Asymmetric synthesis

Asymmetric synthesis
Asymmetric synthesis, also called chiral
synthesis, enantioselective synthesis or
stereoselective synthesis, is organic synthesis
which introduces one or more new and desired
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
activity
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
CO2-

HO

Hypertensive agent
L-Methyldopa

Me
NH3+
HO

Ph

Ph

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

Ph Ph

NMe2

Ph
OCOEt

Darvon

Ph
OCOEt

NMe2

Novrad

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

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 Racemic
Mixtures
Usually, only one enantiomer is biologically active
The other was generally assumed to be completely inactive

Thalidomide is an example where the silent enantiomer

was actually deadly

Other Examples
(S)-asparagine

(R)-asparagine

H2N

NH2
OH
O

H2N

pahit

HO
H

NH2

manis

Estrone
(+)-Estrone

(-)-Estrone
O

HO

OH

Sexual hormone

inactives

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

Cl

OH
HO

H
poison

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

HO

Cl
H

OH

medicinal drug

All of our proteins are made from single enantiomer amino acids
Organisms only use L-amino acids

L-amino acid

Organisms primarily use D-sugars

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

Ph

Me

H-

Ph

Me

Energy

O
Ph

Ph
Me

Me
OH

OH
Enantiomeric transition states

mirror

Examples of reactions which form chiral centres

Hydrogenation of C=C, C=O, C=N bonds:
4

R
R1

R2

H2 gas
catalyst

R3
R2

R1

H
NR
R2

R1

R4
R1

R2

OH 3
R
R
4

i) BH3
ii) H2O2

reducing
agent
R1

NHR
R2
H

Hydroboration of C=C bonds:

3

R2

R1

R2

R1

OH

reducing
agent

Epoxidation of C=C bonds:

4

R3

RCO3H

R4

R3
O

R2

R1
H

R1

R2

R1

R2
16

Examples of reactions which form chiral centres, cont

Hydrocyanation of C=O bonds:

Dihydroxylation of C=C bonds:

R

R1

i) OsO4
ii) hydrolysis

R4
R1

OH
R3
R2
OH

R1

R3
R2

CH2=CH2
catalyst

R1

R2
CN

R2

OH

O
R1

R1

HCN

Addition of Grignard reagent

to C=O bonds:

R3

R1

Hydrovinylation of C=C bonds:

OH

i) RMgBr
ii) acid workup

R2

R1
R

H
17

Examples of reactions which form chiral centres, cont. 2

Enolate alkylation:
R3

R-X

R1

Aldol reaction:

R3

R1

R1

R3
2

4
R6 R

R8
R7

R1

R1

(three chiral
centres)
H
OH

R2

Hydroformylation of C=C bonds:

Diels-Alder (cycloaddition):
R6 R5

(aldehyde)

Enolate

Enolate
(formed by ketone deprotonation)

R5

RCHO

R3

R3

R4
R3

R2

R2
1

R8 R7 R
Four
chiral centres

H
R4
R1

And many, many more.

R3
R2

CO, H2
catalyst

O
R3

R4

R2

R1
H

18

Asymmetric epoxidation of alkenes (1980s)

R

R3

RCO3H

R4

R3

Mechanism? Could you modify this in

an asymmetric manner?

O
R2

R1

R1

R2

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%).
t-butyl peroxide
(oxygen source)

Ti(OiPr)4
(metal for complex
formation)

OH

HO
HO

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

OH

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

The (-)-diethyl tartrate gives the

opposite enantiomer.
19

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

The tartrate and metal form a complex:

EtO2C

OiPr
OiPr

O
OH

Ti
EtO2C

Ti

CO2Et

OH

Ti
PrOi

OH

product

O
OiPr

CO2Et

O
O
O

The substrate
and oxidant
replace two
OiPr ligands.

2 x iPrO ligands
replace the departing product
hence the catalyst is regenerated.

CO2Et

O O

CO2Et

Ti

The oxygen atom is

directed to the alkene.
The alkene is above the peroxide.
Ti
O
O

OH

CO2Et

O O

CO2Et

Ti

side-product

20

Asymmetric epoxidation of alkenes using Mn/Salen

complexes (Jacobsen epoxidation):
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.
catalyst 5 mol%
H

H
N

N
Mn
But

O
tBu

tBu

But

I
O
(hypervalnet iodine
reagent)
Source of oxygen.

