Biomimetic Syntheses of Callistrilones A-E via an Oxidative [3 + 2] Cycloaddition

Article abstract of DOI:10.1021/acs.orglett.8b00238

Concise total syntheses of callistrilones A-E have been achieved from 7 and commercially available α-phellandrene (8). The synthetic strategy, which was primarily inspired by the biogenetic hypothesis, was enabled by an oxidative [3 + 2] cycloaddition fol

Full text of DOI:10.1021/acs.orglett.8b00238

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Biomimetic Syntheses of Callistrilones A−E via an Oxidative [3 + 2]
Cycloaddition
Yonghong Guo, Yuhan Zhang, Mingxing Xiao, and Zhixiang Xie*
State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, P. R. China
S
* Supporting Information
ABSTRACT: Concise total syntheses of callistrilones A−E have been
achieved from 7 and commercially available α-phellandrene (8). The
synthetic strategy, which was primarily inspired by the biogenetic
hypothesis, was enabled by an oxidative [3 + 2] cycloaddition followed
by a Michael addition and an intramolecular nucleophilic addition to
construct the target molecules. Moreover, viminalin I was also synthesized,
and its absolute configuration was unambiguously confirmed.
he Myrtaceae family has a wide distribution in tropical and
warm-temperate regions of the world and is typically
showed that 2 has moderate activity against Gram-positive
bacteria, including multiresistant strains. The unprecedented
pentacyclic ring system and the biosynthetic pathway feature
inspired us to engage in total syntheses of these two
compounds, which have just been accomplished by the
adoption of a biomimetic [3 + 2] cycloaddition as the key
step. Very recently, Li and co-workers isolated callistrilones C−
E, which are closely related to callistrilones A and B in
structure, and accomplished elegant catalytic asymmetric total
syntheses of callistrilones A, C, D, and E.10 Almost at the same
time, callistrilones A, B, and D were biomimetically synthesized
via catalytic Friedel−Crafts alkylation and palladium-catalyzed
Wacker-type oxidative cyclization by Dethe.11 Following our
syntheses of callistrilones A and B, callistrilones C−E were also
synthesized by us with the same strategy. Herein we report
these new biomimetic syntheses of callistrilones A−E.
T
common in many of the world’s biodiversity hotspots.
According to a recently estimated suggestion, the Myrtaceae
family includes approximately 5950 species in ca. 132 genera.1
Many species of this widely distributed family, such as Myrtus
communis L. (Myrtaceae),2 have been used as folk medicine for
centuries because of their significant antimicrobial, antitumor,
and anti-inflammatory properties.3 For example, myrtucommu-
lone A (1), isolated from the plant (Figure 1),4 exhibits strong
In the isolation paper,9 Ye and co-workers postulated
biosynthetic pathways for callistrilones A and B. It has been
reported that acylphloroglucinol and flavesone are two major
components of Callistemon plants.12 In the proposed
biosynthetic pathway, an oxidative [3 + 2] cycloaddition first
takes place between isobutyrylphloroglucinol (7) and α-
phellandrene (8), a common monoterpene in Callistemon
plants, giving rise to intermediates 9 and 10 (Scheme 1).13
Intermediate 9 is coupled with the precursor isobutylidene-
syncarpic acid (11) via Michael addition to deliver callistrilone
E (6)10 and 12,14 which can be transformed to 13 and
callistrilone D (5) via intramolecular nucleophilic addition.
Callistrilone A (2) and callistrilone C (4) are accessed via
epoxidation of 13 and 5, respectively. As shown in Scheme 1,
on the basis of the family tree of biogenetic pathways proposed
for callistrilones A−E, compounds 12 and 13 would be natural
Figure 1. Structures of myrtucommulone A and callistrilones A−E.
antibacterial activity against Gram-positive bacteria.5 Continu-
ing phytochemical investigations of the leaves of Myrtus
communis L. led to the isolation of myrtucommulones J, K,
and L by Cottiglia6 and five meroterpenoids by Wang.7
Recently, three of these isolated meroterpenoids were
synthesized by our group via a biomimetic approach.8
Callistrilones A (2) and B (3), with a new triketone−
phloroglucinol−monoterpene hybrid skeleton, were isolated
from Callistemon rigidus (Myrtaceae).9 Bioactivity research
Received: January 29, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00238
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
conditions,21 but this attempt resulted in the formation of
complicated compounds.
