- Metal-free approach for hindered amide-bond formation with hypervalent iodine(iii) reagents: application to hindered peptide synthesis
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A new bio-inspired approach is reported for amide and peptide synthesis using α-amino esters that possess a potential activating group (PAG) at the ester residue. To activate the ester functionality under mild metal-free conditions, we exploited the facile dearomatization of phenols with hypervalent iodine(iii) reagents. Using a pyridine-hydrogen fluoride complex, highly reactive acyl fluoride intermediates can be successfully generated, thereby allowing for the smooth formation of sterically hindered amides and peptides from bulky amines and α-amino esters, respectively.
- Lee, Hyo-Jun,Huang, Xiao,Sakaki, Shigeyoshi,Maruoka, Keiji
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p. 848 - 855
(2021/02/09)
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- Peptide Mechanosynthesis by Direct Coupling of N-Protected α-Amino Acids with Amino Esters
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In view of developing alternatives to classical peptide synthesis strategies that suffer from low efficacy and negative environmental impact, the reactivity of N-protected α-amino acids, amino esters, and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide was
- Porte, Vincent,Thioloy, Marion,Pigoux, Titouan,Métro, Thomas-Xavier,Martinez, Jean,Lamaty, Frédéric
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supporting information
p. 3505 - 3508
(2016/07/28)
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- Conformation-specific spectroscopy of capped, gas-phase Aib oligomers: Tests of the Aib residue as a 310-helix former
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The conformational preferences of a series of capped peptides containing the helicogenic amino acid aminoisobutyric acid (Aib) (Z-Aib-OH, Z-(Aib)2-OMe, and Z-(Aib)4-OMe) are studied in the gas phase under expansion-cooled conditions. Aib oligomers are known to form 310-helical secondary structures in solution and in the solid phase. However, in the gas phase, accumulation of a macrodipole as the helix grows could inhibit helix stabilization. Implementing single-conformation IR spectroscopy in the NH stretch region, Z-Aib-OH and Z-(Aib)2-OMe are both observed to have minor conformations that exhibit dihedral angles consistent with the 310-helical portion of the Ramachandran map (φ, ψ = -57°, -30°), even though they lack sufficient backbone length to form 10-membered rings which are a hallmark of the developed 310-helix. For Z-(Aib)4-OMe three conformers are observed in the gas phase. Single-conformation infrared spectroscopy in both the NH stretch (Amide A) and CO stretch (Amide I) regions identifies the main conformer as an incipient 310-helix, having two free NH groups and two C10 H-bonded NH groups, labeled an F-F-10-10 structure, with a calculated dipole moment of 13.7 D. A second minor conformer has an infrared spectrum characteristic of an F-F-10-7 structure in which the third and fourth Aib residues have φ, ψ = 75°, -74° and -52°, 143°, Ramachandran angles which fall outside of the typical range for 310-helices, and a dipole moment that shrinks to 5.4 D. These results show Aib to be a 310-helix former in the gas phase at the earliest stages of oligomer growth.
- Gord, Joseph R.,Hewett, Daniel M.,Hernandez-Castillo, Alicia O.,Blodgett, Karl N.,Rotondaro, Matthew C.,Varuolo, Adalgisa,Kubasik, Matthew A.,Zwier, Timothy S.
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p. 25512 - 25527
(2016/09/23)
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- The effect of counterion and tertiary amine on the efficiency of N-triazinylammonium sulfonates in solution and solid-phase peptide synthesis
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A collection of N-triazinylammonium sulfonates, designed according to the concept of "superactive esters", was obtained by treatment of ammonium sulfonates with 2-chloro-4,6-dimethoxy-1,3,5-triazine. The structure of the tertiary amine as well as sulfonate anion influenced their reactivity and stability in N,N-dimethylformamide (DMF) solution. The reagents were successfully used in solution- and solid-phase synthesis of Z-, Boc-, and Fmoc-protected peptides containing natural and unnatural sterically hindered amino acids as well as in [2+1] fragment condensation approaches, yielding the final products in 80-100% yield and high optical purity. In manual SPPS of the [Aib]2[Aib]4-enkephalin analogue and the ACP(65-74) peptide fragment VQAAIDYINEG, several sulfonates yielded peptides significantly faster than TBTU or HATU. Comparative analyses demonstrated that 4-(4,6-di-methoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium 4-toluenesulfonate was the most versatile reagent in a wide range of coupling procedures.
