the combinatorial approach to asymmetric hydrogenation.€¦ ·  · 2016-03-29the combinatorial...

The Combinatorial Approach toAsymmetric Hydrogenation.

Johannes G. de Vries

DSM Pharma Chemicals

and

U ivers roni n

IASOC 2004, IschiaUnlirnited.

1. DSM. A century of changes.

2. Homogeneous catalysis for fine chemicals

3. HTE approach; ligand libraries

4. MonoPhosTMligandsfor asymmerichydrogenation5. Instant Ligand Libraries6. Mechanism

7. The wedding between homogeneous catalysis &biocatalysis

DSM Pharma Chemicals Unlimited.

Evolutionife Science

ProductsPerformanceMaterials

Sustainability

Customer intimacy

Competences 11

mechanical technology

chemical technology

chemistry

polymer technologymaterial science

adv. organic chemistry

biotechnology

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DSM 2002 DSM 2003

Total sales - € 7 bn

Specialties from - 50% to > 80%

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Important technolo~ies

- Asymmetric hydrogenation (olefins, ketones, imines, enamides)- Asymmetric transfer hydrogenation (ketones)- Asymmetric epoxidation- Aromatic substitution

-Heck-Suzuki/Negishi-Sonogashira-Amination-Cyanation

-CO chemistry (hydroformylation, carbonylation, amidocarbonylation)-Isomerisation and racemisation-Oxidation

- benzylic and allylicoxidation- alcoholsto aldehydes or acids- olefins to epoxides

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. Nobel prize winning chemistry

.. Several hundred ligands known

" Many thousands examples on lab-scale

Till about 5 years ago the use of this technology for the production offine chemicals was scarce.

Why?Reviews

H.U. Blaser, F. Spindlerand M. Studer, Appl. Cata/.: A GeneraI, 2001, 221,119.

J.G. de Vries in Encyclopedia of Catalysis, I. Horvath, ed. 2003, Voi 3, P 295.

DSM Pharma Chemicals Unlimited. 15M

1. Time to market constraints in pharmaceuticals productionleads to very short development time

2. Competing technologies

3. Cost

. Cost of metal (Rh or Ru)

. Cost of ligand

. Activity of the catalyst.

. Stability of the catalyst

. Recovery or recyclability

4. Availability of catalysts on short notice

5. Patents and high cost of licensing

6. Reliability, real or perceived

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Goal: Find catalytic solution for customer requests within 3 weeks

Requirements:. Hardware

. Endeavor (8 high pressure reactors)

. Two proprietary reactors for high pressure (96 and 28 vessels)

. HTE Ana/ysis. GC

. HPLC (including chiral HPLC)

. Flow-NMR

. Libraries of ligands

Review: J.G. de Vries and A.H. M. de Vries, Eur. J. Org. Chem., 2003, 799-811.

Review Ligand libraries: C. Gennari, U. Piarulli, Chem. Rev. 2003, 103,3071.

. Libraries of phosphine ligands are not easy to prepare.

. Phosphoramidites on the contrary are easily prepared in 2 steps:

. Diversity from both diol and amine part.

. Chirality from BINOl or TADDOl skeleton or chiral amine.

. Very successful in copper catalysed asymmetric 1,4 addition ofEt2Zn to cyclic enones (B. Feringa et al, RUG)

. Not known for asymmetric hydrogenation!

DSM Pharma Chemicals Unlimited.

(OH

* +OH (

°,

PCl3 * O/P-CI ~NH/Base

...RR'NH +CI, ,R

PCI3 P-NC( 'R'

* (OH

OH

*(OH +HMPT~ (°, ~

OH * P-N(M

RR'NH

0/ eh cat.tetrazole

DSM Pharma Chemicals Unlimited.

DSMPharma Chemicals Unlimited.

R

M. van den Berg, A.J. Minnaard, E.P. Schudde, J. van Esch, A.H.M. deVries, J.G. de Vries and B.L. Feringa, J.Am. Chem. Soc. , 2000, 122, 11539.

