Biomimetic synthesis of myrtucommulone K, N and O

Article abstract of DOI:10.1016/j.tet.2017.05.007

A concise total synthesis of myrtucommulone K, N and O have been developed in 4 steps from commercially available materials. The synthetic strategy was inspired primarily by the biogenetic hypothesis and firstly enabled via a reduction, dehydration sequen

Full text of DOI:10.1016/j.tet.2017.05.007

Accepted Manuscript
Biomimetic synthesis of myrtucommulone K, N and O
Liangbo Lv, Yulong Li, Yuhan Zhang, Zhixiang Xie
PII:
S0040-4020(17)30473-8
10.1016/j.tet.2017.05.007
TET 28673
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 March 2017
Revised Date: 16 April 2017
Accepted Date: 2 May 2017
Please cite this article as: Lv L, Li Y, Zhang Y, Xie Z, Biomimetic synthesis of myrtucommulone K, N and
O, Tetrahedron (2017), doi: 10.1016/j.tet.2017.05.007.
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Biomimetic Synthesis of Myrtucommulone
K, N and O
Leave this area blank for abstract info.
Liangbo Lv, Yulong Li, Yuhan Zhang, and Zhixiang Xie*
State Key Laboratory of Applied Organic Chemistry & College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, P. R. China
H
O
O
+
H
H
H
O
O
O
O
OH
H
DABAL-H
then HCl
Myrtucommulone K
O
H
O
O
H
H
O
Isobutylidene-
syncarpic acid
Flavesone
O
O
O
+
H
H
O
O
Myrtucommulone O
Myrtucommulone N

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Biomimetic Synthesis of Myrtucommulone K, N and O
Liangbo Lv, Yulong Li, Yuhan Zhang and Zhixiang Xie
State Key Laboratory of Applied Organic Chemistry & College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A concise total synthesis of myrtucommulone K, N and O have been developed in 4 steps from
commercially available materials. The synthetic strategy was inspired primarily by the
biogenetic hypothesis and firstly enabled via a reduction, dehydration sequence for preparing
isobutylidenesyncarpic acid followed by a hetero-Diels-Alder reaction to disclose the target
moleculars. In this approach the exocyclic double bond of (−)-β-caryophyllene was more active
than the endocyclic one in hetero-Diels–Alder reaction as the dienophile. The route is
protecting-group-free, concise step, redox and pot economy.
Available online
Keywords:
Biomimetic synthesis
Myrtucommulone
2014 Elsevier Ltd. All rights reserved
.
Hetero-Diels-Alder reaction
Isobutylidenesyncarpic acid
β-caryophyllene
1. Introduction
Myrtus communis L. (Myrtaceae) has a long history as an
antiseptic, disinfectant, and hypoglycemic agent using in
traditional medicine.1 The plant has raised the interests of the
medicinal chemistry and drug discovery community.
Myrtucommulone A was first isolated by Kashman in 1974,
possessing a phloroglucinol ring connected via an isobutyl bridge
to two syncarpic acids (Figure 1).2 This compound exhibits a
strong antibacterial activity against gram positive bacteria.3
Bioactivity-guided fractionation of a dichloromethane extraction
of the leaves of Myrtaceae led to the isolation of
myrtucommulones J, K, and L by Cottiglia in 2012.4 Very
recently five sesquiterpene-based meroterpenoids with three
kinds of new skeletons were isolated from the leaves of
Myrtaceae by Wang and co-workers.5 Unfortunately, these five
sesquiterpene-based meroterpenoids were not named in the
original paper that isolated them. In the paper, one compound of
Figure 1. Structures of Myrtucommulones A, K, N, O and P.
Myrtucommulone A with excellent bioactivity has drawn
particular attention from the synthetic and medicinal community.
Synthesis of myrtucommulone A via an acid catalyzed reaction
has been completed by Jauch.6 We became interested in the
myrtucommulones as it was reported that the biogenetic pathway
of some of this family compounds could be disclosed via a
hetero-Diels−Alder reaction.5 Hetero-Diels−Alder reaction has
been proven to be a powerful method, which was frequently used
in the total synthesis of natural products.7 Our group also used
this method for total syntheses of (−)-spirooliganones A and B8
and biomimetic total synthesis of paeoveitol.9 Herein, we want to
report a biomimetic synthesis of myrtucommulone K, N and O,
which were enabled by hetero-Diels-Alder reaction.
