Total Synthesis and Structural Reassignment of (±)-Cereoanhydride

Article abstract of DOI:10.1021/acs.orglett.6b02424

The first total synthesis of (±)-cereoanhydride has been achieved under the inspiration of its biosynthetic hypothesis. The tricyclic skeleton of trypethelone, the proposed biosynthetic precursor of cereoanhydride, was constructed by an interesting ring e

Full text of DOI:10.1021/acs.orglett.6b02424

Letter
pubs.acs.org/OrgLett
Total Synthesis and Structural Reassignment of ( )-Cereoanhydride
Zhiqiang Ren, Yu Hao, and Xiangdong Hu*
Department of Chemistry & Material Science, Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry
of Education of China, Northwest University, Xi’an 710127, China
S
* Supporting Information
ABSTRACT: The first total synthesis of ( )-cereoanhydride has been achieved under the inspiration of its biosynthetic
hypothesis. The tricyclic skeleton of trypethelone, the proposed biosynthetic precursor of cereoanhydride, was constructed by an
interesting ring expansion of cyclobutenone in one step in which the introduced acetyl group is pivotal to avoid the following
aerial oxidation. On the basis of X-ray crystallographic analysis, the structure of cereoanhydride is reassigned to a spiroketal
structure 2, which should be formed through an isomerization of the originally proposed structure 1.
arine algae derived fungi afford a specific but important
Konig and co-workers postulated that cereoanhydride might
̈
M
source for the discovery of secondary metabolites with
be formed from the oxidation of trypethelone (4), which was
isolated from cultivation of the same fungus in their earlier
work.3 It was also demonstrated that this homologous natural
product 4 possesses cytotoxicity against mouse fibroblast cells
and inhibitory activities toward Mycobacterium phlei, Staph-
ylococcus aureus, and Escherichia coli. Inspired by the
biosynthetic hypothesis, our synthetic plan to the originally
proposed cereoanhydride (1) is illustrated in Scheme 1.
Because that trans relationship between C1 and C15 and
trans fusion on C1−C14 of 1 should cause less steric hindrance
compared with its epimers, we envisioned that the expected
stereochemistry at C1 and C14 could be established via a
diastereoselective hydration of the enol ether motif on C1−
C14 of 3 under thermodynamic conditions. Cyclic anhydride 3
could be obtained through a Baeyer−Villiger oxidation of 4,
which could potentially be generated from 5 through
deprotection and oxidation. For the synthesis of 5, a ring-
expansion process on 6, via an interesting four-electron
electrocyclic ring-opening/6π-electrocyclization cascade of
cyclobutenones, was envisaged. Such chemistry was initially
developed by Moore4 and Liebeskind5 for related arene ring
construction. Commercially available 7, 8 ,and 9 were
considered suitable building blocks for synthesis of 6.
promising bioactivities and unusual molecular structures.1 On
the basis of extensive studies on marine endophytic fungus
Coniothyrium cereale isolated from green algae Enteromorpha sp.
in the Baltic sea, Konig and co-workers reported the isolation of
̈
a new secondary metabolite, cereoanhydride, in 2012.2
Through NMR spectroscopic and mass spectrometric analysis,
the structure of cereoanhydride was originally assigned as 1
(Figure 1). It features a very rare seven-membered cyclic
Figure 1. Structures of originally proposed and reassigned
cereoanhydride.
anhydride, a polysubstituted aromatic ring, and a trans-fused
trimethyltetrahydrofuran ring bearing three stereogenic centers,
making it an attractive synthetic target. Additionally,
cereoanhydride displayed weak inhibition (IC50 = 16 μg
mL−1) to serine protease human leukocyte elastase in
preliminary biological studies. Due to the limited amount of
this compound from the natural source, development of
synthetic pathways to cereoanhydride will build up an
important foundation for further biological evaluations of this
secondary metabolite. Herein, we report the first total synthesis
and the structural reassignment (2) of cereoanhydride.
Our synthesis commenced with the preparation of 12
(Scheme 2). In the presence of magnesium, 9 reacted with 8
smoothly,6 affording 10 in 83% yield following rearrangement
under acidic conditions. The efficient bromine−lithium
exchange of n-butyllithium with 11, which was obtained from
the TBS protection of phenolic hydroxyl of 7, ensured the
Received: August 13, 2016
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.6b02424
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Scheme 1. Synthetic Plan to Proposed Cereoanhydride (1)
Scheme 3. Reduction of 13
13. We postulated that the reduction of 13 only happened on
