Asymmetric Synthesis

Prepared By
Dr. Krishnaswamy. G
Faculty
DOS & R in Organic Chemistry
Tumkur University
Tumakuru
Asymmetric Synthesis
O
O
Al
H
O
R
Li
O
R
O
O
Al
H
O
R
Li
O
R
Favored TS Disfavored TS
For
II M.Sc., III Semester
DOS & R in Organic Chemistry
Tumkur University
Tumakuru

Asymmetric synthesis
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.
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.

Achiral carbonyl compound in the presence of an achiral nucleophile

Chiral carbonyl compound in the presence of an achiral nucleophile

Achiral carbonyl compound with a chiral nucleophile

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)

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
Enantiomeric excess = Optical purity x 100 =
Observed rotationof mixture
Specific rotation of Pure enantiomer
x 100
% R + % S = 100
% ee
50% Major =
2
% ee
50% Minor =
2
+
-

50 %
R
50 %
S
Racemic mixtures
Optically Inactive
20 %
R
80 %
S
60 %
S
20 %
R
20 %
S
Percentage of the
enantiomers
60 %
S
Racemic
mixtures
Excess of S
enantiomer
1 : 1
R & S
Racemic
mixtures
Excess of S
enantiomer
OR
Optically Active
Enantiomeric excess tells us how much more of one enantiomer is present in the mixture.
Racemic mixtures are optically inactive. This is a result of rotating the plane of the light by the
two enantiomers to the same extent but opposite directions.

What is the e.e. of a solution containing 90% (+) and 10% (–)?
Enantiomeric excess (% ee) =
[R] - [S]
[R] + [S]
= % R - % S
% ee = 90% - 10%
% ee = 80%
% R = 90 %
% S = 10 %

What is the % ee of a solution with a specific rotation of –90o where the pure
solution rotates at –135o?
x 100
[α] pure = –135o
Data Given
[α] mixture = –90o
% ee =
–135o
X 100
– 90o
= 0.66 X 100
% ee = 66%

A sample of a pure R-enantiomer has a specific rotation of -40o. A mixture of R/S
enantiomers has an observed optical rotation of +22o. What is the % ee of the
mixture?
[α] pure = –40o
Data Given
[α] mixture = +22o
% ee =
– 40o
X 100
– 22o
= 0.55 X 100
% ee = 55 %
x 100
R
The sample contains 55% more of the (R) enantiomer.
Thus, there is 55 % of (R) enantiomer + 45% of 1:1 mixture of (R = 22.5%) : (S=22.5%).
Therefore, 77.5 % (R) enantiomer and 22.5 % (S) enantiomer in the mixture

If a sample is 55% ee of R stereoisomer. What is the % R in the mixture?
% ee
50% Major =
2
% ee
50% Minor =
2
+
-
% R =
2
55
50 +
% S =
2
55
50 -
% R = 27.550 + % R = 77.5
% S = 27.550 - % S = 22.5

What is the ee of a mixture containing 12.8 mol (R)-2-bromobutane and 3.2 mol
(S)-2-bromobutane?
% ee = 100
Moles of Major – Moles of Minor
Moles of Major + Moles of Minor
X
% ee =
12.8 + 3.2
X 100
12.8 – 3.2
= 0.60 X 100
% ee = 60 %

Asymmetric Induction / Enantio-induction
Internal Asymmetric induction: refers to the control of stereoselectivity exerted by
an existing chiral centre on the formation of a new chiral centre.
Relayed Asymmetric induction: refers to the control of stereoselectivity exerted by
chiral auxiliary on the formation of a new chiral centre.
External Asymmetric induction: refers to the control of stereoselectivity exerted by
chiral reagent / catalyst on the formation of a new chiral centre.
Asymmetric induction is a Key element in Asymmetric synthesis
CHIRAL POOL
CHIRAL AUXILIARY
CHIRAL REAGENT / CATALYST / LIGANDS
Induction
means
Process of
placing

