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Unit V: Synthon approach and retrosynthesis applications

Presentation · March 2021

DOI: 10.13140/RG.2.2.28275.66082

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Unit V: Synthon approach and retrosynthesis applications

• Retrosynthetic analysis is a technique for planning a synthesis, especially of complex organic

molecules, whereby the complex Target Molecule (TM) is reduced into a sequence of progressively
simpler structures (Retrons) along a pathway which ultimately leads to the identification of a simple
or commercially available Starting Material (SM) from which a chemical synthesis can then be
developed.
• Target molecule (TM): The molecule to be synthesized.
• Disconnection: Imaginary bond cleavage corresponding to the reverse of a forward reaction leading
to the immediate precursor. This is also known as transformation and is indicated by a wavy line.

• Retrosynthetic arrow: Disconnection is represented by a double line closed arrow which

indicates the transformation of the molecule into its immediate precursor.

• Synthons: Synthons are the imaginary fragments obtained by disconnection. The concept of bond
polarity with the fragments is of prime importance during disconnection. Synthons are not real
compounds but are idealized ionic or neutral fragments, and they are not reagents.

The above reaction depicts a concerted cycloaddition reaction with neutral fragments as synthons.

Lecture Notes_Dr. Sumanta Mondal_M. Pharm I Sem (Pharmaceutical Chemistry) _GITAM University 1|Page
Unit V: Synthon approach and retrosynthesis applications

• Retron: Each reaction produces a distinct structural element in the product, such as enone from
aldol condensation. This substructure, known as the retron, must be present in a target molecule in
order for the corresponding transformation to be applied to that target.

• Reagents: These are the actual source of the synthons.

i. Alkyl ions
a) Alkyl cation (carbenium ion)

b) Alkyl anion (carbanion)

ii. Alkyl anion (carbanion)

a) Acyl ions

b) Acyl anion: Removal of a proton from a methylene group adjacent to an electron

withdrawing group.

iii. Ethoxy anion

Lecture Notes_Dr. Sumanta Mondal_M. Pharm I Sem (Pharmaceutical Chemistry) _GITAM University 2|Page
Unit V: Synthon approach and retrosynthesis applications

iv. Aldehyde carbonyl as a cation and anion: Because the aldehyde carbonyl carbon lacks electrons,
it is attacked by nucleophiles.

When an aldehyde carbonyl carbon is converted into an anion, it can also be attacked by electrophiles.
The polarity of the electron-deficient aldehyde carbonyl carbon can be reversed, which is referred to
as ‘umpolung.'

Lecture Notes_Dr. Sumanta Mondal_M. Pharm I Sem (Pharmaceutical Chemistry) _GITAM University 3|Page
Unit V: Synthon approach and retrosynthesis applications

❖ Goal of A Retrosynthetic Analysis

▪ A retrosynthetic analysis should always aim to reduce the molecule to similarly sized building blocks of
lower or similar complexity. This process should be repeated until you reach molecules that are commercially
available.
▪ The synthetic plan is composed by selecting an appropriate route based on the analysis and then adding
reagents and reaction conditions. The use of computers aided in the simplification of the synthetic strategy.
▪ Computer programs are divided into two categories:
a) Passive program: The use of computerized libraries to identify structural features of the target
molecule, such as an aromatic ring, an acyclic ring, an alkyl group, and so on. It is a set of data that
allows us to find all the compounds that have a specific substructure that corresponds to the Target
Molecule. There is also a large collection of organic reactions available for use.
b) Active program: A menu with various strategies for retrosynthetic analysis is displayed.
▪ The main operation of a retrosynthetic analysis Active program:
i. Disconnection should result in a dependable and predictable reaction. As a result, a complete
understanding of reactions is required.

Here Route A is a good disconnection as acetylation of an amino group is a known reaction to get the
N-acetyl group. Routes B and C route disconnections are improper as they do not lead to known
reactions.
ii. Disconnect C–X bond

In the preparation of aryl-halides, the halogen is an electrophile in the above-mentioned reactions where alkyl
halides are obtained by nucleophilic attack by a halide.

Lecture Notes_Dr. Sumanta Mondal_M. Pharm I Sem (Pharmaceutical Chemistry) _GITAM University 4|Page
Unit V: Synthon approach and retrosynthesis applications

iii. Disconnection is performed next to the heteroatom in compounds composed of two parts joined by a
heteroatom. For greater simplicity, the molecule is severed in the middle.

