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CH402 Asymmetric catalytic reactions

Prof M. Wills

Think about chiral centres.How would you make these products?

H2N CO2H

Ph

H

PhNMe2

OHH

Ph

OHH

R2

R1H

O

EtO

O

Ph

H

Think about how you would make them in racemic form first, then worry about the asymmetric versions! What does a catalyst need to be able to provide in a catalytic version?

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Examples of reactions which form chiral centres

Hydrogenation of C=C, C=O, C=N bonds:

R2R1

R3R4

R2R1

R3R4

H

H

H2 gas

catalyst

O

R2R1

OH

R2R1H

reducingagent

NR

R2R1

NHR

R2R1H

reducingagent

Hydroboration of C=C bonds:

R2R1

R3R4

R2R1

R3R4

OH

H

i) BH3

ii) H2O2

Epoxidation of C=C bonds:

R2R1

R3R4

R2R1

R3R4

ORCO3H

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Examples of reactions which form chiral centres, cont…

Dihydroxylation of C=C bonds:

R2R1

R3R4

R2R1

R3R4

OH

i) OsO4

ii) hydrolysis

OH

Hydrocyanation of C=O bonds:

O

R2R1

OH

R2R1

HCN

CN

Hydrovinylation of C=C bonds: Addition of Grignard reagent to C=O bonds:

R2R1

R3R4

R2R1

R3R4CH2=CH2

catalyst

H

O

R2R1

OH

R2R1i) RMgBr

Rii) acid workup

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Examples of reactions which form chiral centres, cont. 2…

Enolate alkylation: Aldol reaction:

Diels-Alder (cycloaddition):

And many, many more….

R2R1

R3O

R2R1

R3

R-X

Enolate(formed by ketone deprotonation)

R

O

R2R1

R3O

R1

R3

RCHO

EnolateR2

O

(aldehyde) OH

R

H(three chiralcentres)

Hydroformylation of C=C bonds:

R2R1

R3R4

R5

R7

R6

R8R2

R1

R3R4R5

R7

R6

R8

Fourchiral centres

R2R1

R3R4

R2R1

R3R4CO, H2

catalyst

H

OH

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What properties are required of an asymmetric catalyst?

Turnover,

rate enhancement,

selectivity

The catalyst must recognise the reagents, accelerate the reaction, direct the reaction to one face of a substrate and release the product:

catalyst

substrate 1 substrate 2

+catalyst

+recognition

reaction

(a bond forms)

catalyst

+

release

Product!

Catalyst recycled

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Asymmetric epoxidation of alkenes (1980s)

R2R1

R3R4

R2R1

R3R4

ORCO3H

Sharpless discovered that a combination of diethyl tartrate, titanium isopropoxide and a peroxide.But it requires an allylic alcohol as substrate. The oxidant is used stoichiometrically (i.e. you need one equivalent), but the titanium and tartrate are used in catalytic amounts (ca. 5 mol%).

Mechanism? Could you modify this inan asymmetric manner?

The (-)-diethyl tartrate gives the opposite enantiomer.

OOH

OO

H

t-butyl peroxide(oxygen source)

Ti(OiPr)4 (metal for complex formation)

OH

CO2EtHO

HO CO2Et (+)-diethyl tartrate (source of chirality)

70-90% yield, >90% e.e.

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How the Sharpless epoxidation (of allylic alcohols) works(catalytic cycle):

EtO2C O

OEtO2C

CO2EtO

O CO2Et

Ti

Ti

OiPr

PrOi

OiPr

OiPr

The tartrate and metal form a complex:

O

CO2EtO

O CO2Et

Ti

Ti

O O

OOH

OH

O

O

CO2EtO

O CO2Et

Ti

Ti

OO

O

O OH

OH

2 x iPrO ligandsreplace the departing producthence the catalyst is regenerated.

The substrateand oxidantreplace twoOiPr ligands.

product

side-product

The oxygen atom isdirected to the alkene.The alkene is above the peroxide.

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Asymmetric epoxidation of alkenes using Mn/Salen complexes(Jacobsen epoxidation):

O

O

N

O

NMn

H H

tBu

ButtBu

But

catalyst -5 mol%

IO

(hypervalnet iodinereagent)Source of oxygen.

The iodine reagent transfers its oxygen atom to Mn, then the Mn tranfers in to the alkene in a second step. The chirality of the catalyst controls the absolute configuration.Advantage? You are not limited to allylic alcohols.

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Asymmetric hydrogenation for the synthesis of amino acids:

Addition of hydrogen to an acylamino acrylate results in formation of an amine acid precursor.

The combination of an enantiomerically-pure (homochiral) ligand with rhodium(I) results in formation of a catalyst for asymmetric reactions.

Ph

HO2C NH

O

N-acylated amine acid.

H2

Rh. catalystPh

HO2C NH

O

-acylamino acrylate

H

S

<1 mol%

P P P Rh P

S S.. ..

RR-DiPAMP = a homochiral ligand DiPAMP coordinated to Rh(I)

OMe

MeOOMe

MeO

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Asymmetric catalysis - hydrogenation

Rh-diphosphine complexes control asymmetric induction by controlling the face of the alkene which attaches to the Rh. Hydrogen is transferred, in a stepwise manner, from the metal to the alkene. The intermediate complexes are diastereoisomers of different energy.