Strategies of Asymmetric Induction
CHIRAL
POOL
CHIRAL AUXILIARY
CHIRAL
REAGENT
CHIRAL
CATALYST / LIGANDS
To access enantiomerically pure molecules there is need for adoption of efficient
strategies for asymmetric induction.
Collection of
enantiomerically
pure molecules
available in nature
A chiral molecular
unit that can be
temporarily
incorporated in an
achiral substrate to
guide selective
formation of one of
a possible pair of
enantiomers.
Starting material
must have
prochirality, then
chiral reagent will
be used to get
single enantiomer
Starting material
must have
prochirality,
Chiral catalyst will
be used to get
single enantiomer
Example
Natural L-amino
acids,
α-hydroxy acids
and
Natural D-sugars
Example
Chiral
oxazolidinones
Example
Alphine Borane
BINAL-H
Example
(R, R) DIOP
(S, S) CHIRAPHOS
1st generation
2nd generation
3rd generation
4th generation

BINAL-H is a chiral reagent
OH
OH
(R) - BINOL
LiAlH4
ROH
O
O
(R) - BINAL-H
Al
H
OR
Li
O
O
Al
OR
H
Li
OH
OH
(S) - BINOL
LiAlH4
ROH
O
O
(S) - BINAL-H
Al
H
OR
Li
O
O
Al
OR
H
Li
Preparation

Asymmetric reduction of ketones
(R)-BINAL-H gives the (R)-enantiomer of alcohol
O
O
(R) - BINAL-H
Al
H
OR
Li
R Un
O
Un = Aryl, Heteroaryl, alkene
alkyne
R Un
OH
H
(R) - Alcohol
Application

R Un
O
Un = Aryl, Heteroaryl, alkene
alkyne
R Un
OHH
(S) - Alcohol
O
O
(S) - BINAL-H
Al
H
OR
Li
(S)-BINAL-H gives the (S)-enantiomer of alcohol
Me
O
(S)-BINAL-H
Me
OHH
Example

O
O
Al
H
O
R
Li
O
R
O
O
Al
H
O
R
Li
O
R
Absolute configuration greatly influenced by
 Steric effect
Various electronic factors
Flexibility of molecule

Alpine borane is a chiral reagent
Preparation
THF
Reflux
H
B
9-bora-bicyclo[3.3.1]nonane(1R,5R)-2,6,6-
trimethylbicyclo[3.1.1]hept-2-
ene 9-BBN
-pinene
B
Alpine borane
Midland Reagent
H

Asymmetric reduction of ketones also known as Midland
Reduction
Application
Reaction proceeds through boat like TS

Example
B
Alpine borane
O
CH3
OH
CH3
H
H2O2
NaOH, H2O

(S)-2-PhenylButylMagnesium Chloride [(S)-PBMgCl]
Sterically hindered Grignard reagent transfer a β-H to
carbonyl group instead of undergoing nucleophilic addition
reaction.
MgCl
H
(S)-(2-phenylbutyl)magnesium chloride

MgCl
H


O
Mg
H
O
Cl
Mg
H
O
Cl
Disfavored TS Favored TS
H OH
HO H
MajorMinor
Enantioselective
hydride transfer
Highest
enantioselection
has been reported
for isopropyl
phenyl ketone
(82%)

(-) – Isobornyloxy aluminium dichloride [(-)-iBOAlCl2]
Used to reduce variety of carbonyl compounds with
enantioselection ranging from moderate to high (30-90%)
H
OAlCl2

H
OAlCl2
R
O
R' R

OH
R'
Enantioselective alcohol
Modified Meerwein-Verley-Ponndorf reduction

Chiral enantiopure ligand
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

Asymmetric Epoxidation / Sharpless Asymmetric Epoxidation (SAE)
Primary /
Secondary
allylic alcohol
: t-BuOOH
Ti-tartarate
complex
Chiral
Epoxy Alcohol:
Molecular Sieves
3Ao
CH2Cl2, -20o
C
(Prochiral) (Achiral) (Chiral)
Enantioselective conversion of primary and secondary allylic alcohol into 2, 3-
epoxy alcohol with stoichiometric amount of Titanium (IV) tetraisopropoxide
(Ti(OiPr)4) and chiral catalyst diethyl tartarate (DET) in presence of oxidizing
agent terbutylperoxide (t-BuOOH) in dichloromethane (CH2Cl2) at -20oC.
Only one enantiomer is formed and it depends on the stereochemistry of
catalyst.
Reaction

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

C8H17
OH
Ti(OiPr)4
(+)-DET
t-BuOOH
DCM, -20o
C C8H17
OHO
OH
Ti(OiPr)4
(-)-DET
t-BuOOH
DCM, -20o
C
OHO
Example

