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. Submitted by Roshen Reji Idiculla IIRBS M.G.UNIVERSITY , KOTTAYAM,
KERALA
I express my sincere gratitude to Prof. Kenso Soai (Department of Applied Chemistry, Faculty of
Science Tokyo University of Science)for his valuable advices and corrections in this document.
Cover Page
We can see an organic chemist (let his name be Mr.A) complaining that “natural
products were optically active, while compounds prepared in a laboratory were not” .
Mr.A then hears about the legend of Louis Pasteur . In 1848Pasteur discovered that a
solution of tartaric acid salt (sodium ammonium tartrate) extracted from wine (having
the known dextrorotatory tartaric acid ) rotates plane-polarized light , but that the same
(racemic) compound, when synthesized in the laboratory, did not. The laboratory-
prepared tartrate formed crystals were mirror images of each other (they are hemihedral )
by crystallizing a supersaturated solution of racemic sodium ammonium tartrate below 28
ºC.
Using a magnifying glass and a pair of tweezers, he separated the two types of crystals
,which when dissolved in water, rotated the plane of polarized light in equal amounts, but
in opposite directions. When heating one of the pure enantiomers in basic water the
compound lost its optical activity and reformed the racemate. Pasteur also noted that the
two enantiomers (the known dextrorotatory tartaric acid and the unknown levorotatory
tartaric acid, both having the same melting point) rotated the light in equal amounts, but
in opposite directions, and that a 1:1 mixture of the two did not produce any rotation
because optical activity of one molecule cancelled the effects of the other molecule.
When heating one of the pure enantiomers in basic water the compound lost its optical
activity and reformed the racemate.
So Pasteur decided that the molecules (that are enantiomers or mirror images) were
responsible for creating crystals which are mirror images.
So the laboratory preparation of a chiral compound produces a 1:1 mixture of
enantiomers in the absence of other optically active compounds (usually an
enantiomerically enriched chiral element ). {I call any geometrical figure, or groups of
points, chiral, and say it has chirality, if its image in a plane mirror, ideally realized,
cannot be brought to coincide with itself.” – Lord Kelvin}

2. Pasteur was lucky enough to study a lucky case involving conglomerates. In fact, just
only 5-10% of all racemates are known to crystallize as mixtures of enantiopure crystals
(so is the case of α – Methyl-L-Dopa).
In 1882 he demonstrated that by seeding a supersaturated solution of sodium ammonium
tartrate with one of its enantiomers crystallized preferably the same enantiomer he used
as a seed. This is preferential crystallization (also called resolution by entrainment).
In 1860 Pasteur documented, in his lecture in stereochemistry, that many natural
products were optically active, while compounds prepared in a laboratory were not. As a
solution,he said: „„. . .il faut chercher a` faire agir des forces dissyme´triques, a` recourir
a` des actions de solenoı¨des, de mouvements dissyme´triques lumineux, a` des actions de
substances elles-meˆmes dissyme´triques. . .‟‟. This sentence can be translated as: „„. .
.one needs to use dissymmetric forces, to have recourse to solenoides, to dissymmetric
movements of light, to the action of substances themselves dissymmetric..‟‟.
Nowadays modern organic researchers have the enantiomers separately prepared using
chiral catalysts and auxiliaries, so we are here to discuss what chiral catalysts are, and
how they perform efficiently.
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 themselves
dissymmetric..‟‟.
Enantiomers
were separately
prepared using
chiral catalysts
and auxiliaries

3. The need for stereospecificity of reaction.
Why is there a need for controlling the stereochemical outcome of synthesis (Especially
in drug systems) ?
Enantiomers of a chiral drug have identical physical and chemical properties in an achiral
environment. In a chiral environment, one enantiomer may display different chemical and
pharmacologic behavior than the other enantiomer. Because living systems are
themselves chiral, each of the enantiomers of a chiral drug can behave very differently in
vivo. In other words, the R-enantiomer of a drug will not necessarily behave the same
way as the S-enantiomer of the same drug when taken by a patient. For a given chiral
drug, it necessary to consider the 2 enantiomers as 2 separate drugs with different
properties unless proven otherwise.
This model represents the interaction between a chiral drug and its chiral binding site
(proteins, nucleic acids, and biomembranes like phospholipids and glycolipids). Here,
one enantiomer is biologically active while the other enantiomer is not. The portions of
the drug labeled A, B, and C must interact with the corresponding regions of the binding
site labeled a, b, and c for the drug to have its pharmacologic effect. The active
enantiomer of the drug has a 3-dimensional structure that can be aligned with the binding
site to allow A to interact with a, B to interact with b, and C to interact with c. In contrast,
the inactive enantiomer cannot bind in the same way no matter how it is rotated in space.
Although the inactive enantiomer possesses all of the same groups A, B, C, and D as the
active enantiomer, they cannot all be simultaneously aligned with the corresponding
regions of the binding site.
Sometimes, the inactive enantiomer can bind to another binding site causing harmful
pharmacologic effect.

4. Easson-Stedman
hypothetical
interaction
between the two
enantiomers of a
racemic drug
with a receptor
at the drug
binding sites.
So US Food and Drug Administration (FDA) demands the assessment of each enantiomer
activity for racemic drugs in body and encourages the development of new chiral drugs as
single enantiomers.
The term enantiomer is derived from the Greek word for enemy, εχθρóς,
Aspartame is a potent sweetener with (S,S) configuration, while (S,R) diastereomer has
bitter taste.

