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

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 vivo antineoplastic 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)
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.
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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
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-ß, ()-B-methoxy-(diisopinocamphenyl)borane
  and tetramethylammonium triacetoxyborohydride to
  build the chiral centers.

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Kiyooka Group Work-chiral oxazaborolidinone-promo
ted 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.
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A Chiral Oxazaborolidinone-Promoted Aldol Reaction
Syun-ichi Kiyooka et al., Tetrahedron Asymmetry,
1996, 7(8), 2181-2184.
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Kiyooka Group Work-Promoters Used
Heteroatom Chem. 1997, 17, 245-270.
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Kiyooka Group Work
6
7
8
Opposite to the original target.
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Explanation of the Unexpected Selectivity in the
Aldol Reaction
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disfavored transition state
Favored transition state
J.O.C., 1999, 64(15), 5511-5523.
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Overcome the Problem of Unexpected Selectivity
10
16
33 the recovered 16
After cyclization to the macrolactone,
epimerization at C10 overcame the problem.
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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.

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

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Léger and Co-workers Work C1-C8 fragment of
()-Acutiphycin
Intramolecular Lewis acid-catalyzed reaction
Tetrahedron Lett., 2002, 43, 1147-1150.
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Léger and Co-workers Work C1-C8 fragment of
()-Acutiphycin
69 ee
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Léger and Co-workers Work C1-C8 fragment of
()-Acutiphycin
Lewis Acid TiCl4 (65)
C1-C8 segment of ()-Acutiphycin was achieved in
11 steps with an overall yield of 17.
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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)

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Research -Completed and Ongoing

• Epoxide-opening cascades.
• Carbon-carbon bond formation.
• Target-oriented synthesis.

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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.
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Jamison Nickel catalyzed carbon-carbon bond
formation
Org. Lett. 2000, 2(26), 4221-4223.
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Jamison Nickel catalyzed reductive coupling of
aldehyde and chiral 1,6-Enynes
Org. Lett. 2006, 8(3), 455-458. Tetrahedron.
2006, 62, 7598-7610.
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Jamison Nickel catalyzed reductive coupling of
aldehyde and 1,6-Enynes
Proposed mechanism by Jamison
Org. Lett. 2006, 8(3), 455-458.
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Jamison Group Work-Retrosynthetic Analysis
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Jamison Group Work
37
Jamison Group Work
X
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Jamison Group Work -Retrosynthetic Analysis
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Pd Catalyzed Couplinganti-homopropargylic alcohol
Proposed mechanism by Marshall.
Marshall, J. A. et al. J.O.C., 1999, 64,
5201-5204.
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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.
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Jamison Group Work -Introduced the side chain
5
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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.
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Jamison Group WorkAlkyn addition
Ethoxyethyne and another OH group were introduced.
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Jamison Group WorkJamison-Funk
Ene-Macrolactonisation
Funk, R.L. et al., Synlett., 1989, 36-37.
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Jamison Group Work
1. Citric acid, MeOH
2. TESOTf, 2,6-lutidine
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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.

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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

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Richard E. Taylor