Isolation and Synthesis of Novel Meroterpenoids from Rhodomyrtus tomentosa: Investigation of a Reactive Enetrione Intermediate

Article abstract of DOI:10.1002/anie.201814421

Rhodomyrtusials A–C, the first examples of triketone-sesquiterpene meroterpenoids featuring a unique 6/5/5/9/4 fused pentacyclic ring system were isolated from Rhodomyrtus tomentosa, along with several biogenetically-related dihydropyran isomers. Two bis-furans and one dihydropyran isomer showed acetylcholinesterase (AChE) inhibitory activity. Structures of the isolates were unambiguously established by a combination of spectroscopic data, ECD analysis, and total synthesis. Bioinspired total syntheses of six isolates were achieved in six steps utilizing a reactive enetrione intermediate generated in situ from a readily available hydroxy-endoperoxide precursor.

Full text of DOI:10.1002/anie.201814421

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Accepted Article
Title: Isolation and Synthesis of Novel Meroterpenoids from
Rhodomyrtus tomentosa: Investigation of a Reactive Enetrione
Intermediate
Authors: John Porco, Xu-Jie Qin, Tyler Rauwolf, Pan-Pan Li, Hui Li,
James McNeely, Yuan Hua, and Hai-Yang Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201814421
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Angewandte Chemie International Edition
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COMMUNICATION
Isolation and Synthesis of Novel Meroterpenoids from
Rhodomyrtus tomentosa: Investigation of a Reactive Enetrione
Intermediate
+
+
+
Xu-Jie Qin, Tyler J. Rauwolf, Pan-Pan Li, Hui Liu, James McNeely, Yan Hua, Hai-Yang Liu,* and
John A. Porco, Jr.*
Abstract: Rhodomyrtusials A–C (5–7), the first examples of
triketone-sesquiterpene meroterpenoids featuring
a
unique
6/5/5/9/4 fused pentacyclic ring system were isolated from
Rhodomyrtus tomentosa, along with several biogenetically-related
dihydropyran isomers (8–11). Compounds 5, 6, and 10 showed
acetylcholinesterase (AChE) inhibitory activity. Structures of the
isolates were unambiguously established by a combination of
spectroscopic data, ECD analysis, and total synthesis. Bioinspired
total syntheses of 5, 7, and 8–11 were achieved in six steps
utilizing a reactive enetrione intermediate generated in situ from a
readily available hydroxy-endoperoxide precursor.
Natural products are an important source for the discovery
of new drugs.[1] Species of the Myrtaceae family are rich in
structurally intriguing meroterpenoids which possess various
bioactivities.[ Interestingly, many of the natural products
derived from these species are derived from a common
precursor, syncarpic acid (Figure 1a). Isolates such as
callistrilones A–E, have recently attracted interest due to their
promising antibacterial activity.[ Other examples of natural
products possessing the β-triketone moiety derived from
2]
3]
[
4]
syncarpic acid include rhodomyrtosone A (2), tomentodione
M (3),[ and myrtucommulone K (4). Compound 3 has been
shown to reverse multidrug-resistance in MCF-7 and K562
cells,[5] while 4 and analogues possess anti-cancer properties
against HEP-G2 and MDA-MB-231 cell lines.[ The structural
diversity found in these natural products, coupled with their
diverse biological activities, warrants continued development
of new chemistry to access such scaffolds.
5]
[6]
6]
A preliminary bioactivity assay of the leaves and stems of
Rhodomyrtus tomentosa revealed that the petroleum ether
(
PE) extract showed a significant acetylcholinesterase (AChE)
[
7]
inhibition rate (81%, 500 μg/mL) . Subsequent screening of
the title species using a bioassay-guided method led to the
Figure 1. (a) Natural products derived from syncarpic acid; (b) structures of
rhodomyrtusials A–C (5–7), rhotomentodiones
tomentodiones Q (10) and R (11).
