Mastering chiral substituted 2-oxopiperazines

Risi, Carmela De; Pelà, Michela; Pollini, G. P.; Trapella, Claudio; Zanirato, Vinicio

doi:10.1016/j.tetasy.2010.02.008

Cited by 40 publications

(20 citation statements)

References 95 publications

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“…As eluent was used chloroform; the manifestation of chromatograms was in UV light and iodine vapor. 1 H NMR spectra were recorded on the instrument Bruker AC-300 (300 MHz); internal standard-TMS, solvents-dimethylsulfoxide, deuterium. Mass-spectra were removed on the device LKB 9000 with the input of the substance directly in the ionizing source, the…”

Section: Characterizationmentioning

confidence: 99%

“…Oxopiperazines are amongst the most important scaffolds in today's drug discovery industries. Due to the high number of positive hits encountered in biological screens with this heterocycle and its congeners, the substituted oxopiperazine is widely recognized as a "privileged scaffold" in medicinal chemistry [1]. Fragment of 2-oxopiperazine is a composite element natural substances of various structural complexity and biological activity [2][3][4][5].…”

Section: Introductionmentioning

confidence: 99%

“…All solvents and chemicals used in this work were analytical grade and used without purification.2.2. General Method for the Synthesis ofMethyl-2-Aryl -1,3,4':4,5] Pyrrolo[1, 2-a] Pyrazine-9-Carboxylates 3a, b A mixture of 0.85 g (0.5 mmol) of 2-oxopiperazine 1 and 0.51 mmol of the corresponding N-arylmaleimide in a mixture of 5 mL of methanol and 5 mL of acetic acid are refluxed for 10 h (control-TLC). The precipitate formed is filtered off after cooling, washed with ethanol.…”

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confidence: 99%

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The Synthesis of Novel Annelated 2-Oxopiperazines by the Interaction Methyl (3-Oxopiperazin-2-Ylidene) Acetate with an N-Arylmaleimides

Медведева¹,

Shikhaliev²

2015

JMSE-A

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It is studied that the interaction of methyl (3-oxopiperazin-2-ylidene) acetate with an N-arylmaleimides. It is established that methyl (3-oxo-piperazine-2-ylidene) acetate is reacted with N-arylmaleimides in boiling methanol in the presence of catalytic amounts of acetic acid as the C-N-dinucleophile to form not previously described methyl-1, 6-dioxo-8-[(arylamino)carbonyl]-1, 3, 4, 6, 7, 8-hexahydro-2H-pyrido [1, 2-a] pyrazine-9-carboxylates. An excess of acid (in a mixture of methanol and acetic acid in the ratio 1:1) occurs 1, 3-dipolar cycloaddition of the N-arylmaleimides toward tautomeric form methyl (3-oxo-piperazine-2-ylidene) acetatemethyl (3-oxo-3, 4, 5, 6-tetrahydropyrazine-2-yl) acetate with the formation of new heterocyclic system-methyl-2-aryl-1, 3, 8-trioxodecahydro-1H-pyrrolo [3', 4':4, 5] pyrrolo [1, 2-a] pyrazine-9-carboxylates.

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Section: Characterizationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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The Synthesis of Novel Annelated 2-Oxopiperazines by the Interaction Methyl (3-Oxopiperazin-2-Ylidene) Acetate with an N-Arylmaleimides

Медведева¹,

Shikhaliev²

2015

JMSE-A

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“…[20][21][22][23] Nowadays, because of numerous recurrent positive hits in screenings, piperazine derivatives and especially their keto analogues are considered as important and privileged scaffolds in medicinal chemistry. [24] In this paper, we will focus on 2-oxopiperazines (or piperazin-2-ones, i.e. piperazines featuring a carbonyl function at position 2, see Figure 1b) and their chiral syntheses and/or substitutions.…”

Section: Introductionmentioning

confidence: 99%

The origin of the stereoselective alkylation of 3-substituted-2-oxopiperazines: A computational investigation

