Convergent Synthesis of Kibdelone C

Article abstract of DOI:10.1021/acs.orglett.8b00901

The synthesis of kibdelone C, a polycyclic natural xanthone isolated from a soil actinomycete, was achieved through a convergent approach. A 6?€-electrocyclization was applied to construct the highly substituted dihydrophenanthrenol fragment (B-C-D ring). InBr₃-promoted lactonization was employed to build the isocoumarin ring, which served as a common precursor for the formation of isoquinolinone ring (A-B ring). A key DMAP-mediated oxa-Michael/aldol cascade reaction was developed to install the tetrahydroxanthone fragment (E-F ring). This approach provides a new solution to prepare its derivatives and structurally related natural products.

Full text of DOI:10.1021/acs.orglett.8b00901

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Convergent Synthesis of Kibdelone C
Yihua Dai,† Feixia Ma,† Yanfang Shen,† Tao Xie,† and Shuanhu Gao*,†,‡
†Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China
Normal University, Shanghai 200062, China
‡Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University,
Shanghai 200062, China
S
* Supporting Information
ABSTRACT: The synthesis of kibdelone C, a polycyclic natural
xanthone isolated from a soil actinomycete, was achieved through
a convergent approach. A 6π-electrocyclization was applied to
construct the highly substituted dihydrophenanthrenol fragment
(B−C−D ring). InBr3-promoted lactonization was employed to
build the isocoumarin ring, which served as a common precursor
for the formation of isoquinolinone ring (A−B ring). A key
DMAP-mediated oxa-Michael/aldol cascade reaction was devel-
oped to install the tetrahydroxanthone fragment (E−F ring). This
approach provides a new solution to prepare its derivatives and structurally related natural products.
Notably, kibdelone C (5) displays significant activities against a
range of human tumors by the NCI 60-cell panel assays, such as
the SR tumor cell line and SN12C cell carcinoma (GI50 < 1 nm).2a
Structurally, the kibdelones possess the highly oxygenated
hexacyclic rings containing isoquinolinone (A−B ring), dihy-
drophenanthrenol (B−C−D ring), and tetrahydroxanthone (D−
E−F ring with three stereogenic hydroxyl groups on C-10, -11,
and -13). The intriguing structures of polycyclic xanthones and
their promising biological activities have attracted considerable
attention from the synthetic community.3 Synthetic landmarks of
the polycyclic xanthones include Kelly’s first total synthesis of
cervinomycin A1 and A24 and Suzuki’s first stereoselective total
synthesis of FD-594 aglycon.5 The synthetic breakthrough of the
most challenging hexacyclic tetrahydroxanthones came when
both the Porco6 and Ready7 groups reported the total synthesis of
kibdelone C. More recently, the enantioselective total synthesis
of simaomicin α was also completed by Ready and co-workers.8
Moreover, these studies have also stimulated the related medical
exploration of this family of natural products.6b,7b As part of our
interest in the synthesis of natural xanthones, we have developed
a photoinduced C−O bond formation to construct tetrahydrox-
anthones9 and achieved the total synthesis of xanthone dimer
ascherxanthone A.10 Herein, we report a new approach for the
synthesis of kibdelone C.