A (8) and B (9), and
[
[
[
a]
b]
c]
Dr. X. J. Qin, Mr. Hui Liu, Prof. Dr. H. Y. Liu
State Key Laboratory of Phytochemistry and Plant Resources in
West China, Kunming Institute of Botany,Chinese Academy of
Sciences, Kunming 650201 (PR China)
isolation of three unprecedented meroterpenoids with
/5/5/9/4 pentacyclic ring system, rhodomyrtusials A–C (5–7),
two new biogenetically related isomers, rhotomentodiones A
8) and B (9), and two known analogues, tomentodiones Q (10)
and R (11) (Figure 1b), all of which possess the syncarpic
acid-derived moiety found in 1–4. Herein, we report the
structural elucidation, AChE inhibitory activities, and
biomimetic total syntheses of these metabolites using a
a
6
E-mail: haiyangliu@mail.kib.ac.cn
T. J. Rauwolf, Dr. J. McNeely, Prof. Dr. J. A. Porco, Jr
Department of Chemistry, Center for Molecular Discovery (BU-
CMD), Boston University, 590 Commonwealth Avenue, Boston,
Massachusetts 02215 (United States)
E-mail: porco@bu.edu
P. P. Li, Prof. Dr. Y. Hua
(
[8]
College of Forestry, Southwest Forestry University, Kunming
6
50224 (PR China)
reactive enetrione generated in situ from a hydroxy-
endoperoxide precursor.
[+
]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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COMMUNICATION
Rhodomyrtusial A (5) possessed a molecular formula of
7S,8R,1'R,4'R,5'S,9'S,
experimental and calculated ECD spectra).
respectively,
by
7]
comparing
[
30 44 4
C H O with nine indices of hydrogen deficiency (IHDs)
based on HRESIMS data. Analysis of the 1H and 13C NMR
spectra (Table S1)[ revealed the presence of seven tertiary
and two secondary methyl groups, five methylenes, five
methines, five quaternary carbons, two double bonds, and two
carbonyl carbons. These functionalities accounted for four out
of nine IHDs; the remaining IHDs thus required 5 to have a
In addition to 5–7, two new biogenetically related isomers
8 and 9) and two known analogues (10 and 11) were identified
7]
(
from R. tomentosa. LC-MS analysis indicated that all isolates
were present in the cold extract of the title species (Figure S3).
The structures and absolute configurations of 8 and 11 were
elucidated by spectroscopic data, ECD calculations, and X-ray
crystallography.[7] The previously proposed structure and
absolute configuration of 11[ was confirmed by X-ray
pentacyclic framework. Structural assignment of
5 was
accomplished by analysis of 2D NMR data (Figure S1). HMBC
correlations from Me-12/Me-13 to C-1/C-2/C-3 and from Me-
8]
[
9]
crystallography (Figure 2). Furthermore, X-ray analysis of 8
14/Me-15 to C-3/C-4/C-5 revealed the presence of a β-
unambiguously determined its absolute configuration as
triketone moiety. The location of an isopentyl group and the
construction of one furan ring via a 1,8-oxide bridge were
determined by HMBC correlations from Me-10/Me-11 to C-8
9]
7
R,1'R,4'R,5'S,9'S (Figure 2).[ The unambiguous assignment
[7]
of 8 and analysis of ECD data established the absolute
configuration of 10 as 7S,1'R,4'S,5'R,9'S which is revised from
a previously reported structure.[ Bioactivity assays of the
isolates revealed that 5, 6, and 10 displayed significant AChE
inhibitory activities with IC50 values of 8.8, 6.0, and 6.6 μM,
respectively. These findings are in good agreement with the
AChE inhibitory activity observed from the PE extract.
1
1
and H-7 to C-1/C-6/C-9. H– H COSY cross-peaks of H-1'/H-
'/H -10' along with HMBC correlations from Me-12'/Me-13' to
C-1'/C-10'/C-11' delineated a characteristic cyclobutane ring.
