Total synthesis of selaginpulvilins A and C

Article abstract of DOI:10.1039/c7ob02609a

An efficient formal total synthesis of two compounds from the selaginpulvilin family of natural products, selaginpulvilin A and C, has been successfully achieved. The tetradehydro Diels-Alder (TDDA) reaction between an enyne and alkyne has been utilized for the creation of the necessary fluorene skeleton. Attempts at the conversion of selaginpulvilin A to selaginpulvilin B, F and H were unsuccessful.

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DOI: 10.1039/C7OB02609A
ARTICLE
Total Synthesis of Selaginpulvilins A and C
Bhavani Shankar Chinta,a and Beeraiah Bairea*
Received 00th January 20xx,
Accepted 00th January 20xx
An efficient formal total synthesis of selaginpulvilin family of natural products selaginpulvilin A and C has been successfully
achieved. The tetradehydro Diels-Alder (TDDA) reaction between an enyne and alkyne has been utilized for the creation of
necessary fluorene skeleton. Attempts for the conversion of selaginpulvilin A to selaginpulvilin B, F and H were
unsuccessful.
DOI: 10.1039/x0xx00000x
www.rsc.org/
approach for the formal total synthesis of selaginpulvilin D
4
Introduction
employing the enyne-alkyne dehydro Diels-Alder cyclization as
the key step.4d In continuation, we aimed to extend this
strategy for the total synthesis of other members of
selaginpulvilin family of natural products. In this context, we
Selaginella pulvinata (Selaginellaceae) is a species in the
Chinese Pharmacopeia, which has been well utilized in
traditional Chinese medicines for the treatment of
dysmenorrhea, asthma, and traumatic injury. The
phytochemical investigation on S. pulvinata by the research
group of Yin and co-workers, led to the isolation of four new
natural products selaginpulvilins A−D 1-4 with an
envisioned that, the selaginpulvilin A
1 can be served as a
suitable intermediate for the total synthesis of the natural
products selaginpulvilins B, C, F and H.
unprecedented
9,9-diphenyl-1-(phenylethynyl)-9H-fluorene
skeleton along with several known natural products (Figure
1).1a These compounds 1-4 exhibit the remarkable
phosphodiesterase-4 (PDE4) inhibitory activity with IC50 values
in the range of 0.11−5.13 μM. They found to be the most
potent natural PDE4 inhibitors discovered to date. Further,
phytochemical studies on EtOAc extract of S. pulvinata
resulted in the isolation of eight new analogous
selaginpulvilins E-L 5-12 1b-c
.
Scheme 1 Retrosynthetic plan for selaginpulvilins A-C, F and H
According to our retrosynthetic analysis (scheme 1),
selaginpulvilins B (CHO)
2
, F (CO2H)
6
, H (CH(OMe)2
8
, and C
via
(CH3) could be synthesized from the selaginpulvilin A
3
1
various functional group interconversions (FGI) of
hydroxymethyl group present in it, such as oxidation to
aldehyde and acid, dimethylacetal formation from aldehyde
and deoxygenation to methyl group respectively. The
selaginpulvilin A
1 can be achieved from the fluorenone
derivative 13 via diarylation protocol. This 13 can be generated
from enyne-alkyne 14 via the tetradehydro Diels-Alder (TDDA)
reaction.5 The enyne-alkyne 14 can be synthesized from 2-
Figure 1 Selaginpulvilin natural products
iodo-5-methoxybenzaldehyde 15
.
The unique fluorene2,3 skeleton associated with important
bioactivities, makes selaginpulvilins interesting target
molecules for the synthetic organic chemists. So far there are
four reports appeared on the total synthesis of this family of
natural products.4 Recently we also developed an efficient
Results and Discussion
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To begin with, we synthesized several key building blocks
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DOI: 10.1039/C7OB02609A
15-19, which will be utilized during the designed total
synthesis (scheme 2) employing the literature procedures.
Accordingly, reaction of the m-anisaldehyde with AgNO3 and I2
in methanol at RT, gave the 2-iodo-5-methoxybenzaldehyde 15
in 70% yield.6 Next, the Sonogashira cross coupling7 of TMS-
acetylene with ethyl Z-2-iodoacrylate 16 in presence of
PdCl2(PPh3)2 and CuI in THF and diisopropylamine (DIPA)
generated the coupled product 20.8 Further reduction of the
ester with DiBAL-H gave the primary alcohol 21.8 Protection of
this primary alcohol employing TBS-Cl and imidazole followed
by the deprotection of trimethylsilyl (TMS) group present in 22
with K2CO3-MeOH at RT afforded the corresponding ynenol-
TBS-ether 17. The Z-2-iodoacrylate 16 was synthesized from
the reaction of methyl propiolate with NaI in AcOH under
refluxing conditions.9 The pentyn-3-ol 18 was prepared from
the reaction between ethynyl Grignard and propanaldehyde at
0 °C in THF.10 Another building block, the alkynylbromide 19
was efficiently prepared from commercially available 4-
methoxyphenylacetylene following a known procedure.11
Scheme 3 Synthesis of the enyne-alkyne precursor for TDDA. DIPA: diisopropylamine;
1,2-DCE: 1,2-dichloroethane.
Subsequently, the enyne-diynol 25 was treated with IBX13
in EtOAc at 80 °C. After 3 h, the reaction gave directly the
fluorene derivative 26 via the oxidation followed by the TDDA
cyclization reaction of the resultant ketone 27 (scheme 4).
Next the tetra aryl chiral carbon was generated employing a
