57680-87-2Relevant academic research and scientific papers
Enhancing effects of salt formation on catalytic activity and enantioselectivity for asymmetric hydrogenation of isoquinolinium salts by dinuclear halide-bridged iridium complexes bearing chiral diphosphine ligands
Kita, Yusuke,Yamaji, Kenta,Higashida, Kosuke,Sathaiah, Kandula,Iimuro, Atuhiro,Mashima, Kazushi
, p. 1915 - 1927 (2015/01/30)
Asymmetric hydrogenation of 1- and 3-substituted and 1,3-disubstituted isoquinolinium chlorides using triply halide-bridged dinuclear iridium complexes [{Ir(H)(diphosphine)} 2(μ -Cl)3]Cl has been achieved by the strategy of HCl salt formation of isoquinolines to afford the corresponding chiral 1,2,3,4-tetrahydroisoquinolines (THIQs) in high yields and with excellent enantioselectivities after simple basic workup. The effects of salt formation have been investigated by time-course experiments, which revealed that the generation of isoquinolinium chlorides clearly prevented formation of the catalytically inactive dinuclear trihydride complex, which was readily generated in the catalytic reduction of salt-free isoquinoline substrates. Based on mechanistic investigations, including by 1H and 31P{1H} NMR studies and the isolation and characterization of several intermediates, the function of the chloride anion of the isoquinolinium chlorides has been elucidated, allowing us to propose a new outer-sphere mechanism involving coordination of the chloride anion of the substrates to an iridium dihydride species along with a hydrogen bond between the chloride ligand and the N-H proton of the substrate salt.
Binding mode and structure-activity relationships around direct inhibitors of the Nrf2-Keap1 complex
Jnoff, Eric,Albrecht, Claudia,Barker, John J.,Barker, Oliver,Beaumont, Edward,Bromidge, Steven,Brookfield, Frederick,Brooks, Mark,Bubert, Christian,Ceska, Tom,Corden, Vincent,Dawson, Graham,Duclos, Stephanie,Fryatt, Tara,Genicot, Christophe,Jigorel, Emilie,Kwong, Jason,Maghames, Rosemary,Mushi, Innocent,Pike, Richard,Sands, Zara A.,Smith, Myron A.,Stimson, Christopher C.,Courade, Jean-Philippe
, p. 699 - 705 (2014/05/06)
An X-ray crystal structure of Kelch-like ECH-associated protein (Keap1) co-crystallised with (1S,2R)-2-[(1S)-1-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl) methyl]-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]cyclohexane-1-carboxylic acid (compound (S,R,S)-1 a) was obtained. This X-ray crystal structure provides breakthrough experimental evidence for the true binding mode of the hit compound (S,R,S)-1 a, as the ligand orientation was found to differ from that of the initial docking model, which was available at the start of the project. Crystallographic elucidation of this binding mode helped to focus and drive the drug design process more effectively and efficiently. To dock or not to dock? Nrf2 has become an attractive neuroprotective target, as the Nrf2 pathway provides a natural cell defense mechanism against damage. Targeting its physiological negative modulator Keap1 with small molecules may allow Nrf2 to play its protective role. To this end, an X-ray structure of Keap1 co-crystallised with compound (S,R,S)-1 a was obtained, elucidating its binding mode, which in turn helped to drive the drug design process.
Expanded substrate scope and catalyst optimization for the catalytic kinetic resolution of N-heterocycles
Hsieh, Sheng-Ying,Binanzer, Michael,Kreituss, Imants,Bode, Jeffrey W.
supporting information, p. 8892 - 8894 (2012/11/07)
The scope, reactivity, and selectivity of the chiral hydroxamic acid-catalyzed kinetic resolution of chiral amines are improved by a new catalyst structure and a more environmentally friendly reaction protocol. In addition to increasing selectivity across all substrates, these conditions make possible the resolution of N-heterocycles containing lactams or other basic functional groups that can inhibit the catalyst.
Determination of ring conformation in 1-benzyl-1,2,3,4- tetrahydroisoquinolines and a new synthesis of the chiral compounds
Shinohara, Tatsumi,Takeda, Akira,Toda, Jun,Sano, Takehiro
, p. 430 - 433 (2007/10/03)
The conformation of the piperideine ring in 1-benzyl-1,2,3,4- tetrahydroisoquinolines was determined as 2H3 form with a pseudoaxial position of the 1-benzyl group by circular dichroism (CD) spectral comparison with 1-methyl-1,2,3,4-tetrahydroisoquinolines. The chiral center at C-1 of 1,2,3,4-tetrahydroisoquinoline (TIQ) was constructed in an unambiguous manner by applying a new method of TIQ synthesis utilizing the Pummerer reaction as a key step. Enantiomerically pure (R)- and (S)-1-methyl- and 1- benzyltetrahydroisoquinolines (1) were prepared starting from readily available chiral amines (2) in good overall yields.
