- Preparation of Constrained Unnatural Aromatic Amino Acids via Unsaturated Diketopiperazine Intermediate
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Unnatural aromatic amino acids are useful tools in drug discovery, since their insertion in bioactive peptide sequences can change the side chains spatial orientation, the backbone conformation and above all, their bioactivity. In this communication, we propose a straightforward method to synthesize 2′,6′-dimethyl-tyrosine and 2′,6′-dimehylphenyl-alanine derivatives as handling building blocks for peptide synthesis via unsaturated diketopiperazine (DKP) intermediate.
- Mollica, Adriano,Costante, Roberto,Mirzaie, Sako,Carradori, Simone,Macedonio, Giorgia,Stefanucci, Azzurra,Novellino, Ettore
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p. 2106 - 2110
(2016/11/23)
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- A general method for the facile synthesis of optically active 2-substituted piperazines via functionalized 2,5-diketopiperazines
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Upon utilization of some common methods described in the literature for the synthesis of chiral, 2-substituted 2,5-diketopiperazines, extensive racemization was observed. Further investigation showed that heating in the presence of a mild base racemized the chiral center in the product diketopiperazines. A generalized, readily scalable route was sought and, after investigating the effect of base and temperature, conditions were identified that promoted cyclization without erosion of enantiomeric excess. An array of functionalization was tolerated and this procedure serves as a useful and reliable method for the facile synthesis of this important class of compounds.
- Ashton, Kate S.,Denti, Mitchell,Norman, Mark H.,St. Jean Jr., David J.
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supporting information
p. 4501 - 4504
(2014/08/05)
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- AGRICULTURAL CHEMICAL CONTAINING 2,5-DIKETOPIPERAZINE DERIVATIVE AS ACTIVE INGREDIENT
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Disclosed herein is an agricultural agent containing a 2,5-diketopiperazine derivative capable of controlling plant diseases and promoting plant growth or an agriculturally acceptable salt thereof as an active ingredient.
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Paragraph 0033
(2013/06/05)
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- Linear and cyclic dipeptides with antimalarial activity
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Several natural and synthetic polypeptides possess important antimalarial activity. Shorter peptides with potent antimalarial activity have also been described, among them linear di-, tri-, tetra- and pentapeptides and their cyclic analogs. In an attempt
- Perez-Picaso, Lemuel,Rios, Maria Yolanda,Olivo, Horacio F.,Argotte-Ramos, Rocio,Rodriguez-Gutierrez, Maria
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p. 7048 - 7051,4
(2012/12/12)
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- Efficient microwave assisted syntheses of 2,5-diketopiperazines in aqueous media
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Aqueous in situ one-pot N-Boc-deprotection-cyclization of Nα-Boc-dipeptidyltert-butyl and methyl esters under microwave irradiation afforded 2,5-diketopiperazines (DKPs) in excellent yields. This protocol is rapid, safe, environmentally friendly, and high
- Perez-Picaso, Lemuel,Escalante, Jaime,Olivo, Horacio F.,Rios, Maria Yolanda
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experimental part
p. 2836 - 2849
(2009/12/06)
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- Microwave-assisted synthesis of the Sch?llkopf chiral auxiliaries: (3S)- and (3R)-3,6-dihydro-2,5-diethoxy-3-isopropyl-pyrazine
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A practical and efficient methodology for the laboratory scale preparation of Sch?llkopf's bis-lactim ether chiral auxiliaries (3S)- and (3R)-3,6-dihydro-2,5-diethoxy-3-isopropyl-pyrazine has been developed. The key step is the preparation of the 2,5-diketopiperazine derivative by microwave-assisted heating in water. The protocol avoids reactions at low temperature and the use of high boiling solvents. Only inexpensive and readily available starting materials are required. The bis-lactim ethers were produced in high yields on a multigram scale.
- Carlsson, Anna-Carin,Jam, Fariba,Tullberg, Marcus,Pilotti, ?ke,Ioannidis, Panos,Luthman, Kristina,Gr?tli, Morten
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p. 5199 - 5201
(2007/10/03)
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- Cyclization-activated prodrugs. Synthesis, reactivity and toxicity of dipeptide esters of paracetamol
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Dipeptide esters of paracetamol were prepared in high yields. These compounds are quantitatively hydrolyzed to paracetamol and corresponding 2,5-diketopiperazines at pH 7.4 and 37°C. The reactivity is increased in sarcosine and proline peptides and decreased by bulky side chains at both the N- and C-terminal residues of the dipeptide carrier. Moreover, dipeptide esters of paracetamol did not affect the levels of hepatic glutathione. Thus, dipeptides seem promising candidates as carriers for cyclization-activated prodrugs.
