Chirality

1
 Chiral Molecules

Dissymmetric Molecules.
Molecules devoid of plane of symmetry, center of symmetry and
alternating axis of symmetry.

Types of Chiral Molecules

Molecules with chiral centre.

Molecules with chiral axis
Molecules with chiral plane
Helical molecules

2
 CHIRALITY

The term chiral is used to describe an object that is non-

superimposable on its mirror image.

Human hands are perhaps the most universally recognized example

of chirality.

The Left hand is a non-superimposable mirror image of the right

hand; no matter how the two hands are oriented.

3
Why bother about chirality?

4
 Chirality in Flavor & Fragrance

O
OH
O
OH HO
HO NH 2
NH 2
Asparagine
(R) Asparagine O
Sweet taste O (S) Asparagine
Bitter taste
CH 3
O CH 3
O

Carvone
S-Carvone H C CH 3 H3 C C H
Caraway flavour
H 2C CH 2

R-Carvone
Spearmint flavour

Limonene R-limonene
S-limonene
(Orange odour)
(Lemon odour)
5
Enantiomers are identical until they are placed in a chiral environment.
Nature has chosen to make all its living structures from chiral molecules
(amino acids, sugars) and has selected a single enantiomeric form of
each.

Every amino acid in our body has the S and not the R configuration and
sugars are in D-form.

The different smell and taste of the enantiomers is a result of the

stereogenic interactions in the receptors in the nose and mouth as these
are chiral.

This behaviour is similar to fitting a key into a lock-only the key designed for
a specific lock fits.

Likewise, the odour and and taste causing enantiomers fit only in the
appropriately shaped odour and taste receptors in the nose and mouth.

6
For a flavour and fragrance manufacturer, the distinction between
enantiomers of the same molecule is clearly of great importance.

When it comes to drug molecules, providing the right enantiomer in

pure form can be a matter of life and death.

7
 Thalidomide-Tragedy

O O O O
H H
N N

N H O N H O

O O
R-Thalidomide-Sedative S-Thalidomide-Teratogen

8
When a chiral drug interacts with a biological system the following
possibilities exist:

I) The distomer shows no serious side effects.

II) The distomer exhibits an undesirable side effect.

III) Both isomers have independent therapeutic value.

{Distomer is the enantiomer of a chiral compound that is less potent

for a particular action} .

9
 Chiral chemistry: Comparatively young branch of chemistry

Till the early 1990s, about 90 % of synthetic

chiral drugs were still racemic.

Regulatory changes [after 1992] have a significant effect on the

production of chiral chemicals, particularly those prepared for use in
formulated pharmaceutical and agrochemical products.

Henceforth, if molecule is chiral, only single enantiomers will be

accepted.

10
 Asymmetric synthesis

Conversion of prochiral centre to a chiral centre with unequal

formation of products.

Prochiral centre can be enantiotopic or diastereotopic.

Involvement of diastereomeric transition states is essential for

asymmetric synthesis.

11
 Asymmetric synthesis challenges

The aim of enantioselective synthesis, or catalysis, is to produce

chiral products (a single enantiomer as the ultimate goal) starting
from achiral substrates.

Three of the major approaches towards this goal are the use of
chiral catalysts, the use of chiral reagents, and use of chiral
auxiliaries.

In ideal situations only two diastereomeric transition states can be

desired, and formation of single enantiomer is achieved based on
the difference in Eact.

12
 Asymmetric synthesis challenges

Actually, the situation can be more complex: for instance, both the
substrate and the reagent can exist as a mixture of conformational
isomers, several conformations can be significantly populated, and
they can also exist in different states of aggregation or solvation,
with each of these species showing its own reactivity.

The final result is a weighted average depending on the distribution

and reactivity of the species involved, and a low stereoselectivity is
generally obtained.

13
 Asymmetric synthesis challenges

Several conformations are

usually present, with each
capable of yielding both
enantiomers.

Several diasereomeric
transition states co-exist C-1
leading to poor
enantioselectivity. C-n

S R

14
 Asymmetric synthesis challenges:
Desired situation

large diffrence
in diastereomeric
transition states
Only one
conformation

S R

15
 Asymmetric synthesis challenges

A rational approach to the control of stereoselectivity is based on

careful use of reaction parameters such as use of reagents or
catalysts possessing only symmetry elements of pure rotation,
presence of multiple ligating centers in the reagents, presence of
appropriate bonding & non-bonding interactions between the
substrate / reagent / catalyst etc.
Just as chemists of the Robinson generation worked without
concern for stereochemical factors so we, in the early days, were
working in ignorance of conformational considerations until Derek
Barton showed us the light in 1950.

