Total synthesis of agastaquinone, a diterpenoid quinone isolated from Agastache rugosa

Article abstract of DOI:10.1080/00397911.2020.1825742

Agastaquinone is a tricyclic diterpenoid isolated from Agastache rugose. The first total synthesis of agastaquinone was accomplished based on intramolecular Friedel-Crafts acylation of aryl lactone followed by aromatization leading to the tricyclic phenol

Full text of DOI:10.1080/00397911.2020.1825742

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Total synthesis of agastaquinone, a diterpenoid
quinone isolated from Agastache rugosa
Sangku Lee , Jisu Yoo , Jae-Kyung Jung , Jae Nyoung Kim & Myeong Sik Yoon
To cite this article: Sangku Lee , Jisu Yoo , Jae-Kyung Jung , Jae Nyoung Kim & Myeong Sik
Yoon (2020): Total synthesis of agastaquinone, a diterpenoid quinone isolated from Agastache
rugosa , Synthetic Communications, DOI: 10.1080/00397911.2020.1825742
To link to this article: https://doi.org/10.1080/00397911.2020.1825742
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https://doi.org/10.1080/00397911.2020.1825742
Total synthesis of agastaquinone, a diterpenoid quinone
isolated from Agastache rugosa
Sangku Leea, Jisu Yooa,b, Jae-Kyung Jungb, Jae Nyoung Kimc, and
Myeong Sik Yoond
b
aAnticancer Agent Research Center, KRIBB, Cheongju, Republic of Korea; College of Pharmacy,
c
Chungbuk National University, Cheongju, Republic of Korea; Department of Chemistry, Chonnam
d
National University, Gwangju, Republic of Korea; Department of Pharmaceutical Engineering, Hoseo
University, Asan, Republic of Korea
ABSTRACT
ARTICLE HISTORY
Received 22 July 2020
Agastaquinone is a tricyclic diterpenoid isolated from Agastache
rugose. The first total synthesis of agastaquinone was accomplished
based on intramolecular Friedel-Crafts acylation of aryl lactone fol-
lowed by aromatization leading to the tricyclic phenol core structure
as a key step.
KEYWORDS
Friedel-Crafts acylation;
diterpenoid; quinone;
total synthesis
GRAPHICAL ABSTRACT
Introduction
Agastaquinone, a tricyclic diterpenoid isolated by our research group from the roots of
Agastache rugose, showed nonspecific cytotoxic activities against several human cancer
cell lines in vitro such as A549, SK-OV-3, SK-MEL-2, XF498, and HCT15.[1] It was
reported to show a potent inhibitory effect against human immunodeficiency virus type
1 (HIV-1) protease activity with an IC50 value of 87 uM.[2] As we have been interested
in further biological studies including in vivo activities, the total synthesis of agastaqui-
none should be accomplished, thereby enabling to provide a synthetic way that would
prepare its analogues for the development of new therapeutics. Herein we report a con-
cise total synthesis of agastaquinone. To the best of our knowledge this is the first
report on the total synthesis of agastaquinone.
CONTACT Sangku Lee
Korea; Myeong Sik Yoon
Asan, Republic of Korea.
sangku@kribb.re.kr
msyoon@hoseo.edu
Anticancer Agent Research Center, KRIBB, Cheongju, Republic of
Department of Pharmaceutical Engineering, Hoseo University,
Supplemental data for this article is available at on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

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S. LEE ET AL.
Scheme 1. Retrosynthetic analysis of agastaquinone (1)
Scheme 2. Preparation of aryl bromide 4 and ketone 5
Results and discussion
Scheme 1 depicted the strategy we envisioned to achieve the synthesis of agastaquinone
(1). Quinone 1 would be formed from compound 2 through sequential di-methylation,
olefination, and oxidation procedures. Tricyclic phenol 2 could be constructed from
compound 3 by intramolecular Friedel-Crafts acylation and subsequent aromatization.
Lactone 3 would be generated by Grignard reaction of aryl bromide 4 with ketone 5.

