Total Synthesis of (+)-Aplykurodinone-1

Article abstract of DOI:10.1021/acs.orglett.7b02350

Starting from (R)-citronellic acid and (R)-seudenol, the total synthesis of (+)-aplykurodinone-1, a highly degraded marine steroid, has been achieved in 11 steps and in 19% overall yield with excellent stereochemical control. In addition to the features s

Full text of DOI:10.1021/acs.orglett.7b02350

Letter
pubs.acs.org/OrgLett
Total Synthesis of (+)-Aplykurodinone‑1
Bo Xu,†,⊥ Wen Xun,†,⊥ Tingzhong Wang,§ and Fayang G. Qiu*,‡,†,§
†Guangzhou Institute of Biomedicine and Health, The University of the Chinese Academy of Sciences, 190 Kaiyuan Avenue, The
Science Park of Guangzhou, Guangdong 510530, China
‡Key Lab of Functional Molecular Engineering of Guangdong Province, South China University of Technology, 188 Kaiyuan Avenue,
The Science Park of Guangzhou, Guangdong 510530, China
§The Bestsyn Technologies, 188 Kaiyuan Avenue, The Science Park of Guangzhou, Guangdong 510530, China
S
* Supporting Information
ABSTRACT: Starting from (R)-citronellic acid and (R)-
seudenol, the total synthesis of (+)-aplykurodinone-1, a highly
degraded marine steroid, has been achieved in 11 steps and in
19% overall yield with excellent stereochemical control. In
addition to the features such as an Ireland−Claisen rearrange-
ment, an intramolecular carbonyl−ene cyclization, and an
intramolecular Michael addition, the present synthetic strategy
is accomplished without the use of protecting groups.
he aplykurodins and aplykurodinones,1 isolated from
marine mollusks of the genus Aplysia, are a family of
highly degraded marine steroids (Figure 1). The structures of
The structural complexity and the potential biological
activities of aplykurodinone-1 have attracted considerable
attention from the synthetic community.2 In 2010, Danishefsky
and Zhang2a reported the first total synthesis of aplykurodines-
1 in 22 steps based on an elegant anionic Diels−Alder
cycloaddition strategy. After that, five different syntheses by De
Paolis,2b Yang,2c Tang,2d Chakrabotry,2e and Zhai,2f respectively
(Scheme 1), were reported. Although novel strategies and
methodologies have been employed in these syntheses, all of
them have used Danishefsky’s intermediate. The major
T
Scheme 1. Schematic Summary of the Previous Total
Syntheses of Aplukurodinone-1
Figure 1. Representative structures of aplykurodins and aplykur-
odinones.
the first isolated aplykurodins, i.e., aplykurodin A and
aplykurodin B, were determined via spectroscopic methods
and X-ray crystallographic analysis.1a Aplykurodinone-1,
isolated from the sea hare Siphonota geographica in 2005,1d
possesses an unusual cis-hydrindane moiety and six contiguous
stereochemical centers, one of which is quaternary. Although
the biological profile of aplykurodinone-1 remains unknown,
aplykurodinone B and 4-acetylaplykurodin B have shown
strong ichthyo toxicity (10 ppm) to the mosquito fish
Gambusia affinisat. In addition, 3-epi-aplykurodinone B has
exhibited mild in vitro cytotoxicity against four tumor cell
lines.1c
Received: July 30, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02350
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Organic Letters
Letter
drawback of using this intermediate is the poor control of the
stereochemistry of the 13-methyl group, while the 13-epimer is
difficult to separate. So far, this seemingly simple molecule has
presented significant synthetic challenges. Herein, we report a
new, convergent, yet protecting-group-free total synthesis of
aplykurodinone-1 from simple starting materials.
Since all of the previous work has witnessed difficulty with
the stereocontrolled introduction of the unsaturated side chain
in the later stage, we plan to install the C11 side chain prior to
the construction of the tricyclic core skeleton. The retro-
synthetic analysis (Scheme 2) shows that an Ireland−Claisen
Claisen rearrangement, which was obtained from 1 (LDA,
THF−HMPA) according to Bouillon’s procedure.4 It was
found that the amount of HMPA was critical for achieving high
diastereomeric selectivity. Under the optimized conditions, the
Ireland−Claisen rearrangement of the ketene silyl acetal was
followed by reduction of the resulting silyl ester with
diisobutylaluminum hydride to provide alcohol 2 (dr 11:1 at
C11) in 60% combined yield.5 Dess−Martin oxidation of
alcohol 2 was straightforward to afford aldehyde 3 in 95% yield.
