Lecture 1 on homogeneous hydrogenation and related reactions -emphasis asymmetric hydrogenation

(Rhodium) Asymmetric Hydrogenation was the first successful example of highenantioselectivity using a purely chemical catalyst

Success depends on asymmetry in the product that arises from asymmetry in theligand of cat*

My first lecture traces the evolution of this topic between 1968 and the presentday, and the second provides and understanding of how the reaction happens.

X YX Y X Y

H

H

H

H

Prostereogenicalkene needed

H2, cat* H2, cat*

Product 1 Product 2

Products 1 and 2 are enantiomers

1

The main elements involved as complexes in homogeneoushydrogenation are shown

Wilkinson’s catalyst (1966)- the first practical homogeneoushydrogenation catalyst

RhCl3

Usually as a trihydrate

reflux in C2H5OH

xs. PPh3

ClRh(PPh3)3

NB Change in Rh oxidation state

PPh3

Rh

PPh3

PPh3Cl

idealised square-planarstructure

16e -coordinatively unsaturated

How does Rh(III) become Rh(I)In this procedure; there must be a reducing agent?? How could ethanol participate?

H3CO H

HH

Homogeneous hydrogenation with Wilkinson’s catalyst is selectivefor less substituted double bonds

O O

O O

H2 , cat(PPh3)3RhClO

H2 , cat(PPh3)3RhCl

Fragment of steroid nucleus

H2 , cat(PPh3)3RhCl

carvone dihydrocarvone

What would happen with a heterogeneous catalyst like Pd/C?

The addition of hydrogen to an alkene from a homogeneousrhodium catalyst is stepwise

MLnThe catalyst will be coordinatively unsaturated since it must add both alkene and hydrogen for reaction to occur.

H2C CH3

, H2

MLmH

H

H2C CH3Et

Et

Hydrogen adds cis-; ligands may dissociate to liberate coordination sitesin a multi-step process.

A cis-ligand migration of hydrogen occurs such that a hydridoalkyl complex is formed.The reaction can be reversible leading to isomerization of the alkene.

CH2

CH3

MLmH

Et

H

H H

H

H H

H

MLm

The catalyst is regeneratedin this step

HC CH3Et

H

This step is an elimination of cis-substituents usually termed "reductive elimination".

H2C CH3Et

H HHH

H

H

Dihydride and dihydrogen complexes of known structure - show ushow dihydrogen can add to a transition metal in catalysis

Ph3P Ir PPh3CO

ClPh3P Ir PPh3

H

Cl

H

CO

H2, fast

Vaska's compound 16 e Dihydride 18 e

iPr3P Ir PiPr3

H

Cl

H H2, fastiPr3P Ir PiPr3

H

Cl

H

H

H

16 e Dihydrogen complex 18 e

Metal hydrides may be part bonded to neighbouring carbon

Ru PPri3Pri3P

H

Cl

RhPri3PPri3P

Pri2PCMe2

H

+

X–

Normal hydride Bridged "agostic" hydride

[ Do an “electron count” for both species]!

Cone angles give a qualitative idea of the relative bulk ofphosphines

Bite angles P-M-P provide an important parameter for thecomparison of different chelate ligands

PPh2

PPh2

PPh2

PPh2Fe

PPh2

PPh2

PPh2

PPh2S

O

PPh2 Ph2P

123˚

97˚91˚85˚

112˚

R2P

PR2

M

Bite angle

Different phosphines possess different electronic effects

Increasingdonor ability

The more electron-withdrawing the ligand, the more back-donation from themetal to P. This affects the CO bond:

M C OPR3 M C OPR3

! higher ! lower10

Some critical early developments in asymmetrichydrogenation

NB. Phosphine ligands

Wilkinson's catalyst, ClRh(PPh3)3 demonstrated fast homogeneous hydrogenation of alkenes (1966)

Knowles, Horner showed progress with a simple enantiomericallyenriched phosphine PMe PrPh (15% e.e.) 1968; up to 88% e.e. by 1971

Kagan introduced chelating ligands 1971 DIOP

Knowles claimed high enantiomer excess in enamide reductionCommercial L-DOPA synthesis.(1974).

Trivalent phosphorus is stereochemically far more stablethan trivalent nitrogen

NA B

C N

A

BC

PA B

C P

A

BC

microseconds, 0 ˚C

hours, 100 ˚C

> 109˚

What causes this remarkable difference?

