Asymmetric synthesis

Asymmetric synthesis

Asymmetric synthesis, also called chiralsynthesis, enantioselective synthesis or

stereoselective synthesis, is organic synthesis

which introduces one or more new and desired

elements of chirality. elements of chirality.

This is important in the field of pharmaceuticals

because the different enantiomers or

diastereomers of a molecule often have

different biological activity.

Introduction

• Biologically active molecules are also chiral

• Enantiomers possess different types of activityactivity– Both are active, have different potencies

– Both have similar activity

– Both are active but type of activity is different.

– Only one enantiomer is active, other is devoid of activity

Examples

Hypertensive agent L-Methyldopa

HO

HO

NH3+

CO2-

Me

NMe2

Ph

OCOEt

Ph

Ph

OCOEt

Ph

NMe2

Ph

Ph

DarvonNovrad

Propoxyphene – both enantiomers are biologically active. D isomer is an analgesic while L isomer has antitussive property

Chiral Catalysis for Therapeutic Drugs

• Organisms sense the chirality of bioactive

compounds– Carvone enantiomers bind different chiral taste and odor sensors:

• (S)-Carvone is a component of Dill and Caraway flavor

• (R)-Carvone is a component of Spearmint flavor• (R)-Carvone is a component of Spearmint flavor

Limonene enantiomers bind different chiral

taste and odor sensors:

• (R)-Limonene is a component of Orange flavor

• (S)-Limonene is a component of Lemon flavor

Aspartame enantiomers bind different chiral taste and

odor sensors:

• One enantiomer of Aspartame is 160 times sweeter than

sugar

• The other enatiomer tastes bitter

Chiral Drugs

• Drugs are (or have been) frequently prepared as RacemicMixtures– Usually, only one enantiomer is biologically active

– The other was generally assumed to be completely inactive

• Thalidomide is an example where the “silent” enantiomerwas actually deadly

Other Examples

(S)-asparagine (R)-asparagine

H2N

O

OH

NH2

O

O

OH

H2N H

HO

OH NH2

pahit manis

Estrone

(+)-Estrone (-)-Estrone

O O

Sexual hormone inactives

HO

HH

OH

HH

1-chloro-2,3-propanediol

(R)-1-chloro-2,3-propanediol (S)-1-chloro-2,3-propanediol

Cl OH HO Cl

poison medicinal drug

Cl OH

HO H

HO Cl

H OH

All of our proteins are made from single enantiomer amino acids

– Organisms only use L-amino acids

Organisms primarily use D-sugars

L-amino acid D-amino acid

Organisms’ responses to enantiomers

• Drug receptor sites (usually proteins) are themselves chiral

• Chiral drugs may not be able to bind effectively to elicit the

correct response

Enantiomeric Transition States

Energy

O O

Me MePh PhH-

H

Ph

Me H Me

Ph

mirror

Enantiomeric transition states

OH OH

R S

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

R2R1

H

reducingagent

NR NHRreducingagent

16

R2R1 R2R1

H

agent

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

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

17

Hydrovinylation of C=C bonds: Addition of Grignard reagent

to C=O bonds:

R2R1

R3R4

R2R1

R3R4CH2=CH2

catalyst

H

O

R2R1

OH

R2R1

i) RMgBr

Rii) acid workup

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

Enolate alkylation: Aldol reaction:

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)

18

Diels-Alder (cycloaddition):

And many, many more….

Hydroformylation of C=C bonds:

R2R1

R3R4

R5

R7

R6

R8

R2

R1

R3R4R5

R7

R6

R8

Fourchiral centres

R2R1

R3R4

R2R1

R3R4CO, H2

catalyst

H

OH

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 in

an asymmetric manner?

t-butyl peroxide

19

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.

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

The substrateand oxidant

20

O

CO2EtO

O CO2Et

Ti

Ti

OO

O

O OH

OH

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

and oxidantreplace twoOiPr ligands.

product

side-product

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

Asymmetric epoxidation of alkenes using Mn/Salen

complexes (Jacobsen epoxidation):

N N

H H

catalyst -5 mol%

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.

21

O

O

N

O

N

Mn

tBu

ButtBu

But

I

O

(hypervalnet iodinereagent)Source of oxygen.

Asymmetric hydrogenation for the synthesis of amino acids:

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

precursor.

Ph

HO2C NH

O

N-acylated amine acid.

H2

Rh. catalyst

Ph

HO2C NH

O

αααα-acylamino acrylate

H

S

<1 mol%

22

The combination of an enantiomerically-pure (homochiral) ligand with rhodium(I)

results in formation of a catalyst for asymmetric reactions.

P P P RhP

S S.. ..

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

OMe

MeOOMe

MeO

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.

Rh/DiPAMP

P Rh P

OMe

OMe

Ph

HO C N

OP Rh P

OMe

OMe

Ph

CO HN

O

Less stable, but more reactive - leads to product

23

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

enantioselectivity.

HO2C NH

CO2HNH

More stable,but less reactivecomplex

Ph

CO2HNH

O

H2

HH

H

S

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

ii) hydrolysis (work up)

24

NB

O

PhPhH

Me

Oxazaborolidinecatalyst:

How it works:O

B

H

Ph

PhN

B

O

Me

HHH

Concave moleculehydride directed to one face.

Asymmetric catalysis – Ketone reduction by pressure

hydrogenation (i.e. hydrogen gas)

OHO H

H2 , solvent

Ph2P

PPh2

Ru

H2N

NH2

Ph

Ph

H

H

Very high e.e.from very lowcatalyst loadings

25

Ph2P

PPh2

RuN

NH2

Ph

Ph

H

H

Mechanism

H

H

OMe

Ph

Ph2P

PPh2

RuN

NH2

Ph

PhH

H

H

OHMe

Ph

H2

H2 , solvent

Asymmetric catalysis – Isomerisation

Ph2P

PPh2

[Rh/S-BINAP]

Rh

NMe2 NMe2

Isomerisation (not a reduction!)

H

26

Isomerisation (not a reduction!)

O

H H

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

ZnBr2

then H2, Ni cat (to reduce alkene)

H

OH

(-)-menthol

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

Major product

27

O

The enantiomericcompound is:

O

Mechanism is via: O

N

O

HO2C

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:

28

and even more complex ones:

20 mol%O O

OTBS

H

O3 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!)

Asymmetric catalysis – Organocatalysis

Other applications

catalysed by:

Other applications include:

Diels-Alder reactions:

H

O

NH

CO2H

L-proline

Asymmetric reductiions:

R

+

or pyrrolidines:O

+

O

H

R

H H

CO EtEtO C

O

catalyst

catalyst

29

and oxidations:

or pyrrolidines:

NH

PhNH

PhPh

or other N-heterocycles:

NH

NMe

CO2H

O

Ph

+

PhNH

CO2EtEtO2C

Ph

H

H

O

R

+ RO

OH

H

O

R

O

catalyst

catalyst

(Hantzsch ester-hydride source)

Can you work out the mechanisms?

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

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

O HH

30

several steps

OCl

Cl

O

CO2H indacrinone

OCl

Cl

MeO

The enolate is formedby deprotonation by hydroxide.

N

O

N

HH

CF3

Catalyst:

Enolate is methylatedon the front face (as illustrated)