Stereoselective synthesis of (-)-cytoxazone and its unnatural congener (+)-5-epi-cytoxazone.

An interesting protocol for stereoselective synthesis of (-)-cytoxazone and its unnatural stereoisomer (+)-5-epi-cytoxazone from d-4-hydroxyphenylglycine in overall yields of 10% and 16%, respectively, is described. The stereoselective addition of cyanide to an N-Boc protected aminoaldehyde (tert-butyl ((R)-1-(4-methoxyphenyl)-2-oxoethyl)carbamate) (5) constitutes the key step in this approach, producing a mixture of cyanohydrins 6a and b (1,2-anti and 1,2-syn tert-butyl (2-cyano-2-hydroxy-1-(4-methoxyphenyl)ethyl)carbamate) in 89% yield, with reasonable stereoselectivity (1.0:1.8) in favor of the anti-Felkin product (1,2-syn). A one-pot sequence of three successive steps from this mixture produced the oxazolidinone isomers 9a and b ((4R,5R)- and (4R,5S)-4-(4-methoxyphenyl)-2-oxooxazolidine-5-carboxylate). Chromatographic column separation and reduction of the ester function of both precursors led to (-)-cytoxazone and (+)-5-epi-cytoxazone.