cas 2018-66-8, N-Cbz-L-Leucine | Articles data

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Design and synthesis of novel symmetric fluorene-2,7-diamine derivatives as potent hepatitis C virus inhibitors
Hepatitis C virus (HCV) is an international challenge. Since the discovery of NS5A direct-acting antivirals, researchers turned their attention to pursue novel NS5A inhibitors with optimized design and structure. Herein we explore highly potent hepatitis C virus (HCV) NS5A inhibitors; the novel analogs share a common symmetrical prolinamide 2,7-diaminofluorene scaffold. Modification of the 2,7-diaminofluorene backbone included the use of (S)-prolinamide or its isostere (S,R)-piperidine-3-caboxamide, both bearing different amino acid residues with terminal carbamate groups. Compound 26 exhibited potent inhibitory activity against HCV genotype (GT) 1b (effective concentration (EC50) = 36 pM and a selectivity index of >2.78 × 106). Compound 26 showed high selectivity on GT 1b versus GT 4a. Interestingly, it showed a significant antiviral effect against GT 3a (EC50 = 1.2 nM). The structure-activity relationship (SAR) analysis revealed that picomolar inhibitory activity was attained with the use of S-prolinamide capped with R- isoleucine or R-phenylglycine residues bearing a terminal alkyl carbamate group.
Mousa, Mai H. A.,Ahmed, Nermin S.,Schwedtmann, Kai,Frakolaki, Efseveia,Vassilaki, Niki,Zoidis, Grigoris,Weigand, Jan J.,Abadi, Ashraf H.
(2021/04/16)

SuFExable Isocyanides for Ugi Reaction: Synthesis of Sulfonyl Fluoro Peptides
Herein, the sulfonyl fluoro isocyanides were first developed as a new type of SuFExable synthon, and they are used as building blocks in the Ugi reaction (U-4CR). The Ugi reaction was established and the substrate scope was investigated, and various sulfonyl fluoro α-amino amides and peptides could be reached in a one-step synthesis. Therefore, this protocol opens a new vision for SuFExable building blocks and click chemistry, and it also provides a distinct approach to sulfonyl fluoro peptides.
Xu, Shuheng,Cui, Sunliang
supporting information
p. 5197 - 5202
(2021/07/20)

A Next-Generation Air-Stable Palladium(I) Dimer Enables Olefin Migration and Selective C?C Coupling in Air
We report a new air-stable PdI dimer, [Pd(μ-I)(PCy2tBu)]2, which triggers E-selective olefin migration to enamides and styrene derivatives in the presence of multiple functional groups and with complete tolerance of air. The same dimer also triggers extremely rapid C?C coupling (alkylation and arylation) at room temperature in a modular and triply selective fashion of aromatic C?Br, C?OTf/OFs, and C?Cl bonds in poly(pseudo)halogenated arenes, displaying superior activity over previous PdI dimer generations for substrates that bear substituents ortho to C?OTf.
Kundu, Gourab,Rissanen, Kari,Schoenebeck, Franziska,Sperger, Theresa
p. 21930 - 21934
(2020/10/02)

Enantioselective inclusion of pyrene-1-sulfonate salts of α-amino acids with crystals of α-cyclodextrin
Enantioselective inclusion of α-amino acids with crystals of α-cyclodextrin (α-CD) has been achieved by converting the amino acids into sulfonate salts with pyrene-1-sulfonic acid (PyS). For example, crystals of α-CD selectively include L-leucine/PyS (1:1) salt in a host/guest ratio of ～1 with 92%ee from a solution of the racemic salt in ethanol/N-methylformamide (91:9) at 40 °C. Under conditions optimized for individual amino acids, the PyS salts of valine, phenylalanine, and methionine are also included with good enantioselectivities (up to 86%ee). Mechanistic studies for the inclusion of leucine/PyS salt reveals that the enantioselectivity originates from the difference in stability between the inclusion complexes of D- and L-leucine/PyS salts with α-CD in crystals.
Hattori, Tetsutaro,Kitamoto, Yuichi,Maeda, Tetsuya,Miyoshi, Ikuko,Morohashi, Naoya
(2020/04/01)

PEPTIDOMIMETICS FOR THE TREATMENT OF CORONAVIRUS AND PICORNAVIRUS INFECTIONS
Compounds, compositions and methods for preventing, treating or curing a coronavirus, picornavirus, and/or Hepeviridae virus infection in human subjects or other animal hosts. Specific viruses that can be treated include enteroviruses. In one embodiment, the compounds can be used to treat an infection with a severe acute respiratory syndrome virus, such as human coronavirus 229E, SARS, MERS, SARS-CoV-1 (OC43), and SARS-CoV- 2. In another embodiment, the methods are used to treat a patient co-infected with two or more of these viruses, or a combination of one or more of these viruses and norovirus.
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(2020/12/29)

