Synthesis of biaryls via palladium-catalyzed [2+2+2] cocyclization of arynes and diynes: Application to the synthesis of arylnaphthalene lignans

Article abstract of DOI:10.1002/adsc.200600587

A novel method for construction of biaryls via palladium(0)-catalyzed [2 + 2 + 2] cocyclization of diynes and arynes was developed. By this [2+2+2] cocyclization, various arylnaphthalene derivatives, including a sterically hindered 2,2′-disubstituted-1,1′

Full text of DOI:10.1002/adsc.200600587

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DOI: 10.1002/adsc.200600587
Synthesis of Biaryls via Palladium-Catalyzed [2+2+2] Cocycliza-
tion of Arynes and Diynes: Application to the Synthesis of Aryl-
naphthalene Lignans
Yoshihiro Sato,a,* Takayuki Tamura,a Atsushi Kinbara,a and Miwako Morib
a
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Fax : (+81)-11-706-4982; e-mail: biyo@pharm.hokudai.ac.jp
Health Sciences University of Hokkaido, Ishikari-tobetsu, Hokkaido 061-0293, Japan
b
Received: November 12, 2006
This paper is dedicated to Professor Masakatsu Shibasaki on his 60th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A novel method for construction of biaryls this [2+2+2] cocyclization as a key step, the total
via palladium(0)-catalyzed [2+2+2] cocyclization of syntheses of natural arylnaphthalene lignans, taiwa-
diynes and arynes was developed. By this [2+2+2] nin C, taiwanin E, and dehydrodesoxypodophyllotox-
cocyclization, various arylnaphthalene derivatives, in- in were achieved.
cluding a sterically hindered 2,2’-disubstituted-1,1’-bi-
naphthyl, can be constructed by virtue of a variety of Keywords: arynes; biaryls; cycloaddition; dehydro-
combinations of diynes and aryne precursors. Using desoxypodophyllotoxin; palladium; taiwanin
Introduction
compounds such as IV and V (Scheme 1).[1] On the
other hand, a transition metal-catalyzed [2+2+2] co-
Biaryls are an important class of compounds, not only cyclization of alkynes is a useful and highly atom-eco-
as structures found in a variety of natural products, in- nomic way for the construction of various aromatic
cluding molecules of medicinal interest, but also as a rings,[2] and this advantage compared to the above-
chiral source for asymmetric synthesis. A biaryl skele- mentioned usual aryl-aryl coupling methodology
ton such as III, which consists of two aromatic rings prompted us to utilize the [2+2+2] cocyclization for
attached to each other, is usually constructed through the synthesis of biaryl derivatives. In this context, we
an aryl-aryl coupling reaction between two aromatic have recently established a conceptually new method-
Scheme 1. Synthesis of biaryls via [2+2+2] cocyclization.
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ology for the synthesis of biaryls via Ni(0)-catalyzed catalyzed [2+2+2] cocyclization of diyne 3 and
[2+2+2] cocyclization, by which various biaryls III aryne 2 derived from precursor 2’.[8] We also report
were obtained in excellent yields by the [2+2+2] co- the application of this reaction to the total syntheses
cyclization of alkyne I and two molecules of acetylene of taiwanin C, taiwanin E, and dehydrodesoxypodo-
or by that of diyne II and one molecule of acety- phyllotoxin.
lene.[3]
We speculated that this methodology could be fur-
ther expanded to the construction of various aryl- Results and Discussion
naphthalene skeletons VII if the [2+2+2] cocycliza-
À
tion of diyne VI and an aryne, in which C C bond Synthesis of Arylnaphthalene Derivatives by Pd(0)-
formation occurs three times, would proceed Catalyzed [2+2+2] Cocyclization of Diynes and
(Scheme 2).[4–7]
Benzyne Derived froman Aryne Precursor with CsF
To examine the feasibility of the above-mentioned
plan shown in Scheme 2, we initially investigated the
[2+2+2] cocyclization of diynes 3a–d and benzyne
generated from precursor 2’a[9] (Table 1). When the
reaction of 3a or 3b and aryne precursor 2’a in the
presence of CsF was carried out in CH3CN at room
temperature using a Ni(0) catalyst prepared from Ni-
Table 1. [2+2+2] Cocyclization of diynes 3 and benzyne de-
A
rived from the precursor 2’a in the presence of CsF.[a]
Scheme 2. Plan for [2+2+2] cocyclization of diynes and
arynes.
Thus, the [2+2+2] cocyclization between VI and
an aryne is expected to provide us with novel method-
ology for the synthesis of various arylnaphthalenes 1
in short-step reactions, and these arylnaphthalene de-
rivatives should be key intermediates for the synthe-
ses of chinensin, justicidin B, diphyllin, and taiwanins
C and E (Figure 1). Herein we describe the construc-
tion of an arylnaphthalene skeleton by the palladium-
[a]
All reactions were carried out in CH3CN at room tem-
perature in the presence of 2’a (3 equivs.) and CsF (6
equivs.).
[b]
For runs 1 and 2, the Ni(0) catalyst was prepared by re-
duction of Ni(acac)2 (20 mol%) with DIBAL-H (40
G
mol%) in the presence of PPh3 (80 mol%). For runs 3–9,
5 mol% of Pd2dba3 was used. For runs 5, 7, 8 and 9, 40
mol% of a ligand was used. For run 6, 20 mol% of dppb
was used.
Figure 1. Plan for syntheses of arylnaphthalene lignans.
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Palladium-Catalyzed [2+2+2] Cocyclization of Arynes and Diynes
(acac)2, PPh3, and DIBAL-H,[3] the desired product
Table 2. Pd(0)-catalyzed [2+2+2] cocyclization of various
diynes 3 and benzyne derived from the precursor 2’a and
CsF.
P(o-tol)3 is suitable for this reaction and that the yield
U
of 1ab was greatly improved to 73% (run 7). The re-
action of 3c, having an aldehyde on the alkyne, with
2’a gave the desired product 1ac in only 2% yield
along with a complex mixture of polymerization prod-
ucts as a major product (run 8). On the other hand,
the reaction of 3d, which has an N-methoxy-N-meth-
ylcarboxamide moiety and was synthesized with the
aim of application to the synthesis of natural aryl-
naphthalene lignans, under similar conditions gave
the desired product in 78% yield (run 9).
To estimate the scope and limitations of the reac-
tion, various diynes were subjected to the above opti-
mal reaction conditions. The results are summarized
in Table 2. The reaction of 3e under similar conditions
gave the corresponding arylnaphthalene 1ae in good
yield (77%) (run 1). The reaction of 3f, having a
phenyl group on the alkyne, gave the product 1af in a
slightly lower yield (54%) (run 2). An electron-with-
drawing group on the benzene ring is tolerated in this
reaction, and the reaction of 3g, having a nitro group
on the alkyne, gave the product 1ag in good yield
(66%) (run 3). A substituent (MOM group) at the
ortho-position on the benzene ring is also tolerated,
and the cyclized product 1ah was obtained in 53%
yield from 3h (run 4). The cyclized product 1ai,
having a lactam structure in the arylnaphthalene skel- the sterically hindered 2,2’-disubstituted-1,1’-bi-
eton, was also obtained from the nitrogen-containing naphthyl derivative 1al was also obtained by [2+2+
diyne 3i in good yield (run 5). On the other hand, the 2] cocyclization of diyne 3l and benzyne derived from
reaction of 3j, having no electron-withdrawing sub- 2’a, although the yield was fairly low (run 8).
stituent on the terminus of alkyne, gave the cyclized
product in a low yield (27%, run 6) compared to that
in the case of the reaction of 3i (run 5), which is con- Application of Pd(0)-Catalyzed [2+2+2] Cocycliza-
sistent with the above-described results in the cases of tion of Diyne and Aryne to the Syntheses of Natural
3a and 3b (Table 1, runs 3 and 4). Binaphthyl skele- Arylnaphthalene Lignans: Total Syntheses of
tons can be also constructed by this reaction. Thus, Taiwanins C and E
the reaction of 3k and benzyne derived from 2’a
under the similar conditions gave binaphthyl deriva- Having established the Pd(0)-catalyzed [2+2+2] co-
tive 1ak in 46% yield (run 7). It is noteworthy that cyclization of diynes and benzyne derived from 2’a
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producing various arylnaphthalene derivatives, we
next turned our attention to applications of this meth-
odology to the synthesis of natural arylnaphthalene li-
gnans. Arylnaphthalene lignans, some of which are
shown in Figure 1, occur widely in nature and possess
various biological activities.[11] We planned to synthe-
size the natural arylnaphthalene lignans, taiwanins C
and E,[12] through [2+2+2] cocyclization of diyne 3d
and aryne precursor 2’b. The synthesis of aryne pre-
cursor 2’b was achieved by a procedure similar to that
reported by PØrez and Guitiµn,[6d] as shown in
Scheme 3. TMS ether 5, which was prepared from 4
and HMDS, was reacted with BuLi followed by treat-
ment of the resulting silyl-migration product with
Tf2O, giving 2’b in 83% yield (3 steps).
