Asymmetric synthesis notes

Asymmetric synthesis
Dr. G. Krishnaswamy, DOS & R in Organic Chemistry, TUT Page 1
Enantiomeric Excess
For non-racemic or Scalemic mixtures of enantiomers, one enantiomer is more abundant
than the other. The composition of these mixtures is described by the enantiomeric
excess, which is the difference between the relative abundance of the two enantiomers.
Enantiomeric excess (% ee) =
[R] - [S]
[R] + [S]
= % R - % S
% R + % S = 100
The fraction of the main isomer and minor isomer can be calculated by using the
following formula
% ee
50% Major =
2
% ee
50% Minor =
2
+
-
Optical Purity = Enantiomeric Excess
Enantiomeric excess = Optical purity x 100 =
Observed rotationof mixture
Specific rotation of Pure enantiomer
x 100
Diastereomeric Excess
This is defined by analogy with enantiomeric ratio as the ratio of the percentage of one
diastereoisomer in a mixture to that of the other.

Many of the transformations you will encounter have the potential to create multiple
products – isomers – from a single starting material. The reactions could form a mixture
of constitutional isomers (i.e. regioisomers), diastereomers, or enantiomers.
“Selective” implies that there are factors which favor one product over the other,
while “specific” is usually a sign that there’s something inherent to the mechanism that
leads to only one product.
Regioselective reactions - This is where a starting material forms two (or more)
structural isomers, and one predominates. A good example is Markovnikoff addition of
water.
Stereoselective reactions - a reaction where one stereoisomer of a product is formed
preferentially over another. The mechanism does not prevent the formation of two or
more stereoisomers but one does predominate.
If a chemical reaction produces the two enantiomers of a chiral product in unequal
amounts it is as an enantioselective reaction.

If a stereogenic centre is introduced into a molecule in such a way that diastereoisomers
are produced in unequal amounts the reaction is Diastereoselective.
Stereospecific reactions - A stereospecific reaction is one which, when carried out with
stereoisomeric starting materials, gives a product from one reactant that is a stereoisomer
of the product from the other. 'Stereospecific' relates to the mechanism of a reaction, the
best-known example being the SN2 reaction, which always proceeds with inversion of
stereochemistry at the reacting centre.
If the reaction starts with a chiral material the reaction will be enantiospecific.

If the reaction forms only one diastereoisomer it is diastereospecific.
ALL stereo selective reactions are stereo specific but All stereo specific reaction are not
stereo selective.
Stereo selective reactions Stereo specific reactions
A stereo selective reaction is a reaction in
which there is a choice of pathway, but the
product stereoisomer is formed due to its
reaction pathway being more favourable
than the others
A stereo specific reaction is a reaction in
which the stereochemistry of the reactant
completely determines thte stereochemistry
of the product without any other option
Can result in multiple products Gives a specific product from a certain
reactant
Selectivity of the reaction pathway depends
on differences in steric an electronic effects
Final product depends on the
stereochemistry of the reactant

An asymmetric synthesis refers to a reaction which yields exclusively or predominantly
only one of a set of chiral stereoisomers of compound by the action of a chiral reagent or
auxiliary acting on heterotopic (enantiotopic or diastereotopic) faces, atoms or groups of
a substrate.
In a compound with “n” non identical chiral centres, 2n
chiral stereoisomers are possible.
An asymmetric synthesis yields one of these 2n
stereoisomers predominantly or
exclusively without involving any racemate resolution step.
OR
Asymmetric synthesis refers to the selective synthesis of one of the isomer of chiral
product having a centre or a axis or helical chirality predominantly.

