Protecting Groups

1. RETROSYNTHETIC RETROSYNTHETIC
APPROCH APPROCH
TOTO
ORGANIC SYNTHESISORGANIC SYNTHESIS
PROTECTINGPROTECTING
GROUPSGROUPS
Dr. Shaikh S. NizamiDr. Shaikh S. Nizami
Department of ChemistryDepartment of Chemistry
University of KarachiUniversity of Karachi

2. PROTECTING PROTECTING
GROUPS GROUPS

3. CONTENTSCONTENTS
Definition of Protecting Groups
Criteria for Protecting Groups
Protection of alcohols
Protection of amines
Protection of aldehydes & ketones

4. Definition
OEt
O O
OEt
OOH
NaBH
4
OHOH
LiAlH
4
The ester cannot be directly reduced leaving
the ketone unaffected

5. Solution of problem
The problem may be The problem may be
circumvented in two ways:circumvented in two ways:
a) By the use of protecting a) By the use of protecting
groupsgroups
b) By changing the synthetic b) By changing the synthetic
strategy to the TMstrategy to the TM

6. Solution of problem
If it is necessary to reduce an If it is necessary to reduce an
ester in presence of a ketone thenester in presence of a ketone then
First the ketone must be First the ketone must be
converted to a function which is converted to a function which is
stable to the reducing agent/stable to the reducing agent/
The ester then be reduced andThe ester then be reduced and
ketone subsequently regeneratedketone subsequently regenerated..

7. Protection of a ketone during Protection of a ketone during
reduction of an esterreduction of an ester
OEt
O O
OH
O
OEt
O
OO
OH
OO
overall
HOCH
2
CH
2
OH/H
+
LiAlH
4
H
3
O
+

8. Criteria for protecting groupsCriteria for protecting groups
Simple to introduce in a Simple to introduce in a
molecule, in good yieldmolecule, in good yield
Stable to the reaction conditions Stable to the reaction conditions
for the next stepfor the next step
Easy to remove to get back same Easy to remove to get back same
functional group, in good yieldfunctional group, in good yield

9. PROTECTION OF ALCOHOLSPROTECTION OF ALCOHOLS
Following methods have been Following methods have been
used to protect alcoholic groupused to protect alcoholic group
1. Use of acetals1. Use of acetals
2. Use of alkyl ethers2. Use of alkyl ethers
3. Use of silyl ethers3. Use of silyl ethers

10. PROTECTION OF ALCOHOLSPROTECTION OF ALCOHOLS
1. Use of acetals1. Use of acetals
It includesIt includes
Tetrahydropyranyl (THP) Tetrahydropyranyl (THP)
derivativesderivatives
Methoxyethoxymethyl (MEM) Methoxyethoxymethyl (MEM)
derivativesderivatives

11. Acetals as protecting groups Acetals as protecting groups
for alcohols (THP)for alcohols (THP)
R OH+
O
OOR
Tetrahydropyran
(THP)
H
+
or
OTHPR
RCH
2
OTHP is stable to oxidation, reduction
& base
H
2
O/H
+
R OH
Deprotection
Protection

12. Acetals as protecting groups Acetals as protecting groups
for alcohols (MEM)for alcohols (MEM)
R OH
+
Cl O
O
or
OMEMR
R OH
Methoxethoxymethyl (MEM)
RCH
2
OMEM is stable to
oxidation, reduction & base
H
+
Protection
Deprotection
O O
O
R

13. PROTECTION OF ALCOHOLSPROTECTION OF ALCOHOLS
2. Use of ethers2. Use of ethers
It includesIt includes
benzyl ethersbenzyl ethers
t-butyletherst-butylethers

14. Benzyl ethers as protecting Benzyl ethers as protecting
groups for alcoholsgroups for alcohols
R OH+Cl Ph R O Ph
pyridine
R OH
H
2
/Pd
Benzyl ether is stable to base,
mild acid, oxidation & reduction
Protection
Deprotection

15. t- Butyl ethers as protecting t- Butyl ethers as protecting
groups for alcoholsgroups for alcohols
R OH+
OH
R O
or
H
+
Protection
R OH
H
3
O
+
Deprotection
t-Butyl ether is stable to base,
mild acid, oxidation & reduction

16. PROTECTION OF ALCOHOLSPROTECTION OF ALCOHOLS
3. Use of silyl ethers3. Use of silyl ethers
R OH+Me
3SiCl R O
SiMe
3pyridine
Protection
R OH
orR OTMS
H
+
Deprotection
Trimethylsilyl ether is stable
to base, oxidation & reduction

17. PROTECTION OF ALCOHOLSPROTECTION OF ALCOHOLS
3. Use of silyl ethers3. Use of silyl ethers
Trimethylsilyl ethers are attacked by
certain nucleophiles.
To overcome this problem a number
of more bulky trialkylsilyl protecting
groups have been developed

18. Bulky trialkylsilyl Bulky trialkylsilyl
protecting groupsprotecting groups
OR
Si
OR
Me
Me
Si Si
Ph
Ph
OR
I II III
I, Triisopropylsilyl ether (TIPSOR)
II, t-Butyldimethylsilyl ether (TBDMSOR)
III, t-Butyldiphenylsilyl ether (TBDPSOR)