Asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B

Article abstract of DOI:10.1039/d0sc07089k

The asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B was achieved in 6-7 steps using an easily accessiblemeso-cyclohexadienone derivative. The [6,6]-bicyclic decalin B-C ring and the all-carbon quaternary stereocenter at C-6 were preparedviaa desymmetric intramolecular Michael reaction with up to 97% ee. The naphthalene diol D-E ring was constructed through a sequence of Ti(Oi-Pr)₄-promoted photoenolization/Diels-Alder, dehydration, and aromatization reactions. This asymmetric strategy provides a scalable route to prepare target molecules and their derivatives for further biological studies.

Full text of DOI:10.1039/d0sc07089k

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Asymmetric total synthesis of (+)-xestoquinone and
(+)-adociaquinones A and B†
Cite this: Chem. Sci., 2021, 12, 4747
a
a
a
b
All publication charges for this article Xiao-Long Lu,‡ Yuanyou Qiu,‡ Baochao Yang, Haibing He
have been paid for by the Royal Society
of Chemistry
ab
and Shuanhu Gao
*
The asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B was achieved in 6–7
steps using an easily accessible meso-cyclohexadienone derivative. The [6,6]-bicyclic decalin B–C ring and
the all-carbon quaternary stereocenter at C-6 were prepared via a desymmetric intramolecular Michael
reaction with up to 97% ee. The naphthalene diol D–E ring was constructed through a sequence of
Received 30th December 2020
Accepted 19th February 2021
4
Ti(Oi-Pr) -promoted photoenolization/Diels–Alder, dehydration, and aromatization reactions. This
DOI: 10.1039/d0sc07089k
asymmetric strategy provides a scalable route to prepare target molecules and their derivatives for
further biological studies.
rsc.li/chemical-science
5
b
3b,c,5f,7,9b,d
Various halenaquinone-type natural products with promising ring transfer, Heck,
palladium-catalyzed polyene
5
d
3f
biological activity have been isolated from marine sponges of cyclization, Pd-catalyzed oxidative cyclization, and hydrogen
the genus Xestospongia from the Pacic Ocean. (+)-Halenaqui- atom transfer (HAT) radical cyclization reactions. In this study,
none (1), (+)-xestoquinone (2), and (+)-adociaquinones A (3) we report the asymmetric total synthesis of (+)-xestoquinone (2),
and B (4) bearing a naphtha[1,8-bc]furan core (Fig. 1) are the (ꢀ)-xestoquinone (2 ), and (+)-adociaquinones A (3) and B (4)
1
9c
2,3
4,5
0
most typical representatives of this family. Naturally occurring (Fig. 1).
6,7
(
ꢀ)-xestosaprol N (5) and O (6) have the same structure as 3
The construction of the fused tetracyclic B–C–D–E skeleton
and 4 except for a furan ring, while a naphtha[1,8-bc]furan core and the all carbon quaternary stereocenter at C-6 is a major
can also be found in fungus-isolated furanosteroids (ꢀ)-viridin challenge towards the total synthesis of xestoquinone (2) and
8,9
(
7) and (+)-nodulisporiviridin E (8) (Fig. 1). Halenaquinone (1) adociaquinones A (3) and B (4). Based on our retrosynthetic
was rst isolated from the tropical marine sponge Xestospongia analysis (Scheme 1), the all-carbon quaternary carbon center at
2
exigua and it shows antibiotic activity against Staphylococcus C-6 of cis-decalin 12 could rst be prepared stereoselectively
aureus and Bacillus subtilis. Xestoquinone (2) and adociaqui- from the achiral aldehyde 13 via an organocatalytic
nones A (3) and B (4) were rstly isolated, respectively, from the
4a
Okinawan marine sponge Xestospongia sp. and the Truk
4
b
4a,c
Lagoon sponge Adocia sp., and they show cardiotonic,
4
b,i
4i
4j
4l
cytotoxic, antifungal, antimalarial, and antitumor activi-
ties. These compounds inhibit the activity of pp60v-src protein
tyrosine kinase, topoisomerases I and II, myosin Ca
4d
4e
4f
2+
4c,g
4h,k
ATPase, and phosphatases Cdc25B, MKP-1, and MKP-3.