- Kolesinska, Beata,Rozniakowski, Kamil K.,Fraczyk, Justyna,Relich, Inga,Maria Papini, Anna,Kaminski, Zbigniew J.
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supporting information
p. 401 - 408
(2015/03/03)
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- Synthesis of cyclopentapeptides with three to five Aib units
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Four new Aib-containing cyclopentapeptides have been synthesized by cyclization of the corresponding linear pentapeptides using the diethyl phosphorocyanidate (DEPC)/EtN(iPr)2 method. The linear precursors were prepared via the 'azirine/oxazolo
- Arnhold, Franziska S.,Linden, Anthony,Heimgartner, Heinz
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p. 232 - 244
(2015/03/04)
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- Bis(4,6-dimethoxy-1,3,5-triazin-2-yl) ether as coupling reagent for peptide synthesis
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Bis(4,6-dimethoxy-1,3,5-triazin-2-yl) ether (4) was prepared by treatment of 2-hydroxy-4,6-dimethoxy-1,3,5-triazine with 2-chloro-4,6-dimethoxy-1,3,5- triazine in 61% yield. Ether 4, isoelectronic with pyrocarbonates, was found capable to activate carboxylic acids in the presence of 1,4-diazabicyclo[2.2.2] octane (DABCO) to yield, under mild reaction conditions, superactive triazine esters. Versatility of this new coupling reagent was confirmed by condensation of lipophilic and sterically hindered carboxylic acids with amines in 71-98% yield, and by synthesis of peptides, including those containing Aib-Aib sequence, in solution with high yield and high enantiomeric purity. Copyright
- Jastrzabek, Konrad,Bednarek, Przemyslaw,Kolesinska, Beata,Kaminski, Zbigniew J.
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p. 952 - 961
(2013/07/28)
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- Synthesis of peptides employing protected-amino acid halides mediated by commercial anion exchange resin
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Coupling of protected-amino acid halides (chloride, fluoride) mediated by commercial anion exchange resin for the solution phase synthesis of peptides is described. The reaction was carried out in an organic medium, circumventing the use of an organic base or an inorganic base. The coupling is fast, clean and racemization free. The anion exchange resin functions as a solid-phase basic scavenger, soaking up the HCl produced and allowing the amine to react. The method is extended for the coupling of sterically hindered α,α,- dialkylamino acids. Graphical Abstract: [Figure not available: see fulltext.]
- Bhaskara Redddy,Kumari, Y. Bharathi,Ananda, Kuppanna
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p. 225 - 229
(2013/12/04)
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- N-lipidated oligopeptides immobilized on cellulose as new type of organocatalysts
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A library of supramolecular structures formed by self-organization of N-lipidated tripeptides, dipeptides and Nacylated amino acids attached to cellulose according to the TASP concept via aminophenylamino-1,3,5-triazine was synthesized and the catalytic a
- Fraczyk, Justyna,Kolesinska, Beata,Kaminski, Zbigniew J.
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p. 562 - 571
(2013/09/12)
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- 4-(4,6-Di[2,2,2-trifluoroethoxy]-1,3,5-triazin-2-yl)-4-methylomorpholinium tetrafluoroborate. Triazine-based coupling reagents designed for coupling sterically hindered substrates
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4-(4,6-Di[2,2,2-trifluoroethoxy]-1,3,5-triazin-2-yl)-4-methylomorpholinium tetrafluoroborate (DFET/NMM/BF4) was prepared and used as a reagent for coupling sterically hindered substrates. The formation of the appropriate triazine "superactive" ester in a reaction of DFET/NMM/BF4 with carboxylic acids was confirmed. The efficiency of the reagent has been studied in the synthesis of Leu-enkephaline pentapeptide carried out on a Fmoc-RinkAmide-AM-PS resin, by systematically modifying the -Gly-Gly- fragment for N-methyl or α,α-disubstituted residues and compared with the efficiency of classic aminium salt 2-(1H-benzotriazole-1-yl)-1,1,3,3- tetramethyluronium tetrafluoroborate (TBTU) under a variety of reaction conditions. In syntheses of Aib-Aib (Aib: α-aminoisobutyric acid), MeVal-MeVal, and MeLeu-MeLeu, the considerably superior performance of enkephaline analogues was obtained for DFET/NMM/BF4 relative to TBTU, regardless of reaction conditions. Analysis of the couplings involving triazine reagent suggests that factors controlling efficiency of coupling sterically hindered substrates are the structure of the leaving group permitting formation of the cyclic intermediate or cyclic transition state and the absence of strongly solvating solvents. It has to be considered as highly probable that the absence of strongly solvating milieu favors cyclic intermediates or the cyclic transition state. Arrangement of both components into the cyclic intermediate or cyclic transition state by accumulation of the geminal (vicinal) substituents effect (known as the Thorpe-Ingold effect) would compensate retardation of the coupling process caused by steric hindrance.
