Alkene Cross Metathesis

1
Alkene Cross Metathesis

• Konrad Tiefenbacher
• Seminar 9.11.2005

2
Overview

• Introduction
• Predicting CM Selectivity
• CM in Natural Product Synthesis
• Enantioselecetive Catalysts
• Summary
• Literature (Review Articles)

3
1. Introduction

• Problems
• Excess of one olefin needed
• Purification

4
1. Introduction

• Selective CM possible if
• No Homodimerization of R2 alkene
• Homodimer of R1 alkene consumable

5
2. Predicting CM Selectivity

• Grubbs, R. et al. J. Am. Chem. Soc. 2003, 125,
  11360-11370.

6
2. Predicting CM Selectivity

• ? Selective CM between alkenes of different
  types!
• Type 1 with Type 2 or 3 works best
• Type 2 with Type 3 possible but not as good

Examples of Selective CM between Type 1 and Type
2 alkenes

• Grubbs, R. et al. J. Am. Chem. Soc. 2003, 125,
  11360-11370.

7
2. Predicting CM Selectivity
Examples of Selective CM between Type 1 and Type
3 alkenes
4 Allylic alkene Eq. Type 1
Product Yield
E only!

• Grubbs, R. et al. J. Am. Chem. Soc. 2003, 125,
  11360-11370.

8
2. Predicting CM Selectivity
Examples of Selective CM between Type 1 and Type
3 alkenes
1,1-disubst. Type 1 Eq.
Product Yield E/Z

• Grubbs, R. et al. J. Am. Chem. Soc. 2003, 125,
  11360-11370.

9
2. Predicting CM Selectivity
Examples of Selective CM between Type 2 and Type
3 alkenes
Type 2 Type 3 Eq.
Product Yield E/Z
E only
E/Z 2.0

• Grubbs, R. et al. J. Am. Chem. Soc. 2003, 125,
  11360-11370.

10
2. Predicting CM Selectivity
One Pot Three Component CM!
Type 3 Type 2 T1 T3 T2
Product Yield E/Z
E only
E only
E/Z 8.0
E only

• Grubbs, R. et al. J. Am. Chem. Soc. 2003, 125,
  11360-11370.

11
3. CM in Natural Product Synthesis

• Ghosh, A. et al. J. Am. Chem. Soc. 2004, 126,
  3704.

12
3. CM in Natural Product Synthesis

• Smith, A. et al. J. Am. Chem. Soc. 2001, 123,
  5925.

13
3. CM in Natural Product Synthesis

• Wood, J. et al. J. Am. Chem. Soc. 2004, 126,
  16300.

14
3. CM in Natural Product Synthesis

• Limanto, J. Snapper, M. J. Am. Chem. Soc. 2000,
  122, 8071.

15
4. Enantioselecetive catalyst
Recyclable chiral Ru catalyst
cat

• Hoveyda, A. et al. J. Am. Chem. Soc. 1998, 120,
  2343.

16
4. Enantioselecetive catalyst
Recyclable chiral Ru catalyst
AROM/CM
cat

• Hoveyda, A. et al. J. Am. Chem. Soc. 2002, 124,
  4954-4955.

17
4. Enantioselecetive catalyst
Recyclable chiral Ru catalyst
AROM/CM
cat
With 5 mol cat reactions can be run in air and
with regular THF!

• Hoveyda, A. et al. J. Am. Chem. Soc. 2002, 124,
  4954-4955.

18
5. Summary

• Advantages of CM compared to classical alkene
  formation
• Catalytic process (usually 1 to 5 mol of
  catalyst used)
• Great functional group tolerance (carboxylic
  acids, aldehydes, alcohols) ? minimal substrate
  protection required
• Atom-economic, ethylene only by-product
• Alternative to other transition metal mediated
  cross couplings (e.g. Stille or Suzuki reaction).
  Readily available alkenes are used, no synthetic
  investment in the preparation of elaborated
  coupling partners (e.g. vinyl stannanes, vinyl
  halides, etc.)
• After metathesis Grubbs catalysts can be used in
  situ to hydrogenate the products (approx. 6 7
  bar)

19
6. Review Articles

• 1 Chatterjee, A. Choi, T. Sanders, D.
  Grubbs, R. J. Am. Chem. Soc. 2003, 125,
  11360-11370.
• 2 Connon, S. Blechert, S. Angew. Chem. Int.
  Ed. 2003, 42, 1900-1923.
• 3 Nicolaou, K. Bulger, P. Sarlah, D. Angew.
  Chem. Int. Ed. 2005, 44, 4490-4527.
• 4 Fürstner, A. Angew. Chem. Int. Ed. 2000, 39,
  3012-3043.