WO 02/04466

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Entrv Solvent Temp e.e.

1. CH30H RT

2. CH2CI2 RT 95%

3. CH2CI2 5°C

4. THF RT 93%

5. Acetone RT 92%

6. PrOCH2CH2OH RT 77%

Entrv R R' Solvent e.e. (RT) e.e (O°C)

1. Ph Me CH2CI2 95% 97%

2. Ph H EtOAc 97%

3. H Me EtOAc >99%

4. H H EtOAc >99%

rAYYG~2R' e!jh (~pq)2tI13P4J~MPQPPh~S.Af'y'G02fR'

R~ NHAc H2'GH2GI2 ~ NHAc

M. van den Berg et al., Adv. Synth. Catal. 2003, 345, 308-322.

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.. MonoPhos can be prepared in a single step from commerciallyavailable SINOL (Compare with DUPHOS: 6 steps).

.. MonoPhos is an order of magnitude cheaper than currentlyavailable bisphosphines.

.. The hydrogenation rate can be increased by increasing the H2pressure without loss in enantioselectivity!

.. At S/C ratio of 2000 fuIl conversion in 2 h at 10 bar.

. Method of choice for asymmetric olefin hydrogenation.

.. Large library of ligands available.

DSM Pharma Chemicals Unlimited.DSM

R R Solvent e.e. (RT) e.e. (O°C)

1. H Me CH2CI2 95% 97%

2. 3-MeO H CH2CI2 97%

3. 4- Ph Me CH2CI2 95%

4. 4-0Ac, 3-0Me Me EtOAc 94% 98%

5. 4-Ac Me CH2CI2 99%

MonoPhos

H. Bernsmann et al., submitted to JOC

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o O

~oMeR

.. Synthesis of precursors: ZIE mixtures with predominantly Z

.. Asymmetric hydrogenation of E is facile.

.. Asymmetric hydrogenation of Z is difficult. For R = aryl so far onlya few successful catalyst systems known: Ru-BINAPO, Tangphos(x. Zhanget al.)

.. Two strategies can be developed:

.. find good ligand for Z

.. synthesis of only E(See: D. Heller et al. Angew. Chem. Int. Ed. 2003, 42, 913)

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L

D. Pena et al,J. Am. Chem. Soc.,2002, 124, 14552-3.

Unlimited.

'# What happens if you mix ligands?

RhL1L1

DSM Pharma Chemicals Unlìmited.

Substrate Ligand Solvent e.e.

E- R = CH3 MonoPhos CH2CI2 95%

E- R = CH3 1 CH2CI2 99%

z- R = CH 2 iPrOH 95%3Z- R = Ph 2 iPrOH 92%

~ R'O, /

P-N0/ \

(S)-1, R' = Me, R2= R3= H(S)-3, R' = R2= Me, R3= H(S)-4, R' = Me, R2= H, R3= Br(S)-5, R' = Bn, R2= R3= H

NHAc

R~C02Et

R2

"'-

O, )-PhP-N

0/ H50

g&I/-o /

'P-N/ \y O

~ I (S)-2

90

80

~: 70

60

(S,R)-6 e ntry 9 10 11

DSM Pharma Chemicals 7 = 6 +1; 8 = 6 + 2; etc.Unlimited.

" ...works! (D. Pena et al. Org. Biomol. Chem., 2003, 1,1087.).

" From NMR: Almost exclusive formation of mixed complex in caseof e.e. enhancement.

" Most tested combinations gave lower enantioselectivity than thehomo-catalysts.

" Significantly increases the scope of asymmetric hydrogenation.

" Aiso shown to work with monodentate phosphites. (M.Reetz et al.Angew. Chem. Int. Ed. 2003,42,790.)

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" They can ali be synthesized in 1-2 steps

" Other applications besides hydrogenation: Asymmetric Heck,hydroarylation, hydrosilylation, allylic substitution.

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.. So far ligand libraries have been made manually. Each ligandsynthesised and purified separately.

.. Can we make ligands in a robot?

" What about purification?

