An intramolecular ionic hydrogen bond stabilizes a cis amide bond rotamer of a ring‐opened rapamycin‐degradation product

Abstract

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-d6, 2.0 kcal mol(-1) in CD3CN and 1.1 kcal mol(-1) in CD3OD.

Degradation of rapamycin and its ring-opened isomer: Role of base catalysis

“…31 These results compare well with the recently reported data for CD 3 OD and other organic solvents. 19 Although the isomeric ratio in acidic solution closely matches that seen in our HPLC analysis, it is highly unlikely that isomerization around the amide bond is responsible for the phenomena observed in this study. Moreover, if this reaction would be slow on the time scale of HPLC separation, one should expect an isomer ratio closely matching that seen in the starting material (the anion of 2).…”

“…It is often assumed that compound 3 is formed through the dehydration of 2. [17][18][19] Although possible, this mechanism appears to be not supported by any experimental data.…”

“…A recent NMR study of 3 showed that amide bond rotamerization in organic solvents was highly sensitive to the protonation state of the carboxylic moiety. 19 Almost equal amounts of two rotamers were found for the protonated form;…”

The Application of Electrostatic Dry Powder Deposition Technology to Coat Drug-Eluting Stents

“…In this case, bulk sirolimus powder was fused for 1 min under identical conditions to the coated stents (100°C ). Sirolimus decomposition studies have been reported in the literature (28,29) but not under heat stress. In these cases, sirolimus degradation has been related to the trans and cis variations.…”

Strong effect of methyl group on the strength of ionic hydrogen bond between C2H2 and H3O+

“…The ionic hydrogen bond is an attractive interaction that forms between an ion and a molecule with the bond strength of 5-35 kcal/mol [6]. This strong interaction plays a critical role in many chemical processes, such as ion salvation, surface adsorption, electrolyte, and selfassembly in supramolecular chemistry [7][8][9][10]. It is also of importance in bioenergetics, for example, protein folding, enzyme active centers, formation of membranes and proton transport, and biomolecular recognition [11][12][13][14][15].…”