Scheme 5. Attempts at conversion of 1bd into aldehyde 6.
tion of the lactone moiety in 1bd is relatively difficult
at this stage.[14] On the other hand, when 1bd was
treated with NaOMe in CH2Cl2 at room temperature,
Scheme 3. Synthesis of aryne precursor 2’b.
The reaction of diyne 3d and aryne precursor 2’b ring-opening followed by rearrangement of the lac-
under the above-stated optimized conditions success- tone ring occurred to produce lactone-ester 9 in 78%
fully proceeded and gave the arylnaphthalene deriva- yield (Scheme 6).
tive 1bd in 61% yield (Scheme 4).
Chemoselective reduction of the lactone moiety in
Next, we attempted transformation of arylnaphtha- 9 proceeded successfully, giving lactol 10 in good
lene product 1bd into taiwanins. In order to convert yield. Treatment of 10 with NaBH4 followed by acidic
1bd into aldehyde-lactone 6, chemoselective reduc- work-up gave the desired alcohol-lactone 12 in excel-
tion[13] of the amide moiety in 1bd was initially tried lent yield in a one-pot operation via diol 11. PCC oxi-
using DIBAL-H at À788C (Scheme 5).
dation of 12 afforded the desired aldehyde-lactone 6
However, the desired product 6 was not obtained in 89% yield.
under the conditions used, although lactone-aldehyde
Finally, transformations of aldehyde-lactone 6 into
8a and lactol-aldehyde 8b were obtained in 17% and taiwanins C and E were investigated (Scheme 7).
67% yields, respectively. These products would have
Baeyer–Villiger oxidation of 6 with mCPBA fol-
been produced through reduction of the lactone lowed by hydrolysis of the corresponding formate
moiety in 1bd, indicating that chemoselective reduc- gave taiwanin E in 88% yield (2 steps). The spectral
Scheme 4. [2+2+2] Cocyclization of diyne 3d and aryne precursor 2’b.
G
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Palladium-Catalyzed [2+2+2] Cocyclization of Arynes and Diynes
Scheme 6. Conversion of 1bd into aldehyde 6.
Scheme 7. Total syntheses of taiwanins C and E.
data were identical to those previously reported.[12i] Total Synthesis of Dehydrodesoxypodophyllotoxin
On the other hand, taiwanin C was obtained in 64%
yield directly from the same intermediate 6 in one Encouraged by the successful syntheses of taiwanins
step through a decarbonylation reaction by treatment C and E, we applied the present method to the total
of 6 with a stoichiometric amount of Wilkinsonꢁs cata- synthesis of dehydrodesoxypodophyllotoxin.[17] The
lyst.[15] In addition, conversion of aldehyde-lactone 6 [2+2+2] cocyclization of diyne 3m and aryne precur-
into taiwanin C was also achieved without the use of sor 2’b under the optimized conditions again success-
a stoichiometric amount of expensive rhodium cata- fully proceeded and gave the corresponding product
lyst via Pd(0)-catalyzed hydrogenolysis[16] of triflate 1bm in 71% yield (Scheme 8).
13 derived from taiwanin E (Scheme 7).
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Scheme 8. [2+2+2] Cocyclization of diyne 3m and aryne precursor 2’b.
N
Conversion of 1bm into dehydrodesoxypodophyllo- for the synthesis of various arylnaphthalene lignans
toxin was succesfully achieved in a similar manner to by virtue of a variety of combinations of diynes and
the synthesis of taiwanin C via Pd(0)-catalyzed hydro- aryne precursors.
genolysis of the corresponding triflate 16 (Scheme 9).
The spectral data of the synthetic dehydrodesoxypo-
dophyllotoxin were identical to those previously re- Experimental Section
ported.
General Information
All manipulations were performed under an argon atmos-
phere unless otherwise mentioned. All solvents and reagents
Conclusions
were purified when necessary using standard procedures.
We succeeded in developing the novel method for the
synthesis of biaryls via Pd(0)-catalyzed [2+2+2] co-
cyclization of diynes and arynes, that could apply to
the construction of various arylnaphthalene skeletons
including the sterically hindered 2,2’-disubstituted-
1,1’-binaphthyl. Furthermore, using this cocyclization
as a key step, the total syntheses of taiwanin C, taiwa-
nin E, and dehydrodesoxypodophyllotoxin were ach-
Column chromatography was performed on silica gel 60
(Merck, 70–230 mesh), and flash chromatography was per-
formed on silica gel 60 (Merck, 230–400 mesh).
Preparation of Substrates 3a–j (See Scheme 10). Prop-
2-ynyl 3-(Benzo[d][1,3]dioxol-5-yl)propiolate (3a)
A
To a solution of 3-(benzo[d][1,3]dioxol-5-yl)propiolic acid
N
ieved. The present convergent strategy paves the way (17)[18] (2.21 g, 12 mmol), propargyl alcohol (18a) (1.4 mL,
Scheme 9. Total synthesis of dehydrodesoxypodophyllotoxin.
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Palladium-Catalyzed [2+2+2] Cocyclization of Arynes and Diynes
4-tert-Butyldimethylsilyloxybut-2-ynyl 3-(Benzo[d][1,3]-
G
dioxol-5-yl)propiolate (19)
Following the similar procedure for 3a, the crude product,
which was prepared from 17 (82 mg, 0.42 mmol), the propar-
gylic alcohol 18c[20] (132 mg, 0.66 mmol), DMAP (15 mg,
0.12 mmol), and DCC (133 mg, 0.64 mmol) in CH2Cl2
(2 mL) at room temperature for 1.5 h, was purified by
column chromatography on silica gel (hexane/AcOEt=4/1)
to give 19 as a colorless oil; yield: 195 mg (100%); IR
(nujol): n=2212, 1715, 1602 cmÀ1
;
1H NMR (270 MHz,
CDCl3): d=7.16 (dd, J=1.6, 7.9 Hz, 1H), 7.01 (d, J=1.6 Hz,
1H), 6.80 (d, J=7.9 Hz, 1H), 6.02 (s, 2H), 4.85 (t, J=
2.0 Hz, 2H), 4.37 (t, J=2.0 Hz, 2H), 0.91 (s, 9H), 0.12 (s,
6H); EI-LR-MS: m/z=372 (M+), 329, 315, 241, 173; EI-
HR-MS: m/z=372.1380, calcd. for C20H24O5Si (M+):
372.1393.
4-Hydroxybut-2-ynyl 3-(Benzo[d][1,3]dioxol-5-yl)pro-
U
piolate
To a solution of 19 (273 mg, 0.73 mmol) in CH3CN (3.4 mL)
was added HF-CH3CN solution (prepared by mixing con-
centrated aqueous HF with CH3CN (ratio of 1:9), 0.9 mL) at
08C, and the mixture was stirred at room temperature for
2 h. To the solution was added saturated aqueous NaHCO3
solution, and the mixture was extracted with Et2O. The or-
ganic layer was washed with brine, and dried over Na2SO4.
After removal of the solvent, the residue was purified by
column chromatography on silica gel (hexane/AcOEt=3/2)
to give the corresponding alcohol as a colorless solid: yield:
Scheme 10. Synthesis of substrates 3a–d.