Organophosphorus compound that is used as a chiral ligand
DIOP
(2,3-O-isopropylidene-2,3-dihydroxy-1,4-
bis(diphenylphosphino)butane)
HO
EtO2C OH
CO2Et
O
EtO2C CO2Et
O
MeO OMe
C6H6, TsOH O
TsOH2C CH2OTs
O
LiAlH4
TsCl, Pyridine
O O
Ph2P PPh2
NaPPh2
Preparation

Bidentate C2 symmetric chiral biphosphine catalyst with
chirality in the carbon frame work
 
O O
P P
C2 symmetry
(R) (R)



O
O
P
P
PhPh
PhPh
(R)
(R)
Rh BF4
-
(-) - (R, R)- DIOP Rh-1, 5-
cyclooctadiene tetrafluroborate
complex
EWG
XR
O
1st Quadrant 4th Quadrant
3rd Quadrant2nd Quadrant
H
Rh
Any substituent
COOH, COOR, CO, CN
 
Structural and electronic
requirements in alkene

COOR
HNPh
O
1st Quadrant 4th Quadrant
3rd Quadrant2nd Quadrant
H
(Z)-acetamido cinnamic acid/ester
Rh-Chiral Ligand
H2 atm
COOR
HN
Ph
O
H
(R)
Asymmetric hydrogenation of (Z)-acetamido cinnamic
acid / ester

Conformation of active form of catalyst
Rh
P P
S S
Vacant Quadrant
Vacant Quadrant
Crowded Quadrant
Crowded Quadrant
Axial
Axial
Equatorial
Equatorial
Equatorial Axial
Axial Equatorial
M

Rh
P P
Vacant Quadrant
Vacant Quadrant
Crowded Quadrant
Crowded Quadrant
H
HN
O
COOR
Higher energy intermediate
(Bad fit for catalyst and alkene)

P P
Vacant Quadrant
Vacant Quadrant
Crowded Quadrant
Crowded Quadrant
Rh
H COOR
HN
O
Lower energy intermediate
(Good fit for catalyst and alkene)

(S, S) – CHIRAPHOS
(2S, 3S) – (-) – Bis(diphenylphosphino) butane
OH
OH
TsCl
OTs
OTs
LiPPh2
PPh2
PPh2
Preparation

CHIRAL AUXILIARY
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
Qualities of a Good Chiral Auxiliary
Needs to be available in both enantiomeric forms.
Needs to be easy and quick to synthesize
Must be readily incorporated onto an achiral substrate
It should provide good levels of asymmetric induction leading to high
enantiomeric excess (ee).
Needs to be selectively cleaved from the substrate under mild conditions
Must be recoverable and re-useable

Substrate Chiral Auxiliary
Substrate Chiral Auxiliary
Reaction to form new
Chiral compound
Product Chiral Auxiliary
Chiral Auxiliary
Product
Cleavage of Chiral
auxiliary
Diastereoselective
reaction

N
NH2
OMe
(R)-1-amino-2-methoxypyrrolidine hydrazine
(RAMP)
N
NH2
OMe
(S)-1-amino-2-methoxypyrrolidine hydrazine
(SAMP)
RAMP and SAMP auxiliaries used in asymmetric α-alkylation of aldehyde
and ketones
O NH
O
O NH
O
(S)-4-isopropyloxazolidin-2-one(R)-4-isopropyloxazolidin-2-one
Oxazolidinone auxiliaries used in Evans aldol reaction

Asymmetric α-alkylation of aldehyde and
ketones
Carbon–carbon bond-forming reaction via SAMP /
RAMP method
Reaction occurs through formation of Azaenolates
derived from N,N-dialkyl hydrazones an alternative
to direct ketone and aldehyde enolate alkylations.
N
NH2
OMe
(R)-1-amino-2-methoxypyrrolidine hydrazine
(RAMP)
N
NH2
OMe
(S)-1-amino-2-methoxypyrrolidine hydrazine
(SAMP)

Four Step synthesis of SAMP
S-Proline
Nitrosoamine
Intermediate
SAMP

R-Glutamic acid
Nitrosoamine
Intermediate
RAMP
Six Step synthesis of RAMP

Formation of hydrazone by reaction of SAMP with Aldehydes
Formation of hydrazone by reaction of SAMP with Ketones

Hydrazone reaction with LDA to form Azaenolate

Alkylation reaction of Azaenolate

Auxiliary removal – Two approaches
(1) Ozonolysis (O3)
(2) Quaternization with MeI followed by hydrolysis with
HCl

