Isolation, Structure Elucidation, and Total Synthesis of Myrtuspirone A from Myrtus communis

Article abstract of DOI:10.1021/acs.orglett.9b00108

A pair of enantiomeric triketone-phloroglucinol hybrids, (+)- and (-)-myrtuspirone A (1), featuring an unprecedented 3-isopropyl-3H-spiro[benzofuran-2,1′-cyclohexane] backbone, were isolated from the leaves of Myrtus communis. The absolute configuration o

Full text of DOI:10.1021/acs.orglett.9b00108

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Isolation, Structure Elucidation, and Total Synthesis of Myrtuspirone
A from Myrtus communis
†
,‡,∥
§,∥
‡
,‡
‡
†
‡
Min-Jing Cheng,
Xin-Yi Yang, Jia-Qing Cao, Chao Liu, Li-Ping Zhong, Ying Wang,
§
,†
,‡
Xue-Fu You, Chuang-Chuang Li,* Lei Wang,* and Wen-Cai Ye*
†Department of Chemistry and Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen 518055, P.R.
China
‡
Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy,
Jinan University, Guangzhou 510632, P.R. China
§
Beijing Key Laboratory of Antimicrobial Agents/Laboratory of Pharmacology, Institute of Medicinal Biotechnology, Chinese
Academy of Medical Sciences/Peking Union Medical College, Beijing 100050, P.R. China
*
S Supporting Information
ABSTRACT: A pair of enantiomeric triketone−phloroglucinol hybrids, (+)- and (−)-myrtuspirone A (1), featuring an
unprecedented 3-isopropyl-3H-spiro[benzofuran-2,1′-cyclohexane] backbone, were isolated from the leaves of Myrtus
communis. The absolute configuration of each enantiomer of 1 was determined by X-ray diffraction and chemical calculations.
Furthermore, the gram-scale total syntheses of (±)-1 and (−)-1 were conducted in four steps using a Michael-N-
iodosuccinimide (NIS)-mediated (3 + 2)-annulation reaction. Both (+)- and (−)-1 exhibited antibacterial activities against
Gram-positive bacteria including multidrug-resistant strains.
he plants of the family Myrtaceae are well-known for
triketone−phloroglucinol biogenetically constructed by a (3
2) annulation reaction, which forms an unprecedented 3-
T
producing structurally diverse phloroglucinols with
+
1
various biological activities. In recent years, Myrtaceous
phloroglucinols have attracted substantial attention from
isopropyl-3H-spiro[benzofuran-2,1′-cyclohexane] backbone.
The absolute configuration of each enantiomer of 1 was
determined by X-ray diffraction and electronic circular
dichroism (ECD) calculations. The gram scale site-selective
and enantioselective total synthesis of (±)-1 and (−)-1 was
achieved using a unique Michael−NIS-mediated (3 + 2)-
annulation approach. Furthermore, both (+)-1 and (-)-1
exhibited antibacterial activities against Gram-positive bacteria
including several multidrug-resistant strains (methicillin-
resistant Staphylococcus aureus (MRSA), vancomycin-inter-
mediate S. aureus (VISA), and vancomycin-resistant Enter-
ococcus faecium (VRE)). Herein, we report the structure
elucidation, total synthesis, and antibacterial activities of
myrtuspirone A (1).
2
chemists and pharmacologists. Some Myrtaceous phloroglu-
cinols with new skeletons and significant biological effects had
been reported, such as antitumor phloroglucinol−sesquiterpe-
3
a
3b
nes, anti-inflammatory phloroglucinol−monoterpenes,
3c
antimalarial triketone−phloroglucinol−triketones, and anti-
3d
bacterial triketone−phloroglucinol−monoterpenes. Among
these compounds, triketone−phloroglucinol hybrids consist of
triketone and phloroglucinol monomers, which are biogeneti-
cally linked through a Michael addition or oxidative coupling
4
to form densely functionalized pyran or furan rings.
