Introduction to Retrosynthesis: Approach to Do Disconnection and

Practical Methods to Deal with Complex Molecules

Xinyu He

1,*

and Yuchen Chang

Sendelta International Academy, Shenzhen, 518108, China

The College of Arts and Sciences, University of Washington, Seattle, 98195-4550, U.S.A.

Keywords: Disconnection, Sythons, FGI, FGR, FGA, Dioxygentation Patterns, Synthetic Equivalent.

Abstract: Retrosynthesis analysis is one of the most important ways to do full synthetic routes designing. All of its

concept mainly include disconnection approach and sythons analysis respectively. In this passage, we want

to introduce some of the effective approaches to do disconnection and explain the concept to the people who

want to learn organic synthesis in the future or interested in this area. All about how to do disconnection,

how to find and use synthetic equivalent, how to deal with one and two groups, Electrocyclic, and Illogical

disconnection, how to use FGI, FGA, FGR to make those molecules which cannot be disconnected become

possible, and how to deal with Dioxygentation Patterns etc. Also, at the end, we will discuss some examples

that could enhance the memories.

1 INTRODUCTION

Imagine you're gluing bricks together when you see

a photo of the finished artwork, and that's the end

product. What is the first thing that springs to mind?

The answer is to locate the materials you require and

tie them according to the instruction book. Yes, this

is the conventional technique, as well as how we

normally think about synthesis. Retrosynthesis, on

the other hand, will take the end product and

imagine them into the fragment we already have,

and it is similar to the 'finding materials' step we

discussed before. Retrosynthesis may be thought of

in this way at its most fundamental level.

Retrosynthesis, often known as "the

disconnection approach," is an analytical process in

which a targeted organic molecule is deconstructed

or fragmented to obtain starting material, or

"Synthon". For a long term, many people have used

this train of thought to design their way to synthesis,

but there was not a clear definition. However, in

1964, Prof. Elias J. Corey, who was awarded Nobel

Prize in chemistry due to his great contribution to

synthetic organic chemistry. He was the first to

formalize 'Retrosynthesis' this concept in his book

‘The Logic of Chemical Synthesis’ (Tutor, 2020;

Corey, 1995). It provided different ideas to

synthesize single and complicated target molecules.

For some extremely complex molecules, the basic

goal is to generate precursors that correspond to

available starting materials. In other words,

retrosynthetic analysis is directed towards molecular

simplification. Often, a synthesis will have more

than one possible synthetic route. Retrosynthesis is

well suited for discovering different synthetic routes

and comparing them logically and straightforwardly.

Retrosynthetic analysis is a problem-solving

technique for transforming the structure of a

synthetic target molecule to a sequence of

progressively simpler structures along a pathway

which ultimately leads to a simple or commercially

available starting material for chemical synthesis

(Corey, 1995; Corey, 1988; Retrosynthetic analysis).

Take letters as examples:

Forward Synthesis Retrosynthesis

*A + B → AB *AB => A + B

In order to get AB, A and B should be found first.

Furthermore, retrosynthetic analysis is particularly

effective because there are so many different

intellectual paths to pursue (Wang, 2022). By

accessing its multiple possibilities of approaching

routes, the most cost-effective, environmentally

friendly, and concise path will be selected (Dmitrii A

He, X. and Chang, Y.

Introduction to Retrosynthesis: Approach to Do Disconnection and Practical Methods to Deal with Complex Molecules.

DOI: 10.5220/0012004000003625

In Proceedings of the 1st International Conference on Food Science and Biotechnology (FSB 2022), pages 153-159

ISBN: 978-989-758-638-5

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

153

(A) (B)

Figure 1: The example of the forward (A) and reverse (B) process of the hydrobromination of olefins.

, 2020). Take letters as examples again. In order to

gain molecule ABCD, several ways to synthesis can

be taken:

Ⅰ. A + B → AB => AB + C → ABC =>

ABC + D → ABCD

Ⅱ. A + B →AB => C + D → CD => AB +

CD → ABCD

...

As can be seen, there are many ways to arrange

and design paths to synthesis. Only thing need to be

considered is comparing the advantages and

disadvantages of each way, and select the best way

to be taken.

2 STARTING TO

DISCONNECTION

In the beginning, we mentioned that we may

consider binding bricks as the way to synthesis.

Now, we begin to disconnect some real molecules.

Disconnection means 'breaking' the bond of a

molecule to generate simpler fragments. Actually,

when disconnection occurs, instead of real bond

breaking, it is more like brainstorm and a process in

your head.

More simply, considering the analogy of a

simple game, cutting things into pieces. The

hexagon below shows that disconnection occurs, this

shape is cut into some fragments as the right

example denoted by the arrow. In figure 2, the two

sticks are broken in the middle, and two lines are

made up and down. There are several ways to cut

this shape into pieces. But we need to obey the rules

that keep the number of points at 6.

Figure 2: Showcase of a simple game.

