Asymmetric Fluorination Eric Beaulieu Thursday April 10th, 2008

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

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

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

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 57-88.

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

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

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

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

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

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.

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.

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

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

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.

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

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

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.

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.

Derivatization to Chiral a-Fluoro Carbonyl Compounds 1 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.

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.

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.

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

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

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.

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.

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

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

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

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

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.

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.

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

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.

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

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.

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.

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.

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

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.

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.

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.

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.

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.

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

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.

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…

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

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.

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.

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

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

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.

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.

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.

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

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

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)

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.

Explanation of the Positive Nonlinear Effect

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