5. Reference : Stereochemistry in Drug Action Prim Care Companion J Clin
Psychiatry. 2003; 5(2): 70–73.
Trends in the development of chiral drugs
The improvements in stereoselective bioanalysis led to a new progress in stereoselective
pharmacodynamics and pharmacokinetics, enabling the differentiation of the relative
contributions of enantiomers to overall drug action. A single-enantiomer drug can be
pharmacologically interesting whereas its mirror image can be inactive or display a
different desirable or non-desirable activity. Considering these possibilities, there
appears to be major advantages in using stereochemically pure drugs, such as a reduction
of the total administered dose, enhanced therapeutic window, reduction of intersubject
variability and a more precise estimation of dose–response relationships. These factors
placed stereochemically pure substances in a privileged position.
Regulatory control of chiral drugs began in the US with the publication in 1992 of formal
guidelines on the development of chiral drugs in a document entitled Policy Statement for
the Development of New Stereoisomeric Drugs and was followed in the European Union
(EU) in 1994 by Investigation of Chiral Active Substances . Applicants must diagnose the
occurrence of chirality in new drugs, attempt to separate the stereoisomers, assess the
contribution of the various stereoisomers to the activity of interest and make a rational
selection of the stereoisomeric form that is proposed for marketing.
Chiral switches are drugs that have already been claimed, approved and/or marketed as
racemates or as mixtures of diastereomers, but have since been redeveloped as single
enantiomers.

6. Figure here illustrates 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.
An overall look at the 20-year period from 1983–2002 indicates that single-enantiomers
exceeded achirals whereas racemates represented the minority category at 23% of
worldwide approved drugs. The majority of single-enantiomers was probably driven by
the tide of approved single-enantiomer drugs that occurred since 1998.
In the four-year period from 1983–
1986 (Figure 3), more racemic drugs (32%) were approved compared with single
enantiomer drugs and achiral drugs exceeded both categories of chiral drugs. Single
enantiomers reached 50% of all approved drugs for the first time in 1998, rising to 60%
between 2000–2001.
These trends were probably influenced considerably by the guidelines of the regulatory
agencies in the major jurisdictions, which favored and encouraged, but did not force, the
development of single-enantiomer drugs over racemates , thus accounting for the
dramatic shift of pharmaceutical company interest in manufacturing the safer single
enantiomer and achiral drugs over the problematic racemic drugs. Single enantiomers
took over as the leading category in 2001 (60%) compared with achirals (40%) and
racemates (0%).
Strategies for the synthesis of enantiopure compounds focused on organocatalysis
In 1980 Prof. Seebach coined the term "EPC-synthesis" (synthesis
of enantiomerically pure compounds) to embrace all the processes for the
preparation of chiral enantiopure compounds.

7. The methods used to access enantiomerically pure compounds can be divided into three
categories depending on the type of starting material used.
 Resolution of racemates.
 Synthetic transformations from an enantiomerically pure starting compound. In the
particular case of an easily available natural compound it is called chiral pool
synthesis.
 Stereoselective reactions that involve an enantiopure reagent as a source of
chirality, in stoichiometric (auxiliary) or catalytic amounts, which is not included
in the final product.
In chiral pool approach, chiral source is a natural enantiopure compound whose
stereochemistry will be incorporated into the final the final product (the desired final
product and the chiral compound used are structurally similar).

8. reference http://remotecat.blogspot.in/2015/01/
Amino acids such as proline (1a) and phenylalanine (2a) and derivatives have been used
for a long time in enantioselective catalytic reactions, and peptide-like enzyme mimics
such as 3 or 4 are recently developed.
Both pseudoenantiomeric forms such as quinine 5a and quinidine 6a of cinchona
alkaloids and their derivatives produced impressive results in enantioselective catalytic
reactions.

9. This example shows how catalysts from chiral pool sources are used in asymmetric
synthesis.
CBS (Corey-Bakshi-Shibata) catalyst from S-proline

10. Methyl-substituted oxazaborolidines (B-Me) were more stable and easier to prepare than
the extremely air and moisture-sensitive original B-H analogs. The a rigid bicyclic
(proline based) or tricyclic structure of oxazaborolidine provides high enantiomeric
excess.
BH3 is usually incapable to reduce ketones, but can reduce amides and carboxylic
acids.The coordination of BH3 (Lewis acid) to the tertiary nitrogen atom (Lewis base) of
the CBS catalyst enhances the Lewis acidity of the endocyclic boron atom and
BH3 is activated enough to become a strong hydride donor and hence reduces ketones.
The Lewis acidic boron atom of the catalyst activates the ketone and the Lewis basic
nitrogen atom activates the borane reagent
The CBS catalyst-borane complex then binds to the ketone at the sterically more
accessible lone pair (the lone pair closer to the smaller substituent) via the endocyclic
boron atom. Here ketone and the coordinated borane in the vicinal position are cis to each
other and the unfavorable steric interactions between the ketone and the CBS catalyst are
minimal. The face-selective hydride transfer takes place via a six-membered transition
state

11. So the reaction can be summarized as

12. This was further developed into the field of using chiral oxazaborolidines as catalysts for
the enantioselective reduction of ketones by various boranes.
・Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551. DOI:
10.1021/ja00252a056
・Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988, 53, 2861. DOI:
10.1021/jo00247a044
・Catalyst Preparation: Mathre et al. J. Org. Chem. 1993, 58, 2880. DOI:
10.1021/jo00062a037
・Singh, V. K. Synthesis 1992, 605. DOI: 10.1055/s-1992-26174
・Deloux, L.; Srebnik, M. Chem. Rev. 1993, 93, 763. DOI: 10.1021/cr00018a007
・Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37, 1986.
We have seen that enantiomerically pure compounds can isolated from natural products
from the chiral pool of nature and, can be derivatized . Yet, another possibility is a
racemic synthesis and the subsequent separation of the enantiomers (resolution of
racemates). The resolution of racemates is the separation of a racemic mixture by
physical or chemical methods.
Usually, the separation is carried out after a preceding conversion of the enantiomers into
diastereomers, by treatment with an enantiomer of a chiral substance (the so-called chiral
resolving agent), because diastereomers have different chemical and physical properties
in achiral and chiral environment, whereas entantiomers cannot be separated directly
except in chiral chemical environment.
The example of resolution of 1-phenylethylamine (α-methylbenzylamine) using tartaric
acid, shows resolution via salt formation (ionic bonds). Here racemic acids is (using an
amine as the resolving agent) and bases (using an acid as the resolving agent) can be
separated.

