- Divergent Synthesis of Bioactive Dithiodiketopiperazine Natural Products Based on a Double C(sp3)?H Activation Strategy
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This article provides a detailed report of our efforts to synthesize the dithiodiketopiperazine (DTP) natural products (?)-epicoccin G and (?)-rostratin A using a double C(sp3)?H activation strategy. The strategy's viability was first established on a model system lacking the C8/C8’ alcohols. Then, an efficient stereoselective route including an organocatalytic epoxidation was secured to access a key bis-triflate substrate. This bis-triflate served as the functional handles for the key transformation of the synthesis: a double C(sp3)?H activation. The successful double activation opened access to a common intermediate for both natural products in high overall yield and on a multigram scale. After several unsuccessful attempts, this intermediate was efficiently converted to (?)-epicoccin G and to the more challenging (?)-rostratin A via suitable oxidation/reduction and protecting group sequences, and via a final sulfuration that occurred in good yield and high diastereoselectivity. These efforts culminated in the synthesis of (?)-epicoccin G and (?)-rostratin A in high overall yields (19.6 % over 14 steps and 12.7 % over 17 steps, respectively), with the latter being obtained on a 500 mg scale. Toxicity assessments of these natural products and several analogues (including the newly synthesized epicoccin K) in the leukemia cell line K562 confirmed the importance of the disulfide bridge for activity and identified dianhydrorostratin A as a 20x more potent analogue.
- Thesmar, Pierre,Coomar, Seemon,Prescimone, Alessandro,H?ussinger, Daniel,Gillingham, Dennis,Baudoin, Olivier
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supporting information
p. 15298 - 15312
(2020/10/21)
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- Thermally induced oxidative decarboxylation of copper complexes of amino acids and formation of strecker aldehyde
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In the Maillard reaction, independent degradations of amino acids play an important role in the generation of amino-acid-specific products, such as Strecker aldehydes or their Schiff bases. Such oxidative decarboxylation reactions are expected to be enhan
- Nashalian, Ossanna,Yaylayan, Varoujan A.
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p. 8518 - 8523
(2015/04/22)
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- Cyclic dipeptides: Catalyst/promoter-free, rapid and environmentally benign cyclization of free amino acids
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"The best catalyst is no catalyst." With growing public concern over global warming and the amount of greenhouse gases, it is important to reduce the amount of chemicals and eliminate waste, to obtain better results in a simple, selective, safe, and environmentally benign fashion compared to conventional tedious chemical synthesis. Herein, we disclose an environmentally benign, rapid, catalyst/promoter/coupling reagent-free cyclization procedure of free amino acids to furnish exclusively cyclic dipeptides (2,5- diketopiperazines, DKPs) in excellent or even quantitative yield, along with their solid state self-assembling properties. This process is extremely simple and highly efficient with little or no traditional synthetic skills and without any chromatographic purification. Synthesis of structurally diverse DKPs has been achieved with a dramatic decrease in the reaction time, the amount/number of solvents used, a significant increase in the yield and nearly complete elimination of waste. As a result, this is an excellent example for the environmentally benign, clean and green chemistry concept. The most exciting outcome of our investigation is an unusual case of chiral self-recognition encountered upon the cyclization of rac-pipecolic acid, which resulted in the formation of the meso-product exclusively.
- Nonappa,Ahonen, Kari,Lahtinen, Manu,Kolehmainen, Erkki
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supporting information; experimental part
p. 1203 - 1209
(2011/06/26)
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- Absolute rate constants for the formation of nitrogen-centred radicals from chloramines/amides and their reactions with antioxidants
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Pulse radiolysis techniques have been employed to investigate the one-electron reduction of a variety of chloramines and chloramides. These include models for the side-chain of Lys (6-aminohexanoic acid chloramine and α-N-acetyl-Lys chloramine), Gly chloramine, β-alanine chloramine and two models of protein backbone amides, the chloramides of cyclo-(Gly)2 and cyclo-(Ala)2. The molar absorption coefficients and stabilities of these chloramines/amides have been determined. The one-electron reduction of these chloramine/amide species by hydrated electrons occurs with second-order rate constants of the order of 109-1010 M-1 s-1, and results in cleavage of the N-Cl bonds to yield nitrogen-centred radicals and chloride ions (as measured by high performance ion chromatography). The reactivities of the nitrogen-centred radicals have been investigated with the readily oxidisable quenchers, hydroquinone and Trolox. These quenchers were used as models of the in vivo antioxidants, ubiquinol-10 and α-tocopherol, and react with second-order rate constants between 2 × 107 and 1 × 108 M-1 s-1. No evidence was obtained in these pulse radiolysis experiments for a rapid rearrangement of the oxidising nitrogen-centred radicals to reducing carbon-centred radicals, though such reactions have been indicated in previous EPR studies.
