Total synthesis of an anticancer norsesquiterpene alkaloid isolated from the fungus Flammulina velutipes

Article abstract of DOI:10.1039/c4ob00300d

The first total synthesis of a norsesquiterpene alkaloid (R)-8-hydroxy-4,7,7-trimethyl-7,8-dihydrocyclopenta[e]isoindole-1,3(2H,6H) -dione, isolated from the mushroom-forming fungus Flammulina velutipes, in both racemic and enantiomeric pure forms, is reported. The (-)-enantiomer of the natural product has been synthesized from the d-(-)-pantolactone chiral pool. The synthesis features a one-pot, three-step reaction sequence comprising an enyne RCM/Diels-Alder/aromatization to construct the desired indane skeleton present in the natural product. Our synthesis further confirms the assigned structure and absolute configuration of the natural product. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00300d

Organic &
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Total synthesis of an anticancer norsesquiterpene
alkaloid isolated from the fungus
Flammulina velutipes†
Cite this: Org. Biomol. Chem., 2014,
12, 4098
K. Kashinath, Prakash D. Jadhav and D. Srinivasa Reddy*
The first total synthesis of a norsesquiterpene alkaloid (R)-8-hydroxy-4,7,7-trimethyl-7,8-dihydrocyclo-
penta[e]isoindole-1,3(2H,6H)-dione, isolated from the mushroom-forming fungus Flammulina velutipes,
in both racemic and enantiomeric pure forms, is reported. The (−)-enantiomer of the natural product has
been synthesized from the D-(−)-pantolactone chiral pool. The synthesis features a one-pot, three-step
reaction sequence comprising an enyne RCM/Diels–Alder/aromatization to construct the desired indane
skeleton present in the natural product. Our synthesis further confirms the assigned structure and absol-
ute configuration of the natural product.
Received 10th February 2014,
Accepted 2nd April 2014
DOI: 10.1039/c4ob00300d
www.rsc.org/obc
Introduction
The norsesquiterpene alkaloid (+)-1 was isolated from the
solid culture of the mushroom-forming fungus Flammulina
velutipes fermented on rice by Kai-Shun Bi’s group from
China.1 The structure of (+)-1 was elucidated by spectroscopic
methods and the absolute configuration was assigned using
the circular dichroism data of its [Rh2(OCOCF3)4] complex.
Compound (+)-1 showed cytotoxicity against KB cells in vitro,
with an IC50 value of 16.6 µM by the MTT method. Hence,
alkaloid (+)-1 can be a good starting point for developing
potential drugs for treating human oral cancers. Compound
(+)-1 has a substituted phthalimide unit, fused with a five-
membered ring, which is a privileged motif in medicinal chem-
istry with attractive biological activities. For example, M. Tao
et al. reported compound 2 as a poly(ADP-ribose) polymerase-1
(PARP-1) inhibitor2 with an IC50 value of 40 nM.2b PARP inhibi-
tors are very important compounds in drug discovery, as they
are useful in treating various diseases, cancers and neurological
disorders in particular. There are several candidates that target
PARP, which are currently being tested in human clinical
trials.2d Hence, we became interested in the synthesis of target
compound 1 and its analogues because of the interesting bio-
logical activity and to confirm the absolute stereochemistry of
the natural product. Herein, we report the first total synthesis of
racemate ( )-1 and enantiomer (−)-1 (Fig. 1).
Fig. 1 Structures of natural product (racemic & enantiomeric forms)
and a PARP-1 inhibitor.
Results and discussion
The retrosynthetic analysis of the target molecule is shown in
Scheme 1. The target molecule is visualized from diene and
maleimide via a Diels–Alder reaction followed by aromatiza-
tion. The diene could be prepared by ring-closing metathesis
(RCM) of an enyne, which in turn could be synthesized from
the known intermediate 3 (ref. 3) or pantolactone.
The synthesis of racemate ( )-1 commenced with
a
Grignard reaction of 1-propenyl magnesium bromide on a
known aldehyde 3,3 followed by benzyl protection/TBS protec-
tion of alcohol, which furnished the enyne intermediate 4a/4b.
The enyne 4a/4b, on ring-closing metathesis (RCM) with
Grubbs’ 1st generation catalyst followed by a Diels–Alder reac-
tion4,5 with maleimide, provided 6a/6b in good overall yields.
We have not put much effort into analyzing the stereochemical
CSIR-National Chemical Laboratory, Division of Organic Chemistry,
Dr. HomiBhabha Road, Pune, 411008, India. E-mail: ds.reddy@ncl.res.in;
Fax: +91 20 25902629; Tel: +91 20 25902445
†Electronic supplementary information (ESI) available: 1H &13C spectral data
comparison tables of synthetic vs. natural product. Copies of NMR spectra
(1H & 13C) of all new compounds. See DOI: 10.1039/c4ob00300d
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Scheme 3 Total synthesis of ( )-1.