Owing to their diverse bioactivities, the synthesis of this
family of natural compounds has been extensively studied, with
3a,d,e,5a–c,e,g
published pathways making use of Diels–Alder,
furan
a
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of
Chemistry and Molecular Engineering, East China Normal University, 3663N
Zhongshan Road, Shanghai 200062, China. E-mail: hbhe@chem.ecnu.edu.cn;
shgao@chem.ecnu.edu.cn
b
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug
Development, East China Normal University, 3663N Zhongshan Road, Shanghai
2
00062, China
†
Electronic supplementary information (ESI) available. CCDC 2050867–2050869.
For ESI and crystallographic data in CIF or other electronic format see DOI:
1
0.1039/d0sc07089k
Fig. 1 Structure of halenaquinone-type natural products and viridin-
‡
These authors contributed equally to this work.
type furanosteroids.
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2021 The Author(s). Published by the Royal Society of Chemistry
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11 and enone 12. Acid-mediated cyclization of 10 followed by
oxidation state adjustment could be subsequently applied to
form the furan ring A of xestoquinone (2). Finally, based on the
4b,5c
biosynthetic pathway of (+)-xestoquinone (2)
and our
previous studies, the heterocyclic ring F of adociaquinones A
3) and B (4) could be prepared from 2 via a late-stage cyclization
7
(
with hypotaurine (9).
The catalytic enantioselective desymmetrization of meso
compounds has been used as a powerful strategy to generate
enantioenriched molecules bearing all-carbon quaternary ster-
10,11
eocenters.
For instance, two types of asymmetric intra-
molecular Michael reactions were developed using a cysteine-
derived chiral amine as an organocatalyst by Hayashi and co-
11a,b
workers,
while a desymmetrizing secondary amine-catalyzed
asymmetric intramolecular Michael addition was later reported
by Gaunt and co-workers to produce enantioenriched decalin
11c
structures.
following the suggested retrosynthetic pathway (Scheme 1), we
rst screened conditions for organocatalytic desymmetric
Prompted by these pioneering studies and

intramolecular Michael addition of meso-cyclohexadienone 13
(Table 1) in order to form the desired quaternary stereocenter at
C-6. Compound 13 was easily prepared on a gram scale via
a four-step process (see details in the ESI†).
Scheme 1 Retrosynthetic analysis of (+)-xestoquinone and (+)-ado-
ciaquinones A and B.
10,11
desymmetric intramolecular Michael reaction.
The tetracy-
We initially investigated the desymmetric intramolecular
clic framework 10 could then be formed via a Ti(Oi-Pr)
4
-
17
12–16
Michael addition of 13 using (S)-Hayashi–Jørgensen catalysts,
promoted photoenolization/Diels–Alder (PEDA) reaction
of
a
Table 1 Attempts of organocatalytic desymmetric intramolecular Michael addition
b
c
Entry
Cat. (equiv.)
Additive (equiv.)
Solvent
Time
Yield/d.r. at C2
e.e.
1
2
3
4
5
6
7
(R)-cat.I (0.5)
(R)-cat.I (1.0)
(R)-cat.I (1.0)
(R)-cat.I (1.0)
(R)-cat.I (1.0)
(R)-cat.I (1.0)
(R)-cat.I (1.0)
(R)-cat.I (1.0)
(R)-cat.I (0.5)
(R)-cat.I (0.5)
(R)-cat.I (0.5)
(R)-cat.I (0.2)
—
—
—
—
—
—
—
Toluene
Toluene
MeOH
DCM
Et O
2
MeCN
Toluene/MeOH (2 : 1)
Toluene
Toluene
Toluene
Toluene
10.0 h
4.0 h
4.0 h
10.0 h
10.0 h
10.0 h
4.0 h
4.0 h
6.0 h
6.0 h
6.0 h
9.0 h
52%/10.3 : 1
60%/10.0 : 1
47%/5.5 : 1
28%/24.0 : 1
22%/22.0 : 1
12%/2.6 : 1
47%/10.0 : 1
14a: 96%; 14b: 75%
14a: 93%; 14b: 75%
14a: 86%; 14b: ꢀ3%
14a: 91%; 14b: 7%
14a: 91%; 14b: 65%
14a: 90%; 14b: 62%
14a: 87%; 14b: ꢀ38%
14a: 96%; 14b: 95%
14a: 97%; 14b: 91%
14a: 96%; 14b: 92%
14a: 95%; 14b: 93%
14a: 97%; 14b: 91%
d
e
8
9
AcOH (5.0)
AcOH (2.0)
AcOH (0.2)
AcOH (0.2)
AcOH (0.2)
60% /2.1 : 1
d
e
75% /4.0 : 1
d
e
10
11
12
73% /4.3 : 1
f
e
g
75% /8.0 : 1
h
i
j
Toluene
80% /6.0 : 1
a
All reactions were performed using 13 (5.8 mg, 0.03 mmol, 1.0 equiv., and 0.1 M) and a catalyst at room temperature in analytical-grade solvents,
b
1
unless otherwise noted. The yields and diastereoisomeric ratios (d.r.) were determined from the crude H NMR spectrum of 14 using CH
internal standard, unless otherwise noted. The enantiomeric excess (e.e.) values were determined by chiral high-performance liquid
2
Br as an
2
c
d
e
f
chromatography (Chiralpak IG-H). Compound 13: 9.6 mg, 0.05 mmol, and 0.1 M. Isolated combined yield of 14a + 14b. h Compound 13:
g
1
1
92 mg, 1.0 mmol, and 0.1 M. The d.r. values decreased to 1 : 1 aer purication by silica gel column chromatography. Compound 13:
i j 1
.31 g, 6.82 mmol, and 0.1 M. Isolated combined yield of 12a + 12b. The d.r. values were determined from the crude H NMR spectrum of 12
obtained from the one-pot process.
