Alkylation of α-<i>tert</i>-butoxycarbonylamino ketone enolate anions. A useful synthesis of α-alkyl-α-amino ketones, 2-acylpyrrolidines, and 2-acylpiperidines

Guzmán, A.; Quintero, Clara; Muchowski, Joseph M.

doi:10.1139/v91-298

Cited by 13 publications

(6 citation statements)

References 15 publications

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“…[18] In this work, we report the synthesis of the chiral pyrazinone 2 based on the coupling of the chiral amino ketone 3, obtained in an optically pure form, and alanine. Chiral α-aminoisovalerophenone hydrochloride 3 [19,20] was initially prepared (Method A), [17] from -valine N,N-dimethylamide, obtained by the reaction with dimethylamine hydrochloride in the presence of triethylamine and N,N,NЈ,NЈ-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (TBTU) in acetonitrile at room temperature. The crude amide was allowed to react with phenylmagnesium bromide (3 equiv.…”

Section: Resultsmentioning

confidence: 99%

Asymmetric Synthesis of α-Methyl α-Amino Acids through Diastereoselective Alkylation under Mild Reaction Conditions of an Iminic Alanine Template with a 1,2,3,6-Tetrahydro-2-pyrazinone Structure

2000

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(6R)‐6‐Isopropyl‐3‐methyl‐5‐phenyl‐1,2,3,6‐tetrahydro‐2‐pyrazinone, obtained from (R)‐valine and (S)‐alanine, is highly diastereoselectively alkylated at room temperature by: a) activated alkyl halides under solid‐liquid PTC conditions, b) non‐activated alkyl halides with organic bases, c) electrophilic olefins employing both solid−liquid PTC conditions and organic bases, and d) allylic carbonates by means of palladium catalysis under neutral conditions. Enantiomerically pure (S)‐α‐methyl α‐amino acids 8 are obtained by hydrolysis of the alkylated pyrazinones.

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Section: Resultsmentioning

confidence: 99%

Asymmetric Synthesis of α-Methyl α-Amino Acids through Diastereoselective Alkylation under Mild Reaction Conditions of an Iminic Alanine Template with a 1,2,3,6-Tetrahydro-2-pyrazinone Structure

2000

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“…The solid was dissolved in Et 2 O, and HCl gas was allowed to slowly bubble through the solution, yielding a white solid. The solid was collected by filtration and recrystallized from i -PrOH to yield 0.11 g (16%) of 4 as a white solid: mp 220–221 °C (lit . mp 225–227 °C); IR (diamond, cm –1 ) 1685 (CO); 1 H NMR (DMSO- d 6 ) δ 1.44–1.47 (m, 1H, CH), 1.50–1.77 (m, 4H, 2 × CH 2 ), 1.99–2.18 (m, 1H, CH), 2.34–2.40 (m, 1H, CH), 3.18–3.24 (m, 1H, CH), 4.92–5.12 (m, 1H, CH), 7.59 (t, 2H, J = 7.9 Hz, Ar–H), 7.72 (m, 1H, J = 8.5 Hz, Ar–H), 8.05 (dd, J = 7.0 Hz, 2H, ArH), 9.98 (br s, 2H, NH + ).…”

Section: Methodsmentioning

confidence: 99%

“…The solid was collected by filtration and recrystallized from i-PrOH to yield 0.11 g (16%) of 4 as a white solid: mp 220−221 °C (lit. 26…”

Section: ■ Methodsmentioning

confidence: 99%

Synthetic Cathinone Analogues Structurally Related to the Central Stimulant Methylphenidate as Dopamine Reuptake Inhibitors

Yadav-Samudrala

Eltit

Glennon

2019

ACS Chem. Neurosci.

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Synthetic cathinones are, primarily, stimulant drugs of abuse that act at monoamine transporters (e.g., the dopamine transporter or DAT) as releasing agents or as reuptake inhibitors. In the past few years, the emergence of >150 new synthetic cathinones has attracted considerable attention from medical and law enforcement communities. threo-Methylphenidate (tMP), used clinically for the treatment of ADHD and narcolepsy, is also a DAT reuptake inhibitor. tMP is somewhat structurally similar to abused cathinone stimulants, and the structure− activity relationships (SAR) of tMP have been well-defined. Hence, available tMP literature might assist in understanding the SAR of synthetic cathinones, about which less is known. In the present study, we synthesized and examined eight 2-benzoylpiperidine analogues (4, 6− 12) to determine if tMP SAR might be applicable to cathinone SAR. The benzoylpiperidine analogues were evaluated in a competition assay using live-cell imaging against APP + in HEK293 cells stably expressing hDAT and in cells coexpressing DAT and voltage-gated Ca 2+ channels. All compounds were found to be DAT reuptake inhibitors, and a significant correlation was obtained between the potency of the benzoylpiperidines and tMP binding data (r = 0.91), suggesting that the SAR of tMP analogues might be directly applicable to certain synthetic cathinones as DAT reuptake inhibitors.

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“…Starting from 6c (Aldrich) and 7b, 20 compound 8c was prepared in a similar manner as 8a and was used for its subsequent reaction without further purification (crude yield: ∼100%; HPLC: 92% at 214 nm; HPLC/MS: m/z 381 (MH + )).…”

Section: (2s)-2-[(1rs)-1-methyl-2-oxo-2-phenyl-ethylcarbamoyl)pyrroli...mentioning

confidence: 99%

Rationale, Design, and Synthesis of Novel Phenyl Imidazoles as Opioid Receptor Agonists for Gastrointestinal Disorders

et al. 2004

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A small series of novel, imidazoles 4 have been prepared that exhibit very good binding affinities for the delta and mu opioid receptors (ORs), as well as demonstrate potent agonist functional activity at the delta OR. Representative imidazole 4a (K(i) delta = 0.9 nM; K(i) mu = 55 nM; K(i) kappa = 124 nM; EC(50) delta =13-25 nM) was further profiled for OR related in vivo effects. Compound 4a reduced gastrointestinal (GI) propulsive motility in a dose-dependent and naloxone-reversible manner, based on the results of the mouse glass bead expulsion test (3, 5, and 10 mg/kg, ip) and the mouse fecal pellet output test (1 and 3 mg/kg, ip). Compound 4a showed no analgesic activity as measured by the mouse abdominal irritant test (MAIT) when dosed at 100 mg/kg, sc, but did show significant MAIT activity at doses of both 10 microg (40% inhibition) and 100 microg (100% inhibition) when dosed intracerebroventricularly (icv). Taken together, these in vivo results suggest that 4a acts peripherally when dosed systemically, and that these prototypical compounds may prove promising as medicinal leads for GI indications.

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Alkylation of α-tert-butoxycarbonylamino ketone enolate anions. A useful synthesis of α-alkyl-α-amino ketones, 2-acylpyrrolidines, and 2-acylpiperidines

Cited by 13 publications

References 15 publications

Asymmetric Synthesis of α-Methyl α-Amino Acids through Diastereoselective Alkylation under Mild Reaction Conditions of an Iminic Alanine Template with a 1,2,3,6-Tetrahydro-2-pyrazinone Structure

Asymmetric Synthesis of α-Methyl α-Amino Acids through Diastereoselective Alkylation under Mild Reaction Conditions of an Iminic Alanine Template with a 1,2,3,6-Tetrahydro-2-pyrazinone Structure

Synthetic Cathinone Analogues Structurally Related to the Central Stimulant Methylphenidate as Dopamine Reuptake Inhibitors

Rationale, Design, and Synthesis of Novel Phenyl Imidazoles as Opioid Receptor Agonists for Gastrointestinal Disorders

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