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

The 9R,12S-[tBu(2)Sn](2)O derivative of the macrolide antibiotic erythromyc in A (ErySn-A) is obtained as the sole regio- and stereospecific reaction p roduct from the condensation reaction of (tBu(2)SnOPr)(2)O with erythromyci n A in benzene solution. Complete resonance assignments were achieved, and the covalent structure was derived using various one-dimensional and two-di mensional NMR techniques, including gradient enhanced H-1-Sn-119 heteronucl ear multiple quantum correlation and heteronuclear multiple bond correlatio n spectroscopy. A total of 64 nuclear Overhauser effect-based distance rest raints were used in restrained molecular dynamics simulations within the ex tensible systematic force field. This yielded a unique, well-defined confor mation 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 assign ment 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 m oiety covalently linked to the C9 and C12. carbons of the lactone macrocycl e, and a ketal ring involving C9 with C6. The conformation of the lactone r ing is strongly affected by the derivatization, but both sugar residues ret ain very similar conformations as compared to erythromycin A. The structure also involves a peculiar hydrogen bond between the 11-OH and the distannox ane oxygen, in which the hydrogen atom appears to be delocalized.