Concise Construction of the Tricyclic Core of Bullataketals Enabled by a Biomimetic Intermolecular (3 + 3) Type Cycloaddition

Article abstract of DOI:10.1021/acs.orglett.5b01970

A remarkable TFA-mediated method for the construction of a biologically interesting tricyclic ketal skeleton was uncovered by starting from a variety of readily available acylphloroglucinol and diacylphloroglucinol substrates. This approach, which mimics a biosynthetic olefin isomerization/hemiacetalization/dehydration/(3 + 3) type cycloaddition sequence through a 2H-furan-1-ium intermediate, establishes a viable synthetic strategy for efficient synthesis of bullataketals' analogs.

Full text of DOI:10.1021/acs.orglett.5b01970

Letter
pubs.acs.org/OrgLett
Concise Construction of the Tricyclic Core of Bullataketals Enabled
by a Biomimetic Intermolecular (3 + 3) Type Cycloaddition
Haibo Tan,† Hongxin Liu,† Xinzheng Chen,‡ Yunfei Yuan,† Kai Chen,*,§ and Shengxiang Qiu*,†
†Program for Natural Product Chemical Biology, Key Laboratory Plant Resources Conservation and Sustainable Utilization, South
China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, People’s Republic of China
‡School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen 518055, People’s
Republic of China
§School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, People’s Republic of
China
S
* Supporting Information
ABSTRACT: A remarkable TFA-mediated method for the construction of a biologically interesting tricyclic ketal skeleton was
uncovered by starting from a variety of readily available acylphloroglucinol and diacylphloroglucinol substrates. This approach,
which mimics a biosynthetic olefin isomerization/hemiacetalization/dehydration/(3 + 3) type cycloaddition sequence through a
2H-furan-1-ium intermediate, establishes a viable synthetic strategy for efficient synthesis of bullataketals’ analogs.
tructurally complex natural products continuously serve as
a powerful vehicle for the invention of novel synthetic
a novel strategy which facilitates convergent assembly of the
tricyclic ketal core unit is desirable.
S
strategies; a broad variety of classic sequence reactions
developed for the construction of complex molecule skeletons
and biomimetic total synthesis have emerged in recent years.1,2
Tricyclic ketal skeleton and their architectural derivatives
represent frequently encountered complex motifs3 that are
present in many interesting bioactive natural products (high-
lighted with color in Scheme 1).4 Among these, bullataketals A
In contrast to the former aldol condensation/acetalation
biosynthetic proposal,4a our efforts to construct the tricyclic
ketal core have focused on disclosing the biomimetic synthesis
of bullataketals by deciphering their biogenetic pathway. As
highlighted in Scheme 2, we supposed that the (3 + 3) type
cycloaddition between isobutyrylphloroglucinol 5 and 2H-
furan-1-ium7 (TS-1) ought to be the crucial biosynthetic
transformation for bullataketals A (1), B (2) and myrtucommu-
acetalone 3. Moreover, 2H-furan-1-ium was suggested to
originate from α,β-unsaturated ketone 6 through an olefin
isomerization/hemiacetalization/dehydration sequence based
on the confirmed presence of isobutyrylphloroglucinol 5 in
this plant.8 Based on the speculation and inspection of the
underlying biogenetic transformations, we have successfully
developed a remarkable biomimetic sequence to efficiently
construct the tricyclic ketal core unit of bullataketals A (1) and
B (2). Herein we report the experimental details.
Scheme 1. Biologically Active Natural Products Featuring
Tricyclic Ketal Ring System
The challenge in the experimental realization of this
sequence clearly lies in identifying reaction conditions that
are conducive for simultaneously supporting operations of the
stepwise reactions and avoiding side products. With readily
accessible isobutyrylphloroglucinol 59 and α,β-unsaturated
ketone 610 as the model substrate and TFA as the tentative
catalyst,11 products 4 and 9 were initially isolated with 15%
yield and 2:1 ratio in THF (entry 1). Based on the NMR
(1) and B (2) with a fascinating tricyclic ketal skeleton have
shown potent cytotoxic activity against the P388 cell line with
IC50 = 1.0 μg/mL and excellent antimicrobial activity against
Bacillus subtilis.4a,5 Myrtucommuacetalone 3 exhibited signifi-
cant inhibitory effects against nitric oxide (NO·) production
and antiproliferative activity (IC50 < 0.5 μg/mL).4b Inspired by
their excellent biological activity and novel structure complex-
ity, much effort has been undertaken to develop approaches for
ketal formation, but there is still a lack of efficient methods to
rapidly access this key skeleton.6 Therefore, the development of
Received: July 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01970
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Proposed Biogenetic Pathways of Bullataketals A,
B and Myrtucommuacetalone
Table 1. Optimization of Reaction Conditions
cat.
