Biomimetic total synthesis and structure confirmation of myrtucommulone K

Article abstract of DOI:10.1016/j.tetlet.2017.03.059

A confirmed structure of meroterpenoid myrtucommulone K, which is vastly different from the originally reported one, is conducted. The first biomimetic total synthesis towards the assignment of its absolute configuration has been efficiently accessed in 5 steps, and key to the success was a heteroatom Diels-Alder cycloaddition. The structure of myrtucommulone K was re-elucidated and confirmed by extensive spectroscopic interpretation of 1D and 2D NMR.

Full text of DOI:10.1016/j.tetlet.2017.03.059

Accepted Manuscript
Biomimetic total synthesis and structure confirmation of myrtucommulone K
Wen-Li Zhou, Hai-Bo Tan, Sheng-Xiang Qiu, Guang-Ying Chen, Hong-Xin
Liu, Chao Zheng
PII:
S0040-4039(17)30362-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.03.059
TETL 48760
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
19 January 2017
18 March 2017
21 March 2017
Please cite this article as: Zhou, W-L., Tan, H-B., Qiu, S-X., Chen, G-Y., Liu, H-X., Zheng, C., Biomimetic total
synthesis and structure confirmation of myrtucommulone K, Tetrahedron Letters (2017), doi: http://dx.doi.org/
10.1016/j.tetlet.2017.03.059
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1
Tetrahedron Letters
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Biomimetic total synthesis and structure confirmation of myrtucommulone K
Wen-Li Zhou, a,c Hai-Bo Tan, c Sheng-Xiang Qiu, c Guang-Ying Chen, a Hong-Xin Liu, b,c,* Chao Zheng a,*
a Key Laboratory of Tropical Medicinal Plant Chemistry of Ministry of Education, Collaborative Innovation Center of Tropical Biological Resources, Hainan
Normal University, Hainan Haikou 571158, China
bState Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application,
Guangdong Open Laboratory of Applied Microbiology, Guangdong Institute of Microbiology, Guangzhou 510070, China
cProgram for Natural Products Chemical Biology, Key Laboratory of Plant Resources Conservation and Sustainable Utilization, Guangdong Provincial Key
Laboratory of Applied Botany, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China
ARTICLE INFO
ABSTRACT
Article history:
Received
A confirmed structure of meroterpenoid myrtucommulone K, which is vastly different from the
originally reported one, is conducted. The first biomimetic total synthesis towards the
assignment of its absolute configuration has been efficiently accessed in 5 steps, and key to the
success was a heteroatom Diels-Alder cycloaddition. The structure of myrtucommulone K was
re-elucidated and confirmed by extensive spectroscopic interpretation of 1D and 2D NMR.
Received in revised form
Accepted
Available online
2016 Elsevier Ltd. All rights reserved.
Keywords:
Myrtucommulone K
Biomimetic total synthesis
Structure revision
Heteroatom Diels-Alder cycloaddition
Meroterpenoid
The
meroterpenoids,
which
contain
a
synthesis were also isolated from ethanolic extract of R.
tomentosa leaves.12-13
tetramethylcyclohexenedione or acylphloroglucinol moiety,
have garnered much attention from synthetic community due
primarily to their unusual structural diversities and
stereochemical complexities in recent years.1-7 From the
perspective of natural products research, a wide range of novel
analogous with rare skeletons have been discovered from
biologically meaningful medicinal plants Myrtaceae.1-10
Myrtucommulone K, a unique meroterpenoid, which embraced
a β-triketone moiety and a novel sesquiterpene unit, was
isolated from Myrtus communis L. by Filippo Cottiglia and
coworkers in 2012.11 Its relative configuration was elucidated
by NMR spectroscopy. With our continuing interests in the
discovery and development of new antibacterial and anticancer
constituents from medicinal plants, several novel
meroterpenoids including temetosenol A and tomentodiones
A-B with their structure determined by biomimetic total
Scheme 1. Representative natural meroterpenoids from
Myrtaceae.
