A Categorical Guide to Basic Terminologies, Principles, and

Disconnections in Retrosynthesis

Zixuan Lin

1,*

and Jiaqiu He

Shenzhen Middle School, Shenzhen, Guangdong 518024, China

WLSA Shanghai Academy, Shanghai 201900, China

Keywords:

Organic Chemistry, Retrosynthesis, Disconnection, Synthon, Functional Group.

Abstract:

Retrosynthesis is a powerful tool for the synthetic analysis of organic compounds. Although it is a relatively

newly proposed idea, it has now been put into wide use. All compounds can have several possible

retrosynthetic paths, but the feasibility and practicality of a path is determined by certain concepts and

principles. This paper is an introduction to retrosynthesis, starting with basic concepts, reactions, and guiding

principles, and proceeding to a detailed guide to basic disconnections categorized with regard to the class of

target molecules. This work attempts to provide introductory-level students of organic chemistry with a

handbook allowing them to quickly learn to recognize and design basic retrosynthetic strategies.

1 INTRODUCTION

Retrosynthetic analysis was proposed by American

organic chemist E. J. Corey of Harvard University,

who later won the Nobel prize in Chemistry in 1990

for the proposal (Shampo, 2012). The period between

1960 and 1990 witnessed the evolution of

retrosynthesis, and the concept developed into a

mature subject that now deserves a separate space in

university courses. Early development focused on the

idea of antagonistic methods and perfected the

disconnections (Rao, 2020).

The importance of retrosynthetic analysis lies in

its wide applicability. For example, natural products

including alkaloids, rubber, as well as dyes and

fragrances. Chemists soon starts to separate, purify,

analyze and determine the structure of these

compounds. These substances can be applied in

various fields, such as medicine, plastics, electronics,

etc. (Divakaran, 2008). Retrosynthesis provides a

means for the large-scale production of compounds,

and makes them available for research and use in a

low-cost method for the benefit of mankind.

2 WHAT IS RETROSYNTHESIS?

Retrosynthesis is the process of recursively

decomposing a target molecule into simpler and

available starting materials (Ghosh, 2020). For

instance, a hexagon can be made by first imagining

its constituent pieces, as shown in Figure 1.

Figure 1: Decomposing a hexagon.

Chemical molecules can be made in a similar way,

except that instead of breaking down shapes at

random as done with geometric shapes, molecules

Correspondence author

can be deconstructed by disconnecting bonds, as

shown in Figure 2.

Lin, Z. and He, J.

A Categorical Guide to Basic Terminologies, Principles, and Disconnections in Retrosynthesis.

DOI: 10.5220/0012020200003633

In Proceedings of the 4th International Conference on Biotechnology and Biomedicine (ICBB 2022), pages 301-309

ISBN: 978-989-758-637-8

 2023 by SCITEPRESS – Science and Technology Publications, Lda. Under CC license (CC BY-NC-ND 4.0)

301

Figure 2: Disconnecting a cyclobutene.

In retrosynthesis, the symbol “⟹”represents the

reverse of a synthetic reaction, the symbol “(”

indicates the disconnection of bonds, and “ ↝ ”

indicates electron transfer.

3 CONCEPTS

3.1 Target Molecule (T.M.)

The target molecule is the desired molecule, and the

molecule whose synthesis is being analyzed.

3.2 Disconnection

A disconnection is an analytical operation which

involves the imaginary cleavage of a bond that

deconstructs a molecule into simpler pieces; the

reverse of a synthetic reaction.

Disconnections are in essence the transfer of

electrons. There are two possibilities: after the

disconnection of a single bond, the electrons are

either retained by respective atoms, or they are both

transferred to a single atom (see Figure 3). However,

the latter is more common in retrosynthesis.

Figure 3: Three possibilities of a disconnection

3.3 Synthon

A synthon is a fragment resulting from a

disconnection, usually a cation or an anion (Ghosh,

2020). (It may sometimes be used interchangeably

with “synthetic equivalent”.) There are two kinds of

synthons, namely the negatively charged

nucleophiles and the positively charged nucleophiles,

as shown in Figure 4.

Figure 4: Synthons.

3.4 Synthetic Equivalent

A synthetic equivalent carries out the functions of a

synthon which cannot be used itself, usually because

it is too unstable (Warren, 2002). The concept will be

discussed in more detail in a later section.

3.5 “Fine tuning”

“Fine tunings” are operations on functional groups

that facilitate disconnections. The first and most

common type of fine tuning is functional group

interconversion, or FGI (see Figure 5). It is the

operation of converting a functional group into

another, usually through oxidation. FGI can also be

used for protection of certain functional groups from

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unwanted reactions. FGI is the most frequently used

fine tuning method, and most retrosynthesis involve a

sequence of disconnections and functional group

interconversions. The second is functional group

addition, or FGA (see Figure 6), often used to guide

disconnections, or to enable the installation of other

functional groups (Singh, 2013). The third is

functional group removal, or FGR, which is the

operation of removing a functional group (see Figure

7).

