First Synthesis of the [5-5-6-6] Tetracyclic Framework of Spiropreussione B

Article abstract of DOI:10.1002/ejoc.201700464

Rapid synthesis of the [5-5-6-6] tetracyclic system in the spirobionaphthalene natural product spiropreussione B was achieved. An intramolecular, thermal dehydrogenative Diels–Alder reaction was employed as the key step. Furthermore, this approach was extended to generate a library of structurally novel linear tetracyclic systems of spiropreussione B in a highly efficient manner. This report constitutes the first synthetic approach to the spiropreussione B natural product.

Full text of DOI:10.1002/ejoc.201700464

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Accepted Article
Title: First Synthesis of [5-5-6-6] Tetracyclic Framework of
Spiropreussione B
Authors: Beeraiah Baire and Bhavani Shankar Chinata
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10.1002/ejoc.201700464
European Journal of Organic Chemistry
Communication
First Synthesis of [5-5-6-6] Tetracyclic Framework of
Spiropreussione B
Bhavani Shankar Chinta[a] and Beeraiah Baire*[a]
Abstract: Rapid synthesis of [5-5-6-6]-tetracyclic system present in
a novel spirobionaphthalene natural product spiropreussione B has
been achieved. An intramolecular, thermal dehydrogenative Diels-
Alder reaction has been employed as the key step. Furthermore, this
approach was extended for the generation of library of structurally
novel linear tetracyclic systems of spiropreussione B in a highly
efficient manner. This report constitutes the first synthetic approach
to the spiropreussione B natural product.
[5-5-6-6] tetracyclic system 5 employing an intramolecular
aromatic electrophilic substitution reaction. This 5 can be
obtained via an intramolecular [4+2] cycloaddition reaction of the
enyne-alkyne 6. Synthesis of 6 can be possible from bromo-
aldehyde 7, employing few simple synthetic transformations
including Sonogashira cross coupling.
Introduction
The endophytic fungus Preussia sp. was isolated from a stem of
Aquilaria sinensis (Lour.) Gilg (Thymelaeaceae), collected from
Guangxi Medicinal Arboretum. The ethyl acetate and petroleum
extracts of the ethanol extracts of dry mycelium showed
inhibitory
activities
against
Candida
albicans
and
Staphylococcus aureus. A series of column chromatographic
purifications of the EtOAc extract resulted in the isolation of
three new spirobionaphthalene analogues, spiropreussione B 1,
spiropreussione A 2, and spiropreussomerin A 3.1 Among these
three natural products, spiropreussione B 1 possesses novel
and unique structural features, with a pentacyclic system 4, spiro
fused to 1,8-dihydroxynaphthalene (Figure 1).
To the best of our knowledge so far, there are no reports
appeared in the literature either on the synthesis of partial
frameworks or on the total synthesis of the natural product
spiropreussione B 1. Inspired by the presence of novel and
complex structural unit coupled with the bioactivities of the
spirobionaphthalene derivatives,2 we aimed at the development
of a rapid synthetic strategy for the pentacyclic framework
Scheme 1. Our designed retrosynthetic plan for functionalized pentacyclic
framework of spiropreussione B
Results and Discussion
To begin with, we focused to understand the feasibility of the
proposed dehydrogenative Diels-Alder cyclization for the
generation of [5-5-6-6]tetracyclic systems. Accordingly, we
chose an enyne-alkyne 8 as a model substrate. The synthesis of
enyne-alkyne 8 from commercially available cyclopentanone is
depicted in scheme 2. Treatment of the cyclopentanone with
PBr3 and N,N-dimethylformamide (DMF) in CH2Cl2 at 0 °C gave
the 2-bromo-enal 9 in 87% yield.4 Sonogashira cross coupling5
of 9 with propargylic alcohol 10 in presence of PdCl2(PPh3)2 and
CuI gave the coupled product 11 in good yield.
present in spiropreussione
B
1. We chose a thermal
intramolecular dehydrogenative Diels-Alder cyclization3 reaction
as the key step for the construction of the tetracyclic system.
