938-36-3Relevant academic research and scientific papers
Quantification of the nucleophilic reactivity of nicotine
Byrne, Peter A.,Kobayashi, Shinjiro,Breugst, Martin,Laub, Hans,Mayr, Herbert
, p. 759 - 767 (2016)
Rate and equilibrium constants of the reactions of nicotine and structurally related compounds with benzhydrylium ions have been determined UV-Vis spectroscopically using stopped-flow and laser-flash techniques. The pyridine nitrogen of nicotine was identified as the site of thermodynamically and kinetically controlled attack. Quantum chemical calculations showed that the introduction of a pyrid-3-yl moiety into the 2-position of N-methylpyrrolidine (to give nicotine) reduces the Lewis basicity of the pyrrolidine ring by 24 kJ mol?1, whereas the analogous introduction of a phenyl ring decreases this quantity by only 11 kJ mol?1. Copyright
Cu/Mn bimetallic catalysis enables carbonylative Suzuki-Miyaura coupling with unactivated alkyl electrophiles
Pye, Dominic R.,Cheng, Li-Jie,Mankad, Neal P.
, p. 4750 - 4755 (2017/07/10)
A bimetallic system consisting of Cu-carbene and Mn-carbonyl co-catalysts was employed for carbonylative C-C coupling of arylboronic esters with alkyl halides, allowing for the convergent synthesis of ketones. The system operates under mild conditions and exhibits complementary reactivity to Pd catalysis. The method is compatible with a wide range of arylboronic ester nucleophiles and proceeds smoothly for both primary and secondary alkyl iodide electrophiles. Preliminary mechanistic experiments corroborate a hypothetical catalytic mechanism consisting of co-dependent cycles wherein the Cu-carbene co-catalyst engages in transmetallation to generate an organocopper nucleophile, while the Mn-carbonyl co-catalyst activates the alkyl halide electrophile by single-electron transfer and then undergoes reversible carbonylation to generate an acylmanganese electrophile. The two cycles then intersect with a heterobimetallic, product-releasing C-C coupling step.
Stereoselectivity and Structural Characterization of an Imine Reductase (IRED) from Amycolatopsis orientalis
Aleku, Godwin A.,Man, Henry,France, Scott P.,Leipold, Friedemann,Hussain, Shahed,Toca-Gonzalez, Laura,Marchington, Rebecca,Hart, Sam,Turkenburg, Johan P.,Grogan, Gideon,Turner, Nicholas J.
, p. 3880 - 3889 (2016/07/06)
The imine reductase AoIRED from Amycolatopsis orientalis (Uniprot R4SNK4) catalyzes the NADPH-dependent reduction of a wide range of prochiral imines and iminium ions, predominantly with (S)-selectivity and with ee's of up to >99%. AoIRED displays up to 100-fold greater catalytic efficiency for 2-methyl-1-pyrroline (2MPN) compared to other IREDs, such as the enzyme from Streptomyces sp. GF3546, which also exhibits (S)-selectivity, and thus, AoIRED is an interesting candidate for preparative synthesis. AoIRED exhibits unusual catalytic properties, with inversion of stereoselectivity observed between structurally similar substrates, and also, in the case of 1-methyl-3,4-dihydroisoquinoline, for the same substrate, dependent on the age of the enzyme after purification. The structure of AoIRED has been determined in an "open" apo-form, revealing a canonical dimeric IRED fold in which the active site is formed between the N- and C-terminal domains of participating monomers. Co-crystallization with NADPH gave a "closed" form in complex with the cofactor, in which a relative closure of domains, and associated loop movements, has resulted in a much smaller active site. A ternary complex was also obtained by cocrystallization with NADPH and 1-methyl-1,2,3,4-tetrahydroisoquinoline [(MTQ], and it reveals a binding site for the (R)-amine product, which places the chiral carbon within 4 ? of the putative location of the C4 atom of NADPH that delivers hydride to the C? -N bond of the substrate. The ternary complex has permitted structure-informed mutation of the active site, resulting in mutants including Y179A, Y179F, and N241A, of altered activity and stereoselectivity.
Synthesis of 3-Aryl-1-aminopropane Derivatives: Lithiation-Borylation-Ring-Opening of Azetidinium Ions
Casoni, Giorgia,Myers, Eddie L.,Aggarwal, Varinder K.