two step protocol. The p-anisylmagnesium bromide addition to
26 gave the tert-alcohol 28. A Friedel-Crafts alkylation with the
alcohol 28 and phenol in presence of BF3.Et2O resulted directly
the formation of the trimethoxy-selaginpulvilin A 29 through
the TBS-deprotection. This synthetic scheme constitutes the
formal total synthesis of selaginpulvilin A
1 as the conversion
of 29 to
1
is already known in the literature.4b
Scheme 2 Preparation of the key building blocks. THF: tetrahydrofuran; NBS: N-
bromosuccinimide.
After synthesizing the required building blocks, we next began
our synthesis of selaginpulvilin
Sonogashira cross coupling of 15 with alkynyl-TBS-ether 17
generated the coupled aldehyde 23 in 67% yield.
A 1 (scheme 3). The
Scheme 4 Formal total synthesis of selaginpulvilin A 1
In continuation, we envisioned an opportunity for the total
synthesis of other members of this family of natural products
from the trimethoxy-selaginpulvilin A 29 (scheme 5). A
controlled oxidation of the benzylic alcohol present in 29 can
Ethynylmagnesium bromide addition to the aldehyde 23
,
followed by the coupling of the resultant secondary
propargylic alcohol 24 with the alkynylbromide 19 in presence
of CuCl (10 mol%) and piperidine (5 equiv.), in 1,2-
dichloroethane (1,2-DCE) gave the enyne-diynol 25 in 65%
yield (for two steps).12
provide the aldehyde 30
,
which is the trimethoxy-
selaginpulvilin B. Further oxidation of this aldehyde 30 affords
the acid i.e., trimethoxy-selaginpulvilin F 31, whereas the
dimethylacetal formation gives the trimethoxy-selaginpulvilin
H
32. In another direction deoxygenation of the hydroxyl
group present in trimethoxy-selaginpulvilin A 29 should
generate the trimethoxy-selaginpulvilin C 33
.
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7OB02609A
Scheme 5 Design for the synthesis of selaginpulvilins B, C, F and H
But to our disappointment, there was no oxidation of hydroxyl
group present in 29 occurred (scheme 6). Various conditions
and reagents such as MnO2, IBX, PCC, oxone etc. failed to give
any traces of either the aldehyde or acid. In all cases a slow
decomposition of the starting alcohol 29 was observed.
Further we attempted for the selective mono-deoxygenation
of 29, via a xanthate formation. But there was no clean
reaction under standard xanthate formation conditions.
Scheme 7 Formal total synthesis of selaginpulvilin C 3
Conclusions
In conclusion, the formal total synthesis of two of the
selaginpulvilin family natural products sealiginpulvilin A and C
has been achieved by employing an efficient strategy. The
chemo selective tetradehydro Diels-Alder reaction has been
employed as the key transformation to build the fluorenone
framework. Attempts for the conversion of selaginpulvilin A to
selaginpulvilin B, F and H were unsuccessful.
Scheme 6 Attempts for the oxidation and deoxygenation of trimethoxy-selaginpulvilin
A 29
As the oxidation and deoxygenation reactions on trimethoxy-
selaginpulvilin A 29 found to be not feasible, subsequently, we
envisioned and developed the TDDA based approach for the
Acknowledgements
total synthesis of selaginpulvilin C
3 starting from the iodo-
We thank Indian Institute of Technology Madras, Chennai for
the infrastructure facility and CSIR-INDIA for the financial
support through No. 02 (0209)/14/EMR-II grant. BSC thanks IIT
Madras, Chennai for HTRA fellowship.
aldehyde 15 (scheme 8). Accordingly, the Sonogashira coupling
with the pentyn-3-ol 18 followed by dehydration of the
resultant coupled alcohol using Tf2O and triethylamine gave
the enyne-aldehyde 34 as a ~(1:0.3) mixture of E/Z isomers.
Addition of ethynylmagnesium bromide to the aldehyde 34
and CuCl catalyzed Cadiot-Chodkiewicz coupling of the
resultant secondary propargylic alcohol 35 [a ~ (1:0.3) mixture
of E/Z isomers] with the alkynylbromide 19 gave the required
enyne-alkynol 36 [a ~ (1:0.3) mixture of E/Z isomers] in 50%
overall yield for two steps. Oxidation of the alcohol 36 with IBX
at 80 °C gave the fluorenone derivative 37 (57% yield), after 3
h. Further, a two-step strategy involving p-anisylmagnesium
bromide addition to the fluorenone 37 followed by the Friedel-
Crafts alkylation of phenol with the resultant tert-alcohol in
presence of TfOH gave the target molecule trimethoxy-
selaginpulvilin C 33 in 60% yield (two steps). Conversion of 33
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.
13C and 1H 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
to selaginpulvilin C
3 has already been reported in the
literature;4a hence this synthetic scheme represents the formal
total synthesis of this natural product.
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1
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For full details of all experiments, spectroscopic data and H
&
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Information
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB02609A
Total Synthesis of Selaginpulvilins A and C
Bhavani Shankar Chinta and Beeraiah Baire
Table of contents entry:
TOC text:
An efficient strategy for the formal total synthesis of selaginpulvilins A and C has been reported. This
approach involves 6 and 7 linear synthetic operations associated with 10% and 7% overall yield
respectively for selaginpulvilins A and C.