The tandem ring opening/ring closing metathesis route to oxaspirocycles: An approach to phelligridin G

Article abstract of DOI:10.3390/molecules18022438

Phelligridin G is an unusual natural product that contains an embedded spiro-fused furanone core. We have investigated two furan-based synthetic approaches towards the spirocyclic core structure of this natural product from readily available 2-phenylfurans. Although initial studies involving an oxidative cyclization were unsuccessful, we were ultimately able to access this key system through a sequential intermolecular furan Diels-Alder reaction followed by a metathesis-based reorganization. A related approach led to an expanded C ring to form spiro-fused pyran spirocycles.

Full text of DOI:10.3390/molecules18022438

Molecules 2013, 18, 2438-2448; doi:10.3390/molecules18022438
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
The Tandem Ring Opening/Ring Closing Metathesis Route to
Oxaspirocycles: An Approach to Phelligridin G
Harold D. Cooper 1,2 and Dennis L. Wright 1,2,
*
1
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, USA;
E-Mail: Harold.cooper@uconn.edu
2
Department of Chemistry, University of Connecticut, Storrs, CT 06269, USA
* Author to whom correspondence should be addressed; E-Mail: dennis.wright@uconn.edu;
Tel.: +1-860-486-9274; Fax: +1-860-486-6857.
Received: 4 December 2012; in revised form: 31 January 2013 / Accepted: 7 February 2013 /
Published: 21 February 2013
Abstract: Phelligridin G is an unusual natural product that contains an embedded
spiro-fused furanone core. We have investigated two furan-based synthetic approaches
towards the spirocyclic core structure of this natural product from readily available
2-phenylfurans. Although initial studies involving an oxidative cyclization were
unsuccessful, we were ultimately able to access this key system through a sequential
intermolecular furan Diels-Alder reaction followed by a metathesis-based reorganization.
A related approach led to an expanded C ring to form spiro-fused pyran spirocycles.
Keywords: phelligridin G; Diels-Alder; spiroannulations; metathesis; 2-phenylfurans;
natural products
1. Introduction
There are a variety of therapeutics in use today that are derived from natural products isolated from
various plant, marine or microbial sources. There is increasing evidence from animal studies that
regular administration of powdered medicinal mushrooms can produce anti-cancer effects,
demonstrating both high antitumor activity and restriction of tumor metastasis [1]. One such family of
medicinal fungi has been derived from the species Phellinus igniarius, a member of the Polyporaceae
family. Phelligridins D, E and G (Figure 1) are interesting natural products isolated from the fruiting
body of P. igniarius. The fruiting body of P. igniarius has been long used in its role as a Traditional

Molecules 2013, 18
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Chinese Medicine for the treatment of fester, bellyache and bloody gonorrhea [2]. Phelligridin G
displays significant antioxidant activity, inhibiting rat liver microsomal lipid peroxidation and also
shows moderate selective cytotoxic activity against a human ovarian (A2780) and colon cancer cell
line (HCT-8) [3]. Based on the potential of phelligridin G as an anti-cancer agent, along with its unique
and synthetically challenging spirofused-furanone, we set out to develop a rapid and efficient synthetic
route to the core domain of the natural product.
Figure 1. Structural Derivatives of Phellinus igniarius.
Our retrosynthetic analysis targeted the core domain 1, comprised of the A, B and C rings
characterized by the challenging 2-oxaspiro-[4.4]-octane unit (Scheme 1). We have been interested for
some time in developing furan-based methodologies for the synthesis of polycyclic systems and felt
that phelligridin G offered an excellent target to evaluate two strategies we have pursued. In one path,
the presence of the spiro-fused 3-furanone makes it an attractive target for an electrochemical
annulation strategy through oxidative cyclization of 2. We have worked extensively with furan-terminating
electrochemical oxidative cyclizations and this method has been successful in the formation of 5-, 6-,
and 7-membered carbocycles [4–7]. In a parallel approach to the anodic oxidation, a sequential furan
Diels-Alder reaction to give 3, followed by a ring opening metathesis/ring closing metathesis
(ROM/RCM) process could also deliver the target intermediate, a strategy we have recently employed
in an approach to cyclopamine [8]. Exploration of both strategies would rely on the same two
commercially available building blocks 4 and 5.