, p. 3241 - 3253 (2016/09/12)
In situ generated 2-phenyl-azetidinium ylides react with boronic esters to form acyclic γ-dimethylamino tertiary boronic esters. The transformation is believed to involve the formation of a zwitterionic boronate, which subsequently undergoes ring-opening 1,2-migration, which is promoted by the relief of ring strain. Owing to the configurational instability of the initially formed ylides, which appear to be in equilibrium with the open-chain carbene form, the reaction is not stereospecific. The C-B bond of the γ-dimethylamino tertiary boronic esters can be transformed into a variety of functional groups (C-OH, C-vinyl, C-H, C-BF3), thus giving a diverse selection of 3-aryl-1-aminopropanes, which represent a privileged motif among drug molecules.
Gold-catalyzed oxidative cyclization of chiral homopropargyl amides: Synthesis of enantioenriched γ-lactams
Shu, Chao,Liu, Meng-Qi,Wang, Shan-Shan,Li, Long,Ye, Long-Wu
, p. 3292 - 3299 (2013/06/27)
A gold-catalyzed tandem cycloisomerization/oxidation of homopropargyl amides has been developed, which provides ready access to synthetically useful chiral γ-lactams with excellent ee by combining the chiral tert-butylsulfinimine chemistry and gold cataly
Nicotinic pharmacophore: The pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone NH
Blum, Angela P.,Lester, Henry A.,Dougherty, Dennis A.
experimental part, p. 13206 - 13211 (2011/01/03)
Pharmacophore models for nicotinic agonists have been proposed for four decades. Central to these models is the presence of a cationic nitrogen and a hydrogen bond acceptor. It is now well-established that the cationic center makes an important cation-π interaction to a conserved tryptophan, but the donor to the proposed hydrogen bond acceptor has been more challenging to identify. A structure of nicotine bound to the acetylcholine binding protein predicted that the binding partner of the pharmacophore's second component was a water molecule, which also hydrogen bonds to the backbone of the complementary subunit of the receptors. Here we use unnatural amino acid mutagenesis coupled with agonist analogs to examine whether such a hydrogen bond is functionally significant in the α4β2 neuronal nAChR, the receptor most associated with nicotine addiction. We find evidence for the hydrogen bond with the agonists nicotine, acetylcholine, carbamylcholine, and epibatidine. These data represent a completed nicotinic pharmacophore and offer insight into the design of new therapeutic agents that selectively target these receptors.
A chemo-enzymatic route to enantiomerically pure cyclic tertiary amines
Dunsmore, Colin J.,Carr, Reuben,Fleming, Toni,Turner, Nicholas J.
, p. 2224 - 2225 (2007/10/03)
Deracemization of racemic chiral tertiary amines has been achieved by combination of an enantioselective amine oxidase, obtained through directed evolution, and ammonia borane in a one-pot process. Copyright
Selective and catalytic arylation of N-phenylpyrrolidine: sp3 C-H bond functionalization in the absence of a directing group
Sezen, Bengue,Sames, Dalibor
, p. 5284 - 5285 (2007/10/03)
We herein describe our studies on arylation of N-phenylpyrrolidine, which led to the development of a new transformation for the direct and selective arylation of sp3 C-H bonds in the absence of a directing group. In this method, Ru(H)2(CO)(PCy3)3 4 was used as the catalyst, and preliminary mechanistic studies suggested that Ru(Ph)(I)(CO)(PCy3)2 5 is the key intermediate of the catalytic cycle. A large kinetic isotope effect (kH/kD = 5.4) was observed, which supports the proposal that C-H bond metalation is the slow step. Preliminary examination of the substrate scope showed that in addition to N-phenylpyrrolidine, N-methyl- and N-benzylpyrrolidine, as well as N-benzoylpyrrolidine, were arylated under the reaction conditions. Copyright
N-HETEROCYCLYL-SUBSTITUTED AMINO-THIAZOLE DERIVATIVES AS PROTEIN KINASE INHIBITORS
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Page 72, (2010/02/08)
Aminothiazole compounds with N-containing cycloalkyl at the 2-amino position which are represented by the Formula (I), or a pharmaceutically acceptable prodrug of said compound, or pharmaceutically acceptable salt of said compound, modulate and/or inhibit the cell proliferation and activity of protein kinases.
