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Total Synthesis of Ingenol
Reporter: Yong Lu
Supervisors: Prof. Yang
Prof. Chen
Prof. Tang
2012.12.07
1. Introduction
2. Synthetic Approaches toward Ingenol
3. Summary
4. Acknowledgements
Contents
1
1. Introduction
2. Synthetic Approaches toward Ingenol
3. Summary
4. Acknowledgements
Contents
2
Introduction
Ingenol: isolated from the genus Euphorbia
(大戟属) in 1968 by Hecker
Remarkable Biological Properties:
antitumor
anti-leukemic
anti-HIV properties
Synthetic Challenges:
highly strained in-out stereochemistry of the bicyclo[4.4.1] system
cis-triol of the AB ring
Ingenol
3
Introduction
Park, C. H.; Simmons, H. E. J. Am. Chem. Soc. 1972, 94, 7184.
Small or common-sized rings
Medium (7- to 12- membered) and large rings
Gassman, P. G.; Thummel, R. P. J. Am. Chem. Soc. 1972, 94, 7183.
Gassman, P. G.; Korn, S. R.; Thummel, R. P. J. Am. Chem. Soc. 1974, 96, 6948
4
Introduction
Simmons, H. E.; Park, C. H. J. Am. Chem. Soc. 1968, 90, 2428.
First introduced for bridged bicyclic compounds by Simmons
macrocyclic diamine
(k, l, and m: 6-10)
In-out isomerism:
5
Introduction
In-out isomerism:
bicyclo[4.4.1] undecane
In-out isomerism in Natural Products:
out-out isomer:
no bioactivity
Kato, T.; Hirukawa, T.; Uyehara, T.; Yamamoto, Y. Tetrahedron Lett. 1987, 28, 1439.
Hirukawa, T.; Shudo, T.; Kato, T. J. Chem. Soc., Perkin Trans. 1 1993, 217.
Kato, T.; Hirukawa, T.; Yamamoto, Y. J. Chem. Soc., Chem. Commun. 1987, 977
Hirukawa, T.; Koarai, A.; Kato, T. J. Org. Chem. 1991, 56, 4520.
6
Introduction
Key Players in the Ingenol Field
Core Synthesie:
Total Synthesis:
2004
Wood
total synthesis of (+) - ingenol
2004
Cha
tetracyclic ring system
1987
Winkler
1st tricyclic ring system
2000
Kigoshi
tricyclic ring system
1993
Funk
1st tetracyclic ring system
2001
Wood
tetracyclic ring system
2002
Rigby
tricyclic ring System
2002
Winkler
1st total synthesis of (±) ingenol
2003
Kuwajima
total synthesis of (±) ingenol
2004
Kigoshi
formal synthesis of (+) - ingenol
1997
Kuwajima
tetracyclic ring system
2005
Winkler
tricyclic ring system
2004
Grainger
tricyclic ring system
7
1. Introduction
2. Synthetic Approaches toward Ingenol
3. Summary
4. Acknowledgements
Contents
8
1993
Funk: 1st
tetracyclic ring system
2002
Winkler: 1st
racemic synthesis
2003
Kuwajima: 2nd
racemic synthesis
2004
Wood: 1st
asymmetric synthesis
2004
Kigoshi: Formal
asymmetric synthesis
2002
Rigby:
tricyclic ring system
1968
Hecker: isolation
and characterization
Synthetic Approaches toward Ingenol
A time axis:
Numerous reports on core strategies
9
2002
Winkler: 1st
racemic synthesis
2003
Kuwajima: 2nd
racemic synthesis
2004
Wood: 1st
asymmetric synthesis
2004
Kigoshi: Formal
asymmetric synthesis
1968
Hecker: isolation
and characterization
Synthetic Approaches toward Ingenol
A time axis:
Numerous reports on core strategies
1993
Funk: 1st
tetracyclic ring system
2002
Rigby:
tricyclic ring system
10
Concept:
Funk’s Core Synthesis
Claisen-Ireland Rearrangement
Funk, R. L.; Olmstead, J. A.; Parvez, M.; Stallman, B. J. J. Org. Chem. 1993, 58, 5873. 11
Funk’s Core Synthesis
Claisen-Ireland
Rearrangement 1st tetracyclic ring system
Funk, R. L.; Olmstead, J. A.; Parvez, M.; Stallman, B. J. J. Org. Chem. 1993, 58, 5873. 12
2002
Winkler: 1st
racemic synthesis
2003
Kuwajima: 2nd
racemic synthesis
2004
Wood: 1st
asymmetric synthesis
2004
Kigoshi: Formal
asymmetric synthesis
1968
Hecker: isolation
and characterization
Synthetic Approaches toward Ingenol
A time axis:
Numerous reports on core strategies
2002
Rigby:
tricyclic ring system
1993
Funk: 1st
tetracyclic ring system
1993
Funk: 1st
tetracyclic ring system
13
Rigby’s Core Synthesis
Strategy:
1, 5-H shift
Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799.
out/out in/out
out/out in/out
14
Rigby’s Core Synthesis
Alkoxide-accelerated [1,5]-hydrogen shift
out/out
in/out
not
Rigby, J. H.; Bazin, B.; Meyer, J. H.; Mohammadi, F. Org. Lett. 2002, 4, 799. 15
2004
Wood: 1st
asymmetric synthesis
2004
Kigoshi: Formal
asymmetric synthesis
1968
Hecker: isolation
and characterization
Synthetic Approaches toward Ingenol
A time axis:
Numerous reports on core strategies
2003
Kuwajima: 2nd
racemic synthesis
2002
Winkler: 1st
racemic synthesis
1993
Funk: 1st
tetracyclic ring system
1993
Funk: 1st
tetracyclic ring system
2002
Rigby:
tricyclic ring system
16
Winkler’s racemic synthesis
De Mayo Reaction
Intramolecular dioxenone/alkene [2+2] Photocycloaddition-Fragementation Sequence
pseudo boat
pseudo chair 1st tricyclic ring system
Winkler, J. D.; Henegar, K. E. J. Am. Chem. Soc. 1987, 109, 2850. 17
Winkler’s racemic synthesis
Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T.
