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55RESONANCE ! February 2002

GENERAL ! ARTICLE

Ever since the time of L ouis Pasteur (1822-1895), stereochemis-

try played an important role in the advancement of science. If

Pasteurs landmark deduction that the formation of optically

active organic compounds during the spoilage of wine is due to

a biological process, led to his discovery of microbes, his resolu-

tion of sodium ammonium tartrate based on the shapes of the

crystals led to the idea of requirement of non-superimposablemirror image relationship for an organic compound to be opti-

cally active. In the ensuing years, J H vant Hoff (the first

Chemistry Nobel L aureate 1901, for his work on osmotic pres-

sure)1 and J A Le Bel recognised that attachment of four differ-

ent groups around a tetrahedral carbon atom would lead to non-

super imposable mirror images and discovered the tetrahedral

geometry of organic compounds in 1874 (Box1). A similar idea

helped A Werner (Chemistry Nobel L aureate 1913) to elucidate

the geometrical structures of co-ordination compounds (Box2).

Over the years, several scientists who made immense contribu-

tions to stereochemistry were honoured with the award of the

Nobel Prize D H R Barton and O Hassel (Nobel L aureates

1969, conformational analysis), J W Conforth and V Prelog

(Nobel L aureates 1975, stereochemistry of enzymatic and or-

ganic reactions), C J Pederson, D J Cram and J M L ehn (Nobel

L aureates 1987, molecular and chiral recognition). The 2001Nobel Prize was awarded to W S K nowles, R Noyori and K B

Sharpless for their pioneering work on the development of

catalytic asymmetric reduction and oxidation processes.

Many of the compounds associated with living organisms are

chiral, for example DNA, enzymes, antibodies and hormones.

Thus, the enantiomers of limonene both formed naturally, smell

2001 Chemistry Nobel Prize

Continuing Importance of Stereochemistry

M ari appan Per i asamy

KeywordsKeywordsKeywordsKeywordsKeywords

Stereochemistry, chirality, asym-

metric catalysis.

After a postdoctoral stint atPurdue University, USA

(with H C Brown),

Mariappan Periasamy has

been in the faculty, School

of Chemistry, University of

Hyderabad. His research

interests are in the

development of organome-

tallics and chiral reagents

for applications in synthetic

processes. Recently, as a

hobby, he has initiated a

project on the conversion of

Farm waste to chemical

feedstocks with an

objective of developing

sustainable, renewable and

environmentally benign

energy sources.

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56 RESONANCE ! February 2002

GENERAL ! ARTICLE

differently (Box3) as our nasal receptors are made up of chiral

molecules that interact with these enantiomers differently.

Clearly, biology is very sensitive to chirality and most drugs

consist of chiral moieties. Since a drug must match the receptor

in the cell, often only one of the enantiomers is of interest. In

certain cases, the other enantiomer may be harmful. The story

of the effect of the drug thalidomide is a test case (Box3). In the

early 1960s, the racemic derivative was prescribed to alleviate

morning sickness in pregnant women. Tragically, the drug also

caused deformities in the limbs of children born to these women.

It seems that one enantiomer of thalidomide was beneficialwhile the other caused birth defects. Therefore, pharmaceutical

companies nowadays have to make sure that both enantiomers

of a drug are tested for their biological activity and toxicity

before they are marketed. Obviously, there is a strong demand

for the pure enantiomer required. It is in this context that the

discoveries of the 2001 Chemistry Nobel L aureates have great

significance since the catalytic processes discovered by them are

useful in the efficient manufacture of chiral compounds. A brief

C

H3C

COOH

OH

H C

COO H

CH3HO

H

S-lactic acid R-lactic acid

Box 1.

Co

NH 2

H2N Cl

NH 2

ClH2N

Co

NH 2

Cl NH 2

NH 2

NH 2Cl

Box 2.

Optical isomers ofcis-dichlorobis (ethylen-

ediamine) cobalt (III) ion. The correspond-

ing trans isomer will have a plane of symme-

try and hence will not be optically active.

