Retrosynthesis of a Newly Discovered Molecule in Betula Alnoides

Achieved by Considering a Similar Molecule,

3-Farnesyl-2,4,6-Trihydroxybenzophenon

Jihang Wu

, Rowena Ge

2,*

and Shu Liu

High School Attatched to Northeast Normal University, 377 Boxue St, Jingyue District, Changchun, Jilin, 130117, China

Lafayette College, 111 Quad Drive, Easton, PA, 18042, U.S.A.

Shanghai Experimental Foreign Language School, No.99 Yanji Dong Road, Yangpu District, Shanghai, 200093, China

Keywords:

Retrosynthesis, Benzophenone, 3-Farnesyl-2,4,6-Trihydroxybenzophenon.

Abstract: A recent found type of benzophenone (molecule A), a component of the alcohol extract of Betula alnoides,

has shown antiausterity activity against PANC-1 human pancreatic cancer cells. The molecular structure of

this new type of bezophenone is very similar to that of an already found bezophenone, 3-farnesyl-2,4,6-

trihydroxybenzophenon (molecule B), which demonstrates the availability of examining the production

method of this new bezophenone (molecule A) via considering the molecular structure of the already found

bezophenone (molecule B). In this paper, retrosynthesis (a theoretical analytic method) is applied to these two

bezophenones, in order to determine the types of molecules of the raw materials and a few efficient ways of

production.

1 INTRODUCTION

In a study published in the Journal of Nature Products

on May 19th. 2021, an ethanol extract of Betula

alnoides showed antiausterity activity, a method used

to discover lead compounds by using unprecedented

anticancer activities which target the tolerance of

cancer cells to nutrition starvation, against PANC-1

human pancreatic cancer cells under nutrient-

deprived conditions. According to the study, the

Phytochemical investigation of this active extract led

to the isolation of eight benzophenones (1−8), in

which 6 of them (2-7) are newly discovered and three

xanthones (9−11) (Omar, 2021).

The unknown molecule A (Figure1), one of the

main components of ethanol extract of Betula

alnoides, demonstrates great similarities in molecular

structure with 3-farnesyl-2,4,6-

trihydroxybenzophenone (Figure 2). Therefore, we

intend to use the concept of retrosynthesis to break

down the unknown molecule A (Figure1) through

such similarities.

Corresponding author

Retrosynthesis is an analytic approach based on

the desired product. When synthesizing this planning

process, the following rules should be clearly

understood. First of all, fragment ions produced

should be stable. Secondly, fragments are always in a

form of cations and anions so that they will be able to

switch between each other. Thirdly, the relationship

between the functional groups plays a role in deciding

the order of disconnection. For example, a functional

group that would boost the other to connect should be

disconnected last. Fourthly, electron-withdrawing

groups should be the first ones to be disconnected.

Fifthly, a balance of applying these rules should be

achieved in order to make the entire process as simple

as possible (Tutor, 2020).

Wu, J., Ge, R. and Liu, S.

Retrosynthesis of a Newly Discovered Molecule in Betula Alnoides Achieved by Considering a Similar Molecule, 3-Farnesyl-2,4,6-Trihydroxybenzophenon.

DOI: 10.5220/0012031900003633

In Proceedings of the 4th International Conference on Biotechnology and Biomedicine (ICBB 2022), pages 419-424

ISBN: 978-989-758-637-8

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

419

Figure 1: Molecular Structure of Molecule A.

Figure 2: Molecular Structure of Molecule B.

Considering the structures of molecule, A (Figure

1) and molecule B (Figure 2), they are both mainly

composed of benzophenone and a large chain with 15

carbons. Benzophenone is composed of two aromatic

rings, a structure with closed rings and conjugated

double bonds or lone pairs. One is a simple benzene

ring, the other is a trihydroxybenzene, called

phloroglucinol. The difference here is that between C

6''and C 7'', molecule A has a single bond whereas

molecule B has a double bond. In addition, C 7''of

molecule A is connected to a hydroxide group

whereas that of molecule B is connected to hydrogen.

2 METHODS

2.1 General Disconnecting Sequence

As regards to the rules of retrosynthesis, the general

sequence of disconnecting bonds is listed here. First,

the bond between C 3' and C 1''. Then, the bond

between C 1 and C 7 and the bond between C 1' and

C 7 could both be the second ones to be broken down.

The third step would be to break down the other

aromatic ring. Finally, the three hydroxide groups

could be considered to be disconnected, but not

necessarily. The following content includes the

considerations of the sequence and the mechanism.