- Santos, Cledir,Mateus, Maria Luisa,Dos Santos, Ana Paula,Moreira, Rui,De Oliveira, Eliandre,Gomes, Paula
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p. 1595 - 1598
(2007/10/03)
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- Microwave-assisted synthesis of 2,5-piperazinediones under solvent-free conditions
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A general, efficient and environmentally friendly procedure for the synthesis of 2,5-piperazinediones is described, involving the microwave irradiation of N-Boc dipeptide esters. Georg Thieme Verlag Stuttgart.
- Lopez-Cobenas, Alberto,Cledera, Pilar,Sanchez, J. Domingo,Lopez-Alvarado, Pilar,Ramos, M. Teresa,Avendano, Carmen,Menendez, J. Carlos
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p. 3412 - 3422
(2007/10/03)
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- Solvent-free, efficient synthesis of 2,5-piperazinediones from Boc-protected dipeptide esters under microwave irradiation
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Microwave irradiation allows the efficient, solvent-free transformation of N-Boc dipeptide esters into 2,5-piperazinediones. The microwave-assisted conditions were found to be much better than traditional heating in terms of reaction time, yield and stere
- López-Cobe?as, Alberto,Cledera, Pilar,Sánchez, J. Domingo,Pérez-Contreras, Rafael,López-Alvarado, Pilar,Ramos, M. Teresa,Avenda?o, Carmen,Menéndez, J. Carlos
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p. 1158 - 1160
(2007/10/03)
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- An improved large scale synthesis of the Schoellkopf chiral auxiliaries: (2R)-and (2S)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine
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Syntheses of the Schoellkopf chiral auxiliaries have been carried out on large scale in high overall yields from D- and L-valine. This method avoids the use of highly toxic phosgene or triphosgene, low-temperature reactions, and unstable intermediates.
- Chen, Jianxie,Corbin, Scott P.,Holman, Nicholas J.
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p. 185 - 187
(2012/12/24)
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- Synthesis of optically active ring-A substituted tryptophans as IDO inhibitors
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The first synthesis of optically active 7-methoxy-d-tryptophan as well as other ring-A substituted tryptophans is described.
- Li, Xiaoyan,Yin, Wenyuan,Sarma, P.V.V. Srirama,Zhou, Hao,Jun Ma,Cook, James M.
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p. 8569 - 8573
(2007/10/03)
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- Proteomimetic compounds and methods
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The present invention relates to compounds and pharmaceutical compositions which are proteomimetic and to methods for inhibiting the interaction of an alpha-helical protein with another protein or binding site. Methods for treating diseases or conditions which are modulated through interactions between alpha helical proteins and their binding sites are other aspects of the invention.
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- Efficient asymmetric synthesis of biologically important tryptophan analogues via a palladium-mediated heteroannulation reaction
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A novel and concise synthesis of optically active tryptophan derivatives was developed via a palladium-catalyzed heteroannulation reaction of substituted o-iodoanilines with an internal alkyne. The required internal alkyne 14a or 25 was prepared in greater than 96% de via alkylation of the Schoellkopf chiral auxiliary 19 employing diphenyl phosphate as the leaving group. The Schoellkopf chiral auxiliary was chosen here for the preparation of L-tryptophans would be available from D-valine while the D-isomers required for natural product total synthesis would originate from the inexpensive L-valine (300-g scale). Applications of the palladium-catalyzed heteroannulation reaction were extended to the first asymmetric synthesis of L-isotryptophan 38 and L-benz[f]tryptophan 39. More importantly, the optically pure 6-methoxy-D-tryptophan 62 was prepared by this protocol on a large scale (>300 g). This should permit entry into many ring-A oxygenated indole alkaloids when coupled with the asymmetric Pictet-Spengler reaction. In addition, an improved total synthesis of tryprostatin A (9a) was accomplished in 43% overall yield employing this palladium-mediated process.
