Synthesis of a natural chromenoquinone via the Diels-Alder reaction of pyranobenzyne and furan

Article abstract of DOI:10.1248/cpb.c14-00228

We describe the total synthesis of angular chromenoquinone 1 isolated from Conospermum plants. Iodophenol, a precursor of pyranobenzyne, was prepared by Claisen rearrangement of an iodoresorcinol derivative. Diels - Alder reaction of the pyranobenzyne and

Full text of DOI:10.1248/cpb.c14-00228

820
Note
Chem. Pharm. Bull. 62(8) 820–823 (2014)
Vol. 62, No. 8
Synthesis of a Natural Chromenoquinone via the Diels–Alder Reaction of
Pyranobenzyne and Furan
Kazuaki Katakawa, Ayaka Sato, Mari Iwasaki, Tomofumi Horikawa, and Takuya Kumamoto*
Department of Synthetic Organic Chemistry, Research Institute of Pharmaceutical Sciences, Musashino University;
1–1–20 Shinmachi, Nishitokyo, Tokyo 202–8585, Japan.
Received March 13, 2014; accepted April 28, 2014
We describe the total synthesis of angular chromenoquinone 1 isolated from Conospermum plants. Iodo-
phenol, a precursor of pyranobenzyne, was prepared by Claisen rearrangement of an iodoresorcinol deriva-
tive. Diels–Alder reaction of the pyranobenzyne and a substituted furan proceeded in low regioselectivity to
afford desired 1 and its regioisomer.
Key words naphthoquinone; Diels–Alder reaction; furan; benzyne; total synthesis
Quinones are widely found in plants and microorganisms, reported regioselectivity, which furnished a 2:1 regioisomeric
and show various properties, such as anti-human immunode- mixture of iodophenols 7 and 8. The structures of 7 and 8
ficiency virus (HIV),1) antitumor, and antibiotic activities.2,3) were determined by two dimensional (2D)-NMR analysis.
Angular chromenoquinones, such as teretifolione B4) and its After separation, propargyl group was introduced to 7 in the
trimeric derivative, conocurvone,5) are unique naphthoquinone presence of Cu(II) catalyst and 1,8-diazabicyclo[5.4.0]undec-7-
compounds produced by Conospermum plants. Conocurvone ene (DBU)9,10) by using propargyl ester 9, derived from alco-
possesses anti-HIV activity. We have reported a simple route hol 10 and trifluoroacetic anhydride (TFAA) in situ, to afford
for constructing the naphthoquinone core via the Diels–Alder propargyl ether 5. The regioselectivity of the thermal Claisen
reaction (DAR) of benzyne and a functionalized furan.6) This rearrangement of 5 was unexpectedly low and a mixture of
led us to investigate the construction of more complex qui- the desired product 11 and the regioisomer 12 was obtained
1
none skeletons, which frequently appear in natural products, in a 2:1 ratio,11) estimated from the H-NMR integrals. The
using unsymmetrical benzyne substrates. In this Note, we inseparable mixture of chromenes 11 and 12 was hydrolyzed
describe the application of the DAR approach to constructing to afford the corresponding phenols 1312) and 14, which were
the angular chromenoquinone core and the total synthesis of separated by column chromatography. Desired chromene 13
natural chromenoquinone 1. The total synthesis of 1 starting was treated with Tf2O to give benzyne precursor 4 (Chart 2).
from naphthalene-2,7-diol was reported as part of the struc-
The DAR of the pyranobenzyne, derived from 4, with furan
tural elucidation.4)
36) gave a 1:2 isomeric mixture of the desired hydroquinone
Retrosynthetic analysis in this study is shown in Chart 1. 15 and the undesired 16. The structures of 15 and 16 were
The benzochromene core 1 would be constructed by the DAR determined by 2D-NMR analysis. The solvents used (Et2O,
of pyranobenzyne 2 and substituted furan 3. Benzyne precur- tetrahydrofuran (THF), toluene, 1,2-dimethoxyethane (DME))
sor 4 would be accessible by Claisen rearrangement of propar- did not affect the product ratio. Hydroquinone 15 was oxi-
gyl ether 5.7) Regioselective iodination8) and introduction of dized with FeCl313) to quinone 17 and then debenzylated with
the propargyl moiety to commercially available resorcinol BCl3 to give 1. The spectroscopic data for 1 were identical
monobenzoate (6) would provide 5.