BELOW
ABOVE
Overall Alkylation reaction

Alkylation reaction using Chiral PTC
In a reaction a substrate in an organic phase is reacted chemically with a
reagent in another phase which is usually aqueous or solid. Since these
phases are mutually insoluble, the concentrations of the two reactants in
the same phase are too low for convenient reaction rates.
One way to overcome this difficulty is to use a solvent that will dissolve
both the species.
Another way is to use a transfer agent or catalyst which is capable of
solubilizing or extracting the reagent into the organic phase or conversely,
the substrate into the aqueous phase. Such an agent is termed a phase
transfer catalyst, and the whole process is referred to as phase transfer
catalysis.

Phase Transfer Catalysis can be defined as being
concerned with accelerating or making possible reactions
between chemical species residing in phases which are
mutually insoluble.

Two types of Phase Transfer catalysts
(i) Onium salts or Quats
Onium salts or 'quats' are quaternary ammonium,
phosphonium, sulfonium or arsonium salts. They consist
of ion pairs with a positively charged quaternary centre
Q+ and a counter ion X-.
(ii) Crown ether group of catalysts.
Crowns are defined as macroheterocycles usually
containing the basic unit (-Y-CH2-CH2)n where Y is 0, S or
N.

Asymmetric synthesis using
Chiral Phase Transfer Catalysts
1st Generation Chiral PTC - Ephedrine alkaloid salts – primarily based on
ephedrine.
2nd Generation Chiral PTC - Cinchona Alkaloids - The most intensely
studied group of catalysts has been those prepared by quaternization of
cinchona alkaloids.

3rd Generation Chiral PTC - Anthracenylmethyl Cinchona Alkaloid Quats
4th Generation Chiral PTC - Maruoka Chiral Phase-Transfer Catalyst

One of the most impressive uses of chiral PTC involves the alkylation of
6,7-dichloro-5-methoxy-2-phenyl-1-indanone with methyl chloride with
chiral catalyst. Through a systematic study of reaction conditions, kinetics
and reaction mechanism, a 92% ee of adduct was obtained.

Aldol reaction
When an aldehydes or ketone having atleast one α-hydrogen are treated with
dilute base gives
β-hydroxy aldehydes (Aldehyde + Alcohol = Aldol)
H
O
H
H
O
H

O

R1
OH
R R R
R1
O
HBase
Aldol
or
β-hydroxy ketones (Ketone + Alcohol = Ketol)
R'
O
H
R'
O
R'

O

R1
OH
R R R
R1
O
HBase
Ketol

H

O

R1
OH
R
Aldol
2n
22
4= =
H
O
R1
OH
R
1
H
O
R1
OH
R
H
O
R1
OH
R
H
O
R1
OH
R
2 3 4
There will be formation of two stereogenic centers in the aldol product and
hence it leads to formation of four stereoisomers.

Asymmetric Aldol reaction
In order to achieve stereoselectivity in aldol reaction formation of enolate plays
crucial role.
E or Z - enolate are produced stereoselectively using hindered bases such as LDA
such as LDA or dialkylborontriflate.
In ketones cis-enolate favoured if R is large but trans-enolate favoured if R is
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.
Zimmerman–Traxler
Transition state
X
OLi
Me
O
Li
O
Me
H
H
R1
X
O
Li
O
Me
H
H
R1
X
X R1
O
Me
OH
R1
O
H
Cis enolate Syn Aldol

X
OLi
O
Li
O
H
Me
H
R1
X
O
Li
O
H
Me
H
R1
X
X R1
O
Me
OH
R1
O
H
Trans enolate Anti Aldol
Me
Zimmerman–Traxler
Transition state

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

Why E-enolate / Trans-enolate favours anti product
because there is no steric repulsion in the favoured
transition state

Asymmetric Intramolecular Aldol reaction
O
O
Me
O
Me


OMe
OH
O
N
H
COOH
CHCl3, RT

O
O
Me
O
Me
O
O
Me
N MeN
H
COOH CO2
N
Me
O
O
O
H
O
N
Me
OH
O
O
O
O
Me
OH
O


OMe
OH
O
MECHANISM
Transition state is
controlled and stabilised
by OH---O hydrogen
bonding

