Stereoselective synthesis of (−)‐cytoxazone and its unnatural congener (+)‐5‐epi‐cytoxazone

• Published in: Chirality (New York, N.Y.) Vol. 33; no. 8; pp. 479 - 489
• Main Authors: Miranda, Izabel Luzia, Santos, Pedro Henrique Costa, Kohlhoff, Markus, Purgato, Gislaine Aparecida, Diaz, Marisa Alves Nogueira, Diaz‐Muñoz, Gaspar
• Format: Journal Article
• Language: English
• Published: HOBOKEN Wiley 01.08.2021; Wiley Subscription Services, Inc
• Subjects: Chemistry; Chemistry, Analytical; Chemistry, Medicinal; Chemistry, Organic; Congeners; Cyanides; d‐4‐hydroxyphenylglycine; Isomers; Life Sciences & Biomedicine; oxazolidinone; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; stereoisomer; Stereoisomerism; Stereoisomers; stereoselective addition; Stereoselectivity; Synthesis; oxazolidinone; d-4-hydroxyphenylglycine; ENANTIOSELECTIVE SYNTHESIS; ANALOGS; CYTOKINE MODULATOR; stereoisomer; stereoselective addition; CYTOXAZONE; CONCISE SYNTHESIS; (+)-EPI-CYTOXAZONE
• ISSN: 0899-0042; 1520-636X
• DOI: 10.1002/chir.23334

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.