Figure 5: Functional group interconversion.

Figure 6: Functional group addition.

Figure 7: Functional group removal.

3.6 Guiding Principles

A molecule can have several possible retrosynthetic

routes. While all of them may be correct, certain

strategies are better than others. The following

guiding principles will help you recognize and design

strategic disconnections. The first rule is greatest

simplification. Resulting compounds after a

disconnection should be easier to make than the target

molecule. A disconnection should also have a

reasonable mechanism: a strategic disconnection

should give stable and recognizable synthons, as will

be demonstrated in subsequent examples. The third

principle is minimal fine tuning. While fine tuning

does facilitate disconnections to a certain extent, they

are not simplifying, and frequent use of fine tuning

may lead to redundancy. Lastly, good strategies

should have maximum convergency. Since most

chemical reactions do not have full efficiency, a

synthesis with too many steps will have a low yield.

(Warren, 2002) To avoid the problem, convergent

instead of linear strategies should be employed, as

shown in Figure 8.

Figure 8: Linear and convergent strategies.

Other concepts and principles will be introduced

in application in later sections.

4 DISCONNECTING

STRATEGIES

4.1 One-Group Disconnections

4.1.1 Alcohols

As mentioned previously, disconnections are the

transfer of electrons. Lone pair electrons can serve as

a guide. For instance, the disconnection of alcohols

can start with the transfer of a lone pair electron on

the oxygen atom, as shown in Figure 9.

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Figure 9: Disconnection of an alcohol.

Both ions are stable, so this is considered a

strategic disconnection. Figure 10 shows an

alternative route, where the electron goes the other

way. But the resulting anion is clearly unstable, so

this is an undesirable strategy.

Figure 10: Undesired disconnection for an alcohol.

However, most of the times, there may not be a

disconnection that gives stable synthons. The

problem can be solved by using stable synthetic

equivalents. For instance, Grignard reagents (see

Figure 11) are good synthetic equivalents for unstable

carbanions, while NaBH

and LiAlH

are equivalent

to the hydrogen anion H

. (Warren, 2002)

Figure 11: Grignard reagent as synthetic equivalent

4.1.2 Acids

The disconnection of acids can also start from the

oxygen, as shown in Figure 12.

Figure 12: Disconnection of an acid.

4.1.3 Ketones

A simple retrosynthesis for ketones is to first convert

them to alcohols, and then make the disconnection

(see Figure 13).

Figure 13: Disconnection of a ketone.

4.1.4 Olefins

Olefins can be made by simply disconnecting the

double bond (see Figure 14).

Figure 14: disconnection of an olefin

This is the Wittig reaction, with its mechanism

presented in Figure 15.

Figure 15: mechanism of the Wittig reaction

4.2 Two-Group Disconnections

When a compound contains two oxygenation groups,

they can be used together to guide disconnections.

4.2.1 1, 3-dioxygenated Compounds

Figure 16 shows a few of the variations of the 1,3-

dioxygenation pattern. Note that a double bond is

equivalent to a hydroxy group.

Figure 16: 1, 3-dioxygenated compounds

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1, 3-dioxygenated compounds can generally be

disconnected at the 𝛼, 𝛽 bond (see Figure 17).

Figure 17: General disconnection strategy for 1,3-dioxygenated compounds.

For instance, the 𝛽-hydroxy carbonyl (see Figure

18), 1,3-dicarbonyl (see Figure 19), and 𝛼 , 𝛽 -

unsaturated carbonyl (see Figure 20) compounds can

all be disconnected following the pattern shown in

Figure 17.

Figure 18: Disconnection of a β-hydroxy carbonyl.

Figure 19: Disconnection of a 1,3-dicarbonyl.

Figure 20: Disconnection of an α,β-unsaturated carbonyl.

4.2.2 1,5-dioxygenation

The mechanism of the disconnection of 1,5-

dioxygenation pattern is mostly similar to that of the

1,3-dioxygenation pattern. The compound can be

disconnected at any of its two middle bonds, as

shown in Figure 21.

Figure 21: Disconnection of a 1,5-dioxygenation.

The reverse of this disconnection—the reaction

using 𝛼 , 𝛽 -unsaturated carbonyl compounds as

electrophiles—is called the Michael reaction.

Figure 22 shows a more integrated example, in

which the 𝛼,𝛽-unsaturated ketone has both 1,3- and

1,5-dioxygenation patterns. A good retrosynthetic

path is to first disconnect the C-C double bond, and

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then the 𝛽, 𝛾 bond in the 1,5-dioxygenation pattern,

as shown in Figure 22.

Figure 22: Integrated example of disconnection for a compound with 1,3- and 1,5-dioxygenation patterns.

