A Diels-Alder Aproach to (-)-OvalicinKonrad Tiedenbacher, Vladimir B. Arion, and Johann MultzerAngewandte Chemie International Edition 2007, 46, 2690-2693Presented by Max OsipovCHEM 2320 April 16th 2007OOMeOOHO1Biological Relevance• Isolated from Pseudorotium ovalis cultures• Antiangiogenic activity– Tumor growth suppression– Suicide inhibitor • Methionine Aminopeptidase– HsMetAP2 – Alkylation• Anti-Microsporidosis agent– Protazoan/fungal parasites• Designer analogues – TNP-470Human HsMetAPOOMeOOHOO4OHOOOMeOOHO(-)-Ovalicin(-)-Fumag illinMatthews et al. Protein Science, 2006, (15), 1842-1848OOMeOOHOOHNTNP-470OClDiels-Alder Key-Step– Catalytic approach to Diels-Alder reaction failed to give acceptable ee’s– Keck, Mikami, Corey and MacMillan Catalysts– Auxiliary approach gave desired resultOOMeOOHOOOMeOPGOPG'OHC BrOPG'OPG'CHOBrRetrosynthesisA: Keck B: Mikami C: Corey D: MacMillanConstruction of Core RingOOOMePhBromoacrolein, BF3 . Et2ODCM, -78oC75%OOOMePhBrOOHBrOHBH3.NH3Et2O 89%1) p-MeOC6H4CH(OMe)2 CSA, DCM, 89%2) DIBAL-H, DCM, -10oC - 0oC, 94%OPMBBrOH1) TBSCl, imidazole DCM, 89% 2) NaH, MeI, THF, 99%3) DDQ, DCM, H2O, 89%OPMBO1) NaH, THF, MeOH 98%2) 1 mol% OsO4, NMO acetone/H2O, 92%OHOHOHOOMeOTBSDess-Martin, NaHCO3DCM, 92%OOOMeOTBS10111213 1415 16OBrOHAlOPMBOHOHOSiClSide-Chain Construction and Fragment CouplingOOTBSOORLiOTBSOOROHOHSnBu31) NBS, DCM, 99%2) DMP, NaHCO3 DCM, 94%OBrNNNNPhSOOLHDMS, THF-78oC -> RT70%Br1920 17OOOMeOTBStBuLi, 17Et2O, PhMe78%OOMeOTBSOHTBAF, THF0oC, 30min94%OOMeOHOHDMP, NaHCO3DCM, 90%OOMeOOH[VO(acac)2], tBuOOH, PhH71%OOMeOOHO116222324Conclusion• Total synthesis of (-)-Ovalicin in 15 linear steps• 15% Yield overall• First Diels-Alder approach to Ovalicin• Interesting selective transformationsAny
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