Total syntheses of hyperaspidinols A and B enabled by a bioinspired diastereoselective cascade sequence

Article abstract of DOI:10.1016/j.cclet.2021.08.035

A bioinspired acid-triggered hemiacetalization/dehydration/[3 + 3]-type cycloaddition cascade process was disclosed, diastereoselectively furnishing furo[2,3-b]chromene skeleton under mild conditions. The viability of this approach was demonstrated by syntheses of a series of furo[2,3-b]chromene and pyrano[2,3-b]chromene derivatives. The successful total syntheses of two lignan-phloroglucinol hybrids, hyperaspidinols A and B, exemplified the synthetic utility of our biomimetic methodology.

Full text of DOI:10.1016/j.cclet.2021.08.035

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Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Total syntheses of hyperaspidinols A and B enabled by a bioinspired
diastereoselective cascade sequence
Anquan Zhenga,b,1, Tingting Zhoua,b,1, Sasa Wang c, Wenge Zhanga,d, Xiuxiang Lua,d
,
Huiyu Chenb,∗, Haibo Tan a,∗
a Key Laboratory of Plant Resources Conservation and Sustainable Utilization, Key Laboratory of South China Agricultural Plant Molecular Analysis,
Guangdong Provincial Key Laboratory of Applied Botany, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, China
b School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China
c Guangxi Key Laboratory of Chemistry and Engineering of Forest Products, Guangxi University for Nationalities, Nanning 530006, China
d University of Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A bioinspired acid-triggered hemiacetalization/dehydration/[3 + 3]-type cycloaddition cascade process
was disclosed, diastereoselectively furnishing furo[2,3-b]chromene skeleton under mild conditions. The
Received 14 June 2021
Revised 8 August 2021
Accepted 8 August 2021
Available online xxx
viability of this approach was demonstrated by syntheses of
a series of furo[2,3-b]chromene and
pyrano[2,3-b]chromene derivatives. The successful total syntheses of two lignan-phloroglucinol hybrids,
hyperaspidinols A and B, exemplified the synthetic utility of our biomimetic methodology.
© 2021 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia
Medica, Chinese Academy of Medical Sciences.
Keywords:
Total synthesis
Bioinspried
Diastereoselective
Cascade reaction
Hyperaspidinol
Benzopyran-fused polycyclic ketals are prevalent in diverse nat-
ural products with significant biological properties such as po-
tent L-calcium channel blocking activity, inhibitory activity against
acetylcholine esterase, antioxidative property, and protective ef-
fect on mitochondria [1–5]. Their unique structural characteristics
and potential biological activities have made them privileged phar-
macophores for the development of industrially significant phar-
maceuticals and agrochemicals. Moreover, their fascinating and
complex scaffolds with potential usefulness, which were respon-
sive for various serious diseases or pharmacological applications,
have served as popular synthetic targets and sparked a wide
range of notable synthetic efforts in recent years [6–22]. However,
their access with high stereoselectivity under mild conditions re-
mains to be desired. Herein, we report a bioinspired hemiacetal-
ization/dehydration/[3 + 3]-type cycloaddition cascade to construct
benzopyran-fused polycyclic ketals with generally good diastere-
oselectivities under mild conditions and the first bioinspired total
syntheses of hyperaspidinols A (1) and B (2) via this strategy.
Hyperaspidinols A and B were isolated from Hypericum chinense
L. (Hypericaceae) [23], which served as highly active traditional
herb agents for the treatment of sepsis, acute laryngopharyngitis,
conjunctivitis, hepatitis, and snake bite [24–28]. Structurally, hy-
peraspidinols A and B feature a novel furo[2,3-b]chromene frame-
work (Fig. 1, highlighted in bold) and represent an intriguing
and ubiquitous family of lignan derivatives with fascinating hybrid
skeletons (Fig. 1) [23]. The remarkable potential biological activi-
ties and novel structural features of the two molecules make them
appealing targets for the synthetic community [29–31]. Moreover,
the successful syntheses of hyperaspidinols A and B will pave the
way to efficiently access a series of biologically interesting natural
products with hybrid structures such as melipatulinones A–C [32],
patulignans (Fig. 1) [33] and divergent syntheses of their analogues
towards drug development.