24 mmol), and DMAP (0.43 g, 3.4 mmol) in CH2Cl2 (55 mL)
was added DCC (3.65 g, 18 mmol) at 08C, and the mixture
was stirred at room temperature for 4 h. The mixture was di-
luted with CH2Cl2, and the solution was washed with 5%
aqueous HCl, saturated aqueous NaHCO3, and brine, and
dried. After removal of the solvent, the residue was purified
by flash column chromatography on silica gel (hexane/
AcOEt=12/1) to give 3a as an off-white solid; yield: 2.36 g
(89%); mp 62–638C; IR (neat): n=3268, 2214, 2133,
179 mg 9(4%); mp 95–968C; IR (nujol): n=3517, 2211,
G
1
1681 cmÀ1; H NMR (270 MHz, CDCl3): d=7.17 (dd, J=1.6,
8.3 Hz, 1H), 7.01 (d, J=1.6 Hz, 1H), 6.81 (d, J=8.3 Hz,
1H), 6.03 (s, 2H), 4.86 (t, J=1.6 Hz, 2H), 4.33 (dt, J=1.6,
6.3 Hz, 2H), 1.58 (t, J=6.3 Hz, 1H); EI-LR-MS: m/z=258
(M+), 241, 173; EI-HR-MS: m/z=258.0534, calcd. for
C14H10O5 (M+): 258.0528.
1
1716 cmÀ1; H NMR (270 MHz, CDCl3): d=7.17 (dd, J=1.6,
7.9 Hz, 1H), 7.01 (d, J=1.6 Hz, 1H), 6.80 (d, J=7.9 Hz,
1H), 6.03 (s, 2H), 4.81 (d, J=2.6 Hz, 2H), 2.54 (t, J=
2.6 Hz, 1H); 13C NMR (67.5 MHz, CDCl3): d=53.1, 75.7,
76.8, 78.8, 88.2, 101.7, 108.7, 112.1, 112.5, 129.0, 47.5, 150.1,
153.0; EI-LR-MS: m/z=228 (M+), 173, 146; EI-HR-MS: m/
z=228.0418, calcd. for C13H8O4: 228.0422.
3-Formylprop-2-ynyl 3-(Benzo[d][1,3]dioxol-5-yl)pro-
piolate (3c)
G
To a solution of the above alcohol (86 mg, 0.33 mmol) in
CH2Cl2 (1.6 mL) were added MS 4 Š (643 mg) and PCC
(214 mg, 0.99 mmol) at 08C, and the mixture was stirred at
the same temperature for 1.5 h. The mixture was diluted
with Et2O, and filtered through a pad of Florisil. The filtrate
was concentrated, and the residue was purified by column
chromatography on silica gel (hexane/AcOEt=3/1) to give
3c as a yellowish oil; yield: 57 mg (67%); IR (nujol): n=
Methyl 4-[3-(Benzo[d][1,3]dioxol-5-yl)propioloyloxy]-
G
but-2-ynoate (3b)
2907, 2209, 1714, 1673, 1602 cmÀ1
;
1H NMR (270 MHz,
Following the similar procedure for 3a, the crude product,
which was prepared from the carboxylic acid 17 (200 mg,
1.1 mmol), the propargylic alcohol 18b[19] (181 mg,
1.6 mmol), DMAP (39 mg, 0.32 mmol), and DCC (326 mg,
1.6 mmol) in CH2Cl2 (5 mL) at room temperature for
20 min, was purified by column chromatography on silica
gel (hexane/AcOEt=3/1) to give 3b as an off-white solid;
yield: 258 mg (86%); mp 102–1038C; IR (neat): n=2210,
CDCl3): d=9.25 (s, 1H), 7.21 (dd, J=1.6, 7.9 Hz, 1H), 7.02
(d, J=1.6 Hz, 1H), 6.82 (d, J=7.9 Hz, 1H), 6.03 (s, 2H),
4.99 (s, 2H); EI-LR-MS: m/z=256 (M+), 227, 199; EI-HR-
MS: m/z=256.0363, calcd. for C14H8O5 (M+): 256.0371.
N-Methoxy-N-methyl-4-(tetrahydro-2H-pyran-2-yloxy)-
but-2-ynamide (22)
1
1717, 1602 cmÀ1; H NMR (270 MHz, CDCl3): d=7.18 (dd,
A
solution of 20 (100 mg, 0.71 mmol), 21[21] (137 mg,
1.1 mmol), PdCl2(CH3CN)2 (5.8 mg, 0.02 mmol), PPh3
J=1.6, 8.1 Hz, 1H), 7.01 (d, J=1.6 Hz, 1H), 6.82 (d, J=
8.1 Hz, 1H), 6.03 (s, 2H), 4.92 (s, 2H), 3.80 (s, 3H); EI-LR-
MS: m/z=286 (M+), 271, 173; EI-HR-MS: m/z=286.0476,
calcd. for C15H10O6: 286.0477.
AHCTREUNG
(30 mg, 0.11 mmol), and CuI (15 mg, 0.077 mmol) in Et3N
(3.6 mL) was stirred at 908C for 2 h. The mixture was con-
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centrated, and the residue was purified by column chroma-
tography on silica gel (hexane/AcOEt=8/1 to 2/1) to give
22 as a colorless oil; yield: 98 mg (61%); IR (neat): n=
moval of the solvent, the residue was purified by column
chromatography on silica gel (hexane/AcOEt=3/1) to give
3e as a colorless solid; yield: 203 mg (69% for 2 steps); mp
2240, 1644 cmÀ1
;
1H NMR (270 MHz, CDCl3): d=4.84 (s,
125–1268C; IR (film): n=2207, 1711, 1595, 1514, 1443 cmÀ1
;
1H), 4.44 (s, 2H), 3.88–3.80 (m, 1H), 3.78 (s, 3H), 3.58–3.50
(m, 1H), 3.24 (s, 3H), 1.90–1.55 (m, 6H); EI-LR-MS: m/z=
227 (M+), 167, 127; EI-HR-MS: m/z=227.1156, calcd. for
C11H17NO4: 227.1157.
1H NMR (400 MHz, CDCl3): d=3.80 (s, 3H), 3.89 (s, 3H),
3.92 (s, 3H), 4.93 (s, 2H), 6.85–6.87 (m, 1H), 7.08–7.08 (m,
1H), 7.24–7.26 (m, 1H); EI-LR-MS: m/z=302 (M+), 301,
287, 273, 189, 75; EI-HR-MS: m/z=302.0789, calcd. for
C16H14O6: 302.0732.
4-Hydroxy-N-methoxy-N-methylbut-2-ynamide (18d)
Methyl 4-(3-Phenylpropioloyloxy)but-2-ynoate (3f)
To a solution of 22 (949 mg, 4.2 mmol) in MeOH (11 mL)
was added p-TsOH (80 mg, 0.42 mmol), and the mixture
was stirred at room temperature for 2 h. To the mixture was
added saturated aqueous NaHCO3 solution, and the solution
was concentrated. The solution was extracted with CH2Cl2
and the organic layer was washed with brine, and dried over
Na2SO4. After removal of the solvent, the residue was puri-
fied by column chromatography on silica gel (hexane/
AcOEt=1/2) to give 18d as a colorless oil; yield: 429 mg
To a solution of 3-phenylpropiolic acid (commercially avail-
able from Aldrichꢂ, 200 mg, 0.97 mmol) and 18b (133 mg,
1.2 mmol) in THF (6.3 mL) were successively added PPh3
(306 mg, 1.2 mmol) and a solution of DIAD (0.23 mL,
1.2 mmol) in THF (3.2 mL) at 08C, and the mixture was stir-
red at room temperature for 2 h. The mixture was diluted
with CH2Cl2, and the solution was washed with saturated
aqueous NaHCO3 solution and brine, dried over Na2SO4.
After removal of the solvent, the residue was purified by
column chromatography on silica gel (hexane/AcOEt=10/1)
to give 3f as a colorless solid; yield: 171 mg (72%); mp 50–
528C; IR (film): n=2958, 2223, 1719, 1490, 1435, 1262, 1184,
(81%); IR (neat): n=3395, 2239, 1639 cmÀ1
;
1H NMR
(270 MHz, CDCl3): d=4.45 (s, 2H), 3.79 (s, 3H), 3.24 (s,
3H), 2.78 (br. s, 1H); EI-LR-MS: m/z=143 (M+), 83; EI-
HR-MS: m/z=143.0576, calcd. for C6H9NO3: 143.0582.
