(2-Piperidine)- and (2-pyrrolidine)ethanones and -ethanols as inhibitors of blood platelets aggregation

Jm, Grisar; Gp, Claxton; Kt, Stewart; Rd, MacKenzie; Kariya, Takashi

doi:10.1021/jm00232a006

J. Med. Chem.

1976

DOI: 10.1021/jm00232a006

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(2-Piperidine)- and (2-pyrrolidine)ethanones and -ethanols as inhibitors of blood platelets aggregation

Grisar Jm¹,

Claxton Gp²,

Stewart Kt³

et al.

Abstract: (E)-4-[4-(Methylthio)phenyl]-1-(2-piperidinyl)-3-buten-2-one hydrochloride (44, RMI 14 133A) was found to inhibit ADP-induced aggregation of blood platelets. It was selected from a large series of (2-piperidinyl)- and (2-pyrrolidinyl)ethanones synthesized by a modified Schopf reaction from enolate magnesium salts of beta-keto acids and 2,3,4,5-tetrahydropyridine trimer or 3,4-dihydro-2H-pyrrole trimer, respectively. Evaluation of the compounds was carried out in vitro on human blood platelets. Structure-activi… Show more

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Cited by 9 publications

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Mannich‐type Reactions of Cyclic Nitrones: Effective Methods for the Enantioselective Synthesis of Piperidine‐containing Alkaloids

2018

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Even though there are dozens of biologically active 2-substituted and 2,6-disubstituted piperidines,o nly al imited number of approaches exist for their synthesis.H erein is described two Mannich-type additions to nitrones,one using bketoacids under catalyst-free conditions and another using methyl ketones in the presence of chiral thioureas,w hichc an generate abroad arrayofs uch 2-substituted materials,a swell as other ring variants,i nt he form of b-N-hydroxy-aminoketones.B oth processes have broad scope,w ith the latter providing products with high enantioselectivity (up to 98 %). The combination of these methods,a long with other critical steps,has enabled 8-step total syntheses of the 2,6-disubstituted piperidine alkaloids (À)-lobeline and (À)-sedinone. Scheme 1. Selected piperidine-containing natural products, precedent for enantioselective functionalizations to generate such heterocycles, and two unique approaches based on using nitrones.

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Mannich‐type Reactions of Cyclic Nitrones: Effective Methods for the Enantioselective Synthesis of Piperidine‐containing Alkaloids

2018

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Mannich‐type Reactions of Cyclic Nitrones: Effective Methods for the Enantioselective Synthesis of Piperidine‐containing Alkaloids

2018

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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.

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Asymmetrische α‐Amidoalkylierung: Synthesen enantiomerenreiner α‐substituierter Piperidine mit 1‐Camphanoyl‐1,2,3,4‐tetrahydropyridin

Wanner

Kärtner

1987

Archiv der Pharmazie

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Ph 330[In einer neuartigen. asymmetrischen Synthese wird das homochirale Enamid I diastereoselektiv mit den Silylenolethern 5a-e zu den Amidoalkylierungsprodukte 6/7a-e verknüpft, die für die Gewinnung enantiomerenreiner in a-Stellung R-und S-konfigurierter Piperidinalkohole 9, des Piperidinketons 13, der (R)-Homopipecolinsäure 12R und des Alkaloids (+ )-Sedamin IORR eingesetzt werden.Asymmetrie a-Amidoalkylation. Syntheses ofEnantiomerieally Pure a-Substituted Piperidines with I-Camphanoyl-I,2,3,4-tetrahydropyridine In a novel asymmetrie synthesis the homoehiral enamide I is coupled with the silyl enol ethers 5a-e in a diastercoselectivc fashion to afford the amidoalkylation produets 6/7a-e. These are employed in the synthesis of enantiomerically pure, in a-position Rand S-eonfigurated piperidine alcohols 9, the piperidine ketone 13, (R)-homopipccolie acid 12R and the alkaloid (+ )-sedamine IORR.2-Piperidylethanol ist als Strukturelement in Substanzen mit pharmakologischen Wirkungen weit verbreitet und kommt z. B. in dem Blutplättchenaggregationshemmer 2 ) Ia, dem AntimalariamitteP) Ib und dem ausführlich untersuchten Analgetikum II4) vor. Auch in Naturstoffen wie (-)-Sedamin (IIIa)5) aus Sedum acre und (+ )-Norallosedamin 6a ) (IIIb) aus Lobelia iriflata ist es anzutreffen.

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(2-Piperidine)- and (2-pyrrolidine)ethanones and -ethanols as inhibitors of blood platelets aggregation

Cited by 9 publications

References 3 publications

Mannich‐type Reactions of Cyclic Nitrones: Effective Methods for the Enantioselective Synthesis of Piperidine‐containing Alkaloids

Mannich‐type Reactions of Cyclic Nitrones: Effective Methods for the Enantioselective Synthesis of Piperidine‐containing Alkaloids

Mannich‐type Reactions of Cyclic Nitrones: Effective Methods for the Enantioselective Synthesis of Piperidine‐containing Alkaloids

Asymmetrische α‐Amidoalkylierung: Synthesen enantiomerenreiner α‐substituierter Piperidine mit 1‐Camphanoyl‐1,2,3,4‐tetrahydropyridin

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