Catechol and substituted catechol-derived ortho esters, models for protected active esters in peptide synthesis

Vellaccio, Frank; Phelan, John; Trottier, Robert L.; Napier, Thomas W.; Kemp, D. S.

doi:10.1021/jo00328a020

Cited by 8 publications

(4 citation statements)

References 18 publications

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“…The orthoester is an extremely versatile structural feature, used as a protective group for esters in peptide synthesis and for alcohols in nucleoside synthesis . This functional group is vital for transformations such as the Claisen‐Johnson rearrangement, the synthesis of a variety of nitrogen‐based heterocycles and various condensation reactions .…”

Section: Methodsmentioning

confidence: 99%

Electrochemical Synthesis of Fluorinated Orthoesters from 1,3‐Benzodioxoles

et al. 2019

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A scalable, dehydrogenative, and electrochemical synthesis of novel highly fluorinated orthoesters is reported. This protocol provides easy and direct access to a wide variety of derivatives, using a very simple electrolysis setup. These compounds are surprisingly robust towards base and acid with an unusual high lipophilicity, making them interesting motifs for potentially active compounds in medicinal chemistry or agro applications. The use of electricity enables a safe and environmentally benign chemical transformation as only electrons serve as oxidants.

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Section: Methodsmentioning

confidence: 99%

Electrochemical Synthesis of Fluorinated Orthoesters from 1,3‐Benzodioxoles

et al. 2019

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“…This mechanism is well-accepted by many researchers including computational chemists . However, in 1981, Vellaccio and Kemp, based on their experiment results, showed some skepticism toward this mechanism, but they did not suggest new possible pathways . After the report of catechol monoesters, researchers found that the 2-hydroxyl group in the catechol monoesters could be functionalized (masked) to inactivate the amide bond formation (Scheme c). − They first used masked esters to facilitate peptide elongation and then removed the masked group to activate the esters to be polymerized or cyclized.…”

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confidence: 99%

“…However, the substrate they used to discuss was only a benzene ring without electron-withdrawing group substituents. In 1981, Vellaccio and Kemp pointed out that the basicity of the oxygen was decreased when the benzene ring was substituted with a nitro group and made it less effective at anchimeric assistance . Our group has reported an intermolecular Brønsted acid assistance peptide bond formation strategy recently .…”

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confidence: 99%

“…In 1981, Vellaccio and Kemp pointed out that the basicity of the oxygen was decreased when the benzene ring was substituted with a nitro group and made it less effective at anchimeric assistance. 20 Our group has reported an intermolecular Brønsted acid assistance peptide bond formation strategy recently. 41 Therefore, we cannot rule out the possibility of the intermolecular Brønsted acid catalysis (path II-b).…”

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confidence: 99%

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An Unusual Acceleration of Amination Reactivity by the Proximal Ester Groups in Catechol Diesters: An Efficient Way for Peptide Synthesis

Ikeda²,

Yamamoto

2023

Precision Chemistry

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Peptide bond formation has drawn more and more attention due to its importance in medicinal chemistry and drug discovery. Using active esters to construct peptide bonds is an indispensable strategy in this field. We herein report a fast and efficient amination reaction to synthesize peptides from catechol diesters. Catechol monoesters are good active esters in peptide synthesis due to the anchimeric assistance effect. In previously reported work, the amination reaction was inactivated if the 2-hydroxyl group in the catechol esters was functionalized. However, we found an unusual acceleration of the amination reactivity when the 2-hydroxyl group was functionalized as an ester group. The reaction can be complete in 2−3 min in some cases. This acceleration was found through experimental studies to not result from the anchimeric assistance effect. We proposed a π*−π* interaction pathway between the two proximal ester groups. Some computational studies were made to support this assumption.

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