- Environmentally friendly SPPS I. Application of NaOH in 2-MeTHF/methanol for Fmoc removal
-
Focusing on the step-by-step transformation of the traditional solid-phase peptide synthesis (SPPS) into an environmentally friendly process, we herein report the elimination of environmentally hazardous components (piperidine, DMF and DCM) from this technique. We developed a synthetic protocol that employs sodium hydroxide in a 2-MeTHF/MeOH mixture for Fmoc group cleavage and uses 2-MeTHF alone as the coupling solvent. The protocol was developed with the most frequently used PS/DVB-based resin. This synthetic strategy was used to prepare Leu-enkephalin amide, and the results (crude purity 99%, yield 62%) were fully comparable to those achieved with the traditional protocol using piperidine, DMF and DCM.
- P?ibylka, Adam,Krchňák, Viktor,Schütznerová, Eva
-
-
Read Online
- 2-(4-Sulfophenylsulfonyl)ethoxycarbonyl group: A new water-soluble N-protecting group and its application to solid phase peptide synthesis in water
-
Solid phase peptide synthesis is carried out in organic solvents, creating environmental problems after disposal. To avoid this problem, we aimed to perform solid phase peptide synthesis in water. A new water-soluble N-protecting group, 2-(4-sulfophenylsulfonyl)ethoxycarbonyl (Sps) group, was designed and Sps-amino acids were prepared. To evaluate the utility of this technique, Leu-enkephalin amide was prepared by solid phase synthesis using Sps-amino acids in water.
- Hojo, Keiko,Maeda, Mitsuko,Kawasaki, Koichi
-
-
Read Online
- Core-shell-type resins for solid-phase peptide synthesis: Comparison with gel-type resins in solid-phase photolytic cleavage reaction
-
(Graph Presented) Novel core-shell-type resins with a rigid core and amino-functionalized flexible shell were prepared with 2,4,6-trichloro-1,3,5- triazine (CNC) and Jeffamine ED-600 starting from 1% cross-linked aminomethyl (AM) polystyrene resins. All o
- Kim, Hanyoung,Jin, Ku Cho,Chung, Woo-Jae,Lee, Yoon-Sik
-
-
Read Online
- The application of anisole in greener solid-phase peptide synthesis protocols – Compatibility with green bases in Fmoc removal and new green binary mixture for coupling
-
As a step toward green Fmoc solid-phase peptide synthesis (SPPS), we explored the compatibility of the green bases morpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and NaOH with the green solvent anisole as a replacement for the traditionally used hazardous piperidine in N,N-dimethylformamide (DMF) for the Fmoc removal step. Green Fmoc cleavage protocols were optimized for the Fmoc-Ala-NH-Rink resin model and subsequently verified for other Fmoc-amino acids. Only Gly required a modified NaOH-based protocol with the addition of 5 % water. Furthermore, we evaluated the effects of basic treatment on the notorious aspartimide formation as an undesired side product of SPPS. We also introduced a new green solvent mixture, anisole/dimethyl sulfoxide (DMSO) (4:1) for acylation step, which did not cause racemization. The applicability of these new green protocols was shown during SPPS of the pentapeptides Leu-enkephalin and Aib-enkephalin using polystyrene (PS)-based resins. Additionally, we identified the new sequence-dependent side products that formed after treatment with NaOH in anisole/ethanol (EtOH) (1:1).
- Grepl, Martin,P?ibylka, Adam,Pastorek, Milan,Schütznerová, Eva P?ibylka
-
supporting information
(2021/09/30)
-
- Sustainable Peptide Synthesis Enabled by a Transient Protecting Group
-
The growing interest in synthetic peptides has prompted the development of viable methods for their sustainable production. Currently, large amounts of toxic solvents are required for peptide assembly from protected building blocks, and switching to water as a reaction medium remains a major hurdle in peptide chemistry. We report an aqueous solid-phase peptide synthesis strategy that is based on a water-compatible 2,7-disulfo-9-fluorenylmethoxycarbonyl (Smoc) protecting group. This approach enables peptide assembly under aqueous conditions, real-time monitoring of building block coupling, and efficient postsynthetic purification. The procedure for the synthesis of all natural and several non-natural Smoc-protected amino acids is described, as well as the assembly of 22 peptide sequences and the fundamental issues of SPPS, including the protecting group strategy, coupling and cleavage efficiency, stability under aqueous conditions, and crucial side reactions.