J. Am. Chem. Soc. 2002, 124, 9726.
Advanced Cycloaddtion Precursor
dioxenone moiety
--- a locked enol tautomer of the β-keto ester
allows further functional groups transformation
Advantages of This Precursor:
A ring
--- higher facial selectivity in the cycloaddition step
Cl subtituent
--- facilitate the introduction of D ring
18
Winkler’s racemic synthesis
Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T.
J. Am. Chem. Soc. 2002, 124, 9726. 19
Winkler’s racemic synthesis
Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon, Y. T.
J. Am. Chem. Soc. 2002, 124, 9726.
43 steps
average 80% per step
20
2002
Winkler: 1st
racemic synthesis
2004
Wood: 1st
asymmetric synthesis
2004
Kigoshi: Formal
asymmetric synthesis
1968
Hecker: isolation
and characterization
Synthetic Approaches toward Ingenol
A time axis:
Numerous reports on core strategies
2003
Kuwajima: 2nd
racemic synthesis
1993
Funk: 1st
tetracyclic ring system
1993
Funk: 1st
tetracyclic ring system
2002
Rigby:
tricyclic ring system
21
Kuwajima’s racemic synthesis
Hypothetical Pathway to Ingenane Carbocycle
pinacol rearrangement
Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I.
J. Am. Chem. Soc. 2003, 125, 1498.
22
Kuwajima’s racemic synthesis
Advantageous to Induce the Desired Transformation:
two reaction sites are located closely
facile generation of the cationic species
broaden the bond angle to favor a larger ring cyclization
regenerate the C=C bond for attachment of the D ring
Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I.
J. Am. Chem. Soc. 2003, 125, 1498.
23
Kuwajima’s racemic synthesis
weak LA strong LA
Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I.
J. Am. Chem. Soc. 2003, 125, 1498.
24
Kuwajima’s racemic synthesis
Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I.
J. Am. Chem. Soc. 2003, 125, 1498.
Preparation of the Ring Cyclization Precursor
25
Kuwajima’s racemic synthesis
Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I.
J. Am. Chem. Soc. 2003, 125, 1498.
Construction of Ingenane Tetracarbocycle
--- Tandem Cyclization/Deprotonation Methodology
26
pinacol
rearrangement
Kuwajima’s racemic synthesis
Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I.
J. Am. Chem. Soc. 2003, 125, 1498.
27
Kuwajima’s racemic synthesis
Tanino, K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I.
J. Am. Chem. Soc. 2003, 125, 1498.
28 45 steps, 0.1%
2002
Winkler: 1st
racemic synthesis
2003
Kuwajima: 2nd
racemic synthesis
2004
Wood: 1st
asymmetric synthesis
1968
Hecker: isolation
and characterization
Synthetic Approaches toward Ingenol
A time axis:
Numerous reports on core strategies
2004
Kigoshi: Formal
asymmetric synthesis
2002
Rigby:
tricyclic ring system
1993
Funk: 1st
tetracyclic ring system
1993
Funk: 1st
tetracyclic ring system
29
RCM Strategy toward the Stained Trans-Fused BC Ring Syntem
Kigoshi Wood
D ring --- improve the diastereoselectivity of alkylation
A ring --- constrain the flexible conformation of the pendant
side chain, bring closer the terminal olefins
C6-substituent --- prevent the competing ROM
Watanabe, K.; Suzuki, Y.; Aoki, K.; Sakakura, A.; Suenaga, K.; Kigoshi, H. J. Org. Chem. 2004, 69, 7802.
Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.; Greene, B.; Yusuff, N.; Wood, J. L.
J. Am. Chem. Soc. 2004, 126, 16300.
Synthetic Approaches toward Ingenol
30
Funk’s keto ester
Wood’s asymmetric synthesis
Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.; Greene, B.; Yusuff, N.; Wood, J. L.
J. Am. Chem. Soc. 2004, 126, 16300.
Funk’s keto ester
31
Wood’s asymmetric synthesis
Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.; Greene, B.; Yusuff, N.; Wood, J. L.
J. Am. Chem. Soc. 2004, 126, 16300.
32 steps
0. 2% overall yield
32
Kigoshi’s formal synthesis
Watanabe, K.; Suzuki, Y.; Aoki, K.; Sakakura, A.; Suenaga, K.; Kigoshi, H.
J. Org. Chem. 2004, 69, 7802.
8 steps
12.5%
Funk’s keto ester
Winkler’s aldehyde
33
1. Introduction
2. Synthetic Approaches toward Ingenol
3. Summary
4. Acknowledgements
Contents
34
Summary
Winkler
[2+2] Photocycloaddition
-Fragementation
Funk
Claisen-Ireland Rearrangement
Rigby
1,5-Hydrogen Migration Kuwajima
Cyclization-Pinacol
Rearrangement
Kigoshi and Wood
RCM
35
Acknowledgements
Prof. Zhen Yang, Prof. Jiahua Chen and Prof. Yefeng Tang
Dr. Tianwen Sun, Mr. Dongdong Liu
All members in our lab
Everyone here
36
Thanks for your attention!
Acknowledgements