Synthesis, NMR and X-ray structure analysis of macrolide aglycons

Structure and conformational analysis of spiroketals from 6-O-methyl-9(E)-hydroxyiminoerythronolide A

“…For several decades now, our continuing primary interest lay in 14-membered macrolides and their semi-synthetic 15-membered derivatives targeting therapeutic areas of bacterial [ 32 – 34 ] and parasitic [ 35 ] infections, as well as inflammation [ 36 – 38 ]. In the search for novel scaffolds to be used as a fresh starting point for further derivatisation [ 39 ], we explored modifications to the macrocyclic ring. Oxidative deoximation of 1 in mild acidic media, shown in Scheme 1 , led us to an unexpected macrolide-spiroketal 2 which sparked our interest, not only because the spiroketal is a biologically relevant subunit whose incorporation into macrolide could yield interesting biological activity, but also because this unit provides unique rigidity to the 6-C to 12-C region of the macrocycle allowing for specific orientations of the functional groups.…”

“…Unlike the acid degradation product anhydroerythromycin A, the spiroketal 2 exhibits the much less common [4.5]spiroketal unit connecting 5-C–O–9-C–O–12-C; its existence is made possible by the free 5-OH functionality of the starting aglycon 1 [ 39 , 51 ]. Native macrolide aglycons are rarely found in nature [ 52 ], most likely because they are quickly glycosylated even before macrolactonisation [ 53 ].…”

“…Analysis of HMBC spectra, as well as chemical shift comparison with the parent compound 1 [ 39 ], showed that the 9-C-signal of 2 exhibits a large upfield shift to 107.1 ppm (168.1 ppm in 1 ), as well as intense HMBC cross-peaks with 4-H and 5-H. At the same time, the carbon signal of 12-C in 2 is found at 81.8 ppm (73.4 ppm in 1 ). These suggest their participation in a [4.5]spiroketal ring system.…”

“…Oxime 1 was synthesized according to the previously published procedure [ 39 , 51 , 64 ]. The structures of all compounds were confirmed by NMR spectroscopy, LC–HRMS and molecular modelling.…”

Reinvestigation of the Branimycin Stereochemistry at Position 17-C

“…Drawing from these newly discovered interactions, however, one should be cautious. Having experience with macrocyclic conformational analyses, − we prefer DMSO- d 6 as a solvent because it stabilizes the exchangeable protons through intramolecular hydrogen bonding making their interactions visible. Unfortunately, due to the branimycin molecular size and viscosity of DMSO- d 6 at 25 °C the NOE intensities are close to zero at Larmor frequency of 600 MHz .…”