cas 35418-16-7, tert-butyl 5-oxo-L-prolinate

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Incorporation of cis- and trans -4,5-Difluoromethanoprolines into polypeptides
Substituted prolines exert diverse effects on the backbone conformation of proteins. Novel difluoro-analogues were obtained by adding difluorocarbene to N-Boc-4,5-dehydroproline methyl ester, which gave the trans-adduct as the sole product with 71% yield. Upon cleavage of the N-protection group the free amino acid decomposed rapidly. Its incorporation into the proline-rich cell-penetrating "sweet arrow peptide" was thus accomplished using a dipeptide strategy. Two building blocks, containing either cis- or trans-4,5-difluoromethanoproline, were obtained by difluorocyclopropanation of the aminoacyl derivatives of 4,5-dehydroproline. The resulting dipeptides were stable under standard conditions of Fmoc solid phase peptide synthesis and, thus, suitable to study conformational effects.
Kubyshkin, Vladimir S.,Mykhailiuk, Pavel K.,Afonin, Sergii,Ulrich, Anne S.,Komarov, Igor V.
p. 5254 - 5257
(2012)
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Synthesis of N-Fmoc-(2S,3S,4R)-3,4-dimethylglutamine: An application of lanthanide-catalyzed transamidation
N-Fmoc-(2S,3S,4R)-3,4-dimethylglutamine (6) was synthesized from tert-butyl N-Boc-(2S,3S,4R)-dimethylpyroglutamate (13). This synthesis involved selective deprotection of a Boc group from a lactam nitrogen in the presence of a tert-butyl ester, Fmoc protection of the lactam, and a lanthanide-catalyzed transamidation reaction of the Fmoc-protected lactam, using ammonia and dimethyl-aluminum chloride. The scope of Lewis acid-catalyzed transamidation of acylated lactams was explored through the variation of lanthanide, lactam, acyl group, amine, and aluminum reagent. The reactivity of various metal inflates was found to vary in the following qualitative order: Yb ～ Sc > Er ～ Eu ～ Sm > Ce ～ AgI > CuII ～ Zn. Intriguingly, catalysis was only observed when ammonia was the nitrogen nucleophile; addition of other amidoaluminum complexes to acyl lactams was found to be insensitive to the addition of lanthanides.
Calimsiz, Selcuk,Lipton, Mark A.
p. 6218 - 6221
(2005)
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Regioselective reduction of β-enaminoesters
The regioselective reduction of β-enaminoesters derived from pyroglutamic acid can be readily achieved under mild conditions. Copyright Taylor & Francis, Inc.
Hussaini, Syed Raziullah,Moloney, Mark G.
p. 1129 - 1134
(2005)
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Preparation method of (S)-1 - (benzyloxycarbonyl) -5 -oxo-pyrrolidine -2 - formic acid
The invention discloses a preparation method of (S)-1 - (benzyloxycarbonyl) -5 -oxo-pyrrolidine -2 - formic acid, which mainly solves the complexity in the original process, and is long in period and high in cost. The method specifically comprises first steps of preparing L - benzyloxycarbonyl N - glutamic acid from - L - glutamic acid and a benzyloxycarbonyl donor, second steps of intramolecular condensation cyclization N - benzyloxycarbonyl - L - glutamic acid to obtain the N -benzyloxycarbonyl - L - glutamic acid crude product. The third The crude N - benzyloxycarbonyl - L - glutamic acid crude product and the organic amine base are mixed, and the organic amine salt form is prepared by the solubility of the product in a solvent, fourth (N -) - L - (benzyloxycarbonyl) S oxopyrrolidine -1 - formic acid is prepared by desalinating -5 - benzyloxycarbonyl -2 - glutamic acid. To the method, the high-purity product is prepared, and the yield and the quality are greatly improved.
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Paragraph 0044

(2021/09/01)

An efficient synthetic route tol-γ-methyleneglutamine and its amide derivatives, and their selective anticancer activity
In cancer cells, glutaminolysis is the primary source of biosynthetic precursors, fueling the TCA cycle with glutamine-derived α-ketoglutarate. The enhanced production of α-ketoglutarate is critical to cancer cells as it provides carbons for the TCA cycle to produce glutathione, fatty acids, and nucleotides, and contributes nitrogens to produce hexosamines, nucleotides, and many nonessential amino acids. Efforts to inhibit glutamine metabolism in cancer using amino acid analogs have been extensive.l-γ-Methyleneglutamine was shown to be of considerable biochemical importance, playing a major role in nitrogen transport inArachisandAmorphaplants. Herein we report for the first time an efficient synthetic route tol-γ-methyleneglutamine and its amide derivatives. Many of thesel-γ-methyleneglutamic acid amides were shown to be as efficacious as tamoxifen or olaparib at arresting cell growth among MCF-7 (ER+/PR+/HER2?), and SK-BR-3 (ER?/PR?/HER2+) breast cancer cells at 24 or 72 h of treatment. Several of these compounds exerted similar efficacy to olaparib at arresting cell growth among triple-negative MDA-MB-231 breast cancer cells by 72 h of treatment. None of the compounds inhibited cell growth in benign MCF-10A breast cells. Overall,N-phenyl amides andN-benzyl amides, such as3,5,9, and10, arrested the growth of all three (MCF-7, SK-BR-3, and MDA-MB-231) cell lines for 72 h and were devoid of cytotoxicity on MCF-10A control cells;N-benzyl amides with an electron withdrawing group at theparaposition, such as5and6, inhibited the growth of triple-negative MDA-MB-231 cells commensurate to olaparib. These compounds hold promise as novel therapeutics for the treatment of multiple breast cancer subtypes.
Hossain, Md Imran,Thomas, Ajit G.,Mahdi, Fakhri,Adam, Amna T.,Akins, Nicholas S.,Woodard, Morgan M.,Paris, Jason J.,Slusher, Barbara S.,Le, Hoang V.
p. 7115 - 7128
(2021/02/26)

