1 / 48

Total Synthesis of (+)-Acutiphycin and (+)-trans-20,21-didehydroacutiphycin

Total Synthesis of (+)-Acutiphycin and (+)-trans-20,21-didehydroacutiphycin. Wei Lin Literature Meeting Charette Group. Dec . 5 th , 2006. Introduction. CYANOPHYTA: Blue-Green Algae. Isolated from the blue-green algae Oscillatoria acutissima in 1984 by Moore and co-workers.

page
Download Presentation

Total Synthesis of (+)-Acutiphycin and (+)-trans-20,21-didehydroacutiphycin

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Total Synthesis of (+)-Acutiphycin and (+)-trans-20,21-didehydroacutiphycin Wei Lin Literature Meeting Charette Group Dec. 5th, 2006

  2. Introduction CYANOPHYTA: Blue-Green Algae Isolated from the blue-green algae Oscillatoria acutissima in 1984 by Moore and co-workers. Potent in vivoantineoplastic activity against murine Lewis lung carcinoma, significant cyctoxicity against KB and NIH/3T3 cell lines. Moore, R.E. et al., J.A.C.S.1984, 106, 8193-8197.

  3. Total Synthesis History • In 1995, first total synthesis by Smith Group from Pennsylvania. • In 1999, C10-epi seco acid derivative synthesized by Kiyooka group from Japan. • In 2001, C(9)- C(13) fragment was synthesized by Miftakhov and co-workers from Russia. • In 2002, C(1)- C(8) fragment was synthesized by Léger and co-workers from Merck Frosst center in Quebec • In 2006, second total synthesis by Jamison group from MIT.

  4. Amos B. Smith, III Born in 1944 B.S.- M.S. Bucknell University (1966) Ph.D. Rockefeller University (1972) ResearchAssociate, Rockefeller University (1972-73) Rhodes-Thompson Professor of Chemistry(currently) To date, more than90 architecturally complex natural products have been prepared in his Laboratory.

  5. Research -Completed and Ongoing NPCs

  6. Smith Group Work-Retrosynthetic Analysis J.A.C.S.,1995, 117, 12013-12014. J.A.C.S., 1997, 119, 10935-10946.

  7. Smith Group Work

  8. Smith Group Work Fukuyama* proposed mechanism

  9. Smith Group Work

  10. Smith Group Work

  11. Smith Group Work 4 6

  12. Smith Group Work 3 days

  13. Smith Group Work • The first total synthesis of (+)-Acutiphycin was accomplished in 38 steps with an overall yield of 0.12%. • Applied L-(-)-malic acid, chiral auxilliary AD-Mix-β, (+)-B-methoxy-(diisopinocamphenyl)borane and tetramethylammonium triacetoxyborohydride to build the chiral centers.

  14. Kiyooka Group Work-chiral oxazaborolidinone-promoted asymmetric aldol reactions 5 4 6 3 7 9 8 2 1 Strategy: To construct linearly seco acid 2 by using a series of five aldol reactions at the carbon-carbon bond indicated with slant lines in 3. Tetrahedron Lett.,1999, 40, 1161-1164. J.O.C.,1999, 64(15), 5511-5523.

  15. A Chiral Oxazaborolidinone-Promoted Aldol Reaction Syun-ichi Kiyooka et al., Tetrahedron Asymmetry, 1996, 7(8), 2181-2184.

  16. Kiyooka Group Work-Promoters Used Heteroatom Chem.1997, 17, 245-270.

  17. Kiyooka Group Work 6 7 8 Opposite to the original target.

  18. Explanation of the Unexpected Selectivity in the Aldol Reaction 8 disfavored transition state Favored transition state J.O.C.,1999, 64(15), 5511-5523.

  19. Overcome the Problem of Unexpected Selectivity 10 16 33% + the recovered 16 After cyclization to the macrolactone, epimerization at C10 overcame the problem.

  20. Kiyooka Group Work 83% de

  21. Kiyooka Group Work Which was opposite to the original target. • Highly selective synthesis of C10-epi seco acid derivative of (+)- Acutiphycin was accomplished in 17 steps with an overall yield of 8.2%. • The six stereogenic centers were achieved form hexanal by using the chiral oxazaborolidinone-promoted asymmetrical aldol reactions.

  22. Miftakhov and Co-workers WorkC9-C13 segment of (+)-Acutiphycin levoglucosan Russ. Chem. Bull., Int. Ed., 2001, 50(6), 1101-1106

  23. Miftakhov and Co-workers WorkC9-C13 segment of (+)-Acutiphycin

  24. Miftakhov and Co-workers WorkC9-C13 segment of (+)-Acutiphycin

  25. Miftakhov and Co-workers WorkC9-C13 segment of (+)-Acutiphycin • C9- C13 segment of (+)-Acutiphycin was accomplished from levoglucosan in 9 steps with an overall yield of 16.9%.

