Synthesis of (-)-quinocarcin by directed condensation of alpha-amino aldehydes.
An enantioselective synthesis of the natural antiproliferative agent quinocarcin was achieved by the directed condensation of optically active alpha-amino aldehyde intermediates. Condensation of the N-protected alpha-amino aldehyde 1, prepared in eight steps (19% yield) from (R,R)-pseudoephedrine glycinamide, with the C-protected alpha-amino aldehyde derivative 2, prepared in seven steps (34% yield) from (R,R)-pseudoephedrine glycinamide, afforded the corresponding imine in quantitative yield. Without isolation, direct treatment of this imine intermediate with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and hydrogen cyanide led to cleavage of the fluorenylmethoxycarbonyl (Fmoc) protective group followed by addition of cyanide (Strecker reaction) to form the bis-amino nitriles 3 as a mixture of diastereomers, in 91% yield. Treatment of the diastereomers 3 with trimethylsilyl cyanide and zinc chloride in 2,2,2-trifluoroethanol at 60 degrees C led to stepwise cyclization to form the tetracyclic product 4 (42% yield from 1 and 2). The latter intermediate was transformed into (-)-quinocarcin (1) in five steps (45% yield). The yield of quinocarcin was 19% from 1 and 2 (7 steps), and 4% from pseudoephedrine glycinamide (15 steps).
Kwon
Soojin
S
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Myers
Andrew G
AG
D000447:Aldehydes / Q000737:chemistry*; D004809:Ephedrine / Q000031:analogs & derivatives / Q000737:chemistry; D005998:Glycine / Q000031:analogs & derivatives / Q000737:chemistry; D007546:Isoquinolines / Q000138:chemical synthesis; D009025:Morpholines / Q000737:chemistry; D009570:Nitriles / Q000737:chemistry; D013237:Stereoisomerism
D000447:Aldehydes; D007546:Isoquinolines; D009025:Morpholines; D009570:Nitriles; C018556:glycine amide; C038710:quinocarcin; D004809:Ephedrine; D005998:Glycine