Barry Sharpless, Nobel Lecture, 2001.

16
 Till 1980s practical access to pure enantiomers relied largely on
biochemical or biological methods.

However, the scope of such methods using enzymes, cell cultures,

or whole microorganisms is limited because of the inherent single-
handed, lock-and-key specificity of biocatalysts.

17
 2001 Chemistry Nobel Prize

K. Barry Sharpless
the Scripps Research Institute, La Jolla, California, USA

William S. Knowles
St Louis, Missouri, USA

Ryoji Noyori
Nagoya University, Chikusa, Nagoya, Japan,

18
If we wish to catch up with Nature, we shall need to use the same
methods as she does, and I can foresee a time in which
physiological chemistry will not only make greater use of natural
enzymes but will actually resort to creating synthetic ones.
Emil Fischer, 1902

19
 Asymmetric synthesis: Use of chiral catalyst

A chiral-substrate complex is formed initially.

During the reaction, a stereocentre is created under the influence of

chiral catalyst.

This results in a catalyst-product complex, which then dissociates to

product and catalyst.

The catalyst is not affected by the reaction and is ready to catalyze

the next transformation with a new substrate molecule.

The catalytic cycle goes on until the reaction is complete or the

catalyst becomes inactive due to catalytic poisoning.

20
 Asymmetric synthesis: Use of chiral catalyst

Substrate + Catalyst Catalyst-substrate complex

(achiral) (chiral) (chiral)

Reaction

Catalyst + Product Catalyst-product complex

(chiral) (chiral) (chiral)

21
 Sharpless epoxidation

Oxidation of allylic alcohol with tert-butylhydroperoxide in presence of

either (+) or (-) diethyl tartarate affords the corresponding asymmetric
epoxide in high yield. Use of mol. Sieves recommended.

1) Very high enatioselection (>90% ee)

2) The absolute configuration of the epoxide produced can be

predicted.

3) Gives uniformly high asymmetric induction throughout a range of

substitution pattern.

4) Can be efficiently used for kinetic resolution.

22
 (Z)-Substituted allylic alcohols react much more slowly than the
corresponding (E)-substituted allylic alcohols.

23
Mnemonic for prediction of the stereochemical outcome

'O' (-) DET

R1
R2

R3
OH

'O' (+) DET

L-(+)-DET, Ti(Oi-Pr)4 O
OH
OH

24
 Relative insensitivity to pre-existing chiral centers

In allylic alcohols with pre-existing chiral centers, the diastereofacial

preference of the chiral titanium-tartarate catalyst is often strong
enough to override diastereofacial preferences inherent chiral
olefinic substrate.

25
 O
O
O (+)-DET O
OH > 20:1 O
15 hrs. OH
85%

O
O (-)-DET
O
> 20:1 O
OH 15 hrs.
O
OH

78%
26
 R2
R1

E O
OR
RO O O R3
Ti E E
Ti
O O O
O O
RO t-Bu

E = COOR
27
 Presence of bimetallic titanium complex is suggested

Ti aggregate with octahedral coordination complex.

Oxidation proceeds at a single Ti center.

The second Ti atom does not participate in the oxidation.

28
 OH

O O
OOH
Ti
O
O
O
A
O O
Ti
O O O O
Ti
HO O
O
O O

O
O
HO Ti O O
O
O O Ti
O
O
O
A
B
29
 Mechanism

The reaction proceeds via a Ti(IV) mixed-ligand complex A bearing

allyl alkoxide and TBHP anions as ligands.

The alkyl peroxide is electrophilically activated by bidentate

coordination to Ti(IV) center.

Oxygen transfer to the olefinic bond occurs to provide the complex

B, in which Ti(IV) is coordinated by epoxy alkoxide and t-butoxide.

In complex B, alkoxide products are replaced by allylic alcohol and

TBHP to regenerate A and complete the catalytic cycle.

30
 The Sharpless epoxidation reaction has been utilized widely in the
total synthesis.

Several advantages: high enantioseelectivity, unambiguous

configurational assignments, and epoxide offers a versatile synthon
which can be converted into great many products with predictable
stereochemistry.

31
TOTAL SYNTHESIS OF AMPHOTERICIN B
[ANTIFUNGAL AGENT]

32
 D-(-)-DET O
BnO BnO
OH Ti(O-i-Pr)4 OH
t-BuOOH
98%ee
80%

D-(-)-DET
BnO
OTBDPS OH Ti(O-i-Pr)4
t-BuOOH
60%
O Red-Al
BnO BnO
OTBDPS OH 85% OH OH
OTBDPS Me
dr : 91:9 OH
O

O NH2
Me OH

Me O OH OH OH O
HO
OH
Me O OH
OH
Amphotericin B
(Anti-fungal agent) 33
 Nicolaou, K. C., et. Al.