1 Sridhar Gadre, Century of No-

bel Prizes, Resonance, Vol.6,

No.12, 2001.

Representation of the tetrahe-

dral arrangements of groups in

R- and S-enantiomers of lactic

acid (mirror images of each

other). The bond shown by full

lines lie in the plane of the

paper, and

denotes bonds projecting in front

and back of the plane of the

paper.

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GENERAL ! ARTICLE

review of asymmetric synthesis and the contributions of the

2001 Nobel L aureates will be of interest.

Generally, chemical synthesis of asymmetric compounds results

in racemic mixtures, i.e., 1:1 mixture ofRand Senantiomers

that are mirror images (Boxes1-3). I f the organic substrate

already has an asymmetric centre, stereoselectivity may be an-

ticipated as realised in the addition of nucleophiles to carbonyl

compounds. The diastereomers are now formed in unequal

amounts and the results can be rationalised by Crams rule 2 [1]

(Box4) (D J Cram, 1987 Chemistry Nobel L aureate).

In the nucleophilic addition reaction to carbonyl compounds of

the type shown inBox4, the product contains both the new and

old asymmetric centres and it is not easy to retrieve an asymmet-

ric compound containing only the new asymmetric centre from

this product. However, in the case of nucleophilic addition toa-

keto esters, the product can be readily hydrolysed to obtain the

corresponding asymmetric organic product (Box5). The major

product that would be formed can be predicted with the aid of

Prelogs rule 3 [2] (V Prelog, 1975 Chemistry Nobel L aureate).

N

O

O

NH

O

O

H

N

O

O

HN

O

H

O

Box 3.

Whereas the S-thalido-

mide alleviates morning

sickness in pregnant

women, the R-thalido-

mide causes deformities

in the limbs of children

born to these women.

R- (+) - limonene S - ()-limonene

Smells of oranges Smells of lemons

S- thalidomide R-thalidomide

2 Cramss Rule:Cramss Rule:Cramss Rule:Cramss Rule:Cramss Rule: Nucleophilic

attack on the asymmetric car-

bonyl compound takes place

from the side of the smallest

group attached to the asym-

metric carbon atom.

3 Prelogs Rule:Prelogs Rule:Prelogs Rule:Prelogs Rule:Prelogs Rule: Nucleophilic

attack on the carbonyl group

takes place from the side of the

medium sized methyl group

(backside) in preference attack

from the side of the larger octyl

group.

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GENERAL ! ARTICLE

C2H5

Ph

CH3C2H5

O

1. CH3Li

2. H2O

CH3-Li

Attack prefered

Attack not prefered

C2H5

Ph

CH3C2H5

CH3HO

C2H5

Ph

CH3

C2H5

OHH3C

Major product Minor product

Box 4. Crams Rule

1. CH3MgBr

2. H2O

Major product Minor Product

Ph

O

O

O H

C6H13CH3

Ph O

O

H

C6H13

CH3

CH3HO

Ph O

O

H

C6H13CH3

OHH3C

Ph O

OHCH3HO

Ph O

OHOH

H3C

Hydrolysis

CH3-MgBr

R-isomer S-isomer

Major product Minor product

Box 5. Prelogs Rule

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GENERAL ! ARTICLE

In the above-mentioned asymmetric syntheses, the asymmetric

centres are created because of the presence of asymmetric carbon

atoms in the starting organic substrates. H C Brown (1979

Chemistry Nobel L aureate) discovered a new type of asymmet-

ric synthesis through hydroboration-oxidation of prochiral ole-

finic substrates in which the asymmetric induction is due to the

asymmetric borane reagent, Ipc2BH (Box6) [3]. In this way, the

corresponding alcohols containing asymmetric centre were ob-

tained in very high levels of selectivity (high enantiomeric

excess, e.e.)

The hydroboration-oxidation was the first non-enzymatic trans-

formation in which very high levels of enantioselectivities were

realised. A drawback is that the valuable borane reagent cannot

be recycled as the isopinocampheyl group is also oxidised in this

transformation.