Scheme 1. Biomimetic Pathway Proposed for Callistrilones
A−E
Thus, an extensive screening of reaction conditions was
needed for this oxidative [3 + 2] cycloaddition. Nair and co-
workers reported a [3 + 2] cycloaddition between 2-hydroxy-
1,4-naphthoquinone and conjugated dienes that uses CAN as
an oxidant.26 Following their protocol, treatment of 7 and 8
with CAN gave 9 and 10 in 9% and 14% yield, respectively
(Table 1, entry 1). Encouraged by this initial finding, we
a
Table 1. Screening for an Oxidative [3 + 2] Cycloaddition
b
yield (%)
entry
oxidant
CAN
solvent
T (°C)
9
10
14
1
2
3
4
5
6
7
8
9
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCM
0
9
0
0
AgOAc
Ag2O
50
rt
50
30
50
0
48
50
35
33
trace
19
26
33
40
37
35
Ag2CO3
Mn(OAc)3
PhI(OAc)2
CAN
trace
0
trace
12
4
CAN
THF
0
CAN
acetone
acetone
acetone
acetone
0
14
14
15
24
c
10
CAN
0
d
products as well, which might be discovered from plants in the
future. On the other hand, methylation of 10 then leads to the
formation of intermediate 14, which was also isolated from
Callistemon rigidus.9 Compound 14 is further coupled with the
precursor isobutylidenesyncarpic acid (11) via Michael and
intramolecular nucleophilic additions to deliver callistrilone B
(3).14
11
CAN
0
e
12
CAN
0
a
Conditions: unless indicated otherwise, the reactions were performed
with 7 (0.28 mmol) and 8 (0.56 mmol, 2.0 equiv) in the solvent (5.6
mL) under Ar, and the oxidant (0.64 mmol, 2.3 equiv) was added.
b
c
d
Isolated yields. Oxidant (3.5 equiv). 8 (5.0 equiv) and oxidant (3.5
e
equiv). 8 (10.0 equiv) and oxidant (6.0 equiv).
Inspired by the proposed biogenetic pathway of callistrilones
A−E, the total syntheses of these natural products were
initiated from an oxidative [3 + 2] cycloaddition between 7 and
commercially available compound 8. Isobutyrylphloroglucinol
(7) was synthesized from phloroglucinol by Friedel−Crafts
acylation with isobutyryl chloride in 85% yield.8,15 With 7 in
hand, we then focused on the biomimetic oxidative [3 + 2]
cycloaddition, a powerful approach to construct dihydrobenzo-
furan skeletons from phenols and olefins.16 Several kinds of
oxidants have been applied for the synthesis of dihydrobenzo-
furan derivatives from phenols and olefins, such as single-
electron metal oxidants,17 high-valence iodine reagents,18
DDQ,19 FeCl3/DDQ,20 FeCl3·(H2O)6/DTBP,21 and electro-
chemical oxidation.22 This kind of oxidation has also been
achieved under conditions of photoredox catalysis, such as
continued to test various single-electron metal oxidants. The
representative results are included in Table 1 as entries 2−5.
The reaction gave 10 as the major product when Ag salts and
Mn salts were used as oxidants. The best yield was obtained
using Ag2O as the oxidant. The high-valence iodine reagent
PhI(OAc)2, on the other hand, is not suitable for this reaction
(entry 6). For diverse syntheses of callistrilones, the yield of 9
also needed to be improved. We tried to convert 10 into 9, but
this effort was in vain. As using CAN as the oxidant gave both 9
and 10, we chose this oxidant for further optimization. Various
solvents such as DCM, THF, and acetone were examined to
improve the yield of 9, and the best result was obtained when
acetone was used as the solvent (entries 7−9). When the
amounts of CAN and 8 were increased, the yield of 9 slightly
increased (entries 10−12). It should be noted that the major
compound was 10 in all of these cases because the o-phenol is
more nucleophilic as a result of hydrogen bonding between the
o-phenol and the ketone.27 Moreover, a high concentration of
CAN and long reaction time would decrease the yield.17a
As compound 10 was main product of the oxidative [3 + 2]
cycloaddition, we turned to the total synthesis of callistrilone B
from 10 according to the biosynthetic hypothesis. As shown in
Scheme 2, methylation of 10 delivered biosynthetic inter-
mediate 14, which was isolated from Callistemon rigidus and has
the optical rotation value of +70.9 In 2018, the same group28
reported that the optical rotation value of 14, isolated from the
23
visible light/Ru(bpz)3(PF6)2/(NH4)2S2O8 or visible light/
mesoporous graphitic carbon nitride/air.24 Initially, we used the
procedure of Lei19b and treated compounds 7 and 8 with DDQ
in the presence of a catalytic amount of FeCl3. However, it did
not work. The reason might be the poor solubility of
compound 7 in toluene. Then the solvent was changed from
toluene to DMF. However, oxidative [3 + 2] cycloaddition
between 7 and 8 still did not happen. Instead, a [4 + 2]
cycloaddition25 product from 8 and DDQ was obtained (see
the Supporting Information for details). As DDQ was not a
suitable oxidant for 8 to proceed with this oxidative [3 + 2]
cycloaddition, we turned our attention to FeCl3·(H2O)6/DTBP
B
DOI: 10.1021/acs.orglett.8b00238
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Syntheses of Viminalin I and Callistrilone B
Scheme 3. Syntheses of Callistrilones A, C, D, and E
same plant, was −68.7.29 Viminalin I, isolated from Callistemon
viminalis, was originally proposed as the enantiomer of 14, and
the reported optical rotation value was −30.7.13 Compound 14
synthesized in the present study has an optical rotation value of
−65.3. Obviously, the absolute configuration of viminalin I is
consistent with that shown for 14 in Scheme 2.
