Total Synthesis of Anti-Cancer Meroterpenoids Dysideanone B and Dysiherbol A and Structural Reassignment of Dysiherbol A

Article abstract of DOI:10.1002/anie.202100541

The first total synthesis of marine anti-cancer meroterpenoids dysideanone B and dysiherbol A have been accomplished in a divergent way. The synthetic route features: 1) a site and stereoselective α-position alkylation of a Wieland–Miescher ketone derivative with a bulky benzyl bromide to join the terpene and aromatic moieties together and set the stage for subsequent cyclization reactions; 2) an intramolecular radical cyclization to construct the 6/6/6/6-tetracycle of dysideanone B and an intramolecular Heck reaction to forge the 6/6/5/6-fused core structure of dysiherbol A. A late-stage introduction of the ethoxy group in dysideanone B reveals that this group might come from the solvent ethanol. The structure of dysiherbol A has been revised based on our chemical total synthesis.

Full text of DOI:10.1002/anie.202100541

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How to cite:
International Edition: doi.org/10.1002/anie.202100541
German Edition: doi.org/10.1002/ange.202100541
Total Synthesis
Total Synthesis of Anti-Cancer Meroterpenoids Dysideanone B and
Dysiherbol A and Structural Reassignment of Dysiherbol A
Chuanke Chong, Qunlong Zhang, Jia Ke, Haiming Zhang, Xudong Yang, Bingjian Wang,
Wei Ding, and Zhaoyong Lu*
Dedicated to Professor K. C. Nicolaou on the occasion of his 75th birthday
Abstract: The first total synthesis of marine anti-cancer
meroterpenoids dysideanone B and dysiherbol A have been
accomplished in a divergent way. The synthetic route features:
1) a site and stereoselective a-position alkylation of a Wieland–
Miescher ketone derivative with a bulky benzyl bromide to join
the terpene and aromatic moieties together and set the stage for
subsequent cyclization reactions; 2) an intramolecular radical
cyclization to construct the 6/6/6/6-tetracycle of dysideanone B
and an intramolecular Heck reaction to forge the 6/6/5/6-fused
core structure of dysiherbol A. A late-stage introduction of the
ethoxy group in dysideanone B reveals that this group might
come from the solvent ethanol. The structure of dysiherbol A
has been revised based on our chemical total synthesis.
S
esquiterpene quinones/hydroquinones, one of the most
important class of meroterpenoid natural products,[1] feature
a sesquiterpene core attached to a biosynthetically different
quinone or hydroquinone moiety.[2] This class of naturally
occurring substances exhibit a remarkable range of biological
activities, such as antibacterial,[3] antifungal,[4] anti-HIV,[5]
anti-inflammatory,[6] antioxidative,[7] antitumor,[8] as well as
protein tyrosine phosphatase 1B (PTP1B) inhibitory activ-
ities.[9]
Figure 1. Biosynthetic network of dysideanones B and “F” and dysiher-
bols A–C.
Dysideanone B (1, Figure 1), isolated from the South
China Sea sponge Dysidea avara by Lin and co-workers in
2014,[10] possesses an unprecedented 6/6/6/6-fused tetracyclic
carbon skeleton and showed cytotoxicity against two human
cancer cell lines, HeLa and HepG2, with IC50 values of 7.1 and
9.4 mm, respectively. In 2016, the same group also isolated
dysiherbols A–C (2–4, Figure 1),[11] which share an intriguing
6/6/5/6-fused tetracyclic ring system but differ in their
functionalities at the C3 position (with 2, 3, and 4 containing
a C3-methylene, alcohol, and ketone group, respectively).
Dysiherbol A exhibited potent NF-kB inhibitory activity and
cytotoxicity against the human myeloma cancer cell line NCI
H-929 with IC50 values of 0.49 and 0.58 mm, respectively. On
the other hand, the reported NF-kB inhibitory activity and
cytotoxicity of the two more oxidized members, dysiherbols B
and C (3 and 4), against NCI H-929 were about 10-fold and
20-fold less potent than those of dysiherbol A (2),[11] showing
that the removal of the oxygen functionality at the C3 position
remarkably increased their NF-kB inhibitory and cytotoxic
activities, thus suggesting the possible structural optimization
for structure–activity relationship (SAR) study.