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Scheme 1. Retrosynthetic analysis of Phelligridin G.
2. Results and Discussion
2.1. Electrochemical Studies
The commercially available starting materials 2-furanboronic acid (4) and 3,4-dimethoxybromo-
benzaldehyde (5) were joined through standard Suzuki cross-coupling with bis(triphenylphosphine)-
palladium(II) dichloride to produce the 2-phenylfuran derivative 6 in good yield (Scheme 2). The
aldehyde was homologated with t-butyldimethylsilyl cyanide, followed by reduction of the nitrile
group in the presence of DIBAL-H to give the protected -hydroxyaldehyde after hydrolysis with
dilute sulfuric acid. The α,β-unsaturated aldehyde underwent smooth Wittig olefination to deliver enol
ether intermediate 7. Unfortunately, and despite earlier success with similar systems [9], all attempts to
produce the spiro-fused product through anodic oxidation failed, producing only complex mixtures of
products. Further oxidative studies were attempted using the traditional chemical oxidants cerium(IV)-
ammonium nitrate (CAN) [10] and tris(4-bromophenyl)aminium hexachloroantimonate (BAHA) [11]
which are known to oxidize electron-rich olefins, but these also proved to be ineffective. We believe
that the presence of additional groups with low oxidation potentials such as the dimethoxyphenyl ring
and a 2-aryl furan leads to significant over oxidation and ultimate destruction of the starting material.
The failure to detect any appreciable cyclized material prompted us to explore the alternative
cycloaddition/metathesis approach to this class of compounds.
Scheme 2. Attempted oxidative cyclization to the spirocyclic core.

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2.2. Diels-Alder/Metathesis Studies
The value of oxabicyclic building blocks for the preparation of five-membered heterocycles has
been appreciated for some time [12–14]. Our synthesis of the spirocyclic core of phelligridin G would
be achieved in four steps starting with the previously described furyl-benzaldehyde derivative 6 (Scheme 3).
Olefination of the α,β-unsaturated carbonyl with methyl triphenylphosphonium bromide in the
presence of n-butyl lithium yielded styrylfuran 8. In order to obtain a suitable precursor for the
metathesis-driven bond reorganization, thermal cycloaddition to the furan via standard Diels-Alder
reaction was envisioned. Usually furan is a highly reactive diene, but in this system this reactivity
became highly attenuated due to the presence of the aryl ring in the C2 position. It has been previously
observed that 2-phenylfurans are poor dienes in Diels-Alder cycloadditions as a direct result of their
high π–conjugation, which is destroyed upon formation of the cycloadduct, thus promoting rapid
retro-Diels-Alder reaction [15]. We explored a series of structurally diverse dienophiles based upon
accessibility and reactivity rates to form the cycloaddition products.
Scheme 3. Synthesis of ABC spiroannulated core via Domino ROM/RCM metathesis.