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Scheme 3. Synthesis of agastaquinone (1)
To accomplish the synthetic route for agastaquinone (1), we required aryl bromide 4
and ketone 5. We thus began our synthetic venture with preparation of the known aryl
bromide 4 (Scheme 2).[3] Lithiation of 1,3-dimethoxybenzene (6) and followed by add-
ition of acetone afforded tertiary alcohol 7, which was reduced by treatment with
Et3SiH in the presence of trifluoroacetic acid to yield compound 8.[4] To avoid bromi-
nation at the position located ortho to the two methoxy groups of compound 8, a one-
pot, two step-sequence to prepare aryl bromide was utilized.[3] A sterically controlled
iridium-catalyzed borylation of compound 8 and subsequent bromination with copper
(II) bromide provided aryl bromide 4. On the other hand, ketone 5 was prepared by
alkylation of 1,4-cyclohexanedione monoethyleneketal (9) with ethyl bromoacetate.[5]
With both aryl bromide 4 and ketone 5 in hand, our synthetic approach to agastaqui-
none (1) was outlined in Scheme 3. The reaction of Grignard reagent obtained from aryl
bromide 4 with ketone 5 afforded lactone 3 in 73% yield.[6] After conversion of ketal 3 to
the corresponding ketone 10 by acidic hydrolysis, microwave irradiation of ketone 10 in
the presence of trifluoroacetic acid-trifluoroacetic anhydride (1:1) at 100 ꢀC via Friedel-
Crafts acylation and susequent aromatization furnished tricyclic phenol 2 in 90% yield.[6,7]
Attempts to produce compound 2 directly from ketal lactone 3 via Friedel-Crafts acylation
under acidic conditions (PPA, TFA, H3PO4, H2SO4, AcOH) failed.[8] Unfortunately, all
attempts to effect the Friedel-Crafts acylation provided a complicated mixture of products.
After conversion of ketal 3 to the corresponding ketone 10, the Friedel-Crafts acylation for
the formation of compound 2 could be successful. An acidic condition using trifluoroace-
tic acid-trifluoroacetic anhydride (1:1)[7] and heating by microwave irradiation enhanced
the formation of tricyclic phenol 2 in terms of yield and short reaction times.
Dimethylation of compound 2 and subsequent olefination gave a,b-unsaturated ketone
11. Finally, Oxidation of compound 11 with 30% H2O2 in HCO2H-AcOH (1:1)[9] afforded
agastaquinone (1), which was in good agreement with the reported naturally occuring
agastaquinone in all aspects including 1H NMR, 13C NMR, and HRMS spectra.[1]
Conclusions
In conclusion, we have completed the first total synthesis of agastaquinone in 6 steps
and 10% overall yield from the known compounds 4 and 5. We have described the

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S. LEE ET AL.
efficient synthetic approach to agastaquinone based on intramolecular Friedel-Crafts
acylation of aryl lactone followed by aromatization leading to the tricyclic phenol core
structure, which through sequential dimethylation, olefination and oxidation yielded a
tricyclic diterpenoid quinone, agastaquinone.
Experimental
Preparation of compound 2
A solution of lactone 10 (0.12 g, 0.36 mmol) and trifluoroacetic acid (1 mL) in trifluoro-
acetic anhydride (1 mL) was placed in a microwave vessel (2–5 mL). The vessel was
sealed and subjected to microwave irradiation for 2 h at 100 ꢀC in a Biotage Initiator
microwave synthesizer. After cooling, the mixture was diluted with water, extracted
three times with ethyl acetate. The combined extracts were washed with brine, dried
over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel
1
(4:1 hexane-EtOAc) to afford 0.11 g (90%) of tricyclic phenol 2 as a yellow oil: H NMR
(300 MHz, CDCl3) d 9.54 (s, 1H), 7.01 (s, 1H), 6.53 (s, 1H), 3.95 (s, 3H), 3.88 (s, 3H),
3.65 (s, 2H), 3.59 (m, 1H), 3.29 (t, J ¼ 5.1 Hz, 2H), 2.69 (t, J ¼ 5.1 Hz, 2H), 1.41 (d,
J ¼ 5.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) d 210.4, 158.6, 153.8, 152.4, 132.8, 132.6,
127.6, 120.5, 110.2, 108.7, 99.4, 63.7, 55.0, 44.5, 38.7, 25.4, 24.4, 20.9; HRMS (ESI) m/z
313.1395 [(M-H)þ, calculated for C19H21O4 313.1440]
Funding
This work was supported from the R&D Convergence Program [CAP-16-03-KRIBB] of National
Research Council of Science & Technology (NST) of Republic of Korea and KRIBB Research
Initiative Program.
References
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