this presentation describes ways to enantiomeric product synthesis, hence introducing to chiral catalysts. the temperature effects are discussed with relation to soai autocatalysis. it shows introduction to stereocartography.

1. Chiral Catalyst
natural products were
optically active, while
compounds prepared in
a laboratory were not
: ‘‘. . .one needs to use
dissymmetric forces, to have
recourse to solenoides, to
dissymmetric movements of
light, to the action of
substances themselve
dissymmetric..’’.
Enantiomers
were separately
prepared using
chiral catalysts
and auxiliaries
Submitted by
Roshen Reji Idiculla
ID MS 14/11

2. Why is there a need for controlling
the stereochemical outcome of
synthesis ?
• In a chiral environment, one enantiomer may display different chemical and
pharmacologic behavior than the other enantiomer.
Easson-Stedman hypothetical interaction (three-point-attachment paradigm )
between the two enantiomers of a racemic drug with a receptor at the drug binding
sites. in 1933 used, to rationalize enantioselectivity at adrenergic receptors.

4. Trends in the development of chiral
drugs
• US in 1992 by Policy Statement for the Development of New Stereoisomeric Drugs
• European Union (EU) in 1994 by Investigation of Chiral Active Substances
the total worldwide distribution of 730
approved drugs in 1983–2002 (including 382
in 1991–2002) and the US distribution of 304
FDA approved drugs (NMEs) in 1991–2002
according to their chirality character.
• 1983–2002 - single-enantiomers exceeded
achirals ; racemates are at 23% of
worldwide approved drugs.
• single-enantiomer drugs popularised
since 1998, reaching 50% of all approved
drugs for the first time in 1998, rising to
60% between 2000–2001.

5. Strategies for the synthesis of
enantiopure compounds
In 1980 Prof. Seebach coined the term "EPC-synthesis" (synthesis of enantiomerically
pure compounds) • Resolution of racemates
• chiral pool synthesis- Synthetic transformations
from an enantiomerically pure starting compound
• Stereoselective reactions -enantiopure reagent as a
source of chirality, in stoichiometric (auxiliary) or
catalytic amounts, which is not included in the
final product.

6. Chiral pool
approach
• Amino acids such as proline (1a) and phenylalanine (2a) and derivatives and
peptide-like enzyme mimics such as 3 or 4 are used in enantioselective catalytic
reactions,

7. Catalysts from chiral pool sources
used in asymmetric synthesis.
CBS (Corey-Bakshi-Shibata) catalyst from S-proline

9. The entire reaction can be summarised as

10. Racemic synthesis and the subsequent
separation of the enantiomers (resolution of
racemates)
• Here racemic acids (using an amine as the resolving agent) and bases (using an
acid as the resolving agent) can be separated.

11. Dynamic kinetic resolution (DKR) enables
100% of a racemic compound to be
converted into an enantiopure compound.
KR of secondary allylic alcohols using Sharpless Asymmetric Epoxidation, mediated
by a titanium (IV) isopropoxide catalyst, t-butyl hydroperoxide (TBHP) as terminal
oxidant, and a chiral diethyl tartrate (DET).

13. So what does the “ MIGHTY
ASYMMETRIC CATALYSIS” means ?
• In 1904 Marckwald in a paper entitled ‘‘Ueber asymmetrische Syntheses’’ defined
‘‘Asymmetric syntheses are those reactions which produce optically active substances
from symmetrically constituted compounds with the intermediate use of optically
active materials but with the exclusion of all analytical processes’’
• In 1971, Izumi proposed to divide the asymmetric synthesis into two classes: the
diastereoselective reactions and the enantioselective reactions.(Y. Izumi, Angew.
Chem., Int. Ed. Engl., 1971, 10, 871.)

14. Diastereoselective synthesis using a
chiral auxiliary
Allyl boron reagents mediated synthesis of homoallylic alcohols,

15. Enantioselective synthesis using a
chiral auxiliary
Evans auxillary-controlled Diels-Alder reaction

16. Enantioselective synthesis using chiral
catalyst• substrate in enantioselective synthesis is achiral and contains at least one
prostereogenic unit.
• A chiral reagent or a chiral catalyst differentiate the two enantiotopic faces or
groups of an achiral molecule, providing the preferred formation of one
enantiomer of the product.
• Example is Noyori Asymmetric Hydrogenation. Simple ketones like 11-15 can be
reduced enantiselectively. The system involves a chiral BINAP-RuCl2 pre-cursor, a
chiral 1,2 diamine ligands 7-9 and an alkaline base.

17. • In transfer hydrogenation, hydrogen donor is different from H2 (e.g., propan-2-ol,
HCO2H/NEt3 mixture, HCO2Na/water etc.) . HCO2
- - hydrogen donor.
• Noyori, Ikariya and co-workers discovered the novel (pre)catalysts, trans-[RuCl2{(S)-
binap}{(S,S)-dpen}] 16 and (S)-RuCl[(R,R)-XCH(Ph)CH(Ph)NH2](η6-arene) [X = NTs,
O] 17
trans-[RuCl2{(S)-binap}{(S,S)-
dpen}] 16 can be represented as

18. • In the transition state, the ketone (e.g., acetophenone) orients to minimize
the non-bonded repulsion between the phosphine Ar group and the phenyl
ring of the ketone, and to maximize the electronic NH/π attraction

20. Developing new catalysts based on the prototypes
16 and 17.
• The nitrogen containing chelating ligand directly participates in the act of proton
transfer (in concert with hydride transfer from the metal) via its N–H group, so a
chelating diamine with at least one N–H functionality is needed for activity.
• The chiral ruthenabicyclic complex (R)-RUCY-XylBINAP developed by Takasago
Int. Corp. (acetophenone into (S)-1-phenylethanol with >99% ee )
• Zhou’s chiral iridium catalyst Ir-SpiroPAP bearing a tridentate ligand with an N–
H functionality (acetophenone at 25–30 °C producing the product in 91% yield
and 98% ee, ) are based on the prototypes 16 and 17.

