Metathesis
2
AB + CD AC + BD
http://msn.huanqiu.com/photo/gallery/2012-11/2671259.html http://edu.sina.com.cn/en/2013-07-10/152075337.shtml
Olefin Metathesis
3
2005 The Nobel Prize in Chemistry
Yves Chauvin
Prize share: 1/3Robert H. Grubbs
Prize share: 1/3
Richard R. Schrock
Prize share: 1/3
Hoveyda, A.Zhugralin, A. Nature 2007, 450, 243-251.
In ~1000 total synthesis in 2011,
olefin metathesis was used for times.(Data from Dr. Wulff’s database)
5
Carbonyl-Olefin Metathesis
Carbonyl-olefin Metathesis
Ring-closing
Metathesis
Ring-opening
Metathesis
Cross Metathesis
Importance and Challenges
6
Importance
• 170 total synthesis papers
• 26 papers used olefin metathesis reactions
• 3 reactions are olefination first followed by olefin metathesis
Challenges
• [2+2] cycloaddition is thermally forbidden.
• Stochiometric metal alkylidene catalysts are required.
R. Woodward, R. Hoffmann, Angew. Chem. Int. Ed. 1969, 8, 781-853.
Outline
7
Carbonyl-Olefin
Metathesis
Carbonyl Olefination
Iron(Ⅲ)
Catalyst
Organo-catalysts
Photo-chemical Process
Organo-metallic
“Catalysts”
Carbonyl Olefination
8
+Carbonyl Olefin
Olefin + Olefin
Carbonyl
Olefination
Carbonyl-olefin
Metathesis
Olefin
Metathesis
Wittig Reaction
9
Phosphonium ylide
(Wittig Reagent)
Georg Wittig (1897-1987)
1979 Nobel Prize in Chemistry
B. Maryanoff, A. Reitz, Chem. Rev. 1989, 89, 863-927
Tebbe Reagent
10F. Tebbe, G. Parshall, G. Reddy, J. Am. Chem. Soc. 1978, 100, 3611-3613.
Tebbe Reagent
Stepwise but One-pot Reaction
11K. Nicolaou, M. Postema, C. Claiborne, J. Am. Chem. Soc. 1996, 118, 1565-1566.
Approach toward Maitotoxin
12K. Nicolaou, M. Postema, E. Yue, A. Nadin, J. Am. Chem. Soc. 1996, 118, 10335-10336.
Maitotoxin
Rainier’s Approach
13K. Iyer, J. Rainier, J. Am. Chem. Soc. 2007, 129, 12604-12605.
Methylenation
Product
Metathesis
Product
Applications in Total Synthesis(1)
14Y. Zhang, J. Rohanna, J. Zhou, K. Iyer, J. Rainier, J. Am. Chem. Soc. 2011, 133, 3208-3216.
Applications in Total Synthesis(2)
15G. Keck, Y. Poudel, T. Cummins, A. Rudra, J. Covel, J. Am. Chem. Soc. 2011, 133, 744-747.
Using 1 equiv. of Tebbe Reagent
J. Stille, R. Grubbs, J. Am. Chem. Soc. 1986, 108, 855-856.
K. Nicolaou, M. Postema, C. Claiborne, J. Am. Chem. Soc. 1996, 118, 1565-1566.16
Organometallic “Catalysts”
17
+Carbonyl OlefinCarbonyl-olefin
Metathesis
Carbonyl-olefin
Metathesis+Carbonyl Olefin
Stoichiometric Schrock Catalyst
18G. Fu, R. Grubbs, J. Am. Chem. Soc. 1993, 115, 3800-3801.
Entry Substrate Product Yield(%)
1 86
2 84
3 86
Table 1. Carbonyl-Olefin Metathesis
(Schrock Catalyst (1.0 equiv.), PhH, 20 °C, 30 min)
(342.50 USD/100 mg
from Sigma-Aldrich)
Applications in Total Synthesis
19S. Heller, T. Kiho, A. Narayan, R. Sarpong, Angew. Chem. Int. Ed. 2013, 125, 11335-11339.
B. Hong, H. Li, J. Wu, J. Zhang, X. Lei, Angew. Chem. Int. Ed. 2014, 54, 1011-1015.
Photochemical Process
20
+Carbonyl Olefin
+ Olefin
Carbonyl-olefin
Metathesis
Carbonyl-olefin
MetathesisCarbonyl
Photochemical
process
[2+2] Cycloaddition and [2+2] Cycloreversion
21
Photo-induced [2+2]
cycloaddition
(Paternò–Büchi reaction)
[2+2] cycloreversion
J. Ludwig, P. Zimmerman, J. Gianino, C. Schindler, Nature 2016, 533, 374-379.
Photolysis-Pyrolysis Sequence
22G. Jones, S. Schwartz, M. Marton, J. Chem. Soc., Chem. Commun. 1973, 374-375..
Organo-catalysts
24
+Carbonyl Olefin
+ Olefin
Carbonyl-olefin
Metathesis
Carbonyl-olefin
MetathesisCarbonyl
Organo-
Catalyst
Lewis Acid Catalyst: BF3
25H. Schmalz, A. Soicke, N. Slavov, J. Neudörfl, Synlett 2011, 17, 2487-2490.