1
the MS, H NMR, and 13C NMR data are exactly identical to
those of the reported myrtucommulone K.4 The structure of
myrtucommulone
K
was further confirmed by X-ray
crystallographic analysis and revised by Wang and co-workers as
shown in figure 1.5 For description convenience, we named the
remaining four compounds as myrtucommulone N, O, (+)-
myrtucommulone P and (−)-myrtucommulone P based on the
name of myrtucommulone K (Figure 1). It was noteworthy that
myrtucommulone
O
featured an unprecedented 6/6/9/4
tetracyclic ring system, which possessed two preferred
conformations detected by variable-temperature NMR
spectroscopy experiments.5
2. Results and Discussion
In the isolation paper,5 Wang and co-workers have postulated
that myrtucommulone K, N, O might be biosynthetically derived
from flavesone (β-triketones)10 and (−)-β-caryophyllene11, which
———
Corresponding author. e-mail: xiezx@lzu.edu.cn

2
Tetrahedron
ACCEPTED MANUSCRIPT
O
O
OH
O
Isobutyryl chloride
OH
had been previously isolated from the same plant, respectively.
MeI/NaOMe
AlCl3
(Scheme 1) The precursor flavesone could be selectively reduced
and dehydrated to generate the intermediate
MeOH,reflux
86%
PhNO ,65
℃
2
O
OH
HO
OH
HO
OH
85%
isobutylidenesyncarpic acid, which might be coupled with
different double bonds in (−)-β-caryophyllene through a hetero-
Diels−Alder reaction to form myrtucommulone K, N, O.
Analogically, the biosynthetic pathway for myrtucommulone P
and L were proposed as that isobutylidenesyncarpic acid could be
coupled with α-humulene and sabiene, detected in the same
plant,11 through the same reaction, respectively.4
1
2
Flavesone
O
O
O
O
O
O
ref 18
+
O
O
OH
OH
O
OH
Isobutylidene
syncarpic acid
4
3
side product
O
O
O
N
piperidine
O
pTsOH, or
HCl/NH4Cl,
O
OH
O
O
O
OH
Isobutylidene
syncarpic acid
3
ref 6 and 16a
5
Biosynthetic pathway hypothesized by Weavers and Sterner:
O
O
O
[H]
-H2O
O
O
O
OH
Isobutylidene
syncarpic acid
Flavesone
Scheme 2. Synthesis of the flavesone and isobutylidene syncarpic acid.
With this realization in mind, we went on to our key selective
reduction and dehydration reaction. Flavesone contains three or
more carbonyl groups. The challenge was how to selectively
reduce the side-chain carbonyl group. And it was obvious that the
activities of these three carbonyls in reducing reaction was not
distinguishing enough. We first tried to reduce this side-chain
carbonyl group by utilizing NaBH4. But only complex products
were detected in TLC even in -78oC. (Table 1 entry 1) The
NaBH(OAc)3, a more sluggish reducing agent, was used to
realize the selective reduction.21 But this reagent did not work at
all. (entry 2) The action of triethylsilane in trifluoroacetic acid in
the presence of a catalytic amount of lithium perchlorate
involved regioselective reduction of the side-chain carbonyl
group to hydroxy has been reported by Khlebnikova.22 Following
this procedure an unstable compound, whose structure could not
be assigned due to its unstability, was obtained. And we tried to
trap this unstable compound by ethoxyethene. But this effort also
resulted in vain. (entry 3) Similar results was obtained by using
L-selectride as reducing agent.23 (entry 4) Fortunately, when
DIBAL-H was used as the reducing reagent,24 the
isobutylidenesyncarpic acid was obtained successfully. The
isobutylidenesyncarpic acid was unstable in SiO2 flash
chromatography, so we could not get the exact isolated yield of
Scheme 1. Biogenetic Pathways Proposed for Myrtucommulones K, N, O
and P
There are two challenges in this biomimetic synthetic strategy:
firstly, the side-chain carbonyl of flavesone must be selectively
reduced in appear of three or four carbonyl; secondly, the
synthesis of myrtucommulone O via hetero-Diels-Alder reaction
should be difficult as the endocyclic double bond of the β-
caryophyllene was relatively more active than the exocyclic
one.12 This realization was confirmed by the work of Qiu’s group
that the exocyclic double bond of the β-caryophyllene was
undertaken in hetero-alder reaction and resulted in low yield.,13
The endocyclic double bond of the β-caryophyllene is a preferred
dienophile for hetero-Diels–Alder reaction.14 Very recently, the
second example of this kind hetero-Diels-Alder reaction came
from Wang and co-workers. They reported the exocyclic and
endocyclic double bond of the β-caryophyllene as dienophile for
hetero-Diels–Alder reaction in the total synthesis of Frutescone
D−F.15 These examples released our concern on the hetero-Diels-
Alder reaction.
