34271-30-2Relevant articles and documents
A novel strategy for the asymmetric synthesis of chiral cyclopropane carboxaldehydes
Cheeseman, Matt,Feuillet, Fred J. P.,Johnson, Andrew L.,Bull, Steven D.
, p. 2372 - 2374 (2005)
A new way of combining chiral auxiliaries and substrate-directable reactions for asymmetric synthesis is described that employs a three-step sequence of aldol-cyclopropanation-retroaldol reactions for the stereoselective synthesis of enantiopure cycloprop
Donor-Acceptor Bicyclopropyls as 1,6-Zwitterionic Intermediates: Synthesis and Reactions with 4-Phenyl-1,2,4-triazoline-3,5-dione and Terminal Acetylenes
Potapov, Konstantin V.,Denisov, Dmitry A.,Glushkova, Valeriia V.,Novikov, Roman A.,Tomilov, Yury V.
, p. 15562 - 15576 (2020/11/30)
The bicyclopropyl system activated by incorporation of donor and acceptor groups in the presence of Lewis acids was used as a synthetic equivalent of 1,6-zwitterions. Opening of both cyclopropane rings in 2′-aryl-1,1′-bicyclopropyl-2,2-dicarboxylates (D-A bicyclopropyl, ABCDs) in the presence of GaI3 + Bu4N+GaI4- results in 5-iodo-5-arylpent-2-enylmalonates as products of HI formal 1,6-addition to the bicyclopropyl system. The use of GaCl3 or GaBr3 as a Lewis acid and terminal aryl or alkyl acetylenes as 1,6-zwitterion interceptors allows the alkyl substituent to be grown to give the corresponding acyclic 7-chloro(bromo)-hepta-2,6-dienylmalonates. The reaction of ABCDs with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) catalyzed by Yb(OTf)3 also results in the opening of both cyclopropane rings. The reaction products are tetrahydropyridazine derivatives - (7,9-dioxo-1,6,8-triazabicyclo[4.3.0]non-3-en-2-ylmethyl)malonates - containing one more PTAD moiety in the malonyl group.
5,6,7,8-Tetrahydro-1,6-naphthyridine Derivatives as Potent HIV-1-Integrase-Allosteric-Site Inhibitors
Peese, Kevin M.,Allard, Christopher W.,Connolly, Timothy,Johnson, Barry L.,Li, Chen,Patel, Manoj,Sorensen, Margaret E.,Walker, Michael A.,Meanwell, Nicholas A.,McAuliffe, Brian,Minassian, Beatrice,Krystal, Mark,Parker, Dawn D.,Lewis, Hal A.,Kish, Kevin,Zhang, Ping,Nolte, Robert T.,Simmermacher, Jean,Jenkins, Susan,Cianci, Christopher,Naidu, B. Narasimhulu
, p. 1348 - 1361 (2019/02/24)
A series of 5,6,7,8-tetrahydro-1,6-naphthyridine derivatives targeting the allosteric lens-epithelium-derived-growth-factor-p75 (LEDGF/p75)-binding site on HIV-1 integrase, an attractive target for antiviral chemotherapy, was prepared and screened for activity against HIV-1 infection in cell culture. Small molecules that bind within the LEDGF/p75-binding site promote aberrant multimerization of the integrase enzyme and are of significant interest as HIV-1-replication inhibitors. Structure-activity-relationship studies and rat pharmacokinetic studies of lead compounds are presented.
Asymmetric Reductive Carbocyclization Using Engineered Ene Reductases
Heckenbichler, Kathrin,Schweiger, Anna,Brandner, Lea Alexandra,Binter, Alexandra,Toplak, Marina,Macheroux, Peter,Gruber, Karl,Breinbauer, Rolf
, p. 7240 - 7244 (2018/06/15)
Ene reductases from the Old Yellow Enzyme (OYE) family reduce the C=C double bond in α,β-unsaturated compounds bearing an electron-withdrawing group, for example, a carbonyl group. This asymmetric reduction has been exploited for biocatalysis. Going beyond its canonical function, we show that members of this enzyme family can also catalyze the formation of C?C bonds. α,β-Unsaturated aldehydes and ketones containing an additional electrophilic group undergo reductive cyclization. Mechanistically, the two-electron-reduced enzyme cofactor FMN delivers a hydride to generate an enolate intermediate, which reacts with the internal electrophile. Single-site replacement of a crucial Tyr residue with a non-protic Phe or Trp favored the cyclization over the natural reduction reaction. The new transformation enabled the enantioselective synthesis of chiral cyclopropanes in up to >99 % ee.
Lewis Acid Catalyzed Annulation of Cyclopropane Carbaldehydes and Aryl Hydrazines: Construction of Tetrahydropyridazines and Application Toward a One-Pot Synthesis of Hexahydropyrrolo[1,2- b]pyridazines
Dey, Raghunath,Kumar, Pankaj,Banerjee, Prabal
, p. 5438 - 5449 (2018/05/28)
In this report, a facile synthesis of tetrahydropyridazines via a Lewis acid catalyzed annulation reaction of cyclopropane carbaldehydes and aryl hydrazines has been demonstrated. Moreover, the generated tetrahydropyridazine further participated in a cycloaddition reaction with donor-acceptor cyclopropanes to furnish hexahydropyrrolo[1,2-b]pyridazines. We also performed these two steps in one pot in a consecutive manner. In addition, a monodecarboxylation reaction of hexahydropyrrolo[1,2-b]pyridazine was achieved with a good yield.
