- Synthesis of Carbamates Using Yttria-Zirconia Based Lewis Acid Catalyst
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A variety of amines react with chloroformates in the presence of catalytic amount of yttria-zirconia based catalyst to afford the corresponding carbamates in excellent yields.
- Pandey, Rajesh K.,Dagade, Sharda P.,Dongare, Mohan K.,Kumar, Pradeep
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Read Online
- An efficient, stereocontrolled and versatile synthetic route to bicyclic partially saturated privileged scaffolds
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Herein, we describe the development of a simple, high yielding and stereocontrolled strategy for the synthesis of a series of triazolopiperazines and other biologically relevant fused scaffolds from optically active amino acids. This route was applied to the synthesis of 22 scaffolds containing new, previously inaccessible vectors and used to access a novel analogue of ganaplacide.
- Bond, Andrew D.,Hanby, Abigail R.,King, Thomas A.,Moss, Thomas A.,Sore, Hannah F.,Spring, David R.,Stewart, Hannah L.
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supporting information
p. 6818 - 6821
(2020/07/04)
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- Tailoring the Substitution Pattern on 1,3,5-Triazine for Targeting Cyclooxygenase-2: Discovery and Structure-Activity Relationship of Triazine-4-Aminophenylmorpholin-3-one Hybrids that Reverse Algesia and Inflammation in Swiss Albino Mice
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Here, we report analgesic and anti-inflammatory activity of a series of compounds obtained by appending 4-aminophenylmorpholin-3-one and acyclic, cyclic, or heterocyclic moieties on 1,3,5-triazine. The structures of compounds 4b and 6b are optimized for the best inhibition of COX-2 with IC50 values of 0.06 and 0.08 μM, respectively, and selectivity over COX-1 of 166 and >125, respectively. At the dose of 5 mg kg-1, these compounds significantly reduced acetic acid induced writhings, and their ED50 values were found to be 2.2 and 1.9 mg kg-1, respectively. Besides the cell-based and animal-based experiments showing the modes of action of these compounds targeting COX-2, the interaction behavior of 4b with COX-2 was also characterized, with physicochemical experiments including ITC, NMR, UV-vis, and molecular-modeling studies. Characteristically, these compounds interact with R120, Y355, and W385, the residues responsible for holding the substrate and mediating the process of electron transfer during the metabolic phase of the enzyme.
- Singh, Palwinder,Kaur, Sukhmeet,Kumari, Priya,Kaur, Baljit,Kaur, Manpreet,Singh, Gurjit,Bhatti, Rajbir,Bhatti, Manpreet
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supporting information
p. 7929 - 7941
(2018/09/06)
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- A N-(9-fluorenylmethyloxycarbonyl)-O-tert-butyl-L-tyrosine method for the preparation of
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The invention relates to a method for preparing N-(9-fluorenylmethoxy carbony)-O-tertiary butyl-L-tyrosine. The problem that an enantiomer is easily generated is solved. The method comprises the following synthetic steps: (1) dissolving L-Tyr into a methanol solution, adding SOCl2 and then carrying out reflux reaction, so as to obtain Tyr-OMe.HCl; (2) dissolving the Tyr-OMe.HCl into a water solution, adding AcOEt and Na2CO3 and then reacting with Z-Cl, and controlling the pH of the system at 7-10, so as to obtain Z-L-Tyr-OMe; (3) dissolving the Z-L-Tyr-OMe into a CH2Cl2 solution, adding H2SO4 and isobutene, reacting at normal temperature for 1-10 days, so as to obtain Z-L-Tyr(tBu)-OMe; (4) adding the NaOH solution to the Z-L-Tyr(tBu)-OMe to react, so as to obtain Z-L-Tyr(tBu); (5) dissolving the Z-L-Tyr(tBu) into methanol, adding Pd/C, and leading in hydrogen to react, so as to obtain L-Tyr(tBu); (6) dissolving Z-L-Tyr(tBu) into the water solution, adding the Na2CO3 and THF and then reacting with Fmoc-osu, and controlling the pH of the system at 8-10, so as to obtain Fmoc-Tyr(tBu). By adopting the method, generation of the enantiomer is avoided, and the citric acid is taken as an acidifier, so that the product is more stable, and the reaction processes do not relate to high-temperature and high-pressure reaction, and the method is applicable to large-scale production.