O
O
MeO
MeO
MeO
MeO
Ph3P=CH2 Br
n-BuLi
THF
0oC
6
8
O
(72%)
MeO2C
CO2Me
MeO2C
CO2Me
C6H6
C6H6
55oC
3 days
40oC
24 h
G-II
CO2Me
MeO2C
CO2Me
CO2Me
MeO2C
N
N
Mes
Cl
Mes
Ph
H
O
MeO2C
MeO2C
Ru
O
Cl
O
O
MeO2C
C
PCy3
MeO
MeO
MeO
MeO
MeO
MeO
MeO
Wittig olefination
10mol%
+
CH2Cl2
35oC
Domino
Metathesis
A
B
MeO
11
10
12
9
O
O
(50%)
(55%)
(4%)
(50%)
We found that the sp2-type dienophiles such as n-methylmaleimide, cyanovinyl acetate, dimethyl
fumarate, and fumaryl chloride only returned unchanged starting materials after days of continuous
heating. Using more reactive alkynes seemed promising as we had some success with treating
substituted furan scaffolds with acetylenic dienophiles in previous studies [8]. However, with this
2-phenylfuran no oxabicyclic ether formation was observed at moderate temperatures with
monofunctionalized alkynes such as tosyl acetylene or methyl propriolate. At higher temperatures,
cycloaddition does occur, but this is followed by a spontaneous ring-opening/aromatization
process to produce an undesired phenol. Pleasingly, use of a more deactivated alkyne, dimethyl
acetylenedicarboxylate (DMAD), under mild thermal conditions (rt→40 °C) led to the desired adduct
9 in reasonable yield. We also examined the potential of aldehyde 6 to participate in the [4+2]
cycloaddition. As expected, condensation of aldehyde 6 with DMAD required higher temperatures (55 °C)
as well as longer reaction time, owing to the presence of the electron-withdrawing group which
deactivates the furan ring system. Ultimately, this reaction did produce the adduct 12 in ~50% isolated

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yield, which could be taken on to 9 by olefination. Furthermore, small amounts of Michael product 11
occurred as a byproduct. With the key oxabridged intermediate in hand, we were able to attempt the
key metathesis reaction. The oxabicyclo adduct 9 undergoes a ring opening/ring closing (ROM/RCM)
domino type metathesis using Grubbs 2nd generation catalyst to form spiro compound 10 as a single
diastereomer (as observed by 1H and 13C-NMR) that contains the core structure of phelligridin G. The
release of ring-strain in the bridged bicyclic compound is an important driving force in these types of
reactions and have been increasingly used to generate complex natural products [8,16–19].
In our desire to expand this utility of this methodology, we looked at the highly reactive
perhalogenated cyclopropenes as cycloaddition partners (Scheme 4). With the assistance of these
compounds, we have been able to develop building blocks leading to the synthesis of several natural
products [20,21]. It was felt that the cycloaddition of perhalocyclopropenes would be more efficient as
the initial cycloadduct spontaneously rearranges to the ring-expanded system thus preventing the retro-
Diels-Alder reaction from taking place. Oxabicyclo[3.2.1]octane 14 was easily prepared in a one-pot
sequence that involved heating 6 and tetrachlorocyclopropene (TCCP) 13 at 55 °C for 4 days, followed
by olefination to give 15 without benefit of further purification. Compound 8 under similar reaction
conditions was much less reactive as the alkene seemed to hinder the cycloadduct formation with this
particular dienophile.
Scheme 4. Expansion of the C-ring of the phelligridin G core to form the spiro-fused pyran moiety.
The strained ether-bridged seven-membered ring likely undergoes a ring opening of the endocyclic
double bond followed by closure with the terminal olefin to form the B ring of the spiro-fused product.
For oxabicyclo[3.2.1]octane 15, the GII catalyst was also optimal but heating of the mixture was
unnecessary in this system and produce the highly functionalized spiro-pyran 16 in moderate overall yield.
3. Experimental
General
All reactions were carried out under an inert argon atmosphere with dry solvents under anhydrous
conditions, unless otherwise noted. Commercial grade reagents and solvents were purchased and used
without further purification except as indicated below. Hexanes, tetrahydrofuran (THF), diethyl ether
(Et2O), and dichloromethane (CH2Cl2) were used directly as obtained from a Baker Cycle-tainer™
system. Yields refer to chromatographically and spectroscopically (1H-NMR) homogenous materials,
unless otherwise stated. Reactions were monitored by thin layer chromatography (TLC) carried out on
Whatman silica gel 60 Å precoated plates using UV light as the visualizing agent and an acidic mixture

Molecules 2013, 18
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of DNP or basic aqueous potassium permanganate (KMnO4) and heat as developing agents. Flash
chromatography was performed using Baker silica gel (60 Å particle size). NMR spectra were
recorded on Bruker-500 and 400 instruments and calibrated using the residual undeuterated solvent
1
13
signal as an internal reference (CHCl3 at δ 7.26 ppm for H-NMR, δ 77.1 ppm for C-NMR). The
following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, b = broad. IR Spectra were recorded on Shimadzu FT-IR 8400
spectrometer. Melting points (m.p.) were uncorrected and measured with a Mel-Temp digital melting point
apparatus. High resolution mass spectra (HRMS) were obtained from the University of Connecticut Mass
Spectral Facility by using Direct Analysis in Real Time using an AccuTOF (JEOL) mass spectrometer.