The requisite one-carbon elongation was achieved by using a
Wittig olefination of the aldehyde with methoxymethyltriphe-
nylphosphonium chloride and NaHMDS (96%), and the
product was obtained as a 5:1 mixture of the olefin geometric
isomers. Surprisingly, hydrolysis of the terminal methoxy vinyl
ether 4 with hydrochloric acid yielded aldehyde 5 along with
the undesired carbonyl−ene cyclization products 5a and 5b, in
which a chlorine atom was added instead of the formation of
the desired carbon−carbon double bond (Scheme 4). After
Scheme 2. Retrosynthetic Analysis of Aplykurodinone-1
Scheme 4. Carbonyl-Ene Cyclization of 4
rearrangement combined with a carbonyl−ene cyclization may
be efficient for the construction of the core structure. The
lactone ring of aplykurodinone-1 may be introduced via an
intramolecular Michael addition. The advanced intermediate
RS-2 may be converted into RS-1 by using an epoxidation−
oxidation and epoxide ring-opening reaction sequence. The
bicyclic core structure of RS-2 may be constructed via an
intramolecular carbonyl−ene cyclization, while the quaternary
stereochemical center in RS-3 may be constructed via an
Ireland−Claisen rearrangement. Intermediate RS-4 may be
generated from the coupling of (R)-citronellic acid and (R)-
seudenol, which can be readily prepared from pulegone and 3-
methylcyclohexenone, respectively.3
On the basis of the above analysis, the synthetic strategy
seemed feasible. Thus, esterification of (R)-citronellic acid
(98% ee) with (R)-seudenol (96% ee) provided intermediate 1
in 96% yield (Scheme 3). Since the configuration of C11 is
controlled by the geometry of the enolate carbon−carbon
double bond, the (Z)-enol ether is required for the Ireland−
many unfruitful attempts, we hoped that when treated with 2.5
equiv of p-toluenesulfonic acid in freshly distilled methylene
chloride at room temperature intermediate 4 would undergo
the carbonyl−ene cyclization, and intermediate 6 was obtained
in 20% yield and its C9 epimer 6a in 12% yield. After extensive
optimization, it was found that, to our delight, when a small
amount of water was added to the reaction mixture, aldehyde 5
was obtained as the major product (83%), which, when heated
in toluene at 160 °C for 17 h in a sealed tube, provided the
desired cyclization product 6 in 90% yield6 (Scheme 5). Other
Lewis acids (Me2AlCl, Et2AlCl, SnCl4, Sc(OTf)3) also induced
the carbonyl−ene cyclization7 but in moderate yields, along
with the formation of considerable amounts of epimer 6a.
Stereoselective epoxidation of 6 using a catalytic amount of
VO(acac)2 afforded epoxide 7 (92%) with complete diaster-
eocontrol. Dess−Martin oxidation8 afforded the unstable
epoxyketone, the epoxide of which was partially cleaved to
furnish hydroxyenone 8 on silica gel during chromatography.
Thus, DBU was added to the reaction mixture after the
oxidation, and the epoxide was completely cleaved in one pot
(81%). Since the stereochemistry of the hydroxyl group in 8
was different from that of the natural product, a Mitsunobu
esterification of monomethyl malonate with alcohol 8 was used
to furnish 9 with the desired stereochemistry of the malonate in
89% yield.9 When treated with cesium carbonate in acetonitrile,
intermediate 9 underwent an intramolecular Michael addition
in 87% yield to produce the desired lactone 10, the Krapcho
dealkoxycarbonylation of which furnished the final product
Scheme 3. Synthesis of Aldehyde 5
B
DOI: 10.1021/acs.orglett.7b02350
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Laboratory of Functional Molecular Engineering of Guangdong
Province (2016kf01), South China University of Technology.
Scheme 5. Total Synthesis of (+)-Aplykurodinone-1
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addition. In addition, this synthesis was accomplished without
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02350.
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Detailed experimental procedures and NMR data (PDF)
Crystallographic data for aplykurodinone-1 (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: qiu_fayang@gibh.ac.cn.
ORCID
Fayang G. Qiu: 0000-0002-0850-468X
Author Contributions
⊥Bo Xu and Wen Xun contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China for the financial support of this work (Grant Nos.
21372221 and 21572228) and the Open Fund of the Key
C
DOI: 10.1021/acs.orglett.7b02350
Org. Lett. XXXX, XXX, XXX−XXX