- FORMATION OF N'-ETHYL-S-NORNICOTINE BY TRANSFORMED ROOT CULTURES OF NICOTIANA RUSTICA
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N-Ethylputrescine dihydrochloride has been synthesized by an improved procedure and it is converted by transformed root cultures of Nicotiana rustica into the nicotine analogue, N'-ethyl-S-nornicotine, preferentially in the optically active S-form, with an efficiency similar to that of the corresponding natural process.
- Boswell, Henry D.,Watson, Allan B.,Walton, Nicholas J.,Robins, David J.
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- A Methyl Scan of the Pyrrolidinium Ring of Nicotine Reveals Significant Differences in Its Interactions with a7 and a4b2 Nicotinic Acetylcholine Receptors
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The two major nicotinic acetylcholine receptors (nAChRs) in the brain are the a4b2 and a7 subtypes. A "methyl scan" of the pyrrolidinium ring was used to detect differences in nicotine's interactions with these two receptors. Each methylnicotine was investigated using voltage-clamp and radioligand binding techniques. Methylation at each ring carbon elicited unique changes in nicotine's receptor interactions. Replacing the 19-N-methyl with an ethyl group or adding a second 19-N-methyl group significantly reduced interaction with a4b2 but not a7 receptors. The 29-methylation uniquely enhanced binding and agonist potency at a7 receptors. Although 39- A nd 59-trans-methylations were much better tolerated by a7 receptors than a4b2 receptors, 49-methylation decreased potency and efficacy at a7 receptors much more than at a4b2 receptors. Whereas cis-59-methylnicotine lacked agonist activity and displayed a low affinity at both receptors, trans-59-methylnicotine retained considerable a7 receptor activity. Differences between the two 59-methylated analogs of the potent pyridyl oxymethylene-bridged nicotine analog A84543 were consistent with what was found for the 59-methylnicotines. Computer docking of the methylnicotines to the Lymnaea acetylcholine binding protein crystal structure containing two persistent waters predicted most of the changes in receptor affinity that were observed with methylation, particularly the lower affinities of the cis-methylnicotines. The much smaller effects of 19-, 39-, and 59-methylations and the greater effects of 29- A nd 49-methylations on nicotine a7 nAChR interaction might be exploited for the design of new drugs based on the nicotine scaffold.
- Xing, Hong,Andrud, Kristin W.,Soti, Ferenc,Rouchaud, Anne,Jahn, Stephan C.,Lu, Ziang,Cho, Yeh-Hyon,Habibi, Sophia,Corsino, Patrick,Slavov, Svetoslav,Rocca, James R.,Lindstrom, Jon M.,Lukas, Ron J.,Kem, William R.
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supporting information
p. 168 - 180
(2020/09/12)
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- Development of an R-selective amine oxidase with broad substrate specificity and high enantioselectivity
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Amine oxidases are useful bio-catalysts for the synthesis of enantiomerically pure 1°, 2° and 3° chiral amines. Enzymes in this class (e.g., MAO-N from Aspergillus niger) reported previously have been shown to be highly S selective. Herein we report the development of an enantiocomplementary R-selective amine oxidase based on 6-hydroxy-D-nicotine oxidase (6-HDNO) with broadened substrate scope and high enantioselectivity. The engineered 6-HDNO enzyme has been applied to the preparative deracemisation of a range of racemic amines to yield S-configured products, for example, (S)-nicotine, in high ee. Nicotine rush: An R-selective amine oxidase based on 6-hydroxy-D-nicotine oxidase (6-HDNO) with broadened substrate scope and high enantioselectivity has been developed. The engineered 6-HDNO enzyme is applied to the preparative deracemization of a range of racemic amines to yield S-configured products, for example, (S)-nicotine, in high ee.
- Heath, Rachel S.,Pontini, Marta,Bechi, Beatrice,Turner, Nicholas J.
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p. 996 - 1002
(2014/05/06)
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- Highly enantioselective borane reduction of heteroaryl and heterocyclic ketoxime ethers catalyzed by novel spiroborate ester derived from diphenylvalinol: Application to the synthesis of nicotine analogues
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(Chemical Equation Presented) An asymmetric synthesis for the preparation of nonracemic amines bearing heterocyclic and heteroaromatic rings is described. A variety of important enantiopure thionyl and arylalkyl primary amines were afforded by the borane-mediated enantioselective reduction of O-benzyl ketoximes using 10% of catalyst 10 derived from (S)-diphenylvalinol and ethylene glycol with excellent enantioselectivity, in up to 99% ee. The optimal condition for the first asymmetric reduction of 3- and 4-pyridyl-derived O-benzyl ketoxime ethers was achieved using 30% of catalytic loading in dioxane at 10°C. (S)-N-ethylnornicotine (3) was also successfully synthesized from the TIPS-protected (S)-2-amino-2-pyridylethanol in 97% ee.
- Huang, Kun,Merced, Francisco G.,Ortiz-Marciales, Margarita,Melendez, Hector J.,Correa, Wildeliz,De Jesus, Melvin
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p. 4017 - 4026
(2008/09/21)
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