Synthesis of 4‐Amino Derivatives of 5‐Oxoproline

Краснов, В. П.; Vigorov, A. Yu.; Низова, И. А.; Матвеева, Т. В.; Grishakov, A. N.; Bazhov, Iliya V.; Тумашов, А. А.; Ежикова, М. А.; Кодесс, М. И.

doi:10.1002/ejoc.200700346

Cited by 8 publications

(15 citation statements)

References 30 publications

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“…The assignment of signals in the NMR spectra was carried out via an analogy with [15,18,19] and was confirmed using the data of 2D experiments 1 H-1 H HSQC, HMBC, and 1 H-1 H NOESY for compounds 8a (Figures S31 and S32), 10a (Figures S43-S45), and 14 (Figures S55-S57).…”

Section: Chemistrymentioning

confidence: 77%

“…The structure of compounds 2b, 3-10, and 12-16 was confirmed using 1 H, 19 F, 13 C NMR spectroscopy and elemental analysis. For the NMR spectra of the compounds obtained, see the Supplementary Materials, Figures S1-S61.…”

Section: Chemistrymentioning

confidence: 91%

“…(2S,4S)-4-Amino-1-phenyl-5-oxoproline (1a) [18] and (2S,4S)-4-amino-1-(4-fluorophenyl)-5-oxoproline (1b) [15] were chosen as the starting derivatives of 4-amino Starting from the previously described (2S,4S)-4-[(methyl)(phenyl)amino]-5-oxoproline (11) [19], we synthesized amides with piperidine (12) and morpholine (13) (Scheme 3). The coupling to the amino component (piperidine or morpholine) was carried out under the action of HBTU in DMF.…”

Section: Chemistrymentioning

confidence: 99%

“…The coupling of 5-oxoproline 11 with tert-butyl (S)-phenylalaninate under the action of HBTU in DMF, followed by cleavage of the tert-butyl ester with TFA in compound 15 yielded dipeptide 16 (Scheme 3). Starting from the previously described (2S,4S)-4-[(methyl)(phenyl)amino]-5-o line (11) [19], we synthesized amides with piperidine (12) and morpholine (13) ( 3). The coupling to the amino component (piperidine or morpholine) was carried der the action of HBTU in DMF.…”

Section: Chemistrymentioning

confidence: 99%

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Synthesis and Assessment of Antiplatelet and Antithrombotic Activity of 4-Amino-Substituted 5-Oxoproline Amides and Peptides

Krasnov,

Nizova,

Vigorov

et al. 2023

Molecules

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Venous thromboembolism is a serious problem because it significantly increases the risk of developing vascular complications in elderly patients with obesity or immobilization, cancer, and many other diseases. Thus, there is a need to study new therapeutic strategies, including new medicinal agents for the efficient and safe correction of thrombus disorders. In this work, we have synthesized a number of new amides and peptides of 4-amino-5-oxoprolines and studied their antiplatelet and antithrombotic activity in experiments in vitro and in vivo. It has been found that the newly obtained compounds slow down the process of thrombus formation in a model of arterial and venous thrombosis, without affecting plasma hemostasis parameters. (2S,4S)-4-Amino-1-(4-fluorophenyl)-5-oxoprolyl-(S)-phenylalanine proved to be the most efficient among the studied derivatives. The results obtained indicate the advisability of further studies on 5-oxoproline derivatives in order to design pharmaceutical agents for the prevention and treatment of the consequences of thrombosis.