HMBC correlations from Me-14' to C-3'/C-4'/C-5' and H -15' to
-2'/H
-7' verified the presence of a caryophyllene
8]
9
2
2
1
1
C-7'/C-9', as well as H– H COSY correlations of H-1'/H
2
2
-
3
' and H-5'/H
2
-6'/H
2
1
1
unit. The key H– H COSY cross-peaks of H-7/H-5' verified
Proposed biosyntheses of 5–11 are shown in Scheme 1.
Enetrione (14) may serve as a common precursor allowing for
access to 5–11. In line with the G-factor series of
that the triketone moiety and caryophyllene were connected
via a C-7–C-5' bond. The downfield chemical shifts of C-8 (δ
27.3) and C-4' (δ 89.7) indicated that an oxygen atom was
C
[10]
1
C
endoperoxides, alkylidene 12 may undergo autoxidation to
afford hydroxy-endoperoxide[ (13), which may subsequently
4b]
bridged at C-8 and C-4' to form an additional furan ring,
required to fulfil the last IHD and MS information. ROESY
correlations (Figure S1) of H-9'β/H-6'a; H-6'a/Me-14'; and Me-
undergo Kornblum-DeLaMare rearrangement[
11]
to 14
(Scheme 1a). A DFT model (B3LYP/6-31G**) of 14 (Figure 3)
1
4'/H-7' and H-9' suggested that these protons were β-oriented,
shows a twisted isopropyl ketone (C -C -C -O = –57.1°)
11
12
13
17
which appears to minimize O-O lone pair interactions.[ (–)-
Trans-caryophyllene, a common sesquiterpene, may then
react with 14 via the more reactive endocyclic double bond[13]
in several plausible pathways (Scheme 1c-e, Figure 4) to
furnish 5–11. The flexible, nine-membered ring is known to
exist in two relevant conformations (βα:ββ = 3:1) at room
temperature (Scheme 1b).[ In the βα conformer, the olefinic
methyl group and exocyclic methylene are trans with respect
to one another. Conversely, the ββ conformer is oriented in a
cis conformation. The assigned configurations of
dihydropyrans 8–11 indicate both conformers may react with
12]
whereas H-5' was assigned as α-oriented based on the
observed ROESY correlations of H-1'α/H-3'a and H-3'a/H-5'.
Compared to the calculated ECD curve (Figure S2), the
experimental ECD spectrum of 5 with two negative Cotton
effects [235 nm (∆ε –0.86) and 306 nm (∆ε –2.72)] and a
positive Cotton effect [274 nm (∆ε +8.81)] established its
absolute configuration as 7R,8S,1'R,4'R,5'S,9'S.
14]
enetrione 14 via hetero-Diels Alder (HDA) cycloaddition
Scheme 1e).[15a–k] In contrast stepwise Michael addition of
[16]
(
the βα conformer of caryophyllene (re-face approach Scheme
c) to 14 may also afford zwitterion 15, which, after bond-
1
Figure 2. X-ray crystal structures of 8 and 11.
rotation to 16, may undergo consecutive cyclization to 5. Bis-
furan 7 may also be obtained through a similar stepwise
Michael addition of the  conformer (si-face approach,
Scheme 1d) to 14 may afford intermediate 17, which can
undergo cyclization to 6. Dihydropyrans 8–11 may also be
Rhodomyrtusials B (6) and C (7) possessed the same
molecular formula as 5 by HRESIMS data. Comprehensive
analysis and comparison of NMR data to 5 (Table S1) revealed
that 6 and 7 shared the same planar structure with alternative
stereocenters at C-7, C-8, C-4', and C-5' (Figure S1). ROESY
correlations of H-1'α/H-3'a; H-3'a/Me-14'; Me-14'/H-7; and H-
obtained from
a stepwise pathway involving zwitterionic
intermediates and bis-furans 5–7 may arise from concerted
cycloadditions.