N
Me
O
O
O
H
O
N
Me
O
O
H
O
O
Si face attack
hydrogen
bonding allows
the iminum
double bond to be
almost planar
Re face attack
hydrogen
bonding forces
the iminum
double bond out
of planarity

Michael reaction
Michael reaction is a 1,4-addition (conjugate addition) of
Nucleophile to an alpha-beta unsaturated alkene.
Nucleophile – Michael Donor
α - β unsaturated alkene – Michael Acceptor

2n
21
2= =
R
O
R1
EWG
R

O
R1
EWG
R

O
R1
EWG
Prochiral
Donor
CASE - 1

R2
Prochiral
Acceptor
EWG
R2

EWG
R2

EWG
NuH
Nu
Nu
2n
21
2= =
CASE - 2

R
O
R1
Prochiral
Donor
R2
Prochiral
Acceptor
EWG
R

O
R1
R2

EWG
R

O
R1
R2

EWG
R

O
R1
R2

EWG
R

O
R1
R2

EWG
2n
22
4= =
CASE - 3
SYN
ANTI

Asymmetric Michael reaction
Example for Prochiral Acceptor reaction with Nucleophile

Ph
O
Ph
Ph
O
Ph
1
2
H
3
H
1
2
3
Re face Si face
Ph
O
Ph
R
R
O
Ph
Ph
R
R
1
2
3
1
2
3
S R

Polymer bound Chiral Catalyst in Asymmetric Induction
Homogenously catalysed reactions have major practical limit
Difficulty in separating product from the catalyst or in
removing product.
Expensive transition metal and chiral ligand are not readily
recovered.
Hence to overcome these difficulties homogenous catalyst
have been attached to a variety of heterogeneous supports.
By doing this, the catalyst retains the selectivity of
homogeneous catalyst, still function under mild condition but
acquires essential property of insolubility.

Cave and D’Angelo have prepared polymer-supported Cinchona alkaloid
for use in asymmetric Michael addition reaction.
2-methoxy-indan-1-one and methyl vinyl ketone to get Michael product in
85% yield and 87% ee.
O
CO2Me 
O CO2Me
O
O
Prochiral Donor
N
OMe
OH
N
H
O
O
(H
2C)5
O
(R)
Polymer-supported Cinchona Alkaloid
(R)

Merrifield-supported (S)-4-(4-hydroxybenzyl)oxazolidin-2-one
O
NH
O
O
O
O O
O
N
O
O
O
O
NO
O OB
O
NO
O O
R
OH
RCHO
iPr2NEt
Solid-supported Evans’ syn-aldol reaction
Rachel Green et al, Solid-phase asymmetric
synthesis using a polymer supported
chiral
Evans’-type
oxazolidin-2-one
Nature protocols, 8, 2013

Asymmetric Induction
Internal Asymmetric induction: refers to the control of stereoselectivity exerted by
an existing chiral centre on the formation of a new chiral centre.
1, 2 - Asymmetric Induction
α-C atom adjacent to the prochiral carbonyl group is a C*
Diastereoselective reaction: one diastereomer formed
preferentially
R

O
L
M
S
12

O
R
L
M
S
O
R
L
MS
1
Nu Nu
OH
R
L
MS
Nu
Major Diastereomer
HO
R
L
MS
Nu
Minor Diastereomer
Cram’s Model

Large group SYN to C=O then attack from Medium group
Large group ANTI to C=O then attack from Small group
Major
Major

O
R
L
M
S
O
R
L
M
S
O
R
L
M
S
Nu
Nu
OH
R
L
M
S
Nu
OH
R
L
M
S
Nu
Major
Minor
Felkin-Ahn Model

Addition of Allylmetals to
Carbonyl compounds
Addition of achiral allylmetals to α-chiral carbonyl compounds
Addition of chiral allylmetals to prochiral carbonyl compounds
Metal Metal = B, Sn, Ti
M
L 
L

Metal = B, Sn, Ti

R
H
H
O
R' Metal
R
H
OH
R'
R
H
OH
R'
Stereoselectivity
controlled by
chirality of
-carbon
Metal = B, Sn, Ti
Addition of achiral allylmetals to
α-chiral carbonyl compounds

R
H
O
M
R
OH
R
OH
Stereoselectivity
controlled by
chirality of the ligands in the
allylmetal reagent
M = B, Sn, Ti
L 
L