- -
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Paragraph 0045; 0047
(2017/04/11)
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- Synthesis, bioactivity, docking and molecular dynamics studies of furan-based peptides as 20s proteasome inhibitors
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Proteasome inhibitors are promising compounds for a number of therapies, including cardiovascular and eye diseases, diabetes, and cancers. We previously reported a series of furanbased peptidic inhibitors with moderate potencies against the proteasome b5 subunit, hypothesizing that the C-terminal furyl ketone motif could form a covalent bond with the catalytic residue, threonine 1. In this context, we describe further optimizations of the furan-based peptides, and a series of dipeptidic and tripeptidic inhibitors were designed and synthesized, aiming at improved potency and better solubility. Most of the tripeptidic inhibitors demonstrated improved potency and selectivity as b5 subunit inhibitors in both enzymatic and cellular assays, and good antineoplastic activities in various tumor cell lines were also observed. However, no inhibitory effects were observed for the dipeptidic compounds, which led us to presume that a noncovalent binding mode is adopted. Docking studies and molecular dynamics simulations were carried out to verify this presumption, with results showing that the distance between the furyl ketone motif and Thr1 is slightly too long to form covalent bond.
- Sun, Qi,Xu, Bo,Niu, Yan,Xu, Fengrong,Liang, Lei,Wang, Chao,Yu, Jiapei,Yan, Gang,Wang, Wei,Jin, Hongwei,Xu, Ping
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p. 498 - 510
(2015/03/18)
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- One-step C-terminal deprotection and activation of peptides with peptide amidase from stenotrophomonas maltophilia in neat organic solvent
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Chemoenzymatic peptide synthesis is a rapidly developing technology for cost effective peptide production on a large scale. As an alternative to the traditional C→N strategy, which employs expensive N-protected building blocks in each step, we have investigated an N→C extension route that is based on activation of a peptide C-terminal amide protecting group to the corresponding methyl ester. We found that this conversion is efficiently catalysed by Stenotrophomonas maltophilia peptide amidase in neat organic media. The system excludes the possibility of internal peptide cleavage as the enzyme lacks intrinsic protease activity. The produced peptide methyl ester was used for peptide chain extension in a kinetically controlled reaction by a thermostable protease.
- Arif, Muhammad I.,Toplak, Ana,Szymanski, Wiktor,Feringa, Ben L.,Nuijens, Timo,Quaedflieg, Peter J. L. M.,Wu, Bian,Janssen, Dick B.
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p. 2197 - 2202
(2014/07/21)
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- Highly efficient and selective phosphorylation of amino acid derivatives and polyols catalysed by 2-aryl-4-(dimethylamino)pyridine-N-oxides-towards kinase-like reactivity
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The chemoselective phosphorylation of hydroxyl containing amino acid derivatives and polyols by phosphoryl chlorides catalyzed by 2-aryl-4-(dimethylamino)pyridine-N-oxides is described.
- Murray, James I.,Woscholski, Rudiger,Spivey, Alan C.
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supporting information
p. 13608 - 13611
(2015/01/09)
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- Modular construction of quaternary hemiaminal-based inhibitor candidates and their in cellulo assessment with HIV-1 protease
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Non-peptidomimetic drug-like protease inhibitors have potential for circumventing drug resistance. We developed a much-improved synthetic route to our previously reported inhibitor candidate displaying an unusual quaternized hemi-aminal. This functional group forms from a linear precursor upon passage into physiological media. Seven variants were prepared and tested in cellulo with our HIV-1 fusion-protein technology that result in an eGFP-based fluorescent readout. Three candidates showed inhibition potency above 20 μM and toxicity at higher concentrations, making them attractive targets for further refinement. Importantly, our class of original inhibitor candidates is not recognized by two major multidrug resistance pumps, quite in contrast to most clinically applied HIV-1 protease inhibitors.
