A Proposed Total Synthesis of Sesquiterpenoids from

Chrysanthemum indicum

Weng Xiujie

1,*

, Tsz Laam Kiang

and Wufei Ji

Guangdong Technion-Israel Institute of Technology, Shantou Guangdong, China

Shanghai American School Puxi, Shanghai, 201107, China

Shenzhen College of International Education, Shenzhen Guangdong, 518043, China

Keywords: Retrosynthesis, Sesquiterpenes.

Abstract: The proposed retrosynthesis of a guaianolide-type sesquiterpenoid. The first route begins with the

construction of a 5,7,5-ring sesquiterpenoid through the connection α, β-cyclopentenone derivative from

Pauson-Khand reaction and trans lactone by a special Barbier reagent. Firstly, angelic acid is used to complete

the synthesis via esterification with enclosing central ring sesquiterpenoid. The second route starts with the

fabrication of a modified trans configured lactone with methylene. A following Pauson-Khand reaction

appends α, β-cyclopentenone on the lactone. Finally, angelic acid completes the synthesis by esterification

with exterior hydroxy of sesquiterpenoid.

1 INTRODUCTION

Chrysanthemum indicum is a genus of flowers that

belongs to the Asteraceae family. The dried flower

heads of Chrysanthemum indicum have been used for

tea preparations and have also been used in traditional

Chinese and Korean medicine for the treatment of

fever, migraine, eye irritation, hypertension, vertigo,

and respiratory diseases (Youssef et al. 2020, Kim et

al 2021). Over 190 isolated chemical constituents

have been identified from the Chrysanthemum

indicum plant to date, including phenylpropanoids,

terpenoids, flavonoids, and phenolic acids. Various

extracts and monomeric compounds from

Chrysanthemum indicum have different

pharmacological characteristics, such as having anti-

inflammatory, anti-oxidation, antipathogenic,

anticancer, immune regulation, and hepatoprotective

effects (Shao, Sun, Li, Chen 2020).

New compounds recently isolated from

Chrysanthemum indicum include three guaianolide

lactones and four 9-oxonerolidol glucosides. The

target molecule, compound 1, is a guaianolide-type

sesquiterpenoid isolated from Chrysanthemum

indicum flowers. (Kim et al 2021) Compound 1 may

provide some pharmacological value, as its molecular

structure is similar to the tumor inhibitors eupatorin

acetate and eupachlorin acetate, which are found in

Eupatorium rotundifolium. (Kupchan, Kelsey,

Cassady 1968)

In this paper, two detailed retrosynthetic

strategies and proposed synthetic routes of producing

the target molecule are presented

2 THE ANALYSIS OF

SESQUITERPENOIDS FROM

CHRYSANTHEMUM INDICUM

2.1 Sesquiterpenoids from

Chrysanthemum Indicum

Scheme 1: Three new guaianolide lactones (1−3) and four

new 9-oxonerolidol glucosides (5−8) isolated from the

flowers of Chrysanthemum indicum.

666

Xiujie, W., Kiang, T. and Ji, W.

A Proposed Total Synthesis of Sesquiterpenoids from Chrysanthemum indicum.

DOI: 10.5220/0011253200003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 666-670

ISBN: 978-989-758-595-1

Compound 1 features six contiguous stereocenters,

four of which are situated on common atoms

connecting two rings. A feature of critical importance

is the stereochemistry surrounding the lactone ring in

the synthetic design. Specifically, the 5,7-fused

lactone being trans-configured poses difficulties.

Furthermore, the α, β-cyclopentenone structure is

also synthetically challenging.

2.2 Synthetic Difficulties of Compound

Scheme 2: Molecular formula of Compound 1.

3 SYNTHETIC ROUTE OF

COMPOUND 1

3.1 Synthetic Route 1 of Compound 1

3.1.1 Retrosynthetic Strategy for Synthetic

Route 1.

Scheme 3: Retrosynthetic Strategy for Synthetic route 1.

After evaluating the structure of compound 1, the first

retrosynthetic analysis was proposed. The target

molecule can be divided into three major fragments,

the eastern angelic acid, the western α, β-

cyclopentenone structure, and the southern trans

configured lactone. Disconnecting the 5,7,5-ring

system and the angelic acid eliminates the possibility

of the eastern angelic acid side structure interfering

with other synthesis reactions. The hydroxyl group on

the seven-membered ring is a good cleavage point

from a retrosynthetic perspective as it provides a

convenient separation of the α, β-cyclopentenone

structure and the southern trans configured lactone.

