Approach to a new dihydrofuran-fused cyclic system by a remarkable switching of endo/exo selectivity of a [4+2] cycloaddition reaction

Article abstract of DOI:10.1002/ejoc.200701050

An efficient synthesis of a new class of dihydrofuran-fused tetracyclic compounds, possessing a 2-oxa-furano-steroidal framework, has been achieved by successive electrocyclic reactions of benzocyclobutene derivatives. It has been revealed that the stereoselectivity of a key intramolecular [4+2] cycloaddition reaction can be controlled by installation of a bulky silyl substituent onto the furan ring resulting in the formation of the exo adducts, the opposite selectivity to that observed in our past related studies. Preliminary examinations of the bioactivities of the synthesized compounds have been performed and have revealed that they have potential as anti-influenza agents. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701050

FULL PAPER
DOI: 10.1002/ejoc.200701050
Approach to a New Dihydrofuran-Fused Cyclic System by a Remarkable
Switching of endo/exo Selectivity of a [4+2] Cycloaddition Reaction
Yuji Matsuya,*[a] Yoshiaki Imamura,[a] Tatsuro Miyahara,[a] Hiroshi Ochiai,[a] and
Hideo Nemoto*[a]
Keywords: Cycloaddition / Quinodimethanes / Pericyclic reaction / Diastereoselectivity / Anti-influenza agent
An efficient synthesis of a new class of dihydrofuran-fused
tetracyclic compounds, possessing a 2-oxa-furano-steroidal
of the exo adducts, the opposite selectivity to that observed
in our past related studies. Preliminary examinations of the
framework, has been achieved by successive electrocyclic re- bioactivities of the synthesized compounds have been per-
actions of benzocyclobutene derivatives. It has been revealed
that the stereoselectivity of a key intramolecular [4+2] cyclo-
addition reaction can be controlled by installation of a bulky
silyl substituent onto the furan ring resulting in the formation
formed and have revealed that they have potential as anti-
influenza agents.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
ity).[2,3] In this paper, we describe a concise synthesis of
compounds 4 based on successive electrocyclic reactions of
benzocyclobutene derivatives containing a furyl substruc-
ture and an interesting switching of stereoselectivity of the
reaction by variation of the substituents.
Introduction
Furan-fused polycyclic systems are widely found in natu-
ral compounds and known to exhibit significant biological
activities, including antifungal, antibiotic, antiviral, and
anti-inflammatory.[1] In the course of our model studies on
the synthesis of furan-fused polyketides, halenaquinone,
and xestoquinone,[2] we found that dihydrofuran-fused
tetracyclic compounds, represented by general structure 1,
exert notable antiproliferative effects against viruses, includ-
ing influenza A and B.[3] More recently, we also reported
that this class of compounds can enhance hyperthermia-
induced apoptosis in human lymphoma U937 cells.[4] Novel
structural characteristics make them a promising lead com-
pound for the discovery of a new type of therapeutic agent.
In addition, these compounds form a partial framework (A,
B, C, and E rings) of furano-steroids, exemplified by virid-
ine (2)[1b,5] and wortmannin (3),[1a,6] and thus represent a
new motif for advanced drug design and discovery. As a
part of structure–activity relationship (SAR) studies of the
dihydrofuran-fused compounds 1, we undertook the syn-
thesis of new analogous compounds 4, which possess a 2-
oxa-furano-steroidal framework and a methoxymethyl sub-
stituent, as found in the wortmannin structure. During the
synthetic study we encountered a high degree of exo selec-
tivity in the key intramolecular [4+2] cycloaddition of o-
quinodimethane due to the influence of a bulky silyl group,
unlike our previous synthesis of 1 (exclusive endo selectiv-
Results and Discussion
Readily available 5-methoxybenzocyclobutene-1-car-
bonitrile (5)[7] was deprotonated by LDA and then exposed
to Weinreb amide 6[8] to yield an acylated product 7 in 69%
yield. Reduction of the ketone with sodium borohydride in
MeOH produced the corresponding alcohol 8 as a dia-
stereomeric mixture (ca. 1:1) which was allowed to react
with 3-(bromomethyl)furan in the presence of sodium hy-
dride to afford furylmethyl ether 9. This compound was
heated in refluxing o-dichlorobenzene (180 °C) with a view
to preparing the target ring system 11 by intramolecular
[a] Graduate School of Medicine and Pharmaceutical Sciences,
University of Toyama,
2630 Sugitani, Toyama 930-0194, Japan
Fax: +81-76-434-5047
E-mail: nemotoh@pha.u-toyama.ac.jp
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
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Approach to a New Dihydrofuran-Fused Cyclic System
[4+2] cycloaddition of intermediate o-quinodimethane 10. lylation by treatment with TBAF. Thus, the diastereomers
However, instead an inseparable mixture of many products 17 and 18 were successfully isolated from both 14a and 14b
was formed (Scheme 1). These disappointing results are as single isomers (Scheme 3).