Figure 1. Spiropreussione B and other spirobionaphthalene natural products
According to our retrosynthetic plan (Scheme 1), the pentacyclic
system 4 of spiropreussione B 1, can be generated from a linear
Scheme 2. Synthesis of enyne-alkyne precursor for TDDA reaction
[a]
Department of Chemistry, Indian Institute of Technology Madras,
Chennai-600036, INDIA
*Email: beeru@iitm.ac.in
Next, dehydration of tert-alcohol present in 11, with POCl3 and
triethylamine in CH2Cl2 at 0 °C afforded the enyne-aldehyde 12.
Treatment of the aldehyde 12 with ethynylmagnesium bromide
(0.5 M in THF) in THF resulted in the formation of the sec-
propargylic alcohol 13 in 77% yield. Further oxidation of the
http://chem.iitm.ac.in/faculty/beeraiahbaire/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.xxxx/ejoc.2017xxxxx.
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10.1002/ejoc.201700464
European Journal of Organic Chemistry
Communication
secondary alcohol of 13 with IBX6 at 80 °C in EtOAc gave the
required enyne-alkyne 8. With the key precursor 8 in hand, we
next planned for the intramolecular Diels-Alder cyclization to
generate the tetracyclic system 14.
The [4+2] cycloaddition7 reaction between an enyne (4π) and
alkyne (2π) 15 would result in an arene derivative 16 via a [1,5]H
shift of the initially formed cyclic allene intermediate 17 (Scheme
3). Based on the unsaturation present in the 4π and 2π
components as well as in the product arene 16, the above
reaction is a tetra-dehydrogenative version of the classical Diels-
Alder reaction and termed as the tetradehydro Diels-Alder
reaction (TDDA).3 Accordingly, the enyne-alkyne 8 upon heating
in 1,2-dichlorobenzene (1,2-DCB) at 110 °C for 7 h, to our
delight resulted in the formation of the expected cyclised product
14 in 65% yield (Scheme 3).8
Scheme 4. Synthesis of structurally divergent enyne-alkyne precursors
Alkynyl bromides consisting of aryl acetylenes, propargylic
alcohols, homo-propargylic alcohols, and -OTBS ethers were
utilized in the cross coupling reaction to generate the diynols
20b-h. All these substrates 20b-h, when subjected to IBX
oxidation conditions at 80 °C, cleanly and smoothly underwent
the oxidation-cycloaddition cascade to afford the corresponding
cyclised products 21b-h in moderate to good yields (Scheme 5).
Scheme 3. The tetradehydro Diels-Alder reaction and generation of [5-5-6-6]
tetracyclic system of spiropreussione B
Encouraged by this result, we next planned to generate a library
of diversely functionalized [5-5-6-6]-tetracyclic systems of
spiropreussione
B
1. Accordingly,
a
three-step Cadiot-
Chodkiewicz coupling–oxidation–TDDA cyclization strategy was
developed, starting from the propargylic alcohol 13 (Scheme 4).
In view of this, the alkyne 13 upon subjection to Cadiot–
Chodkiewicz coupling reaction9 with bromoalkyne10 18 in
presence of CuCl (10 mol%) and piperidine (solvent as well as
base) at 0 °C gave after 30 min., a mixture of two compounds,
the unexpected enynone 19 in 27% yield along with the
expected diynol 20a in 16% yield. The formation of 19 can be
possible via an initial formation of the diynol 20a followed by the
base (piperidine) promoted isomerisation of the propargylic
alcohol to enone.11 Since the standard conditions for the
formation of diyne 20a failed, subsequently, we employed a
modified procedure for the same transformation.12 Therefore,
treatment of the alkyne 13 and alkynyl bromide 18 with 5 equiv.
of piperidine (base) and 10 mol% of CuCl at 0 °C in 1,2-
dichloroethane resulted in clean formation of the expected diynol
20a in 79% yield after 30 min. (Scheme 4). Next oxidation of the
secondary alcohol 20a with IBX in EtOAc at 80 °C for 2 h, gave
directly the tetracyclic product 21a in 67% yield (for two steps),
via the TDDA cyclization reaction of the initially formed ketone
22a.
