Stability of medium-bridged twisted amides in aqueous solutions

Abstract

"Twisted" amides containing nonstandard dihedral angles are typically hypersensitive to hydrolysis, a feature that has stringently limited their utility in water. We have synthesized a series of bridged lactams that contain a twisted amide linkage but exhibit enhanced stability in aqueous environments. Many of these compounds were extracted unchanged from aqueous mixtures ranging from the strongly basic to the strongly acidic. NMR experiments showed that tricyclic lactams undergo reversible hydrolysis at extreme pH ranges but that a number of compounds in this structure class are indefinitely stable under physiologically relevant pH conditions; one bicyclic example was additionally water-soluble. We examined the effect of structure on the reversibility of amide bond hydrolysis, which we attributed to the transannular nature of the amino acid analogs. These data suggest that medium-bridged lactams of these types should provide useful platforms for studying the behavior of twisted amides in aqueous systems. © 2009 American Chemical Society.