The aryloxyacetic acid produced in the preceding reaction can be easily obtained by reacting a phenol
and chloroacetic acid in the presence of NaOH. As a result, the proper disconnection is at the “b” site.
Because the amide can be made from an acid chloride and an amine, the proper disconnection occurs at
the “a” site.
iv. The disconnection at the heteroatom in open-chain compounds is also determined by the stability of the
synthons.

Both of these disconnections are near the heteroatom and in the middle, resulting in equal-sized
synthons. However, route “a” is preferred because it produces a more stable secondary cation.
❖ Manipulation of the Functional Groups
▪ When disconnection fails to produce reliable reactions, the functional groups must undergo the following
changes: Functional Group Interconversion (FGI), Functional Group Addition (FGA), Functional Group
Removal (FGR), and the unmasking of latent functional groups by deprotection or other conversions.
Functional group manipulation can result in significant reductions in molecular complexity.
(i) Functional Group Interconversion (FGI):
When the disconnection of a functional group does not result in a proper precursor, FGI substitutes one
functional group for another. Disconnection is not possible in the following reaction because there is no
corresponding reaction to introduce group X directly on the benzene ring. As a result, FGI must convert
it to group Y because group Y can be disconnected to provide the appropriate starting materials.

Lecture Notes_Dr. Sumanta Mondal_M. Pharm I Sem (Pharmaceutical Chemistry) _GITAM University 5|Page
Unit V: Synthon approach and retrosynthesis applications

o For example, aniline on bromination yields 2, 4, 6-tribromoaniline, implying that group

interconversions must be performed. The amino group is easily obtained by reducing the nitro group.
So, in the reaction described above, the first step is functional group interconversion, followed by
disconnection.

o Similarly, Preparation of p-bromoaniline from aniline is shown below.

(ii) Functional Group Addition (FGA):

o Some functional groups require the addition of a disconnection-ready group to the immediate
precursor.
o One example is the simple dehydration of β–hydroxy ketone, which results in α, β-unsaturated
ketone.

(iii) Functional Group Removal (FGR):

o To obtain the precursor needed for the target molecule, a functional group must be extracted.
The two hydroxyl groups must be omitted in the following example since the precursor
contains an olefinic double bond.
o Beckmann rearrangement of the lactam yields the target molecule caprolactam. In order to obtain a
lactam, the first retro step is to add a keto group. Both FGR and FGI are involved in this reaction.

Lecture Notes_Dr. Sumanta Mondal_M. Pharm I Sem (Pharmaceutical Chemistry) _GITAM University 6|Page
Unit V: Synthon approach and retrosynthesis applications

(iv) Interconvertible Functional Groups

o If the carbon skeleton remains unchanged, it is simple to interconvert the functional groups. The
carboxylic group, for example, can be used to create a variety of functional groups, as seen below:

o Example: Alcohols, on the other hand, can be considered core functional groups because they
can be transformed into a variety of other functional groups. Many functionalized aliphatic
compounds begin with alcohols as the starting material.

❖ The following conditions should be considered when planning a synthesis based

on retrosynthetic analysis:
▪ The initial materials for each stage are available.
▪ In the synthesis, less qualified reactions should be used. Easy, high-yielding processes should
be used in the reactions. They can practice on a large scale. At each point, the yield must be
considered.
▪ When preparing a synthesis, hazardous chemicals should be avoided because they need more
costly equipment to ensure proper handling and containment. More importantly, they put the
person handling them in danger. For large-scale planning, this is a vital factor.
Lecture Notes_Dr. Sumanta Mondal_M. Pharm I Sem (Pharmaceutical Chemistry) _GITAM University 7|Page
Unit V: Synthon approach and retrosynthesis applications
▪ Time would be saved if the number of steps was held to a minimum. The linear approach is
favoured over convergent synthesis. When the starting materials are cheap and readily
available, and the experimental conditions are simple, a long scheme can be chosen. When there
are fewer steps, more expensive starting materials are used.
▪ Commercially available starting compounds with a linear skeleton up to six carbon atoms and
one functional group include -COOH, -CHO, -OH, -X, -NH2, and others. Easy aromatic
compounds, alkenes, monomers for plastics, and other small molecules are commercially
available. Amino acids, simple sugars, and other naturally occurring plant materials are
favoured.
❖ Basic retrosynthetic key steps

Lecture Notes_Dr. Sumanta Mondal_M. Pharm I Sem (Pharmaceutical Chemistry) _GITAM University 8|Page
 Unit V: Synthon approach and retrosynthesis applications

Chemistry is necessarily an experimental science: its conclusions are drawn from data, and its principles
supported by evidence from facts-“Michael Faraday”

Lecture Notes_Dr. Sumanta Mondal_M. Pharm I Sem (Pharmaceutical Chemistry) _GITAM University 9|Page

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