Inspired by the biogenetic pathway of myrtucommulones K,
N, O and P, the total syntheses of these natural products could
start with preparing the flavesone. Flavesone was first isolated
and prepared by Hellyer.16 Following the Hellyer's procedure the
flavesone was synthesized from phloroglucinol by Friedel–Crafts
acylation17 and methylation in 73% overall yield. (Scheme 2)
With flavesone in hand, we focused on transforming this
compound to isobutylidene syncarpic acid. Usually the
isobutylidene syncarpic acid was synthesized from syncarpic acid
with isobutyraldehyde under acidic conditions.18 According to the
previous reports, one side product 4 would be produced. To avoid
this side reaction, treating syncarpic acid with isobutyraldehyde
under basic condition to obtain the Mannich base product was
reported by Jauch,6 which was similar to the report by Crow et
al.16a When the Mannich base product 5 was transformed to
isobutylidene syncarpic acid, it was immediately used in the next
reaction as the acid was unstable and was prone to isomerize.19
(Scheme 2) The biosynthetic pathway of isobutylidene syncarpic
acid from flavesone via reduction and dehydration was proposed
by Weavers and Sterner.20 But this biomimetic synthesis
hypothesis has not been realized in the Lab. (Scheme 2)
1
this compound. Screening the reaction temperature, the H NMR
of crude product showed that the purity of the
isobutylidenesyncarpic acid was better at low temperature.25
o
(entry 5-8) In the -78 C, the isobutylidene syncarpic acid was
obtained almost in quantity yield. And we also trapped this
unstable acid, which was prepared in different temperature, with
ethoxyethene to afford compound 6. By evaluating the yield of
compound 6, it was found that -78 oC was optimal for this
reduction which was correlated with the NMR results. (entry 5-8)
With the crude isobutylidenesyncarpic acid in hand, our
efforts were focused on synthesis of the myrtucommulones K, N
and O (Scheme 3). Prepared from flavesone by reduction and
dehydration sequence, the crude isobutylidenesyncarpic acid was
utilized in the next step immediately without further purification.
When the crude isobutylidenesyncarpic acid was treated with β-
caryophyllene in toluene, most of the isobutylidene syncarpic
o
acid was transformed to compound 720b, 26 in 80 C. In order to
inhibit the isomerization and oxidation of isobutylidenesyncarpic

isobutylidenesyncarpic acid still happened. After improving the
acid, this reaction was operated in neat with AheCatiCngE. PThTeEneDat MANUSCRIPT
o
mixture of the isobutylidenesyncarpic acid and (−)-β-
reaction temperature to 80 C, the compound 7 was not detected
o
caryophyllene was first tried in 60 C. But the isomerization of
in TLC. So the reaction was undertaken in 80 oC.
Table 1. Reducing Agent Screening for Selectively Reduced a
Entry
reducing agent
solvent
temp (oC)
yield (%)a
NaBH4
MeOH
-78
complex
1
2
NaBH(OAc)3
Et3SiH
HOAc/MeCN
CF3CO2H
THF
rt to reflux
NR
rt
0
unstable product
3
L-selectride
DIBAL
unstable product
4 c
5 c
6
THF
0
82b
84b
88b
89b
DIBAL
THF
-30
-60
-78
DIBAL
THF
7
DIBAL
THF
8
a Isolated yields after purification by flash chromatography.
b The yield of compound 6.
acid from flavesone by a reduction, dehydration sequence; 2.
biomimetic [4+2] hetero-Diels-Alder cycloaddition to construct
the target molecular. And this work first realized the biomimetic
synthesis hypothesis of the isobutylidenesyncarpic acid in lab.
The features of this strategy are protecting-group-free, concise
step, redox and pot economy. This strategy would provide an
efficient access to construct other natural and unnatural products
classed by biomimetic [4+2] hetero-Diels-Alder cycloaddition
with isobutylidenesyncarpic acid and terpene precursor. For
example, the bimimetic synthesis of myrtucommulone L, a
member of the large family of myrtucommulone, is underway in
our lab.
4. Experimental section
4.1. General
General Experimental Methods. Unless otherwise stated, all
reactions were performed in oven-dried or flame-dried glassware
under an atmosphere of dry nitrogen. Solvents were purified and
dried by standard methods prior to use. All commercially
available reagents were used without further purification unless
otherwise noted. Column chromatography was performed on
silica gel (200-300 mesh). NMR spectra were recorded on Bruker
400MHz and Oxford 600 MHz spectrometers in the CDCl3 or
DMSO. Chemical shifts are reported as δ values relative to
Scheme 3. Synthesis of Myrtucommulones K, N and O.