probably due to the multiplicity of possible reactions of the
intermediate 10, including the formation of 5-5-6-fused
compound 12. In fact, the formation of 12 was suggested
1
by careful H NMR analysis of the crude reaction mixture.
This undesirable side-product clearly arises from the cyclo-
addition of 10 to the 2,3-double bond of the furan moiety
(and not the 4,5-double bond). To circumvent this problem,
a bulky and removable silyl group was preinstalled onto the
2-position of the furan ring. Thus, silylated furylmethyl
ethers 13a and 13b were synthesized from 8 according to
the foregoing method, by using known silylated (bromo-
methyl)furan derivatives[9] as the reagents (Scheme 2).
Scheme 1.
Scheme 3.
The relative configurations of the methoxymethyl group
and hydrogen atoms on the dihydrofuran ring were unam-
biguously determined by NOE experiments (indicated in
Scheme 3) for each compound, whereas the configuration
of the cyano group remained unclear. For compound 17,
however, the cyano group could be converted into a formyl
Scheme 2.
group by DIBAL reduction (although it did not work well
Gratifyingly, the thermal reaction of compound 13a was for 18), and observation of an NOE between the formyl
cleaner in comparison with the case of the non-silylated proton and the adjacent hydrogen suggested a trans rela-
substrate 9, and the required tetracyclic adduct 14a could tionship between the cyano group and the methoxymethyl
be isolated as a mixture of two stereoisomers, along with group in compound 17.
the side-products 15 and 16, in the yields indicated in
To determine the configuration of the cyano group of 18,
Scheme 3. The ring-opened olefin product 16 may be both 17 and 18 were transformed into aromatized furan
formed by [1,5] sigmatropic rearrangement of the o-quino- derivatives 19 and 20, respectively, through a three-step oxi-
dimethane intermediate (probably a geometric isomer of 10), dation sequence (Scheme 4).[2b] The dihydrofuran part of
as previously discussed.[10] Furthermore, 14b was synthe- each was phenylselenenylated in the presence of MeOH fol-
sized in a higher yield than 14a. Although the two isomers lowed by syn elimination via a selenoxide to give a 2-meth-
of 14b, as well as those of 14a, were inseparable at this oxy-2,5-dihydrofuran structure which was treated with CSA
stage, chromatographic separation was achieved after desi- or TFA to furnish the aromatized products 19 and 20.
Eur. J. Org. Chem. 2008, 1426–1430
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Y. Matsuya, Y. Imamura, T. Miyahara, H. Ochiai, H. Nemoto
FULL PAPER
Comparison of various spectroscopic data revealed that
these compounds were stereoisomers and, therefore, there
is a cis relationship between the cyano and methoxymethyl
groups in compound 20 (and inevitably in 18).
Scheme 5.
pounds suppressed the virus proliferation to around 50% of
the control experiment (without drug treatment).[12] These
findings will provide a new perspective for the SAR consid-
erations of the dihydrofuran-fused tetracyclic compounds.
Scheme 4.