loading
ratio
(4:9)
b
c
entry solvent
catalyst
t
time
yield
1
THF
TFA
TFA
TFA
TFA
TFA
TFA
TFA
AcOH
MsA
TFA
TFA
TFA
7.0 equiv
7.0 equiv
7.0 equiv
7.0 equiv
7.0 equiv
7.0 equiv
7.0 equiv
7.0 equiv
7.0 equiv
7.0 equiv
20 equiv
7.0 equiv
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
12 h
12 h
12 h
2.0 h
1.0 h
1.0 h
1.0 h
1.0 h
1.0 h
1.0 h
1.0 h
1.0 h
15%
<10%
<10%
68%
45%
56%
73%
<10%
33%
75%
54%
91%
2:1
−
−
2
H2O
3
ACN
4
CHCI3
toluene
DCE
2:1
3:2
2:1
2:1
2:1
2:1
2:1
2:1
2:1
5
6
7
DCM
DCM
DCM
8
9
d
10
11
12
DCM
DCM
e
DCM
a
Conditions: 6 (0.2 mmol), acylphloroglucinol 5 (0.24 mmol), TFA
spectroscopy, both of them featured the fascinating tricyclic
ketal skeleton and presumably formed due to the alternative
regioselectivity of the two phenol group in either the ortho- or
para-position.12 It merits attention that 4 and 9 could be
successfully separated by silica gel column chromatography but
tautomerized rapidly under neat or CDCl3 conditions.13 In an
attempt to improve the yield of this sequence, the reaction
conditions such as solvents, substrate loadings, and catalysts
were optimized. As a result, the solvent effect was shown to be
fairly significant during this transformation. When apolar
solvents were used, the desirable products 4 and 9 were
obtained with better yields under otherwise comparable
conditions, especially in DCM (73% yield, entry 7). During
the optimization process, the most intractable problem was the
poor solubility of acylphloroglucinol 5 in apolar solvents, which
led to the formation of a double (3 + 3) type cycloaddition
byproduct. The critical solution was to dissolve acylphlor-
oglucinol 5 and α,β-unsaturated ketone 6 in THF first and then
DCM after removing THF.14 With this operation, the yield was
dramatically increased to greater than 90% (entry 12, Table 1).
With the optimal conditions established, we next surveyed
the scope of this biomimetic sequence. A series of structurally
variable acylphloroglucinol derivatives 1015 were then subjected
to the above-defined conditions, and the results were compiled
in Figure 1. The reactivity appeared to be quite general, yielding
the corresponding tricyclic ketals 11 and 12 for each case in
excellent yields in the range 82−96% and with isomeric ratios
of nearly 3:2. Neither the length nor the steric hindrance of
acetyl substituents in the phloroglucinol ring seemed to have
posed a significant influence on the reaction efficiency and
isomeric ratios (11a−11k, 12a−12k). Notably, we observed
that as the more lipophilic acetyl substituents were induced to
the acylphloroglucinol substrates, better yields would be
provided. Moreover, the comparably competent substrates
with a more nucleophilic acetyl substituent (10a−10e and 10j−
10k), which tended to generate aldol condensation or Michael
addition byproducts with 2H-furan-1-ium, showed no notable
loss in the reactivity and selectivity.
b
(1.4 mmol, 0.1 mL), solvent (7.0 mL), rt, 1.0 h. Yields of isolated
products. The ratio (4:9) was accorded to the crude product and
measured by H NMR 2.0 equiv of 5 were used. 5 and 6 were
dissolved in THF (1.0 mL) first and dissolved again in DCM after
removing THF.
c
d
e
1
Figure 1. Surveying the scope of phloroglucinol substrates.
Conditions: 6 (0.2 mmol), acylphloroglucinol 10 (0.24 mmol), TFA
(1.4 mmol, 0.1 mL), DCM (7.0 mL), rt, 1−3 h. Yields of isolated
products. The ratio (11:12) was estimated by 1H NMR measurements
of the crude product.
When a range of diacylphloroglucinols16 had been examined,
the reactivity is virtually irrespective of the diacetyl substitution,
as the corresponding cycloaddition products 11l−11s were all
consistently isolated in almost quantitative yields. In contrast to
acylphloroglucinols, the inseparable regioisomers 12 were not
observed in the diacylphloroglucinols attributed to their
symmetrical structures. Moreover, all the yields of diacylphloro-
glucinols were slightly higher than those of acylphloroglucinols,
B
DOI: 10.1021/acs.orglett.5b01970
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
because the generation of the trace double (3 + 3) type
cycloaddition byproduct was prevented by the additionally
introduced acetyl substituents. The TFA-mediated biomimetic
(3 + 3) type cycloaddition sequence clearly tolerates a broad
spectrum of phloroglucinol partners.
Scheme 3. Experimental Probes on Reaction Mechanism
To further extend the scope of this protocol, various α,β-
unsaturated ketone 13 analogs were also examined (Figure 2).
