1. Asymmetric Fluorination
Eric Beaulieu
Thursday April 10th, 2008

2. Outline Introduction:
-Fluorine facts
-Why incorporate fluorine in organic molecules
-Examples of fluorinated molecules
Methods of Accessing Fluorine Bearing Chiral Centers :
-Enzymatic kinetic resolution
-Fluorinated enolates
-Nucleophilic fluorination
-Electrophilic fluorination:
-Substrate-controlled (chiral auxiliaries)
-Agent-Controlled
Conclusion / Acknowledgements

3. Fluorine Facts 19F Atomic Number : 9 Relative Atomic Mass: 18.998
Group # 17 (halogens)
Quantum # I = ½ (like 1H), abundance ≈ 100%
Bond
Average
Bond Strength (KJ/Mol)
Average Bond Length
(Å)
C-F
485
1.39
C-C
356
1.53
C-O
336
1.43
C-H
416
1.09
Element
Van der Waals radii (Å)
Electronegativity (Pauling) F
1.47
3.98 O
1.52
3.44 N
1.55
3.04 C
1.70
2.55 H
1.20
2.2

4. Why Incorporate Fluorine Into Organic Molecules ?
Organofluorine materials
-fluoroplastics: ie Teflon (PTFE)
-fluoroelastomers (gaskets, hoses, wiring insulation…)
-liquid crystals
Synthetic building blocks
-where fluorine serves as a leaving group
-to construct complex fluorine containing molecules
Biologically active/useful compounds
-electronegativity of fluorine influences the effect of neighbouring
functionalities
-C-F bond strength renders it resistant to metabolic processes
-incorporation of fluorine usually increases lipid solubility
(bioavailability )
-synthesis of isosteric analogues of drugs
-useful for studying biochemical processes
Filler, R., Kobayashi, Y. in Biomedical Aspects of Fluorine Chemistry, Eds. Kodansha/Elsevier Biomedical Press, 1982

5. Why Incorporate Fluorine Into Organic Molecules ?
Isostere of O vs H
Bond
Average
Bond Strength (KJ/Mol)
Average Bond Length
(Å)
C-F
485
1.39
C-C
356
1.53
C-O
336
1.43
C-H
416
1.09
Element
Van der Waals radii (Å)
Electronegativity (Pauling) F
1.47
3.98 O
1.52
3.44 N
1.55
3.04 C
1.70
2.55 H
1.20
2.2
Smart, B. E. in Organofluorine Chemistry: Principles and Commercial Applications;
Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum Press: New York, 1994; Chapter 3, pp

6. Vinyl Fluorides as Peptide (Amide) Bond Isosteres
Non-hydrolyzable bond
No rotational freedom
Taguchi, T. et al. J. Fluorine Chem. 2006, 127, 627.

7. Fluorinated Activity-based Fluorescent Protease Probe
Yao, S. Q. et al. Chem. Commun. 2004, 1512

8. Example of a Fluorinated Drug: Advair Diskus®
(fluticasone propionate)
GlaxoSmithKline
Asthma Medication

9. Metabolic Oxidation Inhibition by Fluorine
Back, D. J. et al. J. Steroid Biochem. Mol. Biol. 1993, 46, 833.

10. Accessing Fluorine Bearing Chiral Centers
Fluorinated
Enolates
Enzymatic kinetic
resolution
Nucleophilic
Fluorination
Electrophilic
Fluorination

11. Enzymatic Kinetic Resolution
Kitazume, T. et al. J. Org. Chem. 1986, 51, 1003.
Kalaritis, P. et al. J. Org. Chem. 1990, 55, 812.
Kalaritis, P., Regenye, R. W. Org. Synth. 1990, 69, 10.

12. Enzymatic Kinetic Resolution
Kitazume, T. et al. J. Org. Chem. 1986, 51, 1003.
Kalaritis, P. et al. J. Org. Chem. 1990, 55, 812.
Kalaritis, P., Regenye, R. W. Org. Synth. 1990, 69, 10.

