Synthesis, resolution and absolute configuration of 4-amino-3-phenylpiperidine

Schramm, Heiko; Christoffers, Jens

doi:10.1016/j.tetasy.2009.10.019

Cited by 14 publications

(5 citation statements)

References 13 publications

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“…From the aldehyde 9 the corresponding oxime was formed under buffered conditions [ 30 ] and the crude material was directly submitted to reduction with LiAlH 4 [ 31 ] to furnish amine 10 as a practically pure compound (72%) ( Scheme 3 ). The conversion of amine 10 with chlorouracil 3 proceeded with NEt 3 as base in EtOH at elevated temperature.…”

Section: Resultsmentioning

confidence: 99%

A robust synthesis of 7,8-didemethyl-8-hydroxy-5-deazariboflavin

Bender¹,

Mouritsen²,

Christoffers³

2016

Beilstein J. Org. Chem.

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SummaryThe biosynthetic precursor of redox cofactor F420, 7,8-didemethyl-8-hydroxy-5-deazariboflavin, was prepared in four steps from 6-chlorouracil, 2-chloro-4-hydroxybenzaldehyde and bis-isopropylidene protected D-ribose. The latter aldehyde was transformed to the corresponding protected ribitylamine via the oxime, which was submitted to reduction with LiAlH4. Key advantage compared to previous syntheses is the utilization of a polyol-protective group which allowed the chromatographic purification of a key-intermediate product providing the target compound with high purity.

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Section: Resultsmentioning

confidence: 99%

A robust synthesis of 7,8-didemethyl-8-hydroxy-5-deazariboflavin

Bender¹,

Mouritsen²,

Christoffers³

2016

Beilstein J. Org. Chem.

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“…Aldehyde 4 was prepared by acid‐catalyzed conjugate addition of N ‐Boc‐protected allylamine to acrolein (67 % yield) as reported previously 11. Oxime formation proceeded under standard conditions15 to give compound 11 (Scheme , 87 %). Of the several known methods for nitrile oxide formation we used chloramine‐T in MeCN at reflux, as recommended by Hassner et al,16 which furnished annulated isoxazoline 8 directly in 74 % yield.…”

Section: Resultsmentioning

confidence: 99%

Nitrile Oxide versus Nitrone – Switching Regioselectivity of Intramolecular 1,3‐Dipolar Cycloadditions towards the Preparation of Aminopiperidinecarboxylates

Würdemann

Christoffers

2013

Eur J Org Chem

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3‐(Allylamino)‐ and 3‐(propargylamino)propanal were converted via the corresponding oximes into nitrile oxides, which readily underwent intramolecular 1,3‐dipolar cycloadditions to furnish a piperidine‐annulated isoxazole or isoxazoline. The annulated isoxazoline was transformed into orthogonally carbamate‐protected cis‐ and trans‐4‐aminopiperidine‐3‐carboxylates, both representing interesting scaffolds for combinatorial chemistry. Through sequences of amidations and deprotections two triply functionalized products were obtained as examples for diversification. After Boc removal, the piperidino‐annulated isoxazole was also subjected to diversifying reactions, such as reductive amination, amidation, and the formation of sulfonamido‐ and ureido‐substituted derivatives.

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“…The relative configuration of these diastereomers were assigned by comparison to literature data and using the coupling constants from the 1 H-NMR spectra. 14) Amine 11e, which has a chloro group on the para position of the benzene ring, was obtained by reduction with LiAlH 4 since dechlorination occurred during reduction with metal sodium.…”

Section: Synthesismentioning

confidence: 99%

Development of κ Opioid Receptor Agonists by Focusing on Phenyl Substituents of 4-Dimethylamino-3-phenylpiperidine Derivatives: Structure–Activity Relationship Study of Matrine Type Alkaloids

Teramoto

Yamauchi

Sasaki

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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A series of new κ opioid receptor (KOR) agonists were developed from the lead compound 4-dimethylamino-1-pentanoylpiperidine (3), a matrine-type alkaloid. Derivatives of 3 were synthesized with a variety of phenyl substituents and evaluated for their antinociceptive effects. Additionally, their selectivity for an opioid receptor was investigated for cis-4c and d, and trans-4g, all of which had high activity exerted through the KOR.Key words antinociceptive effect; kappa opioid receptor; piperidine; matrine; writhing test; mouse We previously reported that (+)-matrine (1) and (+)-allomatrine (2), a typical matrine type lupine alkaloid isolated from some Sophora plants (Leguminosae), have antinociceptive properties identical to those of pentazocine 1) (Fig. 1). The effects of (+)-matrine are mediated mainly through activation of κ opioid receptors (KOR) and partially through μ receptors (MOR), while the effects of (+)-allomatrine are mediated only through activation of KOR.2) Because the skeleton of the matrine type alkaloids differs from those of conventional KOR agonists, such as ethylketocyclazocine, 3) U-50488 4,5) and nalfurafine (TRK-820), 6) they have the potential to be derivatized into novel KOR agonists that may not induce side effects such as dysphoria and psychotomimetic actions 7,8) (Fig. 2). In fact, the structure-activity relationship (SAR) between the antinociceptive effects of these alkaloids and their structures is very interesting. During the development of new KOR agonists, compound 3 was identified as a lead compound by determining the essential structure required for the antinociceptive effects of (+)-matrine.9-11) When compound 3 was derivatized and tested, the antinociceptive effects of 4-dimethylamino-1-pentanoyl-3-phenylpiperidine (4a) were more potent than those of the lead compound 3. On the basis of the Topliss method, 12) we designed and synthesized phenyl derivatives of 4a in an effort to further improve the activity. Herein, we report the synthesis of the derivatives of 4a and their pharmacological effects. SynthesisThe synthetic route to the intermediates, cis-and trans11a-e, is shown in Chart 1. Hydrazones 7a-e were prepared by condensation of commercially available 2,4,6-triisopropylbenzenesulfonyl hydrazide 5 and the respective acetophenones 6a-e. Allylic alcohols 8a-e were obtained through the Shapiro reaction with acrolein.13) Oxidation of 8a-e with MnO 2 yielded the respective dienones, followed by cyclization via a double aza-Michael reaction with benzylamine using microwave irradiation to give piperidones 9a-e.13) Piperidones 9a-e were converted to oximes 10a-e and subsequently reduced with metal sodium in EtOH to yield the separable diastereomers cis-and trans-11a-d, the 3,4-cis (matrine type) and 3,4-trans configuration compounds (allomatrine type). The relative configuration of these diastereomers were assigned by comparison to literature data and using the coupling constants from the 1 H-NMR spectra. 14) Amine 11e, which has a chloro group on the para position of the be...

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Synthesis, resolution and absolute configuration of 4-amino-3-phenylpiperidine

Cited by 14 publications

References 13 publications

A robust synthesis of 7,8-didemethyl-8-hydroxy-5-deazariboflavin

A robust synthesis of 7,8-didemethyl-8-hydroxy-5-deazariboflavin

Nitrile Oxide versus Nitrone – Switching Regioselectivity of Intramolecular 1,3‐Dipolar Cycloadditions towards the Preparation of Aminopiperidinecarboxylates

Development of κ Opioid Receptor Agonists by Focusing on Phenyl Substituents of 4-Dimethylamino-3-phenylpiperidine Derivatives: Structure–Activity Relationship Study of Matrine Type Alkaloids

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