1. Development and understanding of
an improved catalytic system for
the synthesis of phenylalanine
derivatives
Manchester
31st March 2010
Andrew Ross
Prof. Richard Jackson
University of Sheffield

2. Amino acids
There are 20 proteinogenic amino acids

3. Amino acids
There are 20 proteinogenic amino acids

4. Phenylalanine derivatives
L-DOPA
Cryptophycin
K13
Aspartame

5. Synthesising amino acids
There are 3 main ways to synthesise α amino acids:
• Asymmetric hydrogenation
• Glycine anion alkylation
• Use of the chiral pool

6. Asymmetric hydrogenation
For review see: Tang, W. et al. Chem. Rev. 2003, 103, 3029
Tang, W. et al. Org. Lett. 2010, 12, 1104

7. Glycine anions

8. Maruoka , K. et al. Chem. Commun. 2007, 1487
Phase transfer alkylation

9. Using the chiral pool

10. Jackson group work
Serine Aspartic acid Glutamic acid
β anion γ anion δ anion

11. Jackson group work
Serine Aspartic acid Glutamic acid

12. Jackson group work
Serine Aspartic acid Glutamic acid

13. Synthesis of organozinc reagents
Jackson, R.F.W. et al. Org. Synth. 2005, 81, 77
Zn* = Activated Zinc

14. Iodoalanine
Dondoni, A. et al. Org. Synth. 2000, 77, 64
Jackson, R.F.W. et al. Org. Synth. 2005, 81, 77

15. Previous cross coupling conditions
Jackson, R.F.W. et al. Tetrahedron 2008, 64, 681
Jackson, R.F.W. et al. J. Org. Chem. 1992, 57, 3397
Jackson, R.F.W. et al. J. Org. Chem. 1998, 63, 7875

16. Previous cross coupling conditions
Jackson, R.F.W. et al. J. Org. Chem. 1992, 57, 3397
Jackson, R.F.W. et al. J. Org. Chem. 1998, 63, 7875
Jackson, R.F.W. et al. Tetrahedron 2008, 64, 681

17. Previous cross coupling conditions
Jackson, R.F.W. et al. Tetrahedron 2008, 64, 681
Jackson, R.F.W. et al. J. Org. Chem. 1992, 57, 3397
Jackson, R.F.W. et al. J. Org. Chem. 1998, 63, 7875

18. Previous cross coupling conditions

19. Previous cross coupling conditions

20. Why do we need a dipolar aprotic solvent?
Jackson, R.F.W. et al. Chem. Eur. J. 2008, 14, 8798

21. Why do we need a dipolar aprotic solvent?
Jackson, R.F.W. et al. Chem. Eur. J. 2008, 14, 8798

22. Cross coupling reaction

23. Biarylphosphine ligands
For review see: Mauger, C. et al. Aldrichimica Acta 2006, 39, 17

24. Biarylphosphine ligands
Buchwald, S. et al. Organometallics 2007, 26, 2183
Palladium in oxidation state 2
Palladium in oxidation state 0

25. Knochel’s work
Knochel, P. et al. J. Org. Chem. 2008, 73, 8422
Uses 2:1 ratio of SPhos to palladium
Uses Pd(II) which needs reducing

26. Preparation of phenylalanine derivatives
• Excess of aromatic iodide used
• Yield calculated based on iodoalanine
• Mass balance made up by protonation
• Standard reaction chosen

27. Which phosphine?
Pd precursor Mol % Ligand Mol % Yield (%)
Pd2dba3 2.5 P(o-tol)3 10 76
Pd2dba3 2.5 RuPhos 10 85
Pd2dba3 2.5 SPhos 10 80

28. Pd source
Pd precursor Mol % Ligand Mol % Yield (%)
Pd(OAc)2 1 RuPhos 2 25
Pd(OAc)2 1 SPhos 2 63
Pd2dba3 0.5 RuPhos 2 24
Pd2dba3 0.5 SPhos 2 73

29. Decreasing palladium loading
Pd precursor Mol % Ligand Mol % Yield (%)
Pd2dba3 2.5 RuPhos 10 85
Pd2dba3 2.5 SPhos 10 80

