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The Journey of Azadirachtin
--- Dead Ends and Detours
Supervisors: Prof. Zhen Yang & Jiahua Chen
Reporter: Weiwu Ren
2008-01-11
Contents
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Introduction
Dead Ends and Detours – An Example
Total Synthesis of Azadirachtin
Summary
Acknowledgement
2
Contents
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Introduction
Dead Ends and Detours – An Example
Total Synthesis of Azadirachtin
Summary
Acknowledgement
3
Guanacastepene
IMDA
Heck
Tandem RCM
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Tandem Cyclization
RCM/Robinson
Stille/[2+2]
4
Dead Ends and Detours
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Planning
Starting
Materials
Dead Ends
Target
Molecule
Detours
5
Our Attitudes
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Reality
Several Steps
Condition B
Starting
Materials
Condition A
Product
Condition C
OR
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Contents
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Introduction
Dead Ends and Detours – An Example
Total Synthesis of Azadirachtin
Summary
Acknowledgement
7
Brevetoxin B
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Brevetoxin B
A marine neurotoxin
First reported by Nakanishi in 1981
23 stereocenters
All trans-contiguous ether rings
Lin, Y.; Nakanishi, K. J. Am. Chem. Soc. 1981, 103, 6773.
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First-generation Retrosynthetic Analysis OPSS
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Nicolaou, K. C.; Hwang, C. -K.. J. Am. Chem. Soc. 1986, 108, 6800.
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Work with Model
Nicolaou, K. C.; Hwang, C. -K. J. Am. Chem. Soc. 1990, 112, 3040.
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But…
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Nightmare!!!
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Is the Strategy Useless?
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Unfortunately, however, all attempts to achieve the bis(thionation)
of the macrodilactone precursor failed… The lactone carbonyl flanked
by the methyl group, defiantly resists the action of Lawesson’s
reagent, presumably due to its hindered nature…
------ K. C. Nicolaou
Significance:
1. Investigation of the chemistry of the molecule
Brevetoxin B and the basis of the following total
synthesis;
2. Developing a full body of methodology to build
fused seven-membered rings;
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Contents
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Introduction
Dead Ends and Detours – An Example
Total Synthesis of Azadirachtin
Summary
Acknowledgement
13
Azadirachtin
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16 Contiguous Stereogenic Centers
7 Tetrasubstituted Carbons
4 Different Ester Groups
2 Hydroxy Groups
1 Acid and Base-Sensitive Hemiketal
1 Strained and Sterically-hindered Epoxide
2 Intramolecular Hydrogen Bonds (strong: C11OH - O13 weak: C7OH – C20OH)
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Story Line
1968
1986
1986
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Beginning
Isolation and Structure
Determination of
Azadirachtin
1996
1996
2006
2007
2007
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Hop Skip and Jump
1985-1986
1975
1968
First report of the
isolation of
Azadirachtin by
Morgan group
The first
complete
structure was
reported but not
correct
The correct
structure was
submitted and
was confirmed by
X-ray analysis
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First Isolation
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Isolated from the seeds of
Azadirachta indica A. Juss in India
( 印度苦楝树 )
Named Azadirachtin
( Azadirachta indica )
High activity against the desert locust
（沙漠蝗虫）
Molecular formula：C29H38O16(642.222)
Butterworth, J. H.; Morgan, E. D. J. Chem. Soc., Chem. Commun. 1968, 23.
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Right Molecular Formula & Partial StructureOPSS
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Butterworth, J. H.; Morgan, E. D. J. Chem. Soc., Chem. Commun. 1968, 23.
Molecular Formula : C35H44O16 （Triterpenoid）
Butterworth, J. H.; Morgan, E. D. J. Chem. Soc., Perkin Trans. I 1972, 2445.
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The First Complete Structure
Nakanishi’s Azadirachtin
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Correct Structure
Based on: PRFT/CWD 13C NMR
Hypothetical Relationship with Known Terpenoids
Zanno, P. R.; Muira, I.; Nakanishi, K. J. Am. Chem. Soc. 1975, 97, 1975.
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Ley’s Modification
Ley’s Modification
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Correct Structure
Based on: 1D NOE & 2D NOESY
Bilton, J. N.; Broughton, H. B.; Ley, S. V. J. Chem. Soc., Chem. Commun. 1985, 986.
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Finally, the Correct Structure
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Azadirachtin
W.
Broughton,
Kraus.; M.H.Bokel.;
B.; Ley,
A.S.
Klenk.;
V. J. Chem.
H. P. Khnl.
Soc.Tetrahedron
Chem. Commun.
Lett. 1985,
1986,26,
46.6435.
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First isolated by Morgan(1968)
Confirmed by X-ray analysis(1986)
Partial structure(1972)
Azadirachtin
Ley’s modification
(1985)
The first complete structure
(1975)
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Story Line
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1968
1986
1986
1996
1996
Ley’s Monodrama（独角戏）
2006
2007
2007
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Ley’s Idea
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We recognise this coupling involves the formation of a
difficult bond, but therein lies the challenge.