When an unconscious effort to compare the spectra of
myrtucommulone K (1) and tomentodione A (8), we were
surprised to find that they showed unexpected similarity in
NMR spectral data, while possessing quite different plane
structures. By the inspiration and confidence from the
* Corresponding authors: Chao Zheng, Tel./fax: +86-898-65888762; E-mail: zhengchaoustc@163.com;
Hongxin Liu, Tel./fax: +86-20-37252958; E-mail: liuhx@gdim.cn.

2
Tetrahedron
structural assignment of tomentodione A13 attributed to its X-
ray diffraction analysis, the structural mystery between these
two molecules might be ascribed to the inevitable
of Friedel-Crafts acylation, methylation, and Retro-Claisen
condensation with phloroglucinol and acyl chloride as start
materials in the scheme 3. With the syncarpic acid 10 in hand,
we initiated our precious established proline-mediated
Knoevenagel condensation approach by the treatment of start
materials syncarpic acid 10 (1.0 equiv.) and isobutyraldehyde
11 (1.0 equiv.) at room temperature in DCM under an air
atmosphere (Entry 1 in Table 1).13 Dissatisfying, the reaction
condition seemed to be incompatible with the aforementioned
substrates, tending not to provide any desired product. This
frustrating result might be rationalized by the much more steric
hindrance of isobutyraldehyde 11 than that of isovaleraldehyde,
which could efficiently provide the corresponding product
within 95% yield13. Therefore, how to directly construct the
α,β-unsaturated skeleton of key intermediate i had turned out
to be one of the most crucial transformations in the whole
method.
misapprehend
in
the
structure
interpretation
of
myrtucommulone
K because of its spectra complexity.
Therefore, we envisioned that myrtucommulone K should be a
very similar analog of tomentodione A with a putative
structure depicted in Figure 1. In this regard, a structural re-
evaluation of myrtucommulones K was required. Interestingly,
when we prepared this manuscript, similar efforts towards the
revision of myrtucommulones K’s structure was reported by
14
Ye’s group through its isolation from Myrtus communis.
Herein, we reported the structure confirmation of
myrtucommulones K and its derivatives based on their first
biomimetic total synthesis.
In an attempt to succeed this reaction under the similar
conditions, the contributing factors such as solvents, catalysts,
loadings and experimental operations that could facilitate this
cascade reaction were examined. As a result, the change of the
solvents and amount of catalyst loadings failed to promote the
desired transformation. Instead, the kinds of catalysts had been
proved to be fairly significant for the reaction efficiency (Entry
4-8 in Table 1). After careful modification, the morpholin-4-
ium 2,2,2-trifluoroacetate 16 was proved to be the most
effective catalyst to afford compound i in almost quantitative
yield (Entry 10), which showed superiority over other
protocols reported by Kong16 and Crow17-19. Although a slight
excess of catalyst morpholin-4-ium 2,2,2-trifluoroacetate 16
(Entry 11) had beneficial effects on the reaction yield and
efficiency, we still decided to employ 10% amount of
morpholin-4-ium 2,2,2-trifluoroacetate 16 in the following
reactions so as to maintain an economical protocol. Moreover,
it merits attention that the active precursor i was successfully
Figure 1. The structure of myrtucommulone K.
Based on the speculation and inspection of the hypothesis,
the total synthesis of myrtucommulone K mirrored the general
approach reported in our earlier work towards the total
synthesis of tomentodione A.13 As outlined in scheme 2, the
putative structure of myrtucommulone K could be readily
assembled from the segments of β-caryophyllene and hetero-
diene i, while the access of key precursor hetero-diene i could
be accomplished by the enamine-catalyzed Knoevenagel
condensation from isobutyraldehyde 11 and syncarpic acid 10.
characterized by NMR for the first time20-21
biomimetic Diels-Alder cycloaddition between
.
The key
β-
caryophyllene and compound i was performed in reflux
toluene or neat condition, generating the desired 1 (Scheme 3).