[*] C. Chong, Q. Zhang, J. Ke, H. Zhang, X. Yang, B. Wang, Prof. Dr. Z. Lu
State Key Laboratory of Medicinal Chemical Biology,
College of Pharmacy, Nankai University
38 Tongyan Rd, Tianjin 300350 (China)
E-mail: zlu@nankai.edu.cn
Dr. W. Ding
Tianjin Key Laboratory of Human Development and Reproductive
Regulation, Tianjin Central Hospital of Gynecology Obstetrics,
Nankai University
This collection of meroterpenoids has attracted much
attention from the synthetic community due to their diverse
structures and varied biological activities.[12] Recently, Jana
and co-workers reported the construction of dysideanone
carbotetracycles[13] and the biological evaluation of synthetic
dysideanone analogues.[14] In 2017, Echavarren et al. disclosed
the assembly of the tetracyclic carbon skeleton of dysiherbol
by using a gold(I)-catalyzed formal [3+2] cycloaddition
reaction.[15] To date, however, the total synthesis of dysidea-
none B and dysiherbol A have not been accomplished
156 Third Rd, Tianjin 300052 (China)
Prof. Dr. Z. Lu
State Key Laboratory of Natural Medicines,
China Pharmaceutical University
24 Tongjiaxiang, Nanjing 210009 (China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202100541.
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successfully. Herein, we report the first total synthesis of
dysideanone B and dysiherbol A and the revision of the
structure of dysiherbol A.
traced back to Wieland-Miescher ketone derivative 15 and
benzyl bromide 16.
With the retrosynthetic analysis in mind, we started the
adventure from the synthesis of common precursors for the
cyclization reactions, as shown in Scheme 1. To this end, the
more reactive unconjugated ketone functionality of Wieland-
Miescher ketone derivative 17, which could be efficiently
From the viewpoint of biogenesis, it was postulated that
dysideanone B and dysiherbols A–C might be derived from
two common sesquiterpene hydroquinone meroterpenoids,
avarol 5[16] or neoavarol 6,[17] also known from Dysidea
sponges, as depicted in Figure 1. Thus, dehydrogenation of the
C1–C10 single bond in avarol 5 or neoavarol 6 gives rise to
unconjugated diene 7 as a key branching point, from which
a putative 6-endo-trig cyclization connecting C6’ of the
hydroquinone moiety with C1 of the neighboring double
bond would give the 6/6/6/6-fused tetracyclic framework as
found in intermediate 8. Oxidation of the hydroquinone
moiety within the latter intermediate to a quinone followed
by the introduction of an ethoxy group could then furnish
dysideanone B (1). It should be noted that the ethoxy group
might come from the solvent EtOH in the extraction
process.[10] According to the structural types of isolated
sesquiterpene quinone/hydroquinone meroterpenoids,[2] the
internal alkene congener of dysideanone B might also be
a natural product, which we tentatively named as “dysidea-
none F” (9). On the other hand, intermediate 7 could undergo
a 5-exo-trig cyclization, which joins C6’ with C10 to give the
=
dysiherbol core structure 10. Hydration of its C3 C4 bond
would provide dysiherbol A (2), whereas a formal dihydrox-
ylation of the same double bond would afford dysiherbol B
(3). Further oxidation of the secondary alcohol at C3 in
dysiherbol B (3) could furnish dysiherbol C (4).
Inspired by the above biosynthetic hypothesis, we under-
took a retrosynthetic analysis of both dysideanone B (1) and
dysiherbol A (2), as depicted in Figure 2. We envisioned that
the ethoxy group within dysideanone B (1) could be intro-
duced at a late stage and the quinone moiety could be
obtained via oxidation of the protected and more stable
hydroquinone 11. Disconnection of the C6’ and C1 single
bond revealed alkene bromide 12 as a potential precursor. On
the other hand, dysiherbol A could be synthesized from
alkene 13 through oxidation state adjustment and deprotec-
tion of the methyl groups. Disassembly of the C6’ and C10
single bond would give the aforementioned alkene bromide
12. The methyl group at C8 position of 12 was envisioned to
derive from ketone functionality of 14 through methylenation
and diastereoselective reduction. Finally, ketone 14 could be
Scheme 1. Synthesis of cyclization precursors 20 and 12. p-TsOH·-
H2O=p-toluenesulfonic acid monohydrate, brsm=based on recovered
starting material.