These stereochemical investigations revealed that the
only difference between the two isomers 17 and 18 was the
relative configuration of the methoxymethyl group. This im-
plies that the intramolecular [4+2] cycloaddition proceeded
via an exo transition state (TS-1) in which the cyano group
is oriented inwards in the o-quinodimethane (Scheme 5).[11]
In our previous studies on the synthesis of dihydrofuran-
fused compounds 1, the exclusive formation of all-cis-fused
cycloadducts was observed in all cases. This stereochemical
outcome should involve an endo transition state (TS-2)
probably as a result of preferable secondary interactions be-
tween orbitals.[2,3] In the present case, however, an unfavor-
able steric repulsion between the trialkylsilyl group and the
aromatic ring may disfavor TS-2, impeding the formation
of 21. Consequently, the selective formation of 17 and 18
possessing a common tetracyclic core with the same stereo-
chemistry was achieved. These results clearly suggest that a
silyl group introduced onto the furan ring can act as a tra-
celess regulator of the stereoselectivity of the formation of
the furan-fused tetracyclic system. Namely, substrates pos-
sessing the silyl group are a suitable choice when requiring
exo adducts, whereas endo adducts are usually formed with-
out such sterically demanding substituents. It is important
to note that both the installation and removal of stereocon-
trolling silyl groups are quite easily performed on the furan
ring.
The bioactivities of the new type of dihydrofuran-fused
compounds 17 and 18 were briefly examined with a focus
on anti-influenza virus activity. These compounds possess
quite a different molecular shape in a stereochemical sense
from compounds 1, which have previously been reported as
antivirus agents,[3] because of the different stereochemistry
at the ring fusion. Whereas compounds 1 have the all-cis-
fused system, which enforces a rigid cage-type conforma-
tion, compounds 17 and 18 are likely to have a rather
planar conformation. In spite of such a dissimilarity, these
compounds exhibited potent antivirus activity against the
influenza A virus comparable to that of the trifluoromethyl-
ated derivative 22, the most potent and promising com-
Table 1. Inhibitory effects of compounds 17, 18, and 22 on the
growth of influenza A/aichi/2/68 virus in MDCK cells at 10 µ
concentration.[a]
Compound
Virus yield (% of control)
17
18
22
54.4Ϯ6.2
47.8Ϯ10.1
52.5Ϯ6
[a] Data shown are the means Ϯ SD of three experiments.
Conclusions
In this study we have succeeded in the concise synthesis
of dihydrofuran-fused tetracyclic compounds with a 2-oxa-
furano-steroid-like framework. The synthesis requires only
five steps from the starting benzocyclobutene 5 and a
number of analogues bearing various substituents would be
accessible through the present synthetic pathway. In ad-
dition, the introduction of a bulky silyl group onto the fu-
ran moiety could control the stereochemical outcome of a
Diels–Alder reaction, in contrast to our past syntheses of
all-cis-fused ring systems such as 1. A thorough investiga-
tion of the biological profiles of compounds 17 and 18 is
underway and will be reported in due course.
Experimental Section
General Remarks: All nonaqueous reactions were carried out under
argon. Reagents were purchased from commercial sources and used
as received. Anhydrous solvents were prepared by distillation over
pound in our previous study (Table 1).[3b] All three com- CaH2 or purchased from commercial sources. 1H and 13C NMR
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Approach to a New Dihydrofuran-Fused Cyclic System
spectra were obtained with a Varian UNITY plus 500 instrument
using the chloroform peak as the internal reference. Mass spectra
were measured with a JEOL D-200 or AX 505 mass spectrometer
using the electron-impact ionization method (EI, 70 eV). IR spectra
were recorded with a JASCO FT/IR-460Plus spectrometer. Column
chromatography was carried out by employing Cica Silica Gel 60
(spherical, neutral, 40–50 µm or 63–210 µm). Compound 5 was
prepared according to the reported method.[7]
39.6 ppm. IR (neat): ν = 2235 cm–1. MS (EI): m/z = 313 [M]+.
˜
HRMS (EI): calcd. for C18H19NO4 313.1306 [M]+; found 313.1306.
1
Data for Compound 13a: H NMR (270 MHz, CDCl3): δ = 7.57–
7.55 (m, 1 H), 7.05–7.02 (m, 1 H), 6.90–6.76 (m, 2 H), 6.43–6.33
(m, 1 H), 4.73–4.69 (m, 1 H), 4.55–4.47 (m, 1 H), 3.79–3.38 (m, 11
H), 0.28 and 0.25 (s, 9 H) ppm. 13C NMR (67.5 MHz, CDCl3): δ
= 160.0, 146.3, 142.3, 141.2, 133.8, 133.1, 131.7, 131.6, 124.7, 124.6,
117.4, 117.0, 111.4, 111.2, 108.0, 107.9, 80.0, 78.8, 73.5, 73.4, 65.6,
65.2, 59.4, 59.3, 55.6, 55.5, 45.1, 45.0, 40.0, 39.6, –1.11, –1.17 ppm.