Scheme 2. Retrosynthetic analysis of mytucommulone K.
The implementation of the total synthesis commenced with
the preparation of syncarpic acid 10 by the established
protocol, which could be readily accessed through a sequence

3
Table 1. Optimization of Knoevenagel condensation.
structure of
1
through extensive 1D and 2D NMR
spectroscopic analyses. The H and 13C NMR data of the
synthetic compound 1a was startlingly similar to those of the
natural product tomentodione A from the plant R. tomentosa,13
which also belongs to the family Myrtaceae. The 1D and 2D
NMR spectra of 1a (Table S1) demonstrated the existence of a
β-triketone moiety in the molecule.5,6 However, extensive
elucidation of 2D NMR spectra of 1a suggested that the
sesquitepene moiety was displayed as a caryophyllene instead
of the reported one. The 1H-1H COSY experiment revealed the
presence of two fragments (Figure 2): a (C-14′/C-13′/C-12′/C-
11'/C-5/C-6/C-7), and b (C-3/C-2/C-1/C-9/C-10). The HMBC
correlations from H-11′ to C-1′, C-5′, and C-4′ suggested that
the isopropyl group was attached to C-11' of the syncarpic acid
moiety. In addition, based on the above two fragments a and b,
the HMBC correlations from H-15 to C-7 and C-9, H-1 to C-8,
H-12 to C-11, H-13 to C-1, C-10, and C-11, H-14 to C-3 and
C-4 suggested that 1a embraced a caryophyllene moiety when
taking our earlier report into account.13
1
Gratifyingly, the structure of 1a is reasonable for that of
myrtucommulone K, because it was found to be identical in all
aspects to those of the isolated natural product, judging from
The relative configuration of 1a was determined through
interpretation of the proton coupling constants and NOESY
correlations (Figure 2). The relative stereochemistry of C-1
and C-9 in the caryophyllene unit was deduced to be identical
to that of natural β-caryophyllene. This conclusion was drawn
from the informative NOE correlations observed between H-
9/H3-13, which suggested that the two protons were isofacial,
and were arbitrarily assigned as an α-orientation. Whereas the
observed NOE interactions between H-5/H-1 and H-5/H-3β
indicated that H-5 was β-oriented. Finally, the correlation
between H3-12/H-11′ revealed that the isobutyl group at C-11′
was also α-oriented. Given that β-caryophyllene was used in
the total synthesis and possessed the same optical activity
between the natural and synthetic products, the
1
their H- and 13C- NMR spectrum (Table S1). It was worthy
mentioning that, in addition to the expected product 1a, two
other separable species 1b and 1c were also obtained in
moderate yields (1:1). They were spectroscopically assigned to
be the epi- or regio-isomers of 1a, which shared similar
skeletons to the newly-discovered natural products
tomentodione B15 and rhodomentone A15, respectively. It is not
yet clear whether these two structurally intriguing analogs 1b
and 1c are also natural products that might have circumvented
isolation and identification so far from Myrtaceae plants
species. If so, further studies on topics pertaining to these
compounds would spawn.
myrtucommulone
K
was
thus
assigned
as
(2aR,4aR,10S,10aS,13aS)-10-isopropyl-2,2,4a,6,6,8,8-
heptamethyl-13-methylene-1,2,2a,3,4,4a,10,10a,11,12,13,13a-
dodecahydrocyclobuta[6,7]cyclonona[1,2-b]chromene-
7,9(6H,8H)-dione 1a as depicted in Figure 1.
In summary, we have accomplished the first stereoselective
total synthesis of myrtucommulone K and its structural analogs
Scheme 3. The synthetic routine of myrtucommulone K (1a)
and its analogues.
