NEACT 72 nd Annual Summer Conference St. Joseph’s College, Maine. August 1-4, 2011 Magic Fluorine Chemistry for Medicinal Chemistry Applications Wei Zhang University of Massachusetts Boston [email protected] Presentation Outline • Fluorine facts • History background • Commercial applications • Medicinal chemistry - Organofluorine Chemistry - Fluorous Chemistry Fluorine Facts Atomic Number: 9 Relative Atomic Mass: 18.998 Group # VIIA (halogens) Quantum # I = ½ (19 F NMR, MRI) 19 F Abundance ≈ 100% Element Van der Waals Electronegativity radii ( Å) (Pauling) F 1.47 3.98 Bond Average Average Bond O 1.52 3.44 Bond Strength Length N 1.55 3.04 (KJ/Mol) (Å) C 1.70 2.55 C-F 485 1.39 H 1.20 2.2 C-C 356 1.53 C-O 336 1.43 C-H 416 1.09 History of Fluorine • Hydrogen fluoride (HF) was first reported by Scheele in 1771. • In 1836 Dumas and Pelig reported the synthesis of organofluorine compound fluoromethane . • In 1886 Henri Moissan isolated molecular elemental fluorine gas (F 2). • Belgian chemist Swarts’ work between 1890 and 1938 on simple aliphatic fluorocarbons is widely considered as establishing the foundations of organofluorine chemistry . • The chemistry of perfluorinated (fully fluorinated) organic compounds began in 1926 when Lebeau and Damiens synthesized carbon tetrafluoride (CF 4). History of Fluorine (continue) • In the 1930’s, Midgley and Henne extended Swarts’ exchange reaction methods for chlorofluorocarbon (CFC). • In WWII, Uranium hexafluoride (UF 6) used in the U-235 enrichment process for making atomic bombs. • DuPont and GM were the pioneers of the application of CFCs as refrigerants . Later CFC’s found diverse applications as fire extinguishers, blowing/cleaning agents. • Most recent applications are related to organofluorine products (containing F-C bonds). Nature Occurring Organofluorine Compounds • Only 13 known nature organofluorine compounds (2003) • Most of these are tropical plant metabolites makes the plants acutely toxic (traces of fluoroacetic acid found in the plant, gifblaar (Dichapetalum cymosum ) in the South African veldt are believed to be responsible for numerous cattle deaths from errant grazing) • Mother nature (the best chemist) does not seem to specialize in fluorine chemistry • F is the 13 th most abundant element in the earth’s crust (Fluorspar, CaF 2) Why? Possible reasons: • Nature needs fluoride ion (F -) to be a nucleophile in aqueous solution. But fluoride ion is generally only available in insoluble mineral forms, and even the soluble ones provide a fluoride ion so well-solvated it is a poor nucleophile, which makes ionic or radical fluorination mechanisms unlikely. • First fluorinase enzyme was only found until 2002 (Nature, 416, 279). Material Chemistry - Fluoropolymers Teflon Polytetrafluoroethylene (PTFE ) Non-stick cookware waterproof breathable fabrics Stainmaster carpet Biocompatible materials for implants and cosmetic surgeries Fluoromaterails and Solvents Surfactant Liquid crystals Organic layer Aqueous layer Fluorous layer C6F14 Ionic liquids Fluorinated solvents Medical Application - 19 F MRI Nuclear Magnetic Resonance Imaging Bio Application - Artificial Blood Perfluorodecaline good O 2 and CO 2 dissolving power, nontoxic and highly stabile