KOH followed by heating with urea in ethylene glycol7 furn-
ished the desired compound 8. The final step, deprotection of
the benzyl group, was performed using 10% Pd/C under the
blanket of a hydrogen atmosphere, which furnished the
racemic norsesquiterpene alkaloid ( )-1 in 83% yield
(Scheme 3). The spectral data (1H NMR, 13C NMR and MS)
were compared with the isolated natural product and were
found to be identical.1
Scheme 1 Retrosynthetic analysis for the target molecule.
outcome of the Diels–Alder product, as the resulting stereocen-
ters will be destroyed in the next step (during aromatization).
Aromatization followed by deprotection of the benzyl/TBS
group in adduct 6a/6b should have provided the target mole-
cule. However, all the efforts to aromatize 6a/6b were unsuc-
cessful (Scheme 2).6
After the successful synthesis of racemate ( )-1, we turned
our attention to the synthesis of the natural product in an
enantiopure form. We have chosen pantolactone as the start-
ing material to access both the enantiomers of the
target alkaloid as both the antipodes are commercially avail-
able and it is also a favourite chiral pool from our group for
total syntheses.4,8 The known lactol 9,8c prepared from
D-(−)-pantolactone, on undergoing a Wittig reaction,9 resulted
in primary alcohol 10 in 92% yield. The alcohol 10 was sub-
jected to Swern oxidation to give an aldehyde, which on homo-
logation (methoxymethyl Wittig reaction followed by
hydrolysis),10 produced the desired aldehyde 11 in good overall
yield. The key enyne intermediate (+)-4 was prepared using the
Ohira–Bestmann reagent11 in which the aldehyde arm of 11
was transformed to the corresponding alkyne. The spectral
data (1H NMR & 13C NMR) and TLC analysis of compound
(+)-4 were compared to that of compound 4a and were found
to be identical. The compound (+)-4 was transformed to the
target compound (−)-1 by using the same protocol developed
for the synthesis of the racemate ( )-1 through the intermedi-
acy of (−)-7 and (+)-8 (Scheme 4). The optical rotation of the
synthesized (−)-1 was found to be comparable but with the
opposite sign. This exercise confirms the absolute configur-
ation of the secondary alcohol present in the natural product
as “S”. The natural isomer (+)-1 can be obtained starting from
L-(+)-pantolactone by following the same route.
At this stage, we changed the strategy to use one of our pre-
viously developed4 one-pot enyne RCM/Diels–Alder/aromatiza-
tion sequence to construct the indane skeleton. The revised
plan started from the previously synthesized intermediate 4a,
which upon RCM using Grubbs’ 1st generation catalyst fol-
lowed by the Diels–Alder reaction with dimethyl acetylene-
dicarboxylate (DMAD) and subsequent treatment with DDQ,
provided the aromatized compound 7 in a moderate yield
(∼40%). The indane derivative 7 on ester hydrolysis using aq.
Conclusion
In summary, we have achieved the first total synthesis of nor-
sesquiterpene alkaloid (1), an anticancer agent, isolated from
the fungus Flammulina velutipes. The enantiospecific synthesis
Scheme 2 Initial attempts towards the target molecule.
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light, iodine vapours, or by immersion in ethanolic solutions
of phosphomolybdic acid, para-anisaldehyde, or KMnO4 fol-
lowed by heating with a heat gun for ∼15 s. Column chromato-
graphy was performed on silica gel (100–200 or 230–400 mesh
size). High resolution mass spectra (HRMS, ESI) were recorded
with an ORBITRAP mass analyser (Q Exactive). Mass spectra
were measured by electrospray ionization with an MSQ LCMS
mass spectrometer. Infrared (IR) spectra were recorded on an
FT-IR spectrometer as thin films. Optical rotations were
recorded on a P-2000 polarimeter at 589 nm. Chemical nomen-
clature was generated using Chem Bio Draw Ultra 13.0.
Melting points of solids were measured in a melting point
apparatus.
(((5,5-Dimethyloct-2-en-7-yn-4-yl)oxy)methyl)benzene (4a)
To a solution of 2,2-dimethylpent-4-ynal 3 (ref. 3) (2.0 g,
18 mmol) in dry diethyl ether (50 mL) 1-propenyl magnesium
bromide (0.5 M in THF, 44 mL, 22 mmol) was added slowly at
0 °C and stirred for 1 h. The reaction mixture was quenched by
addition of saturated aqueous ammonium chloride (30 mL),
the organic layer was separated and the aqueous layer was
extracted with diethyl ether (50 mL × 2). Combined organic
layers were washed with a brine solution (30 mL), dried over
Na2SO4 and the solvent was evaporated under reduced
pressure to afford 2.2 g of crude 5,5-dimethyloct-2-en-7-yn-4-ol.