Why we always need a chiral component to achieve asymmetric synthesis?
The answer is if both reactant and reagent ate achiral resulting transition state is
enantiomeric and results in racemic products.
Achiral carbonyl compound in the presence of an achiral nucleophile:
The two faces (Re and Si) of the achiral compound are enantiotopic. The nucleophile
can attack either face leading to two possible transition states. If the nucleophile is itself
achiral then these two transition states are enantiomeric and therefore equal in energy.
The two enantiomeric transition states lead to the formation of the two enantiomeric
products in equal amount, in which case a racemic mixture is formed. In other words, if
there is no chiral information in the reaction, then a racemic mixture will always result.
Chiral carbonyl compound in the presence of an achiral nucleophile:
If the carbonyl compound is including within its structure a stereogenic centre, the two
faces of the carbonyl group are now diastereotopic and no longer enantiotopic. Therefore

these two transition states are different in energy and consequently, one of the two
diastereomers will be formed preferentially.
Achiral carbonyl compound with a chiral nucleophile:
The two faces of the carbonyl compound are enantiotopic and the nucleophile can attack
either one. However since the nucleophile is chiral, the two transition states for these two
reactions must be diastereomeric. Therefore the reaction leads to the preferential
formation of one diastereomer as the two diastereomeric transition states are not equal in
energy.
Hence, asymmetric synthesis takes place via diastereomeric transition states and takes
advantage of the difference in energy between these two transition states in order to
obtain predominantly one product.
All asymmetric reactions are stereoselective reactions but stereoselective reactions where
products are achiral are not asymmetric reactions.

Asymmetric synthesis or reaction is further classified into
(1) Enantioselective asymmetric synthesis
A reaction step where one chiral center is generated predominantly such
asymmetric reactions are said to be enantioselective asymmetric synthesis.
An essential feature of an enantioselective synthesis is that the reactant must be
prochiral with one or more Sp3
or Sp2
prochiral centres.
(2) Diastereoselective asymmetric synthesis
A reaction where two chiral centres are generated in a single step, four possible
isomers are formed i.e. RR, SS, RS & SR out of which exclusive formation of one
isomers take place are said to be Diastereoselective asymmetric synthesis.
An essential feature of Diastereoselective synthesis is that the reactant/s is chiral
and enantiopure with one or more prochiral units.

Asymmtericsynthesis
Chiralreagent
controlled
Prochiralreactant
+
Chiralreagent
(1:1)
Diastereoselective asymmetric
synthesis
Enantioselectiveasymmetric
synthesis
Chiralcatalyst
controlled
Prochiral reactant
+
Achiralreagent
+
Chiralcatalyst
(1:1:<1)
Substrate
controlled
ChiralAuxiliary
+
Achiralreagent
Chiralreactant
+
Achiralreagent
(1:1)
Chiralreactant
+
Chiralreagent
(Match /
Mismatch)
Chiralreactant
+
Achiralreagent
+
Chiralcatalyst
(1:1:<1)
Overview of asymmetric synthesis

Asymmetric Epoxidation / Sharpless Asymmetric Epoxidation (SAE)
In 1980, Sharpless and Katsuki reported enantioselective conversion of primary and
secondary allylic alcohol into 2, 3-epoxy alcohol with stoichiometric amount of
Titanium (IV) tetraisopropoxide (Ti(Oi
Pr)4) and chiral catalyst diethyl tartarate (DET) in
presence of oxidizing agent terbutylperoxide (t-BuOOH) in dichloromethane (CH2Cl2) at
-20o
C. Only one enantiomer is formed and it depends on the stereochemistry of catalyst.
Reaction:
Primary /
Secondary
allylic alcohol
: t-BuOOH
Ti-tartarate
complex
Chiral
Epoxy Alcohol:
Molecular Sieves
3Ao
CH2Cl2, -20o
C
(Prochiral) (Achiral) (Chiral)
Optically active ligand diethyl tartarate:
O
O
O
O
OH H
H OH
(-)-(S, S) diethyl tartarate
D-(-)-DET
O
O
O
O
H OH
HO H
(+)-(R, R) diethyl tartarate
L-(+)-DET
Essential components of Sharpless asymmetric epoxidation
(1) Titanium tetraisopropoxide [Ti(OiPr)4]
(2) Chiral enatiopure ligand
D-(-)-Diethyltartarate [(-)-DET]
L-(+)-Diethyltartarate [(+)-DET]
(3) Molecular sieves, 3Å
(4) Epoxidation reagent-Tertiarybutylhydroperoxide [TBHP]
(5) Reactant-Prochiral allylic alcohol

