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PART B

ORGANIC SYNTHESIS

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1

What is Synthesis?
Synthesis involves combining two or more chemical entities
through covalent bonds to generate a more complex molecule
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2

Is Synthesis of Any Value?
Synthesis is important to the food and cosmetics industry, but
also finds wide application in medicine
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Synthesis has served to supplement the natural source
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4

Organic Synthesis
What are the Essentials in Synthesis?
Since organic synthesis is applied organic chemistry, to stand a

realistic chance of succeeding in any synthesis, the student
ought to have a good knowledge-base of organic chemistry in
the following areas:

Protecting group chemistry
Asymmetric synthesis
Functional group transformations (SCH 202 & SCH 206)

Substitution reactions (SCH 102)
Addition reactions (SCH 202 and SCH 206)
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Strategies for synthetic planning (Retrosynthetic analysis)

5

Protecting Groups in Organic
Synthesis

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6

Challenges in Organic Synthesis
Chemoselectivity can be Elusive

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Selective functionalization of poly-functional molecules is an
important attribute in multi-step organic synthesis
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8
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Protecting Groups in Organic Synthesis
What is a protecting group?
A protecting group (PG) is a molecular unit that is introduced
onto a specific functional group (FG) in a poly-functional
molecule to block its reactivity under reaction conditions
needed to make modifications elsewhere in the molecule
...

(b) It should be resistant (inert) to the reagents employed in the
subsequent reaction steps in which the group being masked
(protected) is desired to remain deactivated (protected)
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10

Protecting Groups in Organic Synthesis

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The common functional groups that are reactive to nucleophilic
or electrophilic reagents whose selective transformation may
present challenges do regularly require deactivation by masking
with a protecting group
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No wonder, the common protecting groups for alcohols are
ether-protecting groups
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12

Protecting Groups for Alcohols
What Kind of Ethers?
Except for benzyl ethers, hadly are alcohols protected as alkyl
ethers
...
The O-Si bond formed is strong and less reactive to
strong bases compared to the O-H bond in the parent alcohol
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14

Protecting Groups for Alcohols
Tert-Butyldimethylsilyl Ether Protecting Group
Formation

Imidazole neutralizes the HCl produced in the reaction to
suppress side-reactions that could arise from it
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Fluoride sources:
 Hydrofluoric acid (HF)
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 Tetrabutylammonium fluoride, Bu4N+F- (TBAF)

16

Protecting Groups for Alcohols
(Synthetic Applications using Silyl Protecting Groups)
The bulkiness of TBDMS and TBDPS ether protecting groups can
be used to advantage to direct it to the least hindered primary
hydroxyl group leading to selective protection of a primary
hydroxyl group in the presence of a secondary hydroxyl group
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19

Protecting Groups for Alcohols
(Perspectives in Synthesis)
Benzyl ether protecting groups can be used along with silyl
ether protecting groups to protect poly alcohols during
synthesis
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20

Protecting Groups for Diols
(Cyclic Acetal Protecting Groups)
Acetonide Protecting Groups for 1,2-Diols
The formation of thermodynamically stable five membered ring
systems is feasible
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21

Protecting Groups for Alcohols
(Perspectives in Synthesis)
Synthetic Applications of Cyclic Acetal Protecting Groups

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22

Protecting Groups for Aldehydes and Ketones
(Acetal and Ketal Protecting Groups)
Acetal Protecting Group
Formation

Cleavage
Acid catalysed hydrolysis (dilute HCl/ H2O or TFA/ H2O)

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23

Protecting Groups for Aldehydes
(Synthetic Perspectives)

Apart from the use of PCC, selective oxidation of an alcohol may
be challenging to achieve in the presence of an aldehyde
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Methyl Esters
Formation

Cleavage
O
R C OCH3
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LiOH
H2O2

R CO2H

+

CH3OH
25

Protecting Groups for Carboxylic Acids
(Esters)
Methyl, ethyl and benzyl esters can be prepared based on the
following rationale:

Best approach:

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26

Protecting Groups for Carboxylic Acids
(Esters)
Mechanism of DCC coupling

+

N C N

O
R C O

+

O
R

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O
H

R'

+

O
H
N C N

+

O
R C O

O
O C R
N C
N
H

H
N C N

O
R C O
C N
N
H

R' O H +

H
N C N

O
R C O H

O
R

O
H

R'

O
H
N C N

+

O
R

O

R'

+

O
H
H
N C N

27

Protecting Groups for Carboxylic Acids
(Esters)
Ethyl Esters
Formation

Cleavage
O
R C OCH2CH3

LiOH

R CO2H

+

CH3CH2OH

H2O2

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28

Protecting Groups for Carboxylic Acids
(Esters)
Benzyl Esters
Formation

Cleavage: By hydrogenolysis

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29

Protecting Groups for Amino Groups
(Carbamate Protecting Groups)

Carbamates combine half of the stability of amides and half of
the reactivity of esters
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