to the literature data.14) The oxidation of its regioisomer 16
Our attempts at the iodination of 6 could not reproduce in the same manner gave a complex mixture. Application of
(diacetoxyiodo)benzene (DIB)-oxidation in methanol15) gave
quinone monoacetal 18. Subsequent debenzylation and de-
acetalization with BCl3 gave 19, the corresponding regioiso-
Fig. 1. Representative Natural Chromenoquinones
The authors declare no conflict of interest.
*To whom correspondence should be addressed. e-mail: t_kum632@musashino-u.ac.jp
Chart 1. Retrosynthetic Analysis of 1
© 2014 The Pharmaceutical Society of Japan

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821
Chart 2. Synthesis of Benzyne Precursor 4
Chart 3. Synthesis of Chromenoquinones 1 and 19
mer of 1 (Chart 3).
were added. The whole was filtered and the precipitates
We have achieved the total synthesis of natural chromeno- were washed with H2O until the filtrate indicates neutral pH
quinone 1 via the DAR of pyranobenzyne and furan as a and dried in air. The crude (32.3g) was recrystalized from
key step. The regioselectivity of several steps in this series benzene to yield 7 (12.9g, colorless powder, 35%). After
of transformation is low, which will be improved by further the mother liquid was concentrated in vacuo, the residue
examination. Regioisomer 19 will be useful as a candidate for was purified over SiO2 column chromatography (AcOEt–
exploring the structure–activity relationship of this series of CHCl3=5:95) to give two fractions. Polar fraction (7.64g)
chromenoquinones.
which included 7 mainly was recrystalized from benzene to
give 7 (4.91g, colorless needles, 13%) and less polar fraction
(10.7g) was also recrystalized from benzene to give 8 (7.70g,
Experimental
General Commercially available reagents and anhydrous colorless powder, 21%)
solvents were used without further purification. Flash chroma-
mp: 163–165°C. IR: 3330, 1708cm−1. 1H-NMR (DMSO-
tography was carried out with Silica gel 60N (40–50µm) from d6) δ: 10.07 (1H, s), 8.15 (2H, dd, J=7.7, 1.3Hz), 7.76 (1H, tt,
Kanto Chemical Co. IR spectra were recorded on a JASCO J=7.7, 1.3Hz), 7.64 (1H, d, J=8.7Hz), 7.62 (2H, t, J=7.7Hz),
FT/IR-4100 spectrophotometer with Attenuated Total Reflec- 6.77 (1H, d, J=2.7Hz), 6.59 (1H, dd, J=8.7, 2.7Hz). 13C-NMR
tance Unit ATR PRO450-S. Electron ionization (EI)-MS and (DMSO-d6) δ: 163.7, 158.8, 151.6, 138.9, 134.3, 129.9, 129.1,
electrospray ionization (ESI)-MS were recorded on a JEOL 128.7, 115.9, 111.0, 77.4. High resolution (HR)-EI-MS: m/z
GC-Mate II and a Thermo Scientific Orbitrap in positive 339.9593 (Calcd for C13H9IO3: 339.9597).