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the desired absolute conguration of the angular methyl group
at C-6, (R)-cat.I was used for further screening. In the presence
of this catalyst, the intramolecular Michael addition afforded
14a (96% e.e.) and 14b (75% e.e.) in a ratio of 10.3 : 1 and 52%
combined yield (entry 1, Table 1). We assumed that the enan-
tioselectivity of the reaction was controlled by the more steri-
cally hindered aromatic group of (R)-cat.I, which protected the
upper enamine face and allowed an endo-like attack by the si-
face of cyclohexadienone, as shown in the transition state TS-
A (Table 1). In order to increase the yield of this reaction and
improve the enantioselectivity of 14b, we further screened
solvents and additives. Increasing the catalyst loading from 0.5
to 1.0 equivalents and screening various reaction solvents did
not improve the enantiomeric excess of 14b (entries 2–7, Table
11d,e
1). Therefore, based on previous studies,
we added 5.0
equivalents of acetic acid (AcOH) to a solution of compound 13
and (R)-cat.I in toluene, which improved the enantiomeric
excess of 14b to 95% with a 60% combined yield (entry 8, Table
1). And, the stability of (R)-cat.I has also been veried in the
presence of AcOH (see Table S2 in the ESI†). Further adjustment
of the (R)-cat.I and AcOH amount and ratio (entries 9–12, Table
1
) indicated that 0.2 equivalents each of (R)-cat.I and AcOH were
the best conditions to achieve high enantioselectivity for both
4a and 14b, and it also increased the reaction yield (entry 12,
1
Table 1). The enantioselectivity was not affected when the
optimized reaction was performed on a gram scale: 14a (97%
e.e.) and 14b (91% e.e.) were obtained in 80% isolated yield
(entry 12, Table 1). We also found that the gram-scale experi-
ments needed a longer reaction time which led a slight decrease
of the diastereoselectivity. The purication of the cyclized
products by silica gel ash column chromatography indicated
that the major product 14a was epimerized and slowly con-
verted to the minor product 14b (entry 11, Table 1). Both 14a
Scheme 2 PEDA reaction of 11 and enone 12.
and found that the absolute conguration of the obtained cis-
decalin was opposite to the required stereochemistry of the
natural products (see Table S1 in the ESI†). In order to achieve
Scheme 3 Total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B.
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2021 The Author(s). Published by the Royal Society of Chemistry
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and 14b are useful in the syntheses because the stereogenic
center at C-2 will be converted to sp hybridized carbon in the
Conclusions
2
following transformations. Therefore, the aldehyde group of In summary, we developed a concise approach for the asym-
analogues 14a and 14b was directly protected with 1,3-pro- metric total synthesis of (+)-xestoquinone (2) in 6 steps and of
panediol to give the respective enones 12a and 12b for use in the (+)-adociaquinones A (3) and B (4) in 7 steps from a known
subsequent PEDA reaction.
compound 13. Organocatalytic desymmetric intramolecular
Aerward, we selected the major cyclized cis-decalins 12a Michael addition was used to construct the cis-decalin skeleton
0
and 12a (obtained by using (S)-cat.I in desymmetric intra- bearing the all-carbon quaternary carbon center at the C-6
molecular Michael addition, see Table S1 in the ESI†) as the position. The B–C–D–E tetracyclic framework was then
dienophiles to prepare the tetracyclic naphthalene framework prepared through a Ti(Oi-Pr) -mediated PEDA reaction, and
4
1
0 through a sequence of Ti(Oi-Pr) -promoted PEDA, dehydra- further modications led to the desired naphtha[1,8-bc]furan
4
tion, and aromatization reactions (Scheme 2). When using 3,6- core. The application of this strategy to the synthesis of struc-
dimethoxy-2-methylbenzaldehyde (11) as the precursor of turally related natural products is currently under investigation.
