4. 1 INTRODUCTION
Chemical synthesis, the process that converts one or more
compounds into different compounds via execution of a
series of reactions, is a powerful tool for human being. It
provides humans with many useful products that are
important in many important fields, such as
pharmaceutical, construction, agriculture, and higher-
technology industries.
An analytical approach to Organic Synthesis in which the target molecule is broken into fragments through a
series of logical disconnections to get the best plausible and likely starting materials (i.e., synthons or
building blocks) for the target molecule is called Synthon approach.
Figure 1.
5. 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
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.
Figure 2.
6. 2 BASIC RULES
Rule -1 Disconnection of a bond should be done in such a way that it produces stable fragments. While
carrying out a disconnection the molecule is broken down by one bond at a time.
Rule-2 The number of fragments generated by disconnection should be as small as possible. So, the
synthesis of target molecule can be carried out in possible steps.
Figure 3.
Figure 4.
7. RULE -3 A bond joining a carbon to a hetero atom always broken with the electron pair on-hetero atom.
RULE -4 Sometimes a disconnection carried out does not generate sufficient stabilized fragments, but such
fragments can be obtained by using FGI or by introducing an additional electron withdrawing group and then
removing it after synthesis.
Figure 5.
8. 3 DISCONNECTION
As the consequence of a disconnection, one of the three
things may happen: both electrons go to the left synthon
(A hypothetical fragment of a compound that is a building
block for the target molecule), both electrons go to the
right synthon, or the electrons are split between the two
synthons. The three ways can be illustrated with the
compound (Aspirin - a common pain reliever) below If the
bond is disconnected as shown in Figure 7, either
one of the three retrosynthetic steps shown in Figure 8
must happen.
Figure 6. Structure of Acetylsalicylic acid (Aspirin)
Figure 7. Disconnection of the bond
(2-Acetoxybenzoic acid)
10. Synthetic Equivalents
In a practical setting, these idealized synthons are only
hypothetical since they are too unstable to exist. Therefore,
scientists use synthetic equivalents in place of these
synthons, which are much more stable and share the same
electrophilic or nucleophilic functions as the hypothetic
synthons. These synthetic equivalents are the compounds that will be used in a scientific laboratory.
For the example
above, the synthetic equivalents of the two synthons are
shown in Figure 9. The negative synthon is replaced with
a benzoic acid, which has a hydrogen bond, creating the
partial negative charge on the oxygen; the positive
synthon is replaced with acetic anhydride (replaced with a
carboxylic acid group), which creates a partial positive
charge on the carbon due to the polar bond.
Figure 9. Synthetic equivalents of the synthons
11. Functional group interconversion (FGI)
Figure 10 shows the compound was an intermediate in the synthesis of the potential anti-obesity drug .The
problem of chemoselectivity can be avoided by a tool called “Functional Group Interconversion”. In
the case of a multistep synthesis, this method is very beneficial. This technique works by converting one
functional group to another. But it has nothing to do with a disconnection because the functional group is only
being converted without adding or reducing another functional group. The reason we want to carry out a
functional group interconversion is due to chemoselectivity as we have previously discussed. For example, the
retrosynthesis of an antihypertensive drug Ofornine 1-(2-(4-Pyridinylamino)benzoyl)piperidine.
Figure 10. retrosynthesis Figure 11. synthesis
14. 5 CONCLUSION
The intention of this review is to describe the function and
usage of retrosynthetic analysis. In general, retrosynthesis
has become an important tool for the development of
chemistry. For every molecule, retrosynthesis can be used
to predict starting materials and reliable reactions.
Through retrosynthetic analysis, not only can we
artificially synthesize substances that do not exist in nature,
but also create more efficient and higher output routes for
already existing pathways, which may greatly reduce the
cost and time.
15. REFERENCE
1. Holton, Robert A., et al. (1994) First total synthesis of taxol. 1. Functionalization of the B ring. Journal of the
American Chemical Society, 116.4: 1597-1598.
2. Ghosh SK., Planning of synthesis, In Advanced General Organic Chemistry- a Modern Approach, New Central
Book Agency Ltd., Kolkata, 2007; pp. 1197, 1198,1227,1228,1247.
3. Clayden, Greeves, Warren and Wothers, Retrosynthetic analysis, In Organic Chemistry, Oxford University Press
Inc., Newyork, 2001; pp. 773-778 .
4. Clayden, J. and Greeves, N. et al. (2001) Multiple step syntheses: avoid chemoselectivity problems. Organic
Chemistry. [e-book]. 2nd ed. OX2 6DP: Oxford University Press, Great Clarendon Street, Oxford. pp. 698-699
5. Clayden, J. and Greeves, N. et al. (2001) Functional group interconversion. Organic Chemistry. [e-book]. 2nd
ed. OX2 6DP: Oxford University Press, Great Clarendon Street, Oxford. pp. 699-702
6. https://ajrconline.org/HTMLPaper.aspx?Journal=Asian%20Journal%20of%20Research%20in%20Chemistry;PID
=2010-3-1-
1#:~:text=synthons%20or%20building%20blocks)%20for%20the%20target%20molecule%20is%20called,mole
cule%20through%20some%20key%20intermediate.