The essential elements of the synthesis of anenantiomerically pure phosphine

MeP(O)OH

Ph

Me

OPri

SOCl2, then l-menthol P

O

PhMe

Me

OPri

PO

MePh

+

RP SP

separate by recrystallisation

Me

OPri

PO

PhMe

RP

2-MeOC6H4MgBr PO

PhMe

Inversion

OMe H2PO

MeOMe

(i) Basethen Cu(II) (ii) HSiCl3

Bu3N

PPhOMe

PPh OMe

(i) Retention(ii) Inversion

(R,R)-DIPAMP

The initial observation (above) and the first successful development(below) in asymmetric hydrogenation

CH2

CO2H

CH3CO2HH

"15% optical purity"

H2, pressure,60 ˚C, MeOH

Cl3RhP3, 0.15%

PMe

Me Me

"69% optical purity"

CO2H

H

MeOCHN

MeO

AcOH2, 1 atm20 ˚C, MeOHalkene2RhP2Cl

CO2H

H

MeOCHN

MeO

AcOH

H

88% (S)-enantiomer

PMe

OMe

≥ 95% optical purity

Reactions Ligands

Synthesis of dehydroamino acids from aldehydes. The productsare prostereogenic (prochiral)

O

H

HO2C

H2C

NHCOMe

AcOH, Ac2O90˚ O

N

O

MeO

HNMe

CO2H

NaOH

O

N

O

Me

H

H

H

CO2H

HNMe

HOHBr, AcOH

HBr,AcOH

(Z)-isomer

(E)-isomer

Can you suggest a mechanism for these steps?

Substrate

Kagan’s catalyst for the synthesis of N-acetylphenylalanine - firstuse of chelating diphosphine

NHCOMeHO2C NHCOMeHO2C

O

O

CH2PPh2

CH2PPh2

Me

Me

0.2 mol%[ClRh(C8H14)2]2

H2, EtOH, C6H6

1 bar, 20˚C

72% e.e. (R)

R,R-DIOP

H

HC2 axis

HO

HO

CO2H

CO2H

H

HTartaric acidDIOP

The Monsanto process for the synthesis of dehydroaminoacids (WS Knowles) post 1975

MeO

MeO

Ph

P

Ph

P

Rh+

OAc

NHCOMe

OMe

HO2C

OAc

NHCOMe

OMe

HO2C

H2, MeOH

3 bar, 50˚C

1/ >10000 catalyst/ substrate

96% e.e; 100% e.e. after recrystallisation / MeOHBF4

-

OH

NH2

OH

HO2CL-DOPA

Chelating ligandMedical use of L-DOPA?

How to make cationic rhodium catalysts for asymmetrichydrogenation - use in MeOH

Rh X–

Rh X–

+

+

RhCl3

refluxin i-PrOH

refluxin i-PrOH

X = Clthenion-exchange with e.g.BF4

–, PF6–, CF3SO3

–

RhP

P

+

– 1 alkene X–

RhP

P

+

X–

– 1 alkene

How does the oxidation state of Rh change from (III) to (I) in the first step?

chelatediphosphine

chelatediphosphine

What happens to the dialkene during catalytic hydrogenation?

The product configuration is fixed by cis-ligand transfer ofhydrogen from rhodium to the alkene

H H

N CO2H

O

Me

H

H H

N CO2H

O

Me

H

H H

N CO2H

O

Me

H

H H

N CO2H

O

Me

H

H H

N CO2H

O

Me

H

RhH2

RhH2

H

H

H

H

1 2

3

Si-face aboveRe-face below

Re-coordination

Si-coordination

(S)-product

(R)-product

H2 transfer

H2 transfer

Successful asymmetric hydrogenation with rhodium complexes= polar functional group that can also bind to the metal to

form a chelate

CH2

Ph EtCH3

Ph EtHlow e.e.

CH2

Ph CO2HCH3

Ph CO2HH fair e.e.

CH2

Ph NHCOMe

CH3

Ph NHCOMeHhigh e.e.

H2

H2H2

CH2

Ph NH

O

Me

H2Rh+

Strong binding

CH2

Ph

H2Rh+

Less strong binding

HO

O

20

Ligand development 1 - BINAP

PPh2PPh2

C2 symmetry, only racemises > 150˚ C

synthesisedfrom:

OHOH

BINOL availableas either enantiomer

Why is it possible for BINAP, BINOL to exist as stable enantiomers?What about the corresponding biphenyls?

Ligand development 2 - DUPHOS and BPE. Now the chiral element is inthe substituents around P, not the chelate.

P

Me

Me

P

Me

Me

P

Me

Me

P

Me

Me

(S,S)-DUPHOS (S,S)-BPEmay vary alkyl groups

Me

Me

HO

HOsource of 5-ring chirality

Ligand development 3 - BisPP*; even simpler NB. The products are isolated as borane complexes

PCH3CH3

nasty, reactive

P PBut

Me

MeBut

BH3

reagents

PCH3CH3

BH3

nice, stable

P PBut

But

MeBut

reagents

DescribeP-B bonding?

What about the P-CH2-P analogue - any good?

Ligand development 4 - Phanephos. This provides anexample of planar chirality

PPh2

Ph2P

Br

Br

achiral chiral(one enantiomer shown)

X

X X

X

Enantiomers

Any other simple examples of planar chirality?