Chiral tetraaryl-and tetraalkynylborates as chiral solvating agents for tetraalkylammonium salts
The application of tetracarbon-substituted chiral borate sodium salts (NaBR*4) as NMR chiral solvating agents for various tetraalkylammonium salts (R4NX) has been successfully demonstrated. Ion exchange between R4NX and NaBR*4 proceeded in excellent yields and provided the corresponding dia-stereomeric salts (R4NBR*4). The ee values of the R4NX salts were determined by1H NMR analysis of R4NBR*4. Two types of chiral borates, tetraaryl-and tetraalkynylborates with optically active 1,1′-binaphthyl components were used. At the beginning of this research, we investigated the efficacy of a known chiral tetraar-ylborate developed by Pommerening et al. for R4NX. To expand the possibility of further structural design of the chiral borate, we designed chiral tetraalkynylborates as a new structure. Their synthesis and application are also described.
Tayama, Eiji,Sugawara, Takeshi
supporting information
p. 803 - 811
(2019/01/18)

Expanding the chemical space of anti-HCV NS5A inhibitors by stereochemical exchange and peptidomimetic approaches
Here we report a series of potent anti-HCV agents bearing a symmetrical benzidine l-prolinamide backbone with different capping groups including alkyl/aryl carbamates of natural and unnatural valine and leucine amino acids. All compounds were investigated for their inhibitory activity in an HCV replicon assay on genotype 1b. The novel compounds share some chemical and clinical attributes of commercially available NS5A inhibitors. Compounds 5 and 6 with unnatural capping residue and ethyl and isobutyl carbamates showed EC50 values in the picomolar range with a low toxicity profile and selectivity indices of several orders of magnitude. These findings enlarge the chemical space from which NS5A inhibitors may be discovered by adopting unnatural amino acids, amino acids other than valine and carbamates other than methyl as the capping groups.
Ramsis, Triveena M.,Abdel Karim, Shereen E.,Vassilaki, Niki,Frakolaki, Efseveia,Kamal, Ahmed A. M.,Zoidis, Grigoris,Ahmed, Nermin S.,Abadi, Ashraf H.
(2018/05/30)

Synthesis and evaluation of chirally defined side chain variants of 7-chloro-4-aminoquinoline to overcome drug resistance in malaria chemotherapy
A novel 4-aminoquinoline derivative [(S)-7-chloro-N-(4-methyl-1-(4-methyl-piperazin-1-yl)pentan-2-yl)-quinolin-4-amine triphosphate] exhibiting curative activity against chloroquine-resistant malaria parasites has been identified for preclinical development as a blood schizonticidal agent. The lead molecule selected after detailed structure-activity relationship (SAR) studies has good solid-state properties and promising activity against in vitro and in vivo experimental malaria models. The in vitro absorption, distribution, metabolism, and excretion (ADME) parameters indicate a favorable drug-like profile.
Dola, Vasantha Rao,Soni, Awakash,Agarwal, Pooja,Ahmad, Hafsa,Raju, Kanumuri Siva Rama,Rashid, Mamunur,Wahajuddin, Muhammad,Srivastava, Kumkum,Haq,Dwivedi,Puri,Katti
(2017/03/09)

Synthesis and biological activity of peptide proline-boronic acids as proteasome inhibitors
On the basis of the application of proline-boronic acid as pharmacophore in the kinase inhibitors and our previous research results, using proline-boronic acid as warhead, two series of peptide proline-boronic acids, dipeptide proline-boronic acids (I) and tripeptide proline-boronic acids (II), were designed and synthesized. All the synthesized compounds were first evaluated for their biological activity against MGC803 cell, and then, the best compound II-7 was selected to test its anti-tumor spectrum on six human tumor cell lines and proteasome inhibition against three subunits. The results indicated that series II have much better biological activities than series I. The compound II-7 exhibited not only excellent biological activities with IC50 values of nM level in both cell and proteasome models, but also much better subunit selectivity. Thus, proline-boronic acid as warhead is reasonable in the design of proteasome inhibitors.
Han, Liqiang,Wen, Yanzhao,Li, Ridong,Xu, Bo,Ge, Zemei,Wang, Xin,Cheng, Tieming,Cui, Jingrong,Li, Runtao
p. 4031 - 4044
(2017/07/05)

Development of novel dipeptide-like rhodesain inhibitors containing the 3-bromoisoxazoline warhead in a constrained conformation
Novel dipeptide-like rhodesain inhibitors containing the 3-bromoisoxazoline warhead in a constrained conformation were developed; some of them possess Ki values in the micromolar range. We studied the structure-activity relationship of these derivatives and we performed docking studies, which allowed us to find out the key interactions established by the inhibitors with the target enzyme. Biological results indicate that the nature of the P2 and P3 substituents and their binding to the S2/S3 pockets is strictly interdependent.
Ettari, Roberta,Pinto, Andrea,Previti, Santo,Tamborini, Lucia,Angelo, Ilenia C.,La Pietra, Valeria,Marinelli, Luciana,Novellino, Ettore,Schirmeister, Tanja,Zappalà, Maria,Grasso, Silvana,De Micheli, Carlo,Conti, Paola
p. 7053 - 7060
(2015/11/11)