prepared from commercially available material in two steps in
either racemic or enantiomeric form,[18] was chemoselectively
protected as a glycol acetal to give enone 15 in 94% yield. The
combination of bicyclic enone 15 with the bulky benzyl
bromide 16 proved challenging with O- or C7-alkylation
byproducts observed at different reaction temperatures. After
optimization, the desired C9-alkylation product ketone 14
was obtained as a single diastereoisomer in satisfactory
isolated yield (72%) under a thermodynamically controlled
condition (tBuOK in THF at 408C). It should be noted that
=
the C C bond at C9 and C10 migrates to C1 and C10 position
under this condition and the incoming electrophile benzyl
bromide 16 approaches the generated enolate from the
opposite side of the angular methyl group at the ring junction
due to steric hindrance, thus affording a single diastereoiso-
mer.
With alkylation product 14 readily available, we pro-
ceeded to the synthesis of cyclization precursors. However,
the methylenation of sterically hindered carbonyl group in
=
Figure 2. Retrosynthetic analysis for dysideanone B and dysiherbol A.
ketone 14 with Wittig reagent (Ph3P CH2) led to an
2
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unexpected cyclization byproduct 18 through an intramolec-
structure of 25 was verified by X-ray crystallographic
analysis.[21]
Having successfully constructed the tetracyclic framework
ular arylation reaction[19] and a subsequent Wittig reaction,
while the methylenation with Peterson reagent, Tebbe
reagent, or Julia reagent did not give any of the desired
products. Much to our delight, the methylenation problem
was solved by employing Nysted reagent[20] with TiCl4 as
Lewis acid, rendering the desired product terminal alkene 19
in 31% yield and recovering 54% of starting material ketone
14. Subjection of intermediate 19 to heterogenous hydro-
genation conditions (10% Pd/C) resulted in the migration of
for dysideanone B, we proceeded to the final stage of the total
synthesis of dysideanone B. Thus, as depicted in Scheme 2,
methylenation of ketone 24 proceeded smoothly (87% yield)
with Wittig reagent to afford terminal alkene 11, whose
methyl protected hydroquinone moiety was oxidized using
AgO and HNO3, delivering quinone 26 in 86% yield and
setting the stage for the introduction of the ethoxy group. A
series of ethoxy group introduction reactions were performed.
Metal mediated reactions (e.g., EtOH with Co(OAc)2, Mn-
(OAc)3·2H2O, Ni(OAc)3·4H2O, or AgOAc)[22] led to either
low yields or decomposition of starting material. Finally, we
=
the exocyclic C C bond to the C7 and C8 position to give an
=
endocyclic C C bond byproduct, which could not be selec-
tively reduced without affecting the other olefin moiety. On
the other hand, homogenous hydrogenation of intermediate
19 with (Ph3P)3RhCl only gave 15% of desired product 20 and
76% of its C8-epimer 21 (d.r. = 1:5). Delightedly, the
diastereoselectivity reversed when the more advanced inter-
mediate ketoalkene 22 was subjected to the same reaction
conditions, affording the desired product 12 in 84% yield and
its C8-epimer 23 in 11% yield (d.r. = 8:1). It is noteworthy
that the bromide at C6’ and internal alkene between C1 and
C10 survived under this condition.
With alkene bromide 12 in hand, we focused our attention
on the investigation of cyclization reaction for the construc-
tion of the 6/6/6/6-tetracycle of dysideanone B, as shown in
Scheme 2. We envisioned that a C6’ radical, generated from
the parent aryl bromide, would attack the alkene from C1 to
give the more stable tertiary radical on C10, which then reacts
with a HC donor to form the 6/6/6/6-fused tetracyclic core of
dysideanone B. Thus, alkene bromide 12 was subjected to
radical reaction conditions (nBu3SnH and AIBN, Scheme 2).
