Abstract
1-Azatricyclo[3.3.1.1(3,7)]decan-2-one (3), the parent compound of a rare class of 90°-twisted amides, has finally been synthesized, using an unprecedented transformation. These compounds are of special interest as transition-state mimics for the enzyme-catalyzed cis-trans rotamer interconversion of amides involved in peptide and protein folding and function. The stabilization of the amide group in its high energy, perpendicular conformation common to both systems is shown for the rigid tricyclic system to depend, as predicted by calculation, on its methyl group substitution pattern, making 3 by some way the most reactive known "amide".
Highlights
There is a compelling body of evidence that the cis−trans rotamer interconversion of amide bonds in peptides and proteins plays a fundamental role in countless biochemical processes
It is possible to design a stable molecule as a meaningful TS mimic if any conformational motion of the molecular fragments bearing the characteristic features of the TS would lead to a sharp overall potential energy increase
In 1998 we reported the synthesis of the “highly twisted amide” 1,16 an extreme case of a bridged lactam,[17] with the N C O fragment embedded in the rigid 1-azaadamantane skeleton, as a potential TS mimic for the cis−trans rotamer interconversion of the amide bond
Summary
There is a compelling body of evidence that the cis−trans rotamer interconversion of amide bonds in peptides and proteins plays a fundamental role in countless biochemical processes. TSs correspond to lowest saddle points on reaction potential energy surfaces, and their structures typically involve unusual bond angles and partial bonds which cannot be mimicked using direct connectivity with first or second row elements.[13,14] it is possible to design a stable molecule as a meaningful TS mimic if any conformational motion of the molecular fragments bearing the characteristic features of the TS would lead to a sharp overall potential energy increase. This is possible in rigid systems, where conformational motions are severely restricted. A stable TS mimic can only offer a crude approximation of the corresponding short-lived TS,[15] but the degree of the approximation can be assessed by high-level computational techniques
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