Although several such stoichiometric asymmetric reagents have

been developed over the years, there have been sustained efforts

towards the development of asymmetric synthetic methods that

would require only catalytic amounts of chiral moieties. The

first breakthrough in this field came in 1968 through the work of

the 2001 Nobel L aureate, Knowles who showed that a chiral

CH 3CH 3

H 3B:THF

Ipc2BHCH 3H 3C

H H

CH 3

H 3C

Ipc 2BO

H CH 3

H3C

HO

HH2O 2/N aO H

Ipc2BH

S-(-)-2-Butanol

>90% ee

(+)--Pinene2BH

(>95% ofSisomer and < 5% ofR isomer)

Box 6.

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GENERAL ! ARTICLE

transition metal based catalyst could transfer chirality to a non-

chiral substrate in asymmetric hydrogenation, resulting in chiral

product with one of the enantiomers in excess [4]. The discov-

ery of the Wilkinson catalyst (Ph3P)

3RhCl in the 1960s

(G Wilkinson, 1973, Chemistry Nobel L aureate) as a homoge-

neous hydrogenation catalyst helped K nowles in making chiral

Rh catalysts using optically active phosphines. K nowles dem-

onstrated that the rhodium catalyst prepared using (-)-methyl-propylphenylphosphine (69% ee) gave a modest asymmetric

induction (15% ee) in the hydrogenation ofa-phenylacrylic acid

(Box7) [4].

Soon Knowles group at the Monsanto Co, USA came up with a

process using the cationic rhodium complex containing the

bidentate phosphine ligand, DiPAMP, for the manufacture of

L -DOPA, which had proved useful in the treatment of

Parkinsons disease (Box8). Thus, the spectacular success ofthis L-DOPA synthesis has significantly contributed to the

explosive growth of research aimed at the development and

application of other catalytic asymmetric reactions in ensuing

years.

In 1980, the other 2001 Chemistry Nobel L aureate, Noyori

discovered the atropisomeric C2 chiral diphosphine BINAP

HPh

HOOC H

P

H3CH 2CH2C

CH 3

(-)-methylpropylphenylphosphine, 69% ee

Rh-(-)-MPPP complex catalyst

H2

CH CH 3

Ph

HOOC

(+)-hydrotopic acid

15% ee

(-)-MPPP

Box 7.

The spectacular

success of this L-

DOPA synthesis

has significantly

contributed to the

explosive growth of

research aimed at

the development

and application of

other catalytic

asymmetric

reactions in

ensuing years.

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GENERAL ! ARTICLE

Rh-Catalyst=[Rh(R,R)-DiPAMP(COD)]+

BF4-

H2

100% yield, 95% ee

COOH

NHCOCH3

H3CO

H3

CCOO

COOH

NHCOCH3

H3CO

H3CCOO

H

H3O+

COOH

NHCOCH3

HO

HOH

COD

PP

OCH3H3CO

(R,R)-DiPAMP-

L-DOPA

Rh-Catalyst

(Box9) [5]. The corresponding Rh(I) and Ru(I I) complexes are

remarkably effective in several asymmetric reactions [5].

Whereas the Rh(I )-BINAP complexes are useful in reactions

like asymmetric hydrogenation ofa-(acylamino)acrylic acids oresters and in the enantioselective isomerisation of allylic amines

to enamines, the BINAP-Ru(I I) catalysts have enormous scope

in several transformations, like hydrogenation ofa-arylacrylic

acids, asymmetric hydrogenation of functionalised ketones and

in selective transfer hydrogenation of carbonyl compounds in

the presence of CC double bonds (Box10).

Box 8. Knowles Monsanto Process for the Manufacture of L-DOPA.

P

P

Ph Ph

Ph Ph

P

P

PhPh

PhPh

(S) - BINP (R)-BINAP

Box 9.

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GENERAL ! ARTICLE

Box 10.