Moreover, the detection of this transformation in CDCl3 was
also conducted by NMR. It ambiguously disclosed that 6 could
rapidly be transformed to 19 after treatment with TFA. Finally,
after treating the freshly generated 2H-furan-1-ium 19 with
acylphloroglucinol 5, the corresponding cycloaddition products
4 and 9 would be produced smoothly. The readily conceivable
results indicated that the 2H-furan-1-ium 19 has played the key
role in this sequence process.
The reactivity coupled with the mechanistic investigations
collectively pointed to a plausible mechanism shown in Scheme
4. The sequence would be initiated by a proton acid-catalyzed
Scheme 4. Proposed Mechanism
Figure 2. Surveying the scope of α,β-unsaturated ketone substrates.
Conditions: 13 (0.2 mmol), acylphloroglucinol 5 (0.24 mmol), TFA
(1.4 mmol, 0.1 mL), DCM (7.0 mL), rt, 1−12 h. The ratio was
1
accorded to the crude product and measured by H NMR.
This reaction tends to provide the corresponding tricyclic ketal
products 14a−14b with a lower yield but better regioselectivity
as the steric bulk of α,β-unsaturated ketone 13 was increased.
Moreover, the tertiary hydroxyl group in α,β-unsaturated
ketone 13 played a crucial role in this transformation. Indeed,
when the (E)-4-hydroxy-1-phenylbut-2-en-1-one was used, the
(3 + 3) type cycloaddition almost did not proceed (14c, Figure
2). This could be attributed to the weaker stability of the
generated 2H-furan-1-ium intermediate, which led to the
formation of the 2-phenylfuran byproduct. When (E)-4-oxo-
4-phenylbut-2-enoic acid derivatives were explored, the reaction
proceeded cleanly in 12 h. It was notable that, unlike the case of
(E)-4-hydroxy-1-phenylbut-2-en-1-one substrates, the tricyclic
ketal products were not observed in (E)-4-oxo-4-phenylbut-2-
enoic acid, but instead the corresponding linear lactone 15a−
15c was isolated as the only product in excellent yields ranging
from 79% to 88%. The above discovery could be used as an
efficient protocol to synthesize biologically significant benzo-
furan-2(3H)-one derivative.
Mechanistic experiments were then conducted to shed light
on the potential reaction pathways, as summarized in Scheme 3.
With phloroglucinol 5 as the model substrate, using α,β-
unsaturated ketone 16 instead of 6 has led to complete
inhibition of the intended reaction. The result had strongly
implied the involvement of the 2H-furan-1-ium intermediate
during the reaction process. In order to further confirm this
speculation, the α,β-unsaturated ketone 6 was treated with TFA
in DCM at room temperature. To our delight, the 2H-furan-1-
ium intermediate 19, which was fully characterized by NMR
and HRMS analysis,17 was formed in nearly 70% yield after 1 h.
tandem olefin E/Z isomerization and hemiacetalization to
generate the hemiacetal precursor 20. The further dehydration
of 20 under acidic conditions gave rise to the critical 2H-furan-
1-ium 19 and in turn induced the (3 + 3) type cycloaddition
with acylphloroglucinol 10 to afford the desirable products 11
and 12, which could rapidly tautomerize at room temperature.
It is noted that the (3 + 3) type cycloaddition was possibly the
rate-determining step from the obvious observation of 2H-
furan-1-ium 19 during the reaction process.
In summary, motivated by the fascinating biosynthetic
hypotheses of bullataketals A, B and myrtucommuacetalone,
we have developed a remarkable TFA-mediated approach,
which mimics a biosynthetic olefin isomerization/hemiacetal-
lization/dehydration/(3 + 3) type cycloaddition sequence, for
rapid construction of the tricyclic ketal core unit of bullataketals
A and B. The key point of this discovery would be the reliable
generation and application of the 2H-furan-1-ium intermediate.
Moreover, we have also established a viable synthetic strategy
for the efficient synthesis of bullataketals analogs and their
potential uses in medicinal chemistry as well as diversity-
oriented natural product synthesis. The total synthesis of
bullataketals A, B and myrtucommuacetalone, along with
solving the intractable chiral control and regio-isomerization
problem, is now underway and will be reported in due course.
C
DOI: 10.1021/acs.orglett.5b01970
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01970.
■
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S
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AUTHOR INFORMATION
Corresponding Authors
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*E-mail: cekchen@scut.edu.cn.
*E-mail: sxqiu@scbg.ac.cn.
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the National Science and Technology Major Projects
of China (2014ZX10005002-005) and the Foundation of Key
Laboratory of Plant Resources Conservation and Sustainable
Utilization (South China Botanical Garden, Chinese Academy
of Sciences) for financial support. We also thank Prof. David
Zhigang Wang (Peking University) for helpful discussions.
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DOI: 10.1021/acs.orglett.5b01970
Org. Lett. XXXX, XXX, XXX−XXX