21. 1st industrial application of asymmetric
hydrogenation - Monsanto Process
• was developed by Knowles and co-workers at Monsanto, (Monsanto Process )
using cationic rhodium complex having DIPAMP [Rh(R,R)-Di-
PAMP)COD]+BF4
-,
• for producing the rare amino acid L-DOPA (used to treat Parkinson’s disease)
• The L-DOPA synthesis is based on asymmetric hydrogenation reaction of
enamides, to form chiral amino acid in 95% ee,

22. Green shows (R,R-
Di-PAMP) and
blue shows the
solvent molecules

23. Information on the mechanism of
diastereo or enantioselectivity.
Selectivity is mainly a kinetic phenomenon.
It is influenced by
 reaction conditions,
 steric and/or electronic features of catalyst/substrate.

24. Eyring equation gives k(rate of formation) of T.S = (kBT/h)exp(-G#/RT)
• If k1’ and k2’ are very small with respect to k1,
k2, k-1,k-2, selectivity depends on the free
energy difference between transition states
T.S.1 and T.S.2.
• So
[𝑅 𝑖𝑠𝑜𝑚𝑒𝑟]
[𝑆 𝑖𝑠𝑜𝑚𝑒𝑟]
= exp(
− 𝐺#
𝑅𝑇
) = ratio of
diastereoisomeric products .
• lower the temperature, greater the selectivity
(based on Curtin-Hammet equation).
• But here oxidative addition
of H2 is rate limiting step,
and irreversible, and
enantioselection is
determined at this step.
• k1’ and k2’ are very larger and
non-linear relationship
between selectivity and
temperature was observed.
• So, G# = H - TS.
• S between 2
diastereomeric states is
usually small.

25. • ln
𝑘1′
𝑘2′
=
− 𝐺#
𝑅𝑇
=
− 𝐻#
𝑅𝑇
+
 𝑆#
𝑅
, selectivity (ratio of product formation rates )
• reaction temperature determines the sign of the specificity.
• G# = 0, at isokinetic T, where isoinversion (observed selectivity can be
inverted) occurs.
• A value of G# between 2.5 and 3.0 k cal/mol may result in 98–100% ee,.
• G# of about 12 kJ/mol give a fully stereospecific reaction
By substracting activation
parameters for high and low T
regions,
δH = ΔΔH2 – ΔΔH1
δΔΔS2 = ΔΔS2 – ΔΔS1

26. Temperature and autocatalysis in
aiding the homochirality of nature
Asymmetric nonlinear effects denotes a nonlinear
relationship between the enantiomeric purity of the
catalyst (eecatalyst) and the enantiomeric purity of the
product (eeprod).
eeprod = ee0 *eecatalyst
ee0 = ee in reaction product obtained using enantiopure
reagents

27. Asymmetric Amplification in DAIB catalysed
dialkylzinc addition to aldehyde

28. Mutual antagonism –inhibiting the
enantiomer

29. Soai’ asymmetric autocatalysis

30. 2 intermediates are formed

33. Asymmetric catalysis – A novel
chemistry to win the Nobel
Prize – 2001

34. Transition metals used in chiral
catalysts
• Ability to form five or more chemical bonds.
• They often have multiple accessible oxidation states (of similar energies).
• The tendency to accept electron pairs, forming coordination compounds.

35. Why was Rh used in Monsanto
Process instead of other transition
metals?

36. Alkene substrates best used for
asymmetric hydrogenation

37. Types of chirality in chiral catalysts-
The chirality of the complex catalyst is due to the presence of a chiral
ligand in most cases.
Central Chirality
Type Catalysis
Axial Chirality
Type Catalysis
Planar Chirality
Type Catalysis
Helical Chirality
Type Catalysis

38. Stereocartography (the mapping of
stereodiscriminating regions around a chiral
catalysts) - using quadrant diagrams
Place the catalyst’s center of mass at the origin of a Cartesian coordinate system and
place a uniform three-dimensional grid around that catalyst.
Then it is translated accordingly to 2D plane . The shaded diagonal quadrants
represent space that is occupied by substituents on the ligand that extend forward,
whereas the unshaded rectangles correspond to less-occupied space.

39. Then it is translated accordingly to 2D plane . The shaded diagonal quadrants
represent space that is occupied by substituents on the ligand that extend forward,
whereas the unshaded rectangles correspond to less-occupied space.
Binding of the prochiral faces of an olefin to
a metal, for example, would give rise to
diastereomers in which the more-stable
diastereomer contains the R1 and
R′ substituents positioned in the open,
unshaded quadrants

40. Select the transition state of the molecules reacting in the presence of the catalyst.
At each grid point, a large number of orientations of the probe molecule relative to the
catalyst are sampled deterministically and intermolecular energy is computed for that
particular grid point
Repeat these calculations at all grid points for the (R) probe and its antipodal (S) form.
Grid points with little or zero energy difference are deemed to be non-
stereodifferentiating. Contrarily, those grid points with large energy differences between
mirror image probes are considered to be enantiodiscriminating.

41. Studying Diels Alder reaction using
Quadrant Diagrams

42. Conclusion
The importance and practicality of asymmetric synthesis as a tool to obtain
enantiomerically pure compound is attributed mainly to explosive
development of chiral catalysts and the more efficient methods to study their
reaction mechanisms. Chiral catalysts are a boon to organic synthesis.