To a suspension of NaH (1.4 g, 36 mmol, 60% in mineral
oil) in dry DMF (50 mL) was added the above obtained alcohol
in DMF (10 mL) at 0 °C. After being stirred at 0 °C for 30 min,
BnBr (2.2 mL, 18 mmol) and TBAI (670 mg, 1.8 mmol) were
added at 0 °C and the mixture was stirred at rt for 2 h. Water
(30 mL) was added and extracted with diethyl ether (50 mL ×
3). The organic layer was washed with brine solution (20 mL),
dried over Na2SO4, and evaporated in vacuo. The residue was
purified by column chromatography (2% ethyl acetate in
hexanes) to afford 4a (3.5 g, 79%, pale yellow liquid) as a ∼3 : 2
Scheme 4 Enantiospecific total synthesis of (−)-1.
of unnatural enantiomer starting from D-(−)-pantolactone con-
firmed the previously assigned absolute configuration of the
natural product. Another highlight of the present work is the
use of the one-pot procedure by combining three reactions to
construct the appropriately substituted indane skeleton. As the
structure of the target alkaloid (1) is close to one of the known
potent PARP-1 inhibitors (2), the synthesized compounds and
the related ones are expected to show interesting biological
activities.
E, Z mixture. IR νmax (film): 3306, 2968, 2938, 2359, 1506 cm−1
;
1H NMR (400 MHz, CDCl3) (mixture of E, Z): δ 7.39–7.34 (m,
8H), 7.33–7.27 (m, 2H), 5.95–5.81 (m, 1H), 5.79–5.65 (m, 1H),
5.52–5.35 (m, 2H), 4.66–4.53 (m, 2H), 4.39–4.26 (m, 2H),
4.12–4.00 (m, 1H), 3.58 (d, J = 8.7 Hz, 1H), 2.43–2.30 (m, 2H),
2.26–2.17 (m, 2H), 2.05–1.91 (m, 2H), 1.81 (td, J = 6.8, 1.4 Hz,
3H), 1.71 (td, J = 7.1, 1.3 Hz, 3H), 1.08–1.03 (m, 6H), 1.03–0.97
(m, 6H); 13C NMR (100 MHz, CDCl3): δ 139.2, 139.1, 130.7,
129.6, 128.1, 128.0, 127.6, 127.5, 127.2, 127.1, 85.7, 82.6, 78.5,
70.1, 70.0, 69.8, 69.7, 38.2, 37.6, 29.0, 28.9, 23.5, 23.1, 22.4,
22.1, 17.9, 13.7; MS: 265 (M + Na)+; HRMS calculated for
C17H22ONa 265.1563, found 265.1561.
Experimental
General
All reactions were carried out in oven-dried glassware under
argon or nitrogen unless otherwise specified, with magnetic
stirring. Air sensitive reagents and solutions were transferred
tert-Butyl((5,5-dimethyloct-2-en-7-yn-4-yl)oxy)dimethylsilane
(4b)
via a syringe or a cannula and were introduced into the appar- To a solution of the above synthesized 5,5-dimethyloct-2-en-7-
atus via rubber septa. All reagents, starting materials, and sol- yn-4-ol (500 mg, 3.3 mmol) in dry DCM (20 mL) were added
vents were obtained from commercial suppliers and used imidazole (671 mg, 9.9 mmol) and TBSCl (1.5 g, 9.9 mmol) at
without further purification. Reactions were monitored by thin 0 °C. After being stirred at 0 °C for 1 h the reaction mixture
layer chromatography (TLC) with 0.25 mm precoated silica gel was allowed to warm to rt and stirred overnight. Water (20 mL)
plates (60 F254). Visualization was accomplished with either UV was added and extracted with diethyl ether (50 mL × 2). The
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organic layer was washed with brine solution (20 mL), dried mixture was cooled to room temperature, and freshly distilled
over Na2SO4, and evaporated in vacuo. The residue was purified dimethyl acetylenedicarboxylate (DMAD) (0.5 mL, 4.1 mmol)
by column chromatography (hexanes) to afford 4b (720 mg, was added and heated at 120 °C for 10 h. Cooled to room
83%, pale yellow liquid) as a ∼1 : 1 E, Z mixture. IR νmax (film): temperature, DDQ (562 mg, 2.5 mmol) was added and stirred
1
3310, 2957, 2886, 2117, 1719 cm−1; H NMR (200 MHz, CDCl3) for 8 h, the reaction mixture was filtered through a Celite pad
(mixture of E, Z): δ 5.68–5.25 (m, 4H), 4.29 (d, J = 9.3 Hz, 1H), and washed with dichloromethane, the filtrate was evaporated
3.83 (d, J = 7.7 Hz, 1 H), 2.33–2.00 (m, 4H), 1.96 (q, J = 2.8 Hz, to dryness and the crude product was purified by column
2 H), 1.71–1.62 (m, 6H), 0.95–0.86 (m, 30H), 0.04 (d, J = 3.0 Hz, chromatography (5% ethyl acetate in hexanes) to furnish 7
6H), 0.00–0.05 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 131.3, (0.32 g, 40% for three steps); IR νmax(film): cm−1 2925, 1732,
127.6, 125.5, 82.9, 79.5, 77.3, 77.0, 76.7, 72.8, 69.7, 39.1, 38.4, 1435, 1267; 1H NMR (500 MHz, CDCl3): δ 7.37–7.29 (m, 5H),
28.6, 28.5, 25.9, 25.8, 25.7, 23.1, 22.7, 22.2, 21.8, 18.1, 17.7, 7.19 (s, 1H), 4.86 (s, 1H), 4.70 (d, J = 11.3 Hz, 1H), 4.58 (d, J =
−3.8, −4.2, −5.0, −5.1; MS: 289 (M + Na)+.