- Jastrzabek, Konrad G.,Subiros-Funosas, Ramon,Albericio, Fernando,Kolesinska, Beata,Kaminski, Zbigniew J.
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experimental part
p. 4506 - 4513
(2011/07/08)
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- PS-IIDQ: a supported coupling reagent for efficient and general amide bond formation
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Polystyrene-IIDQ, a polymer-supported coupling reagent, was synthesized in three steps from Merrifield resin in 86% overall conversion. This reagent efficiently coupled carboxylic acids to amines in good yields and high purities, required no pre-activation step, and was tolerant of the order of reagent addition. PS-IIDQ was observed to be more efficient than polymer-supported carbodiimides (PS-EDC and PS-DCC) and gave higher yields than HATU for general amide bond formation, including the coupling of anilines and hindered substrates. When evaluated with five carboxylic acids and nine amines (including anilines and secondary amines) PS-IIDQ gave an average isolated yield of 73%.
- Valeur, Eric,Bradley, Mark
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p. 8855 - 8871
(2008/02/11)
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- Fluorous Coupling Reagents: Application of 2-Chloro-4,6- bis[(heptadecafluorononyl)oxy]-1,3,5-triazine in Peptide Synthesis
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Benzyloxycarbonyl N-protected and C-terminus methyl ester protected amino acids react in THF in the presence of 4-methylmorpholine and fluorous condensation reagent, 2-chloro-4,6-bis[(heptadecafluorononyl)oxy[-1,3,5- triazine, to form di- and tripeptides
- Markowicz, Marcin W.,Dembinski, Roman
-
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- 2-Mercaptopyridine-1-oxide-based peptide coupling reagents
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The thiouronium salts S-(1-oxido-2-pyridinyl)-1,1,3,3-tetramethylthiouronium hexafluorophosphate (HOTT) and tetrafluoroborate (TOTT), and S-(1-oxido-2-pyridinyl)-1,3-dimethyl-1,3-trimethylenethiouronium hexafluorophosphate (HODT) and tetrafluoroborate (TODT), prepared from 2-mercaptopyridine-1-oxide and 1,1,3,3-tetramethylurea (TMU) or 1,3-dimethylpropyleneurea (DMPU), have been employed as reagents in solution and solid-phase peptide coupling chemistry. Furthermore, 2-mercaptopyridine-1-oxide has been employed as racemization-reducing additive combined with the new thiouronium salts and other frequently used peptide coupling reagents such as DCC or TBTU.
- Albericio, Fernando,Bailén, Miguel A,Chinchilla, Rafael,Dodsworth, David J,Nájera, Carmen
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p. 9607 - 9613
(2007/10/03)
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- Microwave-enhanced solution coupling of the α,α-dialkyl amino acid, Aib
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The difficult coupling of α-aminoisobutyric acid (Aib), during the synthesis of dipeptides (1-6), was carried out using PyBOP/HOBt and HBTU/HOBt reagents by application of microwave energy in the presence of solvent. Room temperature, conventional heating
- Santagada, Vincenzo,Fiorino, Ferdinando,Perissutti, Elisa,Severino, Beatrice,De Filippis, Vincenzo,Vivenzio, Beniamino,Caliendo, Giuseppe
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p. 5171 - 5173
(2007/10/03)
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- 1-Ethyl 2-halopyridinium salts, highly efficient coupling reagents for hindered peptide synthesis both in solution and the solid-phase
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1-Ethyl-2-halopyridinium salts, BEP, FEP, BEPH and FEPH, were synthesized and proved to be very effective for the synthesis of hindered peptides containing N-methylated or C(α),C(α)-dialkylated amino acid residues. HPLC monitoring of model reactions indicated that these pyridinium salts demonstrated higher reactivities, lower racemization than the commonly used halogenated uronium and phosphonium salts. The efficiency of these pyridinium type coupling reagents was further proved by the synthesis of a series of hindered oligopeptides and active esters with good yields and convenient workup. The 8-11 tetrapeptide fragment of Cyclosporin A (CsA) and the pentapeptide moiety of Dolastatin 15 were also successfully synthesized using these pyridinium salts. The efficiency of these pyridinium type coupling reagents for SPPS was also demonstrated by the solid-phase synthesis of the extremely hindered 8-11 peptide segment of CsA and the linear undecapeptide of CsO. The mechanism of the pyridinium salt mediated coupling reactions was also studied by 1H NMR, IR and HPLC. It was proposed that the major reactive intermediates were the corresponding acyl halide and acyloxypyridinium salts of the N-protected amino acid or peptide. (C) 2000 Elsevier Science Ltd.