Myrtus communis L. (Myrtaceae), an herbal medicine with
antibacterial and insecticidal effects, is native to the
5
Mediterranean region. As part of our search for structurally
unique and biologically interesting natural products, we
reported the isolation of several new phloroglucinol
3d,6
derivatives from M. communis.
In a continuation of that
investigation, a pair of enantiomeric triketone−phloroglucinol
hybrids, (+)-1 and (-)-1, with a new carbon skeleton were
isolated from the leaves of M. communis. Structurally,
myrtuspirone A (1) represents the first example of a
Received: January 9, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00108
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Myrtuspirone A (1) was obtained as colorless crystals. The
molecular formula of 1 was deduced as C H O from the
25
32
7
+
quasimolecular ion at m/z 445.2224 [M + H] (calcd for
C H O 445.2221) in its HRESIMS. The UV spectrum of 1
2
5
33
7
displayed absorption maxima at 226 and 290 nm. The IR
spectrum showed characteristic absorption bands for the
−
1
Figure 2. X-ray ORTEP drawing of 1.
aromatic ring (1589, 1456 cm ), hydroxyl group (3461
−
1
−1
1
cm ), and carbonyl groups (1709, 1631 cm ). The H
NMR spectrum of 1 suggested the presence of five tertiary
methyl groups [δ 1.89 (3H, s), 1.46 (3H, s), 1.35 (3H, s),
H
1
.31 (3H, s), 1.23 (3H, s)], an isopropyl unit [δ 1.00 (3H, d,
H
J = 7.0 Hz), 0.53 (3H, d, J = 6.6 Hz)], an isobutyryl moiety
δH 3.92 (1H, septet, J = 6.7 Hz), 1.10 (3H, d, J = 6.7 Hz),
.10 (3H, d, J = 6.7 Hz)], and a methine group [δ 4.22 (1H,
[
1
H
13
d, J = 2.5 Hz)]. The C NMR and DEPT spectra of 1
exhibited 25 carbon signals, including those for a benzene ring
(
δC 163.0, 161.1, 155.1, 106.1, 103.8, 98.5), an oxygenated
spiro carbon (δ 98.7), and four carbonyl groups (δ 210.7,
C
C
2
08.1, 202.8, 202.2) (Table S1). The above data suggested
that 1 could be a triketone−phloroglucinol hybrid.
A comparison of the NMR data of 1 with those of the
Figure 3. Calculated and experimental ECD spectra of (+)-1 and
−)-1.
7
known compound 6-methylisomyrtucommulone B indicated
(
that 1 comprises an isobutyl syncarpic acid moiety (1a) and
an isobutyrylphloroglucinol unit (1b) (Figure 1). The H− H
1
1
spectrum of (−)-1 displayed the opposite Cotton effects at
the same wavelengths, which corresponded to the 3R isomer
(
Figure 3). On the basis of the above evidence, the absolute
configurations of (+)-1 and (−)-1 were established to be 3S
and 3R, respectively.
Myrtuspirone A (1) represents the first example of an
unusual spirodihydrobenzofuran triketone. Some natural
products with a spirodihydrobenzofuran unit had been
8
reported to exhibit different biological activities, and thus,
they have attracted considerable interest from the synthetic
9
community. Therefore, an enantioselective total synthesis of
1
was conducted. Biogenetically, compound 1 is composed of
1
1
Figure 1. Key H− H COSY and HMBC correlations of 1.
simple building blocks, 2 and 3 (Figure 4). With this in mind,
it was envisioned that 1 could be prepared from 2 and 3 via a
COSY spin system from H-3 to H-9/H-10 together with the
(
3 + 2) annulation reaction followed by methylation.
HMBC correlations between H-3 and C-2/C-6′/C-3a/C-4/C-
7
a as well as between H-15 and C-6/C-7a suggested that 1a
and 1b were connected via C-2−O−C-7a and C-3−C-3a
bonds, forming a dihydrofuran ring (ring B) and a spiro
carbon (C-2) (Figure 1). Thus, the planar structure of 1 was
determined. The complete structure of 1 was further
determined by X-ray diffraction analysis (Figure 2). The
space group P2 /c of the crystal, together with the lack of
1
optical activity or Cotton effects, indicated that 1 was a
racemate. Chiral separation of 1 by HPLC led to the isolation
of two enantiomers, (+)-1 and (−)-1 (Figure S1).