- Ma,Liu,Li,Flippen-Anderson,Yu,Cook
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p. 4525 - 4542
(2007/10/03)
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- Comparative study of synthetic approaches to 1- arylmethylenepyrazino[2,1-b]quinazoline-3,6-diones
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The transformation of 3-arylmethylenepiperazine-2,5-diones (1) into 1- arylmethylene-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones (2) was studied. Four synthetic methods were compared, namely direct condensation with the product of the reaction be
- Cledera, Pilar,Avendano, Carmen,Menendez, J. Carlos
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p. 12349 - 12360
(2007/10/03)
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- Practical synthesis of Schollkopf's bis-lactim ether chiral auxiliary: (3S)-3,6-dihydro-2,5-dimethoxy-3-isopropyl-pyrazine
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Practical methodology for the bis-O-methylation of (3S)-isopropyl-piperazine-2,5-dione 4 on a 45 g scale to generate Schollkopf's bis-lactim ether chiral auxiliary (3S)-3,6-dihydro-2,5-dimethoxy-3-isopropyl-pyrazine 1 has been developed. Monomethylated intermediates 5 and 6 are reported for the first time. The gelling effects of 4 in a range of common solvents are also described.
- Bull, Steven D.,Davies, Stephen G.,Moss, William O.
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p. 321 - 327
(2007/10/03)
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- Preparation of dipeptoid mimetics for the tetrapeptide cholecystokinin, CCK(30-33)
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The diastereoselective synthesis of 2,3-methanophenylalanine methyl esters (5) has been achieved in 58% yield. The preparation of the dehydropeptides (1, R = Me; 2, R = H) and the cyclopropylpeptides (3, R = Me; 4, R = H) possessing good binding affinities for the CCK-A and CCK-B receptors is described. Conformational studies of the dipeptide esters 1 and 3 indicated the presence of a β-turn within the peptide backbone, although there was no preference in type. The Phe and Trp moieties, however, did prefer to be situated on the same side of the peptide turn which is favourable for receptor binding.
- Walford,Campbell,Horwell
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p. 188 - 191
(2007/10/03)
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- THE "GAS-SOLID-PHASE" 2,5-DIOXOPIPERAZINE SYNTHESIS. CYCLIZATION OF VAPOROUS DIPEPTIDES ON SILICA SURFACE
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The "gas-solid-phase" method is used for the preparation of both symmetric and asymmetric 2,5-dioxopiperazines via cyclization of vaporous linear dipeptides in the presence of silica.
- Basiuk, Vladimir,Gromovoy, Taras Yu.
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p. 461 - 466
(2007/10/02)
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- Entry into 6-methoxy-D(+)-tryptophans. Stereospecific synthesis of 1-benzenesulfonyl-6-methoxy-D(+)-tryptophan ethyl ester
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A strategy for the synthesis of optically active ring-A methoxylated indole alkaloids which employs the Moody azide/Schollkopf chiral auxiliary protocol has resulted in the successful preparation of 1-benzenesulfonyl-6-methoxy-D(+)-tryptophan ethyl ester 16. This amino ester is required for the synthesis of Alstonia bisindole alkaloids including macralstonine 2 via an enantiospecific Pictet-Spengler reaction
- Allen,Hamaker,La Loggia,Cook
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p. 2077 - 2102
(2007/10/02)
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- CHIRAL LIGANDS CONTAINING HETEROATOMS. V ENANTIOSELECTIVE KETONE REDUCTION USING CHIRAL DIAMINES/METAL HYDRIDE SYSTEMS
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New chiral reducing agents prepared from zinc or magnesium dichloride, optically active diamines and diisobutylaluminium hydride, have been studied.These complexes were used in the reduction of a series of prochiral ketones and, compared with similar tin(
- Falorni, Massimo,Giacomelli, Giampaolo,Lardicci, Luciano
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p. 765 - 769
(2007/10/02)
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- A Mechanism for bitter Taste Sensibility in Peptides
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To estimate the steric distance between the bitter taste determinant sites in peptides, some cyclic dipeptides, amino acid anilides, amino acid cyclohexylamides, and benzoyl amino acids were synthesized and their tastes were evaluated.The diketopiperazine ring of cyclic dipeptides acted as a bitter taste determinant site due to its hydrophobicity.The steric distance between 2 sites was estimated as 4.1 Angstroem from the molecule models of cyclic dipeptides composed of typical amino acids in the bitter peptides.Due to the hypothesis of two bitter taste determinant sites, which bind with the bitter taste receptor via a "binding unit" and a "stimulating unit," a mechanism for the bitterness in peptides was postulated.