---- S. V. Ley
Ley, S. V. Pure Appl. Chem. 1994, 66, 2099.
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1st Synthesis
Ⅰ. Develop a flexible approach
for the total synthesis
Ⅱ. Study the functional groups
responsible for activity
(potential active center)
Ley, S. V.; Santafianosa, D. Tetrahedron Lett. 1987, 28(2), 221.
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Construction of This Fragment
Ley, S. V.; Santafianosa, D. Tetrahedron Lett. 1987, 28(2), 221.
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Absolute Configuration
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Method:
Modified Mosher methodology using high field FT NMR techniques
Ley, S. V.; Lovell, H. J. Chem. Soc., Chem. Commun. 1992, 1304.
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Ley’s Other Work
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Azadirachtin
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Story Line
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1968
1986
1986
1996
1996
Ley
Cambridge
Nicolaou
Scripps
Murai
Hokkaido
Watanabe
Tokyo
2006
2007
2007
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Ley’s Attempts on the Direct Coupling
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Complex ‘Right’ to Simple ‘Left’
Complex ‘Left’ to Simple ‘Right’
Ley, S. V. Pure Appl. Chem. 2005, 77, 1115.
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Ways to Go
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Dead Ends
Detour
Introduce this bond in an
earlier step of the synthesis!
Prof. Watanabe
Connect the two parts through other
functional groups and then close the
desired bond intramolecularly!
Prof. Ley & Prof. Nicolaou & Prof. Murai
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First Participant — Watanabe
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1) Watanabe, H.; Watanabe, T.; Mori, K. Tetrahedron 1996, 52, 13939.
2) Watanabe, H.; Watanabe, T.; Mori, K.; Kitahara, T. Tetrahedron Lett. 1997, 38, 4429.
3) Watanabe, H.; Mori, N.; Itoh, D.; Kitahara, T. Angew. Chem. Int. Ed. 2007, 46, 1512.
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Watanabe’s Model
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Watanabe, H.; Mori, N.; Itoh, D.; Kitahara, T.; Mori, K. Angew. Chem. Int. Ed. 2007, 46, 1512.
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Tandem Radical Cyclization
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Watanabe, H.; Watanabe, T.; Mori, K.; Kitahara, T. Tetrahedron Lett. 1997, 38, 4429.
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Murai’s Model Study
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Ireland – Claisen Rearrangement
1) Ishihara, J.; Fukuzaki, T.; Murai, A. Tetrahedron Lett. 1999, 40, 1907.
2) Yamamoto, Y.; Ishihara, J.; Kanoh, N.; Murai, A. Synthesis 2000, 1894.
3) Fukuzaki, T.; Kobayashi, S.; Ishihara, J.; Kanoh, N.; Murai, A. Org. Lett. 2002, 4, 2877.
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Ireland-Claisen Rearrangement
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Fukuzaki, T.; Kobayashi, S.; Ishihara, J.; Kanoh, N.; Murai, A. Org. Lett. 2002, 4, 2877.
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Diastereoselectivity
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Fukuzaki, T.; Kobayashi, S.; Ishihara, J.; Kanoh, N.; Murai, A. Org. Lett. 2002, 4, 2877.
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K. C. Nicolaou’s Model Study
2002
Radical
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2002
Organometallic
2005
2003
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From Radical Chemistry
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Nicolaou, K. C.; Follmann, M.; Roecker, A. J. Angew. Chem. Int. Ed. 2002, 41, 2103.
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From Organometallic Chemistry
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Nicolaou, K. C.; Roecker, A.; J Follmann, M. Angew. Chem. Int. Ed. 2002, 41, 2107.
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Brief Summary
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Greatest Challenge: C8-C14 Bond
Azadirachtin
Ley
Watanabe
Murai
Nicolaou
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Story Line
1968
1986
1986
1996
1996
2006
2007
2007
Total Synthesis
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Relay Study
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Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633.
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Back to ‘Azadirachtin’
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Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633.
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Retrosynthetic Analysis
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Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.
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Left ‘Shoulder’
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Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.
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Right ‘Arm’
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Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.
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Total Synthesis
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Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.
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Total Synthesis
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Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.
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Contents
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Weiwu Ren
Introduction
Dead Ends and Detours – An Example
Total Synthesis of Azadirachtin
Summary
Acknowledgement
50
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Summary
Isolation and Structure Determination (18 years)
Total Synthesis (22 years)
Ley and More Than 35 Co-workers
Total Yield: 0.00015%
71 Steps (longest linear sequence 48 steps)
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Summary
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Logic!
Convergence!
Accuracy!
Dead Ends ?
Detours ?
Beginning !
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Contents
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Introduction
Dead Ends and Detours – An Example
Total Synthesis of Azadirachtin
Summary
Acknowledgement
53
Acknowledgement
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Prof. Yang & Prof. Chen
Prof. Shi & Prof. Yu
All the Members of Our Lab
All the Audience
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No Dead Ends
Less Detours
More success!!!
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Weiwu Ren
Thank You！！！
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