The construction of southern trans configured lactone

relies on the nucleophilic attack of the Barbier

reagent 14 to the aldehyde of the α, β-

cyclopentenone, leading to transesterification. The

stereostructure of the lactone is also a synthetic

challenge. The construction of the α, β-

cyclopentenone 13 with exterior 2-chloro-isopropyl

chain could be achieved through a PK reaction of

designed alkynes and alkenes. However, since the

reaction does not possess chiral selectivity, it may

lead to the formation of impurities.

3.1.2 Synthetic Route 1

Scheme 4: Synthetic route 1.

The first proposed synthetic route begins at

compound 17, an α, β-cyclopentenone 18 decorated

with various groups that is derived from the Pauson-

Khand (PK) reaction between 17 and propyne.

Theoretically, compound 14 is one of the derived

isomers formed from the reaction. Since the PK

reaction does not possess chiral selectivity, the

formation of 18 may be in a low yield. Noteworthily,

the Nazarov Cyclization reaction of specific modified

divinyl ketones constructs 18, which reduces the

byproducts resulting from the PK reaction.

Compound 19 can be merged with allylic bromide

under In

-mediated allylation conditions to produce

lactone 20 in good yield and with the correct trans

configuration in the major diastereomer. (Hu,

Musacchio, Shen, Tao, Maimone, 2019)

The following steps focus on correcting the

different attached functional groups and closing the

centric seven-member ring. DDQ (2,3-dichloro-5,6-

dicyanobenzoquinone) hydrolyzes the PMB (4-

methoxybenzyl ester) protecting group in compound

19, and compound 20 is formed with a free alcohol

group. A Dess-Martin periodinane oxidation is

applied for aldehyde generation in compound 12. To

close the centric seven-member ring and form

compound 21, zinc and titanocene (III) complexes are

A Proposed Total Synthesis of Sesquiterpenoids from Chrysanthemum indicum

667

used as catalysts, which allows the allylic chloride

group in compound 12 to act as a nucleophilic zinc

reagent that adds to the aldehyde in a Barbier

reaction. (Estévez et al. 2009) This reaction mitigates

potential compatibility issues that may have been

present if a Grignard reagent had been used instead,

as a Barbier reaction can work with a reactive group.

The resulting compound, compound 21, is the core

framework of the target molecule. Finally, Steglich

esterification between angelic acid and compound 21

completes the formation of the target molecule.

An alternate proposed sub-route for forming the

target molecule after compound 12 is created

employs exogenous transition-metals in combination

with SnCl

as catalysts, and the addition of catalytic

quantities of PdCl

, which can close the centric ring.

This produces 22 in high yield, but gives the incorrect

stereochemical outcome at the hydroxyl group, which

contrasts the correct outcome in 21. (Hu, Musacchio,

Shen, Tao, Maimone, 2019)

However, the incorrect stereo configuration on

the hydroxyl group of 22 can be amended by the

Mitsunobu reaction to give the target molecule, 1.

3.2 Synthetic Route 1 of Compound 1

3.2.1 Retrosynthetic Strategy for Synthetic

Route 2

Scheme 5: Retrosynthetic Strategy for Synthetic route 2.

A second viable retrosynthetic analysis was also

proposed. In this retrosynthetic route, the target

molecule is disconnected into two major fragments,

the eastern angelic acid, and the 5,7,5-ring system.

The fused centric seven-member ring is cleaved due

to the presence of a hydroxyl group. The fabrication

of the α, β-cyclopentenone is a challenge in the

synthetic design. This could be resolved by a PK

reaction of alkyne 24 and an alkene with chlorine,

which then modifies the α, β-cyclopentenone.

Consequently, the structure of the core framework,

the 5,7,5-ring system, is formed. The unusual

structure of compound 24 requires further synthetic

consideration. The structure of compound 24 is

similar to the β-hydroxy-γ-vinyl-γ-lactone 26, which

is a common building block in natural products.

Hence, a retrosynthetic path connecting compound 24

and the β-hydroxy-γ-vinyl-γ-lactone 31 can be

formed. Due to the high reactivity of the exterior

vinyl bond at the α- position on the lactone, the

modification of α-position will be at a later stage. To

obtain 25, the vinyl bond in β-hydroxy-γ-vinyl-γ-

lactone 26 requires a chain extension and

transformation of the vinyl to an alkyl. Furthermore,

its hydroxyl also requires chain prolongation and

further functionalization. Compound 26 has a

structure similar to many natural products, which

results in multiple potential synthetic strategies. The

synthetic strategy for creating D-glucono-δ-lactone

was chosen. (Song, Hollingsworth 2001)

3.2.2 Synthetic Route 2. Preparation of the

Modified Stereo Lactone 36

Scheme 6: Synthetic route 2: Preparation of the modified

stereo lactone 36.