Entry Substrate Product Yield (%)
1 87
2 38
3 75
Table 1. Carbonyl-Olefin Metathesis (BF3•OEt2(1.5 equiv. ), -40 °C, CH2Cl2, 1 h)
Lewis Acid Catalyst: TrBF4
26V. Naidu, J. Bah, J. Franzén, Eur. J. Org. Chem. 2015, 1834-1839.
8 examples,
5%-85% yield.
Hydrazine Catalyst
27A. Griffith, C. Vanos, T. Lambert, J. Am. Chem. Soc. 2012, 134, 18581-18584.
Traditional methods: [2+2]
This method: [3+2]
DFT-computed Transition States
29X. Hong, Y. Liang, A. Griffith, T. Lambert, K. Houk, Chem. Sci. 2014, 5, 471-475.
[3+2] Cycloaddition Step
(First Transition State)
30X. Hong, Y. Liang, A. Griffith, T. Lambert, K. Houk, Chem. Sci. 2014, 5, 471-475.
Entrya Substrate ΔGact ΔGrxn ΔEstrain ΔEdist
1 21.6 -34.0 -26.4 19.7
2 24.4 -18.9 -3.7 23.2
3 25.0 -13.8 0.4 23.3
4 24.0 -20.3 -9.6 19.9
5 18.3 -21.3 -6.7 16.8
6 26.0 -13.6 -1.0 25.9
a All energies are in kcal/mol.
1
2
34
5
6
14
16
18
20
22
24
26
28
30
15 20 25 30
ΔGact
(kcal/ mol)
ΔEdist (kcal/mol)
Table 1. First Transition State for different substrates
Scheme 1. Correlation between activation energy
and distortion energy.
Ring-Opening Step
(Second Transition State)
31
Entrya Substrate ΔGact ΔGrxn ΔEstrain
1 18.8 -5.0 -28.1
2 23.9 -3.6 -26.9
3 33.7 9.3 -7.2
4 35.3 11.2 -10.4
5 38.8 8.4 -10.0
6 40.3 5.5 0.0
a All energies are in kcal/mol.
X. Hong, Y. Liang, A. Griffith, T. Lambert, K. Houk, Chem. Sci. 2014, 5, 471-475.
Table 1. Second Transition State for different substrates
Scheme 1. Correlation between activation energy and
distortion energy.
1
2
34
56
15
20
25
30
35
40
45
-35 -30 -25 -20 -15 -10 -5 0 5
ΔGact
(kcal/mol)
ΔEstrain (kcal/mol)
Iron(Ⅲ) Catalyst
32
+Carbonyl Olefin
+ Olefin
Carbonyl-olefin
Metathesis
Carbonyl-olefin
MetathesisCarbonyl
Iron(Ⅲ)
Catalyst
FeCl3-Catalyzed Carbonyl-Olefin Metathesis
J. Ludwig, P. Zimmerman, J. Gianino, C. Schindler, Nature 2016, 533, 374-379.33
Same Method Developed by Li’s Group36
L. Ma, W. Li, H. Xi, X. Bai, E. Ma, X. Yan, Z. Li, Angew. Chem. Int. Ed. 2016, 128, 10566-10569.36
Synthesis of 2,5-Dihydropyrroles
37L. Ma, W. Li, H. Xi, X. Bai, E. Ma, X. Yan, Z. Li, Angew. Chem. Int. Ed. 2016, 128, 10566-10569.
Proposed Mechanism
38L. Ma, W. Li, H. Xi, X. Bai, E. Ma, X. Yan, Z. Li, Angew. Chem. Int. Ed. 2016, 128, 10566-10569.
Mechanistic Probes by Schindler’s Group
39J. Ludwig, P. Zimmerman, J. Gianino, C. Schindler, Nature 2016, 533, 374-379.
ZStruct
40J. Ludwig, P. Zimmerman, J. Gianino, C. Schindler, Nature 2016, 533, 374-379.
Scheme 2. Possible products after first step.
Scheme 1. Strategy for ZStruct method.
Computed Mechanism
41J. Ludwig, P. Zimmerman, J. Gianino, C. Schindler, Nature 2016, 533, 374-379.
A
B
C
D
E
Scheme 1. Reaction pathway and enthalpic profile.
Compound ProductYield
(%)
ΔHact
(kcal/mol)
99 15.3
70 15.4
60 16.5
72 17.3
49 18.2
49 20.7
62 20.5
Table 1. Computation of different substrates
Scheme 1. Correlation between yield and activation
enthalpy.
Computation of Substrates
J. Ludwig, P. Zimmerman, J. Gianino, C. Schindler, Nature 2016, 533, 374-379.42
Conclusion
44
Method Comparison
Carbonyl Olefination
Wittig Reagent Followed by Olefin metathesis:
Two steps, need for pre-functionalized reagent.
Tebbe Reagent:
Need for excess amount.
Organometallic
“Catalysts”
No turnover, need for stoichiometric amount,
expensive, wide substrate scope.
Photochemical
ProcessHarsh condition, reforming starting materials.
Organo-catalysts Catalytic, mild conditions, limited substrate scope.
Iron(III) Catalyst Catalytic, mild conditions, wide substrate scope.
Acknowledgement
46
Dr. Wulff
Dr. Huang
Xiaopeng, Aliakbar, Yubai, Yijing,
Xiaojing, Shuang, Deen, Saeedeh, Dan, Tayeb.