A Bioinspired Cascade Sequence Enables Facile Assembly of Methanodibenzo[b,f][1,5]dioxocin Flavonoid Scaffold

Article abstract of DOI:10.1021/acs.orglett.7b03630

A remarkable bioinspired EDDA-mediated method for the selective construction of biologically interesting and highly strained bridged methanodibenzo[b,f][1,5]dioxocin flavonoid scaffold was uncovered by starting from a variety of readily available acylphloroglucinol and 2-hydroxycinnamaldehyde substrates. This method merges a fascinating olefin isomerization/hemiacetallization/dehydration/[3 + 3]-type cycloaddition cascade reaction driven by an in situ generated chromenylium intermediate and provides a convenient and viable synthetic strategy for the efficient access of such flavonoid analogues.

Full text of DOI:10.1021/acs.orglett.7b03630

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Bioinspired Cascade Sequence Enables Facile Assembly of
Methanodibenzo[b,f ][1,5]dioxocin Flavonoid Scaffold
Hongxin Liu,†,‡ Yu Wang,† Xueying Guo,† Luqiong Huo,† Zhifang Xu,† Weimin Zhang,‡
Shengxiang Qiu,† Bao Yang,*,† and Haibo Tan*,†
†Program 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
‡State 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
S
* Supporting Information
ABSTRACT: A remarkable bioinspired EDDA-mediated method for the selective
construction of biologically interesting and highly strained bridged
methanodibenzo[b,f][1,5]dioxocin flavonoid scaffold was uncovered by starting
from a variety of readily available acylphloroglucinol and 2-hydroxycinnamalde-
hyde substrates. This method merges a fascinating olefin isomerization/
hemiacetallization/dehydration/[3 + 3]-type cycloaddition cascade reaction
driven by an in situ generated chromenylium intermediate and provides a
convenient and viable synthetic strategy for the efficient access of such flavonoid
analogues.
he architectural complexity of natural products has
Tfascinated synthetic scientists, and the challenges
associated with their intricate structure have continuously
served as a powerful vehicle to fuel synthetic methodology
innovation.1 Among the greatest achievements in accessing
structural complexity stands the emergence of tandem reactions
and biomimetic synthetic pathways in recent years.2,3 The
methanodibenzo[b,f ][1,5]dioxocin skeleton represents a di-
verse family of structurally privileged motifs that are prevalent
in many interesting bioactive natural products and pharma-
ceuticals (highlighted in Scheme 1).4,5 Although they are useful
scaffolds with potential usefulness for the treatment of many
diseases,6 the protocols for efficient creation of such bridged
methanodibenzo[b,f ][1,5]dioxocin skeleton are less explored
probably due to their cleft-shaped structure and rigidity.7 Thus,
a fairly novel strategy toward convergent assembly of these
tetracyclic bridged core by bold retrosynthetic disconnection
inspired by nature will be a highly desirable and challenging
task.
Motivated by our ongoing research program on efficiently
accessing such similar polycyclic skeletons in a biomimetic [3 +
3] cycloaddition pathway,8 we are intrigued by the possibility of
forging these complex bridged scaffolds through a biomimetic
strategy. The proposed biogenetic pathway for the formation of
methanodibenzo[b,f][1,5]dioxocin skeleton usually proceeds
through a carbonyl reduction followed by a cationic cyclization
from the common flavonoid as shown in Scheme 2A. On the
basis of this scenario, we anticipated that an olefin isomer-
ization/hemiacetalization/dehydration sequence will transform
2-hydroxycinnamaldehyde 11 to a highly reactive chromeny-
lium intermediate 13 (Huckel aromatic compound),9,10 which
̈
Scheme 1. Biologically Active Natural Products Featuring a
Methanodibenzo[b,f][1,5]dioxocin Ring System
can “click” on a phloroglucinol nucleophile to trigger the crucial
[3 + 3]-type cycloaddition or carbonyl addition/biomimetic
cationic cycloaddition cascade downstream (Scheme 2B),
leading to the methanodibenzo[b,f][1,5]dioxocin flavonoid
skeleton in a highly efficient manner. If this proposal is
successful, it will allow us to synthesize an array of these novel
and biologically meaningful flavonoid analogues without further
elaboration. Herein, we report the experimental details of the
selective olefin isomerization/hemiacetalization/dehydration/
[3 + 3] cycloaddition bioinspired cascade sequence with readily
Received: November 22, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03630
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
yield (entries 9−14). Satisfyingly, when dioxane was used as a
cosolvent with toluene (entry 15), the cascade sequence
rendered ortho-product 18 in higher than 80% yield and
showed an excellent regioselective profile (>20:1), thereby
laying a solid foundation in terms of practicality and operational
simplicity.