13. Kinetic resolution (KR) utilizes different chemical properties of the racemic starting
materials.and different reaction rate of the enantiomers with a chiral non racemic
catalysts and reagents. The maximum chemical yield for this process is 50% for each
enantiomer and one of them is chemically modified. But the maximum chemical yield
for the desired enantiomer is 50%.
Dynamic kinetic resolution (DKR) enables 100% of a racemic compound to be
converted into an enantiopure compound. Here interconversion of the (R) and (S)
enantiomers occurs. So the catalyst can selectively react with a single enantiomer,
providing almost 100% chemical yield.
This example shows how kinetic resolution of secondary allylic alcohols using
Sharpless Asymmetric Epoxidation.
Sharpless asymmetric epoxidation of allylic alcohols is mediated by a titanium (IV)
isopropoxide catalyst, t-butyl hydroperoxide (TBHP) as terminal oxidant, and a chiral
diethyl tartrate (DET).
The active catalytic species is considered to be the titanium dinuclear complex.( J. Am.
Chem. Soc. 1984, 106, 6430. J. Am. Chem. Soc. 1991, 113, 106.)

14. The mechanism begins with the displacement of the isopropoxide ligands on the titanium
by DET, TBHP, and finally by the allylic alcohol reagent. Oxidation of the olefin with
TBHP then occurs where the chiral DET dictates the face of attack and leads to a
steroselective epoxy alcohol. Selectivity occurs through minimum repulsion between
allylic carbon and carboxylic ester.
Either (+)- or (-)-DET gives the corresponding enantiomer of the product 2,3-epoxy
alcohol can be obtained; ie the epoxidation is totally reagent controlled. The absolute
configuration of the epoxide products depends only on the absolute configuration of the
DET ligand.
The attack of the alkene moiety along the O–O bond with the concomitant formation of
the epoxide C–O bonds occurs through transfer of an electrophilic oxygen atom to the
alkene π-system
Based on this reaction, following works were developed.
the same procedure can effect the kinetic resolution of secondary allylic alcohols

15. J. Am. Chem. SOC., Vol. 109, No. 19, 1987
Till now, we have seen how chiral catalysts influence the chiral pool approach and
kinetic resolution. But the major influence of chiral catalysts along with chiral auxiliaries
lies in the field of the „ mighty asymmetric synthesis‟.

16. The realm of applying chiral catalysts to symmetric synthesis is termed “asymmetric
catalysis”.
So what does the “ MIGHTY ASYMMETRIC CATALYSIS” means ?
Stereoselective synthesis
A chemical reaction in which new elements of chirality are introduced in a substrate
molecule.
(symmetry elements –
1. Dissymmetry: The absence of reflective symmetry elements. All dissymmetric
objects are chiral.
2. Asymmetry: The absence of all symmetry elements. All asymmetric objects are
chiral. )
This produces the stereoisomeric (enantiomeric or diastereoisomeric) products in
unequal amounts. This is known as Enantioselective synthesis, chiral synthesis
or asymmetric synthesis
(reference : IUPAC GOLD BOOK)
In 1904 Marckwald in a paper entitled „„Ueber asymmetrische Syntheses‟‟ defined
asymmetric synthesis as: „„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‟‟
Asymmetric synthesis, also called chiral, enantioselective, or stereoselective synthesis, is
a reaction or reaction sequence in which configuration of one or more new stereocenters
are selectively formed. In asymmetric synthesis an achiral molecule is enantioselectively
converted into a chiral molecule or a chiral molecule is diastereoselectively converted
into a new chiral molecule
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.)

17. In the diastereoselective synthesis a chiral auxiliary is bound to a substrate which
contains for example a keto group. The two faces of the carbonyl become diastereotopic
and may react at different rates with an achiral reagent. The mixture of diastereomers that
are formed becomes a mixture of enantiomers after removal of the chiral auxiliary.
Allyl boron reagents mediated synthesis of homoallylic alcohols, proceeds via
coordination of Lewis basic carbonyl oxygen and Lewis acidic boron . This activates
carbonyl as it is more electrophilic and weakens B–C bond, making the reagent more
nucleophilic
Alkyl substituent in pseudo-equatorial position (1,3-diaxail strain) and alkene geometry
controls the relative stereochemistry.
E-alkene gives anti product and Z-alkene gives syn product.
Enantioselective Diels-Alder - Evans auxillary-controlled Diels-Alder reaction
The Lewis acid chelates between the carbonyl groups of the dienophile which activates
the alkene and locks the conformation so that the bulky isopropyl group blocks one face

18. of the system in the s-cis conformation. Cyclopentadiene undergoes Diels-Alder reaction
on the less hindered face.
Enantioselective synthesis using chiral catalyst
The substrate in enantioselective synthesis is achiral and contains at least one
prostereogenic unit. A chiral reagent or a chiral catalyst may well differentiate the two
enantiotopic faces or groups of an achiral molecule, providing the preferred formation of
one enantiomer of the product.
The asymmetric hydrogenation using a chiral transition metal based catalyst could
transfer chirality to a non- chiral substrate such as alkenes, ketones, and imines, resulting
in chiral product with one of the enantiomers in excess .
In Noyori Asymmetric Hydrogenation of functionalized ketones catalysed by BINAP-
Ruthenium (II) Complexes (catalysts having both chiral bisphosphine and chiral diamine
ligands), discovered by Noyori and co-workers.
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.