PEPTIDOMIMETIC COMPOUNDS AND ANTIBODY-DRUG CONJUGATES THEREOF
This invention relates to peptidomimetic linkers and anti-body drug conjugates thereof, to pharmaceutical compositions containing them, and to their use in therapy for the prevention or treatment of cancer.
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Page/Page column 207

(2015/07/07)

Structure-guided design and optimization of dipeptidyl inhibitors of norovirus 3CL protease. Structure-activity relationships and biochemical, X-ray crystallographic, cell-based, and in vivo studies
Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of antinorovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection.
Galasiti Kankanamalage, Anushka C.,Kim, Yunjeong,Weerawarna, Pathum M.,Uy, Roxanne Adeline Z.,Damalanka, Vishnu C.,Mandadapu, Sivakoteswara Rao,Alliston, Kevin R.,Mehzabeen, Nurjahan,Battaile, Kevin P.,Lovell, Scott,Chang, Kyeong-Ok,Groutas, William C.
p. 3144 - 3155
(2015/04/27)

ORGANOGOLD COMPLEXES AND METHODS FOR MAKING THE SAME
The present invention relates to chiral ligands deriving from α- and β-amino acids, and from metal complexes formed from the same. The ligands are useful with catalytic gold complexes, particularly Au(I) complexes.
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Paragraph 0451; 0452

(2014/02/16)

Nitrile-containing enzyme inhibitors and ruthenium complexes thereof
The invention provides nitrile-containing protease inhibitors caged to ruthenium compounds. The nitrile-caged ruthenium compounds provide inactivated inhibitors that can be delivered to surface or site for activation, for example, but exposure to light. The invention also provides methods for delivering protease inhibitors to subjects for the therapeutic treatment of conditions such as cancer.
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Paragraph 0156

(2014/04/18)

Synthesis of enantiopure free and N-benzyloxycarbonyl-protected 3-substituted homotaurines from naturally occurring amino acids
Enantiopure N-benzyloxycarbonyl-protected and free 3-substituted homotaurines were synthesized from naturally occurring amino acids via N-benzyloxycarbonyl protection, Arndt-Eistert homologation, reduction, esterification with thioacetic acid, and oxidation with performic acid. The current method is a convenient, practical, and salt-free method for the synthesis of enantiopure 3-substituted homotaurine with moderate to good yields.
Zheng, Yongpeng,Xu, Jiaxi
p. 5197 - 5206
(2014/12/10)

β,γ-Diamino acid: An original building block for hybrid α/γ-peptide synthesis with extra hydrogen bond donating group
Using a β,γ-diamino acid, several small hybrid α/γ peptides have been synthesized and their conformations investigated through extensive NMR studies and molecular dynamics. A tripeptide and a tetrapeptide have thus shown several hydrogen bonds in solution, including a 13-membered ring involving the β-nitrogen.
Stanovych, Andrii,Guillot, Rgis,Kouklovsky, Cyrille,Miclet, Emeric,Alezra, Valrie
p. 2753 - 2757
(2015/02/19)

Synthesis, screening and docking of small heterocycles as Glycogen Phosphorylase inhibitors
A series of morpholine substituted amino acids (phenylalanine, leucine, lysine and glutamic acid) was synthesized. A fragment-based screening approach was then used to evaluate a series of small heterocycles, including morpholine, oxazoline, dihydro-1,3-oxazine, tetrahydro-1,3-oxazepine, thiazoline, tetrahydro-1,3-pyrimidine, tetrahydro-1,3-diazepine and hexahydro-1H-benzimidazole, as potential inhibitors of Glycogen Phosphorylase a. Thiazoline 7 displayed an improved potency (IC50 of 25 μM) and had good LE and LELP values, as compared to heterocycles 1, 5, 9e13 and 19 (IC50 values of 1.1 mM e23.9 mM). A docking study using the crystal structure of human liver Glycogen Phosphorylase, provided insight into the interactions of heterocycles 5, 7, 9e13 and 19 with Glycogen Phosphorylase.
Schweiker, Stephanie S.,Loughlin, Wendy A.,Lohning, Anna S.,Petersson, Maria J.,Jenkins, Ian D.
p. 584 - 594
(2015/03/14)

Potent inhibition of norovirus by dipeptidyl α-hydroxyphosphonate transition state mimics
The design, synthesis, and evaluation of a series of dipeptidyl α-hydroxyphosphonates is reported. The synthesized compounds displayed high anti-norovirus activity in a cell-based replicon system, as well as high enzyme selectivity.
Mandadapu, Sivakoteswara Rao,Gunnam, Mallikarjuna Reddy,Galasiti Kankanamalage, Anushka C.,Uy, Roxanne Adeline Z.,Alliston, Kevin R.,Lushington, Gerald H.,Kim, Yunjeong,Chang, Kyeong-Ok,Groutas, William C.
p. 5941 - 5944
(2013/10/22)