Gratifyingly, myrtucommulone N and another mixture were
obtained after flash column chromatography. Based on the NMR
spectrum of this mixture, we realized that this mixture might be
consistent of myrtucommulone
K
and
O
or other
diastereoisomers. The mixture was undertaken semi-preparative
HPLC chromatography purification, and Myrtucommulone K
and O were obtained in 25% and 42% yield, respectively. The
1H,13C NMR spectra and the X-ray crystallographic structure27 of
myrtucommulone K, N and O were in agreement with the
literature data.5 This remarkable result was really surprising as
previous works12 revealed that the endocyclic double bond of the
β-caryophyllene showed more active than the exocyclic one. But
in our system, the exocyclic double bond was seemed more
active according to the yield of myrtucommulone K, N and O.
(Scheme 3)
1
internal trimethylsilane (δ 0.00 for HNMR and 77.00 for 13C
1
NMR) and DMSO d6 (δ 2.50 for H NMR and 39.52 for 13C
NMR). High resolution mass spectra (HRMS) were obtained on a
4G mass spectrometer by using electrospray ionization (ESI)
analyzed by quadrupole time-of-flight (Q-TOF). Optical rotations
were measured on a Rudolph Autoplo IV polarimeter.
4.2. Experimental procedures and data of synthetic
intermediates
3. Summary
4.2.1. Acylphloroglucinol (2).
Anhydrous phloroglucinol (5.0 g, 39.6mmol) was suspended
in nitrobenzene (40 mL). AlCl3 (21.0 g, 158.0 mmol) was added
at room temperature to give a dark brown solution. The reaction
Myrtucommulone K, N and O have been synthesized in 4
steps from commercially available materials. The key steps are:
1. first enabled biomimetic synthesis of isobutylidenesyncarpic

4
Tetrahedron
ACCEPTED MANUSCRIPT
mixture was stirred at room temperature for 30 min. Isobutyryl
(ddd, J = 14.2, 8.2, 6.3 Hz, 1H), 1.36 (s, 3H), 1.31 (s, 3H), 1.28
chloride (4.6 mL, 43.6 mmol) was added, and the reaction
mixture was heated at 65°C for 18 hours. The reaction mixture
was then quenched by pouring into ice- hydrochloric acid and the
product was extracted with EtOAc (3 x 100 mL). The product
was then extracted into solution (2 x 100 mL) by saturated
solution of Na2CO3. The aqueous extracts were neutralized with
conc. HCl to give a yellow precipitate. The product was extracted
back into EtOAc (3 x 100 mL), then washed with water and
brine, dried over MgSO4, filtered and concentrated under reduced
pressure. Purification by flash chromatography on SiO2
(petrol/EtOAc, 4:1 → 2:1 as eluent) gave acylphloroglucinol 2
(6.7 g, 85%) as a pale yellow viscous liquid. 1H NMR (400 MHz,
DMSO): δ 12.25 (s, 2H), 10.33 (s, 1H), 5.81 (s, 2H,), 3.87 (sep, J
= 6.8Hz, 1H), 1.06 (d, J = 6.8Hz, 6H); 13C NMR (100MHz,
DMSO) δ 209.2, 164.3, 164.0, 102.7, 94.6, 38.0, 19.0. ESI m/z
195.0793 [M-H]- (calcd for C10H12O4:195.0736).
(s, 3H), 1.26 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H), 0.83 (d, J = 6.9 Hz,
3H), 0.78 (d, J = 6.9 Hz, 3H). 13C NMR (CDCl3, 100 MHz) δ
213.2, 197.8, 169.0, 111.8, 99.6, 65.0, 55.5, 47.9, 33.0, 29.6,
28.2, 26.6, 25.6, 24.8, 22.3, 20.7, 19.1, 15.2. HRESIMS m/z
309.2061 [M + H]+ (calcd for C18H28O4: 309.2060).
Compound 6b: IR (neat, cm-1) ν 2964, 2873, 2371, 1717, 1655,
1618, 1468, 1382, 1261, 1154, 1109, 1060, 977, 884, 797, 756,
704, 667; H NMR (400 MHz, CDCl3) δ 4.87 (dd, J = 7.5, 2.7
Hz, 1H), 3.94 (dq, J = 9.4, 7.1 Hz, 1H), 3.58 (dq, J = 9.4, 7.1 Hz,
1H), 2.79 (ddd, J = 8.7, 7.7, 5.2 Hz, 1H), 2.34 (dq, J = 13.7, 6.9
Hz, 1H), 1.93 – 1.75 (m, 2H), 1.39 (s, 3H), 1.29 (s, 3H), 1.27 (s,
6H), 1.22 (t, J = 7.1 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H), 0.65 (d, J
= 6.8 Hz, 3H). 13C NMR (CDCl3, 100 MHz) δ 213.2, 198.0,
169.1, 112.9, 101.9, 65.3, 55.6, 48.0, 34.9, 28.1, 27.8, 26.1, 25.2,
24.8, 22.8, 20.8, 16.7, 15.2. HRESIMS m/z 309.2061 [M + H]+
(calcd for C18H28O4: 309.2060).
