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Retrosynthetic Analysis and
Synthetic Planning

Vancomycin is an antibiotic used against bacteria that cause
2:24 PM food poisoning
...

Retrosynthetic analysis is based on known reactions (e
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The synthetic plan generated from the retrosynthetic analysis
will be the roadmap to guide the synthesis of the target
molecule
...


Syntheses can be grouped into two broad categories:
(i) Linear syntheses
(ii)Convergent syntheses
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Linear Synthesis
Definition
In linear synthesis, the target molecule is synthesized through a
series of linear transformations
...


The linear synthesis is fraught with failure for its lack of
flexibility leading to potential large losses in the material already
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invested in the synthesis at the time of failure
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A convergent synthesis is shorter and more efficient than a
linear synthesis leading to a higher overall yield
...

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Retrosynthetic Analysis
Consider the retrosynthetic analysis of Muscalure, the
pheromone of the domestic housefly, to illustrate the concept
of retrosynthetic analysis:

The retrosynthetic analysis of any target molecule must be
based on known chemical reactions for it to stand a realistic
chance of being translated to a chemical synthesis
...


A thorough evaluation of the alternative retrosynthetic
pathways should be made to identify the pathway that best
stands a realistic chance of being translated to an efficient
2:24 PM chemical synthesis
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Consider the chemical syntheses of Muscalure to appreciate
how the two retrosynthetic plans fit in, but most importantly,
note the use of specific reagents that transform the
intermediates in the retrosynthetic scheme eventually to the
target molecule
...


Comparing the two synthetic pathways shows that while the
Wittig route is convergent, the stereochemistry of the double
bond is not stereospecifically controlled
...

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Synthetic Planning
Retrosynthetic analysis and synthetic planning requires training
(knowledge of chemistry) and experience (practical application
of the chemistry)
...
One of these
retrosynthetic pathways may turn out to be more practical and

executable than the others
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Terminology of Retrosynthetic Analysis
Disconnection
During retrosynthetic analysis the target molecule is
systematically broken down by a combination of disconnection
and functional group interconversion (FGI)
...
A
good disconnection must achieve the greatest simplification of
the target molecule
...

The complete set of disconnections and functional group
interconversions for a specified target molecule is what
constitutes a retrosynthetic pathway or plan
...

A retrosynthetic arrow (⇒): This open arrow represents
going from the target molecule “backwards” to simpler
molecules (retrons)
...


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Terminology of Retrosynthetic Analysis
Functional Group Interconversion
Functional group interconversion (FGI) describes a process of
converting one functional group to another: e
...
an alcohol to
an aldehyde, alkyne to alkene etc
...

Revisit the retrosynthetic analysis of Muscalure to identify the
disconnections and Functional group interconversions
...

The disconnection of a bond based on this innate polarity may

lead to two pairs of idealized (imaginary) fragments called
synthons from which a functional group may be generated
...
g
...
It may not necessarily correspond to a real molecule
...
g
...


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Strategies in Synthetic Planning
(a) Strive for success and good cost management
In planning a synthesis generate a large number of
retrosynthetic pathways to the target molecule: Examine
these retrosynthetic pathways to identify among them an
optimal synthetic route for which reagents are readily
available and inexpensive
...
This will
make possible the formulation of a convergent synthesis with
several mini-syntheses leading to the target molecule
...


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Strategies in Synthetic Planning

(d) Identify and exploit any inherent symmetry in a target
molecule
Exploiting any symmetry in a TM or its intermediate can
dramatically simplify its retrosynthesis
...


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Strategies in Synthetic Planning
(e) Introduce reactive functional groups at a late stage in the
synthesis
It is often difficult to selectively react at a less reactive
functional group when a more reactive functionality is
present within the same molecule
...

The retrosynthetic analysis of 2,4-dichlorophenoxyacetic acid
(2,4-D), a common herbicide for the control of broadleafed
weeds, is shown below:

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Strategies in Synthetic Planning
Synthesis of the Weed-Killer, 2,4-D
Based on the preceding retrosynthetic plan, 2,4dichlorophenoxyacetic acid (2,4-D) can be synthesized as shown
below:

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Strategies in Synthetic Planning
Alternative Synthesis of the Weed-Killer, 2,4-D
The synthesis of 2,4-D can also be approached based on the
alternative retrosynthetic and synthetic plan highlighted below:

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Strategies in Synthetic Planning
(f) During retrosynthetic analysis introduce additional functional
groups, if necessary, to facilitate further disconnection:
Functional group addition (FGA) strategy

The functional group addition strategy in retrosynthetic
analysis involves introducing additional functional groups at
strategic locations in a retron, if necessary, to guide further

disconnections based on known powerful bond making
reactions
...
g
...

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Strategies in Synthetic Planning
Functional Group Addition Strategy
For example, one may introduce a carbonyl group in a
substituted cyclohexane target molecule which may help
guide introduction of a substituent through enolate alkylation
...


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Sample Retrosyntheses and Syntheses
Retrosynthetic Analysis of Methyl Cinnamate
Methyl cinnamate is found naturally in fruits, like strawberry
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Sample Retrosyntheses and Syntheses
Retrosynthetic Analysis of Dettol

4-Chloro-3,5-dimethylphenol is the active ingredient responsible

for the antiseptic properties of Dettol
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The synthesis of Z-hex-2-enal can be approached based on

partial syn-hydrogenation as shown below:

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Sample Retrosyntheses and Syntheses
Synthesis of Z-Hex-2-enal

The key feature in the synthesis of Z-hex-2-enal is
stereochemistry of the double bond that can stereospecifically

be achieved by partial syn-hydrogenation of an alkyne
...


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CAT 2
ORGANIC SYNTHESIS

MONDAY, 1ST DECEMBER 2014
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