Synthese der Racemate und der Enantiomere von 3‐Alkylthalidomidanaloga und Bestimmung ihrer absoluten Konfiguration

Knabe, J.; Omlor, G.

doi:10.1002/ardp.19893220809

Cited by 15 publications

(7 citation statements)

References 11 publications

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“…Therefore, the development of non-racemizable, chiral analogues of thalidomide has attracted much attention. [13][14][15][16] 3Ј-Fluorothalidimide (2) was developed for this purpose several years ago by a member of our group and by others. 17,18) Although the fluorine atom at the asymmetric center of 2 effectively obstructs racemization, the fluorine atom also introduces substantial electronic alterations into the molecule due to its highest electron negativity of 4.0, alterations that could be expected to significantly modulate biological activity.…”

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confidence: 99%

Synthesis and Configurational Stability of (S)- and (R)-Deuteriothalidomides

Yamamoto

Tokunaga

Nakamura

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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A fundamental question is whether thalidomide (1) is stereospecifically teratogenic. The revival of 1 in the clinical field in the 21st century has re-activated an investigation of the molecular mechanism of the teratogenicity of 1. [1][2][3][4][5][6][7][8] Thalidomide (1) was popular especially for pregnant women as an effective antiemetic for morning sickness in the 1950-60s. The teratogenic side effects, leading to birth defects such as limb reduction, produced one of the most notorious medical disasters of modern medical history, and 1 was consequently withdrawn from the market in 1962. Thalidomide (1) possesses an asymmetric center in the glutarimide ring. Since 1 was marketed as a racemate, it was conceivable that sedative effects of 1 might be associated with one enantiomer and the unexpected teratogenic side effects might be ascribed to the other enantiomer. Twenty years after the thalidomide disaster, only (S)-thalidomide (1) was proved to be teratogenic.9) It was then concluded that the disaster could have been avoided if only the (R)-isomer of 1 had been marketed. However, it is presently unclear whether any of the actions of racemic 1 can be separated out using a pure enantiomer. According to the reports, considerable chiral inversion took place after incubation of enantiomerically pure 1. The strongly acidic hydrogen atom at the asymmetric center of 1 rapidly epimerizes under physiological conditions, rendering bioassay of the enantiomers difficult.10-12) Therefore, elucidation of the difference of biological activities between thalidomide enantiomers previously reported is said to be difficult. Therefore, the development of non-racemizable, chiral analogues of thalidomide has attracted much attention.13-16) 3Ј-Fluorothalidimide (2) was developed for this purpose several years ago by a member of our group and by others.17,18) Although the fluorine atom at the asymmetric center of 2 effectively obstructs racemization, the fluorine atom also introduces substantial electronic alterations into the molecule due to its highest electron negativity of 4.0, alterations that could be expected to significantly modulate biological activity. 19) Incidentally, deuterated drugs have been noted as a new strategy for drug discovery. [20][21][22][23][24][25] They have basically the same properties as hydrogenated compounds, but are resistant to metabolism due to the higher stability of the carbon-deuterium (C-D) bond than that of the carbon-hydrogen (C-H) bond. As a result of our research designed to produce an analogue of thalidomide that is resistant to racemization and is also a close structural mimic, [26][27][28][29] we describe herein the design and synthesis of 3Ј-deuteriothalidomide (3), the most closed isostere of thalidomide (Fig. 1). Deuterium at the 3Ј-position of 3 is expected to effectively block the racemization of thalidomide due to its isotopic effect without major alterations of biological activities. Results and DiscussionOptically pure 3Ј-deuteriothalidomide (3) was synthesized in four steps from ...

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confidence: 99%

Synthesis and Configurational Stability of (S)- and (R)-Deuteriothalidomides

Yamamoto

Tokunaga

Nakamura

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Hydrogenolysis of the Cbz group gave amino lactam 27 in quantitative yield, which renders Knabe’s racemic synthesis of 3-ethyl thalidomide 40 ( 30 ) enantioselective. Reduction of lactam 27 with LiAlH 4 , followed by precipitation as the bishydrochloride salt furnished chiral diamine 28 in 89% yield.…”

Section: Resultsmentioning

confidence: 99%

Sequential Ruthenium Catalysis for Olefin Isomerization and Oxidation: Application to the Synthesis of Unusual Amino Acids

2017

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How can you use a ruthenium isomerization catalyst twice? A ruthenium-catalyzed sequence for the formal two-carbon scission of allyl groups to carboxylic acids has been developed. The reaction includes an initial isomerization step using commercially available ruthenium catalysts followed by in situ transformation of the complex to a metal-oxo species, which is capable of catalyzing subsequent oxidation reactions. The method enables enantioselective syntheses of challenging α-tri- and tetrasubstituted α-amino acids including an expedient total synthesis of the antiepileptic drug levetiracetam.