- Gros, Guillaume,Martinez, Lorena,Gimenez, Anna Servat,Adler, Paula,Maurin, Philippe,Wolkowicz, Roland,Falson, Pierre,Hasserodt, Jens
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supporting information
p. 5407 - 5413
(2013/09/02)
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- New β-strand templates constrained by Huisgen cycloaddition
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New peptidic templates constrained into a β-strand geometry by linking acetylene and azide containing P1 and P3 residues of a tripeptide by Huisgen cycloaddition are presented. The conformations of the macrocycles are defined by NMR studies and those that best define a β-strand are shown to be potent inhibitors of the protease calpain. The β-strand templates presented and defined here are prepared under optimized conditions that should be suitable for targeting a range of proteases and other applications requiring such a geometry.
- Pehere, Ashok D.,Abell, Andrew D.
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supporting information; experimental part
p. 1330 - 1333
(2012/05/20)
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- METHODS AND SYSTEMS FOR PREPARING IRREVERSIBLE INHIBITORS OF PROTEIN TYROSINE PHOSPHATASES
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Described herein are the preparation and use of novel bromo- phosphonomethylphenylalanine amino acid derivatives (BrPmp) and BrPmp-containing peptides as specific, irreversible protein tyrosine phosphatase inhibitors, which are suitable for application in peptide synthesis. These derivatives are particularly advantageous since their synthesis is both easy and scalable, and they are suitable for peptide synthesis. The BrPmp derivatives described herein can be appropriately protected to allow for solid phase peptide synthesis (SPPS) and incorporation into peptides for preparation of protein tyrosine phosphatase inhibitors and inhibitor libraries. The peptides and peptide libraries can be used to identify new protein tyrosine phosphatase specific sequences and profile protein tyrosine phosphatase activity in cell lysates, diagnostic samples and biopsy samples.
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Page/Page column 19
(2011/10/03)
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- A protected l-bromophosphonomethylphenylalanine amino acid derivative (BrPmp) for synthesis of irreversible protein tyrosine phosphatase inhibitors
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Protein tyrosine phosphatases (PTPs) are important therapeutic targets for medicinal chemists and biochemists. General strategies for the development of inhibitors of these enzymes are needed. Several modular strategies which rely on phosphotyrosine mimics are known for PTP inhibitors. Previous strategies include phosphonomethylphenylalanine (Pmp) derivatives which act as competitive inhibitors. Pmp amino acid derivatives have been used to develop specific inhibitors by incorporation into sequences recognized by the PTP of interest. We report the synthesis of a new phosphonotyrosine analog, l- phosphonobromomethylphenylalanine (BrPmp), which acts as an inhibitor of PTPs. The BrPmp derivative was prepared as an Fmoc-protected amino acid which can be used in standard solid phase peptide synthesis (SPPS) methods. The synthesis of the protected amino acid derivative requires 11 steps from tyrosine with a 30% overall yield. Enzyme inhibition studies with the PTP CD45 demonstrate that BrPmp derivatives are irreversible inhibitors of the enzyme. A tripeptide which incorporated BrPmp had increased inhibitory potency against PTP relative to BrPmp alone, confirming that the incorporation of BrPmp into peptide sequences provides additional context to improve enzyme binding.
- Tulsi, Naresh S.,Downey, A. Michael,Cairo, Christopher W.