11.3 Hz, 1H), 3.90 (s, 3H), 3.73 (s, 3H), 2.95 (d, J = 15.9 Hz,
1H), 2.60 (d, J = 15.9 Hz, 1H), 2.40 (s, 3H), 1.28 (s, 3H), 1.17 (s,
3H); 13C NMR (125 MHz, CDCl3): δ 169.2, 168.0, 146.4, 140.6,
138.8, 136.9, 131.0, 129.9, 129.1, 128.3, 128.2, 127.4, 127.3,
8-(Benzyloxy)-4,7,7-trimethyl-4,6,7,8,8a,8b-
hexahydrocyclopenta[e]isoindole-1,3 (2H,3aH)-dione (6a)
A solution of compound 4a (1.0 g, 4.1 mmol) in toluene (5 mL) 89.1, 73.0, 52.3, 52.2, 45.5, 44.5, 28.0, 22.7, 20.0; MS: 405
was degassed for 10 min in a stream of argon and then treated (M
Na)+; HRMS calculated for C23H26O5Na 405.1672,
+
with Grubbs’ 1st generation catalyst (170 mg, 5 mol%) in one found 405.1670.
portion. After being stirred at 50 °C for 12 h, the reaction
mixture was cooled to room temperature and maleimide
(481 mg, 4.9 mmol) was added and heated at 120 °C for 10 h.
8-(Benzyloxy)-4,7,7-trimethyl-7,8-dihydrocyclopenta[e]-
isoindole-1,3(2H,6H)-dione (8)
The reaction mixture was concentrated under reduced pressure To a solution of 7 (80 mg, 0.2 mmol) in EtOH (2 mL), KOH
and purified by column chromatography (20% ethyl acetate in (35 mg, 0.62 mmol, in 0.5 mL water) was added and stirred for
hexanes) to furnish 6a (0.770 g, 55% for two steps). mp 3 h at room temperature. Solvent was removed under reduced
132–134 °C; IR νmax (film): 3162, 3065, 2929, 1761, 1691, 1468, pressure and the residue was acidified with 1 N HCl (pH ∼3)
1454 cm−1 1H NMR (400 MHz, CDCl3): δ 8.07 (bs, 1H), and extracted with ethyl acetate (10 mL × 2). The combined
;
7.46–7.40 (m, 2H), 7.36 (t, J = 7.3 Hz, 2H), 7.30 (d, J = 7.1 Hz, organics were dried over anhydrous Na2SO4 and concentrated
1H), 5.41 (bs, 1H), 4.82 (q, J = 11.5 Hz, 2H), 4.45 (d, J = 8.8 Hz, under reduced pressure to afford crude acid.
1H), 3.24 (t, J = 7.9 Hz, 1H), 3.02 (t, J = 7.6 Hz, 1H), 2.53 (t, J =
The above acid was taken in ethylene glycol (0.5 mL), urea
6.6 Hz, 1H), 2.36 (bs, 1H), 2.10 (bs, 2H), 1.41 (d, J = 7.3 Hz, (12 mg, 0.2 mmol) was added and heated at 150 °C for 2 h.
3H), 1.16 (s, 3H), 0.95 (s, 3H); 13C NMR (100 MHz, CDCl3): The reaction mixture was cooled to rt, quenched with water
δ 178.0, 177.7, 142.2, 139.4, 128.3, 127.6, 127.5, 124.1, 86.4, (5 mL) and extracted with ethyl acetate (10 mL × 2). Combined
73.8, 47.7, 45.6, 43.3, 43.2, 42.3, 31.7, 27.1, 20.7, 16.9; MS: 338 organic layers were washed with brine solution (5 mL) and
(M − H); HRMS calculated for C21H25O3NNa 362.1727, found dried over Na2SO4. The crude material obtained after removal
362.1724.