Design, synthesis, and biological evaluation of novel dipeptide-type SARS-CoV 3CL protease inhibitors: Structure-activity relationship study
This work describes the design, synthesis, and evaluation of low-molecular weight peptidic SARS-CoV 3CL protease inhibitors. The inhibitors were designed based on the potent tripeptidic Z-Val-Leu-Ala(-pyrrolidone-3-yl)-2-benzothiazole (8; Ki = 4.1 nM), in which the P3 valine unit was substituted with a variety of distinct moieties. The resulting series of dipeptide-type inhibitors displayed moderate to good inhibitory activities against 3CLpro. In particular, compounds 26m and 26n exhibited good inhibitory activities with Ki values of 0.39 and 0.33 μM, respectively. These low-molecular weight compounds are attractive leads for the further development of potent peptidomimetic inhibitors with pharmaceutical profiles. Docking studies were performed to model the binding interaction of the compound 26m with the SARS-CoV 3CL protease. The preliminary SAR study of the peptidomimetic compounds with potent inhibitory activities revealed several structural features that boosted the inhibitory activity: (i) a benzothiazole warhead at the S1′ position, (ii) a γ-lactam unit at the S1-position, (iii) an appropriately hydrophobic leucine moiety at the S2-position, and (iv) a hydrogen bond between the N-arylglycine unit and a backbone hydrogen bond donor at the S3-position.
Thanigaimalai, Pillaiyar,Konno, Sho,Yamamoto, Takehito,Koiwai, Yuji,Taguchi, Akihiro,Takayama, Kentaro,Yakushiji, Fumika,Akaji, Kenichi,Kiso, Yoshiaki,Kawasaki, Yuko,Chen, Shen-En,Naser-Tavakolian, Aurash,Sch?n, Arne,Freire, Ernesto,Hayashi, Yoshio
p. 436 - 447
(2013/10/01)

Release of guests from encapsulated masked hydrophobic precursors by a phototrigger
Examples of release of organic acids from encapsulated p-methoxyphenacyl esters provided here demonstrate the value of a phototrigger strategy to release chemicals of interest in water from hydrophobic precursors. In this study, a photochemical β-cleavage process centered on the p-methoxyphenacyl group is exploited to release the acid of interest from a water-soluble capsule made up of octa acid.
Jayaraj, Nithyanandhan,Jagadesan, Pradeepkumar,Samanta, Shampa R.,Da Silva, Jose P.,Ramamurthy
supporting information
p. 4374 - 4377
(2013/09/24)

Inhibition of norovirus 3CL protease by bisulfite adducts of transition state inhibitors
Noroviruses are the most common cause of acute viral gastroenteritis, accounting for >21 million cases annually in the US alone. Norovirus infections constitute an important health problem for which there are no specific antiviral therapeutics or vaccines. In this study, a series of bisulfite adducts derived from representative transition state inhibitors (dipeptidyl aldehydes and α-ketoamides) was synthesized and shown to exhibit anti-norovirus activity in a cell-based replicon system. The ED 50 of the most effective inhibitor was 60 nM. This study demonstrates for the first time the utilization of bisulfite adducts of transition state inhibitors in the inhibition of norovirus 3C-like protease in vitro and in a cell-based replicon system. The approach described herein can be extended to the synthesis of the bisulfite adducts of other classes of transition state inhibitors of serine and cysteine proteases, such as α-ketoheterocycles and α-ketoesters.
Mandadapu, Sivakoteswara Rao,Gunnam, Mallikarjuna Reddy,Tiew, Kok-Chuan,Uy, Roxanne Adeline Z.,Prior, Allan M.,Alliston, Kevin R.,Hua, Duy H.,Kim, Yunjeong,Chang, Kyeong-Ok,Groutas, William C.
p. 62 - 65
(2013/02/23)

MACROCYCLIC AND PEPTIDOMIMETIC COMPOUNDS AS BROAD-SPECTRUM ANTIVIRALS AGAINST 3C OR 3C-LIKE PROTEASES OF PICORNAVIRUSES, CALICIVIRUSES AND CORONAVIRUSES
Antiviral protease inhibitors, including macrocylic transition state inhibitors and peptidomimetics are disclosed, along with related antiviral compounds, and methods of using the same to treat or prevent viral infection and disease. The compounds possess broad-spectrum activity against viruses that belong to the picornavirus-like supercluster, which include important human and animal pathogens including noroviruses, sapoviruses, enteroviruses, poliovirus, foot-and-mouth disease virus, hepatitis A virus, human rhinovirus (cause of common cold), human coronavirus (another cause of common cold), transmissible gastroenteritis virus, murine hepatitis virus, feline infectious peritonitis virus, and severe acute respiratory syndrome coronavirus.
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(2013/11/19)

ORGANOGOLD COMPLEXES AND METHODS FOR MAKING THE SAME
The present invention relates to chiral ligands deriving from a- and β-amino acids, and from metal complexes formed from the same. The ligands are useful with catalytic gold complexes, particularly Au(l) complexes.
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Page/Page column 59

(2012/10/18)

An improved large scale procedure for the preparation of N-Cbz amino acids
A simple and scalable method for the preparation of N-Cbz protected amino acids is presented which uses a mixture of aqueous sodium carbonate and sodium bicarbonate to maintain the appropriate pH during the addition of benzyl chloroformate. The method has been extended to other N-protections and is amenable to large scale preparation of an intermediate toward Zofenopril, an ACE inhibitor.
Pehere, Ashok D.,Abell, Andrew D.
experimental part
p. 1493 - 1494
(2011/05/16)