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experimental part
p. 8679 - 8686
(2011/02/25)
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- Incorporation of phosphole moieties into the side chain of tyrosine and phenylalanine
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A tyrosine derivative with a phosphole moiety covalently attached to the phenolic hydroxy group was successfully prepared through P-O bond-forming reaction, via a nucleophilic substitution reaction at the phosphorus, by slow addition of N-CBz-protected tyrosine methyl ester to a chlorophosphole adduct in the presence of triethylamine, albeit with a low yield. Furthermore, a phenylalanine derivative with a phosphole-containing side chain was conveniently synthesized by Stille cross-coupling reaction of a stannylphosphole reagent with N-Boc-protected 4-iodophenylalanine methyl ester, using Pd(dba)2 as catalyst, in the absence of any additional ligand. These molecules must be seen as valuable building blocks for the preparation of metalloproteins of interest for chemical, biological, and medical applications
- Bisaro, Fabrice,Lefloch, Pascal
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experimental part
p. 3081 - 3085
(2011/02/26)
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- Facile incorporation of a phosphatase activity-dependent quinone methide generating motif into phosphotyrosine
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A novel phosphotyrosine analogue that incorporates a phosphatase activity-dependent quinone methide generating motif is synthesized from tyrosine. Following orthoformylation of the phenol moiety of methyl N-Cbz-tyrosinate, the Fmoc-protected 3-difluoromethyl analogue of phosphotyrosine is obtained by functional group transformations. Georg thieme Verlag Stuttgart.
- Shen, Kui,Qi, Lixin,Ravula, Mohini
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experimental part
p. 3765 - 3768
(2010/06/12)
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- Design, synthesis, and application of enantioselective coupling reagent with a traceless chiral auxiliary
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(Chemical Equation Presented) Stable chiral N-triazinylbrucinium tetrafluoroborate enantioselectively activates racemic carboxylic acids yielding enantiomerically enriched amides, esters, and dipeptides with er from 8:92 to 0.5:99.5. Due to the departure
- Kolesinska, Beata,Kaminski, Zbigniew J.
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supporting information; experimental part
p. 765 - 768
(2009/09/06)
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- Structural and initial biological analysis of synthetic arylomycin A 2
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The growing threat of untreatable bacterial infections has refocused efforts to identify new antibiotics, especially those acting by novel mechanisms. While the inhibition of pathogen proteases has proven to be a successful strategy for drug development,
- Roberts, Tucker C.,Smith, Peter A.,Cirz, Ryan T.,Romesberg, Floyd E.
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p. 15830 - 15838
(2008/09/19)
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- Structure-activity relationship analysis of the selective inhibition of transglutaminase 2 by dihydroisoxazoles
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Human transglutaminase 2 (TG2) is believed to play an important role in the pathogenesis of various human disorders including celiac sprue, certain neurological diseases, and some types of cancer. Selective inhibition of TG2 should therefore enable further investigation of its role in physiology and disease and may lead to effective clinical treatment. Recently we showed that certain 3-halo-4-,5-dihydroisoxazole containing compounds are selective inhibitors of human TG2 with promising pharmacological activities. Here, we present definitive evidence that this class of compounds targets the active site of human TG2. Structure-activity relationship studies have provided insights into the structural prerequisites for selectivity and have led to the discovery of an inhibitor with about 50-fold higher activity than a prototypical dihydroisoxazole inhibitor with good in vivo activity. A method for preparing enantiomerically enriched analogues was also developed. Our studies show that the 5-(S)-dihydroisoxazole is a markedly better inhibitor of human TG2 than its 5-(R) stereoisomer.
- Watts, R. Edward,Siegel, Mathew,Khosla, Chaitan
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p. 7493 - 7501
(2007/10/03)
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- Studies toward diazonamide A: Initial synthetic forays directed toward the originally proposed structure
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A brief introduction into the chemistry of diazonamide A (1) is followed by first-generation sequences to access the originally proposed structure for this unusual marine natural product. These explorations identified a route capable of delivering a model compound possessing the complete heteroaromatic core of the natural product, highlighting in the process several unanticipated synthetic challenges which led both to new methodology as well as an improved synthetic plan that was successfully applied to fully functionalized intermediates.