4.3 Illogical Disconnections

Disconnections resulting in synthons in which the

normal polarity is reversed are called illogical

disconnections (Ghosh, 2020). As a rule of thumb,

compounds with an even number of C atoms between

two functional groups produce illogical synthons

because of a dissonance of charges arising from their

oxidation patterns (Šunjić, 2016). For instance, while

disconnecting the middle bond of a 1,3-dicarbonyl

results in logical synthons (see Figure 23), a 1,2-

dicarbonyl produces two illogical synthons that react

unfavorably due to a like charges (see Figure 24).

Figure 23: Disconnection of a 1,3-dicarbonyl.

Figure 24: Disconnection of a 1,2-dicarbonyl.

4.3.1 Illogical Synthons

The key to illogical disconnections is recognizing

illogical synthons and replacing them with their

corresponding synthetic equivalents. The synthetic

equivalent of a positively charged illogical synthon is

called an illogical electrophile (see Figure 25), while

that of a negatively charged illogical synthon is an

illogical nucleophile (see Figure 26).

Figure 25: Illogical electrophiles and their synthetic equivalents.

Figure 26: Illogical nucleophiles and their synthetic equivalents.

4.3.2 1,2-dioxygenation

An 𝛼-hydroxy-carbonyl can be disconnected in the

middle, resulting in a benzyl alcohol electrophile and

an illogical nucleophile equivalent to a benzaldehyde,

as shown in Figure 27.

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Figure 27: Disconnection of an α-hydroxy-carbonyl.

The strategy for 1,2-dicarbonyl compounds is

similar. The most convenient way to make a 1,2-

dicarbonyl is to convert it to an 𝛼-hydroxy-ketone

first, and then synthesize it from there (see Figure 28).

Figure 28: Disconnection of a 1,2-dicarbonyl.

The disconnection of 1,2-diols is slightly different.

Figure 29 shows a good approach, which is to use an

olefin as the intermediate and disconnect the double

bond by the Wittig reaction.

Figure 29: Disconnection of a 1,2-diols.

4.3.3 1,4-dixoygenation

The disconnecting strategy for the 1,4-dioxygenation

pattern is similar to that of 1,2-dioxygenated

compounds in essence: disconnection of the 𝛽, 𝛾

bond results in two synthons, one of them illogical.

The disconnection of the 1,4-dicarbonyl shown in

Figure 30 results in a stable acetone nucleophile and

an illogical electrophile, which can be substituted by

its corresponding synthetic equivalent.

Figure 30: Disconnection of a 1,4-carbonyl.

𝛾 -hydroxy-carbonyl compounds can be

disconnected in a similar fashion (see Figure 31).

Figure 31: Disconnection of an α-hydroxy-carbonyl.

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4.3.4 1,6-Dioxygenation

1,6-dioxygenated compounds have a different

synthetic strategy. Instead of disconnecting bonds in

the usual sense, a general strategy is to disconnect the

two oxygenation groups, as shown in Figure 32.

Figure 32: Disconnection of a 1,6-dioxygenated compound.

Subsequent disconnections of the ring structure

will be introduced in a later section.

All compounds with a 1,6-oxygenation pattern

can be made by first converting the corresponding

functional groups to carbonyl groups, and then

reconnecting the bonds in a similar fashion.

4.4 Pericyclic Disconnections

Pericyclic reactions are concerted reactions with

cyclic transition states.

4.4.1 The Common Atom Approach

The common atom approach is a guiding principle for

the retrosynthesis of polycyclic compounds. The

most strategic disconnections are made by breaking

bonds connecting atoms that are common to more

than one ring, for they lead to maximum

simplification. For instance, in the compound shown

in Figure 33, the common atoms are marked in bold

along with the most strategic bonds.

Figure 33: A hetidine analyzed with the common atom approach.

4.4.2 Diels-Alder Reaction

The Diels-Alder reaction is one of the most important

reactions in organic synthesis. It occurs between a

conjugated diene and a dienophile (an alkene or

alkyne), and is sometimes referred to as a [2+4]-

cycloaddition (Gunawardena, 2020). Its

disconnection is easily recognizable as the reverse of

the reaction. Below are the mechanisms of the

disconnection (Byrne, 2013):

Figure 34: Mechanisms of the Diels-Alder reaction.

Below are some examples (Figure 35):

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Figure 35: Examples of the Diels-Alder reaction.

However, it is important to note that although

different types of disconnections have different

mechanisms, they are under the same theoretical

backdrop and are guided by the same principles, and

it is important, therefore, to look at them as a whole

instead of simply treating them as separate operations.

5 CONCLUSION

This work introduces basic retrosynthetic concepts

including terminologies and guiding principles, and

gives a categorical and detailed overview of

disconnections of molecules with different

functionalities. This work summarizes and builds

upon previous introductory works, and can serve as a

guide to retrosynthesis for beginning students of

organic chemistry, providing them with the

knowledge base which will help them in further

studies in the field. However, this paper only covers

representative concepts, disconnections, and

strategies currently, and there will be continued

efforts to make the work more comprehensive and

readable.

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