Inspired by these characteristic scaffolds in pharmaceutically
active natural products, we speculated that hyperaspidinols A and
B could evolve from substantially less complex natural products
hyperione 9 or 10 by hybridization with the corresponding aspidi-
nols C (4) and D (5), which were isolated together with hyperas-
pidinols A and B from the same herb [23]. Our continued inter-
est in biomimetic construction of polycyclic ketal skeletons [34–
38] guided us to speculate that hyperaspidinols A and B might
arise from the methyleneoxonium intermediate 6 via a formal
[3 + 3]-type cycloaddition cascade process (Scheme 1), similar to
our previous strategies utilized in biomimetic total syntheses of
∗
Corresponding authors.
E-mail addresses: chenhuiyu@sit.edu.cn (H. Chen), tanhaibo@scbg.ac.cn (H. Tan).
1
These authors contributed equally to this work.
https://doi.org/10.1016/j.cclet.2021.08.035
1001-8417/© 2021 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Please cite this article as: A. Zheng, T. Zhou, S. Wang et al., Total syntheses of hyperaspidinols A and B enabled by a bioinspired diastere-
oselective cascade sequence, Chinese Chemical Letters, https://doi.org/10.1016/j.cclet.2021.08.035

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Scheme 2. Substrate scope with respect to hydroxyl vinyl ketones.a a) 11a
(0.22 mmol), 12 (0.2 mmol), PTSA (0.02 mmol) in xylene/1,4-dioxane (4:1, 10 mL)
stirred at room temperature for 0.5–3 h; combined yields of the isolated mixture of
13 and 14; ratio (13:14) determined by 1H NMR unless noted otherwise.
Fig. 1. Representative natural products bearing furo[2,3-b]chromene or hybrid
skeletons.
vents could provide almost identical yield and diastereomeric ratio
as those of THF (entries 7 and 8). Attempting to further improve
the yield and selectivity, we then screened several protonic acids as
catalysts. Catalytic amount of pyridinium p-toluenesulfonate (PPTS)
and stoichiometric AcOH were proven to be non-effective, whereas
p-toluenesulfonic acid (PTSA) could trigger the desired transforma-
tion (entries 9–11). Notably, when we occasionally changed the sol-
vent mixture to xylene/1,4-dioxane, both the yield and diastere-
oselectivity were obviously increased (entry 12). However, chang-
ing the ratio of the mixture solvents failed to further improve the
reaction efficiency (entries 13 and 14). Finally, 0.1 equiv. of PTSA
as catalyst in xylene/1,4-dioxane (4:1) were selected as the op-
timal reaction condition (83% yield, >10:1 dr, entry 12, Table 1),
thereby laying a solid foundation for the efficient syntheses of the
benzopyran-fused polycyclic ketals.
With the optimized reaction conditions established, the scope
of the biomimetic cascade reaction with respect to both reac-
tion partners was evaluated. A series of hydroxyl vinyl ketones
(12) could be converted to the corresponding furo[2,3-b]chromene
products 13 and 14 in moderate to high yields with different di-
astereoselectivities as summarized in Scheme 2. Hydroxyl vinyl ke-
tones bearing different aryl groups such as 4-methylphenyl (12b
or 12e), 4-methoxylphenyl (12c), and 4-bromophenyl (12d) were
suitable reaction candidates, delivering the corresponding products
13b-e in 55%–86% yields with good diastereoselectivities. Notably,
hydroxyl vinyl ketones with an alkyl group attached on the α-
carbon gave good yields but with poor diastereoselectivities (13f-g
and 14f-g), probably due to steric effects. Furthermore, hydroxyl
vinyl ketones bearing an extended chain could also undergo this
transformation smoothly albeit with imperfect stereoselectivity, al-
lowing the efficient construction of benzopyran-fused polycyclic
ketals 13h-i and 14h-i.