L-Y-METHYLENEGLUTAMINE COMPOUNDS AND METHODS OF USE
Disclosed are substantially pure L-y-methyleneglutamine, L-y- methyleneglutamic acid, and/or amide derivatives, and methods of use thereof. In particular, the presently disclosed subject matter relates to L-y-methyleneglutamine, L-y-methyleneglutamic acid, and/or amide derivatives thereof, and methods of treating cancer. The method comprises administering one or more substantially pure L-y-methyleneglutamine, L-y-methyleneglutamic acid, and/or amide derivatives to a subject in need thereof.
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Paragraph 0082-0084

(2021/02/12)

The Discovery of Conformationally Constrained Bicyclic Peptidomimetics as Potent Hepatitis C NS5A Inhibitors
HCV NS5A inhibitors are the backbone of directly acting antiviral treatments against the hepatitis C virus (HCV). While these therapies are generally highly curative, they are less effective in some specific HCV patient populations. In the search for broader-acting HCV NS5A inhibitors that address these needs, we explored conformational restrictions imposed by the [7,5]-azabicyclic lactam moiety incorporated into daclatasvir (1) and related HCV NS5A inhibitors. Unexpectedly, compound 5 was identified as a potent HCV genotype 1a and 1b inhibitor. Molecular modeling of 5 bound to HCV genotype 1a suggested that the use of the conformationally restricted lactam moiety might have resulted in reorientation of its N-terminal carbamate to expose a new interaction with the NS5A pocket located between amino acids P97 and Y93, which was not easily accessible to 1. The results also suggest new chemistry directions that exploit the interactions with the P97-Y93 site toward new and potentially improved HCV NS5A inhibitors.
Kazmierski, Wieslaw M.,Miriyala, Nagaraju,Johnson, David K.,Baskaran, Sam
supporting information
p. 1649 - 1655
(2021/10/04)

Rapid and Mild Lactamization Using Highly Electrophilic Triphosgene in a Microflow Reactor
Lactams are cyclic amides that are indispensable as drugs and as drug candidates. Conventional lactamization includes acid-mediated and coupling-agent-mediated approaches that suffer from narrow substrate scope, much waste, and/or high cost. Inexpensive, less-wasteful approaches mediated by highly electrophilic reagents are attractive, but there is an imminent risk of side reactions. Herein, a methods using highly electrophilic triphosgene in a microflow reactor that accomplishes rapid (0.5–10 s), mild, inexpensive, and less-wasteful lactamization are described. Methods A and B, which use N-methylmorpholine and N-methylimidazole, respectively, were developed. Various lactams and a cyclic peptide containing acid- and/or heat-labile functional groups were synthesized in good to high yields without the need for tedious purification. Undesired reactions were successfully suppressed, and the risk of handling triphosgene was minimized by the use of microflow technology.
Fuse, Shinichiro,Komuro, Keiji,Otake, Yuma,Masui, Hisashi,Nakamura, Hiroyuki
supporting information
p. 7525 - 7532
(2021/03/17)

A Stereoselective Synthesis of the ACE Inhibitor Trandolapril
A conceptually novel and stereoselective synthesis of the enantiopure octahydroindole building block and its conversion into the ACE inhibitor trandolapril was achieved. Key steps include the α-allylation of a protected l -pyroglutamic acid derivative, a highly diastereoselective Hosomi-Sakurai reaction and a Ru-catalyzed ring-closing metathesis of a 4,5-diallylated proline. This way, the synthesis of trandolapril was efficiently achieved in 25% overall yield (12 steps).
Chiha, Slim,Spilles, Matthias,Neud?rfl, J?rg-Martin,Schmalz, Hans-Günther
supporting information
p. 813 - 816
(2019/04/25)

