- Synthesis method of lobeline
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The invention discloses a synthesis method of lobeline and belongs to the technical field of organic synthesis. The synthesis method comprises the following steps: sequentially carrying out ring opening reaction, oxidization reaction, dehydration reaction, addition reaction, reduction reaction, protection reaction, substitution reaction, hydrolysis reaction, coupling reaction and hydrolysis ring closing reaction to prepare 2-[(2R,6S)-6-[(2S)-2-hydroxyl-2-phenethyl]-1-methylpiperidine]-1-acetophenone. According to the synthesis method disclosed by the invention, a whole technological route is simple, raw materials are cheap and easy to obtain, the cost is low, reaction conditions are mild, the operation is simple, the chiral purity is high and the yield is high; a chiral center is synthesized through simple chemical reaction and an expensive chiral catalyst is not used, so that the cost is reduced; in the whole technological route, the raw materials are cheap and easy to obtain, the cost is low, the technology is simple, the reaction conditions are mild, the operation is simple and the total yield is high.
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- Mannich-type Reactions of Cyclic Nitrones: Effective Methods for the Enantioselective Synthesis of Piperidine-containing Alkaloids
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Even though there are dozens of biologically active 2-substituted and 2,6-disubstituted piperidines, only a limited number of approaches exist for their synthesis. Herein is described two Mannich-type additions to nitrones, one using β-ketoacids under catalyst-free conditions and another using methyl ketones in the presence of chiral thioureas, which can generate a broad array of such 2-substituted materials, as well as other ring variants, in the form of β-N-hydroxy-aminoketones. Both processes have broad scope, with the latter providing products with high enantioselectivity (up to 98 %). The combination of these methods, along with other critical steps, has enabled 8-step total syntheses of the 2,6-disubstituted piperidine alkaloids (?)-lobeline and (?)-sedinone.
- Lisnyak, Vladislav G.,Lynch-Colameta, Tessa,Snyder, Scott A.
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p. 15162 - 15166
(2018/10/26)
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- 2-[(2R, 6S)-6-[(2S)-2-hydroxy-2-phenethyl]-1-pipecoline]-1-hypnone synthesis method
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The invention discloses a 2-[(2R, 6S)-6-[(2S)-2-hydroxy-2-phenethyl]-1-pipecoline]-1-hypnone synthesis method, and belongs to the field of organic synthesis. (1S, 2S)-1, 2-diphenyl diaminoethane serving as a raw material is subjected to acylation, substitution and the like to prepare chiral amine catalysts. A main route totally includes two steps: synthesizing glutaraldehyde, benzoyl acetic acid and methylamine hydrochloride to form cis-lobelanine; performing asymmetric selective reduction synthesis of 2-[(2R, 6S)-6-[(2S)-2-hydroxy-2-phenethyl]-1-pipecoline]-1-hypnone under mild reaction conditions and under the action of the catalysts. The raw material in the whole process route is cheap and easy to obtain, the catalysts can be recycled and can continue to be used, and the synthesis method is low in cost, simple in process, mild in reaction condition, convenient in operation and high in total yield.