In a similar way. Consider that this hexagon is a

genuine Cyclohexane. Now you must recognize that

more rules or restrictions have appeared. Following

the same procedure to break the C-C bond.

However, if you want to weaken the C-H bond, you

must keep the skeleton formula's amount of invisible

hydrogen constant. It's similar to breaking bonds,

yet they're fundamentally different. As Figure 3

shows, now consider a relatively complex molecule.

In (1,1), we know a reaction to produce the

molecule, then we can also do disconnection on it.

But this is not the only way to produce the target

molecule or the only way to disconnect. Thus, this

lead us to find or try more reaction mechanisms in a

long term. The more we know, the more simply the

synthesis processes.

FXP 1:

(1,1)

(1,2)

Figure 3: Reaction procedure.

3 APPROACH TO

DISCONNECTION

3.1 One Group Disconnection

By now, we know how to do disconnection. Thus,

we now need to consider how to allocate the

electrons when bonds are broken. This is what we

called bond cleavage. We have 3 situations to

consider---Heterolytic cleavage (Left-side),

Heterolytic cleavage(right-side), and homolytic

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cleavage. In Figure 4, Heterolytic cleavage

(right-side), the arrows show the direction of the

electron's movement. When we break bonds, the two

electrons are removed from the left-side molecule

and pulled to the right-side molecule, making the

left-side molecule cationic and the right-side

molecule anionic.

Figure 4: Heterolytic cleavage (right-side).

In Figure 5, there's another way to assign

electrons. And it is similar to Figure 4. Two

electrons are taken and pulled into the left-side

molecule and make it anionic, and the other side

becomes cationic.

Figure 5: Heterolytic cleavage (left-side).

Otherwise, all of the above are synth ions, except

for the final one. It is homolytic cleavage. When we

break a bond, the electrons split and become free

radicals on both sides. However, it is less common

to make free radical (Figure 5) when bond

disconnecting happens.

Figure 6: Homolytic cleavage.

When we finish our retrosynthesis analysis, it's

not easy to find all of the materials we need,

especially for some very complex molecules. So,

how do we go on with our work? Normally, we will

substitute other groups for the synthons we desire,

and these groups are referred to as synthetic

equivalents. A reagent that performs the function of

a synthon but cannot be utilized itself, usually due to

its instability.

For example:

Figure 7: Equivalent function using Grignard reagent.

In Figure 7, it is obvious to see the carbon on the

left is negative. We always use Grignard reagent to

show an equivalent function when we need to do

synthesis of some complex molecules. Since it

shows a negative property in the middle.

In this example, we use the synthetic equivalent

of the anion, the Grignard reagent or alkyl lithium,

in this case because none of the stable anions are

available. And in real retrosynthesis, when we talk

about Et as a synthon, we're talking about EtMgBr

or EtLi. Cause it will lead us to do disconnection

and the whole synthesis process.

3.2 Two Group Disconnection

So far, we finished the one group disconnection,

then how can we deal with the molecules with more

functional groups? We must now consider the

disconnection of the two groups, and I will

demonstrate how to do so using the examples below.

For example, in Figure 9, we have ketone and

alcohol groups, and there are a lot of ways to do

disconnection. The way we are easy to find is

breaking the carbon in the middle and separating it

into two parts. One is ketone and another is alcohol.

Nevertheless, we have a better way to approach

it. The oxygen's delocalized electrons will offer us a

more appropriate approach to detach. Then we

obtained a positive and a negative synthon which is

more common to find.

Figure 9: Two group disconnection.

Furthermore, we need to know what is FGI,

FGA and FGR. And all of these are significant

methods to do disconnection.

Figure 8: Example of retrosynthesis.

Introduction to Retrosynthesis: Approach to Do Disconnection and Practical Methods to Deal with Complex Molecules

155

Figure 10: Example of FGI.

FGI fully spelled Functional Group

interconversion. For this step, we always change

our functional group to others in order to make sure

we can disconnect the bond successfully. In Figure

10, the Carbonyl group was converted to an

Oxhydryl group. And allowing the disconnection to

occur.

FGA is the shorthand of Functional Group

Addition. In real synthesis designing, it is

sometimes necessary to add a functional group in

order to enable the interchange of functional groups

or later cut-off.

Figure 11: Example of FGA.

FGR is an abbreviation for Functional Group

Removal. It means remove a functional group from

a molecule. No like FGI, we need to remove some

certain functional groups and make sure we can do

disconnection. For instance, in Figure 12, we cut off

Br group by doing FGR.

Figure 12: Example of FGR.

3.3 Electrocyclic Disconnection

In this part, I will explain to you a very important

reaction mechanism that can dispose the

complicated molecules effectively. It is Diels -

Alder Reaction. And when we do retrosynthesis, it

is the typical 4+2 disconnection.

Figure 13 below, it is the basic way to display

how the process was. The left diene gets 2 double

bonds, and the dienophile only has one double bond.