- Li, Peng,Xu, Jie-Cheng
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p. 8119 - 8131
(2007/10/03)
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- 2-Bromo-1-ethyl pyridinium tetrafluoroborate (BEP): A powerful coupling reagent for N-methylated peptide synthesis
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2-Bromo-1-ethyl pyridinium tetrafluoroborate (BEP) was firstly utilized to the synthesis of peptides containing N-methyl amino acid residues both in solution and solid phase, and demonstrated high reactivity, low racemization and excellent yields, which w
- Li, Peng,Xu, Jie Cheng
-
p. 204 - 205
(2007/10/03)
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- Total synthesis of cyclosporin O both in solution and in the solid phase using novel thiazolium-, immonium-, and pyridinium-type coupling reagents: BEMT, BDMP, and BEP
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Cyclosporin O (1), an extensively N-methylated immunosuppressive cyclic undecapeptide isolated from Tolypocladium inflatum Gams, was synthesized in 20-23% overall yield via 4 + 7 segment condensation and cyclization by the combined utilization of novel thiazolium- and immonium-type peptide coupling reagents 2-bromo-3-ethyl-4-methyl thiazolium tetrafluoroborate (BEMT) and 5- (1H-benzotriazol-1-yloxy)-3,4-dihydro-1-methyl 2H-pyrrolium hexachloroantimonate (BDMP) as well as compound 2-bromo-1-ethyl pyridinium tetrafluoroborate (BEP). BEMT and BEP, which have been proven to be very efficient for the coupling of peptide segments containing N-alkylated amino acid residues with respect to the fast reaction speed, low racemization, and high yields, were used to construct hindered amide bonds in CsO with the addition of HOAt, whereas the most efficient HOBt-derived immonium type reagent, BDMP, was used to perform the coupling of coded amino acids in CsO. Thus, the highly hindered protected 8-11 tetrapeptide 25 was successfully synthesized using BEMT in 65% yield, and the 1-7 heptapeptide 21 was obtained in 52-55% yield by the rationally combined utilization of BDMP, BEMT, and BEP. The synthesis of the linear undecapeptide 27 of CsO in the solid phase using BEMT and BEP was accomplished for the further evaluation of the effectiveness of these reagents.
- Li, Peng,Xu, Jie Cheng
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p. 2951 - 2958
(2007/10/03)
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- New and highly efficient immonium type peptide coupling reagents: Synthesis, mechanism and application
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A series of novel immonium type coupling reagents BOMI, BDMP, BPMP, DOMP, SOMP, FOMP and AOMP were designed and synthesized. It was shown that most of these reagents were more efficient in peptide synthesis than conventional methods due to the advantages
- Li, Peng,Xu, Jie-Cheng
-
p. 4437 - 4445
(2007/10/03)
-
- BOMI - A novel peptide coupling reagent
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A novel coupling reagent, benzotriazol-1-yloxy-N,N- dimethylmethaniminium hexachloroantimonate (BOMI), was synthesized and successfully applied to the synthesis of oligopeptides, the racemization and the influence of several reaction parameters such as so
- Li, Peng,Xu, Jie Cheng
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p. 3605 - 3608
(2007/10/03)
-
- A novel thiazolium type peptide coupling reagent for hindered amino acids
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A highly efficient coupling reagent, 2-bromo-3-ethyl-4-methyl thiazolium tetrafluoroborate (BEMT), was designed, synthesized and successfully applied to the synthesis of oligopeptides containing N-alkyl or α-C-dialkyl amino acids. Its efficiency was evaluated by HPLC and 1H NMR methods, and demonstrated by synthesis of a number of N-methyl-rich peptide segments with good yields and negligible racemization. The mechanism of coupling was studied by HPLC, 1H NMR and IR monitoring; it is proposed that labile (acyloxy)thiazolium salts and N-protected amino acid bromides were the major active intermediates with concomitant formation of N-ethyl-4-methyl thiazolidones and a small amount of oxazolones and N-protected amino acid anhydrides.
