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  CATHy: enantioselective synthesis by Dynamic Kinetic Resolution WASTE

CATHy examples  DKR:

2. Oxidation chemistry  Oxidation: loss of hydrogen (M w = 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, Ag 2 O, MnO 2

“Oxidant free” oxidations  Use of homogeneous iridium catalyst: spontaneous loss of H 2 gas Org. Lett., 2009, 11, 2039

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

SCRAM: recycling valuable waste  Example: classical resolution of Sertraline:  SCRAM facilitates recycling of late-stage unwanted enantiomer SCRAM TM : 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

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

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 John BlackerProf Steve MarsdenDr Paddy McGowan