The desired 6/6/6/6-fused tetracycles 24 was obtained in 61%
yield and a tetrasubstituted alkene byproduct 25 was isolated
in 23% yield, presumably because the tertiary radical under-
goes b-H elimination from C1 to give internal alkene 25. The
[23]
were pleased to find that Et3N in EtOH under O2 proved
effective for the introduction of ethoxy functionality, afford-
ing dysideanone B (1) in 53% yield and its regioisomer 27 in
36% yield. Driven by our suspicion that the ethoxy group
might come from the solvent EtOH, we opted to mimic the
isolation conditions. In this regard, quinone 26 was heated in
95% EtOH under air and dysideanone B (1) and its
regioisomer 27 were also isolated but in lower combined
yield (64%), revealing that the ethoxy group might come
from the solvent ethanol. The spectroscopic data of synthetic
dysideanone B (1) matched with those reported for the
natural product. The transformation of dysideanone B (1) to
its congener “dysideanone F” (9) was achieved in 92% yield
under acidic condition. The synthesis and characterization of
this hitherto unknown congener might facilitate its isolation
from natural sources in the future.
Having completed the first total synthesis of dysideano-
ne B (1), we turned our attention to the formation of the 6/6/5/
6-fused backbone of dysiherbol A, as depicted in Table 1.
However, the construction of the five-membered ring of
dysiherbol A (2) turned out to be a difficult task. Various
Heck reaction conditions[24] (different Pd catalysts such as
Pd2(dba)3, Pd(OAc)2, and Pd(dppf)Cl2, ligands such as SPhos,
P(o-tol)3, P(2-furyl)3, and BINAP, bases such as DBU, Et3N,
PMP, K2CO3, and NaHCO3) were explored on substrate 20,
but no desired product was observed (Table 1, entry 1). The
C8-epimer 21 was also investigated for the cyclization but did
not give any desired cyclization product (Table 1, entry 2). We
also examined the cyclization reaction on 14, whose ketone
functionality could be transformed to methyl group on C8 at
a late stage. Arylation byproduct 28 was obtained in 81%
yield with DBU as base (Table 1, entry 3), while addition
byproduct tertiary alcohol 29 was isolated in 86% yield with
Et3N as base (Table 1, entry 4) through a Grignard-type
nucleophilic addition of arylpalladium to ketone.[25] Molec-
ular modeling showed that the methoxy group on C5’ of the
benzene ring and the acetal group on C4 of the decalin ring
would be very close if the C10–C6’ single bond was generated.
We expected that the removal of the acetal group on C4 might
reduce the hindrance between these functionalities. To this
end, a range of Heck or reductive Heck reaction[26] conditions
were examined on ketoalkene bromide 12. However, the
desired cyclization product was also not observed. Indeed,
ring contraction byproduct 30 was obtained in 81% yield
when Pd2(dba)3 was used as catalyst with SPhos as ligand and
Scheme 2. Total synthesis of dysideanone B and “dysideanone F”.
AIBN=2,2’-azoisobutyronitrile. Thermal ellipsoids are shown at the
50% probability level.
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Table 1: Attempts for the construction of the 6/6/5/6-tetracycle of dysiherbol A.
Entry
Substrate
Conditions
Result[a]
n.p.[b]
1
various Heck conditions
2
3
4
5
6
various Heck conditions
n.p.[b]
Pd2(dba)3, SPhos,
DBU
Pd2(dba)3, SPhos,
Et3N
Pd2(dba)3, SPhos,
Et3N
Pd2(dba)3, SPhos,
Et3N
[a] Isolated yield after flash column chromatography. [b] n.p.=no product. dba=dibenzylideneacetone, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene,
SPhos=2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl.
Et3N as base (Table 1, entry 5). The structure of 30 was
elucidated by extensive 2D NMR and X-ray crystallographic
analysis (see SI for a possible mechanism for the formation of
30).[21] Unexpectedly and surprisingly, the desired cyclization
reaction proceeded efficiently when C8-epimer 23 was sub-
jected to the same set of Heck reaction conditions, furnishing
cyclized product 31 in 83% yield as a sole product (Table 1,
entry 6).
The results inspired us to adjust the substrates for the five-
membered ring formation reaction, which is shown in
Scheme 3. Towards this end, ketone 14 was reduced with
lithium aluminium hydride (LiAlH4) in 88% yield (d.r.