Mechanism:
R1 CH2OH
R2 R3
(+)-DET
(-)-DET
Oxygen arrives from
below the plane
Oxygen arrives from
above the plane
R1
R2
O
CH2OH
R3
OR1 CH2OH
R2 R3
Enantiomers
General rule of thumb:
Alcohol group right hand side with (+)-DET epoxide formed below
(-)-DET epoxide formed above
Alcohol group left hand side with (+)-DET epoxide formed above
(-)-DET epoxide formed below
EtO2C O
OEtO2C
CO2EtO
O CO2Et
Ti
Ti
OiPr
PrOi
OiPr
OiPr
The tartrate and metal form a complex:
O
CO2EtO
O CO2Et
Ti
Ti
O O
O
OH
OH
O
O
CO2EtO
O CO2Et
Ti
Ti
O
O
O
O OH
OH
2 x iPrO ligands
replace the departing product
hence the catalyst is regenerated.
The substrate
and oxidant
replace two
OiPr ligands.
product
side-product
The oxygen atom is
directed to the alkene.
The alkene is above the peroxide.

Examples:
C8H17
OH
Ti(OiPr)4
(+)-DET
t-BuOOH
DCM, -20o
C
C8H17
OHO
OH
Ti(OiPr)4
(-)-DET
t-BuOOH
DCM, -20o
C
OHO
Asymmetric Dihydroxylation or Sharpless Dihydroxylation or Bis
hydroxylation
The Sharpless Dihydroxylation or Bishydroxylation is used in the enantioselective
preparation of 1,2-diols from prochiral olefins. This procedure is performed with
an osmium catalyst and a stoichiometric oxidant [K3Fe(CN)6 or N-methyl morpholine
oxide (NMO)]; it is carried out in a buffered solution to ensure a stable pH, since the
reaction proceeds more rapidly under slightly basic conditions.
Enantioselectivity is achieved through the addition of enantiomerically-enriched chiral
ligands [(DHQD)2PHAL & (DHQ)2PHAL]. These reagents are also available as stable,
prepackaged mixtures (AD-mix-α and AD-mix-β, AD = asymmetric dihydroxylation)
AD-mix-β:
K2OsO2(OH)4, K2CO3, K3[Fe(CN)6], (DHQD)2PHAL
NN
O O
N N
O O
NN

AD-mix- α:
K2OsO2(OH)4, K2CO3, K3[Fe(CN)6], (DHQ)2PHAL
NN
O O
N N
O O
N
N
General rule of thumb:
Identify S = Small, M = Medium and L = Large group.
M L
S
Clockwise
DHQD / AD-mix-beta adds OH from top
DHQ / AD-mix-alpha adds OH from bottom
L M
S
Anti clockwise
DHQD / AD-mix-beta adds OH from bottom
DHQ / AD-mix-alpha adds OH from top

Mechanism:
Initial step of Sharpless dihydroxylation is the formation of the osmium tetroxide –
ligand complex (2). Followed by a [3+2]-cycloaddition with the alkene (3) gives the
cyclic intermediate (4). Basic hydrolysis of intermediate liberates the diol (5) and the
reduced osmate (6). Finally, co-oxidant (K3 [Fe(CN6)]) regenerates the osmium tetroxide
– ligand complex (2).
Regioselectivity
In general Sharpless asymmetric dihydroxylation favors oxidation of the more electron-
rich alkene.

