Modeling in organotin chemistry using NMR restraints:: A case study on the 9R,12S-[tBu2Sn]2O derivative of erythromycin A

The 9R,12S-[tBu(2)Sn](2)O derivative of the macrolide antibiotic erythromycin A (ErySn-A) is obtained as the sole regio- and stereospecific reaction product from the condensation reaction of (tBu(2)SnOPr)(2)O with erythromycin A in benzene solution. Complete resonance assignments were achieved, and the covalent structure was derived using various one-dimensional and two-dimensional NMR techniques, including gradient enhanced H-1-Sn-119 heteronuclear multiple quantum correlation and heteronuclear multiple bond correlation spectroscopy. A total of 64 nuclear Overhauser effect-based distance restraints were used in restrained molecular dynamics simulations within the extensible systematic force field. This yielded a unique, well-defined conformation for ErySn-A, which was validated against 17 (3)J(H-1-H-1) and 21 (3)J(C-13-H-1) experimental coupling constants. Complete stereospecific assignment of the diastereotopic tert-butyl groups as well as the identification of the absolute configuration at C9 was achieved. The lactone ring features a tricyclic structure, with the -O-Sn-(tBu)(2)-O-(tBu)(2)Sn-O- organotin moiety covalently linked to the C9 and C12. carbons of the lactone macrocycle, and a ketal ring involving C9 with C6. The conformation of the lactone ring is strongly affected by the derivatization, but both sugar residues retain very similar conformations as compared to erythromycin A. The structure also involves a peculiar hydrogen bond between the 11-OH and the distannoxane oxygen, in which the hydrogen atom appears to be delocalized.