Addition of allylzinc to a-amino acid-derived imines: Synthesis of diamino alcohols by Hydroboration
Imines obtained by condensation of Z-pro- tected or Boc-protected α-amino aldehydes with α-amino tert-butyl esters or with O-silyl-protected amino alcohols were reacted with preformed allyl zinc yielding homoal- lylamines with yields around 50% and selectivities ranging from 50:50 to 90:10. Hydroboration of the terminal double bond furnished diamino alcohols with yields up to 97%. The configuration of the substrates was determined by X-ray-crystallographic analysis of a hydroboration product and comparison of physical data. Springer-Verlag 2010.
Virlouvet, Mickael,Goesmann, Helmut,Feldmann, Claus,Podlech, Joachim
scheme or table
p. 177 - 198
(2010/08/05)

AmIno Acid Homologation by the Blaise Reaction: A new entry into nitrogen heterocycles
(Chemical Equation Presented) A general strategy for the amino acid homologation via Blaise reaction and subsequent reduction is presented. This strategy involves the preparation of protected α-amino nitriles from the corresponding amino acids, followed by the zinc-mediated condensation of tert-butyl bromoacetate, to give the imidazolidones after iminozincate cyclization. Reduction gave the saturated imidazolidinones with cis or trans stereochemistry, depending on the reduction conditions. This strategy was applied to nonfunctionalized amino acids and to functionalized amino acids such as serine and aspartic acid. Additionally, acidic hydrolysis of cis or trans imidazolidinones to the corresponding chiral 4-aminopyrrolidones is described.
Cam, Thuy Hoang,Bouillere, Francelin,Johannesen, Sine,Zulauf, Anais,Panel, Cecilia,Pouilhes, Annie,Gori, Didier,Alezra, Valerie,Kouklovsky, Cyrille
scheme or table
p. 4177 - 4187
(2009/09/08)

Expedient solid-phase synthesis of both symmetric and asymmetric diol libraries targeting aspartic proteases
C2-symmetric diols have been shown to be highly potent against HIV-1 protease (PR). However, gaining access to these compounds has been hampered by the need of multistep solution-phase reactions which are often tedious and inefficient. In this Letter, we have disclosed a solid-phase strategy for rapid preparation of small molecule-based, symmetric and asymmetric diols as potential HIV-1 protease inhibitors. Upon biological screening, we found one of them, SYM-5, to be a potent and selective inhibitor (Ki = 400 nM) against HIV-1 protease.
Shi, Haibin,Liu, Kai,Leong, Wendy W.Y.,Yao, Shao Q.
supporting information; experimental part
p. 3945 - 3948
(2010/03/30)

Azadipeptide nitriles: Highly potent and proteolytically stable inhibitors of papain-like cysteine proteases
(Chemical Presented) Nitrogen instead of carbon: Azadipeptide nitriles resulting from CH/N exchange in the P1 position (see picture) are hitherto unknown. To access these compounds by conversion of amino acid-derived hydrazides with cyanogen bromide both nitrogen atoms of the hydrazide must be substituted. Despite a methylated P2-P1 peptide bond, the azadipeptide nitriles show a strong inhibitory activity against cysteine proteases, and a high stability towards chymotryptic hydrolysis.
Loeser, Reik,Frizler, Maxim,Schilling, Klaus,Guetschow, Michael
supporting information; experimental part
p. 4331 - 4334
(2009/02/08)

Substrate modulation of the activity of an artificial nanoesterase made of peptide-functionalized gold nanoparticles
Nanozymes with a heart of gold: A functional artificial protein has been prepared by grafting a dodecapeptide onto the surface of gold nanoparticles (see picture). The system catalyzes the hydrolysis of carboxylate esters and features enzyme-like properti
Pengo, Paolo,Baltzer, Lars,Pasquato, Lucia,Scrimin, Paolo
p. 400 - 404
(2008/02/04)

A Stereoselective entry into functionalized 1,2-diamines by zinc-mediated homologation of α-aminoacids
A general, stereoselective synthsis of 4,5-disubstituted imidazolidines-2-ones from α-aminoacids has been developed: the key steps are a Biaise reaction of bromoacetate on α-aminonitriles and further reduction. Although reduction with sodium cyanoborohydride afforded a mixture of cis and trans isomers 6a-e with moderate to good stereoselectivity, reduction with sodium in liquid ammonia gave the trans isomers 8a-e with complete stereoselectivity. Acidic hydrolysis of the urea gave 4-amino-pyrrolidinones, which can be precursors to β,γ-diaminoacids or 3-aminopyrrolidines.
Hoang, Cam Thuy,Alezra, Valerie,Guillot, Regis,Kouklovsky, Cyrille
p. 2521 - 2524
(2008/02/05)