30. Decreasing palladium loading
Pd precursor Mol % Ligand Mol % Yield (%)
Pd2dba3 2.5 RuPhos 10 85
Pd2dba3 2.5 SPhos 10 80
Pd2dba3 0.5 RuPhos 2 24
Pd2dba3 0.5 SPhos 2 73

31. Decreasing palladium loading
Pd precursor Mol % Ligand Mol % Yield (%)
Pd2dba3 2.5 RuPhos 10 85
Pd2dba3 2.5 SPhos 10 80
Pd2dba3 0.5 RuPhos 2 24
Pd2dba3 0.5 SPhos 2 73
Pd2dba3 0.25 SPhos 1 72
Pd2dba3 0.15 SPhos 0.6 59
Pd2dba3 0.125 SPhos 0.5 51
Pd2dba3 0.05 SPhos 0.2 48

32. Palladium:phosphine ratio
Mol %
SPhos
Ratio
Pd:P
Yield
1 1:2 72
0.5 1:1 80
None 1:0 17

33. Scope of the reaction
Method A: 79%
Method B: 80%
Method A: 84%
Method B: 29%
Method A: 71%
Method B: 67%
Method A: 53%
Method B: 34%
Method A –
2.5 mol% Pd2dba3, 5 mol% SPhos
Method B –
0.25 mol% Pd2dba3, 0.5 mol% SPhos
Jackson, R.F.W. et al. J. Org. Chem. 2010, 75, 245

34. Scope of the reaction
Method A –
2.5 mol% Pd2dba3, 5 mol% SPhos
Method B –
0.25 mol% Pd2dba3, 0.5 mol% SPhos
Jackson, R.F.W. et al. J. Org. Chem. 2010, 75, 245

35. Ortho substituted aromatics
Method A –
2.5 mol% Pd2dba3, 5 mol% SPhos
Method B –
0.25 mol% Pd2dba3, 0.5 mol% SPhos
Jackson, R.F.W. et al. J. Org. Chem. 2010, 75, 245

36. Phenols
Method A –
2.5 mol% Pd2dba3, 5 mol% SPhos
Method B –
0.25 mol% Pd2dba3, 0.5 mol% SPhos
Jackson, R.F.W. et al. J. Org. Chem. 2010, 75, 245

37. Using 2-iodoaniline
Method A –
2.5 mol% Pd2dba3, 5 mol% SPhos
Method B –
0.25 mol% Pd2dba3, 0.5 mol% SPhos

38. Using 2-iodoaniline
Method A: 99%
Method B: 85%
Method A –
2.5 mol% Pd2dba3, 5 mol% SPhos
Method B –
0.25 mol% Pd2dba3, 0.5 mol% SPhos
Jackson, R.F.W. et al. J. Org. Chem. 2010, 75, 245

39. Dihydroquinoline
• Used as a building block for the synthesis of glycogen
phosphorylase inhibitors
• There are 2 previous syntheses

40. Dihydroquinoline
Rosauer, K. et al. Bioorg. Med. Chem. Lett. 2003, 13, 4385
Birch, A. et al. Bioorg. Med. Chem. Lett. 2007, 17, 394

41. Aromatic bromides
Jackson, R.F.W. et al. J. Org. Chem. 2010, 75, 245

42. Aromatic bromides
Jackson, R.F.W. et al. J. Org. Chem. 2010, 75, 245

43. Aromatic bromides
Jackson, R.F.W. et al. J. Org. Chem. 2010, 75, 245

44. Conclusions
• Biarylphosphine ligands give high yields of phenylalanine derivatives
•1:1 ratio of Pd:phosphine is optimal
•SPhos gives high yields with low Pd loadings
• High yields can be achieved with para, meta and
ortho substitued aromatics iodides
• Good yields can be achieved with para, and ortho substitued
aromatic bromides

45. Acknowledgments
For the work with aromatic bromides:
Hannah Lang
For help and support:
Prof. Richard Jackson
All the Jackson Group
All the staff at the University of Sheffield
Everybody else who has helped me over the past few years
For Funding:
The University of Sheffield
EPSRC
And thank you for listening