2-Furan-2-yl-4,5-dimethoxybenzaldehyde (6). Commercially available 3,4-dimethoxybromo-
benzaldehyde 5 (0.5 g, 2.04 mmol) was added to an argon purged 25 mL flask. Anhydrous THF
(10 mL) was added, followed by 2-furanboronic acid (2 equiv.), and PdCl2(PPh3)2 (0.1 mol equiv.).
Once all the reagents were in solution, 2M aqueous solution of Cs2CO3 (3 mol equiv.) was added to the
flask, which was immediately placed in a preheated oil bath and refluxed with vigorous stirring for
12–24 h. Once the reaction was deemed complete, it was cooled to room temperature, quenched with
H2O, and diluted with Et2O. The aqueous layer was extracted with Et2O (3 × 5 mL) and the combined
organic layers were washed with brine, dried over Na2SO4, and concentrated to give a crude yellow
solid. The crude product was purified by column chromatography on silica gel (6:1 hexane/ethyl
acetate) to yield 6 (95%) as a solid. Rf = 0.38; m.p. = 102 °C; IR (KBr, cm−1): υ: 730, 909, 1280, 2255,
1
3012 H-NMR (400 MHz, CDCl3):  = 3.96–4.04 (m, 6H), 6.58 (s, 2H), 7.13 (s, 1H), 7.54 (s, 1H),
7.62 (s, 1H), 10.27 (s, 1H). 13C-NMR (126 MHz, CDCl3)  = 190.58, 154.46, 153.48, 150.43, 149.04,
143.47, 128.85, 126.67, 115.40, 111.76, 110.38, 108.83, 77.44, 77.12, 76.80, 65.76, 56.00; HRMS
(DART) calcd. for C13H13O4 [M+H]+: 233.0814; found 233.0823.
(tert-Butyldimethylsilanyloxy)-2-furan-2’-yl-‘4,5’-dimethoxyphenyl)acetonitrile. To a flame dried flask was
added t-butyldimethylsilyl cyanide (0.141 g, 1.0 mmol), potassium cyanide (0.003 g, 0.05 mmol), and
18-crown-6 (0.053 g, 0.4 mmol) under an argon atmosphere. A solution of aldehyde 6 (0.116 g,
0.500 mmol) in dry methylene chloride (5 mL) was added dropwise over 30 min to the homogenous
mixture. The reaction was stirred vigorously for 24 h and monitored by TLC. Upon reaction
completion the solvent is removed in vacuo and the crude oily residue was purified by flash
chromatography using 15% EtOAc in hexanes to obtain a pure yellow oil (0.177g, 95% yield).
1
Rf = 0.67; IR (KBr, cm−1) υ: 654, 735, 908, 2254, 2962, 3012 H-NMR (500 MHz, CDCl3):
 = 0.02–0.12 (d, J = 50 Hz, 6H), 0.89 (s, 9H), 3.93–3.95 (d, J = 10 Hz, 6H), 5.89 (s, 1H), 6.53 (s, 2H),
13
7.02 (s, 1H), 7.30 (s,1H), 7.55 (s, 1H). C-NMR (126 MHz, CDCl3)  = 151.8, 149.5, 147.2, 126.6,
121.8, 119.7, 111.8, 110.9, 110.1, 108.9, 61.2, 56.2, 25.7, 18.3, −5.1; HRMS (DART) calcd. for C20H28
NO4Si [M+H]+: 374.1788; found 374.1776.
