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Homogeneous Hydrogen Transfer Chemistry Professor Steve Marsden

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.

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Homogeneous Hydrogen Transfer Chemistry Professor Steve Marsden

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  1. Homogeneous Hydrogen Transfer Chemistry Professor Steve Marsden

  2. Contents • Introduction • Catalytic Asymmetric Transfer Hydrogenation (CATHy) technology • “Oxidant-free” oxidations • Hydrogen-shuffling reactions • Process perspectives • Conclusions

  3. 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”)

  4. 1. Catalytic Asymmetric Transfer Hydrogenation (CATHy) • Asymmetric reduction of ketones/imines • Chiral alcohols/amines industrially important • Classical synthesis: resolution (>50% waste)

  5. 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)

  6. CATHy examples • Chiral amine (below right) – key intermediate in GSK’s Vestipitant (anxiolytic, anti-emetic) • Imine reduction route: • Ketone reduction route:

  7. CATHy examples • Diltiazem – blockbuster anti-hypertensive • Currently made by classical resolution of racemic intermediate • CATHy:enantioselective synthesis by Dynamic Kinetic Resolution WASTE

  8. CATHy examples • DKR:

  9. 2. Oxidation chemistry • Oxidation: loss of hydrogen (Mw = 2) • Frequently requires ‘heavy’ and undesirable reagents – hazards, waste • Example: oxidative formation of heterocycles • Common reagents: Pb(OAc)4, Mn(OAc)3, DDQ, PhI(OAc)2, Ag2O, MnO2

  10. “Oxidantfree”oxidations • Use of homogeneous iridium catalyst: spontaneous loss of H2 gas Org. Lett., 2009, 11, 2039

  11. 3. “Hydrogen-shuffling” chemistry • Exchange of hydrogens – equilibration • Use in racemisation of chiral amines (SCRAM):

  12. SCRAM: recycling valuable waste • Example: classical resolution of Sertraline: • 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

  13. Hydrogen-shuffling: new reactivity • Changing oxidation state changes chemistry • Catalysis can be employed for transient activation of unactive molecules

  14. Amine alkylation in water • Coupling of amines/alcohols (no alkyl halides – PGIs) • SCRAM facilitates this reaction in water Chem. Commun., 2010, 1541 and Org. Proc. Res. Dev., 2010, 13, 1046

  15. 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

  16. Conclusions • Hydrogen-transfer catalysis facilitates: • Hydrogenations – without hydrogen • Oxidations – without oxidants • Hydrogen-shuffling – for unusual/unexpected reactivity • Catalysts potentially readily separable and recyclable

  17. Acknowledgments • University of Leeds: Dr Mohamud Farah, Dr John Cooksey, Stephanie Lucas, Andrea Barzano • University of Bath: Prof Jon Williams, Dr OuridaSaidi • EPSRC (EP/F038321/1) and TSB Prof Steve Marsden Prof John Blacker Dr Paddy McGowan

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