Figure 4. Retrosynthetic analysis of myrtuspirone A (1).
To determine the absolute configurations of (+)-1 and
The key step in this current strategy was the (3 + 2)
annulation reaction to install the dihydrofuran ring. At the
(−)-1, the experimental CD spectra and the calculated ones
3d
using the time-dependent DFT method of each enantiomer
were compared. The measured CD spectrum of (+)-1 showed
positive Cotton effects at 311 (Δε +27.0) and 232 (Δε +4.9)
nm as well as negative effects at 285 (Δε −20.6) and 214 (Δε
outset of this investigation, we tested 2 and 3 in the
presence of oxidants in MeCN at 80 °C (Table 1, entries 1−
3e
4). Disappointingly, neither the desired product 5 nor the
undesired regioisomer 7 were obtained. The reason could be
that the two carbonyl groups on the A ring make the
carbocation unstable, which make this (3 + 2) annulation
−
13.7) nm, which were consistent with the calculated CD
spectrum of the 3S isomer (Figure 3). In contrast, the CD
B
DOI: 10.1021/acs.orglett.9b00108
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of the Reaction Conditions
Scheme 1. Substrate Scope of the Michael-NIS-Mediated (3
a,b
+
2)-Annulation Reaction
yield (%) yield (%)
c
c
entry
reagent
temp (°C)
solvent
MeCN
of 4
of 5
a
1
Cu(OAc)2
2 equiv)
80
0
0
(
a
2
Ag CO
80
MeCN
0
0
2
(
3
2 equiv)
a
3
CAN (2 equiv)
Mn(OAc)3
2 equiv)
80
80
MeCN
MeCN
0
0
0
0
a
4
(
NIS
(
b
5
−10 to +25 DCM
−10 to +25 DCM
−10 to +25 DCM
38
trace
trace
trace
6
2.5 equiv)
NBS
2.5 equiv)
NCS
2.5 equiv)
b
6
(
b
7
20
(
b
8
I2 (3 equiv)
−10 to +25 DCM
−10 to +25 toluene
trace
36
11
trace
a
b
Unless otherwise noted, the reactions were carried out with 2, 2a−d
9
NIS
(
(
0.3 mmol), and 3a−h (0.2 mmol) in CH Cl (1 mL) at 25 °C for
2.5 equiv)
NIS
2.5 equiv)
2
2
b
1.5−6 h, followed by THF (5 mL) and NIS (2.5 equiv) at −10 °C for
1
0
−10 to +25 DCM/
63
trace
b
(
THF
1 h. Isolated yield (%).
a
The reactions in entries 1−4 were carried out with 3 (0.2 mmol), 2
b
(
0.3 mmol), and MeCN (2 mL) at 80 °C. The reactions in entries
−10 were carried out with 3 (0.2 mmol), 2 (0.3 mmol), and CH Cl
isolated in lower yields because the amount of byproduct
5
2
2
3d
generated from the double-Michael addition increased.
(
1 mL) at 25 °C for 6 h, followed by THF (5 mL) and NIS (2.5
c
Having established a reliable method for constructing the
spirodihydrobenzofuran backbone, we turned our attention to
the synthesis of myrtuspirone A (1). The synthesis
commenced with a gram-scale reaction using substrates 2
and 3, and desired product 4 (most likely via intermediate 9)
was obtained in 63% yield on a 2.0 g scale (Scheme 2).
Subsequently, product 4 underwent one transformation; upon
equiv) at −10 °C for 1 h. Isolated yield.