5-Methoxy-1-(2-methoxy-1-oxoethyl)benzocyclobutene-1-carbo-
nitrile (7): 5-Methoxybenzocyclobutene-1-carbonitrile (5) (1.0 g,
6.28 mmol) in dry THF (2 mL) was added to a stirred solution of
LDA (6.91 mmol) in dry THF (20 mL), prepared from diisopropyl-
amine and nBuLi, at –78 °C. After stirring for 10 min, Weinreb
amide 6 (920 mg, 6.91 mmol) in dry THF (2 mL) was added to the
reaction mixture and stirred at –78 °C for 1 h. The reaction was
quenched with a saturated NH4Cl aqueous solution and the aque-
ous mixture was extracted with AcOEt. The organic layer was dried
with MgSO4 and evaporated to leave a residue which was purified
by chromatography on silica gel (AcOEt–hexane, 1:1) to afford 7
(1.0 g, 69%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ =
7.09 (d, J = 7.9 Hz, 1 H), 6.92 (dd, J = 7.9, 2.0 Hz, 1 H), 6.86 (d,
J = 2.0 Hz, 1 H), 4.36 (s, 2 H), 3.90 (d, J = 14 Hz, 1 H), 3.79 (s, 3
H), 3.64 (d, J = 14 Hz, 1 H), 3.52 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 197.0, 160.5, 139.3, 133.8, 125.1, 117.8,
IR (neat): ν = 2236 cm–1. MS (EI): m/z = 385 [M]+. HRMS (EI):
˜
calcd. for C21H27NO4Si 385.1709 [M]+; found 385.1703.
1
Data for Compound 13b: H NMR (270 MHz, CDCl3): δ = 7.59–
7.56 (m, 1 H), 7.05–7.02 (m, 1 H), 6.91–6.76 (m, 2 H), 6.46–6.33
(m, 1 H), 4.74–4.68 (m, 1 H), 4.51–4.44 (m, 1 H), 3.81–3.38 (m, 11
H), 0.88 and 0.87 (s, 9 H), 0.26–0.22 (m, 6 H) ppm. 13C NMR
(67.5 MHz, CDCl3): δ = 160.0, 155.5, 155.3, 146.5, 142.4, 141.3,
133.8, 133.0, 132.8, 124.7, 124.6, 120.2, 120.0, 117.4, 117.0, 111.2,
111.1, 108.0, 107.9, 80.2, 79.1, 73.5, 73.4, 65.8, 65.5, 59.3, 59.2,
55.5, 55.4, 45.1, 45.0, 39.9, 39.6, 26.3, 17.3, 15.2, –5.77, –5.86,
–5.90 ppm. IR (neat): ν = 2230 cm–1. MS (EI): m/z = 427 [M]+.
˜
HRMS (EI): calcd. for C24H33NO4Si 427.2179 [M]+; found
427.2213.
General Procedure for the Thermal Reaction of Compounds 13a and
13b. Formation of the Tetracyclic Compounds 14a and 14b: A solu-
tion of the substrate 13a or 13b (0.2 mmol) in o-dichlorobenzene
(2 mL) was refluxed for 2 h. After disappearance of the starting
material on TLC, the solvent was evaporated in vacuo. The residue
117.5, 107.9, 75.3, 59.8, 55.7, 49.5, 39.6 ppm. IR (neat): ν = 2238,
˜
1735 cm–1. MS (EI): m/z = 231 [M]+. HRMS (EI): calcd. for
C13H13NO3 231.0985 [M]+; found 231.0985.