Chiral Auxiliary
A chiral auxiliary is a chemical compound or unit that is temporarily incorporated into
an organic synthesis so that synthesis is carried out asymmetrically with the selective
formation one of two stereoisomers.
Chiral auxiliaries are optically active compounds that temporarily incorporated into an
organic compound in order to control the stereo chemical outcome of the synthesis.
One of the most utilized auxiliary in asymmetric synthesis is chiral Oxzolidinones
pioneered by Evans.
O N
O O
R
Bn
There are a number of useful ways of removing the oxazolidinone unit.

O N
O O
R
E
R
E
R
E
R
E
PhH2CO
O
HO
O
HO
LiOH, MeOH
LiAlH4
PhCH2OLi
Stereoselective Aldol reaction:
When an aldehydes or ketone having atleast one α-hydrogen are treated with dilute base
gives β-hydroxy aldehydes (Aldehyde + Alcohol = Aldol) or β-hydroxy ketones (Ketone
+ Alcohol = Ketol).
Base catalyzed mechanism of aldol reaction
There will be formation of two stereogenic centers in the aldol product and hence it leads
to formation of four stereoisomers.
E or Z - enolate are produced stereoselectively using hindered bases such as LDA or
dialkylborontriflate. In ketones cis-enolate favoured if R is large but trans-enolate
favoured if R is small

Z-enolates (Thermodynamic) gives predominantly syn aldol products.
E-enolates (Kinetic) gives predominantly anti aldol products.
Most aldol reactions take place via a highly order transition state know as the
Zimmerman–Traxler transition state.

Why Z-enolate / Cis-enolate favours syn product because there is no steric repulsion in
the favoured transition state

E-enolate / Trans-enolate favours syn product because there is no steric repulsion in the
favoured transition state
Evan’s Aldol reaction:
Asymmetric aldol reaction of aldehyde and Evans chiral auxiliary (acyl oxazlidineone)

Chiral Reagents
To control the introduction of chirality regardless of any already present in the substrate.
This can be achieved by chiral reagents.
BINAL-H is a chiral reagent
Example is the enantioselective reduction of ketones with BINAL-H
Me
O
(S)-BINAL-H
Me
OHH
Mechanism:
General rule of thumb
➢ (S)-BINAL-H gives the (S)-enantiomer of alcohol
➢ (R)-BINAL-H gives the (R)-enantiomer of alcohol.

X
EWG
R'
O
R
X = O, NH
EWG = -COOH, -COOR", -CN
Asymmetric Hydrogenation of Alkenes
Reduction of an alkene by addition of hydrogen to one of its two enantiotopic faces can
give all sorts of products crating either one or two chiral centres depending on the
substituents on the alkene.
Homogeneous hydrogenation of alkenes with Wilkinson’s catalyst to become
asymmetric, achiral phosphine ligands should be replaced with chiral phosphine ligand
in the catalyst. The usual solution is to use one chiral molecule containing two
phosphorus atoms and the most important which meets these criteria is BINAP.
Incorporating (R) or (S)-BINAP into a homogeneous hydrogenation with Rh / Ru metal
can lead to high enantiomeric excess in the products because during the migratory
insertion step the complex is forced to transfer hydrogen to only one of the two possible
enantiotopic faces of alkene.
For Rh catalysts, general substrate structure:
• Enamides
• Acrylic acids
• Allylic alcohols

Reactions:
HN
COOH
CH3
O
HN
COOH
CH3
O
H2
(S)-BINAP
Rh(ClO4)2
H
(R)-Amino acid derivative
Noyori found that using Ru metal instead of Rh broadens the scope of the substrate that
will undergo asymmetric hydrogenation. They still need a functional group usually the –
OH group of an alcohol (or) a carboxylic acid.
OH
OR3
R2
R1
H2
(R)-BINAP
Ru(OAc)2
H2
(S)-BINAP
Ru(OAc)2
OH
OR3
R2
R1
OH
OR3
R2
R1
H
H
H
H
OH
R3
R2
R1
H2
(R)-BINAP
Ru(OAc)2
H2
(S)-BINAP
Ru(OAc)2
OH
R3
R2
R1
OH
R3
R2
R1
H
H
H
H
Two important industrial asymmetric hydrogenation syntheses are the production of the
pain killer (S)-Naproxen and the synthetic intermediate and perfumery compound (R)-
Citronellol.