1b and 1c through
a remarkable biomimetic spontaneous
methodology, which mimics a biosynthetic heteroatom Diels-
Alder cycloaddition sequence. Moreover, their structures were
confirmed by the comparison of NMR data and extensive
Having executed the biomimetic total synthesis, the stage
was now set to further confirm the initially established

4
Tetrahedron
150 mL), washed with brine, and concentrated in vacuum. The
crude product was purified by flash chromatography (silica
gel, hexane:EtOAc = 2:l) to afford acetylphloroglucinol (3.32
1
g, 79% yield). H NMR (500 MHz, DMSO-d6): δ 5.81 (s, 2H),
2.54 (s, 3H); 13C NMR (125 MHz, DMSO-d6): δ 203.9, 166.2,
Figure 2. The key 1H-1H COSY, HMBC and NOESY
correlations of myrtucommulone K.
164.7, 105.9, 96.3, 33.5.
The
synthesis
of
4-acetyl-5-hydroxy-2,2,6,6-
spectroscopic analysis. The approach has also established a viable
tetramethylcyclohex-4-ene-1,3-dione. A flame-dried 250 mL
flask was charged with acetylphloroglucinol (5.50 g, 33.0
mmol) and anhydrous MeOH (120 mL). Sodium methoxide
(14.4 g, 266 mmol) was added slowly. After stirring for 10
min, methyl iodide (14.2 mL, 228 mmol) was added dropwise
at 0 oC and kept it stirring at this temperature for 30 min. Then
the ice bath was removed, the reaction mixture was stirred for
another 24 h at room temperature until all the starting material
was consumed. The mixture was then quenched with 2 N HCl
(150 mL). The resulting mixture was extracted with EtOAc
(4×150 mL), and the combined organic phases were dried with
Na2SO4 and then concentrated in vacuo. The residue was
purified by flash chromatography (silica gel; hexane/EtOAc, 5:
l) to afford 4-acetyl-5-hydroxy-2,2,6,6-tetramethylcyclohex-4-
ene-1,3-dione (6.36 g, 86% yield) as a colorless needle crystal.
1H NMR (500 MHz, CDCl3): δ 1.33 (s, 6H), 1.42 (s, 6H), 2.57
(s, 3H); 13C NMR (125 MHz, CDCl3): δ 23.8, 24.3, 27.4, 52.0,
56.7, 109.4, 196.7, 199.1, 201.7, 210.0.
synthetic strategy for efficient total synthesis of other natural
products containing the similar meroterpenoid skeleton, as well as
provided
a
general approach to the preparation of
analogs. Further explorations of this
myrtucommulone
K
synthetic routine to other natural product synthesis, medicinal
chemistry and diversity-oriented synthesis are in progress and will
be communicated in the due course.
1. Experimental section
2. General experimental procedures
Optical rotations were measured on a Perkin-Elmer 341
polarimeter (Perkin-Elmer, Boston, MA, USA). 1D and 2D
NMR spectra were recorded on a Bruker Advance-500
spectrometer with TMS as internal standard (Bruker BioSpin
AG, Fällanden, Switzerland). All solvents were analytical
grade (Shanghai Chemical Plant, Shanghai, China). Silica gel
(200-300 mesh) was used for column chromatography, and
precoated silica gel GF254 plates (Qingdao Marine Chemical
Inc, Qingdao, China) were used for TLC. TLC spots were
visualized under UV light and by dipping into 5% H2SO4 in
alcohol followed by heating.
The synthesis of 5-hydroxy-2,2,6,6-tetramethylcyclohex-4-
ene-1,3-dione (syncarpic acid) 10. 4-acetyl-5-hydroxy-2,2,6,6-
tetramethylcyclohex-4-ene-1,3-dione (6.36 g, 28.5 mmol) was
added to a solution of 6 N HCl aqueous (120 mL). Reflux was
then continued for 24 hours. Following this, the reaction was
cooled, and the aqueous were extracted with EtOAc (4×150
mL). The combined organic phases were washed with brine,
dried over Na2SO4 and concentrated in vacuo. The residue was
further purified by flash chromatography (silica gel; n-
hexane/ethyl acetate, 1:1) to afford syncarpic acid 6 (4.05 g,
3. Preparation of key intermediate i
Synthesis of the key intermediate
i was conducted
according to our previous reported paper.13 Intermediate i, 1a-c
and the copies of their NMR spectra could be found in the
supporting information.
