On the chemistry and high field nuclear magnetic resonance spectroscopy of rapamycin

Abstract

Base catalyzed hydrolysis of rapamycin (C51H79NO13) affords 6 neutral compounds identified chemically and spectroscopically as 2a, 3b, 3d, 5, 2,4-dimethylphenol and L(-)-piperidine-2-carboxylic acid 6, and whose generation was plausibly rationalized. These findings and detailed analyses of 13C NMR and 1H NMR spectra provide independent corroboration of the X-ray derived rapamycin crystal structure 1. Structurally homogeneous in the solid state, rapamycin occurs in solutions as a mixture of 2 conformational isomers (approximately 4:1). Through nearly complete assignment of the high field 1H (400 MHz) and 13C (100.6 MHz) NMR spectra, the isomerism is associated with trans-cis rotation of an amidic bond within the 31-membered macrolide ring. The predominant form corresponds to the conformer portrayed by X-ray analysis.