1-(1-Hydroxy-2-methoxyethyl)-5-methoxybenzocyclobutene-1- was purified by chromatography on silica gel (Et2O/hexane, 1:2) to
carbonitrile (8): Sodium borohydride (27 mg, 0.72 mmol) was
added to a stirred solution of the ketone 7 (166 mg, 0.72 mmol) in
MeOH (3 mL) at 0 °C and the mixture was stirred at the same
temperature for 1 h. After the reaction was complete, the mixture
was diluted with water and then extracted with AcOEt. The organic
layer was dried with MgSO4 and evaporated to leave a residue
which was purified by chromatography on silica gel (AcOEt/hex-
ane, 1:1) to afford the alcohol 8 (153 mg, 91%) as colorless plates (a
1:1 mixture of diastereomers); M.p. 93–95 °C. 1H NMR (270 MHz,
CDCl3): δ = 7.09–7.03 (m, 1 H), 6.92–6.88 (m, 2 H), 4.01–3.98 (m,
1 H), 3.80 (s, 3 H), 3.75–3.39 (m, 4 H), 3.46 (s, 3 H), 2.76–2.58 (m,
1 H) ppm. 13C NMR (67.5 MHz, CDCl3): δ = 160.1, 141.5, 133.7,
133.2, 125.1, 124.6, 120.0, 117.4, 117.2, 108.3, 107.8, 73.7, 73.4,
afford compound 14a (30 mg, 39%) or 14b (43 mg, 50%) as a col-
orless oil (an inseparable mixture of two diastereomers).
1
Data for Compound 14a: H NMR (270 MHz, CDCl3): δ = 7.17–
7.11 (m, 1 H), 7.03–6.80 (m, 2 H), 5.20–4.98 (m, 1 H), 4.58–4.34
(m, 2 H), 4.18–4.00 (m, 3 H), 3.83–3.78 (m, 4 H), 3.50 and 3.46 (s,
3 H), 3.25–2.95 (m, 2 H), –0.10 and –0.16 (s, 9 H) ppm. 13C NMR
(67.5 MHz, CDCl3): δ = 159.6, 158.8, 158.3, 158.2, 132.7, 131.4,
131.1, 130.8, 128.0, 126.7, 120.4, 119.8, 115.2, 114.7, 114.0, 113.9,
112.8, 82.0, 78.7, 78.6, 74.6, 73.0, 70.9, 65.1, 60.1, 59.4, 59.1, 56.2,
55.5, 41.6, 41.5, 33.8, 32.7, –2.16, –2.23 ppm. IR (neat): ν =
˜
2230 cm–1. MS (EI): m/z = 385 [M]+. HRMS (EI): calcd. for
C21H27NO4Si 385.1709 [M]+; found 385.1725.
1
Data for Compound 14b: H NMR (270 MHz, CDCl3): δ = 7.16–
72.8, 72.4, 59.3, 55.6, 45.0, 40.1, 38.8 ppm. IR (KBr): ν = 3431,
˜
7.11 (m, 1 H), 7.00–6.78 (m, 2 H), 5.21–5.06 (m, 1 H), 4.60–3.88
(m, 5 H), 3.82–3.76 (m, 4 H), 3.49 (s, 3 H), 3.38–3.00 (m, 2 H),
0.56 and 0.48 (s, 9 H), –0.09 and –0.10 (s, 6 H) ppm. 13C NMR
(67.5 MHz, CDCl3): δ = 159.1, 158.5, 157.2, 133.0, 131.5, 131.3,
131.1, 128.2, 127.1, 120.2, 119.8, 116.0, 115.1, 115.0, 114.1, 113.3,
112.6, 82.2, 78.9, 78.6, 74.6, 73.0, 71.0, 65.7, 60.3, 59.4, 59.1, 56.1,
55.6, 55.5, 49.1, 41.6, 40.5, 33.7, 32.8, 26.3, 25.9, 25.8, 16.3, 16.0,
2230 cm–1. MS (EI): m/z = 233 [M]+. HRMS (EI): calcd. for
C13H15NO3 233.1052 [M]+; found 233.1053.
General Procedure for the Synthesis of Furylmethyl Ethers 9, 13a,
and 13b: An excess amount of sodium hydride or potassium hydride
was suspended in dry THF and the alcohol 8 (1 mmol) and 3-
bromomethylfuran derivatives (1.1 mmol) were added successively
to the suspension at –35 °C. After stirring at –35 °C for 0.5 h and
0 °C for an additional 2 h, water was added to the reaction mixture
and the resultant aqueous solution was extracted with Et2O. The
organic layer was dried with MgSO4 and evaporated to leave a
residue which was purified by chromatography on silica gel
(CH2Cl2/hexane, 1:1) to afford the ether 9 (128 mg, 41%), 13a
(222 mg, 61%), or 13b (270 mg, 63%) as a colorless oil (a 1:1 mix-
ture of diastereomers).
