protecting groups

RETROSYNTHETIC RETROSYNTHETIC APPROCH APPROCH

TOTOORGANIC SYNTHESISORGANIC SYNTHESIS

PROTECTINGPROTECTINGGROUPSGROUPS

Dr. Shaikh S. NizamiDr. Shaikh S. NizamiDepartment of ChemistryDepartment of ChemistryUniversity of KarachiUniversity of Karachi

PROTECTING PROTECTING GROUPS GROUPS

CONTENTSCONTENTS

Definition of Protecting Groups Criteria for Protecting Groups Protection of alcohols Protection of amines Protection of aldehydes &

ketones

Definition

OEt

O OOEt

OOH

NaBH4

OH OHLiAlH4

The ester cannot be directly reduced leaving the ketone unaffected

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

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..

Protection of a ketone Protection of a ketone during reduction of an during reduction of an

esterester

OEt

O O

OH

O

OEt

OOO

OH

OO

overall

HOCH2CH2OH/H+

LiAlH4

H3O+

Criteria for protecting Criteria for protecting groupsgroups Simple to introduce in a Simple to introduce in a

molecule, in good yieldmolecule, in good yield Stable to the reaction Stable to the reaction

conditions for the next stepconditions for the next step Easy to remove to get back Easy to remove to get back

same functional group, in good same functional group, in good yieldyield

PROTECTION OF PROTECTION OF ALCOHOLSALCOHOLS

Following methods have Following methods have been used to protect been used to protect alcoholic groupalcoholic 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


1. Use of acetals1. Use of acetals It includesIt includes Tetrahydropyranyl (THP) Tetrahydropyranyl (THP)

derivativesderivatives Methoxyethoxymethyl Methoxyethoxymethyl

(MEM) derivatives(MEM) derivatives

Acetals as protecting Acetals as protecting groups for alcohols (THP)groups for alcohols (THP)

R OH +O OOR

Tetrahydropyran(THP)

H+

orOTHPR

RCH2OTHP is stable to oxidation, reduction & base

H2O/H+

R OHDeprotection

Protection

Acetals as protecting Acetals as protecting groups for alcohols (MEM)groups for alcohols (MEM)

R OH

+Cl O

Oor

OMEMR

R OH

Methoxethoxymethyl (MEM)

RCH2OMEM is stable to oxidation, reduction & base

H+

Protection

Deprotection

O OO

R


2. Use of ethers2. Use of ethers It includesIt includes benzyl ethersbenzyl ethers t-butyletherst-butylethers

Benzyl ethers as Benzyl ethers as protecting groups for protecting groups for

alcoholsalcoholsR OH +Cl Ph R O Ph

pyridine

R OH

H2/Pd

Benzyl ether is stable to base, mild acid, oxidation & reduction

Protection

Deprotection

t- Butyl ethers as t- Butyl ethers as protecting groups for protecting groups for

alcoholsalcoholsR OH +

OH R Oor

H+

Protection

R OH

H3O+Deprotection

t-Butyl ether is stable to base, mild acid, oxidation & reduction


3. Use of silyl ethers3. Use of silyl ethersR OH + Me3SiCl R O

SiMe3pyridineProtection

R OH

or R OTMS

H+Deprotection

Trimethylsilyl ether is stableto base, oxidation & reduction


3. Use of silyl ethers3. Use of silyl ethersTrimethylsilyl ethers are attacked bycertain nucleophiles.

To overcome this problem a number of more bulky trialkylsilyl protectinggroups have been developed

Bulky trialkylsilyl Bulky trialkylsilyl protecting groupsprotecting groups

OR

Si

ORMe

MeSi Si

Ph

PhOR

I II III

I, Triisopropylsilyl ether (TIPSOR)

II, t-Butyldimethylsilyl ether (TBDMSOR)

III, t-Butyldiphenylsilyl ether (TBDPSOR)

protecting groups

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