21

Asymmetric hydrogenation for the synthesis of amino acids:

Addition of hydrogen to an acylamino acrylate results in formation of an amine acid
precursor.
<1 mol%
Ph

Rh. catalyst
O

HO2C

Ph

N
H

HO2C
H2

-acylamino acrylate

S
N
H

N-acylated amine acid.

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

results in formation of a catalyst for asymmetric reactions.
MeO

P
..

..

OMe
RR-DiPAMP = a homochiral ligand

OMe
P
S

Rh

P
S

MeO
DiPAMP coordinated to Rh(I)
22

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
OMe
Ph
P
HO2C

Rh

OMe
Ph
P
O

OMe

P
O

Rh

N
H

CO2H

N
H

More stable,
but less reactive
complex

OMe

Less stable, but

more reactive leads to product

H2
Ph
O

S
N
H

CO2H

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

enantioselectivity.

23

Asymmetric catalysis Ketone reduction

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

i) Borane (BH3),
oxazaborolidine catalyst
ii) hydrolysis (work up)

Ph

Oxazaborolidine
catalyst:
H

Ph

Ph

O
B

Concave molecule
hydride directed to one face.
O

How it works:

H Ph

Me
O

H
Me

24

Asymmetric catalysis Ketone reduction by pressure

hydrogenation (i.e. hydrogen gas)
Ph2
P

H2
N

Ph

N
H H2

Ph

Ru
P
Ph2

Very high e.e.

from very low
catalyst loadings

H2 , solvent

Mechanism

Ph
O

Me

Ph2
P
P
Ph2

H
Ru
H

HO H

H
N
N
H2

Ph
OH

Me

Ph

Ph

H2

Ph2
P
P
Ph2

Ru
H

N
N
H2

Ph

Ph

25

Asymmetric catalysis Isomerisation

Ph2
P
Rh
PPh2

NMe2

NMe2

[Rh/S-BINAP]
Isomerisation (not a reduction!)

H
H
ZnBr2
OH

then H2, Ni cat (to reduce alkene)

H
O

R-citronellal, 96-99% e.e.

(-)-menthol
26

Asymmetric catalysis Organocatalysis (no metals)

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

this is not a
chiral centre
O
O

Now this IS a chiral centreS configuration

L-proline
10 mol%:

N
H

CO2H

O
Major product
O

The enantiomeric
compound is:

Mechanism is via: O

O
N
O
HO2C

27

Asymmetric catalysis Organocatalysis (no metals)

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

L-proline

Aldols:
O

10 mol%:

N
H

Me

Me

90% yield

CO2H

OH
4:1 anti:syn

H
Me

DMF

Me

anti product e.e.: 99%

and even more complex ones:

OtBu
20 mol%
O

H2N

H
TBSO

OTBS

O
CO2H

O
O

OH

3 mol% water, rt 2 days.

TBSO

OTBS O

68%, major product: D-fructose

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

28

Asymmetric catalysis Organocatalysis

Other applications
Other applications include:
Diels-Alder reactions:
O

catalyst

catalysed by:

R
L-proline

Asymmetric reductiions:
O
H H

or pyrrolidines:

CO2Et catalyst

EtO
+ 2C

Ph

N
H

Ph

N
H

(Hantzsch esterhydride source)

catalyst
+

R
O

R
Can you work out the mechanisms?

Ph

Ph

N
H

Ph

or other N-heterocycles:
O
NMe

and oxidations:
O

CO2H

N
H

O
R

Ph

N
H

CO2H

29

Asymmetric catalysis Enolate alkylation

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

10 mol% (i.e. 01 eq.) Catalyst

(below), 50% NaOH-toluene

Cl

CH3Cl

MeO

Cl

Cl

98% yield
94% e.e.

MeO

H O H

several steps
N

Catalyst: N
Cl

Cl
MeO
The enolate is formed
by deprotonation by
hydroxide.

CF3

Cl

Cl
Enolate is methylated
on the front face
(as illustrated)

O
CO2H

indacrinone

30