Cézard

Bouvier

Dassonville‐Klimpt

et al. 2016

Computational and Theoretical Chemistry

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2-oxopiperazines and their derivatives are important pharmacophores found in numerous bioactive products. The potency of these compounds depends on the nature and/or position of their substituent(s) as well as on their chirality. Hence, it is important to develop, control and optimize synthetic routes leading to enantiomerically pure substituted 2-oxopiperazines. In this work we report on the origin of this stereoselectivity, upon alkylation of 2-oxopiperazines at position C3, studied by means of quantum chemistry calculations. Indeed, this alkylation with methyl chloride is predicted to afford mainly the exo product with a 98:2 ratio. To this purpose, we model the reaction path leading to both enantiomers by scrutinizing the structures and energetics of the pre-reaction complexes, the transition states and the postreaction complexes. The computational results are in good agreement with the experimental observations, and provide valuable insights into the origins of this specificity. From the conformational analysis of the piperazine ring and of intramolecular interaction patterns, we show that the enantiofacial discrimination is achieved by a subtle balance between sterical hindrance and control of the conformation of the piperazine ring.

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“…Many research groups have been engaged in the stereoselective synthesis of polysubstituted piperazines [4,[43][44][45][46][47][48][49][50][51][52][53] and oxopiperazines [52,[54][55][56][57][58][59][60] and in the majority of cases, in the absence of an asymmetric synthetic strategy, the stereochemistry of the final compounds is dependent on starting material configuration. Readily available, naturally occurring amino-acids have been often used as the source of chirality for starting materials ("chiral pool" approach).…”

Section: Introductionmentioning

confidence: 99%

Stereoselective Synthesis of Polysubstituted Piperazines and Oxopiperazines. Useful Building Blocks in Medicinal Chemistry

Mordini¹,

Reginato²,

Calamante³

et al. 2014

CTMC

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Many pharmaceutical agents include piperazines or oxopiperazines as part of their core structures. The presence of substituents on these heterocycles has a significant influence on the biological activity, thus the search for efficient routes to control the substitution at different ring positions might have a crucial impact, especially to promote the use of such scaffolds in SAR studies. Many research groups have been engaged in the stereoselective synthesis of polysubstituted piperazines and oxopiperazines and in the majority of cases the stereochemistry of the final compounds is dependent on the starting material configuration. In the present minireview we have summarized some of the most significant approaches towards the stereoselective synthesis and functionalization of substituted piperazines and oxopiperazines, with a particular focus on our own contributions mainly based on readily available natural amino-acids as "chiral pool" starting materials. An efficient and scalable route to orthogonally protected 2-oxopiperazines has been developed using the corresponding diamines as key intermediates: diastereoselective elaboration of the resulting heterocycles was possible by metalation and reaction with electrophiles, leading to anti 3,5-disubstituted-oxopiperazines, in agreement with the model for a conventional 1,3-asymmetric induction. Both piperazines and tetrahydropyrazines could be prepared via LiAlH4-mediated reduction of 2-oxopiperazines, depending on reaction conditions. Finally, the diastereoselective synthesis of cyclopropane- containing analogs 2,5-diaza-bicyclo[4.1.0]heptanes was demonstrated by application of the classic Simmons-Smith reaction on enantiomerically enriched dihydro-2H-pyrazines.

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Mastering chiral substituted 2-oxopiperazines

Cited by 40 publications

References 95 publications

The Synthesis of Novel Annelated 2-Oxopiperazines by the Interaction Methyl (3-Oxopiperazin-2-Ylidene) Acetate with an N-Arylmaleimides

The Synthesis of Novel Annelated 2-Oxopiperazines by the Interaction Methyl (3-Oxopiperazin-2-Ylidene) Acetate with an N-Arylmaleimides

The origin of the stereoselective alkylation of 3-substituted-2-oxopiperazines: A computational investigation

Stereoselective Synthesis of Polysubstituted Piperazines and Oxopiperazines. Useful Building Blocks in Medicinal Chemistry

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