of solvent was purified by column chromatography (10% ethyl
acetate in hexanes) to afford 8-(benzyloxy)-4,7,7-trimethyl-7,8-
8-((tert-Butyldimethylsilyl)oxy)-4,7,7-trimethyl-4,6,7,8,8a,8b-
hexahydrocyclopenta[e]isoindole-1,3(2H,3aH)-dione (6b)
dihydrocyclopenta[e]iso-indole-1,3(2H,6H)-dione
8 (51 mg,
73%) as a colorless sticky liquid. IR νmax(film): cm−1 3647,
The compound 6b was synthesized from 4b in 59% yield by 3445, 2923, 1635, 1731, 1457; 1H NMR (400 MHz, CDCl3):
following the procedure used for the synthesis of 6a. mp δ 8.01 (bs, 1H), 7.41–7.18 (m, 6H), 4.84–4.75 (m, 2H), 4.75–4.58
204–206 °C; IR νmax (film): 3244, 2953, 2891, 1772, 1710, (m, 1H), 3.08 (d, J = 16.3 Hz, 1H), 2.69 (s, 3H), 2.52 (d, J = 16.3
1464 cm−1 1H NMR (400 MHz, CDCl3) δ 7.97 (bs, 1H), 5.37 Hz, 1H), 1.40 (s, 3H), 0.99 (s, 3H); 13C NMR (100 MHz, CDCl3):
;
(bs, 1H), 4.55 (d, J = 8.6 Hz, 1H), 3.23 (t, J = 7.8 Hz, 1H), δ 169.1, 168.5, 153.2, 139.1, 138.9, 138.8, 133.2, 129.7, 128.1,
3.10–2.99 (m, 1H), 2.46–2.27 (m, 2H), 2.14–1.91 (m, 2H), 1.39 127.7, 127.5, 127.3, 86.0, 72.6, 44.9, 27.3, 22.4, 17.8; MS: 358
(d, J = 7.3 Hz, 3H), 1.03 (s, 3H), 0.92 (s, 9H), 0.83 (s, 3H), 0.17 (M + Na)+; HRMS calculated for C21H21O3NNa 358.1414, found
(s, 3H), 0.14 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 177.8, 358.1412.
177.7, 142.7, 123.7, 78.6, 47.7, 47.2, 42.8, 42.6, 42.3, 31.8, 26.4,
8-Hydroxy-4,7,7-trimethyl-7,8-dihydrocyclopenta[e]isoindole-
26.0, 20.1, 18.1, 16.9, −3.8, −4.8; MS: 362 (M − H); HRMS cal-
1,3(2H,6H)-dione ( )-1
culated for C20H33ONNaSi 386.2122, found 386.2119.
To a solution of 8 (40 mg, 0.1 mmol) in EtOH (2 mL), 10% Pd/
C (10 mg) was added and stirred for 10 h under a H2 atmos-
phere. The reaction mixture was filtered, concentrated under
Dimethyl 3-(benzyloxy)-2,2,6-trimethyl-2,3-dihydro-1H-indene-
4,5-dicarboxylate (7)
A solution of compound 4a (0.5 g, 2.0 mmol) in toluene (5 mL) reduced pressure and purified by column chromatography
was degassed for 10 min in a stream of argon and then treated (12% ethyl acetate in hexanes) to afford 8-hydroxy-4,7,7-tri-
with Grubbs’ 1st generation catalyst (85 mg, 5 mol%) in one methyl-7,8-dihydrocyclopenta[e]isoindole-1,3-(2H,
6H)-dione
portion. After being stirred at 50 °C for 12 h, the reaction ( )-1 (24 mg, 83%) as a white solid. mp 148–150 °C; IR
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νmax(film): cm−1 3733, 1716, 1738, 1652, 1456; 1H NMR added n-BuLi (1.6 M in hexanes, 14.5 mL, 23.2 mmol) at 0 °C.
(400 MHz, CDCl3): δ 7.86 (bs, 1H, NH proton), 7.25 (s, 1H), After stirring for 30 min, a solution of (S)-3-(benzyloxy)-2,2-
5.08 (s, 1H), 4.52 (s, 1H, OH proton), 2.81–2.73 (m, 2H), 2.63 dimethylhex-4-enal (1.8 g, 7.7 mmol) in dry THF (30 mL) was
(s, 3H), 1.33 (s, 3H), 0.98 (s, 3H); 13C NMR (100 MHz, CDCl3): δ added. After completion of addition, the reaction mixture was
170.1, 169.1, 149.4, 143.0, 138.3, 133.1, 128.8, 127.6, 81.0, 46.0, warmed to room temperature and stirred overnight. The reac-
45.8, 26.4, 21.4, 17.8. MS: 268 (M + Na)+; HRMS calculated for tion mixture was cooled to 0 °C, quenched by the addition of
C14H15O3NNa 268.0944, found 268.0944.
saturated ammonium chloride solution (25 mL) and extracted
with ethyl acetate (50 mL × 3). Combined organic layers were
washed with water (20 mL), brine (20 mL), dried over Na2SO4,
(S)-3-(Benzyloxy)-2,2-dimethylhex-4-en-1-ol (10)
To a stirred solution of ethyl triphenylphosphonium iodide concentrated under reduced pressure and purified by column
(31.0 g, 74.3 mmol) in dry THF (150 mL) was added n-BuLi chromatography (5% ethyl acetate in hexanes) to give 1.3 g
(1.6 M in hexanes, 46.4 mL, 74.3 mmol) at 0 °C. After stirring (65%) of ((((S)-1-methoxy-3,3-dimethylhepta-1,5-dien-4-yl)oxy)-
for 30 min, a solution of (3R)-3-(benzyloxy)-4,4-dimethyltetra- methyl)benzene as a colorless oil.