(tert-Butyldimethylsilanyloxy)-2-furan-2’-yl-‘4,5’-dimethoxyphenyl)acetaldehyde. Silyl cyanide (0.455 g,
1.22 mmol) was dissolved in dry toluene (4 mL) and cooled to −78 °C. DIBAL (0.868 g, 6.1 mmol)
was added dropwise to the flask and the mixture stirred 2 h at this temp. Once the imine is formed, the
reaction was quenched with methanol (2.1 mL) and warmed up to 0 °C. After 2 h, 1N H2SO4 (2 mL)

Molecules 2013, 18
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was added dropwise to the mixture while stirring for 1 h at this temperature. Diethyl ether was added
to dilute the reaction and the aqueous layer was separated. The aqueous layer was extracted with ether
(3 × 3 mL) and the ethereal layer collected, washed with brine, dried over Na2SO4, and the solvent
removed in vacuo. The crude oil was purified by flash chromatography using a 10% EtOAc in hexanes
solution to obtain a pure oil (0.200 g, 44% yield). Rf = 0.49; IR (KBr, cm−1) υ: 732, 913, 1735, 2934,
2959, 3012 1H-NMR (500 MHz, CDCl3): = −0.09−0.02 (d, J = −35 Hz, 6H), 0.87 (s, 9H), 3.91–3.92
(d, J = 5 Hz, 6H), 5.50 (s, 1H), 6.49–6.61 (dd, J = 10, 5 Hz, 2H), 7.07–7.09 (d, J = 10 Hz, 2H), 7.51
(s, 1H). 13C-NMR (126 MHz, CDCl3)  = 198.9, 152.3, 149.3, 148.9, 142.4, 127.2, 122.8, 111.5,
111.2, 110.5, 108.9, 76.2, 56.0, 25.7, 25.7, 18.3, −4.9; HRMS (DART) calcd. for C20H29O5Si [M+H]+:
377.1784; found 377.1760.
tert-Butyl-[1-(2-furan-2’yl-4’,5’-dimethoxyphenyl)-3-methoxyallyloxy]dimethylsilane (7). To
a
stirred solution of dry THF (3 mL) was added methoxymethyltriphenylphosphonium bromide (0.36 g,
0.105 mmol) under argon. The homogenous mixture was cooled to 0 °C followed by addition of NaOt-Bu
base (2 eq.) in one portion. The red-orange suspension was stirred about 30 min as the color persisted
under the above temp. A 0.20 mM solution of 2-furyl benzaldehyde (0.802 g, 3.45 mmol) in THF was
slowly added, and the reaction was monitored by TLC at 0 °C. The reaction was quenched with H2O
(2 mL) and diluted with ether (4 mL). The aqueous layer was extracted with Et2O, and the combined
extracts were washed with H2O and brine, then dried over Na2SO4. Removal of all solvents was done
in vacuo to yield crude an oily residue as E/Z isomers of 7 (0.020 g, 64%). Rf = 0.33; IR (KBr, cm−1):
1
υ: 812, 1278, 1687, 2857, 3233; H-NMR (500 MHz, CDCl3):  = −0.11−0.05 (d, J = −30 Hz, 6H),
0.86 (s, 9H), 3.48 (s,1H), 3.91–3.92 (d, J = 5 Hz, 6H), 4.90–4.94 (m, J = 20 Hz, 1H), 5.59–5.60
(d, J = 5 Hz, 1H), 6.29–6.32 (d, J = 15 Hz, 1H), 6.37–6.48 (m, J = 55 Hz, 2H), 6.97 (s, 1H), 7.22
(s, 1H), 7.49 (s, 1H). 13C-NMR (126 MHz, CDCl3)  = 153.0, 149.2, 148.8, 147.7, 141.8, 135.7, 120.7,
111.4, 110.9, 109.9, 108.1, 107.3, 69.1, 56.1, 56.0, 25.9, 18.4, −4.7, −4.7; HRMS (DART) calcd. for
C22H33O5Si [M+H]+: 405.2097; not detected.