2.2 Breaking Farnesyl Group

(Explanation)

The farnesyl group is a nucleophile that would attract

electrons, or withdraw electrons, from the aromatic

ring. As regards to the fourth rule listed in the

introductions, an electron-withdrawing group should

be disconnected first so the farnesyl group would be

the first one to disconnect. In addition, when

considering whether the first disconnecting functional

group would be the farnesyl group or the hydroxide

group, rule number three gives an answer. The

linkage of nucleophiles for aromatic rings would

deactivate the aromatic ring whereas the hydroxide

group would activate the ring. Here, a deactivating

step could be achieved after there is something that

has already activated the aromatic ring. Therefore, the

hydroxides on the benzene rings should not be

removed before the farnesyl. Besides, when removing

the farnesyl group, a more symmetrical structure with

two aromatic rings would be present, which allows

the following step to be more conveniently presented

(fifth rule). All of these rules support that the farnesyl

group should be disconnected first (Kolesnikov,

2016).

The following steps show Benzene alkylation

(Libretexts, 2020), where the R group represents the

farnesyl group.

Figure 3: Benzene Alkylation.

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420

As shown in Figure 3, firstly, the Cl, linked to the

farnesyl group, link to AlCl3, forming a farnesyl

cation.

Figure 4: Farnesyl Cation Formation.

As shown in Figure 4, secondly, the cation link to

the trihydroxybenzene by electrophilic addition

reaction.

Figure 5: HCl Formation.

As shown in Figure 5, finally, the AlCl4 pushes

the electrons back, splitting the hydrogen, forming a

by-product of HCl (Libretexts, 2020).

2.3 The Separation of the Two

Aromatic Rings

After removing the farnesyl group, the rest of the

structure is mainly composed of benzophenone with

two aromatic rings. The reason why the hydroxides

should still not be separated is that it could also boost

the following linkage of the aromatic ring and the acyl

group. Moreover, steps should be as simple as

possible. The next retrosynthesis step is to separate

the two aromatic rings. As there is a ketone (-R-C=O-

R-) in the middle of this complex, there will be two

pathways of disconnection: the benzene ring or the

trihydroxy benzene ring.

Figure 6: Formation of Acylium Ion and AlCl4-.

As shown in Figure 6, firstly, the reverse reaction

of both of the disconnections would start with a

formation of an Acylium ion and AlCl4, where the

AlCl3 acts as a catalyst. Here the R group would be

either trihydroxybenzene or benzene, which depends

on the pathway retrosynthesis is performed.

i. Breaking benzophenone into Benzene and

Benzoyl chloride, 2,4,6-trihydroxy (acyl chloride)

The reverse reaction mechanism would be a

simple electrophilic substitution.

Figure 7: Linking of the Aromatic Ring.

Retrosynthesis of a Newly Discovered Molecule in Betula Alnoides Achieved by Considering a Similar Molecule,

3-Farnesyl-2,4,6-Trihydroxybenzophenon

421

In Figure 7, the R group refers to the benzene ring.

In this mechanism, the acylium ion acts as a

nucleophile while the tri hydroxybenzene acts as an

electrophile. The inductive effect of the hydroxide

groups could "push" the electron onto the conjugated

double bond in the trihydroxybenzene which will

attach to the nucleophile. The move of electrons

allows the acylium ion and the aromatic ring to link

together.

Then, a deprotonation step formed by AlCl4-

would produce a by-product HCl and target molecule

benzophenone.

Figure 8: Formation of HCl.

Again, in figure 8, here the R group refers to the

benzene ring. In this mechanism, the AlCl4 act as an

electrophile, attaching the hydrogen on the

trihydroxybenzene, "pushing" back a pair of

electrons along the same way back, finally to the

oxygen. And the hydroxide and chloride are split,

forming a molecule of HCl (Libretexts, 2020).

ii. Breaking benzophenone into Phloroglucinol

and Benzoyl chloride (acyl chloride)

This mechanism is very similar to the last one.

The reverse reaction mechanism is also a simple

electrophilic substitution.

Figure 9: Phloroglucinol and Benzoyl Chloride (https://www.chemistry.msu.edu/faculty/reusch/VirtTxtJml/chapt15.htm).

In the Figure 9, the R group refers to

trihydroxybenzene. In this mechanism, the acylium

ion also acts as a nucleophile while the benzene acts

as an electrophile. The difference is that there is no

hydroxide group to "push" the electron pairs to the

nucleophile. The linkage of benzene and the acylium

ion is achieved by moving an electron pair from the

conjugate double bond itself to the acylium ion.

After that, the deprotonation step is very similar.

Figure 10: Formation of the conjugated double bond and HCl

(https://www.chemistry.msu.edu/faculty/reusch/VirtTxtJml/chapt15.htm.)

As shown in Figure 10, the electron pair on the

chloride of AlCl4 passes along the same path to the

benzene ring, forming the conjugated double bond

again. The chloride also attracts the hydrogen and

form a by-product of HCl.