The second synthetic proposal begins with the

construction of compound 27, which undergoes a

Pauson-Khand reaction. Starting from D-glucono-δ-

lactone 27, chiral pool material is used to complete

the synthesis of the β-hydroxy-γ-vinyl-γ-lactone

enantiomers 28, which is further used to synthesize

compound 36. The synthetic route then treats 27 with

30% HBr in AcOH (acetic acid) at 60 ℃. This is

followed by a reaction with Zn dust and 50% aq.

AcOH (acetic acid) at room temperature and then at

reflux, producing compound 28 in 58% over yield.

(Song, Hollingsworth 2001) The free alcohol is then

protected with the TBS (tert-butyldimethylsilyl)

group. The homologation of lactone 29 is carried out

through the Wacker Oxidation of the terminal vinyl

bond to aldehyde, to produce compound 30.

Following this, the Seyferth-Gilbert alkyne formation

is used to generate molecule 31. (Fernandes 2020)

Removal of the TBS (tert-butyldimethylsilyl)

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

668

protection group is driven by hydrochloric acid in

MeOH. Due to the presence of an unsaturated bond,

Oppenauer oxidation is utilized to convert the alcohol

into ketone 33, in preparation for the elongation of the

side chain on the lactone in the next step. The ketone

responds to the Grignard reagent and participates in

C-C coupling reactions, which lengthens the size of

the chains surrounding the lactone, forming

compound 34. The active α-position of lactone is

available for hydroxylation by LDA (Lithium

diisopropylamide) in methanal under a controlled -40

℃ temperature, resulting in 35 in 92% yield.

(Baitinger, Mayer, Trauner 2010) In the presence of

fluoroboric acid, vinyl group formation becomes

possible via the dehydration of the hydroxyl group.

The carbon radical reactivity is inhibited by the non-

coordinating anion, thus producing 36.

3.2.3 Synthetic Route 2. Completion of the

Synthesis of Compound 1

Scheme 7: Synthetic route 2: Completion of the synthesis

of compound 1.

With compound 37 in place, the α, β-cyclopentenone

39 is derived from alkyne 37 and alkene 38, and

undergoes a PK reaction using dicobalt octacarbonyl.

Theoretically, there could be four products of the

reaction, 39 is one of them. To eliminate the ketone

on cyclopentene, treatment of 39 with dithiol in

TsOH (p-Toluenesulfonic acid) is followed by Raney

Nickel in EtOH, which leads to alkenyl shift due to

the conjugation effect, yielding compound 40. A Ti-

catalyzed Barbier-Type allylation generates centric

seven-member ring closure, thus producing the 5,7,5

fused ring system 41 with a hydroxyl group of the

desirable configuration for further esterification.

(Estévez et al. 2009) Angelic acid attaches to the 5,7,5

fused ring system via straightforward DCC-coupling

(DDC: N, N′-Dicyclohexylcarbodiimide) and gives

42. Compound 1, the target molecule, is then formed

via carbonylation on cyclopentenone by t-butyl

chromate. (Dodson 1955)

4 CONCLUSIONS

The compound 1 which isolated from the

Chrysanthemum indicum may exists some

pharmacological value, for its molecular structure is

similar to the tumor inhibitors eupatorin acetate and

eupachlorin acetate, which are found in Eupatorium

rotundifolium. In this paper, two retrosynthetic

strategies and proposed synthetic routes are proposed.

The target molecule, compound 1, is comprised of

three parts: an α, β-cyclopentenone structure, a trans

configured lactone, and an angelic acid structure. By

synthesizing each component and assembling them,

the target molecule can be obtained. Future efforts to

supplement the theoretical synthesis of

Sesquiterpenoids from Chrysanthemum Indicum

could focus on further researching the relevant

stereochemistry. An emphasis could be placed on

fine-tuning the stereochemical challenges of the

proposed synthetic routes.

AUTHOR

CONTRIBUTIONS

X.W., T. K., and W.J. evaluated the construction of

the lactone, researched details regarding the

characteristics of the target molecule, and

participated in the discussion. T. K and W.J.

researched the background of the target molecule.

X.W. designed the major parts of route 1. T. K. and

W.J. helped in the completion of route 1. X.W.

designed route 2 and undertook the writing work of

route 2. All authors worked on the retrosynthesis

strategy and wrote the paper. All authors read and

agreed on the content of the paper.

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