P

P

(S)-BINAP-Ru(OOCCH3)2

Ru

Ph Ph

Ph Ph

O

O

O

O

P

P

(R)-BINAP-RuX2

RuX2

Ph Ph

Ph Ph

X=Cl, Br, I

P

P

(S)-ArBINAP-Ru(diamine)

Ru

ArAr

Ar Ar

Cl

Cl

H2N

NH2

Ar=3,5-(CH3)2C6H3, Ar=p-CH3O-C6H4

(S)-BINAP-Ru(OOCCH3)2(0.5 mol %)

H2

/MethanolH3CO

COOH

H3CO

COOH

CH3

92% yield, 97% ee

(S)-naproxen

an anti-inflammatory agent

HOCH3

O (R)-BINAP-RuX2

H2

Catalyst HOCH3

OH

(R)-1,2-propanediol

Used in the manufacture of

antibacterial levoflaxacin

(S)-ArBINAP-Ru(diamine)

Catalyst

(CH3)2CHOH, K2CO3 90% eeVitamine E building block

Ar

Ar

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GENERAL ! ARTICLE

Powerful tools for achieving catalytic asymmetric oxidation of

olefinic groups were discovered by the other 2001 Chemistry

Nobel L aureate, Sharpless [6, 7]. In 1980, Sharpless group

discovered the catalytic asymmetric epoxidation of allylic alcohols

using titanium tetraisopropoxide, tert-butyl hydroperoxide andan enantiomerically pure dialkyl tartrate (Box11) [6]. This

powerful reaction is highly predictable. When theD(-)-tartrate

ligand (D-(-)-DET) is used in epoxidation, the oxygen atom is

delivered to the top face of the olefin when the allyl alcohol is

depicted as shown in Box11. The epoxy alcohols produced in

this way are versatile synthetic intermediates. For example, (S)-

and (R)-glycidol and (S)- and (R)-methylglycidol have been

R1

R2

R3

OH

"O"

"O"

D-(-)-DETCOOC2H5

COOC2H5

HO

HO

L-(+)-DET

COOC2H5

COOC2H5

HO

HO

R1

R2

R3

OH

O

R1

R2

R3

OH

O

D-(-)-DET

Ti(OiPr)4

t-BuOOH, CH2Cl24A

mol. sieves, -20 0C

L-(+)-DET

Ti(OiPr)4

t-BuOOH, CH2Cl24A

mol. sieves, -20 0C

L-(+)-DET

CH3

H

OH

H3C

CH3

CH3

H

OH

H3C

CH3

O

(70-90% yield, >90% ee)

R1

R2

R3

OH

"O"

"O"

D-(-)-DETCOOC2H5

COOC2H5

HO

HO

L-(+)-DET

COOC2H5

COOC2H5

HO

HO

R1

R2

R3

OH

O

R1

R2

R3

OH

O

D-(-)-DET

4A

mol. sieves, -20 0C

L-(+)-DET

Ti(OiPr)4

t-BuOOH, CH2Cl24A

mol. sieves, -20 0C

L-(+)-DET

CH3

H

OH

H3C

CH3

CH3

H

OH

H3C

CH3

O

Box 11.

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GENERAL ! ARTICLE

produced in ton-scale in industry for the manufacture ofb-

blockers used in the treatment of heart diseases.

Catalytic asymmetric dihydroxylation of olefins is another ma-

jor transformation discovered by the Sharpless group [7]. They

discovered that that the cinchona alkaloid derivatives give pro-

nounced ligand accelerated catalysis (i.e. the OsO4reacts faster

Ph

Ph

acetone/H2O

N

H3CO

RCOO

HH

N

N

H3CO

H

OOCR H

N

DHQD-OCR DHQ-OCR

Os

O

OO

O

Os

O

OO

O

L= DHQD-OCR

L= DHQ-OCR

Ph

Ph

OO

OsO

OL

L

Ph

Ph

OOOs

O O

OsO4 (0.2%)

NMO

NMO

Ph

Ph

HO

OHNMO (1.2 equiv.)