Our synthetic studies began with the synthesis of enetrione
7
/Me-10 supported H-7, Me-14, and the isopropyl at C-8 were
α-oriented, whereas H-5' was β-oriented by correlations of H-
'β/H-5' for 6 (Figure S1). For 7, the observed ROESY
correlations of H-1'α/H-3'b; H-1'α/H-5'; H-5'/H-7; and H-7/Me-
0 indicated these groups were α-oriented, and the β-
orientation of Me-14 was established by the ROESY
(
14). Despite literature examples reporting syntheses of
[17]
enetriones, there remains an absence in methodology for
the synthesis of cyclic enetriones, presumably due to reactivity
of the twisted carbonyl (cf. Figure 2). Alkylidene 12 may be
9
1
synthesized
via
proline-catalyzed
condensation
of
[
18]
[
7]
isovaleraldehyde with syncarpic acid. Metal-mediated allylic
oxidation attempts[19] on 12 were not fruitful and typically led to
correlations of H-3'a/Me-14'). Absolute configurations of 6
and were defined as 7S,8R,1'R,4'S,5'R,9'S and
7
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COMMUNICATION
Scheme 1. Proposed biosyntheses of 5–11. (a) Synthesis of enetrione (14); (b) conformations of trans-caryophyllene; (c) stepwise Michael addition leading to 5;
d) stepwise Michael addition leading to 6; (e) Hetero-Diels-Alder (HDA) cycloadditions leading to 8–11.
(
spontaneous oxidation to endoperoxide 13. After unsuccessful
attempts to obtain 14 via Kornblum-DeLaMare rearrangement,
we rationalized that the elusive enetrione may be generated in
situ from 13. This hydroxy-endoperoxide was previously
reported by our group and was obtained as a mixture of diaste-
reomers, albeit in 51% yield.[ After experimentation, an
improved condition for the synthesis of endoperoxide 13 was
identified (Scheme 2a). Subjection of compound 12 to
2
benzene as solvent and [4+2] cycloaddition with O afforded
13 in 72% combined yield. Exposure of pure 13a to O-
methylation conditions[21] afforded endoperoxide 18 in 25%
yield (Scheme 2b). Endoperoxide methyl ether (18) was
characterized by NMR to assign stereochemistry.[7] In
particular, a key nOe was observed between the –OMe and
isopropyl methyl groups to ascertain syn stereochemistry for
13a. By default, the –OH and isopropyl group in endoperoxide
13b have an anti-relationship.
4b]
[20]
photoenolization conditions (390‒720 nm white LEDs) in
With endoperoxides 13a and 13b in hand, we initiated
studies towards syntheses of 5–11. Initial reactions of either
endoperoxide 13a or 13b and trans-caryophyllene in polar
solvents
such
as
dichloromethane,
dichloroethane,
were unfruitful.
[15i]
nitromethane, trifluoroethanol, and HFIP
Following conditions reported by Takao and co-workers[21],
thermolysis of endoperoxide 13a in the presence of
caryophyllene in toluene at 100 °C afforded 9, 10, and 11, in
Figure 3. DFT-minimized structure of enetrione 14.
10, 10, and 6% yields, respectively. Thermolysis of pure 13b
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COMMUNICATION
(
a)
reactive enetrione (14) in situ (Scheme 4). The less reactive
endoperoxide (13a) may form a cyclic peroxycarbenium
O
2
O , benzene
O
[4b, 23]
H
O
White LED
intermediate (19) after protonation of the peroxy-ketal and
expulsion of water. Deprotonation of the α-peroxy methine
proton and resulting Kornblum-DeLaMare rearrangement[
may afford enetrione (14, Scheme 4a). We believe that
endoperoxide 13b displays heightened reactivity due to the
syn-stereochemical relationship of the α-peroxy hydroxyl group
and the α-peroxy methine hydrogen (Scheme 4b).[24] The more
reactive endoperoxide (13b) may undergo formal, directed
Kornblum-DeLaMare rearrangement to afford 14.[25] This
intermediate can then react with caryophyllene to afford
compounds 5–11.
rt, 43 h
O
O
O
O
11]
OH
,
52%)
, 20%)
(
(
b)
O
O
H
H
O
BuLi (1.0 equiv)
MeOTf (1.15 equiv)
THF, -78 °C, 4 h
H
O
O
O
O
O
nOe
OH
OMe
5%
2
(
a)
Scheme 2. (a) Synthesis of hydroxy-endoperoxides (13); (b) Methylation
and key nOe for the assignment of 13a and 13b.