- Pattison, David I.,Davies, Michael J.,Asmus, Klaus-Dieter
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p. 1461 - 1467
(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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- THE BIOORGANIC CHEMICAL REACTIONS OF N-PHOSPHOAMINO ACIDS WITHOUT SIDE CHAIN FUNCTIONAL GROUP PARTICIPATED BY PHOSPHORYL GROUP
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The bioorganic chemical reactions of N-phosphoamino acids without a side chain functional group are complex and interesting.With the participation of the phosphoryl group, N-phosphoamino acids can self-activate to give the peptides, esters and ester exchange products.An intramolecular mixed phosphorylic-carboxylic anhydride intermediate may exist in these bioorganic chemical processes.Key words: N-Phosphoamino acid; phosphoryl group; phosphorylic-carboxylic anhydride intermediate; NMR.
- Li, Yan-Mei,Zhao, Yu-Fen
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- Conformational effects in reversed-phase liquid chromatographic separation of diastereomers of cyclic dipeptides
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The capacity factors, k′, of 11 cyclic dipeptides (X-Y) including diastereomers have been determined on an RP-HPLC column in 30% and 50% methanol and 10%, 30%, and 50% acetonitrile solutions. These factors are roughly correlated with hydrophobic parameters, such as octanol-water partition coefficients estimated and k′ values for alcohols. For a pair of diastereomers of cyclic (L-X-L-Phe) and (L-X-D-Phe) derivatives k′LL is larger than k′LD and for cyclic (D-Ala-L-Trp) and (L-Ala-L-Trp) k′LL is smaller than k′DL, particularly in highly aqueous solutions. These elution orders can be well predicted by the holistic molecular surface area approach which takes into account the folded structures of cyclic dipeptides. The present results will be useful for prediction of the log k′ values of larger peptides and the hydrophobicity and related properties of peptides.
- Funasaki, Noriaki,Hada, Sakae,Neya, Saburo
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p. 1861 - 1867
(2007/10/02)
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- A novel approach to the synthesis of symmetric optically active 2,5-dioxopiperazines
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'Gas-solid-phase' method for the preparation of some cyclic dipeptides,2,5-dioxopiperazines (diketopiperazines), is described. The method implies cyclodimerization of vaporous aliphatic α-amino acids in the presence of silica at reduced pressure and yields optically active 2,5-dioxopiperazines.
- Basiuk,Gromovoy,Chuiko,Soloshonok,Kukhar
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p. 449 - 451
(2007/10/02)
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- Stereochemistry of Piperazine-2,5-dione Formation by Self-condensation of DL-Amino Acid Esters
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'Racemic' piperazine-2,5-diones (diketopiperazines, dkps) have been synthesized by the self-condensation of DL-amino acid esters without solvent.It was found that 'racemic' dkps consisted of cis- and trans-isomers, and that cis-dkp was preferentially formed in the early stage of the self-condensation, the cis:trans ratios gradually decreasing with increasing reaction time.These results may be attributed to the difference in the rates of cyclization of two kinds of diastereoisomeric dipeptide esters, intermediates in the formation of dkps from DL-amino acid esters.It was further confirmed that the pre-cis-dipeptide ester, which formed cis-dkp, cyclized faster than the pre-trans-dipeptide ester in methanol.Differences in steric hindrance in the cyclization reaction of pre-cis- and pre-trans-isomers may be an important factor in the stereochemistry of self-condensation.
- Naraoka, Hiroshi,Harada, Kaoru
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p. 1557 - 1560
(2007/10/02)
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