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

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Presentation on theme: "Total Synthesis of (+)-Acutiphycin and (+)-trans-20,21-didehydroacutiphycin Wei Lin Literature Meeting Charette Group Dec. 5 th, 2006."— Presentation transcript:

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

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

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) Research Associate, Rockefeller University ( ) Rhodes-Thompson Professor of Chemistry (currently) To date, more than 90 architecturally complex natural products have been prepared in his Laboratory.

5 Research -Completed and Ongoing NPCs 13-Deoxytedanolide (2003) (-)-9-Prenylpaxilline Dactylolide(2002) Salicylihalimide A(2001) Spongistatin 1 & 2(2001) Callystatin A (2001) Phorboxazole A (2001) Zampanolide (2001) Emindole SA (2000) Madinodoline A & B (2000) Discodermolide (1999) Penitrem D (1999) Cylindrocyclophane A (1999) Calyculin A (1998) Macrolactin A (1996)

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

7 Smith Group Work

8 Fukuyama* proposed mechanism

9 Smith Group Work

10

11 4 6

12 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 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, J.O.C., 1999, 64(15),

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

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

17 Kiyooka Group Work Opposite to the original target.

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

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

20 Kiyooka Group Work 83% de

21 Kiyooka Group Work  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. Which was opposite to the original target.

22 Miftakhov and Co-workers Work C9-C13 segment of (+)-Acutiphycin Russ. Chem. Bull., Int. Ed., 2001, 50(6), levoglucosan

23 Miftakhov and Co-workers Work C9-C13 segment of (+)-Acutiphycin

24

25  C9- C13 segment of (+)-Acutiphycin was accomplished from levoglucosan in 9 steps with an overall yield of 16.9%.

26 Léger and Co-workers Work C1-C8 fragment of (+)-Acutiphycin Tetrahedron Lett., 2002, 43, Intramolecular Lewis acid-catalyzed reaction

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

28 Léger and Co-workers Work C1-C8 fragment of (+)-Acutiphycin Lewis Acid: TiCl 4 (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) ( ).  P.D.F., Harvard University (Prof. Eric N. Jacobsen) ( )  Assistant Professor, MIT ( ).  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. 2000, 2(26), J.A.C.S.; 2004, 126, J.A.C.S.; 2004, 126, Org. Lett. 2006, 8(3), Org. lett., 2005, 7(14), Org. Lett., 2005, 7(14), Tetrahedron. 2003, 59, Tetrahedron. 2005, 61, Tetrahedron. 2006, 62, Tetrahedron. 2006, 62, Angew. Chem. Int. Ed. 2003, 42(12), Angew. Chem. Int. Ed. 2004, 43, Adv. Synth. Catal. 2005, 347, J.A.C.S., 2006, 128, J.A.C.S., 2004, 126,

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

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

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

35 Jamison Group Work -Retrosynthetic Analysis

36 Jamison Group Work

37 X

38 Jamison Group Work -Retrosynthetic Analysis

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

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

41 Jamison Group Work -Introduced the side chain 5

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

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

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

45 Jamison Group Work 1. Citric acid, MeOH2. 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. Taylor University of Notre Dame Towards the total synthesis of (+)- Acutiphycin: utilization of homoaldol methodology in the preparation of enantioselective acetate aldol 1987 B.S. SUNY Oswego 1992 Ph.D. Rensselaer Polytechnic Institute Arthur G. Schultz P.D.F, Stanford University, Assistant Professor, Associate Professor, 2004-present Professor

48 Richard E. Taylor


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