Retrosynthetic analysis is a technique used to plan organic syntheses by working backwards from the target molecule. It involves mentally deconstructing the target molecule through sequential disconnections and functional group transformations until commercially available starting materials are reached. Each disconnection produces synthons, which are idealized fragments that represent possible reaction precursors. Common types of disconnections include C-X, C-C, and carbonyl bonds. The goal of retrosynthesis is to simplify the target structure and design multiple possible synthesis routes leading from simple starting materials to the target. It helps chemists discover efficient syntheses by considering the reactivity, selectivity, and availability of materials at each step.

1. RETROSYNTHESIS
PRESENTED BY: PROTTAY DUTTA
Roll no-MPH/10055/20
Mpharm (Pharmaceutical Chemistry dept.)
Birla Institute of Technology, Mesra

2. DEFINITION[ 2 ]
• Retrosynthetic (or antithetic) analysis is a problem solving technique for
transforming the structure of a synthetic target molecule (TGT) to a sequence of
progressively simpler structures along a pathway which ultimately leads to simple or
commercially available starting materials for a chemical synthesis.
• The transformation of a molecule to a synthetic precursor is accomplished by the
application of a transform, the exact reverse of a synthetic reaction, to a TGT.
• Each structure derived antithetically from a target the itself becomes a TGT for a
further analysis. Repetition of this process eventually produces a tree of
intermediates having chemical structural as nodes and pathways from bottom to top
corresponding to possible synthetic routes to the TGT.

3. REFERENCE
1. https://www.ias.ac.in/article/fulltext/reso/024/10/
1071-1086
2. https://www.slideshare.net/ShariqueKhan22/orga
nic-retrosynthesis-by-professor-beubenz
3. S Warren, Designing Organic Synthesis,
Introduction to Synthon Approach, John Wiley &
Sons, NY, 1978.
4. E.J. Corey, J.Am.Soc. 98, 189, (1976).
5. Lemke TL, Williams DA, Roche VF, Zito WS.
Foye’s Principles of Medicinal Chemistry 6th ed.
Lippincott Williams and Wilkins. 2010. p. 504

4. • RETROSYNTHETIC ANALYSIS or
RETROSYNTHESIS “The process of WORKING
BACKWARD from the TM in order to devise suitable
synthetic route”
OR
“The process of mentally breaking down a molecule into a
starting material”
OR
“It is a problem solving technique for transforming the
structure of a synthetic target molecule (TM) to a sequence
of progressively simpler structures along a pathway which
ultimately leads to simple or commercially available starting
materials for a chemical synthesis.”[2]

5. ARROW NOTATION [2]
• 1.Simple reaction arrow “ reacts to give”
• 2. Delocalisation arrow “two different
ways to draw the same delocalised structures”
• 3.Equilibrium arrow ⇌ “two structures are
interconverting”
• 4. Curved arrow “motion of two
electrons” ( Single Headed)
• 5. Fish-hook arrow “motion of one electron”
• 6. Curved arrow ( Double Headed)

7. TERMINOLOGY[ 2 ]
• Target molecule (TM): the molecule to be synthesized
• Retrosynthetic analysis or retrosynthesis: the process of mentally breaking down a
molecule into a starting material
• Disconnection: an imaginary bond cleavage corresponding to a reverse of a real reaction
• Functional Group Interconversion (FGI): the process of converting one functional
group into another by substitution, addition, elimination, reduction, or oxidation
• Transform: the exact reverse of a synthetic reaction
• Retron: structural subunit on the target that enables a transform to operate
• Synthon: idealized fragment resulting from a disconnection, which is related to possible
synthetic operations
• Umpolung: reversal of normal polarization of a molecule or synthon
• Reagent: a real chemical compound used as the equivalent of a synthon
• Synthesis tree: set of all the possible disconnections and synthons leading from the target
to the starting materials of a synthesis

8. • RETROSYNTHETIC ANALYSIS CAN BE DONE
BY TWO METHODS:
a) Disconnection
b) Functional Group Interconversion (FGI)
• a) Disconnection It is a paper operation involving
an imagined cleavage of a bond. As a result of
disconnection usually negative ion and positive ion
are formed which are called ‘SYNTHONS’
Disconnection is shown by a wavy line like ~ or
VVVVVVVV

9. • b) Functional Group Interconversion (FGI) :
The process of writing one functional group for another
to help synthetic planning is known as FGI. FGI can be
done by,
Addition
Substitution
Elimination
Oxidation/Reduction
Free Radical Reaction

10. DISCONNECTIONS[ 4 ]
• C-X disconnections
If we need to make a C-X bond (where X is a heteroatom),a
simple disconnections reveals a carbocationic synthon. We
choose this polarity because X is almost invariably more
electronegative than carbon. The C-X bond could exist in
many different chemical environments which means there will
be a correspondingly wide range of carbocationic synthons
and synthetic equivalents.