A. Chem. Comm., 1292-1293 (1982)

B. JACS, 109, 2205-2208 (1987).
C. JACS, 110, 4572-4685 (1988).
D. JACS, 110, 4685-4696 (1988).
E. JACS, 110, 4696-4705 (1988).

34
SYNTHESIS OF DISPARLURE, THE SEX ATTRACTANT OF THE GYPSY MOTH.

35
 D-(-)-DET n-C10H19
n-C10H19
O O
OH
OH Ti(O-i-Pr)4

t-BuOOH 91% ee (+)-Disparlure

80%

Rossiter, B. E., Kastuki, T. and Sharpless, K. B., JACS, 103, 464-465 (1981)

36
Enantioselective dihydroxylation of olefins

37
 Gradual Development..

Hoffmann in 1912 showed that osmium tetroxide could be used

catalytically in the presence of a secondary oxygen donor for the cis-
dihydroxylation.

Criegee et al reported dramatic rate enhancement for the reaction

by use of tert. Amines.

Sharpless et al first attempted enantioselective dihydroxylation using

(l)-2-(2-menthyl)pyridine as a chiral with low enatioselctivity (3-18%
ee).

38
 Classical Dihydroxylation
HO OH
H H
OsO4 , Base i) OsO4 is Highly Toxic
0C
ii) OsO4 is reqiured in 1:1 Stoichiometry

Dihydroxylation of trans-Stilbene

N N
N N
N N H N N
O O O O H
H H
MeO OMe MeO OMe

N N N N

(DHQD)2-PHAL (DHQ)2-PHAL
in AD-mix- in AD-mix-

When OsO4 is used in combination with enantiomeric ligands from plant

alkaloid, the stiochiometry of OsO4 was reduced to 0.2 -1 mole%.
Opposite sense of Stereochemical induction is achieved on switching between
the ligands. 39
Cl

H OAc
N OH
OH
N H
0.13 eqiv.

NMO (1.2 eqiv)

OsO2 (0.2 eqiv)
Acetone-Water
00 C, 15 Hrs (89%)
CH3
MNO O N -
O

40
 R R'
HO OH
O
O R
R'
R O Os
O R'
L* H2O
"O"
R' O R
O O
O first cycle second cycle
O (low enantioselectivity) Os
(high
O Os enantio- O O
O selctivity) R R'
L*
R' R
OH
HO O O O R L*
O Os
H2O O R' R'
L* R

41
Sharpless Asymmetric Dihydroxylation
Noble Prize 2001

-Diol

-Diol

Synthesis of TAXOL (Anticancer) side chain

Sharpless, B.; Amberg, W.; Bennani, Y. J.Org. Chem. 1992, 57, 2768-2771 42
P-Stereogenic Ligands in Asymmetric Synthesis

43
We felt strongly that, if one wanted to get high ee values, the
asymmetry would have to be directly on the phosphorous.
That is where the action is.
William S. Knowles, Nobel Lecture
(December 8th, 2001)

44
 Gradual Development

In 1965 Wilkinson and co-workers reported that a soluble Rh(I)

complex, [RhCl(PPh3)3], was an excellent pre-catalyst for alkene
hydrogenation under mild conditions.

The research groups led by Knowles [Chem. Commun., 1968, 1445]

and Horner [Angew. Chem. Int. Ed. 1968, 7, 942]independently
replaced the achiral triphenyl phosphine ligands in the Wilkinsons
catalyst by optically enriched P-stereogenic phosphines.

In the initial experiments the optical yields were low, but proved that
enantioselective homogeneous hydrogenation was feasible

45
 H2C COOH
H3C COOH
RhR3Cl

H2

Aryl acrylic acid 15% ee

..

R = P
Pr
Ph CH3
46
 Nobel lecture:

While grouping in this area another seemingly unrelated

development appeared, which played an important role in our
project. This was the discovery that a fairly massive dose of L-DOPA
was useful in treating Parkinsons disease.

It created a sizeable demand for this rare amino acid.

Story of a heavy infusion of naivety [a lack of experience /

wisdom]. Frequently it is not the experts that do the inventing, but
they are the ones who, that once the lead is established, come in
and exploit the area. Our work is an excellent illustration of this
phenomenon.

Wilkinsons catalyst first major step.

Development of methodology for making chiral phosphines by

Mislow and also by Horner, laid the platform.