1162 cmÀ1 1H NMR (400 MHz, CDCl3): d=7.59–7.61 (m,
;
2H), 7.45–7.50 (m, 1H), 7.39 (br. t, J=7.6 Hz, 2H), 4.94 (s,
2H), 3.80 (s, 3H); EI-LR-MS: m/z=241 (M+ÀH), 227, 184,
129, 101; EI-HR-MS: m/z=241.0498, calcd. for C14H9O4:
241.0501.
3-(N-Methoxy-N-methylcarbamoyl)prop-2-ynyl 3-(Ben-
zo[d][1,3]dioxol-5-yl)propiolate (3d)
A
Following the similar procedure for 3a, the crude product,
which was prepared from 17 (405 mg, 2.1 mmol), the propar-
gylic alcohol 18d (358 mg, 2.5 mmol), DMAP (77 mg,
0.63 mmol), and DCC (676 mg, 3.3 mmol) in CH2Cl2
(15 mL) at room temperature for 20 min, was purified by
flash column chromatography on silica gel (hexane/
AcOEt=2/1) to give 3d as a yellowish solid; yield: 576 mg
Methyl 4-[3-(4-Nitrophenyl)propioloyloxy]but-2-ynoate
(3g)
To a solution of 3-(4-nitrophenyl)propiolic acid (CAS Regis-
try No. 2216–24–2, 88 mg, 0.458 mmol) and 18b (63 mg,
0.55 mmol) in THF (3.5 mL) were successively added PPh3
(306 mg, 1.2 mmol) and a solution of DIAD (0.10 mL,
0.55 mmol) in THF (1.5 mL) at 08C, and the mixture was
stirred at 708C for 12 h. The mixture was diluted with
CH2Cl2, and the solution was washed with saturated aqueous
NaHCO3 solution and brine, dried over Na2SO4. After re-
moval of the solvent, the residue was purified by column
chromatography on silica gel (hexane/AcOEt=3/1) to give
3g as a colorless solid; yield: 61 mg (47%); mp 115–1168C;
IR (film): n=2231, 1716, 1597, 1524, 1436, 1349, 1263,
(86%); mp 103–1058C; IR (film): n=2210, 1714, 1644 cmÀ1
;
1H NMR (270 MHz, CDCl3): d=7.17 (dd, J=1.6, 8.1 Hz,
1H), 7.01 (d, J=1.6 Hz, 1H), 6.81 (d, J=8.1 Hz, 1H), 6.03
(s, 2H), 4.96 (s, 2H), 3.79 (s, 3H), 3.24 (s, 3H); EI-LR-MS:
m/z=315 (M+), 284, 255, 183; EI-HR-MS: m/z=315.0731,
calcd. for C16H13NO6: 315.0743.
Methyl 4-[3-(3,4-Dimethoxyphenyl)propioloyloxy]but-
2-ynoate (3e)
1169 cmÀ1 1H NMR (400 MHz, CDCl3): d=8.27 (d, J=
;
To a solution of methyl methyl 3-(3,4-dimethoxyphenyl)pro-
piolate[22] (1.00 g, 4.5 mmol) in MeOH (90 mL) was added
10% aqueous NaOH solution (45 mL), and the mixture was
stirred at room temperature for 13.5 h. The mixture was
acidified by the addition of 1M aqueous HCl solution, and
extracted with AcOEt. The organic layer was washed with
brine, and dried over Na2SO4. After removal of the solvent,
the crude material of 3-(3,4-dimethoxyphenyl)propiolic acid
was obtained, which was used in the next step without fur-
ther purification; yield: 902 mg.
To a solution of the crude carboxylic acid (200 mg,
0.97 mmol) and 18b (132 mg, 1.2 mmol) in THF (6.7 mL)
were successively added PPh3 (304 mg, 1.2 mmol) and a so-
lution of DIAD (diisopropyl azodicarboxylate) (0.23 mL,
1.2 mmol) in THF (3.0 mL) at 08C, and the mixture was stir-
red at 708C for 4 h. The mixture was diluted with CH2Cl2,
and the solution was washed with saturated aqueous
NaHCO3 solution and brine, dried over Na2SO4. After re-
8.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 4.97 (s, 2H), 3.81 (s,
3H); 13C NMR (67.9 MHz, CDCl3): d=153.0, 152.0, 148.7,
133.8, 125.6, 123.8, 84.8, 82.8, 79.6, 78.6, 53.0, 52.7; EI-MS:
m/z=286 (M+À1), 272, 258, 240, 229, 213, 184, 174, 128; EI-
HR-MS: m/z=286.0366, calcd. for C14H8NO6: 286.0351.
Methyl 3-[2-(Methoxymethoxy)phenyl]propiolate
To a solution of 1-(2,2-dibromovinyl)-2-(methoxymethoxy)-
benzene[23] (4.29 g, 13.3 mmol) in THF (44 mL) was added
BuLi (1.47M hexane solution, 27.2 mL, 40 mmol) at À788C,
and the mixture was stirred at the same temperature for
10 min. To the solution was added methyl chloroformate
(3.1 mL, 40 mmol) at À788C, and the mixture was stirred at
08C for 1.5 h. To the mixture was added saturated aqueous
NH4Cl solution, and the mixture was extracted with AcOEt.
The organic layer was washed with brine, and dried over
654
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DEDICATED CLUSTER
FULL PAPERS
Palladium-Catalyzed [2+2+2] Cocyclization of Arynes and Diynes
Na2SO4. After removal of the solvent, the residue was puri-
fied by column chromatography on silica gel (hexane/
AcOEt=50/1) to give the ester as a yellowish oil; yield:
1.51 (52%); IR (neat): n=3021, 2955, 2829, 2224, 1711,
1H), 6.12 (br. S, 1H), 5.26 (s, 2H), 4.15–4.18 (m, 2H), 3.52
(s, 3H), 2.27–2.32 (m, 1H); EI-MS: m/z=243 (M+), 212,
198, 130, 77; EI-HR-MS: m/z=243.0892, calcd. for
C14H13NO3: 243.0895.
1598, 1577, 1491, 1452, 1435, 1404, 1274, 1176 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=7.50–7.55 (m, 1H), 7.35–
7.31 (m, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.97–7.02 (m, 1H),),
5.26 (s, 2H), 3.84 (s, 3H), 3.52 (s, 3H); EI-MS: m/z=220
(M+), 205, 189, 175, 161, 144, 77; EI-HR-MS: m/z=
220.0722, calcd. for C24H16O4: 220.0735.
Methyl 4-{3-[2-(Methoxymethoxy)phenyl]-N-(methoxy-
carbonyl)propiolamido}but-2-ynoate (3i) and Methyl
3-[2-(Methoxymethoxy)phenyl]propioloyl(prop-2-ynyl)-
carbamate (3j)
To a THF solution of LDA, which was prepared in situ by
mixing i-Pr2NH (0.09 mL, 0.65 mmol) and BuLi (1.56M
hexane solution, 0.41 mL, 0.65 mmol) in THF (1.1 mL) at
08C for 15 min, was added a solution of the above-men-
tioned 3-[2-(methoxymethoxy)phenyl]-N-(prop-2-ynyl)pro-
piolamide (52 mg, 0.22 mmol) in THF (1.1 mL) at À788C,
and the mixture was stirred at the same temperature for 1 h.
To the solution was added methyl chloroformate (0.04 mL,
0.45 mmol) at À788C, and the mixture was stirred at the
same temperature for 2 h. To the mixture was added saturat-
ed aqueous NH4Cl solution, and the solution was extracted
with Et2O. The organic layer was washed with brine, and
dried over Na2SO4. After removal of the solvent, the residue
was purified by column chromatography on silica gel
(hexane/AcOEt=6/1) to give 3i (yield: 28 mg, 36%) and 3j
(yield: 38 mg, 59%) as a yellowish oil, respectively.
