Total Synthesis of (+)-Acutiphycin and (+)-trans-20,21-didehydroacutiphycinWei Lin Literature MeetingCharette GroupDec. 5th, 2006

IntroductionIsolated 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 HistoryIn 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 Lger and co-workers from Merck Frosst center in QuebecIn 2006, second total synthesis by Jamison group from MIT.

Amos B. Smith, IIIBorn 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

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

Smith Group Work

Smith Group WorkFukuyama* proposed mechanism

Smith Group Work

Smith Group Work

Smith Group Work46

Smith Group Work3 days

Smith Group WorkThe 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-, (+)-B-methoxy-(diisopinocamphenyl)borane and tetramethylammonium triacetoxyborohydride to build the chiral centers.

Kiyooka Group Work-chiral oxazaborolidinone-promoted asymmetric aldol reactionsStrategy: 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), 5511-5523.123456789

A Chiral Oxazaborolidinone-Promoted Aldol ReactionSyun-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

678Opposite to the original target.

Explanation of the Unexpected Selectivity in the Aldol ReactionFavored transition statedisfavored transition stateJ.O.C., 1999, 64(15), 5511-5523.

8

Overcome the Problem of Unexpected Selectivity1633% + the recovered 16After cyclization to the macrolactone, epimerization at C10 overcame the problem.10

Kiyooka Group Work

83% de

Kiyooka Group WorkHighly 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 WorkC9-C13 segment of (+)-AcutiphycinRuss. Chem. Bull., Int. Ed., 2001, 50(6), 1101-1106levoglucosan

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

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

Miftakhov and Co-workers WorkC9-C13 segment of (+)-AcutiphycinC9- C13 segment of (+)-Acutiphycin was accomplished from levoglucosan in 9 steps with an overall yield of 16.9%.

Lger and Co-workers Work C1-C8 fragment of (+)-Acutiphycin

Tetrahedron Lett., 2002, 43, 1147-1150.Intramolecular Lewis acid-catalyzed reaction

Lger and Co-workers Work C1-C8 fragment of (+)-Acutiphycin69% ee

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

Timothy F. JamisonBorn 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 OngoingEpoxide-opening cascades.Carbon-carbon bond formation.Target-oriented synthesis.

Timothy F. Jamison Nickel catalyzed carbon-carbon bond formationOrg. 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.

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

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

Jamison Nickel catalyzed reductive coupling of aldehyde and 1,6-EnynesProposed mechanism by JamisonOrg. Lett. 2006, 8(3), 455-458.

Jamison Group Work-Retrosynthetic Analysis

Jamison Group Work

Jamison Group WorkX

Jamison Group Work -Retrosynthetic Analysis

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

Wipf Hydrozirconation-Transmetallation Stereoselective Carbonyl AdditionWipf., 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 chain5

Jamison Group Work -SmI2 Reformatsky reactionFor Reformatsky reaction, they tried Zn/Ag-graphite, no desired product generated. When switched to SmI2, 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 2o and 3o carbinols with excellent yield.5

Jamison Group WorkAlkyn addition

Ethoxyethyne and another OH group were introduced.

Jamison Group WorkJamison-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 WorkHighly 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. TaylorUniversity 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

Richard E. Taylor