Scheme 5. Generation of library of functionalized [5-5-6-6]tetracyclic systems
Having developed a three step strategy for the functionalized [5-
5-6-6] tetracyclic system 21a from 13, we further extended this
strategy for the synthesis of divergent tetracyclic systems 21b-h
(Scheme 5) via corresponding diynols 20b-h.
of spiropreussione B 1, and ORTEP diagram for compound 21b
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10.1002/ejoc.201700464
European Journal of Organic Chemistry
Communication
In order to confirm the presence of the tetracyclic framework, X-
ray diffraction analysis was performed for the compound 21b
and its ORTEP diagram13 is presented in Scheme 5.
attempted for the intramolecular ring closure reaction to create
the pentacyclic system 32 (Scheme 7). But to our
disappointment, none of the employed conditions gave the
expected product 32. In some cases the starting material 31 was
recovered and few cases there was a decomposition of 31
observed.
Subsequently, after successful generation of the library of novel
tetracyclic systems we turned our attention to construct the
pentacyclic framework, having appropriate functional groups
(Schemes 6 & 7). Accordingly, p-benzyloxyphenylacetylene 23
was prepared from the commercially available p-iodophenol in
three steps. Initial protection of the hydroxy group with K2CO3
and BnBr in acetone at 65 °C, gave the benzylether 24 in 85%
yield. Sonogashira coupling of 24 with trimethylsilylacetylene
followed by the deprotection of trimethylsilyl- group with K2CO3,
MeOH gave the phenylacetylene derivative 23.
Scheme 7. Attempts for the pentacyclic system of spiropreussione B
Conclusions
In summary, we have developed a linear synthetic strategy for
the first synthesis of functionalized [5-5-6-6] tetracyclic
framework of the natural product spiropreussione B. The
tetradehydro Diels-Alder reaction between an enyne and alkyne
was employed as the key step. Further this strategy was
extended for the generation of library of structurally novel, highly
functionalized [5-5-6-6] tetracyclic systems. Various attempts for
the generation of pentacyclic system have failed.
Acknowledgements
We thank IIT Madras, Chennai for the infrastructure facility. We
thank CSIR-INDIA for the financial support through
No.02(0209)/14/EMR-II grant. BSC thanks IIT Madras for HTRA
fellowship. We thank, Mr. Ramakumar for X-ray diffraction
analysis.
Keywords: Alkynes • Dehydrogenative Diels-Alder reactions •
Enynes • Natural products • Polycyclic compounds.
Scheme 6. Synthesis of advanced [5-5-6-6]tetracyclic system
Next, the Sonogashira coupling of the bromo-enal 9 with the
arylalkyne 23 gave the arenyne-aldehyde 25. Addition of an
ethynylmagnesium bromide to the aldehyde 25 at 0 °C in THF
followed by oxidation of the resultant propargylic alcohol 26 with
IBX in EtOAc, gave the enynone 27 in 50% yield (for two steps).
At this stage, we envisioned an acrylate as the three carbon unit,
for the creation of the fifth ring, after the TDDA cyclization.
Hence, a Sonogashira coupling reaction of the ynone 27 with
(Z)-2-iodoacrylate14 28 gave the enynonate 29. Further heating
the 29 in 1,2-DCB and phenol (10 equiv.) at 150 °C for 3 h,
resulted in the exclusive formation of the linear tetracyclic
product 30 in 59% yield. Upon subjection to hydrogenolysis
conditions with 10% Pd/C in EtOAc at RT, the cyclic compound
30 underwent the reduction of enone and ynoate double bonds
as well the deprotection of benzyl group to give the saturated
phenol derivative 31. Having the required 3-carbon ester and
phenol functional groups at the appropriate positions in 31, we
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European Journal of Organic Chemistry
Communication
Entry for the Table of Contents (Please choose one layout)
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FULL PAPER
Natural Product
Synthesis*
Bhavani Shankar Chinta
and Beeraiah Baire*
Page No. – Page No.
First Synthesis of
Functionalized [5-5-6-6]
Tetracyclic Framework of
Spiropreussione B
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