1
mode, respectively. H- (400MHz) and 13C- (100MHz) NMR
2-Iodo-5-(1,1-dimethyl-2-propynyloxy)phenyl Benzoate
spectra were recorded with JEOL ECX 400 spectrometer with (5) To a solution of 10 (0.22mL, 2.27mmol) and DBU
deuterated chloroform as a solvent and tetramethylsilane as (0.40mL, 2.67mmol) in CH3CN (1.0mL) at 0°C, TFAA
an internal reference otherwise noted. Chemical shifts were (0.32mL, 2.30mmol) was added and stirred for 1h to prepare
reported in ppm and J in Hz.
a solution of 9. In another flask, a solution of 7 (680.4mg,
5-Hydroxy-2-iodophenyl Benzoate (7) To
a
suspen- 2.00mmol) and CuCl2·2H2O (1.0mg, 0.006mmol) in CH3CN
sion of 6 (23.0g, 107mmol) in AcOH (108mL), ICl (7.0mL, (1.5mL) was treated with DBU (0.40mL, 2.67mmol) at 0°C
140mmol) was added at rt. After the solution was stirred for 5min. To this solution, the above mixture of 9 was added
at rt for 1h, H2O (215mL) and Na2SO3 (4.33g, 34.4mmol) at 0°C and stirred at 0°C for 75min. The whole was poured

822
Vol. 62, No. 8
into H2O (7.5mL) and extracted with AcOEt (3×15mL). The (16) To a solution of 4 (138.3mg, 0.319mmol) and furan
combined organic layer was washed with 1N HCl, 1N KOH 3 (138.0mg, 87% w/w purity as a mixture with TIPSOH,
and brine (each 1×5mL) and dried over Na2SO4. The solvent 0.333mmol) in THF (4.0mL), n-BuLi (1.11M in n-hexane,
was evaporated in vacuo and the residue was purified over 0.49mL, 0.544mmol) was added at −78°C. After the solution
SiO2 column chromatography (AcOEt–n-hexane=5:95) to was stirred at −78°C for 15min, further n-BuLi (0.09mL,
give 5 (491.7mg, a colorless oil, 61%).
0.100mmol) was added and stirred at same temperature for
IR: 1739cm−1. H-NMR δ: 8.27 (2H, dif. d, J=8.4Hz), 7.72 further 20min. The H2O (4.0mL) was added and the mix-
(1H, d, J=8.8Hz), 7.67 (1H, tt, J=7.6, 1.1Hz), 7.54 (2H, t, ture was warmed to rt. The whole was extracted with AcOEt
J=7.6Hz), 7.19 (1H, d, J=2.7Hz), 6.94 (1H, dd, J=8.8, 2.7Hz), (3×10mL) and the combined organic layer was washed with
2.61 (1H, s), 1.67 (6H, s). 13C-NMR δ: 164.1, 156.8, 151.4, H2O and brine (each 1×2mL) and dried over Na2SO4. The
138.7, 133.8, 130.5, 129.2, 128.6, 120.5, 116.3, 85.2, 81.6, 74.7, solvent was evaporated in vacuo and the residue was puri-
72.9, 29.5. HR-EI-MS: m/z 406.0082 (Calcd for C18H15IO3: fied over SiO2 column chromatography (AcOEt–n-hexane=
1
406.0066).
1:99–15:85) to give 15 (29.3mg, a reddish brown oil, 18%)
6-Iodo-2,2-dimethyl-2H-chromen-5-ol (13) 5 (396.8mg, and 16 (53.8mg, a yellow oil, 33%).
0.977mmol) was dissolved in N,N-diethylaniline (0.39mL)
15: IR: 3380cm−1. 1H-NMR δ: 1.11 (18H, d, J=7.6Hz),
and heated at 190°C for 30min. The whole was diluted with 1.33–1.41 (3H, m), 1.47 (6H, s), 2.39 (3H, s), 4.89 (2H, s),
AcOEt (15mL) and washed with 5% HCl (1×1.5, 1×1.0mL) 5.56 (1H, d, J=10.2Hz), 5.94 (1H, s), 6.93 (1H, d, J=9.2Hz),
and brine (1×1.0mL) and dried over Na2SO4. The solvent was 7.39–7.45 (3H, m), 7.48 (2H, dd-like, J=7.9, 1.7Hz), 7.78
evaporated in vacuo to give a residue (450.5mg). A portion (1H, d, J=10.2Hz), 7.84 (1H, d, J=9.2Hz). 13C-NMR δ: 11.6,
of the residue (231.0mg) was dissolved in methanolic KOH 14.2, 18.1, 27.4, 74.9, 75.7, 114.1, 1115.1, 17.2, 119.2, 122.3,
(0.54 M, 2.0mL, 1.08mmol) and stirred at rt for 50min. The 122.9, 124.0, 127.1, 128.2, 128.6, 128.9, 136.8, 139.5, 141.9,
reaction mixture was evaporated and the residue was dis- 144.3, 151.2. HR-EI-MS m/z: 518.2828 (Calcd for C32H42O4Si:
solved in H2O (1.0mL) and washed with n-hexane (1.0mL). 518.2852).