Design and Synthesis of Building Blocks for PPII-Helix Secondary-Structure Mimetics: A Stereoselective Entry to 4-Substituted 5-Vinylprolines
In the course of our studies towards the synthesis of proline-based secondary-structure mimetics, we developed a straightforward methodology for the diastereoselective preparation of 4-alkyl-5-vinyl-substituted proline derivatives. Starting from N-Boc-protected tert-butyl pyroglutamate, α-alkylation, lactam reduction and acid-catalyzed methanolysis afforded 4-alkyl-5-methoxyproline derivatives. After BF3-induced formation of an N-acyl-iminium intermediate, the introduction of the 5-vinyl side chain was achieved with high diastereoselectivity by using vinylmagnesium bromide in the presence of AlCl3 or CuBr·SMe2 to afford either the cis- or the trans-product, respectively. The utility of the method was demonstrated in the rapid and efficient construction of new diproline mimetics rigidified in a polyproline-type II helix (PPII) conformation.
Chiha, Slim,Soicke, Arne,Barone, Matthias,Müller, Matthias,Bruns, Judith,Opitz, Robert,Neud?rfl, J?rg-Martin,Kühne, Ronald,Schmalz, Hans-Günther
supporting information
p. 455 - 460
(2018/02/09)

A new synthetic route to acylnitroso intermediates and their applications in HDA and ene reactions
Background: Acylnitroso intermediates are considered as highly reactive and useful transient that have been used to synthesize a broad class of biological active compounds and synthetic drugs. Although there are some reported methods for the generation of these intermediates, but still challenge for mild and environmental benign protocol. Herein, we report the facile in situ synthesis of acylnitroso intermediates and their efficient hetero Diels-Alder (HDA) and ene reactions. Methods: Acylnitroso intermediates were readily obtained by hydrogen peroxide oxidation of hydroxamic acids catalyzed by Cu(I)-, Ir(I)- or Ru(II)-complexes and easily reacted with symmetric and asymmetric conjugated dienes beside their reaction with different alkenes which converted to biological active products. Results: The resulted acylnitroso intermediates were efficiently afforded the hetero Diels-Alder cycloadducts in the presence of cyclopentadiene, cyclohexadiene or α-terpinene in high yields along with good regioselectivity for the later. In case of N-dienyl lactams, the cycloadducts were formed in the yield up to 89% with complete regioselectivity. In the presence of optically active N-dienyl pyroglutamates, diastereoisomers were formed in high yields with up to 72 de. In addition, the transient acylnitroso species were trapped with alkene to form the ene product in yield up to 95 %. As an interesting transformation, the halocyclization of the ene products gave substituted oxazolidone in 77% yield which considered as one of the effective antimicrobial and antibiotic compounds. Conclusion: In a brief, we introduce a mild and effective route to deliver acylnitroso intermediates in situ by using environmentally benign, cost effective, and non-toxic hydrogen peroxide oxidant catalyzed by Cu(I)-, Ir(I)- or Ru(II)-complexes. Good to excellent yields, regio- and diastereoselectivity were obtained by trapping these intermediates in symmetric and asymmetric HDA and ene reactions. Interestingly, the ene products easily transformed to potent drugs.
Fakhruddin, Ahmad,Abu-Elfotoh, Abdel-Moneim,Shibatomi, Kazutaka,Iwasa, Seiji
supporting information
p. 196 - 205
(2018/03/09)

DIAZABICYCLO[4.3.1]DECANE DERIVATIVES FOR TREATMENT OF PSYCHIATRIC DISORDERS
The present invention relates to diazabicyclo[4.3.1]decane derivatives, pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said diazabicyclo[4.3.1]decane derivatives can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions.
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Paragraph 0290-0293

(2017/01/23)

COMPOUNDS FOR THE TREATMENT OF MEDICAL DISORDERS
Compounds, methods of use, and processes for making inhibitors of complement Factor D comprising Formula (I), or a pharmaceutically acceptable salt or composition thereof The inhibitors described herein target Factor D and inhibit or regulate the complement cascade. The inhibitors of Factor D described herein reduce the excessive activation of complement.
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Paragraph 0492

(2017/03/14)

DIAZABICYCLO[4.3.1]DECANE DERIVATIVES FOR TREATMENT OF PSYCHIATRIC DISORDERS
The present invention relates to diazabicyclo[4.3.1 ]decane derivatives (I), pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said diazabicyclo[4.3.1]decane derivatives are specific inhibitors of the FK506 binding proteins (FKBP's) and can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions.
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Page/Page column 92; 94

(2015/08/06)

Diazabicyclo[4.3.1]decane derivatives for treatment of psychiatric disorders
The present invention relates to diazabicyclo[4.3.1]decane derivatives of formula (I), pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said diazabicyclo[4.3.1]decane derivatives are inhibitors of the FK506 binding protein (FKBP's) and can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions.
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Paragraph 0150; 0151

(2015/08/06)

Stereoselective construction of the 5-hydroxy diazabicyclo[4.3.1]decane-2-one scaffold, a privileged motif for FK506-binding proteins
A stereoselective synthesis of a derivatized bicyclic [4.3.1]decane scaffold based on an acyclic precursor is described. The key steps involve a Pd-catalyzed sp3-sp2 Negishi-coupling, an asymmetric Shi epoxidation, and an intramolecular epoxide opening. Representative derivatives of this novel scaffold were synthesized and found to be potent inhibitors of the psychiatric risk factor FKBP51, which bound to FKBP51 with the intended molecular binding mode. (Chemical Equation Presented).
Bischoff, Matthias,Sippel, Claudia,Bracher, Andreas,Hausch, Felix
supporting information
p. 5254 - 5257
(2015/02/19)