- Li, Peng,Jie, Cheng Xu
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p. 8301 - 8304
(2007/10/03)
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- Convergent synthesis of (-)-mirabazole C using a chloroimidazolidium coupling reagent, CIP
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Convergent synthesis of (-)-mirabazole C (1), a tetra thiazoline/thiazole alkaloid isolated from blue-green alga, has been described. The successive thiazoline rings of (-)-mirabazole C were formed by a single-step cyclization mediated by TiCl4 treatment of tripeptide amide 4. Convergent synthesis of the key intermediate 33 derived from three 2-methylcysteine residues was first achieved using a newly developed coupling reagent, 2-chloro-1,3-dimethylimidazolidium hexafluorophosphate (CIP). The effectiveness of CIP for the coupling of α,α-dialkyl amino acids and the reaction pathway of the activation were clarified by the syntheses of model peptides containing an α,α-dimethylamino acid. A practical method of asymmetric synthesis of 2-methylcysteine by alkylation of 2,4-cis-oxazolidinone 23 has also been described.
- Akaji, Kenichi,Kuriyama, Naohiro,Kiso, Yoshiaki
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p. 3350 - 3357
(2007/10/03)
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- Efficient synthesis of alamethicin F-30 using a chloro imidazolidium coupling reagent, CIP
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Alamethicin F-30 has been synthesized in solution using a CIP-additive as a coupling agent and TFA as a final deprotecting reagent. All couplings including those between sterically hindered α,α-dimethyl amino acid were successfully achieved by a 60 min re
- Akaji, Kenichi,Tamai, Yasunori,Kiso, Yoshiaki
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p. 9341 - 9344
(2007/10/02)
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- CF3-BOP, CF3-PyBOP and CF3-HBTU: New peptide coupling reagents specially suited for α-aminoisobutyric acid condensations
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The peptide-coupling reagents CF3-BOP (1b), CF3-PyBOP (1c) and CF3-HBTU (2a) with built-in 1-hydroxy-6-(trifluoromethyl)benzotriazole proved to be highly efficient for the coupling of α-aminoisobutyric acid residues.
- Wijkmans, Jac C. H. M.,Kruijtzer, John A. W.,Marel, Gijs A. van der,Boom, Jacques H. van,Bloemhoff, Wim
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p. 394 - 397
(2007/10/02)
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- Efficient coupling of α,α-dimethyl amino acid using a new chloro imidazolidium reagent, CIP
-
CIP (2-chloro-1,3-dimethylimidazolidium hexafluorophosphate) was an efficient coupling agent for N(α)-protected α-aminoisobutyric acid (Aib) in the presence of an additive. The reactivity was enhanced markedly by a catalytic amount of additive in the order of HOAt ~ HODhbt > DMAP > HOBt. These couplings occurred without detectable racemization.
- Akaji, Kenichi,Kuriyama, Naohiro,Kiso, Yoshiaki
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p. 3315 - 3318
(2007/10/02)
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- PyBOP and PyBroP: Two reagents for the difficult coupling of the α,α-dialkyl amino acid, Aib
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The difficult coupling of α-aminoisobutyric acid (Aib) was carried out using PyBOP and PyBroP in a comparative study with BOP and BroP. These reagents gave good results under simple conditions (one pot, r.t., 1h). Coded amino acids could be coupled with Aib using PyBOP under standard conditions of peptide synthesis without racemization whereas the coupling of two Aib residues required PyBroP/DMAP. A fragment containing an Aib C-terminal could be coupled without epimerization of the penultimate residue.
- Frerot, Eric,Coste, Jacques,Pantaloni, Antoine,Dufour, Marie-Noelle,Jouin, Patrick
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p. 259 - 270
(2007/10/02)
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- 1,1'-Carbonylbis(3-methylimidazolium) Triflate: An Efficient Reagent for Aminoacylations
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Amino acid carboxyl activation and subsequent coupling with nucleophiles frequently suffer from uncertain risks of racemization, complex reagent preparation, or troublesome side-product removal.All of these difficulties are eliminated with a new, simple reagent, 1,1'-carbonylbis(3-methylimidazolium) triflate (CBMIT), obtainable readily by bis-alkylation of carbonyldiimidazole with methyl triflate.Via a highly reactive acyl imidazolium intermediate, CBMIT couples amino acid components or amino acids and alcohols to give peptides and esters, easily isolated in high yield.The reaction medium remains free of any base, and no loss of optical activity is observed.
- Saha, Ashis K.,Schultz, Peter,Rapoport, Henry
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p. 4856 - 4859
(2007/10/02)
-