–5.46, –5.80, –6.66, –6.69 ppm. IR (neat): ν = 2231 cm–1. MS (EI):
˜
m/z = 427 [M]+. HRMS (EI): calcd. for C24H33NO4Si 427.2179
[M]+; found 427.2157.
Desilylation of Compounds 14a and 14b. Formation of 17 and 18:
Tetra-n-butylammonium fluoride in 0.2 mL of THF (2 equiv.) was
added to a stirred solution of compound 14a or 14b (0.1 mmol) in
dry THF (1 mL) at room temperature. After completion of the re-
action (1 h), the reaction mixture was diluted with water and the
Data for Compound 9: 1H NMR (270 MHz, CDCl3): δ = 7.39–7.38 aqueous solution was extracted with Et2O which was then dried
(m, 2 H), 7.04–6.75 (m, 3 H), 6.38–6.36 (m, 1 H), 4.67–4.47 (m, 2
H), 3.78–3.31 (m, 11 H) ppm. 13C NMR (67.5 MHz, CDCl3): δ =
160.1, 143.5, 143.4, 142.4, 141.2, 140.7, 133.8, 133.1, 124.8, 124.6,
122.0, 121.7, 117.4, 117.1, 110.5, 110.3, 108.1, 107.8, 79.8, 78.5,
73.5, 73.4, 65.0, 64.5, 59.4, 59.3, 55.6, 55.5, 45.1, 45.0, 40.1,
with MgSO4. Evaporation of the solvent gave a residue, which was
purified by silica gel column chromatography (AcOEt/hexane, 3:2).
Two isomeric products were separated to afford compound 17
(17 mg, 54% from 14a, 15 mg, 47% from 14b) or 18 (6 mg, 20%
from 14a, 10 mg, 31% from 14b) as colorless needles.
Eur. J. Org. Chem. 2008, 1426–1430
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1429

Y. Matsuya, Y. Imamura, T. Miyahara, H. Ochiai, H. Nemoto
FULL PAPER
Data for Compound 17: M.p. 108–110 °C. 1H NMR (500 MHz,
CDCl3): δ = 7.17 (d, J = 8.1 Hz, 1 H), 7.03 (d, J = 2.6 Hz, 1 H),
6.86 (dd, J = 8.1, 2.6 Hz, 1 H), 6.06 (t, J = 1.7 Hz, 1 H), 5.17 (td,
J = 3.8, 10 Hz, 1 H), 4.70 (dd, J = 7.7, 2.7 Hz, 1 H), 4.49 (dd, J =
13, 1.7 Hz, 1 H), 4.21 (d, J = 13 Hz, 1 H), 4.19–4.11 (m, 1 H), 4.04
(d, J = 10 Hz, 1 H), 3.90 (dd, J = 11, 2.7 Hz, 1 H), 3.80 (s, 3 H),
3.49 (s, 3 H), 3.17 (dd, J = 15, 3.8 Hz, 1 H), 3.04 (dd, J = 15,
3.8 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.0, 142.8,
132.6, 131.1, 126.8, 120.2, 114.0, 112.8, 104.7, 79.2, 77.4, 72.7, 70.8,
59.4, 58.1, 55.8, 40.2, 28.0 ppm. IR (KBr): ν = 2229 cm–1. MS (EI):
˜
m/z = 311 [M]+. HRMS (EI): calcd. for C18H17NO4 311.1158
[M]+; found 311.1165.
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR data for all new compounds.
Acknowledgments
59.7, 58.8, 55.6, 40.5, 32.9 ppm. IR (KBr): ν = 2229 cm–1. MS (EI):
˜
m/z = 313 [M]+. HRMS (EI): calcd. for C18H19NO4 313.1314
This work was partially supported by a SUNBOR GRANT by the
Suntory Institute for Bioorganic Research and a Grant-in-Aid (No.