- Avrutina, Olga,Knauer, Sascha,Koch, Niklas,Kolmar, Harald,Meusinger, Reinhard,Uth, Christina
-
supporting information
p. 12984 - 12990
(2020/06/01)
-
- Fully automated peptide radiolabeling from [18F]fluoride
-
The biological properties of receptor-targeted peptides have made them popular diagnostic imaging and therapeutic agents. Typically, the synthesis of fluorine-18 radiolabeled receptor-targeted peptides for positron emission tomography (PET) imaging is a t
- Davis, Ryan A.,Drake, Chris,Ippisch, Robin C.,Moore, Melissa,Sutcliffe, Julie L.
-
p. 8638 - 8649
(2019/03/21)
-
- CITU: A Peptide and Decarboxylative Coupling Reagent
-
Tetrachloro-N-hydroxyphthalimide tetramethyluronium hexafluorophosphate (CITU) is disclosed as a convenient and economical reagent for both acylation and decarboxylative cross-coupling chemistries. Within the former set of reactions, CITU displays reactiv
- Degruyter, Justine N.,Malins, Lara R.,Wimmer, Laurin,Clay, Khalyd J.,Lopez-Ogalla, Javier,Qin, Tian,Cornella, Josep,Liu, Zhiqing,Che, Guanda,Bao, Denghui,Stevens, Jason M.,Qiao, Jennifer X.,Allen, Martin P.,Poss, Michael A.,Baran, Phil S.
-
supporting information
p. 6196 - 6199
(2017/11/24)
-
- Facile synthesis of N-(9-fluorenylmethyloxycarbonyl)-3-amino-3-(4,5- dimethoxy-2-nitrophenyl)propionic acid as a photocleavable linker for solid-phase peptide synthesis
-
A photocleavable linker, N-(9-fluorenylmethyloxycarbonyl)-3-amino-3-(4,5- dimethoxy-2-nitrophenyl)propionic acid was synthesized from veratraldehyde, with simple reaction and separation steps. This linker was stable under the normal solid-phase peptide sy
- Kim, Jaehi,Kyeong, San,Shin, Dong-Sik,Yeo, Sewon,Yim, Joonhyuk,Lee, Yoon-Sik
-
p. 733 - 736
(2013/05/09)
-
- Effect of residual water and microwave heating on the half-life of the reagents and reactive intermediates in peptide synthesis
-
Precise microwave heating has changed the way many small molecules are being synthesized and, currently, the field of solid-phase peptide synthesis is undergoing dramatic changes owing to the use of microwave heating. To fully reap the benefits of precise microwave heating for the formation of amide bonds in peptide synthesis, it is important to understand the kinetics of formation and break-down of activated esters and their N-acylation of the nascent peptide chain at elevated temperatures. Herein, we present systematic studies of, first, the rate of formation of activated esters by NMR spectroscopy and, second, their N-acylation during peptide synthesis. A study of the amount of residual water in the solvents revealed a significant effect on electrophilic reagents and intermediates. This observation was expanded into a general study of microwave heating in peptide synthesis.
- Pernille Tofteng,Pedersen, S?ren L.,Staerk, Dan,Jensen, Knud J.
-
experimental part
p. 9024 - 9031
(2012/10/18)
-
- Benzotriazole-assisted solid-phase assembly of Leu-Enkephalin, amyloid β segment 34-42, and other "difficult" peptide sequences
-
Microwave-assisted solid-phase syntheses of six "difficult" peptides, H-VVSVV-NH2 (3), H-VVVSVV-NH2(4), H-VIVIG-OH (5), H-TVTVTV-NH2 (6), H-VKDGYI-NH2 (7), and H-VKDVYI-NH2 (8), were achieved utilizing N-(Fmoc-α-aminoacyl) benzotriazoles. Extension to the syntheses of Leu-enkephalin (9) and amyloid-β (34-42) (10) demonstrates that this strategy comprises an efficient route to new and known "difficult" peptides.