4. Material synthesis and nuclear magnetic data
1
78% yield) as a slight yellowish solid. H NMR (500 MHz,
The synthesis of acetylphloroglucinol. Aluminum
trichloride (13.3 g, 100 mmol) was slowly and carefully added
to a solution of phloroglucinol 12 (3.15 g, 25 mmol) in
CH2ClCH2Cl/PhNO2 (1:1, 50 mL) at 0 oC. After stirring at this
temperature for 10 min under nitrogen, acetyl chloride (2.38
mg, 30 mmol) was added. The ice bath was removed, and the
mixture was stirred at 80 oC for 3 h. The crude reaction
mixture was cooled to room temperature and quenched with
water (150 mL). The mixture was extracted with EtOAc (5 ×
CDCl3): ketone: d 1.31 (s, 12H), 3.61 (s, 2H); enol: d 1.40 (s,
12H), 5.74 (brd, J = 2.3 Hz, 1H), 8.00 (br s, 1H); 13C NMR
(125 MHz, CDCl3): ketone: d 21.8, 50.2, 59.1, 204.3, 208.9;
enol: d 24.5, 51.2, 59.1, 101.7, 191.9, 204.3, 212.6.
The
synthesis
of
2,2,4,4-tetramethyl-6-(3-
methylbutylidene)cyclohexane-1,3,5-trione i: To a solution of
syncapic acid 4 (182 mg, 1.0 mmol) and isobutyraldehyde (216
mg, 3.0 mmol) in CH2Cl2 (10 mL), morpholin-4-ium 2,2,2-

5
trifluoroacetate (20 mg, 0.1 mmol) was added in one portion.
The resulting reaction mixture was stirred for 30 min at room
temperature. Then, it was quickly passed through a short pad
(3 cm) of flash chromatography (silica gel; CHCl3) to afford α,
β-unsaturated ketone (224 mg, 95% yield) as a colorless oil,
which was pure enough to be directly used in the next step
Project (2016CXTD007), the Natural Science Foundation of
Hainan Province (20152038), and Hainan Province Education
Department Project (HnKy2015-21).
References and notes
1. For representative reviews, see: I. P. Singh, S. B. Bharate,
Phloroglucinol compounds of natural origin, Nat. Prod. Rep.
2006, 23, 558-591.
2. I. P. Singh, J. Sidana, S. B. Bharate, W. J. Foley,
Phloroglucinol compounds of natural origin: synthetic aspects,
Nat. Prod. Rep. 2010, 27, 393-416.
1
without further purification. H NMR (500 MHz, CDCl3): δ
1.10 (d, J = 6.6 Hz, 6H), 1.30 (s, 6H), 1.31 (s, 6H), 3.35 (m,
1H), 7.24 (d, J = 10.5 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ
21.8, 21.9, 22.3, 28.5, 58.1, 58.5, 130.6, 164.8, 196.5, 199.7,
208.7.
3. J.-A. Richard, R. H. Pouwer, D. Y.-K. Chen, The chemistry of
the polycyclic polyprenylated acylphloroglucinols, Angew.
Chem. Int. Ed. 2012, 51, 4536–4561.
4. For selected recent reports of meroterpenoids, see: L.-Z. Hu, Y.
Zhang, H.-C. Zhu, J.-J. Liu, H. Li, X.-N. Li, W.-G. Sun, J.-F.
Zeng, Y.-B. Xue, Y.-H. Zhang, Filicinic acid based
Meroterpenoids with anti-epstein–barr virus activities from
Hypericum japonicum, Org. Lett. 2016, 18, 2272–2275.
5. C.-J. Li, J. Ma, H. Sun, D. Zhang, D.-M. Zhang, Guajavadimer
A, a dimeric caryophyllene-derived meroterpenoid with a new
carbon skeleton from the leaves of Psidium guajava, Org. Lett.