Scope and limitations of sodium and potassium trimethylsilanolate as reagents for conversion of esters to carboxylic acids
Sodium or potassium trimethylsilanolate act as versatile and very powerful reagents for conversion of a wide variety of esters to carboxylic acids. The reactions were performed in tetrahydrofuran under mild reaction conditions with high to quantitative yields.
Lovric, Marija,Cepanec, Ivica,Litvic, Mladen,Bartolincic, Anamarija,Vinkovic, Vladimir
p. 109 - 115
(2008/02/04)

Circular dichroism studies on absolute configuration assignment of peptidomimetics with a terminal chiral 3-arylpropionic acid unit
The relationship between the molecular structure of peptidomimetics 1 and their chiroptical properties has been studied using circular dichroism spectroscopy. It was demonstrated that the sign of the Cotton effects occurring around 230 and 270 nm enables the direct assignment of stereochemistry at C-1 and C-3 carbon atoms. The TD-DFT calculations of the circular dichroism (CD) spectrum of one of the model compounds confirm the absolute stereochemistry assignment made experimentally. Thus, CD spectroscopy proved to be a simple, reliable and general tool for the determination of the absolute configuration of the stereogenic centers of peptidomimetics with a terminal 3-arylpropionic group.
Frelek, Jadwiga,Fryszkowska, Anna,Kwit, Marcin,Ostaszewski, Ryszard
p. 2469 - 2478
(2007/10/03)

Aqueous phase mono-protection of amines and amino acids as N-benzyloxycarbonyl derivatives in the presence of β-cyclodextrin
A simple and selective protection of amines/amino acids with Cbz-Cl has been achieved in aqueous phase with catalytic amounts of β-cyclodextrin in high yields at room temperature. This reaction proceeds without the formation of any by-products and has advantages over existing methods.
Pavan Kumar,Somi Reddy,Narender,Surendra,Nageswar,Rama Rao
p. 6393 - 6396
(2007/10/03)

Total synthesis of the chlorinated marine natural product dysamide B
Two approaches to the synthesis of (2S,4S)-5,5-dichloroleucine are compared, and the parent amino acid was used in the first total synthesis of the polychlorinaled marine natural product, dysamide B. A key step was the lead tetraacetate-mediated decarboxylation of an α,α-dichloro acid in the presence of 1,4-cyclohexadiene to generate the dichloromethyl group.
Durow, Amanda C.,Long, G. Cliona,O'Connell, Susan J.,Willis, Christine L.
p. 5401 - 5404
(2007/10/03)

α-Chymotrypsin-catalyzed peptide synthesis in frozen aqueous solution using N-protected amino acid carbamoylmethyl esters as acyl donors
A kinetically controlled peptide synthesis catalyzed by α-chymotrypsin was performed in frozen aqueous solution (ice, -24 °C). The yield of the peptide was significantly improved by the use of the carbamoylmethyl (Cam) ester as the acyl donor instead of the conventional ethyl ester. The peptide yield increased up to ca. 90% when N-benzyloxycarbonyl (CBZ)-Phe-OCam and H-Phe-NH2 were used as the acyl donor and nucleophile, respectively. Such an improvement of the peptide yield in ice was also observed in the coupling of other CBZ-amino acid Cam esters as acyl donors. Furthermore, this approach was applied to the synthesis of peptides containing d-amino acids. The peptides such as CBZ-d-Phe-Phe-NH2, CBZ-Phe-d-Phe-NH2 and CBZ-d-Phe-d-Phe-NH2 were also obtained in excellent to moderate yields in ice. A high diastereoselectivity towards the l-l peptide was observed when the racemic amino acid Cam ester was used as the acyl donor in ice.
Salam, Sayed Mohiuddin Abdus,Kagawa, Ken-Ichi,Kawashiro, Katsuhiro
p. 22 - 29
(2007/10/03)

Resolution of non-protein amino acids via Carica papaya lipase-catalyzed enantioselective transesterification
Carica papaya lipase-catalyzed transesterification of the 2,2,2-trifluoroethyl esters of N-benzyloxycarbonylated dl-amino acids carrying aliphatic side chains proceeded smoothly and, in almost all the cases, enantiospecifically (E = >200), affording the l-methyl esters and leaving the d-trifluoroethyl esters intact.
Miyazawa, Toshifumi,Onishi, Kazuki,Murashima, Takashi,Yamada, Takashi,Tsai, Shau-Wei
p. 2569 - 2573
(2007/10/03)

Practical and efficient enantioselective synthesis of α-amino acids in aqueous media
Enantiomerically pure natural and unnatural α-amino acids have been synthesized from a chiral melhyleneoxazolidinone by means of a highly diastereoselective 1,4-conjugate addition of alkyl iodides in aqueous media. The zinc-copper conjugate addition reaction exhibits high chemoselectivity, with the possibility of using functionalized iodides, to afford a single diastereomer in short reaction times and with good yields.
Suarez, Rosa M.,Sestelo, Jose Perez,Sarandeses, Luis A.
p. 3584 - 3587
(2007/10/03)

