Mikael Bergdahl

Asymmetric conjugate additions of TMSI promoted monoorganocuprate reagents, Li[RCuI], to various N-enoyl oxazolidinones ☆

Abstract Diastereoselective conjugate additions to different α,β-unsaturated N -acyl oxazolidinones using various monoorganocuprate reagents, Li[RCuI], are described. The TMSI activated conjugate addition reactions provided high yields (80–98%) and reversed major diastereomers (70–96% de) compared to the conventional copper(I)-promoted additions of Grignard reagents or the addition of Li[RCuI] to precomplexed MgBr 2 /imides.

Solvent affects the conformation of virginiamycin M1(pristinamycin IIA, streptogramin A)

The streptogramins are antibiotics which act by binding two different components at separate nearby sites on the bacterial 50S ribosome, inhibiting protein synthesis. The first component, a macrolactone, is common to many of the streptogramin antibiotics and, thus, is referred to by many names including virginiamycin M1(VM1), pristinamycin IIA, ostreogrycin A and streptogramin A. X-Ray crystallographic studies of VM1 bound to ribosomes and to a deactivating enzyme show a different conformation to that of VM1 in chloroform solution. We now report the results of high resolution 2D NMR experiments that show that the conformation of VM1 in dimethyl sulfoxide and methanol differs from both that in chloroform solution and in the bound form. The 3D structure and the 1H NMR and 13C NMR chemical shifts of VM1 in dimethyl sulfoxide and methanol are described.

The conformational flexibility of the antibiotic virginiamycin M1.

The antibiotic virginiamycin is a combination of two molecules, virginiamycin M1 (VM1) and virginiamycin S1 (VS1) or analogues, which function synergistically by binding to bacterial ribosomes and inhibiting bacterial protein synthesis. Both VM1 and VS1 dissolve poorly in water and are soluble in more hydrophobic solvents. We have recently reported that the 3D conformation of VM1 in CDCl3 solution (Aust. J. Chem. 57:415, 2004; Org. Biomol. Chem. 2:2919, 2004) differs markedly from the conformation bound to a VM1 binding enzyme (Sugantino and Roderick in Biochemistry 41:2209, 2002) and to 50S ribosomes (Hansen et al. in J. Mol. Biol. 330:1061, 2003) as found by X-ray crystallographic studies. We now report the results of further NMR studies and subsequent molecular modeling of VM1 dissolved in CD3CN/H2O and compare the structure with that in CD3OD and CDCl3. The conformations of VM1 in CD3CN/H2O, CD3OD and CDCl3 differ substantially from one another and from the bound form, with the aqueous form most like the bound structure. We propose that the flexibility of the VM1 molecule in response to environmental conditions contributes to its effectiveness as an antibiotic.

Employing the simple monosilylcopper reagent, Li[PhMe2SiCuI], in 1,4-addition reactionsElectronic supplementary information (ESI) available: Typical experimental procedure, 1H-NMR, 13C-NMR, MS and IR spectral data for all ??-silyl carbonyl compounds (PDF). See http://www.rsc.org/suppdata/cc/b2/b210792a/

Conjugate addition reactions using the simple Li[PhMe2SiCuI] reagent to a variety of alpha,beta-unsaturated carbonyl compounds is described; dimethyl sulfide from the purification of CuI plays a key role for very high yields as well as high stereoselectivities in the formation of beta-silyl carbonyl compounds.