Solid-phase S(N)2 macrocyclization reactions to form beta-turn mimics

[GRAPHICS] Efficient solid phase S(N)2 macrocyclization reactions were sought to facil itate preparations of focused libraries of beta-turn mimetics. A very effic ient, but undesired, cyclization reaction to give five-membered ring lactam s 4 was identified in attempts to use O-nucleophiles. Subsequent studies fo cused exclusively on S-nucleophiles. These reactions gave the desired macro cyclization products 1 in high purities and good overall yields. Conformati onal analyses of illustrative macrocyclization products 1 via NMR, CD, and molecular simulations showed that they seem to sample both type I and type II beta-turn conformations in solution. CD studies indicate a curious relat ionship between the preferred conformation and the amino acids encapsulated in the macrocycles.