66851-75-0Relevant academic research and scientific papers
Allenone-Mediated Racemization/Epimerization-Free Peptide Bond Formation and Its Application in Peptide Synthesis
Wang, Penghui,Wang, Xuewei,Wang, Zhengning,Zhao, Junfeng
supporting information, p. 10374 - 10381 (2021/07/26)
Allenone has been identified as a highly effective peptide coupling reagent for the first time. The peptide bond was formed with an α-carbonyl vinyl ester as the key intermediate, the formation and subsequent aminolysis of which proceed spontaneously in a racemization-/epimerization-free manner. The allenone coupling reagent not only is effective for the synthesis of simple amides and dipeptides but is also amenable to peptide fragment condensation and solid-phase peptide synthesis (SPPS). The robustness of the allenone-mediated peptide bond formation was showcased incisively by the synthesis of carfilzomib, which involved a rare racemization-/epimerization-free N to C peptide elongation strategy. Furthermore, the successful synthesis of the model difficult peptide ACP (65-74) on a solid support suggested that this method was compatible with SPPS. This method combines the advantages of conventional active esters and coupling reagents, while overcoming the disadvantages of both strategies. Thus, this allenone-mediated peptide bond formation strategy represents a disruptive innovation in peptide synthesis.
Sustainable Peptide Synthesis Enabled by a Transient Protecting Group
Avrutina, Olga,Knauer, Sascha,Koch, Niklas,Kolmar, Harald,Meusinger, Reinhard,Uth, Christina
supporting information, p. 12984 - 12990 (2020/06/01)
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.
A backbone amide protecting group for overcoming difficult sequences and suppressing aspartimide formation
Abdel-Aal, Abu-Baker M.,Papageorgiou, George,Raz, Richard,Quibell, Martin,Burlina, Fabienne,Offer, John
, p. 360 - 367 (2016/05/19)
A backbone amide bond protecting group, 2-hydroxy-4-methoxy-5-nitrobenzyl (Hmnb), improved the synthesis of aggregation and aspartimide-prone peptides. Introduction of Hmnb is automated and carried out during peptide assembly by addition of 4-methoxy-5-nitrosalicylaldehyde to the peptidyl-resin and on-resin reduction to the secondary amine. Acylation of the hindered secondary amine is aided by the formation of an internal nitrophenol ester that undergoes a favourable O,N intramolecular acyl transfer. This activated ester participates in the coupling and generally gives complete reaction with standard coupling conditions. Hmnb is easily available in a single preparative step from commercially available material. Different methods for removing the amide protecting group were explored. The protecting group is labile to acidolysis, following reduction of the nitro group to the aniline. The two main uses of backbone protection of preventing aspartimide formation and of overcoming difficult sequences are demonstrated, first with the synthesis of a challenging aspartimide-prone test sequence and then with the classic difficult sequence ACP (65-74) and a 23-mer homopolymer of polyalanine.
The effect of counterion and tertiary amine on the efficiency of N-triazinylammonium sulfonates in solution and solid-phase peptide synthesis
Kolesinska, Beata,Rozniakowski, Kamil K.,Fraczyk, Justyna,Relich, Inga,Maria Papini, Anna,Kaminski, Zbigniew J.
supporting information, p. 401 - 408 (2015/03/03)
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.
High-efficiency solid phase peptide synthesis (he -Spps)
Collins, Jonathan M.,Porter, Keith A.,Singh, Sandeep K.,Vanier, Grace S.
supporting information, p. 940 - 943 (2014/03/21)
A series of improvements to the standard solid phase peptide synthesis (SPPS) process allowing for significant gains in product purity along with only a 4 min standard cycle time and a 90% reduction in total waste produced is reported. For example, syntheses of the well-known 65-74acyl carrier protein (ACP) and 1-42β-amyloid peptides were accomplished with 93 and 72% purity (UPLC-MS) in only 44 and 229 min, respectively.
Evaluation of COMU as a coupling reagent for in situ neutralization Boc solid phase peptide synthesis
Hjorringgaard, Claudia U.,Brust, Andreas,Alewood, Paul F.
experimental part, p. 199 - 207 (2012/05/20)
Benzotriazole-based coupling reagents have dominated the last two decades of solid phase peptide synthesis. However, a growing interest in synthesizing complex peptides has stimulated the search for more efficient and low-cost coupling reagents, such as COMU which has been introduced as a nonexplosive alternative to the classic benzotriazole coupling reagents. Here, we present a comparative study of the coupling efficiency of COMU with the benzotriazole-based HBTU and HCTU for use in in situ neutralization Boc-SPPS. Difficult sequences, such as ACP(65-74), Jung-Redeman 10-mer, and HIV-1 PR(81-99), were used as model target peptides on polystyrene-based resins, as well as polyethylene glycol-based resins. Coupling yields obtained using fast in situ Boc-SPPS cycles were determined with the quantitative ninhydrin test as well as via LC-MS analysis of the crude cleavage products. Our results demonstrate that COMU coupling efficiency was less effective compared to HBTU and HCTU with HCTU≥HBTU>COMU, when polystyrene-based resins were employed. However, when the PEG resin was employed in combination with a safety catch amide (SCAL) linker, more comparable yields were observed for the three coupling reagents with the same ranking HCTU≥HBTU>COMU.
PEPTIDE SYNTHESIS. PART 10. USE OF PENTAFLUOROPHENYL ESTERS OF FLUORENYL METHOXYCARBONYLAMINO ACIDS IN SOLID PHASE PEPTIDE SYNTHESIS.
Atherton, Eric,Cameron, Linda R.,Sheppard, Robert C.
, p. 843 - 858 (2007/10/02)
The application of fluorenylmethoxycarbonyl-amino-acid pentafluorophenyl esters to solid phase peptide synthesis under polar reaction conditions is described.Reaction rates are increased in the presence of 1-hydroxybenzotriazole.The technique is illustrated by preparation of decapeptide and dodecapeptide sequences.