Scuba Mouse Medical Application - Drugs ~1/5 Drugs on the market containing fluorine Fluorine in Medicinal Chemistry and Chemical Biology Iwao Ojima (Editor), Wiley-Blackwell, 2009 Features of Organfluorine Molecules Chemically: - small size - lipophilic - high electronegativity - low reactivity Biologically: - electronegativity effect of neighbouring functionalities - strength C-F bonds resistant to metabolic processes - increases lipid solubility (bioavailability) - synthesis of isosteric analogues of drugs - useful for studying biochemical processes Fluorine Chemistry Publisher: Elsevier Editor: W. Dolbier IF (2010): 1.719 ACS Division of Fluorine Chemistry Four Int. Conference Series: 1) Winter Fluorine Conf.; 2) Int. Symp. Fluorine Chemistry; 3) European Symp. Fluorine Chemistry; 4) ACS Nat. Meeting To Annette and Alexander: “The fury of the chemical world is the element fluorine. It exists peacefully in the com- pany with calcium in fluorspar and also in a few other compounds; but when isolated, as it recently has been, it is a rabid gas that nothing can resist.” Scientific American , April 1888 “Fluorine leaves nobody indifferent; it inflames emotions be that affections or aversions. As a substituent, it is rarely boring, always good for a surprise, but often completely unpredictable.” M. Schlosser, Angew. Chem. Int. Ed. 1998, 37, 1496–1513. Fluorous Chemistry A New Field of Fluorine Chemistry Started from 1994 Perfluorinated (fluorous) molecules are lipophobic and hydrophobic Triphasic Cocktail - Organic/aqueous/fluorous Biphasic System - Temperature-dependent miscibility Fluorous Biphasic Catalysis Two phases One phase Two phases “Heavy fluorous” - high fluorine content (60%) Concept of Fluorous Chemistry • Use phase tagging technique for easy separation • Render molecules to fluorous by attaching to fluorocarbon tag Fluorous separation • Fluorous molecules separated from non-fluorous molecules base on fluorophilicity • Fluorous tag are highly selective Non-fluorous Fluorous for separation , but low reactive Handbook of Fluorous Chemistry Gladysz, J. A.; Curran, D. P.; Horvath, I. T. Eds. Wiley-VCH, 2004 . Fluorous Chemistry - Challenges 1) Persistent nature of perfluorinated compounds 2) Potential toxicities of some perfluorinated compounds 3) Cost of F-solvents for BP reaction & LL extraction 4) High fluorine content only good for catalysis “Light Fluorous Synthesis” - A Possible Solution 1) Haircut of heavy fluorous ponytails (lower the cost) 2) Fluorous solid-phase extraction (F-SPE) for seperation 3) No F-solvents for reactions and separations 4) Better solubility/reactivity in common organic solvents Zhang, W. Green Chem. 2009 , 11, 911-920. Heavy and Light Fluorous PMB Linkers Fluorous Separation Techniques “Heavy fluorous” “Light fluorous” Need fluorous solvent Don’t need fluorous solvent F-LLE F-SPE Zhang, W. Tetrahedron 2003, 59 , 4475. Fluorous Silica Gel F-SPE silica gel (~100 mm) Selective retention of light fluorous molecules Zhang, W.; Curran, D. P. Tetrahedron 2006 , 62, 11835. Fluorous SPE (F-SPE) Fluorophobic Solvent Fluorophilic Solvent (MeOH-H2O) (MeOH) OOF F O F I I I S ilica F F F O F O fluorous S i(Me) 2 silica gel R f O F T T T organic O fluorous F fraction