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“…All N-alkylated barbiturates: 5-ethyl-1-methyl-5-n-propyl barbituric acid (1), 1-methyl-5-(2-propyl)-5-(n-propyl) barbituric acid (2), 1,5dimethyl-5-ethyl barbituric acid (3), 1,5-dimethyl-5-phenyl barbituric acid (4) also known as methylheptobarbital or methyleudan, 5-cyclohexyl-5-ethyl-1-methyl-barbituric acid (5), 5-(1-cyclopenten-1-yl)-5-ethyl-1-methyl barbituric acid (6), 1-methyl-5-phenyl-5-propyl barbituric acid (7), 5-(1cyclohexen-1-yl)-1,5-dimethyl barbituric acid (8), 1-methyl-5-butyl-5-phenyl barbituric acid (9), 1-ethyl-5-methyl-5-piperidyl barbituric acid (10), 5-(1-cyclohexen-1-yl)-1ethyl-5-methyl barbituric acid (11), 5-(1-cyclohexen-1-yl)-5methyl-1-propyl barbituric acid (12), and the 3-alkylated analogs of thalidomide: methyl, ethyl, and propyl thalidomide (13,14, and 15, respectively) as racemates and separate enantiomers were given as a gift by Prof. Joachim Knabe, University of Saarbruecken, Germany. 1,2 The absolute configuration and the sign of optical rotation of racemates were confirmed by injecting well-known configuration of separate enantiomers.…”

Section: Methodsmentioning

confidence: 94%

“…They have been used as sedatives, hypnotics, anesthetics, and anticonvulsants. 1,2 On the other hand, thalidomide analogs have potent effects upon the a tumor necrosis factor (TNF-a). Some analogs have far stronger TNF-a effects, while others are potent nonsteroidal androgen antagonists or have antiangiogenesis properties.…”

Section: Introductionmentioning

confidence: 99%

Chiral recognition ability and solvent versatility of bonded amylose tris(3,5‐dimethylphenylcarbamate) chiral stationary phase: Enantioselective liquid chromatographic resolution of racemic N‐alkylated barbiturates and thalidomide analogs

Ghanem

Al‐Humaidi

2007

Chirality

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The chiral recognition ability and solvent versatility of a new chiral stationary phase containing amylose 3,5-dimethylphenylcarabamate immobilized onto silica gel (CHIRALPAK IA) is investigated. Thus, the direct enantioselective separation of a set of racemic N-alkylated barbiturates and 3-alkylated analogs of thalidomide was conducted using different nonstandard solvents as eluent and diluent, respectively in high-performance liquid chromatography (HPLC). The separation, resolution, and elution order of the investigated compounds were compared on both immobilized and coated amylose tris(3,5-dimethylphenylcarbamate) chiral stationary phases (Chiralpak IA and Chiralpak AD, respectively) using a mixture of n-hexane/2-propanol (90:10 v/v) as mobile phase with different flow-rates and fixed UV detection at 254 nm. The effect of the immobilization of the amylose tris(3,5-dimethylphenylcarbamate) chiral stationary phase on silica (Chiralpak IA) on the chiral recognition ability was noted as the bonded phase (Chiralpak IA) was superior in chiral recognition and possesses a higher resolving power in most of the reported cases than the coated one (Chiralpak AD). A few racemates were not or poorly resolved on the immobilized Chiralpak IA or the coated Chiralpak AD when using standard solvents were most efficiently resolved on the immobilized Chiralpak IA upon using nonstandard solvents. Furthermore, the immobilized phase withstands the nonstandard (prohibited) HPLC solvents such as dichloromethane, ethyl acetate, tetrahydrofuran, methyl-tert-butyl ether, and others when used as eluents or as a dissolving agent for the analyte itself. The direct analysis of a real sample extracted from plasma using DCM on Chiralpak IA is also shown.

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Synthese der Racemate und der Enantiomere von 3‐Alkylthalidomidanaloga und Bestimmung ihrer absoluten Konfiguration

Cited by 15 publications

References 11 publications

Synthesis and Configurational Stability of (S)- and (R)-Deuteriothalidomides

Synthesis and Configurational Stability of (S)- and (R)-Deuteriothalidomides

Sequential Ruthenium Catalysis for Olefin Isomerization and Oxidation: Application to the Synthesis of Unusual Amino Acids

Chiral recognition ability and solvent versatility of bonded amylose tris(3,5‐dimethylphenylcarbamate) chiral stationary phase: Enantioselective liquid chromatographic resolution of racemic N‐alkylated barbiturates and thalidomide analogs

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