Scheme 1. Proposed biogenesis of hyperaspidinols A and B.
myrtucommuacetalone [35], sanctis [37], and tomentosones [38]. 6
might generate from hyperione A (9) or B (10) via a retro-Michael
addition/hemiacetalization/dehydration cascade sequence. In this
regard, from the biogenetic perspective, if a one-pot acid-catalyzed
cascade sequence merging the fascinating multistep transforma-
tions was established, it would render straightforward syntheses
of hyperaspidinols A and B (1 and 2) with high efficiency.
With the biomimetic scenario in mind, we first explored the
construction of the benzopyran ketal skeleton. Optimization stud-
ies commenced with an evaluation of solvent, time, and catalyst
by using the readily accessible phloroglucinol 11a [39,40] and hy-
droxyl vinyl ketone 12a [41] as model substrates (Table 1). When
the two substrates were treated with TFA in methanol, only com-
plex mixtures were observed (entry 1). Gratifyingly, switching the
solvent to THF delivered the desired cascade reaction smoothly,
furnishing the corresponding furo[2,3-b]chromene products 13a
and 14a in 74% isolated yield with 8:1 diastereomeric ratio (entry
2).
Encouraged by the aforementioned excellent results, further ef-
forts towards verifying the substrate scope and versatility of the
phenolic reaction partner 11 were also conducted. As shown in
Scheme 3, the phenol substrates with different acyl substituents
such as iso-valeryl (11j) and n-hexanoyl (11k) were well toler-
ated under the standard reaction conditions, which could give
rise to the desired products in good yields and diastereomeric
ratios, thus clarifying excellent tolerance of the developed cas-
cade sequence. Similarly, the ester substituted phloroglucinol (11l)
could also smoothly react with hydroxyl vinyl ketone 12a to af-
ford the polycyclic ketals 13l and 14l in 70% overall yield with a
ratio about 3:1. 3,5-Dimethoxyphenol 11m was also suitable re-
A systematic screening of solvents disclosed that nonpolar sol-
vents such as xylene, dichloromethane, tetrahydrofuran, and their
mixtures worsened the reaction in both yields and diastereoselec-
tivities except for faster reaction rate (entries 2–6). The solvent
screening showed that 1,4-dioxane and xylene/THF mixture sol-
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Table 1
Optimization of reaction conditions.a
Entry
Solvent
Catalyst (equiv.)
Time (min)
Yield (%)b
Ratio (13a:14a)c
1
MeOH
TFA (2.0)
TFA (2.0)
TFA (2.0)
TFA (2.0)
TFA (2.0)
TFA (2.0)
TFA (2.0)
TFA (2.0)
PPTS (0.1)
PTSA (0.1)
AcOH (0.1)
PTSA (0.1)
PTSA (0.1)
PTSA (0.1)
45
90
45
60
60
60
90
60
60
45
60
35
45
30
-
-
2
THF
74
62
58
65
25
65
72
NR
80
NR
83
75
78
8:1
5:1
5:1
8:1
5:1
8:1
8:1
-
3
xylene
4
DCM
5
DCM/xylene (1:1)
DCM/THF (1:1)
1,4-dioxane
6
7
8
THF/xylene (1:2)
THF/xylene (1:2)
THF/xylene (1:2)
THF/xylene (1:2)
xylene/1,4-dioxane (4:1)
xylene/1,4-dioxane (1:1)
xylene/1,4-dioxane (10:1)
9
10
11
12
13
14
10:1
-
>10:1
10:1
10:1
a
Standard conditions: 11a (0.11 mmol), 12a (0.1 mmol), catalyst in solvent (10 mL) stirred at room temper-
ature under N2 unless noted otherwise;
b
Combined yield of the isolated mixture of 13a and 14a;
c
Determined by 1H NMR analysis.