The revisited synthesis of tert-butyl pyroglutamate derivatives
The very common protection reactions of scaffolds by introduction of Boc or tert-butyl groups on lactams or acids in the pyroglutamic series have been revisited in a green perspective. Particularly, reaction conditions allowing a quantitative yield in substitution of bromine in tert-butyl bromide were discovered for the first time, allowing the synthesis of tert-butyl pyroglutamate 4. This synthesis of tert-butyl ester by nucleophilic substitution, realized without using concentrated perchloric or sulfuric acid, could be of interest for acid sensitive compounds. On the other hand, we demonstrated that non toxic N-methylimidazole and tert-butanol can pleasantly replace the problematic toxic 4-dimethylaminopyridine (DMAP) and dichloromethane utilized for the N-carbamoylation of lactam 4. This environmentally improved route to compound 4 allowed the development of a multi-gram supply of protected N-aminoethyl and N-hydroxyethyl γ-glutamine 1 and 2.
Claverie, Christelle,Ghinet, Alina,Gautret, Philippe,Vuong, Chi-Thanh,Rigo, Beno?t
p. 6821 - 6825
(2013/07/26)

Crotonase catalysis enables flexible production of functionalized prolines and carbapenams
The biocatalytic versatility of wildtype and engineered carboxymethylproline synthases (CMPSs) is demonstrated by the preparation of functionalized 5-carboxymethylproline derivatives methylated at C-2, C-3, C-4, or C-5 of the proline ring from appropriately substituted amino acid aldehydes and malonyl-coenzyme A. Notably, compounds with a quaternary center (at C-2 or C-5) were prepared in a stereoselective fashion by engineered CMPSs. The substituted-5-carboxymethyl-prolines were converted into the corresponding bicyclic β-lactams using a carbapenam synthetase. The results demonstrate the utility of the crotonase superfamily enzymes for stereoselective biocatalysis, the amenability of carbapenem biosynthesis pathways to engineering for the production of new bicyclic β-lactam derivatives, and the potential of engineered biocatalysts for the production of quaternary centers.
Hamed, Refaat B.,Henry, Luc,Gomez-Castellanos, J. Ruben,Mecinovic, Jasmin,Ducho, Christian,Sorensen, John L.,Claridge, Timothy D. W.,Schofield, Christopher J.
supporting information; experimental part
p. 471 - 479
(2012/03/07)

Discovery of a novel class of potent and orally bioavailable sphingosine 1-phosphate receptor 1 antagonists
A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P 1) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor growth. Further optimization of our lead series led to the discovery of proline derivatives 37 (XL541) and 38 which had similar efficacy as our first generation analogues at significantly lower doses. Analogue 37 displayed excellent pharmacokinetics and oral exposure in multiple species.
Ibrahim, Mohamed A.,Johnson, Henry W. B.,Jeong, Joon Won,Lewis, Gary L.,Shi, Xian,Noguchi, Robin T.,Williams, Matthew,Leahy, James W.,Nuss, John M.,Woolfrey, John,Banica, Monica,Bentzien, Frauke,Chou, Yu-Chien,Gibson, Anna,Heald, Nathan,Lamb, Peter,Mattheakis, Larry,Matthews, David,Shipway, Aaron,Wu, Xiang,Zhang, Wentao,Zhou, Sihong,Shankar, Geetha
experimental part
p. 1368 - 1381
(2012/04/04)

INDUCTION OF ALPHA HELIX CONFORMATIONS IN PROTEINS AND PEPTIDES
Substituted tricyclic diproline analogues of the formula (I): wherein the variables are as defined herein. Also disclosed are methods for the production thereof, the use thereof for the induction of an alpha-helix conformation in peptides and/or proteins, pharmaceuticals containing said compounds, methods for the production of a peptide library containing said compounds, and peptide libraries containing said compounds.
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(2012/07/14)

Remote chiral induction in vinyl sulfonium salt-mediated ring expansion of hemiaminals into epoxide-fused azepines
The planet of the azepines: Epoxy-fused azepines have been synthesized in a highly selective reaction with hemiaminals and vinyl sulfonium salts. Stereochemistry is controlled by the substituent at the four- or five-position of the hemiaminal. The key step involves ring-opening of the hemiaminal, conjugate addition onto a vinyl sulfonium salt, and epoxidation of the aldehyde by the in situ formed sulfur ylide. Copyright
Yar, Muhammad,Unthank, Matthew G.,McGarrigle, Eoghan M.,Aggarwal, Varinder K.
supporting information; experimental part
p. 372 - 375
(2011/10/09)