Methyl 4-{3-[2-(Methoxymethoxy)phenyl]propioloyl-
oxy}but-2-ynoate (3h)
To a solution of methyl 3-[2-(methoxymethoxy)phenyl]pro-
piolate (1.21 g, 5.5 mmol) in MeOH (70 mL) was added
10% aqueous NaOH solution (55 mL), and the mixture was
stirred at room temperature for 1 h. The mixture was acidi-
fied by the addition of 1M aqueous HCl solution, and the
mixture was extracted with AcOEt. The organic layer was
washed with brine, and dried over Na2SO4. After removal of
the solvent, the crude material of 3-[2-(Methoxymethoxy)-
phenyl]propiolic acid was obtained, which was used in the
next step without further purification; yield: 1.04 g.
To a solution of the crude carboxylic acid (247 mg,
1.2 mmol) and 18b (164 mg, 1.4 mmol) in THF (7.5 mL)
were successively added PPh3 (378 mg, 1.4 mmol) and a so-
lution of DEAD (0.23 mL, 1.4 mL) in THF (4.5 mL) at 08C,
and the mixture was stirred at room temperature for 2.5 h.
The mixture was diluted with CH2Cl2, and the solution was
washed with saturated aqueous NaHCO3 solution and brine,
dried over Na2SO4. After removal of the solvent, the residue
was purified by column chromatography on silica gel
(hexane/AcOEt=10/1) to give 3h as a yellowish oil; yield:
292 mg (80%); IR (neat): n=2956, 2219, 1721, 1597, 1576,
Spectral data of 3i: IR (neat): n=3021, 2957, 2208, 1718,
1659, 1597, 1575, 1490, 1441, 1411, 1262 cmÀ1 1H NMR
;
(400 MHz, CDCl3): d=7.57 (dd, J=7.7, 1.7 Hz, 1H), 7.40
(ddd, J=8.5, 7.4, 1.7 Hz, 1H), 7.16 (br. d, J=8.5 Hz, 1H),
7.02 (m, 1H), 5.28 (s, 2H), 4.75 (s, 2H), 3.96 (s, 2H), 3.77 (s,
2H), 3.53 (s, 2H); EI-MS: m/z=359 (M+), 343, 329, 314,
283, 254; EI-HR-MS: m/z=359.1011, calcd. for C18H17NO7:
359.1005.
Spectral data of 3j: IR (neat): n=3020, 2958, 2208, 1752,
1490, 1452, 1437, 1298, 1265, 1199, 1170 cmÀ1 1H NMR
;
1656, 1597, 1491, 1442, 1279 cmÀ1
;
1H NMR (400 MHz,
(400 MHz, CDCl3): d=7.54 (dd, J=7.7, 1.7 Hz, 1H), 7.41
(ddd, J=8.6, 7.5, 1.7 Hz, 1H), 7.17 (d, J=8.6 Hz, 1H), 7.01
(br. t, J=7.6 Hz, 1H), 5.28 (s, 2H), 4.94 (s, 2H), 3.80 (s,
3H), 3.53 (s, 3H); EI-MS: m/z=301 (M+ÀH), 287, 271, 241,
189, 159, 144, 116, 77; EI-HR-MS: m/z=301.0707, calcd. for
C16H13O6: 301.0712.
CDCl3): d=7.57 (dd, J=7.7, 1.7 Hz, 1H), 7.39 (ddd, J=8.5,
7.5, 1.7 Hz, 1H), 7.16 (br. d, J=8.5 Hz, 1H), 7.01 (ddd, J=
7.7, 7.5, 0.9 Hz, 1H), 5.28 (s, 2H), 4.61 (d, J=2.5 Hz, 2H),
3.96 (s, 3H), 3.53 (s, 3H), 2.22 (t, J=2.5 Hz, 1H); EI-MS:
m/z=301 (M+), 271, 241, 189, 77; EI-HR-MS: m/z=
300.0874 (M+ÀH), calcd. for C16H14NO5: 300.0872.
3-[2-(Methoxymethoxy)phenyl]-N-(prop-2-ynyl)propiol-
amide
Methyl 4-[3-(Naphthalen-1-yl)propioloyloxy]but-2-yno-
ate (3k)
To a solution of the above-mentioned crude 3-[2-(methoxy-
methoxy)phenyl]propiolic acid (100 mg, 0.49 mmol) in
CH3CN (0.6 mL) were added PPh3 (127 mg, 0.49 mmol),
Et3N (0.07 mL, 0.49 mmol), propargylamine (0.03 mL,
Following the similar procedure for 3a, the crude product,
which was prepared from 3-(naphthalen-1-yl)propiolic
acid[25] (1.63 g, 8.3 mmol), the propargylic alcohol 18b[19]
(1.09 g, 9.5 mmol), DMAP (310 mg, 2.5 mmol), and DCC
(2.79 g, 13.5 mmol) in CH2Cl2 (47 mL) at room temperature
for 1.5 h, was purified by column chromatography on silica
gel (hexane/AcOEt=10/1) to give 3k as a yellowish solid;
yield: 1.29 g (53%); mp 92–948C; IR (film): n=3021, 2954,
[24]
0.39 mmol), and CCl4 (0.05 mL, 0.49 mmol) at room tem-
perature, and the mixture was stirred for 10 h. After remov-
al of the solvent, the residue was dissolved in Et2O, and the
Et2O solution was filtered through a pad of Celite. The fil-
trate was washed with saturated aqueous NaHCO3 solution
and brine, and dried over Na2SO4. After removal of the sol-
vent, the residue was purified by column chromatography
on silica gel (hexane/AcOEt=10/1) to give the amide as a
colorless oil; yield: 52 mg (44%); IR (neat): n=3438, 3307,
2250, 2217, 1714, 1586, 1509, 1436, 1273, 1196, 1167 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=8.32 (br. d, J=8.3 Hz, 1H),
7.98 (br. d, J=8.3 Hz, 1H), 7.86–7.91 (m, 2H), 7.62–7.68 (m,
1H), 7.55–7.60 (m, 1H), 7.48 (dd, J=8.3, 7.5 Hz, 1H), 5.00
(s, 2H), 3.82 (s, 3H); EI-MS: m/z=291 (M+ÀH), 277, 233,
3019, 2220, 1653, 1598, 1508, 1452, 1274 cmÀ1 1H NMR
;
(400 MHz, CDCl3): d=7.49 (dd, J=7.5, 1.7 Hz, 1H), 7.33–
7.39 (m, 1H), 7.15 (br, d, J=8.5 Hz, 1H), 6.95–7.02 (m,
179, 163, 151; EI-HR-MS: m/z=291.0658
A
C18H11O4: 291.0657.
Adv. Synth. Catal. 2007, 349, 647 – 661
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655

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Yoshihiro Sato et al.
70.1, 101.4, 108.3, 110.5, 115.3, 120.2, 123.6, 126.1, 127.0,
127.4, 128.8, 130.5, 133.9, 134.3, 144.6, 146.7, 147.6, 148.1,
166.3, 168.9; EI-LR-MS: m/z=362 (M+), 348, 331; EI-HR-
MS: m/z=362.0779, calcd. for C21H12O4: 362.0790.
Methyl 4-{3-[2-(Methoxymethoxy)naphthalen-1-yl]pro-
pioloyloxy}but-2-ynoate (3l)
To a solution of methyl 3-[2-(methoxymethoxy)naphthalen-
1-yl]propiolate[3c] (571 mg, 2.1 mmol) on MeOH (26 mL)
was added 10% aqueous NaOH solution (21 mL), and the
mixture was stirred at room temperature for 1 h. The mix-
ture was acidified by the addition of 1M HCl aqueous solu-
tion, and the mixture was extracted with AcOEt. The organ-
ic layer was washed with brine, and dried over Na2SO4.
After removal of the solvent, the crude carboxylic acid was
obtained, which was used in the next step without further
purification; yield: 563 mg.
Following the similar procedure for 3a, the crude product,
which was prepared from the carboxylic acid (410 mg,
1.6 mmol), the propargylic alcohol 18b[19] (236 mg,
2.1 mmol), DMAP (58.6 mg, 0.48 mmol), and DCC (528 mg,
2.6 mmol) in CH2Cl2 (8.0 mL) at room temperature for
1.5 h, was purified by column chromatography on silica gel
(hexane/AcOEt=10/1) to give 3l as a yellowish oil; yield:
9-(Benzo[d]
[2,3-c]furan-4-carbaldehyde (1ac): Mp. 209–2118C (sublim.);
IR (neat): n=2926, 1679, 1672 cmÀ1 1H NMR (270 MHz,
A
AHCTREUNG
;
CDCl3): d=11.16 (s, 1H), 8.84 (d, J=8.6 Hz, 1H), 8.03 (d,
J=8.6 Hz, 1H), 7.90 (t, J=7.9, 8.6 Hz, 1H), 7.62 (dd, J=
7.9, 8.6 Hz, 1H), 7.00 (d, J=7.9 Hz, 1H), 6.85–6.82 (m, 2H),
6.11 (s, 1H), 6.09 (s, 1H), 5.77 (s, 2H); EI-LR-MS: m/z=
332 (M+), 303; EI-HR-MS: m/z=332.0691, calcd. for
C20H12O5: 332.0684.