19. In transfer hydrogenation, hydrogen donor is different from H2 (e.g., propan-2-ol,
HCO2H/NEt3 mixture, HCO2Na/water etc.) . Here HCO2
-
acts as hydrogen donor.
Noyori, Ikariya and co-workers discovered the novel and very practical (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

20. BINAP/diamine-Ru catalyst gets hydride from H2 and forms Ru- monohydride reaction
intermediate 18, and HCl. It then forms cationic 16 electron Ru amido complex species,
19 (by ligand dissociation). (The entire step can be considered as dissociative ligand
substitution, hence no change in oxidation state of metal centre occurs for 18 and 21).
The Ru atom in the 16e− amido complex cleaves H2 to form the 18e complex
20,(considered as agnostic interaction 3c-2e bond) which undergoes deprotonation from
the η 2
-H2 ligand to generate the reducing Ru dihydride 21. Only the trans-RuH2 21 is
active catalyst.
The reaction passes through a transition state 22 involving hydrogen bonding of
coordinated N-H to the ketone oxygen and simultaneous hydride transfer from Ru to
carbon (thus preventing the formation of metal alkoxide). So this is an example of
bifunctional catalyst . In the transition state, the bulky Ph group is pseudoequatorial.
Protonation of the nitrogen atom of 23 by alcoholic solvent regenerates 19, completes
the catalytic cycle.
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

21. Similarly the precatalyst 17 , in basic alcoholic solution and H2 form catalyst 24. It forms
transition state 25 with ketone thus facilitating the hydride transfer from Ru-H, to the
carbonyl carbon concurrently with a transfer of the acidic proton from N-H to the
carbonyl oxygen. This concerted process results in the formation of an alcohol product
and Ru-amido species 26.
The transition state is stabilized through the CH/π interaction. The catalysts can be
regenerated using molecular hydrogen.(there is an alternate regenerating step involving
concerted hydride
and proton transfer from 2-propanol to 26 as in transfer hydrogenation, eventhough it is
rate limiting step )

22. Catalysts with one N–H functionality were developed, giving good selectivities. 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

23. The chiral ruthenabicyclic complex (R)-RUCY-XylBINAP developed by Takasago Int.
Corp. (acetophenone into (S)-1-phenylethanol with >99% ee ) and 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.
References Dalton Trans., 2016, 45, 6756–6781
In both these reactions chiral auxiliary or catalyst is responsible for the asymmetric
induction.
1st
industrial application of asymmetric hydrogenation - Monsanto Process
1st
industrial application of asymmetric hydrogenation was developed by Knoles 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, with of (Rh(R,R)-DiPAMP)COD)+
BF4
-
as catalyst. It
on acid hydrolysis gives L-DOPA.
These catalysts work best in alcoholic solvents that can stabilize the complex and
separate the ion-pair in order to leave the metal cation naked for reactions . Methanol or
other alcoholic solvents are preferred as they allow fast shuffling of protons from and to
the catalyst.

24. In the solvate complex of catalyst precursor , olefin substrate displaces solvent
molecules, S, by ligand exchange to form a chelate-Rh complex. Here olefinic bond and
the carbonyl oxygen interact with the Rh(I) center. Rh(III) dihydride intermediate is
formed by oxidative addition of H2 to Rh.
The two hydrogen atoms on the metal undergoes migratory insertion to the carbons of the
coordinated olefinic bond through a 5 membered chelate alkyl-Rh(III) intermediate
(which is stabilized by 2o
secondary binding of the carbonyl oxygen of the amide group)
and ligand substitution by solvent molecules. { The π-bonding electrons of the olefin are
used in ζ-bond formation with a M-H ζ*. Formation of the new C-H and M-C ζ
bonds occurs simultaneously with breaking of both π-bond and H-M ζ bond through a 4-
membered transition state. }
According to the kinetic data, the oxidative addition of H2 is rate limiting step, and
irreversible, and enantioselection is determined at this step.
Olefin can be interacted through the Re face and the Si face in the enamide coordinated
complex in a ratio of about 10:1 , leading to 2 enantiomers of phenylalanine
derivatives.

25. Green shows (R,R-Di-PAMP) and blue shows the solvent mlecules.
This reaction itself gives more information on the mechanism of diastereo or enantioselectivity.
Selectivity is mainly a kinetic phenomenon, which is influenced by reaction conditions, steric
and/or electronic features of catalyst/substrate.
Eyring equation gives k(rate of formation) of a particular transition state = (kBT/h)exp(-G#
/RT)
Selectivity depends on the ratio of the rates of formation of each transition states =
= exp(-G1#
/RT) exp(-G2#
/RT) = exp
 
= exp

G #- free energy difference between transition states T.S.1 and T.S.2.

