STEREOSPECIFIC SYNTHESIS, H-1 AND C-13 NMR-SPECTROSCOPY AND X-RAY CRYSTALLOGRAPHIC STUDIES OF 6,6-DIBROMO-3-ALPHA-CYANO-2,2-DIMETHYLPENAM-(1R)-S-OXIDE

A stereospecific synthesis of 6,6-dibromo-3-alpha-cyano-2,2-dimethylpenam-(1R)-S-oxide (2) is described. The X-ray single crystal investigation of this compound shows that if crystallizes in the monoclinic system, space group P2(1), with cell parameters a = 6.194(1), b = 9.363(1), c = 9.869(1) angstrom, beta = 96.55(2)degrees, V = 568(1) angstrom3, and two molecules per unit cell. The structure was solved, from low temperature data, by direct methods, and refined, by least-squares procedures, to a final R = 3.17%, R(w) = 3.38%, for 1221 observed independent reflections. The sulfoxide configuration is R. The thiazolidine presents an envelope shape with the C(3) atom 0.56 angstrom above the other four members of the ring mean plane. Therefore, it exhibits the conformation with alpha-CH3 pseudoequatorial and beta-CH3 and alpha-CN both pseudoaxial. This conformation is different from the one reported for other penicillin sulfoxide derivatives. The geometry of the beta-lactam ring is typical of the fused bicyclic penam nucleus. The ring is non-planar. The N(4) atom displays a pyramidial arrangement. The examination of crystal packing shows that molecules along a are connected by a short C-H...O contact. Reported single crystal studies showed two dominant conformations for the thiazolidine ring in the fused bicyclic penam necleus: the C(3) or 2-beta-3-alpha substituents both pseudoaxial, as found in 2, and the S(1) or 2-beta-3-alpha substituents both pseudoequatorial, adopted by most sulfoxides. Neither of these conformations can explain the nuclear Overhauser effect data. A conformation with the substituents C2-beta-methyl-C3-alpha-H and C2-alpha-methyl-C3-alpha-CN fully eclipsed is in accordance with the experimental results in the solution. The H-1 nuclear magnetic resonance data reflect the influence of the magnetic anisotropy of the CN triple bond on the gem-dimethyl groups, particularly in relation with the geometrical features of the molecule. Comparison of C-13 nuclear magnetic resonance chemical shifts for 2 and its parent penicillin sulfide (1) indicates configurationally dependent substituent effects, the magnitude of which can be used for the stereochemical assignment of sulfoxide groups in this series.