13. Allylation of Fluorinated Silyl Enol Ethers
Paquin, J-F. et al. J. Am. Chem. Soc. 2007, 129, 1034.

14. Nucleophilic Fluorination
Hara, S. et al. Tetrahedron 1999, 55, 4947.
Wakselman, C. et al. J. Org. Chem. 1979, 44, 3406.

15. Attempt at Kinetic Resolution in Nucleophilic Fluorination
Yields and stereochemistry of products not reported!
Sampson, P., Hann, G. L. J. Chem. Soc. Chem. Commun. 1989, 1650.

16. Enantioselective Electrophilic Fluorination: Two Strategies
Substrate-Controlled
Agent-Controlled
Enantioselectivity induced by the
stereochemistry of the substrate
Enantioselectivity induced by the
stereochemistry of the fluorinating agent

17. Substrate-Controlled Stereoselective Electrophilic Fluorination
Stereoselectivity induced by the Evans oxazolidinone

18. Substrate-Controlled Stereoselective Electrophilic Fluorination
Entry R1 R2 R3
de (%)
Yield (%) 1 Ph Me
n-C4H9 97 88 2 H
i-Pr
n-C4H9 96 85 3 Ph Me
t-Bu 96 86 4 H
i-Pr
t-Bu 97 80 5 Ph Me Bn 89 84 6 Ph Me Ph 86 86
1 Absolute stereochemistry not determined
Davis, F. A., Han, W. Tetrahedron Lett. 1992, 33, 1153.

19. Davis, F. A., Han, W. Tetrahedron Lett. 1992, 33, 1153.
Substrate-Controlled Stereoselective Electrophilic Fluorination: Removal of the Chiral Auxiliary
Davis, F. A., Han, W. Tetrahedron Lett. 1992, 33, 1153.

20. Derivatization to Chiral a-Fluoro Carbonyl Compounds1 2 3
Entry R
de (%)
Yield (%)
ee (%) R`
Yield (%)
ee (%) 1 Ph
>97 77
>97 Me 77
>97 2 Ph
>97 77
>97 Ph 85 96 3 Ph
>97 77
>97
CH2=CH- 76
>97 4 Me
>97 80
>97 Ph 80
>97 5
CH2=CH-
>97 95
>97 Ph
Complexe mixture
Davis, F. A., Kasu, P. V. N. Tetrahedron Lett. 1998, 39, 6135.

21. Application of the Substrate-Controlled Asymmetric Fluorination for the Synthesis of a Fluoro-sugar
Davis, F. A. et al. J. Org. Chem. 1997, 62, 7546.

22. Application of the Substrate-Controlled Asymmetric Fluorination for the Synthesis of a Fluoro-sugar
Davis, F. A. et al. J. Org. Chem. 1997, 62, 7546.

23. Substrate-Controlled Asymmetric Fluorination
Reliable method with de’s up to 97%
Two extra steps are necessary (installation and removal of the auxiliary)
Ideally, the chiral carbon-fluorine bond would be formed enantioselectively
in one step

24. Agent-Controlled Enantioselective Electrophilic Fluorination
Lang, R. W., Differding, E. Tetrahedron Lett. 1988, 29, 6087.

25. Synthesis of the First Enantioselective Electrophilic Fluorination Reagent
Oppolzer, W. et al. Tetrahedron 1986, 42, 4035.
Lang, R. W., Differding, E. Tetrahedron Lett. 1988, 29, 6087.

26. The First Enantioselective Electrophilic Fluorination
Entry
Substrate
Product1
Base
Solvent
Temp. (oC)
ee (%)
Yield (%) 1
NaH
Et2O
0 – r.t.
0 – r.t. 70 63 2
LiH
Et2O
r.t.
<10 31 3
LDA
THF
-78 – r.t. 35 27 4
LDA
THF
-78 – r.t. 35
<5
1 Absolute stereochemistry not determined
Lang, R. W., Differding, E. Tetrahedron Lett. 1988, 29, 6087.