26. The difference between racemic reaction and enantioselective reaction lies in recognizing
differences in the two transition states . In a racemic reaction, both the transition states are of
equal energy and producing both R and S isomers in equal amounts to yield a racemic product.
So, G1= G2.
For improved enantioselective reactions the energy difference between the diasteroisomeric
activated complexes has to be amplified to produce larger ee. A value of G# between 2.5 and
3.0 k cal/mol may result in 98–100% ee, depending upon the reaction and G# of about 12
kJ/mol is required for providing a fully stereospecific reaction
In this case, the catalyst interacts with a chiral substrate , lowering the transition state leading to
„R‟ isomer by G# from G, whereas transition state for the formation of „S‟ product may
remain unaffected or may increase . If k1‟ (overall rate constant of the formation of the major
isomer) and k2‟ (overall rate constant of the formation of the minor isomer) are very small with
respect to k1, k2, k-1,k-2, selectivity (ratio of product formation rates ) depends only on the free

27. energy difference between transition states T.S.1 and T.S.2. So
= exp

) = ratio of diastereoisomeric products .
This gives „lower the temperature, greater the selectivity‟ (based on Curtin-Hammet equation).
But in this case, the 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. But it may
affect according to the reaction conditions.
ln =

=

+

, selectivity (ratio of product formation rates ).
H - difference of activation enthalpies betwen the competing reaction channels
S - difference of activation entropies between the competing reaction channels
Differences in enthalpy and entropy work in opposite directions; thus the reaction temperature
determines which of the two factors dominates and decides the sign of the specificity.
G# = 0, at isokinetic T, where isoinversion (observed selectivity can be inverted) occurs.
Inversion temperature is explained by a reaction pathway with at least two enantioselective steps
preferred differentially according to the temperature. Tinv is the temperature value for the
interconversion between two different solvation clusters behaving as two different molecules.
Because of the appearance of inversion temperatures (Tinv), two new sets of parameters for
T>Tinv and for T<Tinv are available which correspond to enthalpy and entropy in each of the
partial selectivity steps.
ΔΔH1 and ΔΔS1 – activation parameter in (T< Tinv)
ΔΔH2 and ΔΔS2 – activation parameter in (T> Tinv)

28. By substracting activation parameters for high and low T regions,
δH = ΔΔH2 – ΔΔH1
δΔΔS2 = ΔΔS2 – ΔΔS1
So each partial selectivity step has a dominance in activation parameters leading to the particular
diastereomeric intermediate.
Isoinversion Temperature Ti =

. Maximum and optimum selectivity if found in this T.
Hence selectivity can be correlated to a T dependent interaction of all relevant rate constants. We
can consider an example in which enantioselectivities vary with isoinversion behavior.
Temperature in aiding the homochirality of nature
Homochirality in biomolecules and nature were generated by simple organic
compounds, such as amino acids, sugars and pyrimidines, which were themselves
chiral with only one enantiomer present in nature.
The interesting question is “ how the molecules possessed unique chiral purity in nature “.
external chiral physical forces like (+) or (-)Circular polarised light (CPL was used by Kagan and
coworkers achieving a 20% ee in photolysis of racemic camphor using 99% with CPL.) and
enantiomorphous environment (like quartz block), were proposed to affect the generation of
molecular asymmetry from a racemic prebiotic environment. Next question is “how this small
imbalance in chirality in simple molecules amplified to form same chirality in biomolecules.”
This process is called asymmetric amplification.
Autocatalysis is a process in which product of a chemical reaction serves as a catalyst for its own
production. Acid catalyzed hydrolysis of an ester is an example of autocatalysis in which the
product carboxylic acid participates in the acid catalysis. Rust formation of iron is also an
example. In asymmetric autocatalysis a chiral product catalyzes its own formation selectively.
In 1953 Frank proposed that if an asymmetric system contains one enantiomer
of a primitive asymmetric catalyst which can catalyze the formation of itself and inhibit the
formation of its enantiomer, then a very small enantiomeric excess could be amplified to produce
a highly enantioenriched product. So he proposed autocatalysis as a mechanism for the
evolution of single chirality from a racemic environment (Frank, F. C. Biochim. Biophys. Acta
1953, 11, 459-463.), even though no actual reaction capable of amplifying chirality was known
at the time.
Soai reaction is the first experimental confirmation of Frank‟s theoretical reasoning of
autocatalysis as a mechanism for the evolution of single chirality from a racemic environment.
The product chiral alkanol acts as an asymmetric catalyst for its own formation, leading to
autocatalytic alkylation of pyrimidine- 5-carbaldehydes with diisopropylzinc with the same
absolute configuration as the triggering alkanol, and with significant amplification of

29. enantiomeric excess (ee) toward single chirality. (alkanol is an alkane having OH group ie..
CnHn + 1 OH eg. Methanol. Just don‟t misinterpret alcohol as the beverage, funny yeah? )
In 1979 Mukaiyama showed that the addition of diethylzinc to aldehyde in the presence of chiral
ligands gave chiral alcohols in presence of amino alcohols as chiral catalysts.
An equal amount of two enantiomers is a racemic mixture or a racemate. The enantiomeric
excess, ee (also called optical purity) gives information on the excess of one enantiomer over the
other. It can vary from 0 (100% racemic) to 1 (100% enantiopure).
Enantiomeric excess = }
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
These non-linear effects can be either positive or negative leading to a product that is of higher
or lower than predictable enantiomeric purity expected for a linear relationship of the eeprod
with the eecatalyst of the catalyst.
Autocatalysis Alone is not enough for chiral amplification.
If both enantiomers of a chiral catalyst are existing in the system and each of them catalyses its
specific production in the matching way, at the end of the reaction giving the same enantiomeric
excess as the catalyst used. This leads to linear proportionality at optimum conditions or (-)
nonlinear (asymmetric depletion)
A reasonable autocatalyst in asymmetric amplification must reproduce itself and also act as an
inhibitor for the production of its enantiomer. This is mutual antagonism. Thus a very small
enantiomeric

30. excess can be amplified to produce a highly enantioenriched product
Hence asymmetric amplification ensues when a chiral catalyst with lower ee offers a chiral
catalyst with higher ee.
Nonlinear Effects in Asymmetrical Stereoselective Reactions
Kagan introduced empirical models for NLEs mainly applied to diastereomeric interactions between
metals and chiral ligands.
Consider reaction, of

31. Monomeric dialkylzinc compounds, being sp-hybridised linear structure with relatively
non-polar carbon bonds, are almost unreactive to aldehyde; but in the presence of
certain donor-ligands, such as amino alcohols, the reactivity towards carbonyl
substrates is improved theough a bent geometry species, thus increasing the polarity of
the zinc-carbon bond
Noyori proposed that the monomeric species in the mechanism act as catalysts in his “monomer
as catalyst model”. The final alkyl transfer is the rate determining step. A linear
relationship of the eeprod with the eecatalyst of the catalyst occurs .