hydrofuran-2-ol 9 (ref. 8c) (3.3 g, 14.8 mmol) in dry THF
To a solution of ((((S)-1-methoxy-3,3-dimethylhepta-1,5-
(30 mL) was added. After completion of addition, the reaction dien-4-yl)oxy)methyl)benzene (1.3 g, 5.0 mmol) in acetone
mixture was warmed to room temperature and stirred over- (30 mL), 2 N HCl (6.2 mL, 12.5 mmol) was added and then
night. The reaction mixture was cooled to 0 °C, quenched by refluxed for 40 min. The reaction mixture was cooled to rt,
the addition of saturated ammonium chloride solution water (20 mL) was added and extracted with ethyl acetate
(30 mL) and extracted with ethyl acetate (50 mL × 3). Com- (50 mL × 2). The combined organics were dried over Na2SO4,
bined organic layers were washed with water (20 mL), brine concentrated under reduced pressure and purified by column
(20 mL) and dried over Na2SO4, concentrated under reduced chromatography (5% ethyl acetate in hexanes) to afford 1.1 g
pressure and purified by column chromatography (5% ethyl (86%) of (S)-4-(benzyloxy)-3,3-dimethylhept-5-enal as a color-
acetate in hexanes) to afford (S)-3-(benzyloxy)-2,2-dimethylhex- less oil. [α]2D4 +10.1 (c 0.7, CHCl3); IR νmax(film): cm−1
1
4-en-1-ol 10 (3.2 g, 92%) as a colorless oil. [α]2D4 +28.9 (c 2.2, 2965, 1705, 1496, 1268; H NMR (200 MHz, CDCl3): δ 9.79 (t,
CHCl3); IR νmax(film): cm−1 3446, 2961, 1668, 1496; 1H NMR J = 3.2 Hz, 1H), 7.44–7.19 (m, 5H), 5.75–5.55 (m, 1H), 5.49–5.26
(400 MHz, CDCl3): δ 7.38–7.28 (m, 5H), 5.75–5.61 (dq, J = 15.2, (m, 1H), 4.54 (d, J = 11.9 Hz, 1H), 4.23 (dd, J = 11.8, 2.1 Hz,
6.7 Hz, 1H), 5.54–5.37 (m, 1H), 4.60 (d, J = 11.9 Hz, 1H), 4.28 1H), 3.41 (d, J = 8.5 Hz, 1H), 2.49–2.14 (m, 2H), 1.77 (dd,
(d, J = 11.9 Hz, 1H), 3.58 (d, J = 9.2 Hz, 1H), 3.54 (dd, J = 10.8, J = 6.3, 1.4 Hz, 3H), 1.14–0.96 (m, 6H); 13C NMR (100 MHz,
5.7 Hz, 1H), 3.37 (dd, J = 11.0, 5.0 Hz, 1H), 2.97 (t, J = 5.7 Hz, CDCl3): δ 203.3, 138.7, 131.7, 128.3, 127.9, 127.8, 127.7,
1H), 1.80 (dd, J = 6.4, 1.4 Hz, 3H), 0.89 (s, 6H); 13C NMR 127.4, 86.9, 70.0, 53.3, 38.4, 25.5, 23.5, 18.0; MS: 269 (M +
(100 MHz, CDCl3): δ 138.3, 131.4, 128.4, 127.8, 127.7, 127.6, Na)+; HRMS calculated for C16H22O2Na 269.1512, found
88.1, 71.6, 70.0, 38.7, 22.7, 19.9, 17.8; MS: 257 (M + Na)+; 269.1508.
HRMS calculated for C15H22O2Na 257.1512, found 257.1508.
(S)-4-(Benzyloxy)-3,3-dimethylhept-5-enal (11)
(S)-(((5,5-Dimethyloct-2-en-7-yn-4-yl)oxy)methyl)benzene (+)-4
To a cooled solution of oxalyl chloride (1.8 mL, 21.2 mmol) in A solution of (S)-4-(benzyloxy)-3,3-dimethylhept-5-enal 11 (4 g,
DCM (30 mL) was added DMSO (3.0 mL, 42.7 mmol) at 16.2 mmol) and dimethyl-1-diazo-2-oxopropylphosphonate
−78 °C. After 20 min, a solution of 10 (2.5 g, 10.6 mmol) in (6.24 g, 32.4 mmol) in MeOH (40 mL) was treated with anhy-
DCM (12 mL) was added and stirred for 1 h. Triethylamine drous K2CO3 (4.5 g, 32.4 mmol) at rt and stirring was contin-
(8.9 mL, 64.1 mmol) was added and stirring was continued for ued for 16 h. The mixture was diluted with diethyl ether
30 min. The reaction was quenched with water (30 mL) and (100 mL) and washed successively with saturated NaHCO3
extracted with DCM (50 mL × 3). Combined organic layers were (20 mL), water (20 mL), brine (20 mL) and dried over Na2SO4.
