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Enantioselective Total Synthesis of (+)-Gliocladin C and (+)-Gliocladine C

Enantioselective Total Synthesis of (+)-Gliocladin C and (+)-Gliocladine C. 石枫 2011-7-9. Larry E. Overman, Org. Lett., 2007, 9, 339 Larry E. Overman, J. Am. Chem. Soc. 2011,133, 6549. (+)-Gliocladine C. (+)-Gliocladin C. They were isolated from fungal secondary metabolites.

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Enantioselective Total Synthesis of (+)-Gliocladin C and (+)-Gliocladine C

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  1. Enantioselective Total Synthesis of (+)-Gliocladin C and (+)-Gliocladine C 石枫 2011-7-9 Larry E. Overman, Org. Lett., 2007, 9, 339 Larry E. Overman, J. Am. Chem. Soc. 2011,133, 6549

  2. (+)-Gliocladine C (+)-Gliocladin C • They were isolated from fungal secondary metabolites. • They showed a wide range of bioactivities.

  3. Enantioselective Total Synthesis of (+)-Gliocladin C Larry E. Overman, Org. Lett., 2007, 9, 339

  4. Sythesis of starting material from isatine: J. Am. Chem. Soc. 1958, 80, 2257 Muthusamy, S. J. Chem. Soc., Chem. Commun. 2002, 824 Overman, L. E. Org. Lett. 2005, 7, 2795

  5. Mukaiyama aldol reaction Rychnovsky’s method CSA: 樟脑磺酸 TBDMS: t-butyl dimethyl silyl DTBMP: 2,6-di-tert-butyl-4-methylpyridine (to prevent desilylation of the siloxy nucleophile)

  6. TBDMSCl: BOP: benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate TBAF:

  7. Mulliez’s method Mulliez, M.; Royer, J. Tetrahedron 1984, 40, 5143 From isatine to (+)-Gliocladin C: 21 steps, ~4% overall yield. next

  8. Mukaiyama aldol reaction: Pioneer work: Mukaiyama, T., Chem. Lett. 1973, 1011; Mukaiyama, T.,J. Am. Chem. Soc. 1974, 96, 7503 Mechanism: back

  9. Mechanism: back Mechanism:

  10. Rychnovsky’s method: Scott D. Rychnovsky, J. Am. Chem. Soc. 1994,116,1753 Mechanism: back

  11. The action of BOP: The action of TMSI: back

  12. Enantioselective Total Synthesis of (+)-Gliocladine C (+)-Gliocladin C Larry E. Overman, J. Am. Chem. Soc. 2011,133, 6549

  13. Steglich-type rearrangement

  14. Soai reduction PPTS: pyridinium p-toluenesulfonate Dess Martin periodinane (DMP): Soai reduction: LiBH4-MeOH (Esters, lactones, and epoxides) Soai, K.; Ookawa, A. J. Org. Chem. 1986, 51, 4000

  15. Sharpless asymmetric dihydroxylation NMO: N-甲基吗啉氧化物

  16. Org. Lett., 2007, 9, 5267. From isatine to (+)-Gliocladin C: 10 steps, 11% overall yield. From precursor of (+)-Gliocladin C to (+)-Gliocladine C: 6 steps, 29% yield.

  17. Mechanism of acid-promoted ionic reduction: back Mechanism of ring-closing: back

  18. Steglich-type rearrangement: Pioneer work: Steglich, W. Tetrahedron Lett. 1970, 11, 4727 Black, T. H. J. Chem. Soc. Chem. Commun. 1986, 1524

  19. Catalytic enantioselective Steglich-type rearrangement : Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 3921 Vedejs, E. J. Am. Chem. Soc. 2003, 125, 13368; Vedejs, E. J. Am. Chem. Soc. 2003, 125, 4166

  20. Mechanism of Steglich-type rearrangement: back

  21. AD-mix a: (DHQ)2PHAL+K2OsO2(OH)4+K3Fe(CN)6 AD-mix b: (DHQD)2PHAL+K2OsO2(OH)4+K3Fe(CN)6 (DHQ)2PHAL (DHQD)2PHAL Sharpless asymmetric dihydroxylation (SAD): Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 4263 Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968 Empirical model:

  22. Mechanism of SAD:

  23. Synthetic applications of SAD: back Armstrong, A. J. Org. Chem. 2000, 65,7020 Burke, S. D. Org. Lett. 1999, 1, 71.

  24. Mechanism of sulfur substitution: back

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