Total synthesis of (s)-(+)-citreofuran by ring closing alkyne metathesis.
A concise total synthesis of citreofuran 4 is described, a structurally unique octaketide derivative belonging to the curvularin family. Key steps involve the elaboration of orsellinic acid methyl ester 5 to acid 14, which converts, on attempted formation of the corresponding acid chloride, to the 3-alkoxyisocoumarin derivative 20. This heterocycle can be used as an activated ester to give ketone 21 on treatment with 3-pentynylmagnesium bromide in the presence of TMSCl as the activating agent. Ring- closing alkyne metathesis (RCAM) of diyne 21 catalyzed by (tBuO)(3)W[triple bond]CCMe(3) affords the strained cycloalkyne 22. Treatment with acid renders its triple bond susceptible to nucleophilic attack by the adjacent carbonyl group, thus leading to a transannular cycloaromatization with formation of the intact skeleton of citreofuran. An X-ray crystallographic study reveals conformational details about this natural product. Finally, it is shown that 4 as well as its protected precursor 23 are able to cleave double-stranded DNA under oxidative conditions.
Fürstner
Alois
A
Max-Planck-Institut für Kohlenforschung, D-45470 Mülheim/Ruhr, Germany. fuerstner@mpi-muelheim.mpg.de
Castanet
Anne-Sophie
AS
Radkowski
Karin
K
Lehmann
Christian W
CW
D000480:Alkynes / Q000737:chemistry*; D000528:Alternaria / Q000737:chemistry; D001203:Ascomycota / Q000737:chemistry; D002384:Catalysis; D018360:Crystallography, X-Ray; D003500:Cyclization; D004249:DNA Damage; D005663:Furans / Q000138:chemical synthesis* / Q000494:pharmacology; D007202:Indicators and Reagents; D008968:Molecular Conformation; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010407:Penicillium / Q000737:chemistry; D013237:Stereoisomerism; D015025:Zearalenone / Q000031:analogs & derivatives* / Q000737:chemistry
D000480:Alkynes; D005663:Furans; D007202:Indicators and Reagents; C477980:citreofuran; D015025:Zearalenone; C013455:curvularin