Total Synthesis of (−)-Hippodamine by Stereocontrolled Construction of Azaphenalene Skeleton Based on Extended One-Pot Asymmetric Azaelectrocyclization
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Abstract:
The first asymmetric total synthesis of (−)-hippodamine has been accomplished via the concise construction of its azaphenalene core, which is featured by the 2,4,6-chiral piperidine synthesis based on one-pot asymmetric azaelectrocyclization in the partially activated substituent system and the subsequent intramolecular Mannich reaction.Keywords:
Piperidine
Mannich reaction
Skeleton (computer programming)
Abstract: Piperidine alkaloids are members of the alkaloid family that is characterized by the presence of a six-membered nitrogen-containing heterocycle. Piperidine alkaloids are found mainly in plants and often exhibit interesting biological and pharmacological activities. Despite the accumulation of these natural products in plants, relatively low quantities of alkaloids are produced in absolute terms and thus synthesis of alkaloids and derivatives thereof remains relevant to identify targets for drug discovery. Throughout the years, researchers have come up with a myriad of methods to synthesize piperidine derivatives. This review describes methods that employ stereoselective Mannich reactions to create the core of piperidine alkaloids. Asymmetric induction in the Mannich reaction has been achieved by a range of methods that have been divided into three conceptual approaches: (1) chiral pool-based (internal asymmetric induction), (2) chiral auxiliary-based (relayed asymmetric induction) and (3) asymmetric catalysis-based (external asymmetric induction). Of each approach, we describe the reaction mechanism and rationalize the stereochemical outcome of the Mannich products.
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In the cyclization reaction of 4-hydroxy-4-[2-(N/-substituted carbamoyl) aminophenyl] piperidine derivatives (3) by treatment with acid, 2-amino-spiro [4H/-3, 1-benzoxazine-4, 4′-piperidine] derivatives (4) were obtained.One of the products, 2-methylamino-spiro [4H/-3, 1-benzoxazine-4, 4′-piperidine] (4g), was converted to 1-(2-hydroxy-2-phenethyl)-2-methylamino-spiro [4H/-3, 1-benzoxazine-4, 4′-piperidine] derivatives (12), which are our target compounds for pharmacological screening tests on antihypertensive activity. However, these compounds did not show any remarkable antihypertensive activity.
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Abstract Benzoyl piperidine product: Benzoyl piperidine thus obtained is a straw‐colored viscous liquid. Upon long standing or seeding with crystalline benzoyl piperidine reactant: 170 g. of piperidine (2.0 moles)
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Piperidine is one of pharmacologically active biogenic amines. While two pathways for piperidine production have been reported, little is known about metabolism of the compound. In the present study, piperidine and its hydroxylated, conjugated and unknown metabolites were detected in rat urine by radiochromatographic analysis. Using GC-MS technique, it was confirmed that 3-hydroxypiperidine and 4-hydroxypiperidine are major metabolites of piperidine of either exogenous or endogenous origin. The findings substantiate the existence of a mechanism which inactivates piperidine in the living body, since both metabolites lack the potent pharmacological activities as those induced by piperidine.
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Piperidine is a saturated heterocyclic ring, considered as a privileged scaffold in view of its role in wide range of biological activities. Piperidine is good candidate molecule for obtaining potent antioxidant agents. The planar nature of this heterocyclic nucleus allows the introduction of substituent groups at different positions on the ring. In the present review, the antioxidant profile of piperidine containing compounds has been focused. The compounds were classified into naturally occurring piperidines, unsaturated piperidines, N-substituted piperidines, piperamides, piperanols, piperidine oximes, and hydrazides.
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Pyrrolidine
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Mannich reaction
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Abstract i) The addition of bromine to β-benzoylethylamine hydrochloride was studied. It was concluded that bromine molecule was added to β-benzoylethylamine hydrochloride in the form linking astride to the carbionium ion and the lone pair of electrons of the nitrogen atom, both of which were formed by prototropy. ii) The bromine addition product of β-benzoylethylamine hydrochloride was treated with alkali for a little while to give N-bromo-β-benzoylethylamine which was very unstable and decomposed to give β-benzoylethylamine hydrobromide.
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ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTThe Preparation of Some Piperidine Derivatives by the Mannich ReactionC. R. Noller and V. BaliahCite this: J. Am. Chem. Soc. 1948, 70, 11, 3853–3855Publication Date (Print):November 1, 1948Publication History Published online1 May 2002Published inissue 1 November 1948https://pubs.acs.org/doi/10.1021/ja01191a092https://doi.org/10.1021/ja01191a092research-articleACS PublicationsRequest reuse permissionsArticle Views1248Altmetric-Citations210LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Piperidine
Mannich reaction
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