The organic layer was extracted with 1N KOH (0.5mL) and
1
16: IR: 3357cm−1. H-NMR δ: 0.85–0.96 (21H, m), 1.43
the combined aqueous layer was acidified with 5% HCl and (3H, s), 1.49 (3H, s), 1.95 (3H, s), 5.11 (2H, s), 5.69 (1H,
extracted with AcOEt (3×10mL). The combined organic layer d, J=10.5Hz), 6.90 (1H, dd, J=8.6, 0.7Hz), 7.18 (1H, brs),
was washed with brine (1×3mL) and dried over Na2SO4. The 7.29–7.36 (4H, m), 7.45 (2H, dd-like, J=7.9, 1.7Hz), 7.96 (1H,
solvent was evaporated in vacuo and the residue was puri- d, J=8.6Hz). 13C-NMR δ: 11.4, 13.6, 17.8, 18.0, 27.9, 28.6,
fied over SiO2 column chromatography (AcOEt–n-hexane= 73.8, 76.5, 101.4, 118.5, 120.5, 125.3, 128.2, 128.3, 128.4,
1:99–15:85) to give 13 (92.3mg, a colorless oil, 61%) and 14 128.8, 130.5, 137.2, 137.4, 141.1, 149.0, 158.2, 179.5. HR-ESI-
(31.8mg, colorless solids, 21%).
MS: m/z 517.2772 [(M−H)+, Calcd for C32H41O4Si: 517.2774].
9-Hydroxy-3,3,8-trimethyl-7,10-dihydro-3H-benzo[f]-
IR: 3438cm−1. 1H-NMR δ: 7.32 (1H, d, J=8.5Hz), 6.66
(1H, d, J=10.0Hz), 6.26 (1H, dd, J=8.5, 0.7Hz), 5.59 (1H, d, chromene-7,10-dione (1) To a solution of 15 (28.9mg,
J=10.0Hz), 5.22 (1H, s), 1.42 (6H, s). 13C-NMR δ: 154.6, 150.1, 0.0557mmol) in methanol (1.1mL), aqueous FeCl3 (0.82 M,
136.5, 129.8, 117.1, 111.5, 109.7, 76.2, 74.9, 27.8. Low resolution 0.15mL, 0.123mmol) was added at rt and the whole was
(LR)-EI-MS: m/z (%) 302 (M+, 22), 287 (100), 252 (52), 250 stirred at rt for 50min. The mixture was poured into H2O
(32), 235 (25), 233 (16), 219 (16), 217 (10), 160 (41), 105 (33).