> 20:1) to give a secondary alcohol, which was then protected
with benzyl ether, affording 32 in 91% yield with the BnO
group of C8 at the axial position. Removal of glycol acetal
within 32 rendered ketone 33 in almost quantitative yield,
which was then investigated for the cyclization reaction.
Gratifyingly, treatment of 33 with Pd2(dba)3, SPhos and Et3N
afforded the desired cyclization product 34 in high yield
(86%). The connectivity of the newly established ring system
was confirmed by single crystal X-ray diffraction analysis of
34.[21] The removal of Bn group and the reduction of newly
formed alkene at C1 and C2 were accomplished with Pd/C
under H2 in one pot in 96% yield. Dess–Martin periodinane
(DMP) oxidation of the released secondary alcohol gave
diketone 35 efficiently (94% yield). Diketone 36, prepared
from 14 with the deprotection of glycol acetal in 95% yield,
was also tested for the cyclization reaction. Much to our
delight, Heck reaction of diketone 36 with Et3N as base
afforded the desired product 37 in 24% yield and addition
byproduct tertiary alcohol 38 in 67% yield. The chemo-
selectivity and the connection of 37 was unambiguously
confirmed by single crystal X-ray diffraction analysis.[21] The
hydrogenation of diketoalkene 37 with 10% Pd/C under H2
resulted in the aforementioned diketone 35 in 96% yield.
Having forged the 6/6/5/6-tetracycle of dysiherbol A, we
switched to our next goal of pursuing the total synthesis of
dysiherbol A (Scheme 4). Direct methylenation of diketone
35 with Wittig reagent, Peterson reagent or Petasis reagent
was met with failure, presumably due to the severe steric
hindrance of the ketone functionalities. Consequently, a two-
step sequence was adopted to achieve this transformation.
Diketone 35 was first transformed through the action of
trifluoromethanesulfonic anhydride (Tf2O) and N,N-diiso-
propylethylamine (DIPEA) to bis(enol-triflate),[27] which was
then coupled with Me4Sn, giving diene 39 in 59% overall yield
for the two steps. The chemo- and diastereoselective reduc-
tion of diene 39 was achieved via heterogeneous hydro-
genation with 10% Pd/C under H2, and the desired mono-
alkene 13 was obtained as a sole diastereoisomer in excellent
4
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to undergo dihydroxylation (e.g., OsO4, K2OsO4·2H2O, and
AD-mix-a). In light of these failures, we switched to the
metal-catalyzed hydrogen atom transfer (MHAT)-initiated
olefin hydration[29] of the alkene within 13. An array of
catalysts (e.g., Fe(acac)3, Co(acac)3, and Mn(dpm)3) and
silanes (e.g., PhSiH3 and Et3SiH) were tested and the
combination of Mn(dpm)3 and PhSiH3 under O2 with
[30]
PPh3
as additive worked well, leading to the tertiary
alcohol 40 in 73% yield. Although the stereochemistry of C4
of alcohol 40 is opposite to that of natural product dysiher-
bol A, the deprotection of methyl groups on hydroquinone
was performed. To our disappointment, no desired product
was observed under various deprotection conditions exam-
ined and an unexpected byproduct was isolated in 45% yield
with BBr3 at 238C. However, the byproduct displayed
identical spectral properties to those reported for the natural
dysiherbol A (1). The single crystal X-ray diffraction analysis
of this byproduct derivative 43 showed an additional ether
ring between C5’ of the benzene ring and C4 of the decalin
moiety instead of C5’-phenol and C4-hydroxy groups.[21] Thus,
the structure of dysiherbol Awas revised as 42. The structures
of dysiherbols B and C may have the same issue and the effort
towards the total synthesis of them is currently underway in
our laboratories, hoping to elucidate the real structure of
these two natural products.
Scheme 3. Synthesis of diketone 35. DMP=Dess–Martin periodinane.
Thermal ellipsoids are shown at the 50% probability level.