Following the preparation of viminalin I (14), the synthesis
of callistrilone B proceeded by testing the Michael and
intramolecular nucleophilic additions of 14 to 11. Compound
11 was prepared from flavesone in one pot.8 To our surprise,
no product was observed when 14 was reacted with 11 under
basic conditions such as NaH and t-BuOK. The results
remained disappointing under Lewis acidic conditions, such
as Ni(ClO4)·6H2O and FeCl3.27 In addition, complex products
were detected when 10 was used instead of 14.
We speculated that the reason for this failure might be that
the electron-donating methoxy group reduces the nucleophil-
icity of 11, and thus, we changed the −OMe group to the
electron-withdrawing −OAc group for further investigations.30
To our delight, after this manipulation the Michael addition
proceeded smoothly in the presence of NaH, giving compound
16 in 85% yield as a single diastereoisomer (Scheme 2).
Treatment of 16 with p-toluenesulfonic acid (PTSA) then
afforded 17.31 A stepwise procedure involving deacetylation
and methylation successfully gave callistrilone B (3). The
spectra and physical properties of the synthesized compound
were identical to those of the reported natural product.7
Moving forward, the Michael addition of 9 with 11
proceeded smoothly to give a pair of regioisomers, callistrilone
E and 12 (Scheme 3). Then callistrilone E and 12 were
successfully converted to 13 and callistrilone D through a
sequence mediated by PTSA in 39% and 21% yield,
respectively. Next, the seemingly simple epoxidation of the
CC bond proved to be challenging. Direct epoxidation of
compound 13 or callistrilone D with m-CPBA or dimethyldiox-
irane (DMDO) provided undesired stereoselective product 19
or 20. It was believed that the steric hindrance was the primary
cause. Therefore, we adapted a stepwise sequence32 to
overcome this obstacle. The best result10 was obtained when
iodohydroxylation of the disubstituted double bond was
conducted with NaI/oxone and then a NaH-promoted
diastereoselective cyclization was implemented to give the
1
desired callistrilones A and C. The H and 13C NMR spectra
were in agreement with the literature data.7,10
In summary, callistrilones A−E have been synthesized via
oxidative [3 + 2] cycloaddition followed by Michael and
intramolecular nucleophilic additions as key reactions. More-
over, viminalin I was also synthesized, and its absolute
configuration was unambiguously confirmed. By providing
efficient access to the 2,3-dihydrobenzofuran core, this
biomimetic oxidative [3 + 2] cycloaddition strategy allowed
us to construct an array of natural and unnatural products from
acylphloroglucinol and α-phellandrene.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00238.
Experimental procedures, crystallographic data, and
1
copies of H and 13C spectra for all new compounds
(PDF)
Accession Codes
CCDC 1818783 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
C
DOI: 10.1021/acs.orglett.8b00238
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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1EZ, U.K.; fax: +44 1223 336033.
M. P. J. Org. Chem. 2013, 78, 7594−7600. (b) Chen, P.-Y.; Wu, Y.-H.;
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xiezx@lzu.edu.cn.
ORCID
(c) Ber
Tetrahedron 2008, 64, 7537−7544. (d) Ber
C.; Canesi, S. Synlett 2008, 2008, 1076−1080. (e) Sabot, C.; Ber
D.; Canesi, S. Org. Lett. 2008, 10, 4629−4632.
́
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Zhixiang Xie: 0000-0001-5809-3084
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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■
We gratefully acknowledge financial support from the NNSFC
(Grant 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 the Fundamental Research
Funds for the Central Universities (lzujbky-2016-ct02).
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