Homogeneous Hydrogen Transfer Chemistry Professor Steve Marsden Contents Introduction Catalytic Asymmetric Transfer Hydrogenation (CATHy) technology “Oxidant-free” oxidations Hydrogen-shuffling reactions Process perspectives Conclusions Introduction Hydrogen – low molecular weight, needs to be transferred efficiently Avoid hazards/bespoke processing where possible Three reaction manifolds: Reduction (“In”) Oxidation (“Out”) Shuffling (“Shake it all about”) 1. Catalytic Asymmetric Transfer Hydrogenation (CATHy) Asymmetric reduction of ketones/imines Chiral alcohols/amines industrially important Classical synthesis: resolution (>50% waste) Catalytic Asymmetric Transfer Hydrogenation (CATHy) Transfer hydrogenation: uses soluble molecule as source of hydrogen Iso-propanol: Formate: Advantages: reduced hazards, scalability (homogeneous – reduced mixing issues), standard kit (standard pressure) CATHy examples Chiral amine (below right) – key intermediate in GSK’s Vestipitant (anxiolytic, anti-emetic) Imine reduction route: Ketone reduction route: CATHy examples Diltiazem – blockbuster anti-hypertensive Currently made by classical resolution of racemic intermediate WASTE CATHy: enantioselective synthesis by Dynamic Kinetic Resolution CATHy examples DKR: 2. Oxidation chemistry Oxidation: loss of hydrogen (Mw = 2) Frequently requires ‘heavy’ and undesirable reagents – hazards, waste Example: oxidative formation of heterocycles XH [O] + R' R X O R' NH2 XH X R' R' N R R N R H N H Common reagents: Pb(OAc)4, Mn(OAc)3, DDQ, PhI(OAc)2, Ag2O, MnO2 “Oxidant free” oxidations Use of homogeneous iridium catalyst: spontaneous loss of H2 gas XH + R' X 1% [Cp*IrI2]2 R O R' toluene, reflux, 24 h NH2 XH X R' R' N R R H N H Org. Lett., 2009, 11, 2039 R N H2 3. “Hydrogen-shuffling” chemistry Exchange of hydrogens – equilibration Use in racemisation of chiral amines (SCRAM): NH NH2 NH2 - H2 + H2 + H2 - H2 SCRAM: recycling valuable waste Example: classical resolution of Sertraline: NHMe NHMe + Ar HO2C Add Ph ( = XH) OH NH2Me X NH2Me X + Ar Ar crystalline Ar = 3,4-dichlorophenyl Ar mother liquors i) SCRAMTM; ii) KOtBu SCRAM facilitates recycling of late-stage unwanted enantiomer SCRAMTM: Org. Proc. Res. Dev., 2007, 11, 642 and Tetrahedron Lett., 2007, 48, 1247 Recycling of sertraline: Org. Proc. Res. Dev., 2009, 13, 1370 Hydrogen-shuffling: new reactivity Changing oxidation state changes chemistry Catalysis can be employed for transient activation of unactive molecules XH unreactive R1 XH YH R2 R1 R2 or R1 R3 Mcat "McatH2" reactive X Y X or R1 R2 R1 R2 R1 R3 Amine alkylation in water Coupling of amines/alcohols (no alkyl halides – PGIs) R1 NH2 + 1% [Cp*IrI2]2 R3 HO R1 H2O, 100oC, 10h R2 R3 O R3 R2 - H2O R2 H N R1 R3 N R2 SCRAM facilitates this reaction in water Chem. Commun., 2010, 1541 and Org. Proc. Res. Dev., 2010, 13, 1046 Process considerations Expensive precious metal catalysts (recycle) Separation of metal from APIs (to ppm levels) Solution: solid-supported catalysts Cp-STAR (TSB-funded) project (Leeds, Cambridge, Yorkshire Process Technology, AstraZeneca, Pfizer) Patented technology allows supporting without loss of activity Conclusions Hydrogen-transfer catalysis facilitates: Hydrogenations – without hydrogen Oxidations – without oxidants Hydrogen-shuffling – for unusual/unexpected reactivity Catalysts potentially readily separable and recyclable Acknowledgments University of Leeds: Dr Mohamud Farah, Dr John Cooksey, Stephanie Lucas, Andrea Barzano University of Bath: Prof Jon Williams, Dr Ourida Saidi EPSRC (EP/F038321/1) and TSB Prof Steve Marsden Prof John Blacker Dr Paddy McGowan