Formal total synthesis of selaginpulvilin D

Article abstract of DOI:10.1039/c7ob00950j

An efficient and mild synthetic strategy for the total synthesis of selaginpulvilin D has been reported. A highly chemoselective enyne-alkyne dehydro Diels-Alder reaction has been employed for the construction of the tricyclic fluorene framework present i

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DOI: 10.1039/C7OB00950J
ARTICLE
Formal Total Synthesis of Selaginpulvilin D
Bhavani Shankar Chinta and Beeraiah Baire
Received 00th January 20xx,
Accepted 00th January 20xx
An efficient and mild synthetic strategy for the total synthesis of selaginpulvilins D has been reported. A highly
chemoselective enyne-alkyne dehydro Diels-Alder reaction has been employed for the construction of the tricyclic
fluorene framework present in the natural product selaginpulvilin D. Improved overall yield (10.5%) has been achieved for
selaginpulvilin D, starting from commercially available m-anisaldehyde in 9 linear, operationally simple synthetic
transformations.
DOI: 10.1039/x0xx00000x
www.rsc.org/
It is the unique skeleton of selaginpulvilins A−L, which may
renders potent activity and makes them rare and promising
lead structures for the development of natural PDE4 inhibitors.
Introduction
Fluorene derivatives are a group of structurally rigid
compounds featuring a 6-5-6 carbocyclic system. They are
considered as privileged structures in pharmaceutical industry
also used in optical and electronic materials.1 Though
numerous synthetic fluorene derivatives were reported in the
literature, the natural fluorenes are very rare. So far, only
about twelve natural fluorene derivatives (includes nine simple
fluorenones, one dihydroazafluoranthene alkaloid, and two
benzofluorenones) have been reported from plant resources.2
Selaginella pulvinata (Selaginellaceae), a species in the Chinese
Pharmacopoeia, has been well used in traditional Chinese
medicines for the treatment of dysmenorrhea, asthma, and
traumatic injury. During the phytochemical investigation on S.
pulvinata by the research group of Yin and co-workers, they
observed that a fraction of the ethanol extract showed
significant phosphodiesterase-4 (PDE4) inhibitory activity.
Subsequent chemical investigation led to the isolation of four
new phenolic natural products selaginpulvilins A−D 1-4 with an
The interesting bioactivities associated with their novel and
unique structures made these natural products attractive
synthetic targets for the total synthesis. Developing short,
efficient and practical synthetic approaches for these
molecules will provide an opportunity to study and explore
their new biological properties. Recently there are three
reports appeared on the total synthesis of this family of
natural products.4 Herein we report an efficient approach for
the formal total synthesis of selaginpulvilin D
4 employing the
enyne-alkyne dehydro Diels-Alder cyclization as the key step.
unprecedented
skeleton
9,9-diphenyl-1-(phenylethynyl)-9H-fluorene
5
, together with four known selaginellin natural
products (Figure 1).3a Compounds 1-4 found to be the most
potent natural PDE4 inhibitors discovered to date, by showing
remarkable inhibitory activities against PDE4 with IC50 values in
the range of 0.11−5.13 μM. In particular selaginpulvilin B 2, the
most active compound showed an IC50 of 0.11 μM, being 5-fold
stronger than the b-positive control. Further, phytochemical
studies on EtOAc extract of S. pulvinata lead to the isolation of
Figure 1 Structures of selaginpulvilins A-L
six new analogues selaginpulvilins E-J 6-11 3b
Recently, two
.
According to our retrosynthetic analysis (Scheme 1), the
selaginpulvilin D 4 can be generated from the corresponding
fluorenone 14 via the creation of tetraarylmethane system from the
diarylcarbonyl system. The fluorenone 14 can easily be obtained
from the enyne-alkyne 15 via a chemoselective dehydro Diels-Alder
reaction.5 The synthesis of 15 was envisioned from commercially
available 3-methoxybenzaldehyde 16 employing simple synthetic
transformations.
more members of this family of natural products,
selaginpulvilin K and L 12 and 13 have also been isolated.3c
a.Department of Chemistry, Institute of Technology Madras, Chennai-600036
b.Email: beeru@iitm.ac.in
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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To create the required diyne moiety on the aldehyde part
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DOI: 10.1039/C7OB00950J
of the 19, we employed a two step strategy. Addition of
ethynylmagnesium bromide to the aldehyde 19 at 0 °C in THF
resulted in the formation of a secondary propargylic alcohol 21
in 88% yield. The cross coupling of the terminal alkyne in the
propargylic alcohol 21 with the alkynylbromide 22 under the
modified Cadiot-Chakowidcz coupling conditions8 i.e., in
presence of CuCl and piperidine (5 equiv.), in 1,2-
dichloroethane (1,2-DCE) gave the enyne-diynol 23 in 63%
yield. The alkynylbromide 22 was efficiently prepared from
commercially
available
4-methoxyphenylacetylene
24
following a known procedure.9
Keeping the required enyne-diyne 23 in hand, next, in
order to test the feasibility of the designed DDA reaction, we
subjected 23 to thermal heating conditions. Heating a solution
of 23 in 1,2-DCB at 150 °C for 28 h, smoothly underwent the
expected cyclisation and provided to our delight directly the
fluorenone derivative 14 in 63% yield. Formation of 14 can be
explained via the highly chemoselective dehydro Diels-Alder
reaction, followed by the air oxidation of the bis-benzylic
alcohol 25 under reaction conditions. Alternatively, we also
thought that converting the alcohol 23 to the corresponding
