The Development of Carbonyl-

Olefin Metathesis

Li Zheng

Dr. Wulff’s Group

11/23/20161

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)

Types of Olefin Metathesis

4Hoveyda, A.Zhugralin, A. Nature 2007, 450, 243-251.

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..

Synthesis of Polycyclic Systems

23R. Valiulin, A. Kutateladze, Org. Lett. 2009, 11, 3886-3889.

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]

Substrate Scope

28A. Griffith, C. Vanos, T. Lambert, J. Am. Chem. Soc. 2012, 134, 18581-18584.

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

Substrate Scope

J. Ludwig, P. Zimmerman, J. Gianino, C. Schindler, Nature 2016, 533, 374-379.34

Proposed Mechanism

35J. Ludwig, P. Zimmerman, J. Gianino, C. Schindler, Nature 2016, 533, 374-379.

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

Mechanism

43J. Ludwig, P. Zimmerman, J. Gianino, C. Schindler, Nature 2016, 533, 374-379.

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.

Outlook

45

+Carbonyl Olefin

+ Olefin

Carbonyl-olefin

Metathesis

Carbonyl-olefin

MetathesisCarbonyl

Acknowledgement

46

Dr. Wulff

Dr. Huang

Xiaopeng, Aliakbar, Yubai, Yijing,

Xiaojing, Shuang, Deen, Saeedeh, Dan, Tayeb.

Thank you!

47