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.