Preferred secondary structures as a possible driving force for macrocyclization

The purpose of the work described in this paper was to explore links that m ay exist between conformational bias in macrocyclic products and the ease w ith which they are formed in solid phase SNAr reactions. Solid phase synthe sis of compounds 2 proceeds more efficiently than of compounds 3 under simi lar conditions. Compounds 2 were designed to mimic p-turn conformations in the dipeptide residues whereas compounds 3 were thought to be unable to sho w a similar conformational preference. The second assertion was shown to be correct but, surprisingly, CD, NMR, and molecular simulation experiments f or 2a indicate another conformation is preferred in solution. This may invo lve H-bonding of the asparagine side-chain to a backbone amide-carbonyl. Mo lecular dynamics simulations indicate that cyclization to form compound 2a is statistically more favorable than that to form 3a. (C) 2000 Elsevier Sci ence Ltd. All rights reserved.