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Journal Article

Total Synthesis of Roseophilin


Fürstner,  Alois
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;


Weintritt,  Holger
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Fürstner, A., & Weintritt, H. (1998). Total Synthesis of Roseophilin. Journal of the American Chemical Society, 120(12), 2817-2825. doi:10.1021/ja973846k.

Cite as: http://hdl.handle.net/11858/00-001M-0000-0024-033F-B
The first total synthesis of the antitumor agent roseophilin 1 is reported. Its intricate macrotricyclic core 2 is obtained by means of a new palladium-catalyzed manifold for the formation of ansa-bridged pyrroles which proceeds via vinyl oxirane 8 and allyl lactone 11 as key intermediates. After conversion of the latter into pyrrolophane 14, a base-induced elimination of the sulfone group followed by the Michael addition of a zincate onto the resulting enone 18 installs the isopropyl substituent in a stereoselective manner. The pyrrolylfuran side chain 3 of roseophilin is prepared from 4-methoxy-2(5H)-furanone (24) and methyl 4-chloropyrrole-2-carboxylate (26) as the starting materials. The appropriate building blocks 25a and 28 derived thereof are combined via a sequence comprising a directed metal−halogen exchange reaction, transmetalation of the resulting lithiopyrrole to the corresponding organozinc compound, a palladium-catalyzed cross coupling of the latter, and a subsequent acid-catalyzed closure of the resulting ketone 29 leading to the furan entity of the target. The triisopropylsilyl-protected side chain 3b is first deprotonated with n-BuLi and then transmetalated with CeCl3 to give a highly nucleophilic organocerium reagent, which readily attacks the sterically hindered 2-(trimethylsilyl)ethoxymethyl-protected keto pyrrole 2c. Deprotection and final dehydration of the tertiary alcohol derivative 30 thus obtained leads to the intact azafulvene chromophore of the natural product and completes our total synthesis of this alkaloid.