Validation of the Distal Effect of Electron-Withdrawing Groups on the Stability of Peptide Enolates and Its Exploitation in the Controlled Stereochemical Inversion of Amino Acid Derivatives

Junming Ho, Michelle L. Coote, Christopher J. Easton

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Theoretical studies had predicted that N-electron-withdrawing substituents, hydrogen bonding, and protonation at amide nitrogen selectively increase the acidity of a distal proton adjacent to the amide carbonyl to the extent that the α-carbonyl acidity of some N-substituted amides exceeds that of typical ketones. Now, in the present work, competitive, base-catalyzed hydrogen-deuterium exchange experiments, with diisopropyl ketone and a series of N-substituted acetamides and diketopiperazines, have established that there is a strong correlation between the calculated acidities and the experimental rates of deprotonation in these systems. The results show that the rates of exchange of the distal protons of N-acylated and N-sulfonylated amides are more than 4 orders of magnitude faster than those of the N-methylated analogues and that the acylated and sulfonylated amides are much more reactive in this regard than diisopropyl ketone. The magnitude and regioselectivity of the distal effect is sufficient for practical applications and has been exploited in the manipulation of N-acetyl α,α′-disubstituted diketopiperazines for the controlled α-deuteration and stereochemical inversion of N-methylamino acids, and in the production of α-deuterated (2R,3S)-N- methylalloisoleucine from the nondeuterated (2S,3S)-isoleucine diastereomer.

Original languageEnglish
Pages (from-to)5907-5914
Number of pages8
JournalJournal of Organic Chemistry
Volume76
Issue number15
DOIs
Publication statusPublished - 5 Aug 2011
Externally publishedYes

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