27. Problematic Secondary Reaction
Low yields (< 34 %)
Low ee (< 10 %)
Lang, R. W., Differding, E. Tetrahedron Lett. 1988, 29, 6087.

28. N-Fluoro-Camphorsultams
Further investigations by Davis and co-workers did not lead to
significant advances with these sultams.
Best Result:
Poor yields and poor to mediocre selectivity
Derivatization of the fluorinating reagent to increase selectivity is limited
Synthesis of the fluorinating reagent is not practical and potentially
dangerous (F2 gas)
Davis, F. A. et al. J. Org. Chem. 1998, 63, 2273

29. Amino Acid derivatives
Towards the Discovery of New Enantioselective Electrophilic Fluorination Reagents
Requirements:
Abundant source of chirality
Possess a site where an electrophilic fluorine
can be appended such as nitrogen…
Amino Acid derivatives

30. Amino Acid Inspired Electrophilic Fluorination Agents
Takeuchi, Y. et al. Chem. Pharm Bull. 1997, 45, 1085.

31. Amino Acid Inspired Electrophilic Fluorination Agents
Entry
Substrate
Fluorinating agent
Base
Product1
ee (%)
Yield (%) 1 3
LDA 9 6 2 6
LDA 54 26 3 6
KHMDS 48 53 4 7
LDA 6 8 5 3
NaH 6 23 6 6
NaH 14 20 7 7
NaH 30 6 8 3
NaH 8 4 9 6
NaH 18 21 10 7
NaH 6 21
1 Absolute stereochemistry not determined
Takeuchi, Y. et al. Chem. Pharm Bull. 1997, 45, 1085.

32. Amino Acid Inspired Electrophilic Fluorination Agents
Best results:
Low yields are probably due to the low reactivity of the fluorinating
reagent or its instability to the reaction conditions.
Low ee values indicate the asymmetric environment surrounding the fluorine
atom is inadequate, cyclic N-fluoro-sulfonamides (sultams) would be more rigid
and possibly better at inducing enantioselectivity.
Takeuchi, Y. et al. Chem. Pharm Bull. 1997, 45, 1085.

33. Synthesis of a Chiral N-Fluoro-Sultam Fluorinating Reagent
Takeuchi, Y. et al. J. Org. Chem. 1999, 64, 5708.

34. Cyclic N-Fluoro-Sulfonamide Fluorinating Reagent: Results
Entry
Substrate R
Fluorinating
agent
Product
Configuration
ee (%)
Isolated
Yield (%) 1 Me
(R)-4 S 74 67 21 Me
(R)-4 S 14 65 3 Et
(R)-4 S 72 70 4 Bn
(R)-4 S 88 79 5 Me
(R)-4 S 54 54 6 Me
(S)-4 R 48 62 7 Et
(R)-4 S 20 73 8 Bn
(R)-4 S 54 63 9 Et
(R)-4 ND 43 48 10 Bn
(R)-4 ND 18 39
1 Reaction carried out in presence of HMPA
Takeuchi, Y. et al. J. Org. Chem. 1999, 64, 5708.

35. Proposed Transition State
Takeuchi, Y. et al. J. Org. Chem. 1999, 64, 5708.

36. Chiral N-Fluoro-Sultam Fluorinating Reagents
Best result:
Yields and selectivity are better but there is still room for improvement.
Possibility of generating both enantiomers of the N-Fluoro-Sultam which
lead to different enantiomers of the product.
N-Fluoro-Sultam is not commercially available and must be prepared
using F2 gas which is not ideal.
Takeuchi, Y. et al. J. Org. Chem. 1999, 64, 5708.

37. Transfer Fluorination:
Using Transfer Fluorination to Obtain Asymmetric Electrophilic Fluorine Sources
Transfer Fluorination:
1. Banks, R. E. et al. J. Fluorine chem. 1995, 73, 255.
2. a) Shibata, N. et al. J. Am. Chem. Soc. 2000, 122, 10728, b) Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.