(2mL) and extracted with CH2Cl2 (1×10, 2×5mL). The com-
6-Iodo-2,2-dimethyl-2H-chromen-5-yl Trifluoromethane- bined organic layer was washed with H2O and brine (each
sulfonate (4) To a solution of 13 (1.80g, 5.95mmol) 1×2mL) and dried over Na2SO4. The solvent was evaporated
and Et3N (1.70mL, 12.2mmol) in CH2Cl2 (14.0mL), Tf2O in vacuo to give crude 17 (30.9mg). A portion of the crude
(1.25mL, 7.43mmol) was added at −78°C. After the solution 17 (30.2mg) was dissolved in CH2Cl2 (2.7mL) and cooled
was stirred at −78°C for 1.5h, H2O (6.0mL) was added and to −78°C. BCl3 in heptane (1.0M, 0.28mL, 0.28mmol) was
the mixture was warmed to rt. The whole was poured into added to the solution and stirred at −78°C for 20min. H2O
H2O (6.0mL) and extracted with Et2O (1×100, 2×50mL). The (2.0mL) was added and the mixture was warmed to rt. The
combined organic layer was washed with brine (1×10mL) whole was extracted with CH2Cl2 (1×10, 2×5mL). The com-
and dried over Na2SO4. The solvent was evaporated in vacuo bined organic layer was washed with H2O and brine (each
and the residue was purified over SiO2 column chromatogra- 1×2mL) and dried over Na2SO4. The solvent was evaporated
phy (AcOEt–n-hexane=1:99–3:97) to give a pale yellow oil in vacuo and the residue was purified over SiO2 column chro-
(2.42g), which was dissolved in pentane. The solution was matography (AcOEt–n-hexane=5:95–15:85) to give 1 (9.3mg,
cooled to −78°C. The precipitates were collected by filtration orange solids, 63%).
and dried under reduced pressure to give 4 (2.21g, colorless
mp: 163–165°C. IR: 3376, 1642cm−1. 1H-NMR δ: 1.47
(6H, s), 2.06 (3H, s), 5.97 (1H, d, J=10.3Hz), 7.07 (1H, d,
needles, 86%).
1
mp: 49–50°C. IR: no characteristic absorption. H-NMR δ: J=8.5Hz), 7.44 (1H, brs), 7.77 (1H, d, J=10.3Hz), 7.98 (1H,
1.45 (6H, s), 5.77 (1H, d, J=10.1Hz), 6.56 (1H, d, J=10.1 Hz), d, J=8.5Hz). 13C-NMR δ: 8.5, 28.0, 76.8, 118.7, 119.7, 121.3,
6.61 (1H, dd, J=8.6, 0.8Hz), 7.57 (1H, d, J=8.6Hz). 13C-NMR 122.0, 123.4, 127.1, 128.7, 135.9, 153.3, 157.7, 183.3, 184.5. HR-
δ: 27.5, 76.7, 77.4, 116.4, 117.4, 118.4, 118.5 (q, JC–F=321.1Hz), EI-MS m/z: 270.0888 (Calcd for C16H14O4: 270.0892).
133.0, 139.4, 145.2, 154.6. HR-EI-MS: m/z 433.9299 (Calcd for
C12H10F3IO4S: 433.9297).
8-(Benzyloxy)-10-methoxy-3,3,9-trimethyl-10-(triisopropyl-
silyloxy)-7,10-dihydro-3H-benzo[f]chromen-7-one (18)
9-(Benzyloxy)-3,3,8-trimethyl-7-(triisopropylsilyloxy)-3H- Methanol (1.0mL) was added to a mixture of 16 (107.9mg,
benzo[f]chromen-10-ol (15) and 8-(Benzyloxy)-3,3,9-tri- 0.208mmol) and DIB (73.7mg, 0.229mmol) and stirred at rt
methyl-10-(triisopropylsilyloxy)-3H-benzo[f]chromen-7-ol for 1h. Saturated aqueous NaHCO3 (1.0mL) was added and

August 2014
823
the whole was poured into H2O (1.0mL). The whole was ex- no Joshi-Gakuin.
tracted with AcOEt (1×10, 2×5mL). The combined organic
layer was washed with H2O and brine (each 1×2mL) and
dried over Na2SO4. The solvent was evaporated in vacuo and
the residue was purified over SiO2 column chromatography
(AcOEt–n-hexane=1:99–9:91) to give 18 (45.5mg, a yellow
oil, 40%).
References and Notes
1) Yang S. S., Cragg G. M., Newman D. J., Bader J. P., J. Nat. Prod.,
64, 265–277 (2001).
2) Scott J. D., Williams R. M., Chem. Rev., 102, 1669–1730 (2002).
3) Herzon S. B., Woo C. M., Nat. Prod. Rep., 29, 87–118 (2012).
4) Cannon J. R., Joshi K. R., McDonald I. A., Retallack R. W., Siera-
kowski A. F., Wong L. C. H., Tetrahedron Lett., 2795–2798 (1975).