Synthesis and cytotoxic activities of goniothalamins and derivatives
Weber, Anja,D?hl, Katja,Sachs, Julia,Nordschild, Anja C.M.,Schr?der, Dennis,Kulik, Andrea,Fischer, Thomas,Schmitt, Lutz,Teusch, Nicole,Pietruszka, J?rg
, p. 6115 - 6125 (2017/09/30)
Substituted goniothalamins containing cyclopropane-groups were efficiently prepared in high yields and good selectivity. Antiproliferative activity was measured on three human cancer cell lines (A549, MCF-7, HBL-100), to show which of the structural elements of goniothalamins is mandatory for cytotoxicity. We found that the configuration of the stereogenic centre of the δ-lactone plays an important role for cytotoxicity. In our studies only (R)-configured goniothalamins showed antiproliferative activity, whereby (R)-configuration accords to natural goniothalamin (R)-1. Additionally, the δ-lactone needs to be unsaturated whereas our results show that the vinylic double bond is not mandatory for cytotoxicity. Furthermore, with a two-fold in vitro and in vivo strategy, we determined the inhibitory effect of the compounds to the yeast protein Pdr5. Here, we clearly demonstrate that the configuration seems to be of minor influence, only, while the nature of the substituent of the phenyl ring is of prime importance.
Copper-catalyzed regio- and stereoselective intermolecular three-component oxyarylation of allenes
Itoh, Taisuke,Shimizu, Yohei,Kanai, Motomu
, p. 2736 - 2739 (2014/06/09)
A copper(II)-catalyzed intermolecular three-component oxyarylation of allenes using arylboronic acids as a carbon source and TEMPO as an oxygen source is described. The reaction proceeded under mild conditions with high regio- and stereoselectivity and functional group tolerance. A plausible reaction mechanism is proposed, involving carbocupration of allenes, homolysis of the intervening allylcopper(II), and a radical TEMPO trap.
Mechanistic investigation of oxidative Mannich reaction with tert-butyl hydroperoxide. the role of transition metal salt
Ratnikov, Maxim O.,Doyle, Michael P.
supporting information, p. 1549 - 1557 (2013/03/14)
A general mechanism is proposed for transition metal-catalyzed oxidative Mannich reactions of N,N-dialkylanilines with tert-butyl hydroperoxide (TBHP) as the oxidant. The mechanism consists of a rate-determining single electron transfer (SET) that is uniform from 4-methoxy- to 4-cyano-N,N-dimethylanilines. The tert-butylperoxy radical is the major oxidant in the rate-determining SET step that is followed by competing backward SET and irreversible heterolytic cleavage of the carbon-hydrogen bond at the α-position to nitrogen. A second SET completes the conversion of N,N-dimethylaniline to an iminium ion that is subsequently trapped by the nucleophilic solvent or the oxidant prior to formation of the Mannich adduct. The general role of Rh2(cap) 4, RuCl2(PPh3)3, CuBr, FeCl 3, and Co(OAc)2 in N,N-dialkylaniline oxidations by T-HYDRO is to initiate the conversion of TBHP to tert-butylperoxy radicals. A second pathway, involving O2 as the oxidant, exists for copper, iron, and cobalt salts. Results from linear free-energy relationship (LFER) analyses, kinetic and product isotope effects (KIE and PIE), and radical trap experiments of N,N-dimethylaniline oxidation by T-HYDRO in the presence of transition metal catalysts are discussed. Kinetic studies of the oxidative Mannich reaction in methanol and toluene are also reported.
Conformational restriction approach to β-Secretase (BACE1) inhibitors: Effect of a cyclopropane ring to induce an alternative binding mode
Yonezawa, Shuji,Higashino, Kenichi,Tanaka, Yoshikazu,Nakano, Toru,Yamamoto, Takahiko,Yamakawa, Hidekuni,Muto, Chie,Hosono, Motoko,Hattori, Kazunari,Yutsudo, Takashi,Sakagami, Masahiro,Takemoto, Hiroshi,Iwamoto, Hideo,Kondo, Yutaka,Togame, Hiroko,Arisawa, Mitsuhiro,Shuto, Satoshi
, p. 8838 - 8858,21 (2020/09/16)
Improvement of a drugs binding activity using the conformational restriction approach with sp3 hybridized carbon is becoming a key strategy in drug discovery. We applied this approach to BACE1 inhibitors and designed four stereoisomeric cyclopropane compounds in which the ethylene linker of a known amidine-type inhibitor 2 was replaced with chiral cyclopropane rings. The synthesis and biologic evaluation of these compounds revealed that the cis-(1S,2R) isomer 6 exhibited the most potent BACE1 inhibitory activity among them. X-ray structure analysis of the complex of 6 and BACE1 revealed that its unique binding mode is due to the apparent CH-π interaction between the rigid cyclopropane ring and the Tyr71 side chain. A derivatization study using 6 as a lead molecule led to the development of highly potent inhibitors in which the structure-activity relationship as well as the binding mode of the compounds clearly differ from those of known amidine-type inhibitors.
Mechanistic studies on au(I)-catalyzed [3,3]-sigmatropic rearrangements using cyclopropane probes
Mauleon, Pablo,Krinsky, Jamin L.,Toste, F. Dean
supporting information; experimental part, p. 4513 - 4520 (2009/09/30)
A comparative study of the Au(I)-catalyzed [3,3]-sigmatropic rearrangement of propargylic esters and propargyl vinyl ethers is described. Stereochemically defined cyclopropanes are employed as mechanistic probes to provide new synthetic and theoretical data concerning the reversibility of this type of rearrangement. Factors controlling the structure-reactivity relationship of Au(I)-coordinated allenes have been examined, therebyallowing for controlled access to orthogonal reactivity.