1
4.2.2. Flavesone.
4.2.5. 8a-hydroxy-3,3,6,6,8,8-hexamethyl-8,8a-
dihydrobenzo[c][1,2]dioxine-5,7(3H,6H)-dione (7).
NaOMe, which was prepared from 1.10 g of Na metal (45.8
mmol) and MeOH (10 mL), was added to a MeOH solution
containing 2-acetyl-1,3,5-trihydroxybenzene
To a stirred solution of isobutylidenesyncarpic acid (48 mg,
0.20 mmol) in dry toluene (0.5 ml) under Ar. was added
dropwise β-caryophyllene (90%, 51 µL, 0.21mmol). After
keeping at 80 oC for 5 hours and then opened into the air
overnight, a suspension of white powder appeared and it was
washed twice with hexane to remove any impurity and then dried
2 (0.51 g, 2.6
mmol) followed by the addition of methyl iodide (2.26 mL, 36.4
mmol). After refluxing for 6 h, the mixture was acidified with 2
M HCl, followed by extraction with EtOAc (3 × 25 mL). After
the organic layer was dried over anhydrous Na2SO4, the solvent
was removed in vacuo, and the residue was purified by silica gel
column chromatography (n-hexane/EtOAc, 8:1) to afford 4-
acetyl-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-ene-1,3-dione
(0.56 g, 86%). IR (neat, cm-1) ν 2980, 2938, 1723, 1672, 1560,
1473, 1421, 1383, 1312, 1088, 1048, 961, 938, 888, 854, 837,
1
in vacuo to afford compound 7 (32 mg, 72%). H NMR (400
MHz, CDCl3) δ 7.10 (s, 1H), 3.69 (s, 1H), 1.44 (s, 3H), 1.31 (s,
6H), 1.30 (s, 3H), 1.26 (s, 3H), 0.99 (s, 3H). 13C NMR (CDCl3,
100 MHz) δ 210.7, 198.3, 143.1, 131.6, 97.3, 79.4, 54.9, 51.6,
26.6, 24.0, 23.9, 23.6, 20.9, 15.1. ESI m/z 291.1176 [M + Na]+
(calcd for C14H20O3: 291.1208).
1
511, 451. H NMR (CDCl3, 400 MHz) δ 3.81 (sep, J = 6.8 Hz,
1H), 1.46 (s, 6H), 1.37 (s, 6H), 1.18 (d, J = 6.8 Hz, 6H); 13C
NMR (CDCl3, 100 MHz) δ 209.9, 208.6, 199.3, 196.8, 108.2,
56.9, 52.2, 35.2, 24.2, 23.8, 19.0. HRESIMS m/z 251.1288 [M-
H]- (calcd for C14H20O4:251.1289).
4.2.6. Myrtucommulone K, N and O.
(−)-β-caryophyllene (0.6 ml, 0.49 mmol) was added dropwise
to isobutylidenesyncarpic acid (34 mg, 0.14 mmol) under Ar,
then the mixture was heated to 80 oC for 6 hours. Directly
purification by flash chromatography on SiO2 (petrol/EtOAc,
60:1 → 32:1 as eluent) gave myrtucommulone N (6.4 mg, 10%)
as a white solid and the colorless oil which was puried by Semi-
Preparative HPLC Chromatography (MeOH/H2O=9:1) affording
myrtucommulone K (16 mg, 25%), myrtucommulone O (27 mg,
42%).
4.2.3. Isobutylidenesyncarpic acid.
A solution of DIBAL-H (0.28 ml,1.0 M in hexanes) was
added dropwise to a suspension of flavesone (36.0 mg, 0.14
mmol) in THF under -78oC. After being stirred for 1 hour under
the same conditions, then the reaction mixture was added with 2
M HCl (1.5 ml) vigorous stiring for 5 minutes. The mixture was
dissolved in 1 M HCl (10 ml) and extracted with CH2Cl2 (3 x 10
mL). The combined organic phases were dried over Na2SO4, and
concentrated in vacuo. The crude compound was clean enough to
be used without further purification. 1H NMR (CDCl3, 400 MHz)
δ 7.19 (d, J = 10.4 Hz, 1H), 3.30 (m, 1H), 1.25 (s, 6H), 1.25 (s,
6H), 1.05 (d, J = 6.4 Hz, 6H). 13C NMR (CDCl3, 100 MHz) δ
208.8, 199.8, 196.6, 164.8, 130.6, 58.5, 58.1, 28.6, 22.3, 21.9,
21.8.