the more electron-poor 1,4-benzoquinone motif. Rather than
be reduced, the side-chain carbonyl of 13 was attacked by one
phenolic hydroxyl generated from the reduction, affording
intermediate 16. The formed hemiketal motif in 16 completely
inhibited further reduction. Moreover, 16 could be easily
oxidized by air, which led to the formation of 13 at the end of
the operation. Besides, there is a high possibility that
intermediate 14 generated from the ring-expansion of 12
would exist in its hemiketal form 16.
Scheme 2. Synthesis and Ring Expansion of 12
At this point, our synthetic route was adjusted as depicted in
Scheme 4. With the purpose of inhibiting the facile aerial
Scheme 4. Synthesis of 4
nucleophilic addition to one carbonyl of 10 and generated
cyclobutenone 12 with high regioselectivity. The latter was the
first substrate submitted to the ring-expansion process under
thermal conditions. However, 13 was obtained consistently as
the major product in poor yields (less than 15%). There was no
formation of expected product 14 observed. It was thought that
the 1,4-diphenol motif in intermediate 14 could be readily
oxidized by air. The application of DDQ at the later stage of the
reaction increased the yield of 13 to 40%.7
With 13 in hand, we anticipated that the carbonyl on the side
chain of 13 could be selectively reduced. The product 17 might
transform into 15 through an intramolecular 1,3-alkoxyl
exchange (Scheme 3). However, the formation of 15 or 17
was not observed under reductive conditions, such as NaBH4
and LiAlH4. After reaction workup and column chromatog-
raphy, the major component obtained was the starting material
oxidation, an acetyl protecting group was introduced on the
hydroxyl of 12, affording 6. To our delight, the ring expansion
of 6 was not followed by oxidation, compound 18 being
obtained in 85% yield. The introduction of the acetyl group not
only successfully inhibited the oxidation of the 1,4-diphenol
motif but also significantly increased the yield of the ring-
expansion product. The reduction of the hemiketal motif of 18
was achieved using Et3SiH and TFA and gave 5 in 86% yield.8
For the synthesis of 4, we envisioned removing the protecting
groups from the middle ring of 5 and following this by an
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oxidative treatment. However, no reaction occurred with 5
using KMnO4, CAN (ceric ammonium nitrate), and PhI-
(OAc)2. Obviously, it is difficult to remove the acetyl group of 5
under oxidative conditions. Thus, we turned our attention to
reductive conditions. To our disappointment, the reduction of
5 with LiAlH4 gave a complex mixture, and no reasonable
product was obtained after column chromatography. Luckily,
treating the crude reduction products with 3 equiv of CAN led
to the formation of 4 in 65% yield over two steps.9
In summary, we have developed a concise approach for the
first total synthesis of cereoanhydride under the inspiration of
the biosynthetic hypothesis from Konig and co-workers. The
̈
entire synthetic route requires nine steps starting from
commercially available materials. Salient features of our route
include two key transformations: (a) the Moore/Liebeskind
ring expansion of cyclobutenone 6 through a four-electron
electrocyclic ring-opening/6π-electrocyclization cascade and
(b) the synthesis of cereoanhydride through Baeyer−Villiger
oxidation of trypethelone, diastereoselective hydration, and
subsequent isomerization in one pot. With the aid of X-ray
crystallographic analysis of the synthesized cereoanhydride, the
structure of the natural product was serendipitously reas-
signed11 to 2 with a spiroketal skeleton. It is postulated that the
originally proposed structure 1 should be an integral precursor
for the formation of 2.
The synthesis of cereoanhydride is demonstrated in Scheme
5. Baeyer−Villiger oxidation of 4 took place smoothly with m-
Scheme 5. Synthesis and Structural Reassignment of
Cereoanhydride
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02424.
Single crystal data for cereoanhydride (2) (CIF)
Experimental procedures, spectroscopic data, and images
1
of H and 13C NMR spectra for all new compounds
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xiangdonghu@nwu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (21002078, 21372184), the
China Postdoctoral Science Foundation (334100041), and
NFFTBS (No. J1210057).
CPBA.10 Due to its poor stability, intermediate 3 was treated
directly with HCl in a mixture of THF and H2O. To our
surprise, cereoanhydride was obtained as the major product
with good diastereoselectivity. The spectroscopic data (HRMS
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