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:

R1 R2

X

R1 R2

XH

H

Cat.

H2 donor

R1 R2

X

R1 R2

XH

H

Cat.

loss of H2

R1 R2

X

R1 R2

XH

H

dif ferentchemistry

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)

NH

NPh

Ph

Rh

Ts

(R,R)-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)

R1 R2

X

X = O, NR

R1 R2

XHOH O

+ +chiral catalyst

R1 R2

X

X = O, NR

R1 R2

XH

+ +HCO2H CO2

chiral catalyst

CATHy examples Chiral amine (below right) – key intermediate in GSK’s Vestipitant

(anxiolytic, anti-emetic) Imine reduction route:

Ketone reduction route:

CF3F3C

NHMe

CF3F3C

NP(O)Ph2

CF3F3C

NP(O)Ph2

0.5% (R,R)-CATHY

TEAF

100% conversion, 15 min.91% ee

100% conversion, 4h>99% ee 60 kg

0.1% (S,S)-CATHY

CF3F3C

O

CF3F3C

OH

TEAF

CATHy examples Diltiazem – blockbuster anti-hypertensive Currently made by classical resolution of racemic intermediate

CATHy: enantioselective synthesis by Dynamic Kinetic Resolution

S

N

MeO

O

AcO

NMe2

S

OH

MeO

O

HO

NH2S

OH

MeO

O

HO

NH2

+

WASTE

CATHy examples DKR:

S

NH

MeO

O

O

S

NH

MeO

O

O

S

NH

MeO

O

HO

S

NH

MeO

O

HO

FAST

FASTSLOW 0.05% CATHY,TEAF

>99.5% ee>99.5% ee

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 Use of homogeneous iridium catalyst: spontaneous loss of H2 gas

S

N

68%

O

N S

80%

Org. Lett., 2009, 11, 2039

3. “Hydrogen-shuffling” chemistry Exchange of hydrogens – equilibration

Use in racemisation of chiral amines (SCRAM):

R1 R2

X

R1 R2

XH

H

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, 1247Recycling 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

NH

Cl94%

F

NH

Ph

82%

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 Marsden Dr Paddy McGowan