11. • The second of these examples is hugely important: these are acylation reactions
• The third of the C-X disconnections is an example of a two-group
disconnection(like the Diels-Alder example)

12. C-C DISCONNECTIONS
• Alcohols-
Alcohols are prime example of the need to disconnect right
next to the hydroxyl functional group. A carbanion synthon
and an α-hydroxyalkyl cation synthon. The synthetic
equivalent of a carbanion synthon is almost invariably an
organometallic compound.

13. Adding an organometallic compound to a
carbonyl compound generates a new
stereocentre and its non-trivial to control which
enantiomer of the product is formed. If we
disconnect one bond further away from the
alcohol in the target we generate a ß-
hydroxyalkyl cation synthon whose synthetic
equivalent we ve seen in an epoxide.Epoxides
are already chiral, so we have a single
enantiomer of the epoxide, we form a single
enantiomer of the product alcohol.

14. • Carbonyl Compounds
By direct analogy with the disconnection of alcohols,simple carbonyl
compounds disconnect back to acyl cation synthons and carbanionic
synthons.

15. • Synthons[3]: 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 following reaction shows a concerted cycloaddition
reaction, where the synthons are neutral fragments.

16. • The symbol signifies a reverse synthetic step and is
called a transform. The main transforms are
disconnections, or cleavage of C-C bonds, and
functional group interconversions (FGI)
• Retrosynthetic analysis involves the disassembly of a
TM into available starting materials by sequential
disconnections and functional group
interconversions(FGI).[4]
• Synthons are fragments resulting from disconnection
of carbon-carbon bonds of the TM. The actual
substrates used for the forward synthesis are the
synthetic equivalents (SE)

17. STEREOSPECIFICITY AND
STEREOSELECTIVITY
• Diels-Alder reaction occurs in one step so that neither dienes nor
dienophile has time to rotate and stereochemistry of each remains
preserved in the product.
• Thus, with respect to the dienophile and the diene the addition is
stereospecific and almost always.
• The Diels- Alder reaction is stereospecific. The cis dienophiles give the
cis product and trans dienophile give trans product.

18. APPLICATION[ 3 ]
• Retrosynthetic analysis is a technique for solving problems in
the planning of organic synthesis. This is achieved by
transforming a target molecule into simpler precursor structures
regardless of any potential reactivity/interaction with reagents.
• Each precursor material is examined using the same method.
This procedure is repeated until simple or commercially available
structures are reached. These simpler/commercially available
compounds can be used to form a synthesis of the target molecule
• The power of retrosynthetic analysis becomes evident in the
design of a synthesis. The goal of retrosynthetic analysis is
structural simplification. Often, a synthesis will have more than
one possible synthetic route.

19. • Retrosynthesis is well suited for discovering
different synthetic routes and comparing them in a
logical and straightforward fashion A database may
be consulted at each stage of the analysis, to
determine whether a component already exists in
the literature. In that case, no further exploration of
that compound would be required. If that
compound exists, it can be a jumping point for
further steps developed to reach a synthesis.

20. GUIDELINES FOR CHOOSING
DISCONNECTIONS[ 2 ]
• 1.Synthesis backwards: The process of breaking
down a target molecule into available starting
materials by disconnection or FGI
• 2.Retrosynthetic arrow: A double line arrow used
to indicate the reverse of a synthetic reaction.
• 3.Synthon: An idealized fragment (usually a cation
or anion) resulting from a disconnection.
• 4. Synthetic equivalent: A real chemical
• 5.Disconnections must correspond to the reverse of
real and workable reactions.

21. • 6. For compounds consisting of two parts joined by a
hetroatom, disconnect next to the hetro atom
• 7. Consider alternate disconnections and choose routes that
avoid chemoselectivity problems. This can often be done by
disconnecting more reactive groups first.
• 8. Evaluate all the possible advantages and disadvantages of
each path- determine the most efficient route for synthesis.
• 9. Evaluation is based on specific restrictions and limitation of
reactions in the sequence, the availability of materials and
other factors.
• 10.In reality, it may be necessary to try several approaches in
the laboratory in order to find the most efficient or successful
route.

22. Thank you