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Homogeneous Hydrogen Transfer Chemistry Professor Steve Marsden PowerPoint Presentation
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Homogeneous Hydrogen Transfer Chemistry Professor Steve Marsden - PowerPoint PPT Presentation


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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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slide1

Homogeneous Hydrogen

Transfer Chemistry

Professor Steve Marsden

contents
Contents
  • Introduction
  • Catalytic Asymmetric Transfer Hydrogenation (CATHy) technology
  • “Oxidant-free” oxidations
  • Hydrogen-shuffling reactions
  • Process perspectives
  • Conclusions
introduction
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
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
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
CATHy examples
  • Chiral amine (below right) – key intermediate in GSK’s Vestipitant (anxiolytic, anti-emetic)
  • Imine reduction route:
  • Ketone reduction route:
cathy examples1
CATHy examples
  • Diltiazem – blockbuster anti-hypertensive
  • Currently made by classical resolution of racemic intermediate
  • CATHy:enantioselective synthesis by Dynamic Kinetic Resolution

WASTE

2 oxidation chemistry
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
oxidant free oxidations
“Oxidantfree”oxidations
  • Use of homogeneous iridium catalyst: spontaneous loss of H2 gas

Org. Lett., 2009, 11, 2039

3 hydrogen shuffling chemistry
3. “Hydrogen-shuffling” chemistry
  • Exchange of hydrogens – equilibration
  • Use in racemisation of chiral amines (SCRAM):
scram recycling valuable waste
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

hydrogen shuffling new reactivity
Hydrogen-shuffling: new reactivity
  • Changing oxidation state changes chemistry
  • Catalysis can be employed for transient activation of unactive molecules
amine alkylation in water
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
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
Conclusions
  • Hydrogen-transfer catalysis facilitates:
  • Hydrogenations – without hydrogen
  • Oxidations – without oxidants
  • Hydrogen-shuffling – for unusual/unexpected reactivity
  • Catalysts potentially readily separable and recyclable
acknowledgments
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