32. Additional arrangement of monomeric products leads either to the formation of homochiral (RR or
SS) or heterochiral (RS equivalent to SR) dimeric complexes, the dimeric species being totally
inactive. Dimerisation seizes large quantities of the minor enantiomer into a catalytically inactive
heterochiral dimer species. The monomers of major enantiomer left over , catalyses the
development of the same enantiomer resulting in chiral amplification .So (2S)DAIB { (-)-3-exo-
(dimethylamino)isoborneol } acts as a catalyst for its own production and an anti-catalyst for the
production of its optical antimer.
If RR, SS, and SR have same equilibrium concentrations are same, then neither enantiomer is
seized preferentially out. There will same enantiomeric excess between R and S, hence initial
disproportion in enantiomers is preserved, but not amplified. This is in linear proportionality.

33. Soai and coworkers developed a starting material having an amino-alcohol-moiety so
that the product could serve as the catalyst, accomplishing asymmetric autocatalysis.
The product chiral alkanol acts as an asymmetric catalyst for its own formation, leading to
autocatalytic alkylation of pyrimidine- 5-carbaldehydes with diisopropylzinc with the same
absolute configuration as the triggering alkanol, and with significant amplification of
enantiomeric excess (ee) toward single chirality. (alkanol is an alkane having OH group ie..
CnHn + 1 OH eg. Methanol. Just don‟t misinterpret alcohol as the beverage, funny yeah? )
This reaction demonstrates the temperature dependent inversion of enantioselectivity in the
asymmetric autocatalysis reaction when activated using many enantioenriched alcohols and
amines. The addition reaction of diisopropylzinc to pyrimidine-5-carbaldehyde in the presence of
enantiopure alcohols or amines gives the pyrimidyl alkanol product at 0 °C with high ee.
However, lowering the reaction temperature to −44 °C affords the opposite enantioselectivity.
(Org. Biomol. Chem., 2017, 15, 555–558).

34. This reaction involve rigid γ-amino alcohols as catalyst. This rigid structure prevents
mononuclear chelation to form the corresponding zinc alkoxide. As no monomer is
formed, no monomeric catalyst is formed.
two molecules of zinc alkoxides interact with a dimeric catalyst, indicating a tetrameric
transition state.
So the dimeric species are forming the catalysts. This was proposed earlier by Kagan in
his ML2 model.

35. 2 intermediates are formed

36. The isoinversion principle and rate studies show the formation of a tetrameric species.
This can occur through 2 transition states, each forming R and S isomers.
The addition of isopropyl group 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.

37. Major References
 R. Noyori. Asymmetric catalysis: Science and opportunities (nobel lecture 2001). Adv.
Synth. Catal., 345:15, 2003.
 Org. Biomol. Chem., 2017, 15, 555
 Soai, K.; Sato, I. Chirality 2002, 14, 548-554.
 Soai, K.; Shibata, T.; Sato, I. Acc. Chem. Res. 2000, 33, 382-390.
 Buhse, T. Tetrahedron: Asymmetry 2003, 14, 1055-1061.
 Angew. Chem. Int. Ed, 38(23):3418–3438, 1999.
 J. Chem. Soc. Chem. Com., page 1690, 1987.
 Angew. Chem. Int. Ed. in English, 30(1):49–69, 1991.
 J. Chem. Soc. Chem. Commun, pages 982–983, 1990.
 K. Soai and T. Kawasaki. Asymmetric Autocatalysis with Amplification of Chirality,
volume 284. Springer Berlin / Heidelberg, 2008.
 J.Am. Chem. Soc., 120(51):13349–13353, 1998.
 Tetrahedron Vol. 50. No. 23, pp. 6819-6824, 1994
 Angew. Chem. Int. Ed. 2008, 47, 6832 –6835

38.  J. Am. Chem. Soc. 1996, 118, 471-472
 J. Am. Chem. Soc. 2011, 133, 17878–17881
 J. Am. Chem. Soc. 2001, 123, 10103-10104
ASYMMETRIC CATALYSIS WINS
Chemistry Nobel honors Knowles, Noyori, Sharpless for chiral syntheses
Asymmetric catalysis – A novel chemistry to win the Nobel
Prize – 2001
The 2001 Nobel Prize in Chemistry was shared by three scientists Karl Barry Sharpless,
Ryoji Noyori, and William S. Knowles for devising techniques for catalytic asymmetric
synthesis using chiral catalysts to accelerate the production of single-enantiomer
compounds for pharmaceutical use and a wide range of other applications.
We have seen the brilliant examples of their work already.
According to the Royal Swedish Academy of Sciences, Stockholm, the discoveries made
by the three men "have had a very great impact on academic research and the
development of new drugs and materials and are used in many industrial syntheses of
drugs and other biologically active compounds."