47
 Mosanto modifications
Enhanced enantioselectivity

..
.. OMe
OMe
P
P
Ph CH3
CH3

PAMP CAMP

48
 Nobel lecture: Knowles

We had hypothesized that to get good results one needed chirality

directly on the phosphorous atom. It made sense, but Professor
Kagan showed us to be totally wrong.

Kagans discovery of DIOP was the wave of the future for a whole
series of bisphosphine ligands with asymmetry on the chiral
backbone.

49
 O
PPh2

PPh2
O

Kagan's DIOP

50
 (R,R)-DiPAMP

P P

OMe MeO

51
 Mosanto L-DOPA Synthesis

COOH COOH
Rh-DiPAMP-COD
NHAc
NHAc H2 MeO
MeO OAc
OAc

H3O+ COOH

NH2
HO
OH

52
 Efficient C2 symmetric diphosphines

R R H3C CH3

Ph2P PPh2
R
DuPhos ChiraPhos

53
 Nobel lecture: Knowles

One system which did not work well in our system was our original
model, -phenylacrylic acid. A number of these aryl propionic acids
have value as non-steroidal anti-arthritics. Here, as is the usual case,
only one enantiomer is active and thus a process to make one isomer
directly was needed. We tried hard to solve this problem even using
ruthenium-ligand systems but without success. It took Professor Noyori
with his BINAP-Ruthenium complex to solve this problem.

54
 Ph2 O
P O CH3
Ru
P O CH3
Ph2 O

(S) BINAP- Ru(OAc)2 COOH

COOH 0.5 mol %
MeO
MeO (S)- naproxen
An anti-inflamatory agent
52% yield, 97 % ee

Reference: R. Noyori, Inorg. Chem, 27, 566 (1988).

55
 Nobel Lecture: Noyori

In 1956, S. Akabori at Osaka reported that metallic Pd drawn on silk

catalyzes asymmetric (heterogeneous) hydrogenation of oximes
and oxazolones [S. Akabori*, S. Sakurai, Y. Izumi, Y. Fujii, Nature
1956, 178, 323.].

This pioneering work, though not effective synthetically, was already

well known throughout Japan.

In 1968, two years after our asymmetric cyclopropanation in 1966,

W. S. Knowles (fellow Nobel laureate in 2001) and L. Horner
reported independently the first homogeneously catalyzed
asymmetric hydrogenation of olefins with chiral monodentate tertiary
phosphineRh complexes, albeit in 315% optical yield[16].

56
 Noyori, Nozaki at Kyoto: First catalytic organometallic asymmetric
synthesis

1 mol % of
chiral Cu
Catalyst Ph COOC2H5 H COOC2H5
+
H H
H Ph
+
10% ee 6% ee
N2CHCOOC2H5

Ph
N
O Chiral Cu catalyst
Cu
O
N

Ph

57
 Industrial asymmetric synthesis of (-)-menthol

Menthol is used in many consumer products such as toothpaste,

chewing gum, cigarettes, and pharmacutical products, with an
estimated worldwide consumption estimated at 4500 tons per year.

The key step in the process is the asymmetric isomerization of N,N-

diethylgeranylamine catalysed by [Rh(S-BINAP)2]+BF4- to the
diethyl enamine intermediate in 96-99% ee.

Citronellal is obtained in 100% ee after hydrolysis; natural citronellal

has an optical puity of 80%.

The TON is improved to 4,00,000 through catalyst recycle.

58
 Industrial asymmetric synthesis of (-)-menthol

NHEt2 NEt NEt2

[Rh(S-BINAP)2]+BF4
BuLi

myrcene
N,N-diethylgeranylamine diethyl enamine intermediate

H3O
+ CHO ZnCl
2 H2

OH OH

Citronellal
(-)-menthol

59
P* N NR2
Rh C Oxidative addition P* + N
H2 Rh
P*
NR2 P*
H
Reductive
Elimination
NR2
P* N +
N Rh
P*
H

60
Optically active terpenoids produced by asymmetric isomerization
of allylamines

Name Usage EE% Production

(tons/year)
(-)-Citronellal Intermediate 96-98 1500

(-)-menthol Pharmaceuticals, 100 1000

Tobaco, Household
products

(-)-Citronellol Fragrances 98 20

(+)-Citronellol Fragrances 98 40

S-7-Methoxy- Insect growth regulator 98 10

citronellal
S-3,7-dimethyl- Insect growth 98 7
1-octanal regulator 61
CHIRAL AUXILIARIES