38. 19F NMR of Transfer Fluorination
Selectfluor
Selectfluor/DHQB (1:0.5)
Selectfluor/DHQB (1:1)
Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.

39. X-Ray Crystallographic Structure of NF-Q.BF4
Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.

40. Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.
First Hit Using Transfer Fluorination to Fluorinate a Cyclic Silyl Enol Ether
Solvent scan:
Entry
Solvent
ee (%)
Yield (%) 1
MeCN 40 80 2
MeCN/THF (1:1) 35 76 3
MeCN/toluene (1:1) 37 65 4
MeCN/H2O (4:1) 29 49 5
DMF 30 53 6
DMF/THF (1:1) 32 61
Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.

41. Cinchona Alkaloid Optimization
Entry
Alkaloid
Configuration
ee (%)
Yield (%) 1
quinine R 44 63 2
quinidine S 35 84 3
DHQ R 54 67 4
DHQB
32.70 $ / mmol (Aldrich) R 81 83 5
DHQ-9-phenantryl ether R 72 61 6
DHQ-4-methyl-2-quinolyl ether R 70
100 7
cinchonine S 23 94 8
cinchonidine R 42 88 9
(DHQ)2PHAL
94.22 $ / mmol (Aldrich) R 82
100 10
(DHQ)2PYR R 70
100 11
(DHQ)2AQN R 70 98
Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.

42. Modification of the Cinchona Alkaloid Hydroxyl Substituent
Entry
Alkaloid -R
ee (%)
Yield (%) 1
DHQ-benzoate 90 82 2
DHQ-4-nitrobenzoate 91 61 3
DHQ-4-methoxybenzoate 87 80 4
DHQ-acetate 86 67 5
DHQ-1-naphthalenecarboxylate 87 61 6
DHQ-anthraquinone-2-carboxylate 86
100 7
DHQ-trifluoroacetate 31 43
Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.

43. Substrates : Indanones and Tetralones
Entry 1 n R 2
Configuration
ee (%)
Yield (%) 1 1a 1 Bn 2a R 89 99 2 1b 1 Me 2b R 53 93 3 1c 1 Et 2c R 73
100 41 1a 1 Bn 2a R 91 86 5 1d 2 Me 2d R 40 94 6 1e 2 Et 2e R 67 71 7 1f 2 Bn 2f S 71 95
1 Reaction was carried out at -40oC for 2 days
Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.

44. Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.
Application of Transfer Fluorination to the Fluorination of Esters and b-Keto Esters
Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.

45. Application of Transfer Fluorination to the Fluorination of Oxindoles
Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.

46. Application of Cinchona Alkaloid N-Fluoroammonium Salts Towards the Synthesis of MaxiPost
MaxiPost is a maxi-K channel opener in phase III
clinical trials for the treatment of acute ischemic stroke
Hewawasam, P. et al. Bioorg. Med. Chem. Lett. 2002, 12, 1023.
Shibata, N. et al. J. Org. Chem. 2003, 68, 2494.

47. Cinchona Alkaloid Directed Electrophilic Fluorination
Best Result:
Good yields and enantioselectivities with a broader substrate scope.
Chiral fluorinating reagent easily prepared in situ.
Different substrate types require different alkaloids
Stoichiometric amount of chiral fluorinating reagent necessary.
A catalytic amount would be ideal…

48. The First Catalytic Enantioselective Electrophilic Fluorination
Togni, A., Hintermann, L. Angew. Chem. Int. Ed. 2000, 39, 4359.

49. Shibata, N., Toru, T. et al. Angew. Chem. Int. Ed. 2005, 44, 4204.
Lewis Acid Catalyzed Enantioselective Electrophilic Fluorination of b-Keto Esters
Entry
Substrate R n
Product
t (h)
ee (%)
Yield (%) 1
t-Bu 1 3 99 76 2 Ad 1 2 99 71 3
L-Men 1 2 99 66 4 Ad 2 3 95 88 5
t-Bu 1 2 93 84 6
t-Bu 2 2 99 86 7 18 83 75
Shibata, N., Toru, T. et al. Angew. Chem. Int. Ed. 2005, 44, 4204.