Scheme 2. Proposed Biogenetic Pathway and the Design of a
Bioinspired Cascade Reaction
With the optimized conditions established, we surveyed the
scope and versatility of this reaction with respect to various
phloroglucinol derivatives 19.11 As shown in Scheme 3, a wide
Scheme 3. Surveying the Substrate Scope of
a
Phloroglucinols
accessible phloroglucinol and 2-hydroxy cinnamaldehyde
derivatives as substrates (Scheme 2B).
To verify this hypothesis, the readily accessible decanoyl-
phloroglucinol 1711 and 2-hydroxycinnamaldehyde 11 were
chosen as model substrates to implement the putative cascade
sequence by judicious selection and modification of reaction
conditions (Table 1). To our delight, when PTSA was used as
a
Table 1. Optimization of Reaction Conditions.
a
11 (0.2 mmol), 19 (0.22 mmol), EDDA (0.02 mmol), toluene (5
b
mL), dioxane (1 mL), reflux, 0.5−4 h. 19 (0.22 mmol), PTSA (0.02
mmol), toluene (5 mL), dioxane (1 mL), reflux, 1 h.
range of phloroglucinols bearing different substituents could be
well tolerated, wherein the corresponding desired tetracyclic
bridged products 20a−n were delivered in moderate to
excellent yields ranging from 54% to 89% within 0.5−4 h.
Moreover, the reaction appeared to be quite selective almost
without detectable amount of possible regioisomer for every
case. It was noticeable that the acetyl substituents on
phloroglucinol substrates 19 have posed a considerable
influence on the reaction efficiency. An obvious increase in
reaction yield was observed, when a more lipophilic acetyl
substituent was introduced to the phloroglucinol skeleton
(19a−g), whereas the steric hindrance of the substituent
seemed to have little influence (19h−k). These results could be
rationally ascribed to the solubility of the in situ generated
chromenylium−phloroglucinol intermediates9 before the cru-
cial [3 + 3] cycloaddition step. It merited attention that
substrates with a nucleophilic acetyl substituent (19a−g,j,k),
which held the potential to generate competitive aldol
condensation or Michael addition byproducts with chromeny-
lium,15 showed no notable loss in reactivity and selectivity.
Meanwhile, when an ester group was installed on the
phloroglucinol unit (19l), this protocol could also be well
tolerated and delivered the desired product 20l with moderate
yield. Notably, simple phloroglucinols 19m and 19n seemed to
be troublesome cases for this methodology, but an alternative
switch of catalyst EDDA to 0.1 equiv of PTSA would
successfully address this issue and furnish the corresponding
products 20m and 20n in a highly efficient manner.
Collectively, the availability of this well-orchestrated cascade
a
Reaction conditions: 11 (0.2 mmol), 17 (0.22 mmol), solvent (6
b
c
mL), rt, 0.5−3 h. Yield of isolated product. The ratio was
d
1
determined by H NMR spectra of the crude mixture. Toluene (5
mL), dioxane (1 mL). EDDA: ethylenediamine diacetate. EDDF:
ethylenediamine ditrifluoroacetate. EDDP: ethylenediamine di(p-
toluenesulfonate). NR: no reaction.
the tentative catalyst to trigger the proposed cascade sequence
in reflux toluene, two regioisomers 18 and 19,12 both featuring
the fascinating tetracyclic bridged skeleton, were formed albeit
in low yield (21% yield, entry 1). The formation of the
regioisomers 18 and 19 could be rationally attributed to the
reactive o- or p-phenol group existing in decanoylphlorogluci-
nol 17, respectively.13 In order to improve its synthetic
efficiency and selectivity, some other protic acids TFA, BzOH,
and AcOH were subsequently evaluated. Unfortunately, all of
them gave inferior results (entries 2−4).14 Further catalyst
screening proved that ammonium salts outperformed protic
acids in terms of both yield and regioselectivity (entries 5−8)
because of the weaker acidic conditions. In particular, EDDA
provided the highest level (entry 6). Variation in the
temperature and the reaction solvents did not improve the
B
DOI: 10.1021/acs.orglett.7b03630
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Letter
sequence exemplified by the aforementioned remarkable results
enabled a broad spectrum of phloroglucinols to be substrates.
Subsequently, we further extended the substrates to a variety
of substituted 2-hydroxycinnamaldehydes 21 for the con-
struction of the structurally diverse and functionalized
methanodibenzo[b,f ][1,5]dioxocin system (Scheme 4). It was
Scheme 5. Experimental Probes on Reaction Mechanism
Scheme 4. Surveying the Substrate Scope of 2-
a
Hydroxycinnamaldehydes
catalyzed conditions to generate the desired product with 90%
yield, thus further confirming the aforementioned deduction.