19590099) for Scientific Research by the Ministry of Education,
Culture, Sports, Science, and Technology of the Japanese Govern-
ment.
[M]+; found 313.1316.
Data for Compound 18: M.p. 179–181 °C. 1H NMR (500 MHz,
CDCl3): δ = 7.20 (d, J = 7.7 Hz, 1 H), 6.87–6.83 (m, 2 H), 5.97 (s,
1 H), 5.28 (td, J = 3.5, 10 Hz, 1 H), 4.36 (d, J = 12 Hz, 1 H), 4.18–
4.11 (m, 3 H), 4.06 (dd, J = 6.4, 2.1 Hz, 1 H), 3.84–3.79 (m, 4 H),
3.50 (s, 3 H), 3.29 (dd, J = 16, 3.0 Hz, 1 H), 3.12 (dd, J = 16,
2.1 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 158.3, 143.4,
131.3, 131.2, 127.4, 119.7, 115.4, 112.9, 104.4, 82.4, 79.3, 74.8, 64.6,
[1] For reviews, see: a) P. Wipf, R. J. Halter, Org. Biomol. Chem.
2005, 3, 2053–2061; b) J. R. Hanson, Nat. Prod. Rep. 1995, 12,
381–384.
59.4, 55.5, 54.1, 41.5, 33.6 ppm. IR (KBr): ν = 2226 cm–1. MS (EI):
˜
m/z = 313 [M]+. HRMS (EI): calcd. for C18H19NO4 313.1314
[2] a) N. Toyooka, M. Nagaoka, H. Nemoto, Synlett 2001, 1123–
1124; b) N. Toyooka, M. Nagaoka, E. Sasaki, H. Qin, H.
Kakuda, H. Nemoto, Tetrahedron 2002, 58, 6097–6101; for the
results of recent synthetic studies by other groups, see: c) H. S.
Sutherland, F. E. S. Souza, R. G. A. Rodrigo, J. Org. Chem.
2001, 66, 3639–3641; d) S. P. Maddaford, N. G. Andersen,
W. A. Cristofoli, B. A. Keay, J. Am. Chem. Soc. 1996, 118,
10766–10773; e) A. Kojima, T. Takemoto, M. Sodeoka, M. Shi-
basaki, Synthesis 1998, 581–589.
[3] a) Y. Matsuya, K. Sasaki, M. Nagaoka, H. Kakuda, N.
Toyooka, N. Imanishi, H. Ochiai, H. Nemoto, J. Org. Chem.
2004, 69, 7989–7993; b) Y. Matsuya, K. Sasaki, H. Ochiai, H.
Nemoto, Bioorg. Med. Chem. 2007, 15, 424–432.
[4] D.-Y. Yu, Y. Matsuya, Q.-L. Zhao, K. Ahmed, Z.-L. Wei, H.
Nemoto, T. Kondo, Apoptosis 2007, 12, 1523–1532.
[5] For recent studies on the synthesis of viridine itself or model
compounds, see: a) E. H. Sessions, P. A. Jacobi, Org. Lett.
2006, 8, 4125–4128; b) E. A. Anderson, E. J. Alexanian, E. J.
Sorensen, Angew. Chem. Int. Ed. 2004, 43, 1998–2001; c)
F. E. S. Souza, R. Rodrigo, Chem. Commun. 1999, 1947–1948.
[6] For synthetic studies of wortmannin and related compounds,
see: a) T. Mizutani, S. Honzawa, S. Tosaki, M. Shibasaki, An-
gew. Chem. Int. Ed. 2002, 41, 4680–4681; b) S. Sato, M. Nak-
ada, M. Shibasaki, Tetrahedron Lett. 1996, 37, 6141–6144; c)
C. A. Broka, B. Ruhland, J. Org. Chem. 1992, 57, 4888–4894.
[7] T. Kametani, M. Kajiwara, K. Fukumoto, Tetrahedron 1974,
30, 1053–1058.
[M]+; found 313.1323.
Transformation of Compounds 17 and 18 into the Aromatized Com-
pounds 19 and 20: Phenylselenenyl chloride (0.27 mmol) was added
to a stirred solution of the substrate 17 or 18 (0.25 mmol) in anhy-
drous MeOH (3 mL) at 0 °C and the mixture was stirred for 2.5 h.