Insights into the reaction mechanism of the prolyl - Acyl carrier protein oxidase involved in anatoxin-a and homoanatoxin-a biosynthesis
Anatoxin-a and homoanatoxin-a are two potent cyanobacterial neurotoxins. We recently reported the identification of the gene cluster responsible for the biosynthesis of these toxins as well as the in-vitro reconstitution of the first steps of this biosynthesis. We now report experimental evidence supporting the proposed reaction mechanism of AnaB, a flavoprotein homologous to acyl-CoA dehydrogenase. AnaB catalyzes the two-electron oxidation of prolyl-AnaD, which is proline linked to the acyl carrier protein holo-AnaD, to dehydroprolyl-AnaD using oxygen as the second substrate. AnaB is thus an oxidase. By using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), we have identified and characterized dehydroprolyl-AnaD, the AnaB product. We estimated an apparent catalytic constant of 1 min- 1 for AnaB catalysis. We synthesized several deuterium-labeled prolines and enzymatically transformed them into their corresponding prolyl-AnaD. These deuterium-labeled prolyl-AnaDs were oxidized in the presence of AnaB, and the deuterium labeling in the remaining substrate and in the product was determined by LC-MS/MS. The data supported a reaction mechanism starting with a rapid enolization followed by a slow oxidation to give the conjugated imine, which in turn was isomerized to pyrroline-5-carboxyl-AnaD. We also showed that cis- and trans-4-fluoro-l-prolyl- AnaD and 3,4-dehydro-l-prolyl-AnaD were transformed into pyrrole-2-carboxyl-AnaD by AnaB. Thus, the 4-fluoro-analogues experienced a β-elimination supporting the AnaB-catalyzed aza - allylic isomerization. We identified by sequence alignment the AnaB active site base, Glu244. We produced, purified, and characterized the E244A AnaB mutant, which is inactive, supporting the catalytic role of E244 as a base.
Mann, Stephane,Lombard, Berangere,Loew, Damarys,Mejean, Annick,Ploux, Olivier
experimental part
p. 7184 - 7197
(2012/07/02)

STRUCTURAL MIMETICS OF PROLINE-RICH PEPTIDES AND THE PHARMACEUTICAL USE THEREOF
The invention relates to compounds of general formula (I), which can be used particularly as structural mimetics of proline-rich peptides and are therefore capable of binding PRM binding domains (proline-rich motif binding domains) of proteins. The invention also relates to the use of said compounds as pharmaceutical active agents and the use of these pharmaceutical active agents for treating bacterial diseases, neurodegenerative diseases and tumours.
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(2011/02/26)

PREPARATION OF ALKYL ESTERS OF N-PROTECTED OXO-AZACYCLOALKYLCARBOXYLIC ACIDS
A process for the preparation of alkyl esters of N-protected oxo-azacycloalkylcarboxylic acids of Formula III: comprises contacting a ketosulfoxonium ylide of Formula II: with an iridium catalyst to obtain Compound III, wherein PG1 is an amine protective group group; k is 0, 1, or 2; and RU, R1, R2, and R3 are defined herein. An embodiment of the process further com rises contacting a compound of Formula I: with a sulfoxonium halide of formula (RU)3S(O)Z, wherein Z is halide, in the presence of a strong base to obtain Compound II. Additional embodiments add a series of process steps leading to the synthesis of 7-oxo-1,6- diazabicyclo[3.2.1]octanes suitable for use as β-lactamase inhibitors.
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Page/Page column 28

(2010/11/17)

PYRROLIDINE COMPOUNDS WHICH MODULATE THE CB2 RECEPTOR
Compounds which modulate the CB2 receptor are disclosed. Compounds according to the invention bind to and are agonists of the CB2 receptor, and are useful for treating inflammation. Those compounds which are agonists are additionally useful for treating pain.
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Page/Page column 144

(2010/08/04)

SPHINGOSINE-1-PHOSPHATE RECEPTOR ANTAGONISTS
This disclosure relates to sphingosine-1 -phosphate (SlP) receptor antagonists, compositions comprising the SlP receptor antagonists and methods for using and processes for making the SlP receptor antagonists. In particularly, this disclosure relates to sphingosine-1 -phosphate 1 (SlPl) receptor antagonists, compositions comprising the SlPl receptor antagonist and methods for using the SlPl receptor antagonist, such as in the treatment of cancer, and processes for making the SlPl receptor antagonists.
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Page/Page column 90

(2010/04/30)

Addressing protein-protein interactions with small molecules: A pro-pro dipeptide mimic with a PPII helix conformation as a module for the synthesis of PRD-binding ligands
X marks the spot: The synthetic tricyclic amino acid X (see structure; C gray, H cyan, N blue, O red, double bond yellow) can be incorporated, without loss of binding ability, as a Pro-Pro substitute into two peptides that bind to the proline-rich motif-recognizing domains Fyn-SH3. The dipeptide analogue X, which is locked in a polyproline type II helix conformation, is created by stereoselective introduction of a vinylidene bridge into a diproline unit.
Zaminer, Jan,Brockmann, Christoph,Huy, Peter,Opitz, Robert,Reuter, Cedric,Beyermann, Michael,Freund, Christian,Mueller, Matthias,Oschkinat, Hartmut,Schmalz, Hans-Guenther,Kuehne, Ronald
supporting information; experimental part
p. 7111 - 7115
(2010/12/18)