Ph

Ph

HO

OH

Os

O

OO

O

L

Os

O

OO

O

LNMO =O N O

CH3

>95% ee

(0.13 equiv.)

(0.13 equiv.)

L

L

Box 12.

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GENERAL ! ARTICLE

with olefins upon co-ordination with quinidine or quinine de-

rivatives), producing asymmetric diols from olefins using cata-

lytic amounts of OsO4and the chiral ligand and stoichiometric

quantities ofN-methylmorpholine oxide or K3Fe(CN)

4(Box

12). In recent years, new ligands and improved proceduresappeared, making the Sharplesss catalytic asymmetric dihy-

droxylation an extremely useful reaction [7].

In addition to being useful in the manufacture of compounds of

medical importance, the discoveries of the 2001 Chemistry

Nobel L aureates are also useful in the production of agro-

chemicals including pheromones, flavours, fragrances and sweet-

ening agents. Moreover, their work gives access to new mol-

ecules, thereby contributing to more rapid advances of research not only in chemistry but also in material science, biology and

medicine.

Inspired by the achievements of the 2001 Chemistry Nobel

L aureates in catalytic asymmetric reduction and oxidation pro-

cesses, there have been enormous efforts by scientists on the

development of catalytic asymmetric CC bond forming pro-

cesses that further widen scope of catalytic asymmetric synthe-

ses. Also, in recent years there have been remarkable advance-

ments on efforts towards amplification of chirality in asymmet-

ric catalysis (i.e., obtaining higher ee of the product using a

ligand with lower ee) and asymmetric autocatalysis (i.e., a chiral

compound catalysing its formation). These developments are

relevant to the origin of homochirality, which is prevalent in

Nature but continues to remain a mystery. Hence, the field of

stereochemistry continues to be one of the challenging and

rewarding areas of research.

Suggested Reading

[1] D J Cram and F A A Elhafez,J . Am. Chem. Soc., Vol.74, p.5828, 1952.

D J Cram and J D Knight, J . Am. Chem. Soc., Vol.74, p.5835, 1952.

[2] V Prelog,H elv. Chim. Acta., Vol .36, p. 308, 1953.

[3] H C Brown, N R Ayyangar and G Zweifel, J . Am. Chem. Soc., Vol. 86,

p.397, 1964.

[4] W S Knowles and M J Saba-

cky,Chem. Commun., p.1445,

1968.

W S Knowles, Acc. Chem.

Res., Vol.16, p.106, 1983.

[5] A Miyashita and others, J .

Am. Chem. Soc., Vol.102,p.7932, 1980.

T Ohta, H Takaya and R

Noyori, I norg. Chem., Vol.

27, p.566, 1988.

M Kitamura and others,J .

Am. Chem. Soc., Vol.110,

p.629, 1988.

T Ohkuma and others, J .

Am. Chem. Soc., Vol.117, p.

2675, 1995.

[6] T Katsuki and K B Sharp-

less, J . Am. Chem. Soc.,Vol.102, p. 5974, 1980.

[7] E N Jacobsen and others,J .

Am. Chem. Soc. , Vol.110, p.

1968, 1988.

H C Kolb, M S Van Nie-

uwenhze and K B Sharpless,

Chem. Rev., Vol.94, p.2483,

1994.

[8] M B Smith and J March,

Advanced Organi c Chemis-

t r y, 5th edition, Wiley

Interscience, NY, 2001.[9] F A Carey and R J Sundberg,

Advanced Organi c Chemis-

t r y, 3rd edition, Plenum

Press, NY, 1990.

[10] E L Eliel and S H Wilen,

Stereochemi str y of O rgani c

Compounds, John Wiley and

Sons, Inc., NY, 1994.

Address for Correspondence

Mariappan Periasamy

School of Chemistry

University of Hyderabad

Central University PO

Hyderabad 500046, India.

Email:[email protected]

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Feb2002p55-65