0
diene, no reaction occurred between 12a/12a and 11 under UV
4
irradiation at 366 nm in the absence of Ti(Oi-Pr) (Scheme 2A).
Conflicts of interest
In contrast, the 1,2-dihydronaphthalene compounds 16a and
0
1
6a were successfully synthesized when 3.0 equivalents of There are no conicts to declare.
13a,e
Ti(Oi-Pr)4 were used. Based on our previous studies,
the
desired hydroanthracenol 15a was probably generated through
the chelated intermediate TS-B and the cycloaddition occurred
Acknowledgements
18
through an endo direction (Scheme 2B). The newly formed b- We thank the National Natural Science Foundation of China
0
hydroxyl ketone groups in 15a and 15a could then be dehy- (21971068 and 21772044), the “National Young Top-Notch
0
drated with excess Ti(Oi-Pr)
4
to form enones 16a and 16a . These Talent Support Program”, the Program of Shanghai Academic/
results conrmed the pivotal role of Ti(Oi-Pr)
4
in this PEDA Technology Research Leader (18XD1401500), the Program of
reaction: it stabilized the photoenolized hydroxy-o-quinodi- Shanghai Science and Technology Committee (18JC1411303),
methanes and controlled the diastereoselectivity of the the “Shuguang Program” supported by the Shanghai Education
reaction.
Development Foundation (grant numbers 19SG21), the
0
Subsequent aromatization of compounds 16a and 16a with Program for Changjiang Scholars and Innovative Research
ꢁ
2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) at 80 C afforded Team in University and “the Fundamental Research Funds for
0
compounds 10a and 10a bearing a fused tetracyclic B–C–D–E the Central Universities” for generous nancial support.
skeleton. The stereochemistry and absolute conguration of
1
0a were conrmed by X-ray diffraction analysis of single crys-
Notes and references
tals (Scheme 3). The synthesis of (+)-xestoquinone (2) and
+)-adociaquinones A (3) and B (4) was completed by forming
(
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0
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0
also synthesized from 10a in order to determine in the future
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2021 The Author(s). Published by the Royal Society of Chemistry
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T. M. Arisco, R. A. Valiulin, G. A. Metzel and 18 Based on our previous studies (ref. 13a and e), we concluded
A. G. Kutateladze, Angew. Chem., Int. Ed., 2011, 50, 9423– that Ti(Oi-Pr) plays a key role in the PEDA reaction, which
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4
9
chelated with the photo-generated Z-dienol and ortho
methoxy group of 11, forming a relatively stable complex.
This complex may exist as a dimeric titanium complex,
given the observed relationships between the Ti dosage
and reaction yield (ref. 13a). The ortho methoxy may serve
as a key neighbouring group that helps to stabilize the
(
1
Chem. Soc., 2016, 138, 2110–2113; (k) D. M. Kuznetsov,
O. A. Mukhina and A. G. Kutateladze, Angew. Chem., Int.
Ed., 2016, 55, 6988–6991; (l) A. Mavroskous, K. Rajes,
P. Golz, A. Agrawal, V. Ruß, J. P. G ¨o tze and
M. N. Hopkinson, Angew. Chem., Int. Ed., 2020, 59, 3190–
short-lived
photoenolized
hydroxy-o-quinodimethane
diene, which then interacts with dienophile 12a to give
a chelated intermediate TS-B. Then the activated enone
reacts with the diene component from the endo direction.
Aer dissociation, cycloaddition product 15a was
generated stereospecically.
3
194.
1
7 For the reviews of Hayashi–Jørgensen catalysts, see: (a)
K. L. Jensen, G. Dickmeiss, H. Jiang, Ł. Albrecht and
4752 | Chem. Sci., 2021, 12, 4747–4752
© 2021 The Author(s). Published by the Royal Society of Chemistry