A unified strategy targeting the thiodiketopiperazine mycotoxins exserohilone, gliotoxin, the epicoccins, the epicorazines, rostratin a and aranotin
A unified synthetic strategy directed towards mycotoxins belonging to the thiodiketopiperazine family is reported. The building blocks for a number of natural products-including exserohilone, gliotoxin, the epicoccins, the epicorazines, rostratin A and aranotin-have been synthesised stereoselectively from a common precursor. This key intermediate was constructed through an efficient and highly diastereoselective[2+2] cycloaddition between a ketene and an enecarbamate derived from l-pyroglutamic acid. The annelation of the second ring was accomplished through ring-closing metathesis and enol ether-olefin ring-closing metathesis to provide both cis-and trans-annelated azabicyclic cyclohexenones, as well as an annelated sevenmembered cyclic enol ether. A Pd-catalysed elimination of allyl acetate gave rise to the cyclohexadienol structure of gliotoxin. Dimerisation of one building block to afford the diketopiperazine core was demonstrated.
Gross, Ulrike,Nieger, Martin,Br?se, Stefan
supporting information; experimental part
p. 11624 - 11631
(2010/11/17)

Parallel solution-phase synthesis of (2S,4E)-4-(arylaminomethylidene) pyroglutamic acids
A library of twelve N(4')-substituted di-tert-butyl (2S,4E)-4- arylaminomethylidene-5-oxopyrrolidine-1,2-dicarboxylates 6/6'a-l were prepared in 47-90% yield by parallel acid-catalysed treatment of di-tert-butyl (2S,4E)-4-[(dimethylamino)methylidene]-5-oxopyrrolidine-1,2-dicarboxylate (4) with anilines 5a - j, ethyl glycinate (5k), and ethyl β-alaninate (31). Acidolytic deprotection of compounds 6a - c, e - j afforded the corresponding (2S,4E)-4-arylaminomethylidene-5-oxopyrrolidine-2-carboxylic acids 7a - c, e - j in 39-99% yield. The configuration around the C=C double bond in the enaminones 6 and 7 was determined by NMR spectroscopy.
Svete, Jurij,Groselj, Uros,Baskovc, Jernej,Dahmann, Georg,Stanovnik, Branko
scheme or table
p. 811 - 820
(2011/01/10)

Stereoselective synthesis of the epicoccin core
A short, convergent, and asymmetric synthesis of the epicoccin core was achieved using a phosphite-promoted one-step condensation of a complex proline-type amino acid. Key features of the assembly of this amino acid were a double-bond isomerlzation/vlnylation/ring-closing metathesis strategy as well as an efficient, highly deastereoselective [2 + 2] cycloaddition of a ketene to an enecarbamate, derived from L-pyroglutamic acid.
Gross, Ulrike,Nieger, Martin,Braese, Stefan
supporting information; experimental part
p. 4740 - 4742
(2009/12/22)

Synthesis of alexine-like compounds from chiral five-membered endocyclic enecarbamates
Stereoselective syntheses of enantiomerically enriched trihydroxy pyrrolizidine and indolizidines were accomplished from a common chiral endocyclic enecarbamate. The synthetic strategy features an efficient [2+2] cycloaddition of ketenes to the endocyclic enecarbamate and a highly regioselective Baeyer-Villiger oxidation of the intermediate azabicyclic-cyclobutanones. These new heterocycles are compounds structurally related to the alexines.
Valle, Marcelo Siqueira,Retailleau, Pascal,Correia, Carlos Roque Duarte
p. 1957 - 1960
(2008/09/19)

ANALOGS OF GLYCYL-PROLYL-GLUTAMATE
Embodiments of this invention include novel analogs of Glycyl-Prolyl-Glutamate (GPE) and compositions containing such analogs of GPE. Of these, certain analogs have modified proline residues. Other embodiments of this invention include uses of analogs of GPE to protect neural cells from degeneration and/or death in response to injury or disease. Disorders treatable with compounds and compositions of this invention include hypoxia/ischemia, toxic injury, and chronic neurodegenerative disorders including Parkinson''s disease.
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(2008/06/13)

Substrate-dependent dihydroxylation of substituted cyclopentenes: Toward the syntheses of carbocyclic sinefungin and noraristeromycin
Carbocyclic nucleosides are of considerable interest for the development of new therapeutic agents. A key reaction in the preparation of many such nucleoside analogues is dihydroxylation of appropriately substituted cyclopentenes. Although often considered a routine reaction, in this paper, we report the dramatic influence of substituents on the facial selectivity of dihydroxylations. The substituted cyclopentene substrates are derived from acylnitroso cycloaddition reactions of cyclopentadiene, followed by N-O reduction and efficient enzymatic resolution. The results are directly utilized in a very efficient asymmetric synthesis of an antiviral carbocyclic nucleoside, noraristeromycin 5. Extensions toward the synthesis of carbocyclic sinefungin 7 document the importance of realizing the substituent dependence of the dihydroxylation reaction.
Jiang, May Xiao-Wu,Jin, Bohan,Gage, Jennifer L.,Priour, Alain,Savela, Gordon,Miller, Marvin J.
p. 4164 - 4169
(2007/10/03)