3
e
reaction more difficult. Next, 2 was treated with 3 in CH Cl
2
2
at 25 °C, followed by NIS (2.5 equiv) at −10 °C in one pot
Table 1, entry 5). To our delight, the reaction proceeded
smoothly to provide 4 in 38% yield. However, the yield
dramatically decreased when the NBS, NCS, or I was used
instead (Table 1, entries 6−8). Then, the reaction conditions
were further optimized by changing the solvents. Ultimately,
we found that treating 2 with 3 in CH Cl , followed by THF
and NIS (2.5 equiv) in one pot (Table 1, entry 10), was the
optimal method, and the substrate underwent regioselective
3 + 2)-annulation to give 4 in 63% yield without the
formation of side products 6 and 7 (see the Supporting
Information).
(
treatment of 4 with ZnMe in THF, Negishi coupling product
2
2
(±)-myrtuspirone A (1) was generated in 65% yield.
Furthermore, inspired and encouraged by our previous
3d
work, we treated compound 2 with 3 in the presence of
2
2
3
d,10
catalyst (S)-C1 in PhMe at −70 °C for 6 days,
followed
by THF and NIS (2.5 equiv) in the same pot. Rewardingly,
spiro-compound (−)-4 was obtained in 55% yield on a 1.0 g
scale (Scheme 2). Compound (−)-4 also readily underwent a
(
Negishi coupling reaction with ZnMe to provide (−)-myr-
2
To further investigate the synthetic utility of this optimized
reaction, we examined the substrate scope of various
substituted triketones and phloroglucinols. As shown in
Scheme 1, different substituents on substrates 2 or 2a−d
tuspirone A (1, 90% ee, after recrystallization: >99% ee). The
1
13
H and C NMR spectra of synthetic 1 were identical to
those of the natural product (see the Supporting Informa-
tion).
(
see the Supporting Information for details) were tolerated in
The antibacterial activities of (+)-1, (−)-1, and (±)-1 were
evaluated against six Gram-positive and five Gram-negative
bacteria (see the Supporting Information). All compounds
exhibited moderate antibacterial activities against Gram-
positive bacteria, including three multidrug-resistant strains
(MRSA, VISA, and VRE) with MIC values in the range of 16
to 32 μg/mL. The results also showed that there is no obvious
the (3 + 2)-annulation reaction with different substrates 3a−
h, and the reactions gave the corresponding products 4a−k in
moderate to good isolated yields (43−72%) (see the
Supporting Information for details). Hence, our method has
broad generality for the synthesis of spirodihydrobenzofuran
triketone derivatives. Notably, some products (4h, 4i) were
C
DOI: 10.1021/acs.orglett.9b00108
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Total Syntheses of (± )-1 and (−)-(1)
AUTHOR INFORMATION
Corresponding Authors
■
*
*
*
E-mail: chywc@aliyun.com.
E-mail: cpuwanglei@126.com.
E-mail: ccli@sustc.edu.cn.
ORCID
Ying Wang: 0000-0003-4524-1812
Chuang-Chuang Li: 0000-0003-4344-0498
Lei Wang: 0000-0001-9242-1109
Wen-Cai Ye: 0000-0002-2810-1001
Author Contributions
∥M.-J.C. and X.-Y.Y. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Key R&D Program
of China (No. 2017YFC1703800), the Program for the
National Natural Science Foundation of China (Nos.
8
1822042, 81573307, and U1401225), the Guangdong
Natural Science Foundation for Distinguished Young Scholars
No. 2015A030306022), the Science and Technology
Planning Project of Guangdong Province (No.
016B030301004), the Shenzhen Science and Technology
(
2
Innovation Committee (No. JCYJ20170412152454807), the
Shenzhen Nobel Prize Scientists Laboratory Project
(C17783101), and Project KQTD2016053117035204 sup-
ported by Shenzhen Peacock Plan.
difference in the antibacterial activity of each enantiomer of
myrtuspirone A (1).
In conclusion, a pair of enantiomeric triketone−phloroglu-
cinol hybrids, (+)- and (−)-myrtuspirone A (1), with an
unprecedented skeleton were isolated from the leaves of M.
communis. Furthermore, the bioinspired total syntheses of
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Organic Letters
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