Using Rh(DIPAMP) complexes, asymmetric reductions may be achieved in very high enantioselectivity.

Rh/DiPAMP

P Rh P

OMe

OMe

Ph

HO2C NH

O P Rh P

OMe

OMe

Ph

CO2HNH

O

More stable,but less reactivecomplex

Less stable, but more reactive - leads to product

Ph

CO2HNH

O

H2

HH

H

S

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Asymmetric catalysis - hydrogenation

Other chiral diphosphines are not chiral at P, but contain a chiral backbone which ‘relays’ chirality to conformation of the arene rings.

Rh/Diphosphine complex

P Rh P

face

face

edge

edge

PPh2

PPh2

O

O

PPh2

PPh2H

H

S-BINAP

PPh2

PPh2H

H

Chiraphos

DIOP

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Asymmetric catalysis – Ketone reduction

The reduction of a ketone to a secondary alcohol is a perfect reaction for asymmetric catalysis:

OHO H

i) Borane (BH3),oxazaborolidine catalyst

NB

O

PhPhH

Me

ii) hydrolysis (work up)

Oxazaborolidinecatalyst:

How it works:O

BH

Ph

PhN

BO

Me

HHH

Concave moleculehydride directed to one face.

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Asymmetric catalysis – Ketone reduction by pressure hydrogenation (I.e. hydrogen gas)

Ph2P

PPh2

Ru N

NH2

Ph

Ph

H

H

Mechanism

H

H

OMe

Ph

Ph2P

PPh2

Ru N

NH2

Ph

PhH

H

H

OHMe

Ph

H2

OHO H

H2 , solvent

Ph2P

PPh2

Ru

H2N

NH2

Ph

Ph

H

H

Very high e.e.from very lowcatalyst loadings

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Asymmetric catalysis – Isomerisation

Ph2P

PPh2

[Rh/S-BINAP]

Rh

NMe2 NMe2

Isomerisation (not a reduction!)

H

O

H H

R-citro-nellal, 96-99% e.e.

ZnBr2

then H2, Ni cat (to reduce alkene)

H

OH

(-)-menthol

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Asymmetric catalysis – Organocatalysis (no metals)

10 mol%:

Some time ago, it was found that proline catalyses the asymmetric cyclisation of a diketone (known as the Robinson annelation reaction).

O O

O

this is not a chiral centre

NH

CO2H

L-proline

O

Now this IS a chiral centre-S configuration

O

O

The enantiomericcompound is:

O

Major product

Mechanism is via: O

NO

HO2C

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Asymmetric catalysis – Organocatalysis (no metals)

10 mol%:

This is now the basis for many other reactions e.g.:

H

O O

Aldols:

NH

CO2H

L-proline

Me

H

Me DMF

H

O OH

Me Me

90% yield

4:1 anti:syn

anti product e.e.: 99%

and even more complex ones:

20 mol%O O

OTBS

H

O 3 mol% water, rt 2 days.TBSO

O

OtBu

CO2HH2N

O OH

OTBS OTBSO

O

68%, major product: D-fructose precursor

(it turns out that most amines act as catalysts!)

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Asymmetric catalysis – Organocatalysis Other applications

catalysed by:

Other applications include:

Diels-Alder reactions:

H

O

NH

CO2H

L-proline

Asymmetric reductiions:

and oxidations:

R

+

or pyrrolidines:

NH

Ph NH

PhPh

or other N-heterocycles:

NH

NMe

CO2H

O

Ph

O

+

O

H

R

PhNH

H HCO2EtEtO2C

O

PhH

H

O

R

+ RO

OH H

O

R

O

catalyst

catalyst

catalyst

(Hantzsch ester-hydride source)

Can you work out the mechanisms?

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Asymmetric catalysis – Enolate alkylation

OCl

Cl

MeO

10 mol% (i.e. 01 eq.) Catalyst(below), 50% NaOH-toluene

CH3Cl

OCl

Cl

MeO

98% yield94% e.e.

several steps

OCl

Cl

O

CO2H indacrinone

The reaction proceeds via a complex in which the catalyst and the enolateare bound by a hydrogen bond (at least, that's the theory):

OCl

Cl

MeO

The enolate is formedby deprotonation by hydroxide.

N

O

N

HH

CF3

Catalyst:

Enolate is methylatedon the front face (as illustrated)

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Asymmetric catalysis – Enolate alkylation for synthesis of amino acids.

Ph N

10 mol% Catalyst (below),

50% NaOH - toluenePhCH2Br

full conversion90-95% e.e.

several steps

By using an amino acid precursor with a relatively low pKa, it is possible to alkylate under relatively mild conditions:

Think about the mechanismand the enantiocontrol.

N

O

N

HHCatalyst:

Ph

OtBu

O

Ph N

Ph

OtBu

O

Ph

H3NO

O

Ph

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Asymmetric catalysis – Addition to an aldehyde (C-C bond forming reaction) – for interest only.

H

O

H

HO Et

Et2Zn, toluene (solvent)

(-)-DAIB (see below)See table for results

NMe2

OH

NMe2

OH

(-)-DAIB

(two pictures of the same molecule)

Results:

mol% DAIB used(relative to aldehyde)

0 (i.e. none)

2 (0.02 eq.) 100 (1.0 eq.)

Yield

0%

97%

0%

E.e.

-

98

-

How come a little bit of amino alcoholcatalyses the reaction, but a lot of it doesn't?