olycyclic xanthone natural products (1−8) are a family of
Ppolyketides that share a common angular hexacyclic skeleton
(Figure 1).1 The kibdelones and isokibdelones (1−5), a
subgroup of hexacyclic tetrahydroxanthone, were isolated from
a rare soil actinomycete Kibdelosporangium sp. by Capon and co-
workers,2 and exhibit potent antibacterial activity, nematocidal
activity, and cytotoxicity against several human cancer cell lines.2a
Though the structures are different in dozens of ways,
polycyclic xanthones possess the same core structure of
dihydrophenanthrenol fragment (B−C−D ring). Therefore, we
envisioned building the tricyclic 12 first through 6π-electro-
cyclization, which could be used as a platform to install A ring and
E−F ring through a convergent approach (Scheme 1). To access
the tetrahydroxanthone fragment (E−F ring), a late-stage
Received: March 19, 2018
Figure 1. Polycyclic xanthone natural products.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00901
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Organic Letters
Letter
known aldehyde 1311 was efficiently transformed into triflate 14
(79%) through methylation on a large scale. Pd-catalyzed
Sonogashira coupling of 3-bromo-2,5-dimethoxyphenol
(15)7a,12 with ethynyltriisopropylsilane followed by desilylation
obtained terminal alkyne 16 (74%, two steps). The chiral
hydroxyl groups of F ring was introduced from lactone 17, which
was prepared from commercially available D-(+)-xylose using the
literature procedure.13 Treatment of 17 with Ag2O (using NaH as
base led to racemization) and BnBr in the presence of catalytic
KI14 gave the benzylic ether 18 (85% brsm). The ester was
reduced with diisobutylaluminum hydride (DIBAL-H) followed
by treatment with freshly prepared Seyferth−Gilbert reagent to
afford alkyne 20 (79%, dr = 13:1) in one pot.15 After
transformation of the acetonide to benzylidene acetal, the
primary alcohol 11 was provided by reduction with TMSCl/
NaBH3CN6a,16 in 42% yield.
Scheme 1. Retrosynthetic Analysis of Kibdelones
With these fragments in hand, we started to build the
dihydrophenanthrenol moiety (B−C−D ring). A second
Sonogashira coupling reaction was applied to connect 14 with
16, which furnished internal alkyne 21 (81%, two steps) after
protection with triisopropylsilyl group (Scheme 3). One of the
Scheme 3. Construction of Fragment 12 Bearing B−C−D ring
cascade cyclization of precursor 9 was designed involving either a
Lewis acid promoted alkyne−Prins/hydroxyl trapping cycliza-
tion (path a) or a base-mediated oxa-Michael/aldol cyclization
(path b). Subsequently, the chiral alkyne 11 and tetracyclic
moiety 10 could be connected via a Barbier reaction. We
anticipated forming the isoquinolinone (A−B ring) from
isocoumarin which can be introduced by a Sonogashira coupling
of triflate 12 with pentyne followed by a Lewis acid promoted
lactonization.
Our synthesis commenced with the preparation of the
fragments 14 and 15 and the chiral alkyne 11 (Scheme 2). The
Scheme 2. Preparation of Fragments 14, 16, and 11
methyl groups on the B ring was removed selectively with BCl3 to
give phenol, and then stereoselective hydrogenation using
Lindlar catalyst yielded the desired cis-alkene 22. To close the
C ring, the photoinduced 6π-electrocyclization was investigated,
and we found that the introduction of the bulky −OTIPS group
helped to control the regioselectivity of the cyclization on C-5
over C-17. Finally, after irradiation of 22 under high-pressure
mercury lamp, tricyclic triflate 23 was obtained in 61% yield over
three steps by the following base-mediated triflation, and the
structure of 23 was confirmed by X-ray crystal analysis. Moreover,
the C-22 cyclization phenol (10%, three steps) was also obtained
along with 23 after triflation (see details in the SI). Removal of the
TIPS group using TBAF afforded the corresponding phenol, and
Et2AlCl was proved to be the best Lewis acid to introduce the
hydroxymethyl on the ortho-position of the phenol group
through Friedel−Crafts reaction. The resulting primary alcohol
was oxidized with MnO2 to give aldehyde 12 in 68% yield over
two steps. We considered that 12, containing the basic B−C−D
tricyclic skeleton, could be used as a platform to install A ring and
E−F ring through the modification of functional groups on C-7
and -23.
