Facile macrocyclizations to beta-turn mimics with diverse structural, physical, and conformational properties.
On-resin S(N)Ar reactions were performed to prepare the macrocyclic beta-turn mimics 1a-n (Scheme 1 and Table 1). These reactions occurred more efficiently than completely analogous macrocyclization reactions that do not involve an iodinated aromatic electrophile. The synthesis was also modified to allow introduction of an alkyne via a solid-phase Sonogashira reaction (giving compound 2, Scheme 2) and an aryne via a solid-phase Suzuki reaction (giving compound 3, Scheme 2). Conformational analyses of three illustrative compounds, i.e., 1i, 2, and 3, were performed using a combination of NMR, circular dichroism, and computer-aided molecular simulation methods. Overall, the preferred conformations of all three molecules tended to be type-I-like beta-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 preferred orientation of the turn frameworks. This study illustrates how iodinated electrophiles can be used in solid-phase S(N)Ar reactions to increase the molecular and conformational diversity in a library.
Park
C
C
Texas A&M University, Chemistry Department, P.O. Box 30012, College Station, Texas 77842, USA.
Burgess
K
K
D000480:Alkynes / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D003198:Computer Simulation; D006571:Heterocyclic Compounds / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D009579:Nitrobenzoates / Q000737:chemistry
C427646:2-fluoro-3-iodo-5-nitrobenzoic acid; D000480:Alkynes; D000596:Amino Acids; D006571:Heterocyclic Compounds; D009579:Nitrobenzoates