Cyclodextrin-mediated deacylation of amino acid esters with marked stereoselectivity.
With respect to the hydrolysis (deacylation) of Z-D(L)-amino acid esters (N-(benzyloxycarbonyl)-D(L)-amino acid p-nitrophenyl esters) mediated by alpha-, beta- and gamma-cyclodextrins (CyDs), a remarkably high enantioselectivity (L/D=9.0) was observed for the deacylation of Ala substrate with gamma-CyD. The kinetic results on the basis of the Michaelis-Menten principle indicate that the enantioselectivity should be mainly originated in the deacylation process of substrates following the formation of gamma-CyD-substrate (1 : 1) complexes. The computer modeling (molecular mechanics) studies on the inclusion complexes are also described.
Goto, Koichi,Nakashima, Kentaro,Tanoue, Osamu,Nukushina, Satoshi,Toudo, Isao,Imamura, Chikara,Ihara, Yasuji,Matsumoto, Yoko,Ueoka, Ryuichi
p. 1283 - 1285
(2007/10/03)

Flash vacuum pyrolysis of stabilised phosphorus ylides. Part 17. Preparation of aliphatic amino acid derived γ-alkoxycarbonyl-amino-β-oxo ylides and pyrolysis to give α,β-acetylenic γ-amino acid and GABA analogues
A series of eleven α-aminoacyl stabilised phosphorus ylides 9-19 have been prepared by condensation of N-alkoxycarbonyl protected amino acids with Ph3P = CHCO2Et using a carbodiimide peptide coupling reagent. Upon flash vacuum pyrolysis at 600 °C, these undergo extrusion of Ph3PO to give the corresponding α,β-acetylenic γ-amino esters 21-29, 33 and 34 in moderate yield. In two cases the terminal alkynes 30 and 31 are also formed. The β-aminoacyl ylide 20 from β-alanine similarly gives the α,β-acetylenic δ-amino ester 35 upon pyrolysis. Regioselective addition of HBr to the triple bond of one acetylenic ester 25 was observed giving a mixture of E and Z α-bromoacrylates 36. Hydrogenation of the N-Cbz acetylenic esters 21-23 and 33 results in N-deprotection and hydrogenation of the triple bond to afford the chiral GABA analogues 37-40 in 70 ->95% ee as determined by 19F NMR of their Mosher amides. Fully assigned 13C NMR spectra of all the ylides and acetylenic ester derivatives are presented.
Aitken, R. Alan,Karodia, Nazira,Massil, Tracy,Young, Robert J.
p. 533 - 541
(2007/10/03)

6-substituted amino-4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivatives as cysteine protease inhibitors
Novel 6-substituted amino-4-oxa-1-azabicyclo[3,2,0]heptan-7-one compounds, as well as the pharmaceutically acceptable salts thereof and diastereoisomers thereof, of formula I, are disclosed, which exhibit excellent cysteine protease inhibitory activity and may be used for treatment of different diseases such as muscular dystrophy, arthritis, myocardial infarction, Alzheimer's disease, bacterial infection, common cold, osteroporosis and cancer metastasis.
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(2008/06/13)

Phenylhydrazide as an enzyme-labile protecting group in peptide synthesis
The enzymatic cleavage of amino acid phenylhydrazides with the enzyme tyrosinase (EC 1.14.18.1) offers a new, mild, and selective method for C-terminal deprotection of peptides. The advantages of the described methodology are the very mild oxidative removal of the protecting group at room temperature and pH 7, a high chemo- and regioselectivity, and the availability of the biocatalyst. Even in oxygen-saturated solution, the oxidation of sensitive methionine residues was not observed. These features make the methodology suitable for the synthesis of sensitive peptide conjugates. Mechanistic data suggest that the hydrolysis of the oxidized adducts proceeds by a free-radical mechanism.
Voelkert, Martin,Koul, Surrinder,Mueller, Gernot H.,Lehnig, Manfred,Waldmann, Herbert
p. 6902 - 6910
(2007/10/03)

A novel concept in combinatorial chemistry in solution with the advantages of solid-phase synthesis: Formation of N-betaines by multicomponent domino reactions
Advantages of solid-phase and liquid-phase synthesis are combined in a new concept of combinatorial chemistry: a domino sequence comprising Knoevenagel and hetero-Diels-Alder reactions, with subsequent hydrogenation starting from protected aminoaldehydes, 1.3-dicarbonyl compounds, and enol ethers leads to N-heterocycles of high diversity with a betaine structure, which are isolated in highly pure form by precipitation with diethyl ether (see scheme), Cbz = benzylocycarbonyl, Bn = benzyl.
Tietze, Lutz F.
p. 903 - 905
(2007/10/03)

Simple and efficient preparation of (R)- and (S)-enantiomers of α-carbon deuterium-labelled α-amino acids
A procedure for the synthesis of (R)- and (S)-enantiomers of α-carbon deuterium-labelled α-amino acids, exemplified for (R)- and (S)-[2-2H1]-Leu is described. Starting from the respective (S)- or (R)-enantiomer or from the racemic mixture of an α-amino acid the selective proton exchange at the α-carbon is carried out by racemization via a Schiff base in monodeuterated acetic acid as solvent which serves as deuterium source. After N-protection the racemic mixture is liquid chromatographically separated into the individual (R)- and (S)-enantiomers on preparative scale employing a chiral anion exchanger based on carbamoylated quinine as chiral selector. After deprotection the enantiomerically pure products can be obtained in good yields.
Mitulovi, Goran,Laemmerhofer, Michael,Maier,Lindner, Wolfgang
p. 449 - 461
(2007/10/03)