2-(4,4-Dimethoxy-2-vinylphenyl)furan (8). To a stirred solution of dry THF (36 mL) was added methyl
triphenylphosphonium bromide (1.52 g, 4.32 mmol) under argon. The homogenous mixture was
cooled to 0 °C followed by dropwise addition of a 2.5 M solution n-BuLi in hexanes (1.25 eq.). The
red-orange suspension was stirred about 30 min as the color persisted under the above temp. A 0.53 mM
solution of 2-furylbenzaldehyde (6, 0.802 g, 3.45 mmol) in THF was slowly added, and the reaction
was complete at 0 °C after 10–15 mins. The reaction was quenched with sat. aq. NH4Cl (10 mL) and
diluted with EtOAc (20 mL). The aqueous layer was extracted with EtOAc, and the combined extracts
were washed with H2O and brine and then dried over Na2SO4. Removal of all solvents was done in
vacuo to yield a crude solid material, which was purified by silica gel column chromatography
(hexane/EtOAc, 10:1) to yield olefin 8 as a yellow oil (0.568 g, 72%). Rf = 0.43; IR (KBr, cm−1): υ:
730, 909, 1266, 2254, 3007 1H-NMR (500 MHz, CDCl3):  = 3.93–3.95 (d, 6H, J = 3.3 Hz), 5.24–5.26
(dd, J = 5, 5 Hz, 1H), 5.59–5.62 (d, J = 15 Hz, 1H), 6.42–6.49 (d, J = 35 Hz, 2H), 7.99–7.05 (m, J = 30 Hz,
1H), 7.03 (s, 1H), 7.12 (s, 1H), 7.48 (s, 1H). 13C-NMR (126 MHz, CDCl3)  = 152.64, 148.91, 141.91,
135.98, 128.73, 122.63, 114.14, 111.56, 110.39, 109.39, 56.16, 56.11; HRMS (DART) calcd. for
C14H15O3 [M+H]+: 231.1021; found 231.1000.

Molecules 2013, 18
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1-(4’,5’-Dimethoxy-2’vinylphenyl)-7-oxabicyclo[2.2.1]hepta-2,5diene-2,3-dicarboxylic acid dimethyl
ester (9). Dimethoxybenzylfuran 8 (343 mg, 1.49 mmol) was added to a flame dried vial in benzene
(0.37mL) to make a 3 mM solution, followed by addition of DMAD (233 mg,1.64 mmol) at room
temperature. The reaction stirred vigorously until everything was in solution, then placed in a
preheated oil bath at 40 °C. The reaction was monitored by TLC using a 30% EtOAc in hexanes
solution. Upon completion the solvents were removed in vacuo to afford a crude oil, which was
purified by silica gel chromatography (SiO2, 7 g, 25% EtOAc in hexanes to yield cycloadduct 9 as an
1
oil (0.264 g, 55%). Rf = 0.21; IR (KBr, cm−1): υ: 731, 908, 1268, 2345, 3016; H-NMR (500 MHz,
CDCl3):  = 3.57 (s, 3H), 3.74 (s, 3H), 3.84–3.86 (d, J = 10 Hz, 6H), 5.14–5.16 (d, J = 10 Hz, 1H),
5.50–5.54 (d, J = 20 Hz, 1H), 5.75 (s, 1H), 6.92–7.02 (dd, J = 15, 15 Hz, 1H), 7.01–7.03 (d, J = 10 Hz,
2H), 7.27–7.28 (dd, J = 5 Hz, 1H), 7.47–7.48 (d, J = 5 Hz, 1H). 13C-NMR (126 MHz, CDCl3)
 = 164.9, 162.7, 158.8, 149.4, 149.2, 148.6, 145.2, 144.7, 134.7, 130.0, 123.6, 114.7, 110.9, 109.4,
97.9, 83.5, 55.9, 52.4; HRMS (DART) calcd. for C20H21O7 [M+H]+: 373.1287; found 373.1280.
4’5’Dimethoxyspiro[5-oxafuryl-2,3 di(methoxycarbonyl)-4-vinyl]-1,1’[1H]indene (10). To a solution
of oxabicyclic ether 9 (177 mg, 0.475 mmol) in dry dichloromethane (47.5 mL) was added a solution
of Grubbs 2nd generation catalyst G-II (40 mg, 0.0475 mmol) in 1 mL CH2Cl2 at room temperature.
The reaction was stirred vigorously at room temperature then placed into a preheated oil bath at 35 °C.