H
B
O
H
O
O
O
H
O
OH
O H - H2O
O
O
O
OH
O
O
O
(90 °C, 43 h) without caryophyllene present resulted in a
mixture of endoperoxide diastereomers 13a and 13b in a 1.5
to 1 ratio.[ Additionally, thermolysis of 13a or 13b in the
presence of trans-caryophyllene without desiccant at 60 °C
gave no conversion to the natural products. These findings led
(
b)
7]
O
H
O
H
O
O
OH
-
H2O
O
O
O
O
us to evaluate thermolytic conditions with molecular sieves
O
O
OH
O
M.S.) as desiccant.[ Thermolysis of 13b in the presence of
22]
O
(
trans-caryophyllene and 4Å M.S. in toluene at 60 °C afforded
, 7, and 8–11, in 4, 4, 19, 5, 8, and 15% yields, respectively
55% combined) after HPLC purification (Scheme 3).[7]
Scheme 4. Proposed mechanism for enetrione formation.
5
(
We conducted initial DFT calculations (B3LYP/STO-3G) of
zwitterionic intermediates 15 and 17 (vide supra, Scheme 1c–
d) to probe the proposed, stepwise Michael addition pathway.
Interestingly, more than half of the conformers converged to
product during the optimization process, which led us to
investigate concerted pathways in silico. Indeed, we
successfully located asynchronous, concerted transition states
c
connecting 5 (Figure 4, PBEh-3C, TS5 ) and 7 to 14-βα with
activation barriers competitive with production of 8–11.[
7]
A
pseudo-concerted transition state connecting 6 and 14-ββ was
also located, but the calculated activation barrier was
inconsistent with the observed yields. Preliminary quasi-
classical trajectory analysis suggests that this is due to a
bifurcating potential energy surface (PES).[26] A more extensive
Scheme 3. Synthesis of 5, 7, and 8–11.
computational exploration will be reported in due course.
Interestingly, thermolysis of 13a with trans-caryophyllene and
4
Å M.S. resulted in a conversion that was approximately 20%
[
7]
as efficient when the same reaction was run with 13b. The
reaction conditions shown in Scheme 3 produced trace bis-
furan 6, but the compound was never successfully isolated. We
also considered the use of Lewis and Br
catalysts. Utilization of Ni(ClO • 6 H O, Cu(ClO
Cu(BF • 6 H O, and various rare earth metal triflates did not
ønsted acids as
4
)
2
2
4
)
2
• 6 H O,
2
3
)
2
2
result in product formation. Use of trifluoroacetic acid (TFA) did
not afford adducts, likely due to the strength of the acid and the
propensity of caryophyllene to rearrange under strongly acidic
conditions.[13] Reactions with acetic acid as additive in toluene
at 60 °C afforded products 5 and 8–11; however, the results
were inconsistent.
c
Figure 4. (a) DFT-minimized structure of TS5 ; (b) ChemDraw rendition of
TS5 .
c
To better understand the modes of reactivity for 14, we
investigated additional alkene reaction partners (Scheme 5).
Reactions involving the 1,1-disubstituted alkene of
caryophyllene were not observed (cf. Scheme 3). To study
Based on our experiments, we propose plausible
dehydrative mechanisms for either 13a or 13b to produce the
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COMMUNICATION
reactivity with 1,1-disubstituted alkenes, methylene
cyclohexane was chosen as a simplified reaction partner
as well as four biogenetically related dihydropyran isomers
from R. tomentosa. Two bis-furans and one dihydropyran were
found to exhibit AChE inhibitory activities. Six of the seven
isolates were synthesized in six steps utilizing a reactive
enetrione generated in situ from a readily available hydroxy-
endoperoxide. Further evaluation of alkene reaction partners
identified additional modes of reactivity for the enetrione.
