Efficient Peptide Coupling Involving Sterically Hindered Amino Acids

Katritzky, Alan R.; Todadze, Ekaterina; Angrish, Parul; Draghici, Bogdan

doi:10.1021/jo0704255

Cited by 40 publications

(25 citation statements)

References 52 publications

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“…Enantiopure dipeptides (LL and LD configuration) were obtained in 70-98% yield in high purity (>99%), without the use of chromatography (Scheme 4 and Table 2). 15,[17][18][19][20]38,39 Scheme 4 Preparation of dipeptides using N-(protected a-aminoacyl)benzotriazoles Cbz-L-Phe-L-Ala-OH 98 15 7…”

Section: Preparation Of Dipeptidesmentioning

confidence: 99%

Chiral Acylation with N-(Protected α-Aminoacyl)benzotriazoles for Advantageous Syntheses of Peptides and Peptide Conjugates

Katritzky¹,

Angrish²,

Todadze³

2009

Synlett

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N-(Protected a-aminoacyl)benzotriazoles are efficient intermediates for N-and O-aminoacylation. These intermediates enable fast preparations of biologically relevant peptides and peptide conjugates in high yields and purity, under mild reaction conditions, with full retention of the original chirality. The developed methodology allows simple solution-and solid-phase preparative techniques to generate complex peptides and peptide conjugates and serves as a platform for generating diverse medicinal chemistry building block libraries involving amino acid and heterocyclic moieties crucial for drug development.

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Section: Preparation Of Dipeptidesmentioning

confidence: 99%

Chiral Acylation with N-(Protected α-Aminoacyl)benzotriazoles for Advantageous Syntheses of Peptides and Peptide Conjugates

Katritzky¹,

Angrish²,

Todadze³

2009

Synlett

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“…To overcome this issue, triphosgene was introduced to generate Fmoc‐amino acid chloride in situ. However, triphosgene has the drawback that it requires extreme anhydrous conditions, which otherwise lead to complete cleavage of the peptide sequence from resin …”

Section: Growing the Peptide Chain Using Nmaa In Solid‐phasementioning

confidence: 99%

N‐methylation in amino acids and peptides: Scope and limitations

et al. 2018

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Active pharmaceutical ingredients (APIs) can be divided into two types, namely chemical and biological entities. Traditionally, the former has been associated with the so-called small molecules. The revival of peptides in pharmaceutical industry results from their importance in many biological roles. However, low metabolic stability and the lack of oral availability of most peptides is the main drawback for peptide to fulfill that paradigmatic situation. In this regard, efforts are being channeled into addressing this issue by introducing restrictions into the flexible peptide backbone, mainly through N-methyl amino acids (NMAAs) or development of small cyclic peptides. In many cases, both the above restrictions are combined with the aim to enhance oral availability. The synthesis of NMAAs is complex and their introduction into the peptide chain brings additional synthetic challenges and also sometimes leads to side-reactions. Here we discuss the most efficient methods for the synthesis of NMAAs (either in solution or in solid phase) and also their introduction into peptide sequences. Special attention is also given to the detection of side reactions and the most efficient way to prevent them.

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“…There are many reports on the coupling reaction between free and a-N-protected amino acids with different a-carboxyl activating agents. The active ester has been by far the most used: both phenols and N-hydroxy compounds such as 4-nitro- [13,48], 2,3,4,5,6-pentafluorophenol [49][50][51], 1-hydroxybenzotriazole [52][53][54][55][56], benzisoxazolium salts [57,58], N-hydroxysuccinimide [59,60], and N-hydroxy-3-azaspiro [5,5]undecane-2,4-dione [61] have been employed to this purpose. These intermediates are stable and the coupling reaction can be carried out under the experimental conditions suitable to dissolve the free amino acids (water with or without an organic cosolvent, presence of an inorganic or organic base).…”

Section: Introductionmentioning

confidence: 99%

α‐N‐Protected dipeptide acids: a simple and efficient synthesis via the easily accessible mixed anhydride method using free amino acids in DMSO and tetrabutylammonium hydroxide

Verardo

Gorassini

2013

Journal of Peptide Science

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The importance of dipeptides both in medicinal and pharmacological fields is well documented and many efforts have been made to find simple and efficient methods for their synthesis. For this reason, we have investigated the synthesis of α-N-protected dipeptide acids by reacting the easily accessible mixed anhydride of α-N-protected amino acids with free amino acids under different reaction conditions. The combination of TBA-OH and DMSO has been found to be the best to overcome the low solubility of amino acids in organic solvents. Under these experimental conditions, the homogeneous phase condensation reaction occurs rapidly and without detectable epimerization. The present method is also applicable to side-chain unprotected Tyr, Trp, Glu, and Asp but not Lys. This latter residue is able to engage two molecules of mixed anhydride giving the corresponding isotripeptide. Moreover, the applicability of this protocol for the synthesis of tri- and tetrapeptides has been tested. This approach reduces the need for protecting groups, is cost effective, scalable, and yields dipeptide acids that can be used as building blocks in the synthesis of larger peptides.

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Efficient Peptide Coupling Involving Sterically Hindered Amino Acids

Cited by 40 publications

References 52 publications

Chiral Acylation with N-(Protected α-Aminoacyl)benzotriazoles for Advantageous Syntheses of Peptides and Peptide Conjugates

Chiral Acylation with N-(Protected α-Aminoacyl)benzotriazoles for Advantageous Syntheses of Peptides and Peptide Conjugates

N‐methylation in amino acids and peptides: Scope and limitations

α‐N‐Protected dipeptide acids: a simple and efficient synthesis via the easily accessible mixed anhydride method using free amino acids in DMSO and tetrabutylammonium hydroxide

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