Isolation and synthesis of (-)-(5S)-2-Imino-1-methylpyrrolidine-5- carboxylic acid from cliona tenuis: Structure revision of pyrostatins
(-)-(5S)-2-Imino-1-methylpyrrolidine-5-carboxylic acid (1), previously reported as the N-acetyl-β-D-glucosaminidase inhibitor pyrostatin B, has been isolated from the organic extracts of the burrowing sponge Cliona tenuis. The structure of 1, including its absolute stereochemistry, was characterized from its spectral data and chemical transformations and confirmed by total synthesis. The synthesis of 1 reveals that the structure of pyrostatin B has been incorrectly assigned. Comparison of NMR spectral data strongly suggests that pyrostatins A and B are identical to 5-hydroxyectoine and ectoine, respectively.
Castellanos, Leonardo,Duque, Carmenza,Zea, Sven,Espada, Alfonso,Rodriguez, Jaime,Jimenez, Carlos
p. 4967 - 4970
(2007/10/03)

NOVEL CYANOPYRROLIDIDES, METHODS FOR THE PRODUCTION THEREOF, AND USE OF THE SAME AS MEDICAMENTS
The invention relates to compounds of formula (I) wherein the radicals have the designations cited in the text. The invention also relates to the stereoisomer forms and the physiologically compatible salts thereof, the physiologically functional derivatives thereof, and methods for producing the same. The inventive compounds are suitable for treating illnesses of the metabolism such as type 2 diabetes.
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(2010/02/10)

ACE-INHIBITORS HAVING ANTIOXIDANT AND NO-DONOR ACTIVITY
Multifonctional ACE inhibitor compounds are provided, that combine ACE-inhibiting activity with capability to scavenge superoxide and other reactive oxygen species, and that may further function as nitric oxide donors. The compounds are useful for preventing or treating various disorders, including cardiovascular, and diabetes associated disorders.
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Page/Page column 60

(2010/02/07)

A study of polychlorinated leucine derivatives: Synthesis of (2S,4S)-5,5-dichloroleucine
The first total synthesis of (2S,4S)-5,5-dichloroleucine has been achieved in 11 steps from L-pyroglutamic acid. A key step is the dichlorination process on the hydrazone of aldehyde 13 with CuCl2 in triethylamine.
Ardá, Ana,Jiménez, Carlos,Rodríguez, Jaime
p. 3241 - 3243
(2007/10/03)

NOVEL PEPTIDES AS NS3-SERINE PROTEASE INHIBITORS OF HEPATITIS C VIRUS
The present invention discloses novel peptide compounds which have HCV protease inhibitory activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such peptides as well as methods of using them to treat disorders associated with the HCV protease.
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(2008/06/13)

Inhibitors of hepatitis C virus NS3 protease
The present invention relates generally to a novel class of pyrimidinones of Formula (I): that are useful as serine protease inhibitors, and more particularly as Hepatitis C virus NS3 protease inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of using the same.
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(2008/06/13)

Asymmetric synthesis of potent glycosidase and very potent α-mannosidase inhibitors: 4-amino-4-deoxy-L-erythrose and 4-amino-4,5-dideoxy-L-ribose
Pyrrolidine amino-sugars, cyclic iminoalditols as well as linear aminoalditols in 4-amino-L-erythrose and 4-amino-5-deoxy-L-ribose series were synthesised by asymmetric hetero-Diels-Alder reaction followed by chemical transformations. 4-Amino-4-deoxy-L-erythrose and 4-amino-4,5-dideoxy-L-ribose were potent β-D-glucosidase, α-D-mannosidase, α- and β-D-galactosidase inhibitors. We have shown that the ribose derivative was a very potent inhibitor of α-D-mannosidase.
Behr, Jean-Bernard,Chevrier, Carine,Defoin, Albert,Tarnus, C.éline,Streith, Jacques
p. 543 - 553
(2007/10/03)

Synthesis of 1,2-dithiolane analogues of leucine for potential use in peptide chemistry.
[reaction: see text]1,2-Dithiolanes present several points of interest for both peptide and medicinal chemistry, yet no chiral alpha-amino acids containing this five-membered heterocyclic system are available. We report here the first synthesis of N- and C-protected derivative of (S)-2-amino-3-(1,2-dithiolan-4-yl)propionic acid (Adp) and its 1,3-dithiolic form.
Morera, Enrico,Pinnen, Francesco,Lucente, Gino
p. 1139 - 1142
(2007/10/03)

Asymmetric synthesis of 2-methyl cyclohexane carboxylic acids by heterogeneous catalysis: Mechanistic aspects
The catalytic hydrogenation of (S)-alkyl-N-(2-methylbenzoyl)pyroglutamates was studied over supported rhodium and ruthenium catalysts at room temperature and a pressure of 5 MPa. The reaction was diastereoselective with the predominant formation of (1S,2R)-2-methylcyclohexane carboxylic acid with a diastereomeric excess (de) of up to 96%. The most stable conformation was determined by means of a combination of modelling calculations, NMR spectroscopy and X-ray structural determination. In this conformation, the carbonyl group of the pyroglutamate auxiliary shields one face of the aromatic ring. The observed selectivity may thus be explained by a preferential adsorption at the unshielded face which avoids steric repulsion by the C=O group to result in a cis hydrogenation. The addition of an amine, the nature of the support (alumina or active carbon) or of the metal (Rh or Ru) were shown to give additional stabilisation of the adsorption at the unshielded face to increase the diastereoisomeric excess.
Besson, Michele,Delbecq, Francoise,Gallezot, Pierre,Neto, Samuel,Pinel, Catherine
p. 949 - 958
(2007/10/03)