fraction - Use MeOH-H2O as elution solvent - Cartridge can be reused after wash with acetone or THF Zhang, W.; Curran,Curran, D.D. P. SynlettTetrahedron 2001, 14882006 , 62, 11837 . Fluorous SPE C H O HN 4 9 O HN C4H9 Solvent Blue O HN C7F15 O F F-Orange Left tube: beginning of fluorophobic wash (80:20 MeOH:H2O); Center tube: end of fluorophobic wash; Right tube: end of fluorophilic wash (100% MeOH) Light Fluorous Compounds OH Cl Reagents Cl N N N N + N Cl N N (AcO) I N O O Rf 2 N Ph O O N P N Ph O H H N N Rf Co O O Rf H Sn C6F13 (CH 2)n O t-Bu t Bu Rf PPh2 N O PdCl2 O 2 O O Rf F-Tag Catalysts H Si O NC O Rf C8F17 (CH 2)n N N O O O NC O N O N O H Ph O Linkers S O Ph N N O S O S N SH Ph N HO F O O O O Scavengers Cl O OH Fluorous Synthesis I. Fluorous Molecules - Catalysts - Reagents - Scavengers - Linkers (Tags) II. Fluorous Separation Tools - Liquid-liquid extraction - Solid-phase extraction - Chromatography Zhang, W. Tetrahedron 2003, 59 , 4475. Fluorous Techniques for Medichem Applications 1) Solution-phase reaction kinetics 2) Easy adaptation of literature procedures 3) Monitoring reactions by TLC, HPLC, LC-MS, or NMR 4) Chromatography-free separations (F-SPE) 5) Integrating with microwave, MCR, DOS, SPS… 6) Recovery of fluorous materials Medicinal Chemistry in Drug Discovery It takes 12 to 15 years and costs $0.8 to 2 billions to develop a new drug Medichem • Medichem program requires large numbers of compounds (libraries) for screening • Compound purification is the bottle-neck in library synthesis • Combinatorial Chemistry and high-throughput synthesis Integrated Fluorous Technology for parallel and HTP Synthesis Fast reaction Quick analysis Easy separation + + MW Reactor LC-MS F-SPE Zhang, W. Topics Curr. Chem. 2006, 266 ,145. Fluorous Tagging Strategies Tagging reagents/catalysts/scavengers F Reagent F-SPE + clean product F Derivative Tagging reactants for parallel and mixture syntheses de-tag + F F F-SPE Curran, D. P. Angew. Chem. Int. Ed. Eng. 1998 , 37 , 1175. Zhang, W. Tetrahedron 2003 , 59, 4475. Synthesis of Sclerotigenin Analogs O R1 OMe NH2 OMe R2 NH2 . HCl O NH2 CO H CHO NaBH(OAc) 1 2 2 F-Bn OMe 3 R R OMe N DIPEA, AcOH EDCI, NMP O C8F17 O OMe HN DCM, 25 oC F-Bn F-SPE O R1 64-95% NO Me 2 H O O2N PhN N OLi CO2Cl 2 Zn, AcOH O R R1 O N O N THF N t- BuN=P(NMe ) N sonication 2 3 1 reflux, 1 h 2 1 R2 R O F-Bn F-SPE R R HPLC F-SPE N 72-90% N 21-73% F-Bn F-Bn 43-69% (2 steps) O O 90:5:5 TFA-H 2O-DMS OMe µw O 120 oC,10 min N F-SPE F-Bn = N 63-100% 2 1 C8F17 O OMe R R N O H Only one step needs LC purification 144 9 analogs Lu, Y.; Nagashima, T.; Miriyala, B.; Conde, J.; Zhang, W. J. Comb. Chem. 2010, 12 , 125. Microwave-Assisted Fluorous Multicomponent Reactions F µw µw F F-SPE F-SPE excess non-fluorous F-intermediate fished clean product components out by F-SPE Atom economy, fast reaction, simple separation Zhang, W. Comb. Chem. High Throughput Screening 2007 ,10, 219. Synthesis of Benzodiazepinediones NHBoc O R3 CO R R1 2 H2N O OH R1 OR Ugi N R4 R3 N O + H BocHN O R2 CHO KOH, MeOH, rt 2 CN R4 F-SPE R C8F17O2SO OSO2C8F17 H H O O N N Suzuki 1 R3 1 R3 R R O N O 5 N deBoc R PhB(OH)2 O 4 O HN R4 HN R Pd(pddf)Cl AcCl, MeOH, 35 oC 2 K2CO3 R2 F-SPE R2 R5 C8F17O2SO acetone/toluene/H2O (4:4:1), w.