The reaction was quenched with a saturated NaHCO3 solution, the
aqueous mixture was extracted with AcOEt, and then the com-
bined organic layers were washed with brine. After drying with
MgSO4, the solvent was evaporated to leave a residue which was
subjected to silica gel column chromatography (AcOEt/hexane,
1:1). The selenenylated product thus obtained was dissolved in
THF (2 mL) and 30% H2O2 was added to the solution at 0 °C.
After continuous stirring for 1 h, the reaction mixture was diluted
with a saturated NaHCO3 solution, extracted with AcOEt, and
dried. Evaporation of the solvent followed by column chromatog-
raphy on silica gel (AcOEt/hexane, 1:1) gave an intermediate, a 2-
methoxy-2,5-dihydrofuran derivative, in 78% (66 mg from 17) or
86% yield (73 mg from 18), respectively. These intermediates were
treated with organic acid at room temperature for 15 h (CSA in
acetone or TFA in CH2Cl2). After washing with a saturated
NaHCO3 solution followed by column chromatography (AcOEt/
hexane, 1:1), the aromatized product 19 (30 mg, 51%) or 20 (30 mg,
43%) was isolated.
Data for Compound 19: Colorless viscous oil. 1H NMR (300 MHz,
CDCl3): δ = 7.28–7.24 (m, 2 H), 7.17 (s, 1 H), 6.91 (dd, J = 8.5,
2.7 Hz, 1 H), 5.18 (d, J = 15 Hz, 1 H), 4.82 (dd, J = 15, 1.4 Hz, 1
H), 4.26 (dd, J = 16, 2.5 Hz, 1 H), 4.12–3.88 (m, 3 H), 3.84 (s, 3
H), 3.72–3.69 (m, 1 H), 3.59 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 158.7, 149.5, 134.7, 132.4, 131.3, 127.4, 119.7, 117.5,
115.6, 114.5, 114.2, 80.1, 74.2, 63.4, 60.0, 55.7, 41.0, 28.6 ppm. IR
[8] This compound was prepared from methoxyacetyl chloride and
N,O-dimethylhydroxylamine in the presence of triethylamine.
[9] a) S. Katsunuma, K. Hori, S. Fujiwara, S. Isoe, Tetrahedron
Lett. 1985, 26, 4625–4628; b) D. Goldsmith, D. Liotta, M.
Saindane, L. Waycole, P. Bowen, Tetrahedron Lett. 1983, 24,
5835–5838; c) E. J. Bures, B. A. Keay, Tetrahedron Lett. 1987,
28, 5965–5968.
[10] T. Kametani, M. Tsubuki, Y. Shiratori, Y. Kato, H. Nemoto,
M. Ihara, K. Fukumoto, J. Org. Chem. 1977, 42, 2672–2676.
[11] We suppose that the o-quinodimethane intermediate, having an
outward-oriented cyano group, would be largely transformed
into compound 16 by the [1,5]-sigmatropic rearrangement
pathway.
(neat): ν = 2230 cm–1. MS (EI): m/z = 311 [M]+. HRMS (EI): calcd.
˜
for C18H17NO4 311.1158 [M]+; found 311.1143.
Data for Compound 20: Colorless needles; m.p. 178–180 °C. 1H
NMR (300 MHz, CDCl3): δ = 7.27–7.21 (m, 2 H), 7.00 (d, J =
2.7 Hz, 1 H), 6.93 (dd, J = 8.5, 2.7 Hz, 1 H), 5.14 (dd, J = 15,
1.4 Hz, 1 H), 5.03–5.00 (m, 1 H), 4.85 (dd, J = 15, 1.4 Hz, 1 H),
4.09–3.92 (m, 2 H), 3.85 (s, 3 H), 3.24 (s, 3 H), 3.06–3.03 (m, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.0, 149.3, 135.1,
131.6, 131.1, 126.5, 121.2, 116.8, 115.2, 112.5, 111.9, 76.1, 67.5,
[12] The virus yields as a percent of the control were estimated by
a plaque titration method. Details of the experimental condi-
tions for the assay are described in ref.[3b]
Received: November 7, 2007
Published Online: January 24, 2008
1430
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Eur. J. Org. Chem. 2008, 1426–1430