39. Transition metals used in chiral catalysts
A transition element must have an incomplete d subshell in either the neutral atom or its
ions. Thus the Group 12 elements (Zn, Cd, Hg) are members of the d block but are not
transition elements. Group 12 atoms do, however, share several (structural) properties
with the transition metals and are sometimes also considered as transition-metals or post
transition-metals.
Elements towards the left of the d block are often referred to as early and those towards
the right are referred to as late.
1st
main transition series (period 4) has elements from Sc ([Ar]3d1
4s2
) to Zn
([Ar]3d10
4s2
). 2nd
main transition series (period 5) has elements from yttrium Y
([Kr]4d1
5s2
) to cadmium Cd ([Kr]4d10
5s2
). 3rd
main transition series (period 6) has
elements from hafnium Hf ([Xe]5d1
6s2
) to gold Au([Xe]5d10
6s2
).
The incomplete or partially filled d-orbitals allows the metals in the catalysts to form five
or more chemical bonds., having multiple accessible oxidation states (of similar
energies).and having tendency to accept electron pairs, forming coordination compounds.
The coordination of substrate to the metal fixes the conformation of the substrate.
To obtain a closed (by filling up the nd, (n+1)s and (n+1)p orbitals) d shell and hence a
noble-gas configuration (based on 18 electron rule), a transition metal coordinates
electron-donating ligands. The 4d- and 5d-series metals only rarely form simple M2+
(aq)
ions. the 4d- and 5d-series metals form many M(II) complexes with many ligands in very
stable d6 octahedral complexes, and in rarer square-pyramidal d6 complexes having
bulky ligands. So the 4d- and 5d-series elements often exhibit higher coordination
numbers than their 3d-series.
Palladium(II) and platinum(II) form many square-planar d8 complexes

40. The most important metals platinum, palladium, iridium, rhodium, ruthenium and
osmium comprise the „ platinum group‟ and are very useful. These can frequently form
coordinatively unsaturated 16-electron complexes and coordinatively saturated 18-
electron complexes rule. These heavier d metals have increasing stability of high
oxidation states, and easily undergo oxidative addition reactions and reductive
eliminations, hence useful as catalysts in catalytic reaction cycles. The presence of bulky
ligands stabilizes the square planar geometry and facilitates reductive elimination.
The products formed from oxidative addition to the electronegative platinum group
metals (compared to other transition metal groups )are less stable.This resistance to
oxidation is largely due to strong intermetallic bonding and high ionization
energies. Hence they easily undergo reductive eliminations. They also have have slower
migratory insertions (the electron count around the metal decreases) and slower 𝛽-
hydride elimination (increased electron count).
ζ-Bond metathesis reactions are common for early d-metal complexes where there are
not enough electrons on the metal atom for it to participate in oxidative addition.
Ru and Os can exist in oxidation states up to +8 (e.g. in OsO4), and Pd and Pt prefer the
+2 oxidation state.
Ir and Rh have not been observed in oxidation states higher than +6. the effective nuclear
charge increasing to the right in the period, stabilizes d electrons, and makes the element
less prone to oxidation.
For Rh and Ir, the most common oxidation state is +3 and, especially with π-acceptor
ligands, +1 is frequently encountered; while +2 and +5 are less common. Iridium, being
in the sixth period easily achieve higher oxidation states due to its lower effective nuclear
charge (which decreases down a group also resulting in increased polarizability or
„softness‟ of the metal).
Catalyst [Rh(R,R)-Di-PAMP)COD]+
of Knowles involves a Rh(I)/Rh(III) dihydride
mechanism, the catalyst of Noyori trans-[RuCl2{(S)-binap}{(S,S)-dpen}] progresses
through Ru(II) throughout and is classified as a monohydride hydrogenation cycle.
Rh,Pt and Pd have increased atomic size, and thus ability to coordinate more or bigger
ligands in oxidative addition . After the product is formed, the bulky ligands create
strained environment around the metal, so one of them readily dissociates to leave an
open coordination site at which a substrate can bind and undergo reaction.
Wilkinsons hydrogenation catalyst, Rh(Cl)(PPh3)3easily undergo oxidative addition to
form octahedral complex, Rh(H)2(Cl)(PPh3)3. The 3 large triphenylphosphines create a

41. strained environment around the metal, so one of them readily dissociates to leave an
open coordination site at which an alkene can bind and undergo hydrogenation.
For iridium, which is a bigger and forms stronger bonds with the phosphine ligands, the
three triphenylphosphines are much less prone to dissociate, making Ir(Cl)(PPh3)3 a poor
hydrogenation catalyst.
Co(Cl)(PPh3)3 does not act as a hydrogenation catalyst either. Cobalt, also being in
group nine and with very small space, has much lower tendency to oxidize, and thus does
not undergo oxidative addition at all.
Why was Rh used in Monsanto Process instead of other transition metals?
L M ζ-donation from the bonding electrons and L M π-back donation into the
antibonding orbital of L weakens H-H bond . If metal is electron rich, the H-H cleavage
will be homolytic, resulting in oxidative addition, increasing the formal oxidation state of
the metal by two.
By adding more electron donating or electron withdrawing ligands can vary the degree of
back-donation from the metal, hence shifting the equilibrium in either direction.
Especially, the ligand trans to the dihydrogen ligand will have a strong influence on the
degree of H–H and H– M bonding. Adding a strong ζ-donor or π-acceptor in the trans
position, stabilizes dihydrogen towards oxidative addition by decrease of L M donation
or L M back-donation respectively.