9-(Benzo[d]
ACHTREUNG
methyl-1-oxonaphtho
AHCTREUNG
1
(neat): n=1768, 1646 cmÀ1; H NMR (270 MHz, CDCl3): d=
7.99 (d, J=8.7 Hz, 1H), 7.93 (d, J=8.3 Hz, 1H), 7.69 (t, J=
7.5 Hz, 1H), 7.53 (t, J=7.5 Hz, 1H), 6.97 (d, J=7.5 Hz,
1H), 6.89–6.79 (m, 2H), 6.08 (s, 1H), 6.05 (s, 1H), 5.43 (s,
2H), 3.55 (s, 3H), 3.39 (s, 3H); EI-LR-MS: m/z=391 (M+),
331; EI-HR-MS; m/z=391.1065, calcd. for C22H17NO6:
391.1056.
283 mg (50%); IR (neat): n=3021, 2210, 1719, 1260 cmÀ1
;
1H NMR (400 MHz CDCl3): d=8.23 (br. d, J=8.4 Hz, 1H),
7.92 (d, J=8.9 Hz, 1H), 7.81 (br. d, J=8.1 Hz, 1H), 7.61
(ddd, J=8.4, 7.0, 1.3 Hz, 1H), 7.45 (ddd, J=8.1, 7.0, 1.1 Hz,
1H), 7.43 (d, J=8.9 Hz, 1H), 5.40 (s, 2H), 4.99 (s, 2H), 3.81
(s, 3H), 3.58 (s, 3H); EI-MS: m/z=352 (M+), 321, 239, 194;
EI-HR-MS: m/z=352.0942, calcd. for C20H16O6: 352.0947.
Methyl
9-(3,4-Dimethoxyphenyl)-1,3-dihydro-1-oxo-
[2,3-c]furan-4-carboxylate (1ae): Mp 67–698C; IR
naphtho
AHCTREUNG
(film): n=2953, 1768, 1719, 1592, 1511, 1453 cmÀ1; H NMR
(270 MHz, CDCl3): d=3.87 (s, 3H), 4.00 (s, 3H), 4.11 (s,
3H), 5.64 (s, 2H), 6.88–6.95 (m, 2H), 7.04–7.07 (m, 1H),
7.75–7.81 (m, 1H), 7.93–7.96 (m, 1H), 9.11 (m, 1H); EI-LR-
MS: m/z=378 (M+), 363, 347, 331, 75; EI-HR-MS: m/z=
378.1103, calcd. for C22H18O6: 378.1106.
1
ACHTREUNG
Methyl 1-Oxo-9-phenyl-1,3-dihydronaphtho
carboxylate (1af): Mp 225–2308C; IR (film): n=3020, 2952,
1769, 1719, 1261, 1216 cmÀ1 1H NMR (400 MHz, CDCl3):
d=9.14 (d, J=8.7 Hz, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.78
(ddd, J=8.8, 6.8, 1.3 Hz, 1H), 7.50–7.58 (m, 4H), 7.33–7.38
(m, 2H), 5.65 (s, 2H), 4.11 (s, 3H); EI-MS: m/z=318 (M+),
243, 215, 129, 101, 77; EI-HR-MS: m/z=318.0891, calcd. for
C20H14O4: 318.0892.
G
A solution of Pd2
G
P
ACHTREUNG
;
under vacuum at 1008C for 2 h just before its use,
6.0 equivs. to substrate diyne) in degassed CH3CN (0.04M
to Pd catalyst) was stirred at room temperature for 20 min.
To the catalyst solution was added a solution of substrate
diyne and benzyne precursor (3.0 equivs. to diyne) in
CH3CN (0.16M to diyne) via a cannula at 08C, and the mix-
ture was stirred at room temperature until the diyne disap-
peared on TLC. To the mixture was added saturated aque-
ous NH4Cl solution, and the solution was stirred for 1 h with
exposure to air. Then the mixture was extracted with
AcOEt, the organic layer was washed with brine and dried
over Na2SO4. After removal of the solvent, the residue was
purified by column chromatography on silica gel to give the
cyclized product.
Methyl 9-(4-Nitrophenyl)-1,3-dihydro-1-oxonaphtho
c]furan-4-carboxylate (1ag): Mp 263–2658C; IR (film): n=
1766, 1718, 1514, 1347, 1027 cmÀ1 1H NMR (270 MHz,
A
;
CDCl3): d=9.16 (d, J=8.6 Hz, 1H), 8.43 (d, J=8.6 Hz, 2H),
7.83 (ddd, J=8.6, 6.6, 1.3 Hz, 1H), 7.69 (d, J=7.9 Hz, 1H),
7.50–7.70 (m, 3H), 5.69 (s, 2H), 4.13 (s, 3H); EI-MS: m/z=
363 (M+), 348,334, 319, 303, 288, 276, 257, 230, 201, 189; EI-
HR-MS: m/z=363.0747, calcd. for C20H13NO6: 363.0743.
Methyl 9-[2-(Methoxymethoxy)phenyl]-1-oxo-1,3-dihydro-
9-(Benzo[d]
C
naphtho
(film): n=3019, 2956, 2852, 1764, 1712, 1600, 1490, 1438,
1404, 1283, 1258, 1195 cmÀ1 1H NMR (400 MHz, CDCl3):
A
1H NMR (270 MHz, CDCl3): d=7.96 (d, J=8.3 Hz, 1H),
7.89 (s, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.64 (dd, J=7.1,
8.3 Hz, 1H), 7.50 (dd, J=7.1, 8.3 Hz, 1H), 6.98 (d, J=
7.9 Hz, 1H), 6.86–6.82 (m, 2H), 6.08 (d, J=6.7 Hz, 1H),
6.08 (d, J=6.7 Hz, 1H), 5.45 (s, 2H); EI-LR-MS: m/z=304
(M+), 275; EI-HR-MS: m/z=304.0737, calcd. for C19H12O4:
304.0735.
;
d=9.12 (d, J=8.7 Hz, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.77
(ddd, J=8.8, 6.8, 1.2 Hz, 1H), 7.45–7.55 (m, 2H), 7.34 (d,
J=8.3 Hz, 1H), 7.15–7.22 (m, 2H), 5.67 (d, J=16.0 Hz,
1H), 5.62 (d, J=16.0 Hz), 5.09 (d, J=7.0 Hz, 1H), 4.90 (d,
J=7.0 Hz, 1H), 4.10 (s, 3H), 3.18 (s, 3H); EI-MS: m/z=378
(M+), 346, 316, 274; EI-HR-MS: m/z=378.1102, calcd. for
C22H18O6 (M+ÀH): 378.1103.