Computational studies have identified a valid asynchronous,
(
Scheme 5, entry 1). In this case, three structurally unique
products were obtained in 45% overall yield. Spirocycles 19
and 21 may arise from the concerted cycloaddition pathways
previously described; production of 20 demonstrates a new
mode of reactivity for enetrione 14 involving an Alder-ene
reaction.[
27]
To further explore the reactivity of 14, 2,3-
reaction partner
Scheme 5, entry 2). Spirocycle 22 was isolated as the major
dimethylbutadiene was evaluated as
a
concerted pathways to bis-furan
5
and 7. Further
(
pharmacological studies, synthesis and biological studies of
triketone-sesquiterpene meroterpenoids, and exploration of
the reactivity of 14 and related enetriones are currently in
progress and will be reported in due course.
product in 53% yield, revealing that enetrione 14 also
participates in normal demand [4+2] cycloadditions.
Dihydropyran diastereomers 23a/23b were also isolated as
minor products in 16% yield. This mixture of diastereomers
was thermolyzed in toluene (100 °C, 24 h) which resulted in
partial conversion to 22, presumably via Claisen
rearrangement.[ Use of the electron-rich reaction partner
dihydrofuran (Scheme 5, entry 3) afforded tris-furan 24 and
dihydropyran 25 in 73% combined yield. These initial studies
illustrate four distinct modes of reactivity for enetrione 14 which
allow for the synthesis of structurally intriguing small molecules
from a common reagent.
Acknowledgements
7]
These studies were funded by the National Natural Science
Foundation of China (U1802287 and 31600283), the National
Institutes of Health (R35 GM-118173), , Major Bio-Medical
Project of Yunnan Province (2018ZF005), Youth Innovation
Promotion Association CAS, Key Research and Development
Plan of Yunnan Province–Special Project of Science and
Technology in Yunnan Province (2017IB007), and Innovation
Team of the Ministry of Education (IRT-17R49) and DARPA
(
(
W911NF-18-1-0025). We thank Professor Jonathan George
University of Adelaide) for helpful discussions and Thomas
Purgett, Dr. Kyle Reichl, and Dr. Wenhan Zhang (BU) for
assistance with the manuscript.
Keywords: Myrtaceae • Rhodomyrtus tomentosa • total
synthesis • caryophyllene • Hetero-Diels-Alder
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Scheme 5. Investigation of alkene reaction partners with enetrione 14.
[
[
4]
5]
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2015, 80, 9584–9591.
In summary, we have isolated the bis-furans
rhodomyrtusials A–C, three novel triketone-sesquiterpene
meroterpenoids featuring a 6/5/5/9/4 pentacyclic ring system
X. Zhou, Y. Xia, Y. Zhang, J. Luo, C. Han, H. Zhang, C. Zhang, L.
Yang, L. Kong, Oncotarget, 2017, 8, 101965–101983.
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[
6]
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This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201814421
COMMUNICATION
COMMUNICATION
+
+
Xu-Jie Qin, Tyler J. Rauwolf, Pan-Pan
+
Li, Hui Liu , James McNeely, Yan Hua,
Hai-Yang Liu,* and John A. Porco, Jr.*
Page No. – Page No.
Isolation and Synthesis of Novel
Meroterpenoids from Rhodomyrtus
tomentosa: Investigation of a Reactive
Enetrione Intermediate
Novel meroterpenoids were isolated from R. tomentosa and characterized which
led to a hypothesis for their biosynthesis. In situ generation of a reactive enetrione in
the presence of the sesquiterpene caryophyllene led to efficient chemical syntheses
of four of the five meroterpenoids, as well as two biogenetically related cycloadducts,
in a biomimetic, six-step sequence. Further evaluation of alkene reaction partners
identified additional modes of reactivity for the enetrione reagent.
This article is protected by copyright. All rights reserved.