Myrtucommulone O: colorless blocks; m.p. 130-132 C; [α]20
o
D
−32 (c 0.5, CHCl3); IR(neat, cm-1) ν 3405, 2959, 2925, 2856,
1714, 1645, 1605, 1459, 1384, 1261, 1070, 1026, 856, 800, 759,
679, 667. HRESIMS m/z 441.3365 [M + H]+ (calcd for
C29H45O3: 441.3363).
Myrtucommulone N: colorless blocks; m.p. 140-142°C; [α]20
D
+42 (c 0.5, CHCl3); IR (neat, cm-1) ν 3409, 2954, 2931, 2870,
4.2.4. 2-ethoxy-4-isopropyl-6,6,8,8-tetramethyl-2,3,4,8-
tetrahydro-5H-chromene-5,7(6H)-dione (6).
1717, 1652, 1632, 1466, 1383, 1286, 1180, 1117, 1051, 887, 860,
778, 733; H NMR (CDCl3, 400 MHz) δ 4.89 (s, 1H), 4.82 (s,
1
1H), 2.33 (m, 3H), 2.11 (m, 1H), 2.02 (m, 3H), 1.86 (m, 2H),
1.55 (m, 3H), 1.37 (m, 1H), 1.32 (s, 3H), 1.28 (s, 3H), 1.24 (s,
6H), 0.99 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H), 0.82 (d, J = 7.0 Hz,
3H), 0.72 (d, J = 7.0 Hz, 3H). 13C NMR (CDCl3, 100 MHz) δ
213.9, 197.4, 171.0, 152.4, 114.6, 111.1, 83.5, 55.3, 53.9, 47.6,
42.1, 40.6, 38.6, 38.5, 36.1, 35.5, 35.3, 33.6, 31.8, 30.5, 25.1,
25.1, 24.6, 24.0, 22.4, 21.8, 21.3, 20.3, 19.6. HRESIMS m/z
441.3361 [M + H]+ (calcd for C29H45O3: 441.3363).
Ethyl vinyl ether (0.5 ml) was added dropwise to compound
isobutylidenesyncarpic acid (35 mg, 0.15 mmol) in sealed tube
under Ar, then the mixture was heated to 40 C for 4 hours.
Directly purification by flash chromatography on SiO2
(petrol/EtOAc, 30:1 as eluent) gave compound 6a (25 mg, 56%)
and compound 6b (15mg, 33%) as colorless oil.
Compound 6a: IR (neat, cm-1) ν 2967, 2929, 2874, 2372, 1718,
o
1655, 1618, 1460, 1383, 1267, 1158, 1116, 1056, 970, 885, 792,
757, 665; H NMR (400 MHz, CDCl3) δ 5.18 (dd, J = 8.2, 3.2
Hz, 1H), 3.90 (dq, J = 9.5, 7.1 Hz, 1H), 3.61 (dq, J = 9.5, 7.1 Hz,
1H), 2.73 (td, J = 6.3, 4.6 Hz, 1H), 2.03 – 1.88 (m, 2H), 1.58
o
Myrtucommulone K: colorless blocks; m.p. 151-152 C; [α]20
1
D
+126 (c 0.5, CHCl3); IR (neat, cm-1) ν 3405, 2952, 2932, 2869,
1712, 1645, 1611, 1460, 1380, 1292, 1187, 1117, 1037, 958, 889,
864, 814, 735; H NMR (CDCl3, 400 MHz) δ 4.92 (s, 1H), 4.91
1

12. Lawrence, A. L.; Adlington, R. M.; Baldwin, J. E.; Lee, V.;
(s, 1H), 2.71 (dd, J = 4.8, 3.4 Hz, 1H), 2.43 A(mC, 2CHE), P2.T17E(Dm, MANUSCRIPT
Kershaw, J. A.; Thompson, A. L. Org. Lett., 2010, 12, 1676-
1679.
13. Liu, H.-X.; Chen, K.; Yuan, Y.; Xu, Z.-F.; Tan, H.-B.; Qiu, S.-X.
1H), 2.07 (m, 2H), 1.76 (m, 5H), 1.55 (m, 5H), 1.39 (s, 3H), 1.37
(s, 3H), 1.35 (s, 3H), 1.34 (s, 6H), 1.17 (d, J = 6.8 Hz, 3H), 0.98
(s, 3H), 0.95 (s, 3H), 0.69 (d, J = 7.0 Hz, 3H). 13C NMR (CDCl3,
100 MHz) δ 214.2, 198.3, 170.4, 151.2, 112.7, 111.1, 85.7, 57.0,
55.3, 48.0, 44.2, 41.9, 39.6, 36.6, 36.5, 35.7, 34.5, 30.0, 26.8,
26.1, 26.0, 25.8, 25.3, 25.0, 24.4, 23.7, 23.1, 21.9, 19.9.