washed with water (30 mL), brine (30 mL), dried over Na2SO4 The solvent was removed in vacuo and the residue was purified
and concentrated under reduced pressure to give (S)-3-(benzyl- by column chromatography (2% ethyl acetate in hexanes)
oxy)-2,2-dimethylhex-4-enal (1.90 g, 77%) as a colorless oil. to furnish (S)-(((5,5-dimethyloct-2-en-7-yn-4-yl)oxy)methyl)-
[α]2D4 +26.8 (c 1.1, CHCl3); IR νmax(film): cm−1 2975, 1731, 1496, benzene (+)-4 (3.0 g, 76%) as a colorless oil. [α]D26 +6.2 (c 1.0,
1
1205; H NMR (200 MHz, CDCl3): δ 9.52 (s, 1H), 7.39–7.13 (m, CHCl3); IR νmax(film): cm−1 3307, 2961, 2359, 2130, 1590,
5H), 5.82–5.61 (m, 1H), 5.47–5.30 (m, 1H), 4.57 (d, J = 12.1 Hz, 1473, 1065; 1H NMR (500 MHz, CDCl3): δ 7.34–7.28 (m, 4H),
1H), 4.27 (d, J = 12.1 Hz, 1H), 3.77 (d, J = 8.7 Hz, 1H), 1.79 7.26–7.24 (m, 1H), 5.72–5.60 (m, 1H), 5.44–5.33 (m, 1H), 4.56
(dd, J = 6.4, 1.5 Hz, 3H), 1.10 (s, 3H), 0.96 (s, 3H); 13C NMR (d, J = 11.9 Hz, 1H), 4.32–4.25 (m, 1H), 3.53 (d, J = 8.5 Hz, 1H),
(50 MHz, CDCl3):
δ 206.0, 138.4, 132.4, 128.3, 127.6, 2.34–2.24 (m, 1H), 2.21–2.11 (m, 1H), 1.97–1.89 (m, 1H), 1.76
127.5, 126.6, 83.8, 69.8, 49.9, 19.6, 17.9, 16.7. MS: 255 (M + (d, J = 6.4 Hz, 3H), 1.01(s, 3H), 0.97 (s, 3H); 13C NMR
Na)+; HRMS calculated for C15H20O2Na 255.1356, found (125 MHz, CDCl3): δ 139.2, 130.7, 128.1, 127.6, 127.5, 127.2,
255.1353.
127.1, 85.7, 82.7, 70.1, 69.8, 37.6, 29.0, 23.5, 22.4, 17.9; MS:
To a stirred solution of (methoxymethyl) triphenylphospho- 265 (M + Na)+; HRMS calculated for C17H22ONa 265.1563,
nium chloride (8.0 g, 23.2 mmol) in dry THF (120 mL) was found 265.1561.
4102 | Org. Biomol. Chem., 2014, 12, 4098–4103
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Paper
Dimethyl (R)-3-(benzyloxy)-2,2,6-trimethyl-2,3-dihydro-1H-
indene-4,5-dicarboxylate (−)-7
4 S. E. Kurhade, A. I. Sanchawala, V. Ravikumar, D. Bhuniya
and D. S. Reddy, Org. Lett., 2011, 13, 3690–3693.
5 Selected references for tandem enyne metathesis/Diels–
Alder reactions: (a) S. Kotha, D. Goyal and A. S. Chavan,
J. Org. Chem., 2013, 78, 12288–12313; (b) E. A. Tiong,
D. Rivalti, B. M. Williams and J. L. Gleason, Angew. Chem.,
Int. Ed., 2013, 52, 3442–3445; (c) M. W. Grafton,
L. J. Farrugia and A. Sutherland, J. Org. Chem., 2013, 78,
7199–7207; (d) A. V. Subrahmanyam, K. Palanichamy and
K. P. Kaliappan, Chem. – Eur. J., 2010, 16, 8545–8556;
(e) S. Kotha, M. Meshram and A. Tiwari, Chem. Soc. Rev.,
2009, 38, 2065–2092; (f) R. Ben-Othman, M. Othman,
S. Coste and B. Decroix, Tetrahedron, 2008, 64, 559–567;
(g) L. Evanno, A. Deville, B. Bodo and B. Nay, Tetrahedron
Lett., 2007, 48, 4331–4333; (h) K. C. Majumdar,
H. Rahaman, S. Muhuri and B. Roy, Synlett, 2006, 0466–
0468; (i) M. Rosillo, G. Domínguez, L. Casarrubios,
U. Amador and J. Pérez-Castells, J. Org. Chem., 2004, 69,
2084–2093; ( j) Y.-K. Yang and J. Tae, Synlett, 2003, 2017–
2020; (k) S. Kotha, N. Sreenivasachary and E. Brahmachary,
Eur. J. Org. Chem., 2001, 787–792; (l) D. Bentz and
S. Laschat, Synthesis, 2000, 1766–1773; (m) S. Kotha,
N. Sreenivasachary and E. Brahmachary, Tetrahedron Lett.,
1998, 39, 2805–2808.