As the arrow denotes, electrons from the dienophile

attack the carbon (1) and make a bond between the

diene and dienophile over there.

The double bond on the top of the diene

(between C (1) and C (2)) will further relocate to

carbon (2) and (3), then the double bond below will

connect with dienophile. All the six π bonds will

shift at the same time, and eventually formed

cyclohexene.

Figure 13: Basic process of electrocyclic disconnerction.

3.4 Illogical Disconnection (Connection)

Illogical disconnection is not a common way to do

disconnection, since it is making a bond rather than

breaking a bond. The reaction below is a

representative example to introduce this method.

Using the double bonds on the aldehydes and

combining them to form a single double bond and

abandon the oxygen. Finally, we'll get cyclohexene.

We may achieve this by using ozone, and the

reaction is known as Ozonolysis.

Figure 14: Example of illogical disconnection.

3.5 Dioxygentation Patterns

In this part, it is clear to see that the main purpose of

this process is dealing with ‘oxygen’. We will face

to a following of reactions, and I think the basic

synthetic way is to simplify problems into the model

we have worked out in the past.

3.6 1dioxygentation Patterns

As shown, once we see these patterns, we should

convert them into OH-groups by using FGI, then

OH-groups could disconnect to olefin.

3.7 2dioxygentation Patterns

For these molecules, FGI is used and we will have a

carbonyl and a hydroxyl group. Then we can repeat

the steps (Two groups disconnection) we mentioned

before.

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Figure 15: 1dioxygentation patterns.

Figure 16: 2dioxygentation patterns.

3.8 3dioxygentation Patterns

In this part, we need to convert the groups into two

carbonyl groups, and disconnect them into two parts.

Figure 17: 3dioxygentation patterns.

3.9 4dioxygentation Patterns

For these molecules, we want to make di-carbonyl

groups, thus we need to use two carbonyl groups.

And we have equivalent molecules. Using the

conjugate addition mechanism, when these two

molecules come into contact, the anion will attack

the double bond and form the di-carbonyl

compound.

3.10 5dioxygentation Patterns

For these molecules, we need to convert into alkene

with two carbonyl groups and repeat the step

(Illogical Disconnection) again.

Figure 19: 5dioxygentation patterns.

4 FOCUS ON MAXIMIZING

SIMPLIFICATION (FOCUS ON

SYMMETRY)

Efficient and concise synthetic routes based on the

symmetry of the molecule are gaining widespread

attention, and such synthetic routes can be

two-directional synthesis.

Figure 18: 4dioxygentation patterns.

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157

Figure 20: Synthetic routes of two-directional synthesis.

Figure 21: Process of reaction.

Figure 22: Process of reaction.

eg: sparteine has symmetry by introducing the

carbonyl group on the central methylene and then

symmetrically using the inverse Mannich cut on

both sides to highly simplify the molecule. This

yields three basic raw materials: piperidine,

formaldehyde, and acetone, all of which are

synthesized by the classical standard reaction.

Some target molecules do not have symmetry per

se, but have potential symmetry, and after certain

inverse synthetic transformations, a symmetric

molecule or a symmetric synthetic route can be

obtained, thus simplifying the synthetic design. For

example, there is no symmetry factor in Pummerer's

ketone molecule, but the two radicals obtained after

the cut is from the same precursor.

Addition of auxiliary functional groups followed

by cleavage (FGR).

Some target molecules can be cut off only after

the addition of appropriate functional groups to find

the correct route of synthesis. In the example figure

22, there is no functional group, and when a

hydroxyl group is introduced into the cyclohexyl

group, it can be cut further.

In the retrosynthetic transformation of the target

molecule, it is required that some necessary

structural unit exists in the target molecule, and only

when such a structural unit exists or such a

substructure can be generated, can the target

molecule be effectively simplified and

easy-to-access starting materials be deduced, such as

the following structural units of A, B is the basic

retron of Diels-Alder reaction, Robinson formation,

respectively.

Figure 23: Structural units.

The core problem of retrosynthesis analysis is

transformation, and inverse retron and synthon are

two aspects of this core problem, the former is the

necessary structural unit for transformation, and the

latter is the structural unit to be obtained by

transformation.

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5 CONCLUSION

The trend of organic synthesis is not to blindly

pursue new compounds, but to design and synthesize

compounds that are expected to have excellent

properties or have great significance. The

retrosynthetic analysis method takes a complex

synthetic problem and decomposes it into several

simple synthetic problems by dissecting it step by

step from tedious to simple through the inverse

method, and then forms a synthetic route from

simple to complex molecules. It makes many

difficult applications possible and saves research

costs, such as the application of drug synthesis. Such

a mode of thinking can also be applied to different

disciplines, such as synthetic aperture radar for

meteorological and atmospheric motion studies,

mathematical studies of inverse matrices, economic

reverse logistics.

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E. J. Corey, X-M. Cheng (1995). The Logic of Chemical

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E. J. Corey (1988). "Retrosynthetic Thinking - Essentials

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