The reaction was monitored by 1H-NMR. After 24 hrs of heating, the reaction was removed from heat
and concentrated to a crude brown oil. Purification of the residue by flash chromatography using 25%
EtOAc in hexanes afforded pure spirocyclic compound 10 (0.048g, 50%). Rf = 0.21; IR (KBr, cm−1): υ:
732, 907, 1255, 2253, 2955; 1H-NMR (500 MHz, CDCl3):  = 3.56 (s, 3H), 3.81 (s, 3H), 3.87–3.89 (d,
J = 10 Hz, 6H), 5.28–5.30 (d, J = 20 Hz, 1H), 5.48–5.51 (d, J = 15, 1H), 5.76–5.78 (s,1H) 5.99–6.04
(m, 1H), 6.16–6.17 (d, J = 5.5 Hz, 1H), 6.61–6.62 (d, J = 5.5 Hz, 1H), 6.76 (s, 1H), 6.89 (s, 1H).
13C-NMR (126 MHz, CDCl3)  = 163.1, 162.3, 150.3, 148.4, 142.9, 136.7, 136.6, 135.7, 133.7, 128.8,
127.0, 118.1, 107.8, 105.8, 99.38 86.4, 56.5, 56.6, 52.6; HRMS (DART) calcd. for C20H21O7 [M+H]+:
373.1287; found 373.1283.
1-(2’-Formyl-4’,5’dimethoxyphenyl)-7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylic acid dimethyl
ester (12). Dimethoxyfurylbenzaldehyde 6 (343 mg,1.49 mmol) in benzene (0.37 mL) was added to a
flame dried vial to make a 3 mM solution, followed by addition of DMAD (233 mg, 1.64 mmol) at
room temperature. The reaction was stirred vigorously until everything was in solution, then added to a
preheated oil bath at 50 °C. The reaction was monitored by TLC using a 30% EtOAc solution in
hexanes as eluent. Upon completion the solvents were removed in vacuo to afford a crude oil, which
was purified by silica gel chromatography (SiO2, 7 g, 25% EtOAc in hexanes) to yield cycloadduct 12
as an oil. Diastereomers were obtained, which could be separated via column chromatography
(0.202 g, 50% of desired product 12). Rf = 0.085; Rf = 0.17; m.p. = 175 °C; IR (KBr, cm−1): υ: 730,
1
912, 1291, 1684, 3024; H NMR (500 MHz, CDCl3):  = 3.63 (s, 3H), 3.81 (s, 3H), 3.97–3.98 (d,
J = 5 Hz, 6H), 5.76 (s, 1H), 7.21 (s, 1H), 7.25 (s, 2H), 7.30–7.33 (dd, J = 5, 5 Hz, 1H), 7.45 (s, 1H),
10.03 (s, 1H). 13C-NMR (126 MHz, CDCl3)  = 190.9, 164.1, 162.7, 156.8, 153.5, 148.9, 148.3, 144.9,
143.3, 129.9, 126.9, 114.6, 110.3, 96.6, 82.6, 56.2, 56.1, 52.3, 52.2; HRMS (DART) calcd. for
C19H18O8:[M+H]+: 375.1080; found 375.1069.

Molecules 2013, 18
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4’,5’-Dimethoxy-2-(2,3,4,4-tetrachloro-8-oxabicyclo[3.2.1]octa-2,6-dien-1-yl-benzaldehyde
(14).
Dimethoxyfurylbenzaldehyde 6 (0.237 mmol) was dissolved in benzene to make a 2.97 M solution at
room temperature, followed by addition of tetrachlorocyclopropene (1 eq.). The homogeneous mixture
was stirred vigorously, heated to 55 °C and stirred for 3–4 days. The reaction was monitored by TLC
using a 25% EtOAc in hexanes solution. Upon completion the solvents were removed in vacuo to
afford a crude solid, which was purified by flash chromatography (SiO2, 9 g, 25% EtOAc in hexanes)
to yield a yellow solid of 14 (0.42g, 68%). Rf = 0.67; m.p. = 175 °C; IR (KBr, cm−1): υ: 733, 907,
1
1277, 1516, 2938; H-NMR (500 MHz, CDCl3):  = 3.98–4.07 (d, J = 43 Hz, 6H), 5.46 (s, 1H), 7.00
(s, 1H), 7.30 (s, 1H), 7.59 (s, 1H), 10.23 (s, 1H). 13C-NMR (126 MHz, CDCl3)  = 190.1, 153.0, 150.2,
144.7, 138.7, 129.4, 127.9, 122.5, 112.6, 110.3, 94.2, 82.6, 75.2, 64.1, 63.3, 56.3, 56.2; HRMS
(DART) calcd. for C16H13Cl4O4 [M+H]+: 410.9540; found 410.9540.