- Nicolaou,Snyder, Scott A.,Huang, Xianhai,Simonsen, Klaus B.,Koumbis, Alexandros E.,Bigot, Antony
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p. 10162 - 10173
(2007/10/03)
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- Chemistry and biology of diazonamide A: Second total synthesis and biological investigations
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As an especially unique target for chemical synthesis, diazonamide A has the potential to be constructed through a plethora of synthetic routes, each attended by different challenges and opportunities for discovery. In this article, we detail our second total synthesis of diazonamide A through a sequence entirely distinct from that employed in our first campaign, one whose success required the development of several special strategies and tactics. We also disclose our complete studies regarding the chemical biology of diazonamide A and its structural congeners, and more fully delineate the scope of our protocol for Robinson-Gabriel cyclodehydration using pyridine-buffered POCl 3.
- Nicolaou,Hao, Junliang,Reddy, Mali V.,Rao, Paraselli Bheema,Rassias, Gerasimos,Snyder, Scott A.,Huang, Xianhai,Chen, David Y.-K.,Brenzovich, William E.,Giuseppone, Nicolas,Giannakakou, Paraskevi,O'Brate, Aurora
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p. 12897 - 12906
(2007/10/03)
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- Total synthesis of TMC-95A and -B via a new reaction leading to Z-enamides. Some preliminary findings as to SAR
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A full account of the total syntheses of proteasome inhibitors TMC-95A and -B is provided. A key feature of the syntheses involved installation of a cis-propenylamide moiety by a thermal rearrangement of an α-silylallyl amide. The scope and mechanism of the enamide-forming reaction are discussed. Also provided are some preliminary results from SAR studies. It was found that simplified analogues can retain the full potency of proteasome inhibition.
- Lin, Songnian,Yang, Zhi-Qiang,Kwok, Benjamin H. B.,Koldobskiy, Michael,Crews, Craig M.,Danishefsky, Samuel J.
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p. 6347 - 6355
(2007/10/03)
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- Synthesis and biological activity of new potential agonists for the human adenosine A2A receptor
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New adenosine derivatives have been synthesized and tested as putative agonists of adenosine receptors. Compounds 2-6 derive from the introduction of several types of substituents (electron donating, electron withdrawing, and halogens) in the para-position of the phenyl ring of the parent compound 1, and compound 7 lacks the hydroxyl group of amino alcohol 1. In radioligand binding assays using recombinant human A1, A2A, A2B, and A3 receptors, all compounds showed very low or negligible affinity for A1 and A2B receptors but compounds 3, 5, and 7 displayed a remarkably potent affinity for the A2A receptor with Ki values of 1-5 nM. Bromo derivative 3 displayed a selectivity A1/A2A = 62 and A3/A2A = 16 whereas the presence of a hydroxyl group (compound 5) improved the selectivity of A 1/A2A and A3/A2A to 120- and 28-fold, respectively. When the methoxy derivative 4 lacks the hydroxyl group on the side chain (compound 7), the binding affinity for A2A is increased to 1 nM, improving selectivity ratios to 356- and 100-fold against A1 and A3, respectively. In Chinese hamster ovary cells transfected with human A2A and A2B receptors, most compounds showed a remarkable activity for the A2A receptor, except chloro derivative 2, with EC50 values ranging from 1.4 to 8.8 nM. The compounds behaved as good A2A agonists, and all were more selective than 5′-(N-ethylcarboxamino)adenosine (NECA), with A2B/A 2A ratios of cAMP accumulation ranging from 48 for compound 2 to 666 for compound 7 while the corresponding A2B/A2A ratio for NECA was only 9. Compounds 1, 3, 5, and 7 also displayed higher selectivities than NECA up to 100-fold in isolated aortas of rat and guinea pig. In guinea pig tracheal rings precontracted by carbachol, compounds 2 and 4 were more potent than adenosine (100-fold) and NECA (10-fold), whereas compounds I and 7 displayed similar effects to NECA. Pretreatment of the tracheal rings with A2, A2A, and A2B receptor antagonists 3,7-dimethyl-L-propargylxanthine, 8-(3-chlorostyryl)caffeine, and alloxazine produced a marked inhibition of the tracheal relaxations induced by compounds 1, 2, and 4, but none of the compounds showed selectivity toward any of the adenosine receptors.