5) Decosterd L. A., Parsons I. C., Gustafson K. R., Cardellina II J.
H., McMahon J. B., Cragg G. M., Murata Y., Pannell L. K., Steiner
J. R., Clardy J., Boyd M. R., J. Am. Chem. Soc., 115, 6673–6679
(1993).
6) Katakawa K., Yonenaga D., Terada T., Aida N., Sakamoto A.,
Hoshino K., Kumamoto T., Heterocycles, 88, 817–825 (2014).
7) Example of regioselective Claisen rearrangement of propargyl ether
of resolcinols; Box V. G. S., Burke B. A., McCaw C., Heterocycles,
12, 451–452 (1979).
1
IR: 1658cm−1. H-NMR δ: 0.86–0.91 (21H, m), 1.43 (3H, s),
1.45 (3H, s), 1.89 (3H, s), 2.62 (3H, s), 5.07 (1H, d, J=11.2Hz),
5.22 (1H, d, J=11.2Hz), 5.65 (1H, d, J=10.5Hz), 6.87 (1H,
dd, J=8.6, 0.7Hz), 7.35–7.28 (3H, m), 7.44–7.41 (3H, m), 7.95
(1H, d, J=8.6Hz). 13C-NMR δ: 11.3, 13.7, 17.9, 18.1, 27.9, 28.5,
50.2, 73.6, 76.5, 97.7, 118.2, 118.9, 121.0, 125.0, 128.1, 128.2,
128.4, 128.9, 130.0, 137.4, 137.8, 141.6, 148.3, 158.1, 179.6. HR-
ESIM-S: 549.3042 [(M+H)+, Calcd for C33H45O5Si: 549.3036].
8-Hydroxy-3,3,9-trimethyl-7,10-dihydro-3H-benzo[f]-
chromene-7,10-dione (19) 18 (21.3mg, 0.0388mmol) was
subjected to debenzylation in the same condition from 17 to 1
(vide supra). The obtained residue was purified over SiO2 col-
umn chromatography (AcOEt–n-hexane=5:95–20:80) to give
19 (10.2mg, yellow solids, 97%).
8) Nicolet B. H., Sampey J. R., J. Am. Chem. Soc., 49, 1796–1801
(1927).
9) Godfrey Jr. J. D., Mueller R. H., Sedergran T. C., Soundararajan N.,
Colandrea V. J., Tetrahedron Lett., 35, 6405–6408 (1994).
10) Ding C. Z., Synth. Commun., 26, 4267–4273 (1996).
11) Application of platinum catalyst gave low selectivity (1:1). Example
of catalystic cyclizaton of propargyl ether; Pastine S. J., Youn S. W.,
Sames D., Tetrahedron, 59, 8859–8868 (2003).
12) Yao T., Yue D., Larock R. C., J. Org. Chem., 70, 9985–9989 (2005).
13) Hume P. A., Sperry J., Brimble M. A., Org. Biomol. Chem., 9,
5423–5430 (2011).
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30, 1727–1734 (1977).
15) Li C., Johnson R. P., Porco J. A. Jr., J. Am. Chem. Soc., 125, 5095–
5106 (2003).
1
mp: 208–210°C. IR: 3347, 1646cm−1. H-NMR δ: 1.47 (6H,
s), 2.05 (3H, s), 5.93 (1H, d, J=10.3Hz), 7.00 (1H, dd, J=8.4,
0.7Hz), 7.27 (1H, brs), 7.82 (1H, d, J=10.3Hz), 7.95 (1H, d,
J=8.4Hz). 13C-NMR δ: 8.8, 28.0, 77.1, 120.1, 120.2, 120.8,
121.4, 123.5, 127.5, 128.6, 134.6, 152.2, 160.2, 180.1, 187.9.
HR-EIMS: 270.0887 (Calcd for C16H14O4: 270.0892).
Acknowledgments This work was partly supported by
The Uehara Memorial Foundation and a Grant from Musashi-