Preferred Secondary Structures as a Possible Driving Force for Macrocyclization

Abstract

The purpose of the work described in this paper was to explore links that may exist between conformational bias in macrocyclic products and the ease with which they are formed in solid phase S N Ar reactions. Solid phase synthesis of compounds 2 proceeds more efficiently than of compounds 3 under similar conditions. Compounds 2 were designed to mimic β-turn conformations in the dipeptide residues whereas compounds 3 were thought to be unable to show a similar conformational preference. The second assertion was shown to be correct but, surprisingly, CD, NMR, and molecular simulation experiments for 2a indicate another conformation is preferred in solution. This may involve H-bonding of the asparagine side-chain to a backbone amide-carbonyl. Molecular dynamics simulations indicate that cyclization to form compound 2a is statistically more favorable than that to form 3a.