2.4 Comparison of 3i. and 3ii.

There are two explanations for the effects that a

substituent exerts on the reactivity of a benzene ring:

Firstly, it depends on the inductive effect of the

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substituent. Except for metals and carbon, most

elements have much higher electronegativity than

hydrogen. As a result, sigma bonds are formed

between substituents containing nitrogen, oxygen,

halogen atoms, and an aromatic ring that gives an

inductive electron. Secondly, the conjugation of a

substituent function with the aromatic ring is another

important result. The electron pair donates or

withdraws electrons with the help of conjugated

interaction to form a benzene ring. If the atom bonded

to the ring contains nitrogen, oxygen, and halogens

which have one or more non-bonding valence shell

electron pairs, electrons may move into the aromatic

ring according to p-pie conjugation. Finally, the

benzene ring may receive electrons from polar double

and triple bonds.

In this paper, 3-farnesyl-2,4,6-

trihydroxybenzophenone(B) only has several double

bonds on its farnesyl chain while there is a hydroxyl

group located at 3’’ on the unknown compound. The

rules for oxygen are utilized on it and the hydroxyl

group actives benzene, making the following reaction

easier to happen

(https://www.chemistry.msu.edu/faculty/reusch/Virt

TxtJml/chapt15.htm.)

2.5 The Separation Between the Other

Aromatic Ring and the Acyl Group

No matter which passway it has gone through in the

last step, the next step would be just to break down

the linkage between the acyl group with the other

aromatic ring. And the step would be basically the

same as before. Therefore, the advantage of

hydroxide boosting the linkage between the aromatic

ring and the acyl group would ultimately appear for

both sequences.

2.6 The Separation of the Three

Hydroxides

This step is optional because the trihydroxybenzene,

phloroglucinol (which is made from glucosides, plant

extracts and resins), is a common raw material, and

could simply be considered as a final molecule in the

process of planning retrosynthesis (Hoool, 2018).

2.6.1 Converting Molecule B to A

This step could be achieved by altering the reactant of

farnesyl of the benzene alkylation

(https://www.chemistry.msu.edu/faculty/reusch/Virt

TxtJml/chapt15.htm.), which means converting the

farnesyl group into a similar one with a hydroxide on

C 7'' and no double bonds between C 6'' and C 7''. The

reason why adding the hydroxide onto the farnesyl

group first is that the reaction would be easier to target

without disruptions.

This step is an electrophilic addition reaction

Figure 11. Conversion of Molecule B to A

In Figure 11, the proton acts as a nucleophile and

the double bond between C 6'' and C 7'' acts as an

electrophile, where hydrogen is linked onto C 6''.

Then a carbocation is formed at C 7'', which acts as a

nucleophile, attacked by the lone pair of the water

molecule, and the hydroxide is linked onto C 7''.

According to the inductive effect, the hydroxide

group is more likely to locate on C 7'' than C 6'' as

there is more inductive effect on C 7'' that would

stabilize it. This theory is the same as the inductive

effect on C 2'' and C 10'', which means these two are

also not "favorited". In addition, when considering

the inductive effect of C 3'' and C 11'' compared with

C 7'', the inductive effect is not as symmetrical as that

of C 7''. Therefore, both of these two considerations

support that the hydroxide group would be the mostly

located on C 7'', with a small proportion of the other

Cs.

When considering the way of extracting only the

target molecule with hydroxide group located on C

7'', their slightly different boiling points would allow

fractional distillation to separate them and isolate the

wanted products.

2.6.2 Conclusion and Evaluation

In conclusion, we aim to use a known compound to

deduce a new one that obtains a similar structure by

connecting and breaking functional groups or

inducing and moving electrons. This research paper

promotes the understanding of the retrosynthesis

process of 3-farnesyl-2,4,6-trihydroxybenzophenone.

Retrosynthesis of a Newly Discovered Molecule in Betula Alnoides Achieved by Considering a Similar Molecule,

3-Farnesyl-2,4,6-Trihydroxybenzophenon

423

The results suggest that it may be a relatively simple

way to find a new medicine that targets pancreatic

cancer.

Since the retrosynthesis shown above have not

been proven in a real experiment, the feasibility of

such methods is unknown. Other factors such as

financial restrictions, potential safety hazards, and the

duration of a total experiment should be considered to

achieve practicality. Furthermore, only two routes

were analyzed so it was possible that simpler ways

were neglected. In addition, distillation should be

performed in conditions as perfect as possible so

common experimental tools may not be able to

separate the desired product because it may be mixed

with other molecules that have similar boiling points.

Overall, further testification and research are required

to determine the hypothesis provided in this paper.

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