ketone 15 might activate the substrate towards the DDA
reaction and may lead to the efficient synthesis of fluorene
derivative 14. Accordingly, when the diynol 23 was treated
with IBX10 in EtOAc at 80 °C directly resulted in the formation
Scheme 1 Designed retrosynthetic plan for selaginpulvilin D
Results and Discussion
To begin with, we aimed to synthesize the key precursor
for the Diels-Alder reaction (Scheme 2). Accordingly, treatment
of m-anisaldehyde 16 with AgNO3 and I2 in methanol at RT,
gave the 2-iodo-5-methoxybenzaldehyde 17 in 71% yield.6 The
Sonogashira cross coupling7 of 17 with 1-butynol in presence
of PdCl2(PPh3)2 and CuI in THF and diisopropylamine (DIPA)
generated the coupled product 18 in excellent yield (81%)
after 14 h at RT. Reaction of hydroxy-aldehyde 18 with p-TsCl
and triethylamine (TEA) in presence of catalytic amount of
DMAP at RT for 36 h, directly provided the enyne moiety 19 via
the corresponding tosylate 20 intermediate.
of the cyclised fluorenone derivative 14 via
a highly
chemoselective DDA reaction between an enyne and alkynone
of the in situ generated ketone 15 (Scheme 3).
Scheme 3 Efficient generation of fluorene framework of selaginpulvilin D via a
highly chemoselective enyne-alkyne dehydro Diels-Alder reaction. 1,2-DCB: 1,2-
dichlorobenzene
It is noteworthy to mention here that, both the alcohol 23
and ketone 15 can in principle undergo two different modes of
Diels-Alder reactions, namely, either between an enyne and
alkyne (tetradehydro Diels-Alder (TDDA) reaction) or between
diyne and alkyne i.e., hexdehydro Diels-Alder (HDDA)
Scheme
2 Preparation of the enyne-alkyne precursor for DDA reaction. THF:
tetrahydrofuran; DIPA: diisopropylamine; DMAP: 4-(dimethylamino)pyridine; 1,2-DCE:
1,2-dichloroethane; NBS: N-bromosuccinimide
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reaction.11 Surprisingly, we could not detect any traces of the We thank Indian Institute of Technology Madras, Chennai for
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DOI: 10.1039/C7OB00950J
products 26 and 27, which can be obtained from the 23 and 15 the infrastructure facility, CSIR-INDIA for the financial support
respectively, via the HDDA reaction. This clearly supports the through No.02(0209)/14/EMR-II grant. BSC thanks IIT Madras,
fact that, activation energy12 for the TDDA reaction is much Chennai for HTRA fellowship.
lower than that required for the HDDA reaction and hence
possibility for the chemoselective dehydro Diels-Alder
reaction.
Experimental Section
Reactions were monitored by thin-layer chromatography (TLC)
carried out on Merck silica plates using UV light and
anisaldehyde or potassium permanganate stains for
visualization. Column chromatography was performed on silica
gel (60−120 mesh) using hexanes and ethyl acetate as eluents.
NMR data were recorded on 400 and 500 MHz spectrometers.
1
13C and H chemical shifts in NMR spectra were referenced
1
relative to signals of CDCl3 (δ 7.263 ppm for H and 77.16 ppm
for 13C). Chemical shifts δ and coupling constants J are given in
ppm (parts per million) and Hz (hertz), respectively.
Multiplicities were given as: s (singlet); d (doublet); t (triplet); q
(quartet); dd (doublets of doublet) or m (multiplets). HRMS
were recorded by electron spray ionization (ESI) method on a
Q-TOF Micro with lock spray source. Known compounds data
have been compared with the reported data, and references
were given appropriately. Characterization data for new
compounds are given below. 1H and 13C (proton decoupled)
Scheme 4 Formal total synthesis of selaginpulvilin D
NMR spectra for all new compounds are given in the ESI
Reagents were purchased from chemical companies.
After synthesizing the tricyclic system 14 of the
selaginpulvilin D , next we focused to generate the required
4
tetra-arylmethane present in the natural product. Accordingly
addition of p-anisylmagnesium bromide to the tricyclic ketone
14 in THF at 0 °C generated the triarylmethanol 28 in excellent
yield (84%). In continuation, treatment of the tertiary alcohol
28 with phenol in presence of TfOH (20 mol%) afforded the
1
For full details of all experiments, spectroscopic data and H
&
Information
13C-NMR data for all new compounds see the Supporting
biarylated fluorene derivative 29
,
i.e., trimethylated
selaginpulvilin D, in good yield (73%) after 1 h via the aromatic
electrophilic substitution reaction. Conversion of 29 to the
Notes and references
natural product selaginpulvilin D
4 via demethylation reaction
1
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D 4
. In the literature, both the reported total syntheses4a,b for
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Our strategy involves nine mild, linear steps and provides the
access to the selaginpulvilin D with an overall yield of 7.5%
4 have the overall yields of 4.4% and 17%.
4
(or 10.5% from iodo-anisaldehyde 17).
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Conclusions
In conclusion we have developed a linear, mild and
efficient synthetic scheme for the formal total synthesis of
selaginpulvilin D, with an overall yield of 10.5%. We employed
the dehydro Diels-Alder reaction of an enyne-alkyne unit for
the generation of the tricyclic fluorene derivative in a highly
chemoselective manner. Further extension of this strategy for
other members of this selaginpulvilin family of natural
products is in progress in our laboratory.
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Formal Total Synthesis of Selaginpulvilin D
Bhavani Shankar Chinta and Beeraiah Baire
Table of contents entry:
TOC text:
An efficient formal total synthesis of selaginpulvilin D has been achieved, employing a chemoselective
dehydro Diels-Alder reaction as the key step.