H2
OH
H2
O
OH
MeO
(S)-BINAP
Ru(OAc)2
O
OH
MeO
(S)-BINAP
Ru(OAc)2
OH
(S)-Naproxen
(R)-Citronellol
NMR Spectroscopy and Stereochemistry
A working knowledge of NMR spectroscopy can give both conformational and
Configurational information.
The chemical environment around a proton can be determined from chemical shifts.
Chemical shift and coupling constant data give information regarding the relative
stereochemistry of diastereomers.
Chemical Shifts
Diastereotopic protons will have different chemical shifts, this will only tell you that
diastereomers are present, cannot necessarily tell which is which by inspection only by
comparison to known structures.
Spatial orientation may place certain protons in shielding/deshielding portions of
functional groups.
A proton or a group of protons which are coplanar with aromatic ring, C=C, C=O
groups are deshielded while the protons which are held above their pi electron clouds are
shielded.
Due to anisotropic effect of the σ bond
stereochemistry determination on the basis of
chemical shift

Coupling Constants (J)
It helps to deduce which isomer we are observing by analysing the magnitude of the
coupling constants values.
Determination of Absolute Configuration
Several different methods available
Two main strategies:
(1) chiral solvating agent – chiral solvent or additive (e.g. shift reagent)
(2) chiral derivatizing agent – chiral auxiliary

1. Chemical Shift Reagent
These are the agents used to cause shift in the NMR spectra.
The amount of shift depends on,
➢ Distance between the shift reagent and proton.
➢ Concentration of shift reagent.
The advantages of using shift reagents are
➢ Gives spectra which are much easier to interpret.
➢ No chemical manipulation of sample is required.
➢ More easily obtained.
Paramagnetic materials can cause chemical shift, e.g., Lanthanides.
➢ Complexes of Europium, Erbium, Thallium and Ytterbium shift resonance to
lower field.
➢ Complexes of Cerium, Neodymium and Terbium shift resonance to higher field.
Europium is probably the most commonly used metal to cause shift in the NMR spectra.
Two widely used complexes of Europium are
1. Tris (dipivalomethanato) europium(III) [Eu(dpm)3] and
2. 1,1,1,2,2,3,3-heptafluoro-7,7-dimethyl-octanedionatoeuropium(III) [ Eu( fod)3].
Almost all organic functional groups that are Lewis bases have been found to respond to
these reagents. When the shift reagent is chiral, it can complex with enantiomers and
generate separate resonances from which enantiomeric ratios may be obtained.

2. Chiral Derivatizing Agents
Requirement to act as Chiral Derivatizing Agents are
• Polar or bulky group to ﬁx a particular conformation.
• A functional group to allow for attachment of substrate.
• A group able to produce an efﬁcient and space-oriented anisotropic effect –
Shields/deshields L1 and L2 in each diastereomer.
Chiral derivatizing which fulfils the above criteria is Mosher’s acid
OH
F3C
Ph OMe
O
(R)-MTPA
MTPA = Methoxy Trifluoro Phenyl Acetic acid
IUPAC Name of Mosher's acid
(R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid
(S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid
OH
F3C
MeO Ph
O
(S)-MTPA
Mosher analysis with MTPA
H
C
HO
L2
L1
O
F3C
Ph OMe
O H
C
L2
L1
O
F3C
MeO Ph
O H
C
L2
L1
(R)-MTPA
(S)-MTPA
1
H, 13
C NMR
1
H, 13
C NMR
• Ph of (R)-MTPA shield L2 ligand
• Ph of (S)-MTPA shields L1 ligand

The sign (+ or –) of ΔδL1 and ΔδL2 allows for determination of conﬁguration of the
compound.

Asymmetric synthesis notes

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Asymmetric synthesis notes