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[摘要]：Theoretical studies had predicted that N-electron T 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 a-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 alpha,alpha'-disubstituted diketopiperazines for the controlled alpha-deuteration and stereochemical inversion of N-methylamino acids, and in the production of a-deuterated (2R,3S)-N-methylalloisoleucine from the nondeuterated (2S,3S)-isoleucine diastereomer. |
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