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An intramolecular ionic hydrogen bond stabilizes a cis amide bond rotamer of a ring‐opened rapamycin‐degradation product
Author(s) -
Zhou Casey Chun,
Stewart Kent D.,
Dhaon Madhup K.
Publication year - 2005
Publication title -
magnetic resonance in chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.483
H-Index - 72
eISSN - 1097-458X
pISSN - 0749-1581
DOI - 10.1002/mrc.1501
Subject(s) - conformational isomerism , chemistry , intramolecular force , hydrogen bond , ring (chemistry) , triethylamine , sulfoxide , amide , carboxylate , stereochemistry , medicinal chemistry , molecule , organic chemistry
Rapamycin ( 1) , a macrolide immunosuppressant, undergoes degradation into ring‐opened acid products 2 and 3 under physiologically relevant conditions. The unsaturated product ( 3) was isolated and studied in this work. Unlike 1 , which has its amide primarily in a trans conformation in solution, 3 has both cis and trans conformations in approximately a 1:1 ratio in dimethyl sulfoxide (DMSO). The amount of cis rotamer was increased dramatically in the presence of an organic base such as triethylamine. The detailed NMR results indicate that the cis rotamer is stabilized through an intramolecular ionic hydrogen bond of the carboxylate anion with the tertiary alcohol as part of a nine‐membered ring system. This hydrogen bond was characterized further in organic media and the trans – cis rotamer equilibria were used to estimate the relative bond strengths in several solvents. The additional stabilization arising from this ionic hydrogen bond in the cis rotamer was determined to be 1.4 kcal mol −1 in DMSO‐ d 6 , 2.0 kcal mol −1 in CD 3 CN and 1.1 kcal mol −1 in CD 3 OD. Copyright © 2004 John Wiley & Sons, Ltd.