Presentation on theme: "Total Synthesis of (+)-Acutiphycin and (+)-trans-20,21-didehydroacutiphycin Wei Lin Literature Meeting Charette Group Dec. 5 th, 2006."— Presentation transcript:
Total Synthesis of (+)-Acutiphycin and (+)-trans-20,21-didehydroacutiphycin Wei Lin Literature Meeting Charette Group Dec. 5 th, 2006
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
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.
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.
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)
Smith Group Work -Retrosynthetic Analysis J.A.C.S., 1995, 117, 12013-12014. J.A.C.S., 1997, 119, 10935-10946.
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.
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
A Chiral Oxazaborolidinone-Promoted Aldol Reaction Syun-ichi Kiyooka et al., Tetrahedron Asymmetry, 1996, 7(8), 2181-2184.
Kiyooka Group Work -Promoters Used Heteroatom Chem. 1997, 17, 245-270.
Kiyooka Group Work 6 7 8 Opposite to the original target.
Explanation of the Unexpected Selectivity in the Aldol Reaction Favored transition state disfavored transition state J.O.C., 1999, 64(15), 5511-5523. 8
Overcome the Problem of Unexpected Selectivity 16 33% + the recovered 16 After cyclization to the macrolactone, epimerization at C10 overcame the problem. 10
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.
Miftakhov and Co-workers Work C9-C13 segment of (+)-Acutiphycin Russ. Chem. Bull., Int. Ed., 2001, 50(6), 1101-1106 levoglucosan
Miftakhov and Co-workers Work C9-C13 segment of (+)-Acutiphycin
C9- C13 segment of (+)-Acutiphycin was accomplished from levoglucosan in 9 steps with an overall yield of 16.9%.
Léger and Co-workers Work C1-C8 fragment of (+)-Acutiphycin Tetrahedron Lett., 2002, 43, 1147-1150. Intramolecular Lewis acid-catalyzed reaction
Léger and Co-workers Work C1-C8 fragment of (+)-Acutiphycin 69% ee
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%.
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)
Research -Completed and Ongoing Epoxide-opening cascades. Carbon-carbon bond formation. Target-oriented synthesis.
Pd Catalyzed Coupling anti-homopropargylic alcohol Proposed mechanism by Marshall. Marshall, J. A. et al. J.O.C., 1999, 64, 5201-5204.
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.
Jamison Group Work -Introduced the side chain 5
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
Jamison Group Work Alkyn addition Ethoxyethyne and another OH group were introduced.
Jamison Group Work Jamison-Funk Ene-Macrolactonisation Funk, R.L.; et al., Synlett., 1989, 36-37.
Jamison Group Work 1. Citric acid, MeOH2. TESOTf, 2,6-lutidine
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.
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