MHRESIMS m/z 441.3361 [M + H]+ (calcd for C29H45O3:
441.3363).
Org. Biomol. Chem., 2016, 14, 7354–7360.
14. (a) Baldwin, J. E.; Adlington, R. M.; Wilkinson, P. J.; Marquez, R.;
Adamo, M. F. A. Heterocycles, 2003, 59, 81 - 85. (b) Takao, K.-I.;
Noguchi, S.; Sakamoto, S.; Kimura, M.; Yoshida, K.; Tadano, K.-
I. J. Am. Chem. Soc. 2015, 137, 15971−15977. (c) Lam, H. C.;
Spence, J. T. J.; George, J. H. Angew. Chem. Int. Ed. 2016, 55,
10368–10371.
15. Hou, J.-Q.; Guo, C.; Zhao, J.-J.; He, Q.-W.; Zhang, B.-B.; Wang,
H. J. Org. Chem. 2017, 82, 1448–1457.
16. Bick, I. R. C.; Blackman, A. J.; Hellyer, R. O.; Horn, D. H. S. J.
Chem. Soc., 1965, 3690–3693.
Acknowledgments
We gratefully acknowledge financial support from the NSFC
(Grant Nos. 21272104 and 21672088), the program for
Changjiang Scholars and Innovative Research Team in
University (PCSIRT: IRT_15R28), the Program for New Century
Excellent Talents in University (NCET-12-0247 and lzujbky-
2012-56), and the Fundamental Research Funds for the Central
Universities (No. lzujbky-2016-ct02). We sincerely thank Dr.
Bencan Tang (University of Nottingham Ningbo China) for
helpful discussions.
17. (a) Crombie, L.; Jones, R. C. F.; Palmer, C. J. J. Chem. Soc.
Perkin Trans. 1 1987, 317–331. (b) Mani, R.; Venkataraman, K.
Curr. Sci. 1954, 23, 220 – 221. (c) Gokan, N.; Kikuchi, H.;
Nakamura, K.; Oshima, Y.; Hosaka, K.; Kubohara, Y. Biochem.
Pharmacol. 2005, 70, 676–685. (d) Kolokythas, G.; Kostakis, I.;
Pouli, N.; Marakos, P.; Kletsas, D.; Pratsinis, H. Bioorg. Med.
Chem. 2003, 11, 4591–4598. (e) Mateeva, N. N.; Kode, R. N.;
Redda, K. K. J. Heterocycl. Chem. 2002, 39, 1251–1258. (f)
Maloney, D. J.; Deng, J.-Z.; Starck, S. R.; Gao, Z.; Hecht, S. M. J.
Am. Chem. Soc. 2005, 127, 4140–4141. (g) Tada, M.; Chiba, K.;
Takakuwa, T.; Kojima, E. J. Med. Chem. 1992, 35, 1209–1212.
18. (a) Kalsi, P. S.; Singh, J.; Crow, W. D.; Chhabra, B. R.
Phytochemistry 1987, 26, 3367–3369. (b) Givelet, C.; Bernat, V.;
Danel, M.; André-Barrès, C.; Vial,H. Eur. J. Org. Chem. 2007,
3095–3101. (c) Bernat, V.; André-Barrès, C.; Baltas, M. Saffon,
N.; Vial, H. Tetrahedron 2008, 64, 9216–9224.
Supplementary Material
Supplementary data associated with this article can be found
in the online version, at
19. Wu, L.; Luo, J.; Zhang, Y. L.; Zhu, M. D.; Wang, X. B.; Luo, J.
G.; Yang, M. H.; Yu, B. Y.; Yao, H. Q.; Dai, Y.; Guo, Q. L.; Chen,
Y. J.; Sun, H. B.; Kong, L. Y. Tetrahedron Lett. 2015, 56, 229–
232.
References and notes
1. (a) Leonti, M.; Casu, L.; Sanna, F.; Bonsignore, L. J.
Ethnopharmacol. 2009, 121, 255−267. (b) Alipour, G.; Dashti, S.;
Hosseinzadeh, H. Phytother. Res. 2014, 28, 1125−1136.
2. Kashman, Y.; Rotstein, A.; Lifshitz, A. Tetrahedron 1974, 30,
991−997.