The compound (−)-7 (0.33 g, 42%) was synthesized from (+)-4
by following a similar procedure mentioned for the synthesis
of 7. The NMR data were found to be identical with 7;
[α]2D5 −59.3 (c 1.7, CHCl3).
(R)-8-(Benzyloxy)-4,7,7-trimethyl-7,8-dihydrocyclopenta-
[e]isoindole-1,3(2H,6H)-dione (+)-8
The compound (+)-8 (56 mg, 64%) was prepared from (−)-7 by
following a similar procedure mentioned for the synthesis of
8. The NMR data were found to be identical with 8; [α]2D5 +7.8
(c 0.2, CHCl3).
(R)-8-Hydroxy-4,7,7-trimethyl-7,8-dihydrocyclopenta[e]-
isoindole-1,3(2H, 6H)-dione (−)-1
The compound (−)-1 (28 mg, 77%) was synthesized from (+)-8
by following a similar procedure mentioned for the synthesis
of ( )-1. The optical rotation of the synthesized (−)-1 was
found to be comparable but with opposite sign ([α]2D6 −21.4
(c 0.4, MeOH) vs. [α]2D5 +22.3 (c 0.4, MeOH)).
6 We have tried several reagents such as DDQ, MnO2, TFA
and Br2 by varying reaction parameters, but we were not
successful in obtaining the desired aromatized product.
7 (a) E. Ohshima, K. Yanagawa, H. Manabe, I. Miki and
Y. Masuda, US patent, US0056117, 2001; (b) R. A. W. N. Filho,
M. A. T. Palm-Forster and R. N. de Oliveira, Synth. Commun.,
2013, 43, 1571–1576.
Acknowledgements
The Ministry of Earth Sciences (MOES, New Delhi) is acknowl-
edged for the financial support under the program “Drugs
from Sea.” KK thanks CSIR, New Delhi for the award of a
research fellowship.
8 See previous publications from this group where
a
D-(−)-pantolactone chiral pool was used in the total syn-
thesis: (a) B. M. Rajesh, M. V. Shinde, M. Kannan,
G. Srinivas, J. Iqbal and D. S. Reddy, RSC Adv., 2013, 3,
20291–20297; (b) K. Kashinath, P. S. Swaroop and
D. S. Reddy, RSC Adv., 2012, 2, 3596–3598; (c) A. K. Hajare,
V. Ravikumar, S. Khaleel, D. Bhuniya and D. S. Reddy,
J. Org. Chem., 2010, 76, 963–966; (d) A. K. Hajare,
L. S. Datrange, S. Vyas, D. Bhuniya and D. S. Reddy, Tetrahe-
dron Lett., 2010, 51, 5291–5293; (e) D. S. Reddy, G. Srinivas,
B. M. Rajesh, M. Kannan, T. V. Rajale and J. Iqbal, Tetra-
hedron Lett., 2006, 47, 6373–6375.
Notes and references
1 Z.-Y. Xu, Z.-A. Wu and K.-S. Bi, Chin. Chem. Lett., 2013, 24,
57–58.
2 See references related to PARP-1 inhibitors (a) D. Dunn,
J. Husten, L. D. Aimone, M. A. Ator and S. Chatterjee,
Chem. Biol. Drug Des., 2013, 82, 348–350; (b) M. Tao,
C. H. Park, R. Bihovsky, G. J. Wells, J. Husten, M. A. Ator
and R. L. Hudkins, Bioorg. Med. Chem. Lett., 2006, 16, 938–
942; (c) D. Dunn, J. Husten, M. A. Ator and S. Chatterjee,
Bioorg. Med. Chem. Lett., 2012, 22, 222–224; (d) T. Ekblad,
E. Camaioni, H. Schuler and A. Macchiarulo, FEBS J., 2013,
280, 3563–3575; (e) S. Chatterjee, J. L. Diebold, D. Dunn,
R. L. Hudkins, R. Dandu, G. J. Wells and A. L. Zulli,
US patent, US0276497A1, 2006.
9 A. V. R. Rao, M. K. Gurjar, D. S. Bose and R. R. Devi, J. Org.
Chem., 1991, 56, 1320–1321.
10 S. G. Levine, J. Am. Chem. Soc., 1958, 80, 6150–6151.
11 (a) S. Ohira, Synth. Commun., 1989, 19, 561–564;
(b) S. Müller, B. Liepold, G. J. Roth and H. J. Bestmann,
Synlett, 1996, 521–522.
3 P. Magnus, L. M. Principe and M. J. Slater, J. Org. Chem.,
1987, 52, 1483–1486.
This journal is © The Royal Society of Chemistry 2014
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