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Section: Chemistrymentioning

confidence: 77%

Section: Chemistrymentioning

confidence: 91%

Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

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Synthesis and Assessment of Antiplatelet and Antithrombotic Activity of 4-Amino-Substituted 5-Oxoproline Amides and Peptides

Krasnov,

Nizova,

Vigorov

et al. 2023

Molecules

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“…Dimethyl (2S,4RS) 4 bromo N phthaloylglutamate (1),21 (2S,4S) 4 [(methyl)(phenyl)amino] 5 oxoproline,22 and methyl (2S,4S) 5 oxo 4 phenylaminoproline(12) 29 were prepared according to known procedures. Indoline, DDQ, (Bu 3 Sn) 2 O, BH 3 •Me 2 S (Lancaster), Boc 2 O (Fluka), and DMAP (ICN Bio medicals, Inc.) were used.…”

mentioning

confidence: 99%

Synthesis of the (2S,4S)-stereoisomers of 4-(indol-1-yl) and 4-arylamino derivatives of 5-oxoproline, proline, and 2-hydroxymethylpyrrolidine

et al. 2011

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Nucleophilic substitution of the halogen atom in dimethyl (S) 4 bromoglutamate followed by removal of the protecting groups and closure of a lactam ring afforded (2S,4S) 4 (indolin 1 yl) 5 oxoproline. The indoline fragment was oxidized into the indole fragment to give (2S,4S) 4 (indol 1 yl) 5 oxoproline; reduction of the carbonyl groups with BH 3 yielded (2S,4S) 4 (indol 1 yl)prolines and (2S,4S) 2 hydroxymethyl 4 (indol 1 yl)pyrrolidines. Reduction of (2S,4S) 4 arylamino 5 oxoprolines with BH 3 to the corresponding (2S,4S) 4 arylaminoprolines and (2S,4S) 4 arylamino 2 hydroxymethylpyrrolidines was studied.(S) 5 Oxoproline (pyroglutamic acid) plays an impor tant role in metabolic processes occurring in living organ isms. The 5 oxoproline fragment is part of thyroliberin and other neuropeptides and peptide hormones. 1 4 Ami noproline and 4 amino 5 oxoproline derivatives, which are of special interest because they can be modified at the amino group and contain an additional chiral center, are used in organic synthesis as chiral building blocks, 2-6 also for the preparation of substituted prolinols (2 hydroxyme thylpyrrolidines) employed as catalysts in asymmetric syn thesis. 7,8 Some 4 aminoproline derivatives are known as metalloproteinase inhibitors 9 and antidiabetic agents. 10 When incorporated in a peptide chain, the 4 aminoproline fragment changes its conformation and hence biological activity. 11-13 trans 4 Aminoproline is a metabolite of the fungus Ascochyta caulina and exhibits herbicidal activi ty. 14 (2R,4R) 4 Amino 4 carboxyproline is a powerful and selective group II agonist of metabotropic glutamate re ceptors, which accounts for its anticonvulsant in vivo ef fect 15,16 and makes it promising for the treatment of neu rodegenerative diseases. 17 The goal of the present work was to develop a meth od for the synthesis of 5 oxoprolines, prolines, and 2 hydroxymethylpyrrolidines containing 4 arylamino or 4 indol 1 yl substituents, because the indole frag ment is known to be part of some physiologically ac tive compounds 18-20 and 4 (indol 1 yl) 5 oxoprolines and 4 (indol 1 yl)prolines have not been document ed hitherto. 4 (Indol 1 yl) 5 oxoproline derivatives were synthe sized from dimethyl (2S,4RS) 4 bromo N phthaloyl glutamate (1) 21 via nucleophilic substitution of the brom ine atom followed by removal of the protecting groups, closure of a lactam ring, and oxidation of the indoline fragment into an indole one.Reflux of bromide 1 with indoline in acetonitrile gave a mixture of diastereomers of dimethyl (2S,4RS) 4 (indol in 1 yl) N phthaloylglutamate (2a,b) (Scheme 1).The ratio of diastereomers 2a and 2b in the reaction mixture was 77 : 23 ( 1 H NMR and HPLC); i.e., the nucleophilic substitution of the Br atom from bromide 1 under the action of indoline is a stereoselective process, much the same as with other arylamines. 22-24 Diastereo mer 2a (de 97%) was isolated by twofold crystallization from methanol.To assign the diaminopentanedioic acid residue in dia stereomers 2a and 2b to the threo or erythro ...

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