RESUMEN
[reaction: see text] A concise stereoselective approach to both orthogonally protected (2S,4R)- and (2S,4S)-4-hydroxyornithine, key constituents of the biphenomycin- and clavalanine-type antibiotics, respectively, has been developed. The approach is based on bis(oxazoline) copper(II)-complex-catalyzed diastereoselective Henry reactions of nitromethane with the homoserine-derived aldehyde 6. The synthesis of this versatile chiral building block has been markedly improved.
Asunto(s)
Ornitina/análogos & derivados , Cobre/química , Estructura Molecular , Ornitina/síntesis química , Oxazoles/química , EstereoisomerismoRESUMEN
An efficient synthetic approach to the core structure 5 of the novel polyketide antibiotic tetrodecamycin (1) was developed. This approach features the acid-catalyzed cyclization of a tert-butyldimethylsilyl protected methyl alpha-(gamma-hydroxyacyl) tetronate, leading to the novel tricyclic ring skeleton exhibited by 5, and an efficient strategy for the parallel introduction of the cis-diol and exo-methylene function. In addition to 5, diastereomer 26, analogue 6 and several derivatives (16, 27-29) were prepared and evaluated for their antibacterial activities against Staphylococcus aureus (including MRSA) and Enterococcus faecalis and for their cytotoxic activities against human leukemia cell lines (HL-60, Jurkat T-cells). While compound 5 did not inhibit the growth of the Gram-positive pathogens (MICs >128 microg mL(-1)), analogue 6 and 2-naphthoyl derivative 27 showed promising antibacterial activities with MICs of 4-16 microg mL(-1). Remarkably, the antibacterial activity of these compounds was paralleled by cytotoxicity (IC(50) 10-23 microM). The reactive exo-methylene moiety was shown to be crucial, but not sufficient by its own, for both the antibacterial and the cytotoxic activities.