42. The “optimum” hydrogen transfer catalyst for hydrogenation reactions should be the
intermediate case, where neither the dihydride nor the dihydrogen complex is too stable.
The relative stability of M–(H)2 vs. M–(H2) is also affected by the metal atom itself,
where the stability of the hydridic species, , increases going down a group.
In the Co–Rh–Ir triad, stoichiometric hydrogenation (under Ar) of dimethyl maleate can
be achieved with [(PR3)M(H2)][PF6] (R = (CH2CH2PPh2) when M = Rh .
The cobalt complex does not undergo oxidative addition of H2 but instead undergoes
ligand substitution upon addition of the alkene. Thus, even if the dihydrogen is minimally
activated, the reaction products are the isomerized alkene and H2(g).
For the iridium complex , the stable compound [(PP3)Ir(H)2][PF6] is formed irreversibly
due to the stronger Ir-H bonds, so the reaction fails as there are no coordination sites
available for the alkene
Alkene hydrogenation requires coordination of the C=C double bond to the metal, which
is strongly directed by steric effects and in square-planar complexes. Very electron rich
metal centers cause excessive back donation hence creating an electron rich species of
metallacyclopropane. So . the alkene cannot act efficiently as an electrophile towards
hydrides and other nucleophiles,
After alkene coordinates to metal forming the η2
-alkene-metal-hydride fragment ,
new alkyl-metal complex initially has an agostic interaction (to hold on to oneself)

43. between the new C-H bond of an already coordinated ligand and the metal atom with the
newly freed up coordination site .
Then reductive elimination of the alkyl group along with another hydride ligand from the
metal, form the product alkane .Being the reverse of oxidative addition, reductive
elimination is promoted by electron withdrawing ligands that stabilize the low-valent
metal.
Alkene substrates best used for asymmetric hydrogenation
The rhodium and ruthenium diphosphine based catalytic systems are reliant on on a
secondary coordination to achieve high activity and enantioselectivity. Without the
additional heteroatom coordination, the metal-alkene complex obtains significantly more
conformational freedom and the steric environment directly around the alkene presented
by the P,P-ligands is then not enough to retain high enantioselectivity.
Since the substrate competes with alcoholic solvent molecules for coordination to the
metal, non-chelating alkenes are reduced much more slowly than alkenes bearing
coordinating functional groups. Attempts to use P,P-ligated Rh and Ru systems for
asymmetric hydrogenation of alkenes lacking an adjacent coordinating group absolutely
proven unsuccessful.
Benzene rings can (theoretically) act as coordinating groups by π-stacking with aryl-
groups from the ligands, but usually alkenes containing aromatic hydrocarbons are
considered non-coordinating.

44. Types of chirality in chiral catalysts
The area of chiral catalysts was born when Wilkinson reported a soluble Rh-based
hydrogenation catalyst [(PPh3)3RhCl], for the hydrogenation of unhindered olefins and
Knowles replaced triphenylphosphine of the Wilkinson‟s catalyst with resolved chiral
methylpropylphenyl-phosphane as a chiral ligand this led to development of several
chiral ligands like CAMP, (which was used in the industrial process of L-DOPA. Then
CAMP (88% e.e ) was improved by DIPAMP (95% e.e ). These ligands show central
chirality
Central Chirality Type Catalysis- Central chirality (point chirality) refers to chirality that
arises from the existence of chiral center(s) in sp3
C, P,S,N etc.
Kagan et al. developed a new ligand DIOP, (which showed comparable results to
CAMP) from tartaric acid, which had the chirality shifted from the phosphorus to the
backbone, thus disproving the hypothesis that a chiral phosphorus centre was
compulsory to obtain good chiral catalyst. DIOP shows axial chirality. The shift of
chirality from the phosphorus to the backbone enabled much easier synthesis of these
chiral ligands , leading to developments of ligands namely
Axial chirality Type Catalysis - arises from the existence of the non-planar arrangement
of four groups (a, b and c, d) in pairs about a chiral axis. two substituents ({a and b} or {d
and c}) are placed around an axis forming non-superimposable mirror images and have

45. restricted rotation around the axis connecting the two substituents. Here each pair
consists of two different substituents (a must be unequal to b and c unequal to d). eg.
allenes, alkylidenecycloalkanes, spiranes , adamantanes and atropisomeric biaryl
compounds wherein the aryl-aryl bond rotation is restricted due to the steric between
ortho-substituents,(biphenyl, binaphthyl etc).
Planar chirality Type Catalysis- arises from the arrangement of two subunits of a
molecule in different planes (this leads to a chiral plane), but cannot rotate due to steric or
rotational strain in the molecule. This inability to rotate through the plane causes an
inability to freely interconvert between conformations . this creates a chiral plane in
molecule.

46. Helical chirality (helicity)- a molecule posses a chiral helix instead of chiral centre. The
chirality arises from the twisting nature of the structure around a fixed line called the
helical axis.
Stereocartography (the mapping of stereodiscriminating regions around a chiral
catalysts) - using quadrant diagrams
To understand how asymmetry is transmitted from the catalyst to the substrate, it is
necessary to know the three-dimensional structure of the ligated catalyst.

47. The most common method to
transfer asymmetry from a catalyst to the substrate relies on steric biasing. Other
catalyst–substrate interactions, such as π-interactions between aromatic groups on the
catalyst and substrate, or hydrogen bonding between the catalyst and substrate, etc., can
also play important roles and may be used in combination with steric biasing.
Quadrant diagram- A generic model for steric biasing of chiral metal–ligand adducts has
been advanced to facilitate the prediction of the facial stereoselectivity in catalyst–
substrate complexes and transition states. In this model, the environment around the
metal is divided into quadrants in which the horizontal dividing line is congruent with a
plane or pseudoplane in the catalyst.
(1) 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.
(2) 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.

48. C-2 symmetric ligands halves the number of possible transition states available on coordination
with a substrate, so has reduced number of substrate –catalyst arrangements in C-2 ligands than
non C-2 systems.
Binding of the prochiral faces of an olefin to a metal, for example, would give rise to
diastereomers in which the more-
positioned in the open, unshaded quadrants
(1) Select the transition state of the molecules reacting in the presence of the catalyst.
(2) 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
(4) Repeat these calculations at all grid points for the (R) probe and its antipodal (S)
form. .
(3) 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.

49. Studying Diels Alder reaction using Quadrant Diagrams
Conclusion
The importance and practicality of asymmetric synthesis as a tool to obtain
enantioerically 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.