Total synthesis of the turrianes and evaluation of the DNA-cleaving properties.
The first total synthesis of three naturally occurring cyclophane derivatives belonging to the turriane family of natural products is described. Their sterically hindered biaryl entity is formed by reaction of the Grignard reagent derived from aryl bromide 10 with the oxazoline derivative 18, and the macrocyclic tether of the targets is efficiently forged by ring closing metathesis. While conventional RCM catalyzed by the ruthenium-carbene complexes 33 or 34 invariably leads to the formation of mixtures of both stereoisomers with the undesirable (E)-alkene prevailing, ring closing alkyne metathesis (RCAM) followed by Lindlar reduction of the resulting cycloalkynes 37 and 38 opens a convenient and stereoselective entry into this class of compounds. RCAM can either be accomplished by using the tungsten alkylidyne complex [(tBuO)3 [triple bond] WCCMe3] or by means of a catalyst formed in situ from [Mo(CO)6] and para-trifluoromethylphenol. The latter method is significantly accelerated when carried out under microwave heating. Furthermore, the judicious choice of the protecting groups for the phenolic -OH functions turned out to be crucial. PMB-ethers were found to be compatible with the diverse reaction conditions en route to 3-5; their cleavage, however, had to be carried out under carefully optimized conditions to minimize competing O-C PMB migration. Turrianes 3-5 are shown to be potent DNA cleaving agents under oxidative conditions when administered in the presence of copper ions.
Fürstner
Alois
A
Max-Planck-Institut für Kohlenforschung, Mülheim/Ruhr, Germany. fuerstner@mpi-muelheim.mpg.de
Stelzer
Frank
F
Rumbo
Antonio
A
Krause
Helga
H
D000475:Alkenes / Q000737:chemistry; D002384:Catalysis; D003500:Cyclization; D053938:DNA Fragmentation / Q000187:drug effects*; D004278:DNA, Superhelical / Q000737:chemistry / Q000187:drug effects; D004988:Ethers, Cyclic / Q000737:chemistry*; D007202:Indicators and Reagents; D010080:Oxazoles / Q000737:chemistry*; D010946:Plants, Medicinal / Q000737:chemistry*
D000475:Alkenes; D004278:DNA, Superhelical; D004988:Ethers, Cyclic; D007202:Indicators and Reagents; D010080:Oxazoles