Methyl
naphtho[2,3-c]furan-4-carboxylate (1ab): Mp. 218–2198C;
IR (nujol): n=1770, 1717 cmÀ1 1H NMR (270 MHz,
9-(Benzo[d][1,3]dioxol-5-yl)-1,3-dihydro-1-oxo-
ACHTREUNG
Methyl 9-[(2-Methoxymethoxy)phenyl]-2-methoxycarbon-
yl-1-oxo-2,3-dihydro-1H-benzo[f]isoindole-4-carboxylate
(1ai): Mp 70–748C; IR (film): n=3020, 2955, 1785, 1722,
CDCl3): d=9.10 (d, J=8.7 Hz, 1H), 7.93 (d, J=7.9 Hz, 1H),
7.81–7.75 (m, 1H), 7.59–7.53 (m, 1H), 6.99 (d, J=7.9 Hz,
1H), 6.84–6.83 (m, 2H), 6.09 (d, J=6.3 Hz, 2H), 5.64 (s,
2H), 4.10 (s, 3H); 13C NMR (67.5 MHz, CDCl3): d=52.5,
1
1607, 1492, 1440, 1282, 1255, 1177 cmÀ1; H NMR (400 MHz,
CDCl3): d=8.86 (d, J=8.8 Hz, 1H), 7.78 (br. d, J=8.5 Hz,
656
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DEDICATED CLUSTER
FULL PAPERS
Palladium-Catalyzed [2+2+2] Cocyclization of Arynes and Diynes
1H), 7.72 (ddd, J=8.7, 6.6, 1.3 Hz, 1H), 7.46–7.7.53 (m,
1H), 7.46 (ddd, J=8.5, 6.6, 2.6 Hz, 1H), 7.25–7.35 (m, 1H),
7.10–7.18 (m, 2H), 5.17 (s, 2H), 5.11 (d, J=6.8 Hz, 1H),
4.83 (d, J=6.8 Hz, 1H), 4.13 (s, 3H), 3.92 (s, 3H), 3.12 (s,
3H); EI-MS: m/z=435 (M+), 420, 390, 374, 358, 344, 302;
EI-HR-MS: m/z=435.1320, calcd. for C24H21NO7: 435.1318.
9-[(2-Methoxymethoxy)phenyl]-2-methoxycarbonyl-1-
oxo-2,3-dihydro-1H-benzo[f]isoindole (1aj): Mp 201–2038C;
IR (film): n=3060, 3006, 2955, 1771, 1629, 1581, 1489, 1438,
1400, 1271, 1236, 1194 cmÀ1; 1H NMR (400 MHz, CDCl3):
d=7.94 (br. d, J=8.5 Hz, 1H), 7.93 (br. s, 1H), 7.73 (d, J=
8.7 Hz, 1H), 7.58–7.63 (m, 1H), 7.41–7.47 (m, 2H), 7.29 (br.
d, J=8.3 Hz, 1H), 7.10–7.19 (m, 1H), 5.10 (d, J=6.8 Hz,
1H), 4.97 (s, 2H), 4.84 (d, J=6.8 Hz, 1H), 3.91 (s, 3H), 3.13
(s, 3H); EI-MS: m/z=377 (M+), 332, 316; EI-HR-MS:
m/z=377.1259, calcd. for C22H19NO5: 377.1263.
(83% from 4); IR (neat): n=1330, 1142 cmÀ1 1H NMR
;
(270 MHz, CDCl3): d=6.88 (s, 1H), 6.84 (s, 1H), 6.03 (s,
2H), 0.33 (s, 9H); EI-LR-MS: m/z=342 (M+), 327, 194; EI-
HR-MS: m/z=342.0197, calcd. for C11H13O5F3SSi: 342.0205;
anal. calcd. for C11H13O5F3SSi: C 38.59, H 3.83; found: C
38.58, H 3.83.
A
Pd2
N
N
0.20 mmol) were dissolved in CH3CN (1.2 mL), and the mix-
ture was stirred at room temperature for 15 min. The cata-
lyst solution was added via a cannula using CH3CN (1.0 mL)
for washing to a solution of 3d (160 mg, 0.51 mmol), 2’b
(530 mg, 1.6 mmol) and CsF (472 mg, 3.1 mmol) in CH3CN
(1.8 mL) at 08C, and the mixture was stirred at room tem-
perature for 4 h. To the mixture was added saturataed aque-
ous NH4Cl solution, and the solution was extracted with
AcOEt. The organic layer was washed with brine and dried
over Na2SO4. After removal of the solvent, the residue was
purified by column chromatography on silica gel (hexane/
AcOEt=3/2) to give 1bd (yield: 134 mg, 61%) as a yellow-
ish solid along with the recovery of unchanged 2’b (257 mg,
48% recovery). 1bd: Mp 239–2418C (decomp.); IR (neat):
Methyl
9-(Naphthalen-1-yl)-1-oxo-1,3-dihydronaphtho-
[2,3-c]furan-4-carboxylate (1ak): Mp 215–2228C; IR (film):
n=3019, 2952, 1771, 1694, 1605, 1508, 1437 cmÀ1; H NMR
1
(400 MHz, CDCl3): d=9.16 (br. d, J=8.7 Hz, 1H), 8.04 (d,
J=8.3 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.77 (ddd, J=8.7,
6.6, 1.3 Hz, 1H), 7.65 (dd, J=8.3, 7.0 Hz, 1H), 7.58 (br. d,
J=7.5 Hz, 1H), 7.39–7.50 (m, 3H), 7.22–7.28 (m, 1H), 7.04
(br. d, J=8.3 Hz, 1H),), 5.69 (s, 2H), 4.14 (s, 3H); EI-MS:
m/z=368 (M+ÀH), 353, 293; EI-HR-MS: m/z=368.1053,
calcd. for C24H16O4: 368.1048.
1
n=1762, 1653 cmÀ1; H NMR (270 MHz, CDCl3): d=7.26 (s,
1H), 7.25 (s, 1H), 6.97 (d, J=7.9 Hz, 1H), 6.83–6.74 (m,
2H), 6,10–6.06 (m, 4H), 5.35 (s, 2H), 3.51 (s, 3H), 3.43 (s,
3H); EI-LR-MS m/z=435 (M+), 375; EI-HR-MS: m/z=
435.0942, calcd. for C23H17NO8: 435.0954.
Methyl
1,3-dihydronaphtho
180–1848C; IR (nujol): n=1771, 1725, 1593, 1508, 1239, 802,
776 cmÀ1 1H NMR (400 MHz, CDCl3): d=9.17 (br. d, J=
9-[2-(Methoxymethoxy)naphthalen-1-yl]-1-oxo-
ACHTREUNG
;
8.8 Hz, 1H), 8.04 (d, J=9.0 Hz, 1H), 7.90 (d, J=8.3 Hz,
1H), 7.77 (ddd, J=8.8, 6.8, 1.3 Hz, 1H), 7.63 (d, J=9.0 Hz,
1H), 7.60 (br. d, J=7.9 Hz, 1H), 7.39–7.45 (m, 1H), 7.31–
Transformation of 1bd into Taiwanins C and E;
7.37 (m, 1H), 7.15–7.21 (m, 1H), 6.79 (br. d, J=8.5 Hz, Reduction of 1bd with DIBAL-H Producing 8a and
1H), 5.69 (s, 2H), 5.16 (d, J=7.0 Hz, 1H), 4.96 (d, J=
7.0 Hz, 1H), 4.14 (s, 3H), 3.15 (s, 3H); EI-MS: m/z=428
(M+), 398, 383, 366, 351, 339, 324, 308; EI-HR-MS: m/z=
428.1263, calcd. for C26H20O6: 428.1260.
8b (Scheme 5)
A
To a solution of 1bd (40 mg, 0.09 mmol) in CH2Cl2 (1 mL)
was DIBAL-H (1.0M toluene solution, 0.1 mL, 0.01 mmol)
at À788C, and the mixture was stirred at the same tempera-
ture for 4 h. To the solution was added an additional
DIBAL-H (0.1 mL, 0.01 mmol) at the same temperature,
and the mixture was stirred for 1.5 h. To the mixture were
successively added MeOH (0.03 mL) and saturated potassi-
um sodium tartrate aqueous solution at À788C, and the so-
lution was warmed to room temperature. The solution was
extracted with Et2O, and the organic layer was washed with
brine, dried over Na2SO4. After removal of the solvent, the
residue was purified by column chromatography on silica
gel (CH2Cl2/Et2O=30/1~8/1) to give 8a (yield: 6 mg, 17%)
and 8b (yield: 23 mg, 67%).