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Paragraph 0045; 0046; 0047; 0054; 0055
(2017/06/02)
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- Lobeline esters as novel ligands for neuronal nicotinic acetylcholine receptors and neurotransmitter transporters
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Vesicular monoamine transporter-2 (VMAT2) is a viable target for development of pharmacotherapies for psychostimulant abuse. Lobeline (1) is a potent antagonist at α4β2* nicotinic acetylcholine receptors, has moderate affinity (Ki = 5.46 μM) for VMAT2, and is being investigated currently as a clinical candidate for treatment of psychostimulant abuse. A series of carboxylic acid and sulfonic acid ester analogs 2-20 of lobeline were synthesized and evaluated for interaction with α4β2* and α7* neuronal nicotinic acetylcholine receptors (nAChRs), the dopamine transporter (DAT), serotonin transporter (SERT) and VMAT2. Both carboxylic acid and sulfonic acid esters had low affinity at α7* nAChRs. Similar to lobeline (Ki = 4 nM), sulfonic acid esters had high affinity at α4β2* (Ki = 5-17 nM). Aromatic carboxylic acid ester analogs of lobeline (2-4) were 100-1000-fold less potent than lobeline at α4β2* nAChRs, whereas aliphatic carboxylic acid ester analogs were 10-100-fold less potent than lobeline at α4β2*. Two representative lobeline esters, the 10-O-benzoate (2) and the 10-O-benzenesulfonate (10) were evaluated in the 36Rb+ efflux assay using rat thalamic synaptosomes, and were shown to be antagonists with IC50 values of 0.85 μM and 1.60 μM, respectively. Both carboxylic and sulfonic acid esters exhibited a range of potencies (equipotent to 13-45-fold greater potency compared to lobeline) for inhibiting DAT and SERT, respectively, and like lobeline, had moderate affinity (Ki = 1.98-10.8 μM) for VMAT2. One of the more interesting analogs, p-methoxybenzoic acid ester 4, had low affinity at α4β2* nAChRs (Ki = 19.3 μM) and was equipotent with lobeline, at VMAT2 (Ki = 2.98 μM), exhibiting a 6.5-fold selectivity for VMAT2 over α4β2 nAChRs. Thus, esterification of the lobeline molecule may be a useful structural modification for the development of lobeline analogs with improved selectivity at VMAT2.
- Hojahmat, Marhaba,Horton, David B.,Norrholm, Seth D.,Miller, Dennis K.,Grinevich, Vladimir P.,Deaciuc, Agripina Gabriela,Dwoskin, Linda P.,Crooks, Peter A.
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experimental part
p. 640 - 649
(2010/05/02)
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- Synthesis of (-)-lobeline via enzymatic desymmetrization of lobelanidine
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The bioactive alkaloid (-)-lobeline was synthesized via the stereoselective acylation (desymmetrization) of meso-lobelanidine by vinyl acetate in the presence of Candida antarctica lipase B.
- Chenevert, Robert,Morin, Pierre
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experimental part
p. 1837 - 1839
(2009/05/26)
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- Pd-catalyzed enantioselective aerobic oxidation of secondary alcohols: Applications to the total synthesis of alkaloids
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Enantioselective syntheses of the alkaloids (-)-aurantioclavine, (+)-amurensinine, (-)-lobeline, and (-)- and (+)-sedamine are described. The syntheses demonstrate the effectiveness of the Pd-catalyzed asymmetric oxidation of secondary alcohols in diverse contexts and the ability of this methodology to set the absolute configuration of multiple stereocenters in a single operation. The utility of an aryne C-C insertion reaction in accessing complex polycyclic frameworks is also described.
- Krishnan, Shyam,Bagdanoff, Jeffrey T.,Ebner, David C.,Ramtohul, Yeeman K.,Tambar, Uttam K.,Stoltz, Brian M.
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supporting information; experimental part
p. 13745 - 13754
(2009/02/06)
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- Process for manufacturing of chiral lobelin
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The present invention relates to a shortened process for preparing L-lobeline by rhodium-catalysed asymmetric hydrogenation on an industrial scale.
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Page/Page column 2-3
(2008/06/13)
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- A highly stereoselective asymmetric synthesis of (-)-lobeline and (-)-sedamine
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A highly stereoselective asymmetric synthesis of (-)-sedamine and (-)-lobeline is described from benzaldehyde in 16 and 17 steps with an overall yield of 20% and 14%, respectively. The key intermediate syn-3,4-epoxyalcohol was prepared in a highly diastereomeric fashion (>99% ee, dr) and served as a common intermediate for both alkaloids.
- Felpin, Francois-Xavier,Lebreton, Jacques
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p. 9192 - 9199
(2007/10/03)
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