62
 Chiral oxazolidines

CH3
H
N Ph H
N
O
O O
O
A B

63
 O OH
OB(n-Bu)2 O OH
NaOMe
R R'CHO N R'
N MeO R'
O R
O R
O
O (C)
(A)
O OH O OH
OB(n-Bu)2 NaOMe
R'CHO Ph R' MeO R'
R N
Ph N R
R
O
O
O
O (D)
(B) Syn-aldol products with > 99% de
Use of A and B results in the
formation of enantiomeric products C and D

64
 Asymmetric Aldol

Z-enolates are used [prepared by O

using di-n-butylboron & TEA]
O N n-Bu
Stereoselectivity results from H
bidentate chelation of the boron
O B n-Bu
via a chair-type transition state
R O
Me

65
CHIRAL OXAZOLIDINONES AS CHIRAL AUXILIARIES FOR
ASYMMETRIC DIELS ALDER REACTIONS

66
 O O

R1 N O R1
R2AlCl COX

O O

R1 N O
R1
R2AlCl COX
Ph

Evans, D. A.; Chapman, K. T.; Bisaha, J., JACS, 1988, 110,

1238

67
 Ca-Si face
O R
R O Al R _
N + O R2AlCl2
N
O O H
O
Ca-Re face R

endo, Me Me
Ca-Si approach COX
COX

Evans, D. A.; Chapman, K. T.; Bisaha, J., JACS, 1988, 110,

1238

68
 Research Area Of Our Group .

We focus on synthesizing novel

chiral molecules and to study
their application various chiral
OH
discriminating processes. OH

Hetero-atoms such as Oxygen

and Nitrogen are two important
legating sites in our molecules.
N CH3

N OH
H

69
 Furo fused Binol ..

In 2007, our group publishd first report

of synthesis and application of furo
fused binol and its crown.
O
Publications..
OH
OH

70
 Moving ahead .. in target Oriented Research

O OH
O
OH
OH OH

O O

With the success of furo fused Binol , we extended our interest

in synthesizing a new hetero-helicene molecule.
BINOL to HELICENE . Just a transfer of chirality
DST, India gave us the financial support to our group to carry
out this challenging research project.

71
O
O a) NaBH4 O
O
OR b) HCl

72
Following mechanism was considered possible for the above conversion:

O OH
OR NaBH4
OR
H
O O

O H
+ R + OR
O
OH2 O

73
The reaction with l-menthol and (-)borneol, chiral maximum % ee was
99%,

New J. Chem., 2004, 28, 1420-1422.

74
 Secondary alcohols, especially with aryl substituent, generate
carbocation on treatment with acid, this can be attacked by an
internal nucleophile.

This Concept was used for some important schemes

75
 Cascade synthesis of racemic 3arylphthalides
Sudhir Patil
Indian J. Chem., 46B, 2007, 710-712

O
O O
NaBH4
R'
R' Amberlyst-15(H+)
O R
R Et

76
Cascade Enantioselective synthesis of 3-arylphthalides using
chiral auxiliary route
Suchitra Kamath, Synthesis, 2008, 1832-1834

O
O O
NaBH4 -MeOH , 00 C

O
aq. HCl , 00 C

NH
ee = 75-85%
Ar
H Me

77
 Cascade Enantioselective synthesis of -aryl- -butyrolactone
with a delayed steroselective step
Suchitra Kamath, Tetrahedron, 64, 2008, 2992-2996

It was established with HPLC data that the reduction step was not
stereoselective, the further cyclization occurs with diastereo-
selectivity.

78
O OH
H H
N Ar NaBH4 N Ar
H
O H Me O H Me

No diastereoselective
reduction based on
HPLC analysis

- 50 C - 00 C
6M HCl

ee = 67 - 73 %

79
Kinetic Resolution Of Amino Esters
R
H O R R
N H
CH3 H2N COOR' N
COOR' + H CH3
H N COOR' +
N O O H NH2
H N O O
THF
O CH3 o H
-10 C , 12 hrs CH3
(S)- Isomer PhCOCl,
Pyridine
ee = 89-92%
"Benzimidazolide" 0o C

2 R
O

N COOR'
H
H

(R)- Isomer
Unreacted aminoester
converted to N-Benzoyl amino ester

80
Benzimidazolide : A successful Chiral Auxilliary for Kinetic Resolution of
Amioesters (2005-2008)

The above chiral benzimidazolide was used for enantioselective

benzoylation of chiral racemic amines and amino esters with ee 90%

Kamath, S. S. & Karnik, A. V., J. Org. Chem, 2007, 72, 7435-7438.

Kamath, S. S. & Karnik, A. V., Tetrahedron Asymmetry 2008, 19, 45-48.

81