- Bosch, M. Pilar,Campos, Francisco,Niubó, Itziar,Rosell, Gloria,Díaz, J. Luis,Brea,Loza, M. Isabel,Guerrero, Angel
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p. 4041 - 4053
(2007/10/03)
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- HYDROXYMORPHOLINONE DERIVATIVE AND MEDICINAL USE THEREOF
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A compound represented by the following formula (I) wherein R1 and R2 are each a lower alkyl group optionally having substituents, which has a calpain inhibitory activity, or a salt thereof is provided.
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- Syntheses of amino alcohols and chiral C2-symmetric bisoxazolines derived from O-alkylated R-4-hydroxyphenylglycine and S-tyrosine
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Chiral C2-symmetric bisoxazolines 1b-f and 2b,c, derived from 4′-O-alkylated R-4-hydroxyphenylglycine or S-tyrosine, were prepared. As intermediates, a series of chiral amino alcohols possessing substituted phenolic groups was prepared and fully characterized.
- Caplar, Vesna,Raza, Zlata,Katalenic, Darinka,Zinic, Mladen
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- The second total synthesis of diazonamide A
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The uniquely woven, highly strained molecular architecture and the potent antitumor activity of diazonamide A (1) make this natural product an attractive synthetic target. The key steps in this total synthesis of 1 include a novel Sml2-induced
- Nicolaou,Bheema Rao, Paraselli,Hao, Junliang,Reddy, Mali Venkat,Rassias, Gerasimos,Huang, Xianhai,Chen, David Y.-K.,Snyder, Scott A.
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p. 1753 - 1758
(2007/10/03)
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- Novel 6-Hydroxy-3-morpholinones as cornea permeable calpain inhibitors
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A novel series of 6-hydroxy-3-morpholinones, in which the functional aldehyde and the hydroxy group of P2 site form a cyclic hemiacetal, was identified as calpain inhibitors. The placement of isobutyl group at the 2-position of the 3-morpholino
- Nakamura, Masayuki,Miyashita, Hiroyuki,Yamaguchi, Masazumi,Shirasaki, Yoshihisa,Nakamura, Yoshikuni,Inoue, Jun
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p. 5449 - 5460
(2007/10/03)
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- Pd/C-catalyzed chemoselective hydrogenation in the presence of a phenolic MPM protective group using pyridine as a catalyst poison
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Employment of a Pd/C-pyridine combination as a catalyst is a very useful method for the selective removal (hydrogenolysis) of phenolic O-benzyl, N-Cbz and benzyl ester protective groups and for the selective hydrogenation of nitro and olefin functions of phenol derivatives protected with the MPM group. These discriminatory results are apparently attributable to the effect of pyridine. The MPM group could be extensively applied to chemoselective hydrogenation as a protective group for phenolic hydroxyl functions.
- Sajiki, Hironao,Hirota, Kosaku
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p. 320 - 324
(2007/10/03)
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- The total synthesis of proteasome inhibitors TMC-95A and TMC-95B: Discovery of a new method to generate cis-propenyl amides
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Silatropic and ene-like bond reorganizations (see scheme, left) were the key steps in the first total synthesis of the title compounds, which only differ in stereochemistry at the remote C36 stereocenter. Other key steps include a Suzuki biaryl construction, a diastereofacial dihydroxylation reaction, and a macrolactamization.
- Lin, Songnian,Danishefsky, Samuel J.
