new enantioselective transformations of oxocarbenium ions requires novel strategies that address the weak binding capabilities of these intermediates. We demonstrate herein a novel cooperative catalysis system for selective reactions with oxocarbenium ions. This new strategy has been applied to a highly selective and rapid oxa-Pictet–Spengler reaction and highlights a powerful combination of an achiral hydrogen bond donor with a chiral Br?nsted acid.
- Maskeri, Mark A.,O'Connor, Matthew J.,Jaworski, Ashley A.,Davies, Anna V.,Scheidt, Karl A.
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supporting information
p. 17225 - 17229
(2018/12/05)
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- Scope of the Reactions of Indolyl- and Pyrrolyl-Tethered N-Sulfonyl-1,2,3-triazoles: Rhodium(II)-Catalyzed Synthesis of Indole- and Pyrrole-Fused Polycyclic Compounds
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An efficient synthesis of tetrahydrocarboline-type products and polycyclic spiroindolines has been achieved. The transformation proceeds via rhodium(II)-catalyzed intramolecular annulations of indolyl- and pyrrolyl-tethered N-sulfonyl-1,2,3-triazoles. The reaction could be tuned toward either the formal [3 + 2] cycloaddition or the C-H functionalization reaction depending on the electronic and structural features of the substrates, leading to the production of a variety of structurally related heterocyclic compounds.
- Fu, Liangbing,Davies, Huw M. L.
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supporting information
p. 1504 - 1507
(2017/04/13)
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- Dearomatization of tryptophols via a vanadium-catalyzed asymmetric epoxidation and ring-opening cascade
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An enantioselective epoxidation of tryptophols followed by an intramolecular epoxide opening reaction was realized by chiral vanadium catalysts derived from C2 symmetric bis-hydroxamic acid (BHA) ligands. 3a-Hydroxyfuroindoline derivatives with up to 89% yield and 90% ee were obtained under mild reaction conditions.
- Han, Long,Liu, Chuan,Zhang, Wei,Shi, Xiao-Xin,You, Shu-Li
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supporting information
p. 1231 - 1233
(2014/02/14)
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- SMALL MOLECULE INDUCERS OF GDNF AS POTENTIAL NEW THERAPEUTICS FOR NEUROPSYCHIATRIC DISORDERS
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The invention provides a compound having the structure (I), wherein A is a substituted or unsubstituted ring; Z is present or absent and when present is (II), wherein n is 0, 1, 2, 3, or 4; Y is -(CR11R12)-, -NH(CR11R12)- or -O(CR11R12)- wherein R11 and R12 are each hydrogen or combine to form a carbonyl; and wherein R1 to R10 are herein as described.
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Page/Page column 101; 102
(2013/03/26)
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- A tandem isomerization/prins strategy: Iridium(III)/Bronsted acid cooperative catalysis
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Working together: A mild and efficient isomerization/protonation sequence generates pyran-fused indoles by cooperative catalysis between cationic iridium(III) and Bi(OTf)3. Three distinct cyclization manifolds lead to the corresponding bioactive scaffolds in good yields. In addition, N-substituted indoles can be synthesized enantioselectively in the presence of a chiral phosphate. Copyright
- Lombardo, Vince M.,Thomas, Christopher D.,Scheidt, Karl A.
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supporting information
p. 12910 - 12914
(2014/01/06)
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- SMALL MOLECULE INHIBITORS OF ISOPRENYLCYSTEINE CARBOXYL METHYLTRANSFERASE WITH POTENTIAL ANTICANCER ACTIVITY
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The present invention generally relates to inhibitors of isoprenylcysteine carboxyl methyltransferase (Icmt), in particularly to compounds that inhibit Icmt activity and pharmaceutical compositions thereof. The invention also relates to methods of disease treatment using the same.
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Page/Page column 65
(2011/02/24)
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- Amino derivatives of indole as potent inhibitors of isoprenylcysteine carboxyl methyltransferase
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The enzyme isoprenylcysteine carboxyl methyltransferase (Icmt) plays an important role in the post-translational modification of proteins that are involved in the regulation of cell growth. The indole acetamide cysmethynil is by far the most potent and widely investigated Icmt inhibitor, but it has modest antiproliferative activity and may have pharmacokinetic limitations due to its lipophilic character. We report here that cysmethynil can be structurally modified to give analogues that are as potent in inhibiting Icmt but with significantly greater antiproliferative activity. Key modifications were the replacement of the acetamide side chain by tertiary amino groups, the n-octyl side chain by isoprenyl and the 5-m-tolyl ring by fluorine. Moreover, these analogues have lower lipophilicities that could lead to improved pharmacokinetic profiles.
- Go, Mei-Lin,Leow, Jo Lene,Gorla, Suresh Kumar,Schüller, Andreas Peter,Wang, Mei,Casey, Patrick J.
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experimental part
p. 6838 - 6850
(2010/11/18)
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- A2 ADENOSINE RECEPTOR AGONISTS
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Disclosed are AZB adenosine receptor (AR) agonists of formula (I), in which R1, R2, R3, R4, Z, and n are defined herein. The invention also provides compositions comprising at least one compound of formula I and methods of use thereof, for example, in the treatment of septic shock, cystic fibrosis, restenosis, erectile dysfunction, inflammation, myocardial ischemia, and reperfusion injury.
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Page/Page column 21
(2009/03/07)
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- Structure-activity relationships of 2,N6,5′-substituted adenosine derivatives with potent activity at the A2B adenosine receptor
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2, N6, and 5′-substituted adenosine derivatives were synthesized via alkylation of 2-oxypurine nucleosides leading to 2-arylalkylether derivatives. 2-(3-(Indolyl)ethyloxy)adenosine 17 was examined in both binding and cAMP assays and found to be a potent agonist of the human A2BAR. Simplification, altered connectivity, and mimicking of the indole ring of 17 failed to maintain A2BAR potency. Introduction of N6-ethyl or N6-guanidino substitution, shown to favor A2BAR potency, failed to enhance potency in the 2-(3-(indolyl)- ethyloxy)adenosine series. Indole 5″- or 6″-halo substitution was favored at the A2BAR, but a 5′-N-ethylcarboxyamide did not further enhance potency. 2-(3″-(6″-Bromoindolyl)ethyloxy)adenosine 28 displayed an A2BAR EC50 value of 128 nM, that is, more potent than the parent 17 (299 nM) and similar to 5′-N- ethylcarboxamidoadenosine (140 nM). Compound 28 was a full agonist at A 2B and A2AARs and a low efficacy partial agonist at A 1 and A3ARs. Thus, we have identified and optimized 2-(2-arylethyl)oxo moieties in AR agonists that enhance A2BAR potency and selectivity.
- Adachi, Hayamitsu,Palaniappan, Krishnan K.,Ivanov, Andrei A.,Bergman, Nathaniel,Gao, Zhan-Guo,Jacobson, Kenneth A.
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p. 1810 - 1827
(2008/02/06)
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- Pyridine compounds
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A compound selected from those of formula (I): wherein: W represents optionally substituted naphthyl, n represents an integer from 2 to 3 inclusive, Z represents a single bond, A represents nitrogen, Q represents nitrogen, M, together with the carbon of pyridyl to which it is bonded, represents thieno, furo, pyrrolo or oxopyrrolo, Its optical isomers and pharmaceutically-acceptable acid or base additional salts thereof, and Medicinal products containing the same which are useful in the treatment of CNS disorders. It being understood that “aryl” is phenyl, naphthyl, dihydronaphthyl, or tetrahydronaphthyl.
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