2016, 18, 168–171.
6. Y. Gao, G.-Q. Wang, K. Wei, P. Hai, F. Wang, J.-K. Liu,
Isolation and biomimetic synthesis of ( )-guajadial B, a novel
meroterpenoid from Psidium guajava, Org. Lett. 2012, 14,
5936–5939.
Method 1: The α, β-unsaturated ketone i (224 mg, 0.95
mmol) and β-caryophyllene (1.0 g, 5.0 mmol) were dissolved
in dry toluene (5 mL). After being heated to reflux for 3 h
under nitrogen atmosphere, the reaction was cooled to room
temperature and purified directly by flash chromatography
(silica gel, hexane/ethyl acetate, from 100:1 to 10:1) to give a
mixture (250 mg, 60% yield) as a colorless solid. The mixture
(50 mg) was further purified by semi-prep-HPLC (MeOH/H2O,
90:10, v/v, 2 mL/min) to obtain compounds 1b (9.0 mg, tR = 20.0
min), 1a (10 mg, 21.0 min) and 1c (12.0 mg, tR = 27 min). 1a:
7. L.-Z. Hu, Y.-B. Xue, J.-W. Zhang, H.-C. Zhu, C.-M. Chen, X.-
N. Li, J.-J. Liu, Z.-Z. Wang, Y. Zhang, Y.-H. Zhang, ( )-
Japonicols A–D, Acylphloroglucinol-based meroterpenoid
enantiomers with anti-KSHV activities from Hypericum
japonicum, J. Nat. Prod. 2016, 79, 1322–1328.
8. J.-Q. Cao, X.-J. Huang, Y.-T. Li, Y. Wang, L. Wang, R.-W.
Jiang, W.-C. Ye, Callistrilones
A
and B, triketone–
phloroglucinol–monoterpene hybrids with a new skeleton from
Callistemon rigidus, Org. Lett. 2016, 18, 120–123.
[α]20D +43 (c 0.10, CHCl3), 1b: [α]20D +36 (c 0.10, CHCl3), 1c:
[α]20 -27 (c 0.10, CHCl3). H (500 MHz) and 13C (125 MHz)
9.
L. Wu, J. Luo, X. B. Wang, R. J. Li, Y. L. Zhang, L. Y. Kong,
Calliviminones C–H: six new hetero- and carbon-Diels–Alder
adducts with unusual skeletons from the fruits of Callistemon
viminalis, RSC Adv. 2015, 5, 93900–93906.
1
D
NMR spectral data were the same as the natural compound.
Method 2: The α, β-unsaturated ketone i (224 mg, 0.95
mmol) and β-caryophyllene (1.0 g, 5.0 mmol) were neatly
mixed. The mixture was stood at room temperature for 24 h
under nitrogen atmosphere. After the start material was
disappeared while checking by TLC, the reaction mixture was
purified directly by flash chromatography (silica gel,
hexane/EtOAc, from 100:1 to 10:1) to give a mixture (225 mg,
54% yield) as a colorless solid. The mixture (225 mg, 54%
yield) was further purified by semi-prep-HPLC (MeOH/H2O,
90:10, v/v, 2 mL/min) to obtain compounds 1b (9.0 mg, tR = 20.0
min), 1a (10 mg, 21.0 min) and 1c (12.0 mg, tR = 27 min). The
product was identical to all aspects of the natural one.
5. Appendix A. Supplementary data
10. M. Shao, Y. Wang, Y.-Q. Jian, X.-J. Huang, D.-M. Zhang, Q.-
F. Tang, R.-W. Jiang, X.-G. Sun, Z.-P. Lv, X.-Q. Zhang, W.-C.
Ye, Guadial A and psiguadials C and D, three unusual
meroterpenoids from Psidium guajava, Org. Lett. 2012, 14,
5262–5265.