- Ishibashi, Norio,Kouge, Katsushige,Shinoda,Ichizo,Kanehisa, Hidenori,Okai, Hideo
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p. 819 - 828
(2007/10/02)
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- Neighboring Residue Effects: Evidence for Intramolecular Assistance to Racemization or Epimerization of Dipeptide Residues
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Dipeptides, their methyl esters, diketopiperazines (DKP), and N-substituted derivatives were racemized at high temperatures (approximately 120 deg C) in aqueous phosphate buffered solutions at pH values close to pH of maximum racemization (approximately 8).The racemization of the dipeptides Ala-Gly and Gly-Ala followed reversible first-order kinetics.The initial rate of racemization of DKP was very fast but soon slowed down, supposedly due to hydrolysis.The resulting rate was similar to that of the dipeptides.Esters of dipeptides followed racemization patterns similar to DKP.The racemization rate constants of the dipeptides studied were shown to be independent of the concentration of the dipeptide and the concentration of buffer.A carboxy-terminal proline residue greatly increased the rate of racemization (epimerization) of the amino-terminal residue.Increasing the basicity of the N-terminal amino acid residue increased the rate of racemization (or epimerization) of the C-terminal residue unless the C-terminal was sterically hindered as the Ile and Val.Decreasing the basicity of the N-terminal amino acid residue decreased racemization or epimerization for nonhindered C-terminal amino acids.These results support the influence of neighboring groups in the racemization or epimerization of dipeptides.DKP formation is a competing reaction allowing racemization or epimerization in dipeptides.Dipeptide racemization or epimerization is proposed to be the result of combination of intramolecular base assistance and DKP formation.
- Smith, Grant Gill,Evans, Robert C.,Baum, Rocky
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p. 7327 - 7332
(2007/10/02)
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- ENANTIOSELECTIVE SYNTHESIS OF NON-PROTEINOGENIC AMINO ACIDS VIA METALLATED BIS-LACTIM ETHERS OF 2,5-DIKETOPIPERAZINES
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Bis-lactim ethers 1 of 2,5-diketopiperazines contain a chiral inducing center, an acidic CH-bond and two sites susceptible to hydrolysis.They react with BuLi to give Li compounds of type 4, 15, 29 or 32, which possess a prochiral C atom.They readily add electrophiles (such as alkylating agents or carbonyl compounds) with unusually high diastereoface differentiation.In many cases the d.e-value (d.e. = diastereomeric excess = asymmetric induction) of the adduct exceeds 95percent.On hydrolysis the adducts are cleaved liberating the chiral auxiliary (used to build up the bis-lactim ether 1) and the target molecules, the optically active amino acid methyl esters of type 8, 19, 25 or 36.The two amino acid esters are separable either by fractional distillation or (eventually after further hydrolysis to amino acids) by chromatography.Transition state models are discussed that could explain the exceptionally high asymmetric induction and the predictability of the induced configuration.
- Schoellkopf, Ulrich
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p. 2085 - 2092
(2007/10/02)
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- Peptide Decomposition in the Neutral pH Region via the Formation of Diketopiperazines
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In the neutral pH region, the decomposition of the tripeptides Leu-Gly-Gly and Gly-Leu-Gly at 130 deg C and the hexapeptide Phe-Gly-Leu-Gly-Val-Gly at 100 deg C has been found to involve the formation of diketopiperazines from the N-terminal position of the peptides.
- Steinberg, Spencer M.,Bada, Jeffrey L.
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p. 2295 - 2298
(2007/10/02)
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- 15N NMR Spectroscopy. 19 - Spectroscopic Characterization of Cyclodipeptides (2,5-Dioxopiperazines)
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Various cyclodipeptides containing glycine, alanine, leucine, valine, phenylalanine, phenylglycine and sarcosine units were synthesized by cyclization of dipeptide pentachlorophenyl esters.The 13C and natural abundance 15N NMR spectra of these heterocycles were measured in trifluoroacetic acid and compared with the spectra of the corresponding amino acids and polypeptides.The 13C NMR carbonyl signals of all cyclodipeptides show a 1.5-4.0 ppm upfield shift relative to the corresponding polypeptides.The 15N NMR signals show no such consistent relationship.The substituent effects and the neighbouring residue effects observed in the 15NMR spectra of the cyclodipeptides are different from those of polypeptides, while the one bond N-H coupling constant of cis and trans amide groups was almost identical.The nitrogen and the carbonyl signal of the Gly units in cyclo-Gly-Phe show an extraordinary downfield shift, reflecting the interaction of the phenyl group with the 2,5-dioxopiperazine ring.
- Kricheldorf, Hans R.
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