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p. 512 - 515
(2007/10/03)
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- Tyrosine alkoxyguanidines as integrin inhibitors
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The present invention relates to novel tyrosine alkoxyguanidine compounds that are inhibitors of alpha V (αv) integrins, for example αvβ3 and αvβ5 integrins, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof. The compounds may be used in the treatment of pathological conditions mediated by αvβ3 and αvβ5 integrins, including conditions such as tumor growth, metastasis, restenosis, osteoporosis, inflammation, macular degeneration, diabetic retinopathy, and rheumatoid arthritis. The compounds have the general formula: where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, m and n are defined herein.
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Page column 29-30
(2008/06/13)
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- Synthesis of the functionalized macrocyclic core of proteasome inhibitors TMC-95A and B
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An ordered assembly of four building blocks (2-5) forms the basis of the synthesis of 1, which contains the core structure of TMC-95A and B - two potent proteasome inhibitore (see scheme; TIPS = triisopropylsilyl, Cbz = benzoxycarbonyl, Boc = tert-Boc = tert-butoxycarbonyl).
- Lin, Songnian,Danishefsky, Samuel J.
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p. 1967 - 1970
(2007/10/03)
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- Cleavage of benzyloxycarbonyl-5-oxazolidinones to α-benzyloxycarbonylamino-α-alkyl esters by alcohols and sodium hydrogen carbonate
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The reaction of benzyloxycarbonyl-5-oxazolidinones with alcohols and sodium hydrogen carbonate to afford the corresponding benzyloxycarbonyl esters is described.
- Allevi, Pietro,Cighetti, Giuliana,Anastasia, Mario
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p. 5319 - 5321
(2007/10/03)
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- Antibody catalyzed modification of amino acids. Efficient hydrolysis of tyrosine benzoate
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Esterase antibody 522c2, the first example of a catalytic antibody specifically programmed to control the reactivity of functional groups on the side chain of tyrosine, accelerates the hydrolysis of benzoate esters of L-tyrosine and tyrosine-containing dipeptides by a factor of 104 and is moderately active against other benzoate esters.
- Benedetti,Berti,Colombatti,Flego,Gardossi,Linda,Peressini
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p. 715 - 716
(2007/10/03)
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- Flexible and convergent total synthesis of cyclotheonamide B
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A convergent approach using two key intermediates, segment A [a L-proline-L-α-hydroxy-β-homoarginine-D-phenylalamine (Pro-hArg-D-Phe) tripeptide] and segment B [a vinylogous L-tyrosine-L-2,3-diaminopropanoic acid (vTyr-Dpr) dipeptide], was developed for the synthesis of cyclotheonamide B. The starting compound for the preparation of the hArg moiety 7, the predominant part of segment A, was N(α)-(benzyloxycarbonyl)-N(ω),N(ω)'-bis(tert-butyloxycarbonyl)-l-ar ginine methyl ester (15), which was converted into the aldehyde 16 and subsequently homologated using [tris(methylthio)methyl]lithium as a carboxylic acid anion equivalent. Coupling with properly protected Pro and D-Phe derivatives gave smoothly the desired Pro-hArg-D-Phe tripeptide derivative 24. The key feature of segment B, i.e., the L-tyrosine-derived α,β-unsaturated γ-amino acid 4, was prepared by a Wadsworth-Emmons olefination of the aldehyde 29 derived from N-(tert-butyloxycarbonyl), O-tert-butyl-L-tyrosine methyl ester (28). Selective N-(tert-butyloxycarbonyl) removal in the presence of the aryl tert-butyl ether present in the fully protected segment B, i.e., 32, was achieved by treatment with trimethylsilyl triflate/2,6-lutidine to give vTyr-Dpr dipeptide derivative 34 in quantitative yield. Coupling of the key intermediates 24 and 34 using 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) afforded the protected linear pentapeptide 35 in high yield. Treatment of 35 with Pd(PPh3)4/morpholine resulted in simultaneous removal of the C-terminal allyl group and the N-terminal allyloxycarbonyl group to yield 36. Ring closure was effected under dilution conditions by treatment with TBTU/1-hydroxybenzotriazole/4-(dimethylamino)pyridine and gave the protected cyclopentapeptide 37 in 61% yield. Oxidation of the hydroxyl group with Dess-Martin periodinane (24 h, 40°C) in the presence of tert-butyl alcohol gave 38, which was then subjected to O,N-deprotection with trifluoroacetic acid/thioanisole. Subsequent HPLC purification afforded cyclotheonamide B in an overall yield of 1.8% in 17 steps.