B
DOI: 10.1021/acs.orglett.8b00901
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Letter
Scheme 4. Convergent Synthesis of Kibdelone C
We then switched our attention to install the isoquinolinone
ring (A−B ring). A third Pd-catalyzed Sonogashira coupling of 12
with pentyne forged 24 (Scheme 4). Inspired by Sakai and
Arcadi’s work,17 we explored the InBr3-mediated ring closure of
24, which underwent the 6-endo-dig cyclization process to form
isocoumarin 10 (91%) stereospecifically. Treatment of the
resulting isocoumarin with methylamine in EtOH and
dehydration afforded isoquinolinone 25,6a,18 whose structure
was confirmed by X-ray crystal analysis. The C-3 demethylation
product 26 (74%) was achieved when the amount of CSA was
increased to 8 equiv. Compound 25 was also effectively
transformed into 26 using BCl3 in 91% yield. The methoxyl
group on C-22 was introduced by oxidation of 26 with PIFA and a
subsequent Zn reduction (46%, 2 steps). Chlorination of 28
proved to be challenging due to its unstable structure. After an
extensive survey of the chlorine sources (NCS, NaClO, Cl2,
TBAC/Oxone, NaCl/Oxone, etc.), we found that the freshly
prepared Mioskowski’s reagent (n-Bu4NCl3)19 in MeCN was the
best reagent for the chlorination and gave the chloride 28 in 43%
yield. Next, we evaluated the construction of the key
tetrahydroxanthone (E−F ring) through the aforementioned
cascade cyclization. Deprotonation of terminal alkyne 11 with n-
BuLi generated an alkynyllithium reagent that could participate in
a nucleophilic addition to aldehyde 28. After separation of the
unreacted 11 and 28, the resulting product was oxidized with
IBX20 to produce the highly reactive intermediate 29, which
could be cyclized via a 5-exo pathway during the purification on
silica gel. Therefore, it was directly used in the next cyclization.
We first investigated the acid-promoted cascade process21
(pathway a, Scheme 1; see details in the Supporting Information)
in a model study (using 25 instead of 28). TiCl4/TBAI, reported
by the Frontier group,22 yielded an iodine-addition product that
was unstable under subsequent base conditions (NaOH,
Cs2CO3, K2CO3). We envisioned the TiCl4 may react with the
phenol group and generate the intermediate 33 first (Figure 2),
and then the α, β-unsaturated ketone 34 is afforded by halo-
Michael addition followed by protonation.23 Other Lewis acids
(I2, In(OTf)3, AuNTf2(PPh3), AuCl(PPh3)) or Brøsnted acids
Figure 2. Proposed mechanism for the TiCl4/TBAI system.
(PTSA, TfOH, HCl, TFA) led to a complicated system. On the
other hand, the base-mediated oxa-Michael/aldol cascade
reaction was also explored. The reactions were either complicated
or decomposed when hydroquinine, MeONa, TBAF, Cs2CO3, or
NaOH was used (for more details, see the SI). Inspired by the
Dake group’s work,24 DMAP was used and yielded the expected
6-endo product. We also inferred that the existence of the highly
reactive free phenol made the corresponding compounds
unstable under most of the aforementioned conditions. Finally,
treatment of the freshly prepared intermediate 29 with DMAP in
dichloromethane provided the desired cyclized product 30 and
its C-10 epimer in 12% brsm yield over three steps (dr = 1:1). The
C-10 epimer epi-30 could be transform to 30 over two steps.
Removal of benzyl groups and the methyl group on C-6 using
1
BCl3 yielded the intermediate 31 in 65% yield, which gave H
NMR, 13C NMR, high-resolution mass spectrometric, and optical
rotation ([α]D22 = +66 (c = 0.14, CHCl3), [α]D23 = +90 (c = 0.20,
CHCl3) reported data) results identical to those previously
reported by the Porco6a and Ready7b groups. Then the total
synthesis of kibdelone C (5) could be achieved using the known
procedure developed by the Porco group6a through a two-step
sequence.
In summary, we developed a convergent approach for the
synthesis of kibdelone C. The highly substituted dihydrophenan-
threnol fragment (B−C−D ring) served as a platform for the
formation of the angular hexacyclic skeleton, which was
efficiently built through a 6π-electrocyclization. It also laid the
C
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00901.
General experimental procedures, characterization data,
1H and 13C NMR spectra of new compounds, and X-ray
data for 23 and 25 (PDF)
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CCDC 1821857−1821858 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: shgao@chem.ecnu.edu.cn.
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Shuanhu Gao: 0000-0001-6919-4577
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the National Natural Science Foundation of
China (21772044), the “National Young Top-Notch Talent
Support Program”, Program of Shanghai Academic/Technology
Research Leader (18XD1401500), and “the Fundamental
Research Funds for the Central Universities” for generous
financial support.
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