Interestingly, when the tetracyclic product 18 was heated in
the presence of PTSA, the regioisomer 19 which could also be
interconverted to 18 was isolated in 30% yield (about 2:1 ratio
with 18), implying that a competitive cationic trapping process
of the o- and p-hydroxyl groups in phloroglucinol 17 would be
inevitable when cationic intermediate 16 (Scheme 2)
generated. Moreover, when an excess amount of methanol or
butanol was used as the cationic-trapping reagent under the
standard conditions, the reaction proceeded smoothly to
provide 18 without any obvious effect and detection of the
cationic trapping products. Due to these informative results and
the better selectivity for the weak acidic conditions (entries 5
and 6, Table 1) than that for the stronger ones (entries 1−4,
Table 1), the pathway involving a concerted [3 + 3]-type
cycloaddition (pathway A in Scheme 2B) seemed to be much
more conclusive for this reaction mechanism. Collectively, the
aforementioned conceivable results strongly indicated that this
cascade reaction probably proceeded involving a remarkable
olefin isomerization/hemiacetalization/dehydration/[3 + 3]-
type cycloaddition sequence through a chromenylium inter-
mediate.
In summary, inspired by the fascinating biosynthetic
hypotheses of the flavonoids bearing a novel methanodibenzo-
[b,f ][1,5]dioxocin skeleton, we have developed an efficient
EDDA-catalyzed olefin isomerization/hemiacetalization/dehy-
dration/[3 + 3]-type cycloaddition cascade reaction driven by
an in situ generated chromenylium intermediate acting as a
“click” role. The culmination of this developed downstream
sequence interpreted the brevity of synthetic route, which
provides a convenient and practical methodology to selectively
construct highly complex and strained bridged methanodi-
benzo[b,f ][1,5]dioxocin flavonoid skeleton with readily acces-
sible phloroglucinol and 2-hydroxycinnamaldehyde derivatives.
Moreover, we have also established a viable synthetic strategy
for the efficient synthesis of such flavonoid analogues, the
availability of which would be highly beneficial to both
biological and medicinal chemistry. The diversity-oriented
total synthesis of natural products in this family along with
their structure−activity relationship study toward drug
discovery is now underway and will be reported in due course.
a
11 (0.2 mmol), 19 (0.22 mmol), EDDA (0.02 mmol), toluene (5
mL), dioxane (1 mL), reflux, 0.5−1 h.
observed that substrates bearing an electron-withdrawing
substituent (−F, −Cl, and −NO2) gave the corresponding
products (22c−e) in 84−88% yields, which mainly out-
performed those of the substrates (21a,b) bearing an
electron-donating substituent, probably due to the higher
reactivity of the in situ generated chromenylium intermediates
for the former ones. Meanwhile, the tested substrates with a
substituent at the C3 or C4 position (21f or 21g) were also
effective for this transformation, providing the corresponding
products 22f or 22g in more than 85% yields. However, it was
noteworthy that a functional group (−CH3 or −C(CH3)3)
located at the C6 position (21h or 21i) would significantly
influence both their reaction efficiency and the selectivity,
resulting in 61% yield for 22h and a trace amount (not
isolated) of 22i.16
After evaluating the reaction scope, mechanistic experiments
were then conducted to shed light on the potential reaction
pathways, as summarized in Scheme 5. Replacing 2-
hydroxycinnamaldehyde 11 with cinnamaldehyde 23 resulted
in a complete inhibition of the intended reaction and any
Michael addition products, strongly implying the involvement
of the chromenylium intermediate in the cascade process. To
probe this speculation, 2-hydroxycinnamaldehyde 11 was
subjected to the standard conditions in the absence of
phloroglucinol. Satisfyingly, the hemiacetal intermediate 1217
and its dimer derivative 2518,19 were then successfully isolated
in 10% and 45% yields, respectively. Both the hemiacetal
intermediate 12 and its dimer derivative 25 could be leveraged
to react with phloroglucinol 17 under the established EDDA-
C
DOI: 10.1021/acs.orglett.7b03630
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03630.
Experimental section, detailed experimental procedures,
and full spectroscopic data for all related compounds
(PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*Tel: +86-20-37081190. E-mail: yangbao@scbg.ac.cn.
*Tel: +86-20-37081190. E-mail: tanhaibo@scbg.ac.cn.
ORCID
(8) (a) Liu, H. X.; Huo, L. Q.; Yang, B.; Yuan, Y. F.; Zhang, W. M.;
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(12) Both the structures of compounds 18 and 19 were fully
characterized by 2D NMR and HMRS spectra. The difference in
regiochemistry between 18 and 19 and the previous examples (refs 9
and 10) might be attributed to the less steric hindered substrate of the
2-hydroxycinnamaldehyde as well as different reaction conditions.
Haibo Tan: 0000-0002-1652-5544
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(NSFC) (81773602, 31600271, and 81502949), Natural
Science Foundation of Guangdong Province
(2015A030310482, 2016A030313149, and 2016A010105015),
Pearl River Science and Technology New Star Fund of
Guangzhou (201605120849569), and the Frontier Science
Key Program of Chinese Academy of Sciences (QYZDB-SSW-
SMC018) for financial support.
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DOI: 10.1021/acs.orglett.7b03630
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