- Katritzky, Alan R.,Haase, Danniebelle N.,Johnsons, Jodie V.,Chung, Alfred
-
supporting information; experimental part
p. 2028 - 2032
(2009/08/07)
-
- 1,1-Dioxonaphtho[1,2-b]thiophene-2-methyloxycarbonyl (α-Nsmoc) and 3,3-dioxonaphtho[2,1-b]thiophene-2-methyloxycarbonyl (β-Nsmoc) amino-protecting groups
-
Of the three theoretically possible, Bsmoc-related, naphthothiophene sulfone-based amino-protecting groups, the two most readily available derivatives, the α- and β-Nsmoc analogues, have been examined as substitutes for the Bsmoc residue in cases where the latter lead to oily protected amino acids or amino acid fluorides. All of the naphtho systems gave easily handled solid amino acid derivatives. The intermediate sulfone alcohol 11 used as the key reagent for introduction of the α-Nsmoc protecting group was readily made from α-tetralone (Scheme 1). The corresponding β-analogue 17 was made similarly on a small scale, but due to the high cost of β-tetralone, an alternate route involving reaction of rhodanine with a-naphthaldehyde was used for large-scale work (Scheme 2). All proteinogenic amino acids were converted to their α- and β-Nsmoc derivatives. Deblocking studies showed that the reactivity toward deblocking by piperidine followed the order α-Nsmoc > Bsmoc > β-Nsmoc. 1H NMR experiments showed that deblocking of the two new systems was mechanistically similar to that previously established for the Bsmoc derivative in that the reaction is initiated by Michael addition to the β-carbon atom of the α,β-unsaturated sulfone system. Application of α- and β-Nsmoc amino acids to the solid-phase synthesis of two model peptides was examined. An advantage of the α-Nsmoc system over the long-known Bsmoc system proved to be the milder conditions needed for the deblocking step relative to the Bsmoc case, which is itself more readily deblocked than the classic Fmoc analogue.
- Carpino, Louis A.,Abdel-Maksoud, Adel Ali,Ionescu, Dumitru,Mansour,Zewail, Mohamed A.
-
p. 1729 - 1736
(2007/10/03)
-
- Solid-phase peptide synthesis in water. Part 3: A water-soluble N-protecting group, 2-[phenyl(methyl)sulfonio]ethoxycarbonyl tetrafluoroborate, and its application to solid phase peptide synthesis in water
-
Chemical synthesis of peptides has been performed in various organic solvents, but the safe disposal of organic solvents is now an important environmental issue. Our aim is to be able to perform solid-phase peptide synthesis in water. For this, we have designed a new water-soluble N-protecting group, 2-[phenyl(methyl)sulfonio]ethoxycarbonyl (Pms), and have studied its introduction onto amino acids. Pms-amino acids were prepared by treating 2-(phenylthio)ethoxycarbonyl amino acids with methyl iodide in the presence of silver tetrafluoroborate. Because sulfur-containing amino acids, such as Met and Cys, were modified by the reaction, we designed a new reagent, 2-[phenyl(methyl)sulfonio]ethyl-4-nitrophenyl carbonate, to introduce the Pms group on amino acids. This reagent is a stable crystalline material and its introduction onto amino acids (including sulfur-containing amino acids) was successful. The solid-phase synthesis of Leu- and Met-enkephalin amides using Pms-protected amino acids was successfully achieved in water.