- Bastiaans, Harold M.M.,Van der Baan, Juul L.,Ottenheijm, Harry C.J.
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p. 3880 - 3889
(2007/10/03)
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- Total synthesis of cyclotheonamide B, a facile route towards analogues
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A flexible, convergent synthesis of cyclotheonamide B (1b) was developed, starting from the constituent amino acids, using conventional benzyl-, t-butyl- and allyl-based protecting groups. By modification of the key intermediates, this approach allows the preparation of cyclotheonamide analogues.
- Bastiaans, Harold M. M.,Van Der Baan, Juul L.,Ottenheijm, Harry C. J.
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p. 5963 - 5966
(2007/10/02)
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- Synthesis of Isodityrosine, Dityrosine and Related Compounds by Phenolic Oxidation of Tyrosine and Phenylglycine Derivatives Using an Electrochemical Method
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The phenolic oxidation of L-tyrosine derivatives by electrolysis and zinc reduction produced the coupling products leading to isodityrosine and dityrosine.The oxidation mode could be controlled by altering halogen substituents (Br or I) at two ortho positions of phenol groups.Additionally, this methodology was applied to 4-hydroxy-D-phenylglycine derivatives, providing the correspoinding oxidative products.
- Nishiyama, Shigeru,Kim, Moon Hwan,Yamamura, Shosuke
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p. 8397 - 8400
(2007/10/02)
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- Amino alcohols as C-Terminal Protecting Groups in Peptide Synthesis
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The synthesis of peptides using amino alcohols as C-terminal protecting groups is described.C-Terminal protection of amino acid could be accomplished by reduction of the terminal carboxyl group to a hydroxymethyl group, and regeneration of the carboxyl group could be achieved by Jones' oxidation.This method was applied to the formation of di- and tripeptides.
- Kashima, Choji,Harada, Kazuo,Fujioka, Yoko,Maruyama, Tatsuya,Omote, Yoshimori
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p. 535 - 540
(2007/10/02)
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- Enzyme-Catalyzed Irreversible Formation of Peptides Containing D-Amino Acids
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Procedures have been developed for the preparation of dipeptides Z-L-Tyr-D-X and Z-L-Phe-D-X using Z-L-Tyr-OMe (or Z-L-Phe-OMe) and D-amino acid esters or amides (D-X) as substrates and soluble or immobilized α-chymotrypsin as a catalyst.The formation of each of these peptides in miscible or immiscible organic solvent-water systems in a kinetically controlled approach is virtually irreversible with no side reactions or racemization.Kinetic studies indicate that D-amino acid esters are about 100 times that of water and 10percent that of L-amino acid esters as a nucleophile in deacylation reactions.The effects of pH, organic solvents, temperature, and substrate and enzyme concentrations on the yield and the stability of the enzyme in syntheses have been studied and the results compared with those in the enzyme-catalyzed formation of L-L-dipeptides.
- West, J. Blair,Wong, Chi-Huey
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p. 2728 - 2735
(2007/10/02)
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- THE CONVERSION OF L-GLUTAMATE TO L-TYROSINE
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The Diels Alder reaction of a glutamate derived dienophile with trans-1-methoxy-3-trimethylsilyloxy-1,3-butadiene affords a spirodienone.This, upon treatment with aqueous base leads to N-CBz-tyrosine.Optical activity is substantially maintained throughout the process.
- Danishefsky, Samuel,Morris, Joel,Clizbe, Lane A.
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p. 1205 - 1208
(2007/10/02)
-