Scheme 4. Substrate scope with respect to 1,3-diketones.a a) 1,3-Diketone
(0.22 mmol), 12a (0.2 mmol), PTSA (0.02 mmol) in xylene/1,4-dioxane (4:1, 10 mL)
stirred at room temperature for 0.5–3 h; combined yield of diastereomers; ratio of
the diastereomers.
Scheme 3. Substrate scope with respect to phenolic reaction partner.a a) 11
(0.22 mmol), 12a (0.2 mmol), PTSA (0.02 mmol) in xylene/1,4-dioxane (4:1, 10 mL)
stirred at room temperature for 0.5–3 h; combined yield of the isolated mixture of
13 and 14; ratio (13:14) determined by 1H NMR unless noted otherwise. a) Ratio of
isolated products of 13 and 14.
Scheme 4, the potential bioactive fragment syncarpic acid 15,
which shared an intriguing tetramethylcyclohexenedione skeleton
responsive for the most characteristic unit of natural polycyclic
polymethylated phloroglucinols mainly encountered in the Myr-
taceae plants [42], was treated with hydroxyl vinyl ketone 12a, and
the desired cascade reaction proceeded smoothly, delivering poly-
cyclic ketals 18a and 18b in 88% yield with good diastereoselec-
tivity. Moreover, 4-hydroxy-2H-chromen-2-one (16), answering for
the biologically meaningful pharmaceutical core scaffold in numer-
ous natural products [43,44] underwent the established reaction,
also providing the desired products 19a and 19b in good com-
bined yield as expected. Remarkably, the common naturally oc-
curring 4-hydroxy-6-methyl-2-pyrone (17) [45] was also success-
fully converted to the targeted polycyclic ketals 20a and 20b in
satisfactory yield. Collectively, the aforementioned representative
structural combinations of the critical natural product fragments
chemologically clarified its promising potential to efficiently access
a focused library of natural products-modified analogues bearing
diverse biologically functional units and might open up new vis-
tas in structural optimizations of related natural products for broad
scientific interest.
action partner, allowing the synthesis of 13m and 14m in rea-
sonable yield with acceptable diastereoselectivity. Moreover, dia-
cylphloroglucinol 11n delivered the corresponding products 13n
and 14n with comparable yield and diastereoselectivity to those of
the monoacylphloroglucinol 11j. Much to our delight, the methyl
substituted phloroglucinols (11o-q) could undergo this transforma-
tion and afford the corresponding furo[2,3-b]chromene products
in yields more than 80% with good to excellent diastereoselectiv-
ities, generating a series of structurally diverse and closely sim-
ilar analogues of melipatulinones A-C, which marked an advan-
tage of this method and strongly indicated the promising utility
of this cascade methodology to efficiently synthesize such lignin-
phloroglucinol hybrid natural products and pharmacological com-
pounds.
The synthetic possibility of this fascinating bioinspired hemiac-
etalization/dehydration/[3 + 3]-type cycloaddition cascade reaction
was further reflected by intelligent orchestrations with straight-
forward structural combinations for the critical fragments of the
pharmaceutically meaningful natural products. As delineated in
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Scheme 7. Biomimetic total syntheses of hyperaspidinols A and B (1, 2).
Scheme 5. Syntheses of critical precursors asipidinols C and D (4, 5).
the diastereoslectivity more than 10:1, and the treatment of 8
with racemic aspidinol 5 gave the desired product in 92% yield
as a 10:1 mixture of diastereoisomers favoring hyperaspidinol B
(2) (Scheme 7). The NMR and HR-ESIMS spectra of the syn-
thetic hyperaspidinol A are in full agreement with literature re-
ports [23], and the synthetic hyperaspidinol B displayed NMR spec-
tral properties in agreement with the reported ones except the
different diastereomeric ratios (about 1:1) in regard to the acyl
group on the phloroglucinol motif [23]. In this regard, the first
total syntheses of hyperaspidinols A and B were accomplished,
which strongly suggested that the aforementioned hemiacetal-
ization/dehydration/[3 + 3]-type cycloaddition cascade sequence
might probably proceed by mimicking their biosynthetic pathway.