Ligand summary. Types of chelate ligand, all with twofoldsymmetry axes (C2)

P

Me

Me

P

Me

Me

(S,S)-DUPHOS

O

O

CH2PPh2

CH2PPh2

Me

Me

H

H

PPhOMe

PPh OMe

(R,R)-DIPAMP

PPh2PPh2

P PBut Me

MeBut

(S)-BINAP

PPh2

Ph2P(R,R)-DIOP

(S,S)-PHANEPHOS

(R,R)-BisPP*

First chelating chiral biphosphine;backbone chirality

Monsanto ligand for L-DOPAsynthesis; P-chirality

Best known of all chiral ligands; axial chirality

Very effective use of alpha-phospholanesubstituents

Example of planar chirality

Simple concept; high enantioselectivity

Phosphoramidites in Asymmetric Hydrogenation.This challenges the 25 yearassumption that chelates are best for asymmetric Rh hydrogenation

AcHN CO2Me

HPh CH2Ph

AcHN CO2Me

H2, L2Rh+

P

P

Me

Me

Me

Me

L2 =O

OP NH

PhMe

L2 = 2 x

89% e.e.94% e.e.

MeOH

Faster

Phosphoramidites in Asymmetric Hydrogenation again

P

P

Me

Me

Me

Me

L2 =O

OP NH

PhMe

L2 = 2 x

H CO2Me

NHAcMe

CO2Me

H2, L2Rh+ NHAcMe

MeOH

94% e.e.67% e.e.

Slower

Hydrogenation of simple enamides with a rhodium catalystand DUPHOS-type ligand

NHAc NHAc

R

H2, 4 atm

iPrOH, -10˚C

95- 97% e.e

R

E and Z mixture

P

P

Me

MeMe

Me

as Rh ligand

NHAc

RN

NMgBr

R

Ac2ORCH2MgBr

Synthesis

Hydrogenation

H

catalystH

enamide

Enol acetates are like enamides and form chelates to the metal -example shows alkene relative reactivities

O

CH2CH3

C5H11 O

C5H11

O

CH2 CH3C5H11

O

2 atm H2, L2Rh+

thf or MeOH

98.5% e.e.

94% e.e.

2 atm H2, L2Rh+

thf or MeOH

P

P

Me

MeMe

Me

L2 =

CH3

O

CH3

O

O

CH3 O

CH3

Asymmetric hydrogenations of tetrasubstituted alkenes;stereospecific at both reacting centres

CO2Me

NHAc

Me

CO2Me

NHAcMe

MeOH, RTH2, 4 atm

MeOH, RTH2, 4 atm

CO2Me

CO2Me

NHAc

Me

NHAc

MeP

P

Me

MeMe

Meas Rh ligand

Rh cat

Rh cat

Single diastereomer of product in each case- what does thistell us about the H2 addition process?

30

Examples of drug precursors synthesised by asymmetrichydrogenation. Need to vary ligand to optimise results

PPh2

Ph2PN

NBoc

AcCO2Me N

NBoc

AcCO2Me

H2, MeOH

86% e.e.

Rh catalyst

Phanephos

CO2HCN

CO2HCN

HH

Rh catalyst

H2, MeOHP P

Me

Trichickenfootphos98% e.e.

The Quadrant Rule for prediction of the hydrogenation of dehydroamino-acids shown with the Monsanto ligand DIPAMP

Ph

RhP Po-An

Ph

o-An

Modified arylphosphine quadrant

bulky

bulky

open

open

(S)-product

Hard to see why Ph is more bulkythan MeO-Ph!!

The quadrant rule for prediction of the stereochemical course ofhydrogenation of dehydroamino-acids phospholanes

RhP P

Phospolane quadrant

bulky

bulky

open

open

R

R

R

R

(s)

It’s an empirical rule - just helps topredict which enantiomer ofdehydroamino acid is formed but offersno understanding of why!

Look into the P-RhP plane from theopposite side to the ligand and splitthe space occupied into quadrants

The Quadrant Rule for prediction of the hydrogenation ofdehydroamino-acids bis-PP*

RhP P

(General) alkylphosphine quadrant L = large; S = small.

bulky

bulky

open

open

S

LS(s)

LSee previous slide

One stereogenic centre is enough! Probably the best ligand for Rhasymmetric hydrogenation

RhP P

L = large; S = small.

bulky

bulky

open

bulky

L

LS(s)

L

P PMe

Me = S

Tert-butyl = L

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IGNobel prizes: Peace: Howard Stapleton of Merthyr Tydfil,Wales, for inventing an electromechanical teenager repellant -- adevice that makes annoying high-pitched noise designed to beaudible to teenagers but not to adults; and for later using thatsame technology to make telephone ringtones that are audible toteenagers but probably not to their teachers