  26. Léger and Co-workers WorkC1-C8 fragment of (+)-Acutiphycin Intramolecular Lewis acid-catalyzed reaction Tetrahedron Lett.,2002, 43, 1147-1150.

  27. Léger and Co-workers Work C1-C8 fragment of (+)-Acutiphycin 69% ee

  28. Léger and Co-workers WorkC1-C8 fragment of (+)-Acutiphycin Lewis Acid: TiCl4 (65%) C1-C8 segment of (+)-Acutiphycin was achieved in 11 steps with an overall yield of 17%.

  29. Timothy F. Jamison • Born in in San Jose • B.S., University of California, Berkeley(1990) • Ph.D., Harvard University (Prof. Stuart L. Schreiber) (1991-1997). • P.D.F., Harvard University (Prof. Eric N. Jacobsen) (1997-1999) • Assistant Professor, MIT (1999-2004). • Associate Professor, MIT (2004-Now)

  30. Research -Completed and Ongoing • Epoxide-opening cascades. • Carbon-carbon bond formation. • Target-oriented synthesis.

  31. Timothy F. Jamison Nickel catalyzed carbon-carbon bond formation Org. Lett., 2005, 7(14), 3077-3080. Tetrahedron. 2003, 59, 8913-8917. Tetrahedron. 2005, 61, 11405-11417. Tetrahedron. 2006, 62, 7598-7610. Tetrahedron. 2006, 62, 11350-11359. Org. Lett.2000, 2(26), 4221-4223. J.A.C.S.;2004, 126, 4130-4131. J.A.C.S.; 2004, 126, 15342-15343. Org. Lett.2006, 8(3), 455-458. Org. lett., 2005, 7(14), 2937-2940. Angew. Chem. Int. Ed.2003, 42(12), 1364-1367. Angew. Chem. Int. Ed.2004, 43, 3941-3944. Adv. Synth. Catal.2005, 347, 1533-1536. J.A.C.S., 2006, 128, 5362-5363. J.A.C.S., 2004, 126, 15342-15343.

  32. Jamison Nickel catalyzed carbon-carbon bond formation Org. Lett.2000, 2(26), 4221-4223.

  33. Jamison Nickel catalyzed reductive coupling of aldehyde and chiral 1,6-Enynes Org. Lett.2006, 8(3), 455-458. Tetrahedron. 2006, 62, 7598-7610.

  34. Jamison Nickel catalyzed reductive coupling of aldehyde and 1,6-Enynes Proposed mechanism by Jamison Org. Lett.2006, 8(3), 455-458.

  35. Jamison Group Work-RetrosyntheticAnalysis

  36. Jamison Group Work

  37. Jamison Group Work X

  38. Jamison Group Work -RetrosyntheticAnalysis

  39. Pd Catalyzed Couplinganti-homopropargylic alcohol Proposed mechanism by Marshall. Marshall,J. A. et al. J.O.C.,1999, 64, 5201-5204.

  40. Wipf Hydrozirconation-Transmetallation –Stereoselective Carbonyl Addition Wipf., P. et al, Tetrahedron Lett.,1994, 35, 5197-5200. Wipf., P. et al, J.Org. Chem., 1998, 63, 6454-6455.

  41. Jamison Group Work-Introduced the side chain 5

  42. Jamison Group Work-SmI2 Reformatsky reaction 5 For Reformatsky reaction, they tried Zn/Ag-graphite, no desired product generated. When switched to SmI2, they succeeded. Martin Sulfrane is specially used for dehydration of 2o and 3o carbinols with excellent yield. Fulvia Orsini, Elvira Maria Lucci, Tetrahedron Lett., 2005, 46, 1909-1911. Richard J. Arhart, J. C. Martin, J.A.C.S., 1972, 94, 5003-5010.

  43. Jamison Group WorkAlkyn addition Ethoxyethyne and another OH group were introduced.

  44. Jamison Group WorkJamison-Funk Ene-Macrolactonisation Funk, R.L.; et al., Synlett.,1989, 36-37.

  45. Jamison Group Work 1. Citric acid, MeOH 2. TESOTf, 2,6-lutidine

  46. Jamison Group Work • Highly convergent total synthesis of (+)-Acutiphycin was accomplished in 18 steps with an overall yield of 3.1%. • Applied nickel catalyzed reductive coupling reaction was not successful in this total synthesis.

  47. Richard E. TaylorUniversity of Notre Dame 1987 B.S. SUNY Oswego 1992 Ph.D. Rensselaer Polytechnic Institute Arthur G. Schultz 1992-1995 P.D.F, Stanford University, 1995-2001 Assistant Professor, 2001-2004 Associate Professor, 2004-present Professor Towards the total synthesis of (+)-Acutiphycin: utilization of homoaldol methodology in the preparation of enantioselective acetate aldol

  48. Richard E. Taylor

More Related