2,3,4,4,Tetrachloro-1-(4’,5’dimethoxy-2’-vinylphenyl-8-oxabicyclo[3.2.1]octa-2,6-diene
(15).
Cyclo-adduct 14 (0.237 mmol) was olefinated as mentioned above to give crude compound 15 which
was purified using flash chromatography on silica gel (hexane/EtOAc, 20:1) to yield a yellow solid
(0.57 g, 45%). Rf = 0.71; IR (KBr, cm−1): υ: 731, 908, 2252, 2941, 3014; 1H-NMR (500 MHz, CDCl3):
 = 3.95–3.99 (d, J = 16 Hz, 6H), 5.18–5.21 (d, J = 12Hz, 1H), 5.39 (s, 1H), 5.54–5.57 (d, J = 12 Hz,
1H), 6.88–7.00 (dd, J = 4 Hz, dd, J = 8 Hz, 1H), 6.93 (s, 1H), 6.96 (s, 1H), 7.09 (s, 1H), 7.19 (s, 1H).
13C-NMR (126 MHz, CDCl3)  = 150.3, 148.4, 145.2, 137.3, 135.1, 132.7, 120.8, 115.0, 113.5, 110.0,
95.6, 82.4, 75.5, 64.7, 63.6, 56.2, 56.1; HRMS (DART) calcd. for C17H15Cl4O3 [M+H]+: 408.9747;
found 408.9767.
4’5’Dimethoxyspiro[6-oxapyrano-2,3,4,4 tetrachloro-5-vinyl]-1,1’[1H]indene (16). Purification of the
crude residue 16 by flash chromatography using 25% EtOAc in hexanes afforded pure spiro-fused
1
pyran. Yield: 0.048 g (48%). Rf = 0.30; IR (KBr, cm−1): υ: 733, 912, 2324, 2861, 2943; H-NMR
(500 MHz, CDCl3):  = 3.90–3.91 (d, J = 5 Hz, 6H), 5.07–5.08 (d, J = 5 Hz, 1H), 5.45–5.47 (d,
J = 10 Hz, 1H), 5.52 (s, 1H) 6.12–6.13 (d, J = 5 Hz, 1H), 6.22–6.28 (m, J = 30 Hz, 1H), 6.59–6.60 (d,
J = 5 Hz, 1H), 6.81(s, 1H), 7.68 (s, 1H). 13C-NMR (126 MHz, CDCl3)  = 150.9, 148.5, 144.9, 137.8,
137.3, 134.3, 132.6, 131.3, 124.9, 121.2, 111.8, 106.5, 84.0, 70.20, 59.53, 56.6, 56.4; HRMS (DART)
calcd. for C17H15Cl4O3 [M+H]+: 408.9747; found 408.9772.
4. Conclusions
The highly oxygenated oxaspirocyclic core of phelligridins G and E presents an interesting
synthetic challenge, while the potential anticancer and antioxidant properties of the molecules make
them compelling targets for study. In this work, we investigated two potential furan-based routes to the
oxaspiro core of these compounds. Initial attempts to affect an electrochemical oxidative cyclization
were complicated by facile over-oxidation of the products. An alternative route involving a
challenging Diels-Alder cycloaddition with a highly substituted 2-styrylfuran, followed by a tandem
ring-opening/ring-closing (domino) metathesis reaction proved successful. It was also possible to
extend this strategy to the higher homolog by using a formal [4+3] cycloaddition reaction with
tetrachlorocyclopropene. Current efforts towards the synthesis of phelligridin G based on this strategy
are ongoing.

Molecules 2013, 18
2447
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/18/2/2438/s1.
Acknowledgments
We are grateful to the National Science Foundation (CHE-0616760) for generous support of this work.
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Sample Availability: Samples of the compounds 6, 9,10, 14, 16 are available from the authors.
© 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).