New strategies for enantioselective syntheses of 1-alkyl- and 1,4-dialkyl-1,2,3,4-tetrahydroisoquinolines: Diastereoselective additions of nucleophiles and electrophiles to isoquinoline mediated by an easily resolved and recycled chiral transition metal auxiliary
Richter-Addo, George B.,Knight, D. Andrew,Dewey, Michael A.,Arif, Atta M.,Gladysz
, p. 11863 - 11873 (2007/10/02)
The chiral rhenium isoquinoline complex [(η5-C5H5)Re(NO)(PPh 3)(iso-NC9H7)]+ TfO- (1) and (CH3)3-SiCH2Li give the addition product (η5-C5H5)Re(NO)(PPh3)(N?CH = CHC(CH)4CCHCH2Si(CH3)3) (2) in 71% yield as a 94:6 SS,RR/SR,RS diastereomer mixture. Similar reactions with RMgX (R = (CH3)2CH, CH3CH2, C6H5CH2, CH3(CH2)2, CH3, CH3(CH2)3) give analogous adducts (3-8) as 89-82:11-18 diastereomer mixtures. Reactions of 2 and ROTf (R = H/D, (CH3)3SiCH2, CH3) give alkyl-1,4-dihydroisoquinoline complexes [(η5-C5H5)Re(NO)-(PPh3)(N = CHCHRC(CH)4CCHCH2Si(CH3)3)] + TfO- in 84-72% yields as 94:6 diastereomer mixtures. Related complexes are prepared from 3-5 and HOTf. These react with NaBH4/CH3OH to give alkyl-1,2,3,4-tetrahydroisoquinoline complexes, which are in turn treated with (CH3CH2)4N+ CN- to give (η5-C5H5)Re(NO)(PPh3)(CN) (17) and the title compounds. A reaction sequence starting with (+)-(S)-1 and (CH3)3SiCH2Li yields (+)-(SS)-NHCH2-CH(CH2Si(CH3) 3)C(CH)4CCHCH2Si(CH3)3 (84% overall, 88% ee) and (+)-(S)-17 (82%, >98% ee). Other optically active alkyl tetrahydroisoquinolines are similarly prepared. Complexes 17 and (+)-(S)-17 are converted to (η5-C5H5)Re(NO)(PPh3)(CH 3) (CH3OTf/NaBH4; 88-53%) and thence to 1 or (+)-(S)-1 (92-74%, >98% ee). A crystal structure and other data confirm the configurations assigned to the preceding compounds.
Chiral Dipole-Stabilized Anions: Experiment and Theory in Benzylic and Allylic Systems. Stereoselective Deprotonations, Pyramidal Inversions, and Stereoselective Alkylations of Lithiated (Tetrahydroisoquinolyl)oxazolines
Rein, Kathleen,Goicoechea-Pappas, Marta,Anklekar, Tarakeshwar V.,Hart, Georgina C.,Smith, Gregory A.,Gawley, Robert E.
, p. 2211 - 2217 (2007/10/02)
The stereoselective alkylation of chiral (tetrahydroisoquinolyl)oxazolines has been investigated.We report the details of this investigation, including an examination of the effect of both temperature and oxazoline substituent structure on the alkylation diastereoselectivity, a comparison of monodentate vs bidentate chelation of the organolithium, an evaluation of the effect of solvent and chelating solvent additives, the regiochemistry of alkylation of (3,4-dehydropiperidino)oxazolines, lithiation-alkylation experiments on stereoselectively deuterated monodentate and bidentate isoquinolinolyloxazolines, and semiempirical molecular orbital calculations on the organolithium diastereomers 13a,b.There are two distinct stereoselective processes involved in the overall transformation. the proposed mechanism includes an oxazoline-alkyllithium coordination complex that controls the selectivity of the deprotonation step, whereas the selectivity of the electrophilic quench is governed by effects that are as yet undetermined.
ENANTIOSELECTIVE ALKYLATION OF α-AMINO CARBANIONSTHE SYNTHESIS OF (S)-1-ALKYL-1,2,3,4 TETRAHYDROISOQUINOLINES
Meyers, A. I.,Fuentes, Lelia M.,Kubota, Yoshikazu
, p. 1361 - 1370 (2007/10/02)
A series of chiral amino alcohols transformed into the formamidine derivative of 1,2,3,4-tetrahydroisoquinolines were evaluated as chiral dipole-stabilized anions.Alkylation with alkyl halides provided the 1-alkyl-1,2,3,4-tetrahydroisoquinolines in both e