3. Rotstein, A.; Lifshitz, A.; Kashman, Y. Antimicrob. Agents Ch.
1974, 6, 539–542.
4. Cottiglia, F.; Casu, L.; Leonti, M.; Caboni, P.; Floris, C.;
Busonera, B.; Farci, P.; Ouhtit, A.; Sanna, G. J. Nat. Prod. 2012,
75, 225−229.
5. Liu, C.; Song, A.; Huang, X.-J.; Tian, H.-Y.; Deng, Y.-Y.; Zhang,
D.-M.; Wang, Y.; Ye, W.-C.; Wang, L. Org. Lett. 2016, 18, 4004–
4007.
6. (a) Jauch, J. International Patent PCT/EP 2009/006226, 2009. (b)
Müller, H.; Paul, M.; Hartmann, D.; Huch,V.; Blaesius,D.;
Koeberle, A.; Werz, O.; Jauch, J. Angew. Chem. Int. Ed. 2010, 49,
2045–2049. (c) Charpentier, M.; Hans, M.; Jauch, J. Eur. J. Org.
Chem. 2013, 19, 4078–4084.
20. (a) Klink, J. W. V.; Brophy, J. J.; Perry, N. B.; Weavers, R. T. J.
Nat. Prod. 1999, 62, 487–489. (b) Appendino, G.; Maxia, L.;
Bettoni, P.; Locatelli, M.; Valdivia, C.; Ballero, M.; Stavri, M.;
Gibbons, S.; Sterner, O. J. Nat. Prod. 2006, 69, 251–254.
21. (a) Lajkiewicz, N. J.; Roche, S. P.; Gerard, B.; Porco, Jr. J. A. J.
Am. Chem. Soc. 2012, 134, 13108−13113. (b) Terauchi, T.; Asai,
N.; Doko, T.; Taguchi, R.; Takenaka, O.; Sakurai, H.; Yonaga, M.;
Kimura, T.; Kajiwara, A.; Niidome, T.; Kume, T.; Akaikeb, A.;
Sugimoto, H. Bioorg. Med. Chem. 2007, 15, 7098–7107.
22. Khlebnikova, T. S.; Isakova, V. G.; Baranovskii, A. V.; Lakhvich,
F. A. Russ. J. Gen. Chem., 2011, 81, 672–679.
23. (a) Hunter, T. J.; Zheng, J.; ƠDoherty G. A. Org. Chem. Front.,
2016, 3, 1120–1125. (b) Uchiro, H.; Kato, R.; Sakuma, Y.; Takagi,
Y.; Arai, Y.; Hasegawa, D. Tetrahedron Lett. 2011, 52, 6242–
6245. (c) Clair, J. J. L.; Lansbury, P. T.; Zhi, B.-X.; Hoogsteene,
K. J. Org. Chem. 1995, 60, 4822-4833.
24. Verotta, L.; Sterner, O.; Appendino, G.; Bombardelli, E.; Pilati, T.
Eur. J. Org. Chem. 2006, 24, 5479–5484.
7. Yuan, C. C.; Du, B.; Yang, L.; Liu, B. J. Am. Chem. Soc. 2013,
135, 9291–9294. For review see: Heravi, M. M.; Ahmadi, T.;
Ghavidel, M.; Heidari, B.; Hamidi, H. RSC Adv., 2015, 5,
101999–102075.
8. Wei, L.; Xiao, M. X.; Xie, Z. X. Org. Lett. 2014, 16, 2784−2786.
9. Zhang, Y. H.; Guo, Y. H.; Li, Z. L.; Xie, Z. X. Org. Lett. 2016, 18,
4578−4581.
10. Petretto, G. L.; Maldini, M.; Addis, R.; Chessa, M.; Foddai, M.;
Rourke, J. P.; Pintore, G. Food Chem. 2016, 197, 124−131.
11. Berka-Zougali, B. B.; Ferhat, M. A.; Hassani, A.; Chemat, F.;
Allaf, K. S. Int. J. Mol. Sci. 2012, 13, 4673−4695.
25. See the Supporting Information.
26. (a) Crow, W. D.; Nicholis, W.; Sterns, M. Tetrahedron Lett. 1971,
18, 1353–1356. (b) Choudhary, M. I.; Khan, N.; Ahmad, M.;
Yousuf, S.; Fun, H.-K.; Soomro, S.; Asif, M.; Mesaik, M. A.;
Shaheen, F. Org. Lett. 2013, 15, 1862–1865.
27. CCDC 1539565-1539567 (myrtucommulone K, N and O) contains
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from the Cambridge
Crystallographic Data Centre (CCDC) via www.ccdc.cam.ac.uk.
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