Facile macrocyclizations to beta-turn mimics with diverse structural, physical, and conformational properties

On-resin SNAr reactions were performed to prepare the macrocyclic p-turn mi mics 1a-n (Scheme 1 and Table I). These reactions occurred more efficiently than completely analogous macrocyclization reactions that do not involve a n iodinated aromatic electrophile. The synthesis was also modified to allow introduction of an alkyne via a solid-phase Sonogashira reaction (giving c ompound 2, Scheme 2) and an aryne via a solid-phase Suzuki reaction (giving compound 3, Scheme 2). Conformational analyses of three illustrative compo unds, i.e., 1i, 2, and 3, were performed using a combination of NMR, circul ar dichroism, and computer-aided molecular simulation methods. Overall, the preferred conformations of all three molecules tended to be type-I-like be ta -turns, but for compound 3 interaction of the electron cloud of the aryl substituent with the oxygen lone pairs seems to cause differences in the p referred orientation of the turn frameworks. This study illustrates how iod inated electrophiles can be used in solid-phase SNAr reactions to increase the molecular and conformational diversity in a library.