Chiral N-dienyl-L-pyroglutamic esters in asymmetric hetero-Diels-Alder reactions with acylnitroso dienophiles
Asymmetric Diels-Alder reaction of the N-dienyl-L-pyroglutamic esters 1a-h with acyl nitroso dienophiles 4a-h gave diastereoisomeric adducts 6a-n, 7a-n with 12-90% de, depending on solvents and temperature. An interpretation was given. The 'allylic effect' (π(C=C) - σ*(N-C) MO interactions) was found to be effective to account for the conformations of the adducts.
Behr, Jean-Bernard,Defoin, Albert,Pires, Joaquim,Streith, Jacques,Macko, Ludwig,Zehnder, Margaretha
p. 3283 - 3302
(2007/10/03)

C-glycosylation of cyclic N-acyliminium ions with trimethylsilyloxyfuran
C-glycosylation of 2-methoxy-5-alkoxycarbonyl pyrrolidines with trimethylsilyloxyfuran allows us to obtain the corresponding pyrrolidines contigus to a α,β-unsaturated butyrolactone.
Pichon, Marianne,Figadere, Bruno,Cave, Andre
p. 7963 - 7966
(2007/10/03)

Studies on pyrrolidones. An improved synthesis of pyroglutamoyl chloride
The reaction of trimethylsilyl pyroglutamate with oxalyl chloride at room temperature easily yields pyroglutamoyl chloride. This unstable compound, obtained with difficulty by other methods, is suitable for the preparation of pyroglutamic esters and amides.
Rigo,El Ghammarti,Gautret,Couturier
p. 2597 - 2607
(2007/10/02)

A NEW SYNTHETIC EQUIVALENT OF THE GLUTAMIC ACID γ-ANION AND ITS APPLICATION TO THE SYNTHESIS OF S-(+)-γ-CARBOXYGLUTAMIC ACID
Protected S-pyroglutamic acid can be deprotonated specifically at the γ-position.The resulting enolate can be converted into γ-carboxyglutamic acid in optically pure form.
Attwood, Michael R.,Carr, Maria G.,Jordan, Steven
p. 283 - 284
(2007/10/02)

1-Hydroxy-3-amino-2-piperidone (δ-N-Hydroxycycloornithine) Derivatives: Key Intermediates for the Synthesis of Hydroxamate-Based Siderophores
Several routes for the synthesis of δ-N-(benzyloxy)cycloornithine (2) from glutamic acid derived starting materials are described.Efficient methods were developed for the synthesis of glutamic acid γ-semialdehyde and γ-hydroxynorvaline derivatives as key substrates for the preparation of δ-N-hydroxyornithine analogues.Thus, the best approaches to the synthesis of 2 were: (1) reductive cyclization of an N-hydroxysuccinimide ester of the O-benzyloxime 4 of α-amino-protected glutamic acid γ-semialdehyde 5 and (2) cyclization of the N-(benzyloxy)amide of δ-bromonorvaline (7).
Kolasa, Teodozyj,Miller, Marvin J.
p. 1711 - 1721
(2007/10/02)

5-Thioxoproline and 5-Thioxoproline Esters - Synthesis and Crystal Structures
5-Thioxoproline (2a) is synthesized from 5-oxoproline (1a) at room temperature with 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (3) in DME.The carboxy group requires no protection because of the mild reaction conditions. 5-Thioxoproline esters are synthesized either by thionation of the corresponding 5-oxoproline esters with 3 or by esterification of 2a.Compounds 2a and 5-thioxoproline methyl ester (2b) both crystallize in the space group P212121 with Z=8.Bond lengths and angles in the compounds are compared, and the small differences explained by differences in hydrogen bond pattern.
Andersen, Torben P.,Rasmussen, Preben B.,Thomsen, Ib,Lawesson, Sven-Olov,Joergensen, Palle,Lindhardt, Peter
p. 269 - 279
(2007/10/02)

Synthesis and Pharmacology of the Potent Angiotensin-Converting Enzyme Inhibitor N--(S)-alanyl-(S)-pyroglutamic Acid
Structure 3a, a potent angiotensin-converting enzyme inhibitor, was prepared in five steps from L-(+)-α-amino-4-phenylbutyric acid by construction of the activated side-chain ester 16, displacement with L-pyroglutamate ester anion, and deblocking.Diastereomer separation was accomplished by chromatography at the diester stage, 17.Pharmacological assays established that 3a parallels enalapril in its ability to inhibit converting enzyme and lower blood pressure.
Johnson, Alexander L.,Price, William A.,Wong, Pancras C.,Vavala, Robert F.,Stump, John M.
p. 1596 - 1602
(2007/10/02)