- Hojo, Keiko,Maeda, Mitsuko,Kawasaki, Koichi
-
p. 1875 - 1886
(2007/10/03)
-
- Peptide synthesis in water IV. Preparation of N- ethanesulfonylethoxycarbonyl (Esc) amino acids and their application to solid phase peptide synthesis
-
A new N-protecting group, ethanesulfonylethoxycarbonyl (Esc), was designed to perform peptide synthesis in both aqueous and organic solvents. Esc-amino acids were prepared by the reaction of Esc-Cl and amino acids. Although Esc-Cl was a highly reactive re
- Hojo, Keiko,Maeda, Mitsuko,Smith, Timothy J.,Kita, Eriko,Yamaguchi, Fumie,Yamamoto, Sachiko,Kawasaki, Koichi
-
p. 422 - 427
(2007/10/03)
-
- Studies on the synthesis of estrogen-GHRPS linkers
-
A series of linkers consisted of estrone, estradiol, and GHRPS (growth hormone releasing peptides) were prepared with carboxyl-methyl or succinyl as the conjugated group. As a protective group in the side chain of Tyr, the Dcb (2,6-dichlorobenzyl) in the intermediates which is unstable to HF can be removed in high yield in the presence of Pd/C (10%), H2, and 4.4% formic acid in methanol.
- Wang, Chao,Zhao, Ming,Cui, Weina,Yang, Jian,Peng, Shiqi
-
p. 1633 - 1641
(2007/10/03)
-
- Studies on the synthesis and anti-Osteoporosis of estrogen-GHRPs linkers.
-
The linkers of estrogen-GHRPs were prepared by the combination of estradiol, estrone, TyrGlyGlyPheLeuOH, and TyrGlyGlyPheLeuOH. Their anti-osteoporosis effect was evaluated by analyzing the data, for instance the weight of the body, femur, femur ash, the content of calcium and phosphor in the femur, the content of calcium and ALP activity in the serum, obtained from the corresponding bioassay in vivo. The results indicated that the anti-osteoporosis potency for estradiol, estrone, TyrGlyGlyPheLeuOH and TyrGlyGlyPheLeuNH(2) may be totally enhanced each other via the corresponding linkers.
- Wang, Chao,Cui, Weina,Zhao, Ming,Yang, Jian,Peng, Shiqi
-
p. 143 - 146
(2007/10/03)
-
- Solid phase syntheses of oligoureas
-
Isocyanates 7 were formed from monoprotected diamines 3 or 6, which in turn can be easily prepared from commercially available N-BOC- or N-FMOC-protected amino acid derivatives. Isocyanates 7, formed in situ, could be coupled directly to a solid support f
- Burgess, Kevin,Ibarzo, Javier,Linthicum, D. Scott,Russell, David H.,Shin, Hunwoo,Shitangkoon, Aroonsiri,Totani, Reiko,Zhang, Alex J.
-
p. 1556 - 1564
(2007/10/03)
-
- 9-Hydroxy-9-(4-carboxyphenyl)xanthene - A new linker for the synthesis of peptide amides
-
The easy synthesis of 9-hydroxy-9-(4-carboxyphenyl)xanthene 1 a new linker for the solid phase peptide synthesis of peptide amides is reported. The cleavage conditions were checked and several peptide amides were synthesized using the TentaGel-resin(TM) o
- Henkel, Bernd,Zeng, Weiguang,Bayer, Ernst
-
p. 3511 - 3512
(2007/10/03)
-
- Application of N-Tritylamio Acid 1-Benzotriazolyl Esters in Peptide Synthesis
-
The application of N-tritylamino acid 1-benzotriazolyl esters 2 in peptide synthesis is investigated using as model compounds leucine-enkephalin (18) and leucine-enkephalinamide (19).The reactions are performed in solution and on the surface of solids.New spectrophotometric methods, based on the facile cleavage of the N-trityl group and on the measurement of the absorbance of the released triphenylmethanol, are used to monitor the coupling steps and to determine the free amino groups on the solid carrier.
- Barlos, Kleomenis,Papaioannou, Dionysios,Sanida, Chariklia
-
p. 1308 - 1318
(2007/10/02)
-
- Catalytic Transfer Hydrogenation in Pepetide Synthesis: Synthesis of 5- and 5-enkephalins
-
The simplicity in the removal of N-protecting groups like benzyloxycarbonyl employed in peptide synthesis by catalytic transfer hydrogenation at room temperature using formic acid in presence of palladium black has been demonstrated by the synthesis of the opioid pentapeptides 5- and 5-enkephalins.
- Sivanandaiah, K. M.,Gurusiddappa, S.
-
p. 857 - 859
(2007/10/02)
-