Metal

Precursors

I(

OHChiral diols *

OH

JPhosphorus - Parall~l I-

Source SyntheslZer

(pC13,HMPT...) tR1"

Amines NH

R(

.1 ParallelReactors

(Fast) I-Analysis

Library("ane vesse~

ane compOlmd")

t HitsProchiralSubstrate

.. ~ 96 wells microplateI \ 2mL,Oleophobicfilter

-O~ I Orbtrt1/~er I

(°,/P-CI°

R)R2NH ..

Et3N

96 wells microplateCollectingplate

Parallel

-+Filtration

11111111

Metal

precursor==

Substrate D- Array 0196 vials (1OmL)

DSM Pharma Chemicals

~CO;,CH3V NHAc

IRh(COD);,]BF4' Ugand

H2 6 bar, 1h

Converslon

90-100

0-10 40-50 80-9060-7020-30

-

..Parallel Reactor

ligand E.e.

<50 85-9055-60 65-70 75-80

NHAc

ÀC02CH3

[Rh(CODhJBF 41 Ligand.H26 bar, 1h

ConversionLigand

E.e.

0-10 20-30 40-50 60-70 80-90

Purified ligands Libraryligands

Ligand Conv.(%)

Ee

(%)

Conv

(%)

Ee

(%)

NEt2 8 46 11 41

Piperidine 11

NH-a-MeBenz

96

NHiPr 100

DSM Pharma Chemicals

55 7 43

94 51 88

95 95 92

Unlimited.

.. This HTE approach enables a very fast synthesis of a widerange of phosphoramidites and their screening in asymmetricolefin hydrogenation of

.. Aiso less easy accessible N-H ligands can be tested.

.. E.e's are slightly lower than for the conventional reaction.However, the order is representative.

.. Can also be applied to other monodentate ligand fanilies

.. Can also be applied in other catalytic chemistry (C-C bondformation)

L. Lefort, J.A.F. Boogers, A.H.M. de Vries and J.G. de Vries, Org Lett, 2004

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~C02CH3 [Rh (COD}zt BF4-/Ligandal0J NHAc~C02CH3l0J NHAc

Rate dependence on Monophos/Rh ratio

100

20

-+-1 eq.

--1.5eq.

2 eq.

3 eq.

80c:o'iij 60....Q)

1: 40oCJ

o

o 2

time (h)

3 4

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~ ~ C02CH3 [Rh (COD)2r BF4-/Ligand

~ NHAc .H

~C02CH3~ NHAc

E.e dependence on MonoPhos/Rh ratio

-+--1 equi

-1.5equi

2 equi

1,5 2

time (h)

2,5 3

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-AsymmetricAmplification!

-More than 1ligandon rhodium?

DSM Pharma Chemicals Unlimited.

100

80

60Q)Q)

40

20

O

1

LR" / O)NHRh -!

L( ~C02H

If the "racemic"catalystisslowerthan theenantiopurecatalyststhe e.e. will be higherthanexpected;positiveasymmetricamplification.

1l

LR" / O)NHRh -!

L( ~C02H

If the "racemic"catalystis faster thantheenantiopurecatalysts:e.e. willbe lowerthanexpected;negativeasymmetricamplification.

1l

Ls" o)Rh' NH

L( ~ C02H

This experimentprovesthe existenceof RhL2'

Sut... ... .

DSM Pharma Chemicals Unlimited.

DSM Pharma Chemicals

. ..it does not rule out the

existenceof catalyticallyactiveRhL.

.NMR, MS and kineticstudiesneeded.

Unlimited.

LR" / ONH

ONH

Rh

L( :::c--- C02H

/Rh

1l L( C02H

LR" / ONH

ONH

Rh

/ C02HLs

/

1lRh

L( C02H

Ls" / ONHRh

L( C02H

Experiment with 5 mol% Rh followed over time with ES-MS (cationic mode):

After 30 min: RhL2(nbd), RhL2(Substrate), RhL3' RhL3(Substrate)

After 60 min: RhL2(nbd), RhL2(Substrate), RhL3' RhL4

After 120 min: RhL2(Substrate), RhL3' RhL4

-No RhL derived complexes found

-RhL3and RhL4cannot lead to products

-From results with mixtures of ligands: Only RhLz(not RhL) is an activecatalyst!