Scheme 6. Synthesis of critical precursor 8.
In
summary,
a
biomimetic
hemiacetaliza-
tion/dehydration/[3 + 3]-type cycloaddition cascade methodology
for the efficient establishment of furo[2,3-b]chromene was defined,
and it was attested by the efficient total syntheses of hyperas-
pidinols A and B. The effectiveness of our strategy is borne out
by the fact that a broad spectrum of novel furo[2,3-b]chromene
derivatives could be constructed in moderate to good yields with
different diastereoselectivities. Further applications of this strategy
in the total syntheses of other natural products with similar skele-
tons are currently ongoing in our laboratory and will be reported
in due course.
Building on the above initial success of the bioinspired method-
ology of hemiacetalization/dehydration/[3 + 3]-type cycloaddition
cascade, the concise total syntheses of hyperaspidinols A and B
were then performed to verify its potent synthetic utility. We ini-
tiated the preparation of the corresponding phloroglucinols 4 and
5 as depicted in Scheme 5. Selective protection of the free phe-
nolic hydroxyl groups with allyl bromide followed by methylation
of 2,4,6-trihydroxybenzaldehyde efficiently afforded aldehyde 24 in
65% yield over 2 steps. Further treatment of aldehyde 24 with
NaBH3CN under acidic condition generated 25 in 94% yield effi-
ciently. Deprotection of the allyl functionalities with Pd(PPh3)4 ex-
pectedly freed the two phenolic hydroxyl groups in moderate yield.
Next, the critical phloroglucinol precursors 4 and 5 (asipidinols C
and D) were delivered propitiously via Friedel-Crafts acylation of
phenol 26 with acyl chlorides 27 and 28 in about 72% and 70%
yield, respectively. Notably, asipidinols C (4) and D (5) were also bi-
ologically active natural products with various pharmaceutical ac-
tivities [46,47] and they were completely synthesized for the first
time in this study.
Declaration of competing interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
Acknowledgments
This work was supported financially by the National Natu-
ral Science Foundation of China (Nos. 81773602, 21901049, and
21801032), Natural Science Foundation of Guangdong Province
(No. 2019A1515011694), Guangdong Special Support Program (No.
2017TQ04R599), Youth Innovation Promotion Association of CAS
(No. 2020342), and Guangxi Natural Science Foundation under
Grant (No. 2018GXNSFBA050015 and AD19245004).
At this stage, efforts were further made to synthesize the other
critical precursor 8. As shown in Scheme 6, 8 was readily prepared
from commercially available acetal 29, which underwent hydrolysis
under an acidic condition to afford butanedial 30 referring to pre-
viously established procedure [48]. Exposure of butanedial 30 to
the Grignard reagent generated in situ from 4-bromo-1,2-(methyl
enedioxy)benzene 31 and magnesium under nitrogen atmosphere
smoothly delivered the symmetrical diol 32 in 65% yield. Selective
mono-oxidation of benzyl diol 32 with Dess-Martin periodinane
(DMP) furnished the targeted aryl ketone 33 in moderate yield. The
morpholine catalyzed aldol condensation followed by dehydration
afforded the critical precursor 8 in 72% yield.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.cclet.2021.08.035.
Acquisition of the critical precursors asipidinols C and D (4, 5)
and hydroxyl vinyl ketone 8 set the stage for the biomimetic to-
tal syntheses of hyperaspidinols A and B via the key biosynthetic
hemiacetalization/dehydration/[3 + 3]-type cycloaddition cascade.
Gratifyingly, aspidinol 4 reacted with hydroxyl vinyl ketone 8
smoothly to generate hyperaspidinol A in excellent yield with
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