The role of the medium in solvent isotope effects on serine protease action
The hydrolysis of N-carbobenzyloxyaminoacyl-O-p-nitrophenyl esters derived from L-leucine, L-phenylalanine, and L-tryptophan, with catalysis by bovine pancreatic α-chymotrypsin at pH 7.00 at 25.00°C in water containing acetonitrile from 15.0% to 60% (v/v)
Tian, Jiaher,Tan, Jue,Schowen, K. Barbara,Schowen, Richard L.
p. 781 - 786
(2007/10/03)

Chiral oxime ethers in asymmetric synthesis. 3. Asymmetric synthesis of (R)-N-protected α-amino acids by the addition of organometallic reagents to the ROPHy oxime of cinnamaldehyde
A new asymmetric synthesis of α-amino acids is described in which the key step is the diastereoselective addition of organometallic reagents to (R)-O-(1-phenylbutyl)cinnamaldoxime 5 to give hydroxylamines 6. Subsequent reductive cleavage of the N-O bond in the hydroxylamine 6 followed by N- protection gave the carbamates 7, which upon oxidation with ruthenium(III) chloride/periodate gave the N-protected amino acids 8. The method was also adapted to the synthesis of a quaternary amino acid 15 from the ketoxime ether 9.
Moody, Christopher J.,Gallagher, Peter T.,Lightfoot, Andrew P.,Slawin, Alexandra M. Z.
p. 4419 - 4425
(2007/10/03)

The phenyl hydrazide as an enzyme-labile protecting group - Oxidative cleavage with mushroom tyrosinase
Amino acid and peptide phenyl hydrazides are selectively cleaved by oxidation to acyl diazenes with mushroom tyrosinase and their subsequent hydrolysis.
Mueller, Gernot H.,Waldmann, Herbert
p. 3549 - 3552
(2007/10/03)

New facile alkoxycarbonylating agent, alkyl pyrazole-1-carboxylates. The preparation and the utilities
Alkyl pyrazole-1-carboxylates (2), which were readily prepared from alkyl chloroformate or carbazate in good yields, were provided as the new facile alkoxycarbonylating agents toward the Grignard reagents for the synthesis of one carbon higher carboxylic esters. Also amines were alkoxycarbonylated by 2 to produce the corresponding urethanes even in an aqueous medium. Benzyl 3,5-dimethylpyrazole-1-carboxylate (2d) could be utilized for the Cbz-protection of amino acids and esters in good yield without any racemization.
Kashima, Choji,Tsuruoka, Shiro,Mizuhara, Saori
p. 14679 - 14688
(2007/10/03)

New synthetic routes to α-amino acids and γ-oxygenated α-amino acids. Reductive denitration and oxidative transformations of γ-nitro-α-amino acids
Transformation of γ-nitro-α-amino acid derivatives into α-amino acids by reductive denitration, into the γ-oxo-α-amino acids by ozonolysis of the corresponding amino acid ester nitronate derivatives, and into γ-hydroxy-α-amino acid derivatives by subsequent reduction of the oxo functionality, can be achieved in good yields. As the γ-nitro-α-amino acid derivatives are prepared from N,O-protected dehydroalanines derivable from the corresponding alanine, serine and cysteine derivatives by specific routes, the overall procedures provide a means for selective conversion of these simple α-amino acids into more complex ones.
Crossley, Maxwell J.,Fung, Yik M.,Kyriakopoulos, Efstathia,Potter, Jeffrey J.
p. 1123 - 1130
(2007/10/03)

Addition of Organolithiums to the (R)-O-(1-Phenylbutyl)hydroxylamine (ROPHy) Oxime of Cinnamaldehyde. Asymmetric Synthesis of α-Aminoacids
A new asymmetric synthesis of α-aminoacids is described in which the key step is the diastereoselective addition of organolithium reagents to (R)-O-(1-phenylbutyl) cinnamaldoxime.
Moody, Christopher J.,Lightfoot, Andrew P.,Gallagher, Peter T.
p. 659 - 660
(2007/10/03)

Mild, selective cleavage of amino acid and peptide β-(trimethylsilyl)ethoxymethyl (SEM) esters by magnesium bromide
Magnesium bromide etherate has been previously shown to cleave β-(trimethylsilyl)ethoxymethyl (SEM) esters of aliphatic acids. This methodology has now been extended to amino acid and peptide derivatives in the presence of protecting groups typically encountered in peptide chemistry, including the Boc, Cbz, Fmoc and Troc carbamates as well as benzyl-, tert-butyl- and tert-butyldimethylsilyl ethers. The stability of fluoride sensitive protecting groups to magnesium bromide allows for added selectivity in the removal of SEM esters in organic synthesis.
Chen, Wei-Chuan,Vera, Matthew D.,Joullie, Madeleine M.
p. 4025 - 4028
(2007/10/03)