Addition of chiral allylmetals to
prochiral carbonyl compounds

Addition of achiral 2-allyl-4,4,5,5-
tetramethyl-1,3-dioxaborolane to
(R)-2-methylbutanal
H
O
B
OH
OH
O
O
Major
Minor
B
OO
H3C H
O
H
H3C H
OH
H
Acyclic TS

Cyclic TS
H
O
B
OH
OH
O
O
Major
Minor
H
O
B O
O
H
H
O
B O
O
H
H
O
B O
O
H

Z-allylboranes give Syn product
E-allylboranes give Anti product

Addition reaction of prochiral carbonyl group of ketone placed at 4th
position to the existing chiral centre will generate chiral centre.
Prelog's Rule
An extension of Cram's idea of reactive conformation to
chiral esters of α-ketoesters (pyruvates)
R
O 
O
O
L
M S
1
2
3
4
Nu
R 
O 
OH
O
L
M S
1
4
Nu

R
OH 
O
O
L
M S
HO
R
O 
O
O
L
M S
12
3
4
PhMgBr
R 
O 
OH
O
L
M S
1
4
Ph
R 
OH
OH
O
Ph
Small group above the plane
nucleophile (Ph-) attack from
above the plane
α-Ketoacid Chiral alcohol
α-Ketoester

R
O 
O
O
L
S M
12
3
4
PhMgBr
R 
O 
Ph
O
L
S M
1
4
HO
R 
OH
Ph
O
HOR
OH 
O
O
L
S M
HO
Small group below the plane
nucleophile (Ph-) attack from
below the plane
α-Ketoacid Chiral alcohol
α-Ketoester

R
O
S
L
M
O
O
Nu
Nu
R
O
S
L
M
OH
O
Nu

Asymmetric synthesis of α – hydroxyacids
Assigning the configuration of secondary and tertiary
alcohols
Application

In 1983, Reetz and Jung reported the reaction of chiral β-alkoxy
aldehydes, unsubstituted at the α-position, with Lewis acidic compound
CH3TiCl3 through a half-chair chelated transition state model (CramReetz
chelate model), which would lead to a chair-like intermediate, to account
for the diastereoselectivity.
H

R
O OBn


12
3
Nu
CH3TiCl3
H 
R
OH OBn

13
H 
R
HO OBn

13
Nu
Nu
1, 3 - Anti
Major
1, 3 - Syn
Minor
 - alkoxyaldehyde

TiLn
O
O
H
R
H
H
Bn
Nu
O
TiLn
O
H
R
Nu
H
Bn
Cram-Reetz Chelate Model
Half-chair chelated transition state

TiCl4, CH2Cl2,
-78o
C
SiMe3
H 
O OBn


12
3

OH OBn
13
1, 3 - Anti
Major
TiCl4, CH2Cl2,
-78o
C
H 
O OBn


12
3
n-Bu 
OH OBn
13
1, 3 - Anti
Major
n-Bu2Zn

Distereoselection in Cylic System
O
O
Axial attack
Equatorial attack
O
Nu
Nu
OH
Trans
Nu
OH
Nu
Cis
Diastereomers

O
H
OH
Cis
OH
H
Trans
LiAlH4
Major (92%)Minor
(8%)
Selective reduction of 4-tert-butylcyclohexanone to a mixture
of trans- and cis-4-tert-butylcyclohexanol by LiAlH4 is an
example of diastereoselectivity, reflecting a preference for
hydride attack at the more hindered axial face of the carbonyl
group.
Formation of axial and equatorial alcohols

O
H
OH
Cis
OH
H
Trans
Li(sec-butyl)3BH
Major
(93%)
Minor
(7%)
B H Li
Selectivity can be reversed by using a larger hydride reagent,
such as Li(sec-butyl)3BH; in which case severe hindrance to
axial approach diverts the reaction to the equatorial face.

O
LiAlH4
OH
H
Endo face
Exo face
H
OH+
Major Minor
O
LiAlH4
OH
H
Endo face
Exo face
H
OH+
Minor Major
Formation of cyclic alcohols
Endo product
Exo product

PhCOOOH
+
Major Minor
OH OH
O
OH
O
O
O
O
O
H
Ph
H
Diastereoselective Oxidation

PhCOOOH
+
MajorMinor
O O
O
O
O
O
O
O
O
H
Ph
O
O
O O

Asymmetric Synthesis

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Asymmetric Synthesis