Group Meeting 14.03.2014 Joséphine Cinqualbre The Total Syntheses of Gu0ferone A and 6-­‐epi-­‐Gu0ferone A Fiene Horeischi, Nicoles Biber, and Bernd Plietker* J. Am. Chem. Soc. ASAP 1 IntroducGon §  Isolated from Guttiferae (Clusiaceae) and Garcinia §  Belong to the polyprenylated polycyclic acylphloroglucinols family(PPAP) SubclassiHication : Type B: PPAPs has a C3 acyl group Endo: C7 trans to the acyl group §  Structural features : bicyclo[3.3.1]nonatrione core decorated with prenyl side chains Usually PPAP with C1, C5 and C7 stereocenters, here additional C6 §  Bioactivities: human colon and ovarian cancer cells, anti HIV, protection against Iron-­‐
induced neuronal cell damage and antimicrobial activities Ciochina, R.; Grossman, R. B. Chem. Rev. 2006, 106, 3963−3986 McCandlish, L. E.; Hanson, J. C.; Stout, G. H. Acta Crystallogr. 1976, 32, 1793−1801 2 Biosynthesis of gu0ferone A Biosynthetic route from monocyclic polyprenylated acylphloroglucinols (MPAPs) Ciochina, R.; Grossman, R. B. Chem. Rev. 2006, 106, 3963−3986 Cuesta-­‐Rubio, O.; Velez-­‐Castro, H.; Frontana-­‐Uribe, B. A.; Cardenas,J. Phytochemistry 2001, 57, 279 3 Retrosynthesis of gu0ferone A Challenges : §  Creation of an additional stereocenter at C6 §  Separation of framework construction and functionalization §  Use substrate induction to control all stereocenters 4 Synthesis of 6-­‐epi-­‐gu0ferone A Huckin, S. N.; Weiler, L. Can. J. Chem. 1974, 52, 1379−1380 Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1986, 25, 947 5 Synthesis of 6-­‐epi-­‐gu0ferone A Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron LeF. 1983, 24, 1793−1796. Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343−18357 6 Synthesis of 6-­‐epi-­‐gu0ferone A Wrong stereochemistry at C6 during organocopper 1,4-­‐addition New strategy! Siegel, D. R.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 1048−1049 7 Synthesis of gu0ferone A : «frustraGng» approach Hopf, H.; Hussain, Z.; Menon, S. R.; Pohl, L. M.; Raev, V.; Jones, P. G. SynleF 2011, 9, 1273−1276 8 Synthesis of gu0ferone A : «frustraGng» approach 9 Synthesis of gu0ferone A : «successful» approach 10 Synthesis of gu0ferone A : «successful» approach 11 Conclusion §  Synthesis of 6-­‐epi-­‐gu0ferone A : 10 steps, overall yield 8,7% §  Synthesis of gu0ferone A : 13 steps, overall yield 13,4% §  Full control of four adjacent stereocenters (C1, C5, C6, C7) §  Base for further total syntheses of higer prenylated PPAps §  Extension to synthesis of exo-­‐type PPAP (i.e. inversion during C1 allylaGon) 12 Thank you for your a5en7on! 13 Biosynthesis of gu0ferone A 14 Biosynthesis of gu0ferone A 15 Synthesis of 6-­‐epi-­‐gu0ferone A allyla7on and deacyla7ng aldol condensa7on 16 Synthesis of 6-­‐epi-­‐gu0ferone A Tandem Michael addi7on-­‐Knoevenagel condensa7on 17 Synthesis of 6-­‐epi-­‐gu0ferone A 1,2 addi7on and prenyla7on 18 Synthesis of 6-­‐epi-­‐gu0ferone A Pd-­‐catalyzed decarboxyla7ve allyla7on Pd2(dba)3CH3Cl Pd(0) Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343−18357 19 Synthesis of 6-­‐epi-­‐gu0ferone A (a)  Plietker, B. Angew. Chem., Int. Ed. 2006, 45, 1469−1473 (b)  Plietker, B.; Dieskau, A.; Möws, K.; Jatsch, A.; Angew.Chem., Int. Ed. 2008, 47, 198−201. 20 (c)  Holzwarth, M.; Dieskau, A.; Tabassam, M.; Plietker, B. Angew. Chem., Int. Ed. 2009, 48, 7251−7255. Synthesis of 6-­‐epi-­‐gu0ferone A (a)  Plietker, B. Angew. Chem., Int. Ed. 2006, 45, 1469−1473 (b)  Plietker, B.; Dieskau, A.; Möws, K.; Jatsch, A.; Angew.Chem., Int. Ed. 2008, 47, 198−201. 21 (c)  Holzwarth, M.; Dieskau, A.; Tabassam, M.; Plietker, B. Angew. Chem., Int. Ed. 2009, 48, 7251−7255. G. Mehta’s 2008 syntheGc approach toward gu0ferone A Njardarson, J. T. Tetrahedron 2011, 67, 7631−7666 22 

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Syllabus