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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, 8193-8197. 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 (1972-73) 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, 12013-12014. J.A.C.S., 1997, 119, 10935-10946.

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, 1161-1164. J.O.C., 1999, 64(15), 5511-5523. 1 2 3 4 5 6 7 8 9

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 Favored transition state disfavored transition state J.O.C., 1999, 64(15), 5511-5523. 8

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), 1101-1106 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, 1147-1150. 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) (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. 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. 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. 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 -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, 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 -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, 1909-1911. Richard J. Arhart, J. C. Martin, J.A.C.S., 1972, 94, 5003-5010. 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, 36-37.

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 1992-1995 P.D.F, Stanford University, 1995-2001 Assistant Professor, 2001-2004 Associate Professor, 2004-present Professor

48 Richard E. Taylor


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