50. Shibata, N., Toru, T. et al. Angew. Chem. Int. Ed. 2005, 44, 4204.
Lewis Acid Catalyzed Enantioselective Electrophilic Fluorination of Oxindoles
Entry
Substrate R
Product
t (h)
ee (%)
Yield (%) 1 Me 35 93 73 2 Ph 5 96 72 3 18 83 75
Shibata, N., Toru, T. et al. Angew. Chem. Int. Ed. 2005, 44, 4204.

51. Optimized Subtrate-Catalyst Complex
Shibata, N., Toru, T. et al. Angew. Chem. Int. Ed. 2005, 44, 4204.

52. Positive Nonlinear Effect
Product
ee %
Shibata, N., Toru, T. et al. Angew. Chem. Int. Ed. 2005, 44, 4204.

53. Enantioselective Fluorination of Malonates
Entry
Lewis acid
Solvent
t (h)
ee (%)
Yield (%) 1
Ni(ClO4)2.6H2O
CH2Cl2 48 89 97 2
Mg(ClO)2
CH2Cl2 48 7 62 3
Zn(OAc)2
CH2Cl2 15 98 90 4
Zn(OAc)2
toluene 24 96 71 5
Zn(OAc)2
Et2O 62 68 52 6
Zn(OAc)2
EtOH 62 86 49
Shibata, N., Toru, T. Angew. Chem. Int. Ed. 2008, 47, 164.

54. Substrate Scope and Functional Group Compatibility
Entry 1 R
t (h)
ee (%)
Yield (%) 1 1a
CH2Ph 15 98 90 2 1b Et 24 96 94 3 1c Me 24 99 90 4 1d Bu 36 99 93 5 1e Ph 24 99 95 6 1f
OPh 15 98 85 7 1g
SPh 24 90 81 8 1h
NPht 18 93 91 9 1i
NPht(4-Br) 24 97 93
Shibata, N., Toru, T. Angew. Chem. Int. Ed. 2008, 47, 164.

55. Synthesis of Fluoro-Alacepril
Angiotensin-converting
enzyme (ACE) inhibitor
used as an antihypertensive
drug
Shibata, N., Toru, T. Angew. Chem. Int. Ed. 2008, 47, 164.

56. Synthesis of Fluoro-Alacepril
Shibata, N., Toru, T. Angew. Chem. Int. Ed. 2008, 47, 164.

57. Conclusion
Organofluorine compounds are important for a variety of reasons
Fluorine bearing chiral centers are accessible using four different methods
The substrate-controlled electrophilic fluorination method is reliable
however it requires additional steps
The agent-controlled electrophilic fluorination method allows us to install
the fluorine atom and the chirality in one step
Excellent enantiomeric excesses and high yields can be obtained with
b-keto esters and malonates using a catalytic amount of an asymmetric
catalyst

58. ONTARIO GRADUATE SCHOLARSHIP PROGRAM (OGS)
Acknowledgements
Professor Louis Barriault
Current Research Group:
Patrick Ang
Steve Arns
Francis Barabé
Geneviève Bétournay
Marie-Christine Brochu
Anik Chartrand
Anna Chkrebtii
Christiane Grisé
Patrick Lévesque
Daniel Newbury
Jason Poulin
Maxime Riou
Catherine Séguin
Past Group Members
ONTARIO GRADUATE SCHOLARSHIP PROGRAM (OGS)

59. Kanemasa,S. et al. J. Am. Chem. Soc. 1998, 120, 3074.
DBFOX/Ph·Ni(ClO4)2.3H2O
Kanemasa,S. et al. J. Am. Chem. Soc. 1998, 120, 3074.

60. Explanation of the Positive Nonlinear Effect

61. Proposed Transition-State Assemblies
Shibata, N. et al. J. Am. Chem. Soc. 2001, 123, 7001.