11. F. Cottiglia, L. Casu, M. Leont, P. Caboni, C. Floris, B.
Busonera, P. Farci, A. Ouhtit, G. Sanna, Cytotoxic
phloroglucinols from the leaves of Mytus communis, J. Nat.
Prod. 2012, 75, 225-229.
12. H.-X. Liu, W.-M. Zhang, Z.-F. Xu, Y.-C. Chen, H.-B. Tan, S.-
X. Qiu, Isolation, synthesis, and biological activity of
tomentosenol A from the leaves of Rhodomyrtus tomentosa,
RSC Adv. 2016, 6, 25882–25886.
13. H.-X. Liu, K. Chen, G.-H. Tang, Y.-F. Yuan, H.-B. Tan, S.-X.
Qiu, Isolation and biomimetic total synthesis of tomentodiones
A-B, terpenoid-conjugated phloroglucinols from the leaves of
Rhodomyrtus tomentosa, RSC Adv. 2016, 6, 48231–48236.
14. C. Liu, S. Ang, X.-J. Huang, H.-Y. Tian, Y.-Y. Deng, D.-M
Zhang, Y. Wang, W.-C. Ye, L. Wang, Meroterpenoids with
new skeletons from Myrtus communis and structure revision of
myrtucommulone K, Org. Lett. 2016, 18, 4004-4007.
15. A. Hiranrat, W. Mahabusarakam, New acylphloroglucinols
from the leaves of Rhodomyrtus tomentosa, Tetrahedron 2008,
64, 11193–11197.
The Supplementary Information is available on the Science
Direct Publications website at http://
16. L. Wu, J. Luo, Y.-L. Zhang, M.-D. Zhu, X.-B. Wang, J.-G.
Luo, M.-H. Yang, B.-Y. Yu, H.-Q. Yao, Y. Dai, Q.-L. Guo, Y.-
J. Chen, H.-B. Sun, L.-G. Kong, Isolation and biomimetic
synthesis of ( )-calliviminones A and B, two novel Diels–Alder
adducts, from Callistemon viminalis, Tetrahedron Lett. 2015,
56, 229-232.
6. Bibliography
7. Acknowledgments
17. W. Crow, T. Osawa, K. Plaz, D. Sutherland, Root inhibitors in
Eucalyptus grandis. 2. Synthesis of the inhibitors and origin of
the peroxide linkage, Aust. J. Chem. 1976, 29, 2525-2531.
18. M. L. Bolte, W. D. Crow, S. Yoshida, Plant growth regulators
in Eucalyptus grandis. IV. Synthetic approaches to G-regulator
analogues, Aust. J. Chem. 1982, 35, 1411-1419.
This research was funded by the Program for Innovative
Research Team in University (IRT-16R19), Hainan Province
Natural Science Foundation of Innovative Research Team

6
Tetrahedron
19. P. S. Kalsi, J. Singh, W. D. Crow, B. R. Chhabra, Biomimetic
synthesis of 2,3-dioxabicyclo [4,4,0] decanes as plant growth
regulators, Phytochemistry 1987, 26, 3367-3369.
20. H. Muller, M. Paul, D. Hartmann, V. Huch, D. Blaesius, A.
Koeberle, O. Werz, J. Jauch, Total synthesis of
myrtucommulone A, Angew. Chem. Int. Ed. 2010, 49, 2045-
2049.
21. K. Wiechmann, H. Müller, V. Huch, D. Hartmann, O. Werz, J.
Jauch, Synthesis and biological evaluation of novel
myrtucommulones and structural analogues that target mPGES-
1 and 5-lipoxygenase, Eur. J. Med. Chem. 2015, 101, 133-149.

7
Graphical abstract

8
Tetrahedron
Highlights
1. The structure of myrtucommulone K
was revised.
2. Its first stereoselective total synthesis
was achieved by biomimetic strategy.
3. Enamime-catalyzed
Knoevenagel
condensation was established to
access precursor i.
4. The active precursor i was successfully
characterized by NMR for the first time.