Careful monitoring of the reaction showed that tertiary
alcohol 40 first underwent elimination with BBr3 to give back
to alkene 13, and subsequent etherification of C5’ oxygen with
alkene and deprotection of the remaining C2’ methyl group to
afford 42. Indeed, etherification product 41 was isolated as
a sole product in 91% yield with 2 equivalents of BBr3 at
À788C. Treatment of 41 with more BBr3 (5 equivalents) at
higher temperature (238C) led to the removal of C2’ methyl
group, affording 42 in 86% yield. Indeed, under the latter set
of conditions, dysiherbol A (42) was also obtained in 72%
yield from alkene 13 directly.
In conclusion, we have accomplished the first total
synthesis of marine anti-cancer meroterpenoids dysideano-
ne B and dysiherbol A and revised the structure of dysiher-
bol A based on chemical synthesis and X-ray crystallographic
analysis. The key transformations of our synthesis include an
intramolecular radical cyclization to construct the 6/6/6/6-
tetracycle of dysideanone B and an intramolecular Heck
reaction to forge the 6/6/5/6-fused tetracyclic core structure of
dysiherbol A. The developed strategy could potentially be
used for the collectively total synthesis of dysiherbols B and C
and structurally related sesquiterpene quinone or hydro-
quinone meroterpenoids. These goals are currently being
pursued in our laboratories, and the results will be reported in
due course.
Scheme 4. Total synthesis and structural reassignment of dysiherbol A.
DIPEA=N,N-diisopropylethylamine, dpm=dipivaloylmethanato,
Tf2O=trifluoromethanesulfonic anhydride. Thermal ellipsoids are
shown at the 50% probability level.
yield (94%). The chemo- and diastereoselectivity of reduc-
tion was unambiguously verified by single crystal X-ray
diffraction analysis.[21]
The next challenge became the regio- and diastereoselec-
tive introduction of a C4 hydroxyl group and the deprotection
of the methyl-capped hydroquinone moiety. To this end,
epoxidation of mono-alkene 13 with H2O2, m-CPBA,
tBuOOH or VO(acac)2 and tBuOOH[28] was explored, but
only led to the skeleton rearrangement, presumably because
of the severe strain of the 6/5-fused ring system. To make
things worse, mono-alkene 13 was also found to be reluctant
Acknowledgements
We are grateful to Profs. Xiao-Jiang Hao (Kunming Institute
of Botany, Chinese Academy of Sciences), Yue Chen and Bo
Su (College of Pharmacy, Nankai University) for helpful
discussion. We thank Dr. Ruocheng (Ronnie) Yu (Rice
University) and Prof. Yang Yang (Huazhong University of
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Science and Technology) for kind help during the preparation
of this manuscript. We acknowledge Dr. Qingxin Cui (Nankai
University) for NMR spectroscopic assistance and Dr.
Quanwen Li (Nankai University) for X-ray crystallographic
analysis. This work was financially supported by the National
Natural Science Foundation of China (No. 21971121), the
Open Project of State Key Laboratory of Natural Medicines
(No. SKLNMKF201909) and the Fundamental Research
Funds for the Central Universities, Nankai University (Nos.
63191140, 63201109).
Conflict of interest
The authors declare no conflict of interest.
Keywords: dysideanone B · dysiherbol A · meroterpenoids ·
natural products · structure elucidation
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Manuscript received: January 13, 2021
Revised manuscript received: March 30, 2021
Accepted manuscript online: April 12, 2021
Version of record online: && &&, &&&&
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7
These are not the final page numbers!

Angewandte
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Communications
Total Synthesis
C. Chong, Q. Zhang, J. Ke, H. Zhang,
X. Yang, B. Wang, W. Ding,
Z. Lu*
&&&& — &&&&
Total Synthesis of Anti-Cancer
Meroterpenoids Dysideanone B and
Dysiherbol A and Structural
The first total synthesis of marine anti-
cancer natural products dysideanone B
and dysiherbol A have been completed
and the structure of dysiherbol A has
been revised. A radical cyclization was
employed to construct the 6/6/6/6 skel-
eton of dysideanone B and a Heck reac-
tion was utilized to forge the 6/6/5/6 core
structure of dysiherbol A.
Reassignment of Dysiherbol A
8
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Angew. Chem. Int. Ed. 2021, 60, 1 – 8
These are not the final page numbers!