- A large part of the rhodium is tied up in inproductive complexes.

DSM Pharma Chemicals Unlimitèd.

~,I

l

193K

~ 211K

221 K

232 K

~- 243 K

254K

242 Hz

b bb b

39Hz(\b

b

b

b

239 Hz

221 Hz

f\f\

a a

c c

PPMT

143,0T

142.0T

141.0T

140.0l

139.0T

138.0T

137.0T

138.0T

135.0T

134,0T

133.0T

132.0T

1310T

130.0l

129.0

Coordination sites of

I the cyclooctadiene,CODomitted for clarity

Rh

Coordination sites ofthe cyclooctadiene,CODomitted for clarity

@ Transition metal catalysed reactions very good for:. Hydrogenation. c-c bondformation. Oxidation

@ Enzymes are very good in:. Hydrolytic reactions. Chiral induction

. Enormous diversity readily available in large numbers!

@ Can we wed the best properties of both?

@ Prior art: Whitesides and Ward (biotin linkedcatalysed bound to Avidin)

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@ Combine homogeneous catalysts that are good inhydrogenation and hydroformylation with anenzymel

@ Enzyme-Ligand-Metal@ Unfavourable weight ratio demands highly active

catalyst

@ Catalyst needs to be stable in aqueous environment@ Attachment at single position in enzyme for

reproducibility.

@ Start: Papain plus rhodium/phosphite complexes

@ Enzyme-S-linker-O-P(ORhRh-(COD)BF 4

DSM Pharma Chemicals Unlimited.

DSMPharma Chemicals Unlimited.

DSM Pharma Chemicals Unlimited.

t o .~N02HNJoN IIDZ)fwe($4~

)o

(50 J.!M)

~N02N-o1:;=9000 at 404 nrn

0,25

-= 0,15~~

~ 0,1

0,05

0,2

-+- LinkerC- Cofactor4C

-Papain- Papain+5%Dioxane

°° 200 400 600 800

t (sec)

DSM Pharma Chemicals Unlimited.

After treatment of the ligated enzyme with [Rh(COD)2]BF4andpurification only a single Rh is bound to the enzyme!

ESI-IVIS

500000

450000

400000

350000

300000

250000

200000

150000

100000

50000

o23400

HydrolyzedHO '- ---~-.--ilRh'~

I'

p"'-- ---

""",inli?

Pap-Phos + HzO

23600 24200 246002440023800 24000

DSM Pharma Chemicals Unlimited.DSM

==(C02MeNHAc

.. Product N-Ac-Ala-OH is racemic

.. Native papain reacted with Rh-precursor and purified inthe sa me manner shows no reactivity.

.. Next step: other enzymes and substrates.

Lavinia Panella, unpublished results

DSM Pharma Chemicals Unlimited.

. Monodentate phosphoramidites are excellent ligands forenantioselective olefin hydrogenation.

. Monophos is at least an order of magnitude cheaper thanexisting bisphosphine ligands.

. A library of 96 phosphoramidite ligands can be made in a singleday and screened in catalysis the next day.

. MonophosTM and other phosphoramiditesare available inresearch quantities via STREM

. Combination of transition metal catalysts with enzymes is apromising new field.

DSM Pharma Chemicals Unlimitèd.

DSM-GeleenAndré de Vries

Jeroen BoogersCharlotte WillansLaurent Lefort

Sjoerd van de WalMath Boesten

Universitv of GroninQen

Michel vd BergAdri Minnaard

Ben L. FeringaDiego PenaLavinia PanellaDick Janssen

Marco Fraaije

IFOK

Detlef Heller

Hans-JG.Vries-de@dsm.com

Financial support: DSM, University of Groningen,Dutch Science Foundation Combichem program,EU (RTN Network Combichem)

Unlimifed.DSM