Total Synthesis of Taiwanins; 5-Bromobenzo[d][1,3]-
T
dioxol-6-yl Trifluoromethanesulfonate (Aryne Pre-
cursor, 2’b)
To
a
solution of 6-bromobenzo[d][1,3]dioxol-5-ol (4)
A
(876 mg, 4.0 mmol) in THF (17 mL) was added hexamethyl-
disilazane (1.3 mL, 6.2 mmol), and the mixture was refluxed
with stirring for 3 h. The mixture was concentrated under
vacuum, and the residual crude 5 was dissolved in THF
(17 mL). To the mixture was added BuLi (1.65M hexane so-
lution, 2.6 mL, 4.3 mmol) at À1008C, and the temperature
of the mixture was raised to À808C for 20 min. The mixture
was again cooled to À1008C, and Et2O (17 mL) and trifluor-
omethanesulfonic anhydride (0.88 mL, 5.2 mmol) were
added to the mixture. The temperature of the mixture was
again raised to À808C for 20 min, and the reaction mixture
was quenched with saturated aqueous NaHCO3 solution at
the same temperature, and the mixture was slowly warmed
to room temperature. The solution was extracted with Et2O,
and the organic layer was washed with brine, dried over
Na2SO4. After removal of the solvent, the residue was puri-
fied by column chromatography on silica gel (hexane/
AcOEt=30/1) to give 2’b as a purplish oil; yield: 1.15 g
8a: IR (nujol): n=2901, 1753, 1673 cmÀ1
;
1H NMR
(270 MHz, CDCl3): d=9.89 (s, 1H), 8.52 (s, 1H), 7.08 (s,
1H), 7.00 (d, J=7.9 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 6.84
(dd, J=7.9, 2.0 Hz, 1H), 6.15 (s, 2H), 6.13 (d, J=5.3 Hz,
1H), 6.13 (d, J=5.3 Hz, 1H), 5.67 (s, 2H); EI-LR-MS:
m/z=376 (M+), 347, 319; EI-HR-MS: m/z=376.0591, calcd.
for C21H12O7: 376.0583.
8b: IR (neat): n=3382, 2922, 1673 cmÀ1
;
1H NMR
(270 MHz, CDCl3): d=9.84 (s, 1H), 7.42 (s, 1H), 7.01 (s,
1H), 6.96 (d, J=7.3 Hz, 1H), 6.84 (d, J=1.3 Hz, 1H), 6.82
(s, 1H), 6.79 (d, J=1.3, 7.3 Hz, 1H), 6.11–6.08 (m, 4H),
5.70–5.61 (m, 1H), 5.44 (dd, J=4.6, 15.2 Hz, 1H), 3.31 (s,
1H);
EI-LR-MS:
m/z=360
(M+ÀOHÀ1),
332
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www.asc.wiley-vch.de
657

DEDICATED CLUSTER
FULL PAPERS
Yoshihiro Sato et al.
(M+ÀOHÀCHO); EI-HR-MS: m/z=360.0626, calcd. for
C21H12O6 (M+ÀOHÀ1): 360.0634.
HCl at 08C, then the mixture was evaporated in order to
remove MeOH and THF. The resultant aqueous layer was
extracted with CH2Cl2, and the organic layer was washed
with saturated aqueous NaHCO3, brine, and dried over
Na2SO4. After removal of the solvent, the residue was puri-
fied by column chromatography on silica gel (CH2Cl2/
Et2O=9/2) to give 12 as a colorless solid; yield: 109 mg
1,3,7,9-Tetrahydro-5-(benzo[d][1,3]dioxol-5-yl)-4-
T
carbomethoxy-1-oxo-2,7,9-trioxaindeno
(9)
ACHTREUNG
(95%); mp 240–2418C; IR (neat): n=3438, 1751 cmÀ1
;
To a solution of 1bd (320 mg, 0.74 mmol) in CH2Cl2 (7 mL)
were successively added MeOH (7 mL) and NaH (88 mg,
60% dispersion in mineral oil, 2.2 mmol) at 08C, and the
mixture was stirred at room temperature for 5 h. To the mix-
ture was added saturated aqueous NH4Cl at 08C, and the so-
lution was evaporated in order to remove MeOH. The resul-
tant aqueous layer was extracted with AcOEt, and the or-
ganic layer was washed with brine, dried over Na2SO4. After
removal of the solvent, the residue was purified by column
chromatography on silica gel (CH2Cl2/Et2O=45/1) to give 9
as a colorless solid; yield: 236 mg (78%); mp 218–2208C;
1H NMR (270 MHz, CDCl3): d=7.47 (s, 1H), 7.13 (s, 1H),
6.95 (d, J=7.5 Hz, 1H), 6.77–6.73 (m, 2H), 6.10 (s, 2H),
6.07 (d, J=6.9 Hz, 1H), 6.07 (d, J=6.9 Hz, 1H), 5.53 (s,
2H), 5.16 (s, 2H); EI-LR-MS: m/z=378 (M+), 349; EI-HR-
MS: m/z=378.0741, calcd. for C21H14O7 (M+): 378.0740.
1,3,6,8-Tetrahydro-4-(benzo[d]
formyl-3-oxo-2,6,8-trioxaindeno
ACHTREUNG
AHCTREUNG
To a solution of 12 (109 mg, 0.29 mmol) in CH2Cl2 (4 mL)
were added MS 4 Š (545 mg) and PCC (186 mg, 0.86 mmol)
at 08C, and the mixture was stirred at the same temperature
for 1.5 h. The mixture was dilute with Et2O, and filtered
through a pad of Florisil. The filtrate was concentrated, and
the residue was purified by column chromatography on
silica gel (CH2Cl2/Et2O=50/1) to give 6 as a yellowish solid;
yield: 96 mg (89%); mp 269–2708C (sublim.); IR (neat): n=
1
IR (neat): n=1732, 1703 cmÀ1; H NMR (270 MHz, CDCl3):
d=8.51 (s, 1H), 6.98 (s, 1H), 6.94 (d, J=7.9 Hz, 1H), 6.74
(d, J=1.6 Hz, 1H), 6.71 (dd, J=1.6, 7.9 Hz, 1H), 6.12 (s,
2H), 6.08 (d, J=2.8 Hz, 1H), 6.08 (d, J=2.8 Hz, 1H), 5.54
(d, J=3.2 Hz, 2H), 3.69 (s, 3H); EI-LR-MS: m/z=406
(M+), 374, 346; EI-HR-MS: m/z=406.0692, calcd. for
C22H14O8 (M+) 406.0688.
1
2907, 1757, 1682 cmÀ1; H NMR (270 MHz, CDCl3): d=10.9
(s, 1H), 8.16 (s, 1H), 7.22 (s, 1H), 6.99 (d, J=7.3 Hz, 1H),
6.80 (s, 1H), 6.79 (d, J=7.3 Hz, 1H), 6.17 (s, 2H), 6.09 (d,
J=6.6 Hz, 2H), 5.70 (s, 1H); EI-LR-MS: m/z=376 (M+),
358, 347; EI-HR-MS: m/z=376.0584, calcd. for C21H12O7
(M+): 376.0583.
1,3,7,9-Tetrahydro-5-(benzo[d]
carbomethoxy-1-hydroxy-2,7,9-trioxaindeno
e]indene (10)
ACHTREUNG
AHCTREUNG
To a solution of 9 (26 mg, 0.064 mmol) in CH2Cl2 (1.6 mL)
was added DIBAL-H (1.0M toluene solution, 0.076 mL,
0.076 mmol) at À788C, and the mixture was stirred at the
same temperature for 2 h. To the mixture were successively
added MeOH (0.03 mL) and saturated aqueous potassium
sodium tartrate solution at À788C, and the solution was
warmed to room temperature. The solution was extracted
with Et2O, and the organic layer was washed with brine,
dried over Na2SO4. After removal of the solvent, the residue
was purified by column chromatography on silica gel
(CH2Cl2/Et2O=50/1 to 6/1) to give 10 (yield: 16 mg, 63%)
as a colorless solid along with the starting material 9 (3 mg,
Synthesis of Taiwanin C from6 Using RhCl (PPh3)3
G
To a solution of 6 (14 mg, 0.037 mmol) in C2H5CN (2 mL)
was added RhCl(PPh3)3 (48 mg, 0.052 mmol), and the mix-
AHCTREUNG
ture was refluxed for 2 h. The reaction mixture was cooled
to 08C, and EtOH was added to the solution. The mixture
was concentrated, and the residue was purified by column
chromatography on silica gel (CH2Cl2/Et2O=60/1) to taiwa-
nin C (yield: 8 mg, 64%) as a colorless solid, whose spectral
data were identical with those previously reported by Padwa
et al.[12n]
12%). 10: Mp 182–1838C; IR (neat): n=3381, 1706 cmÀ1
;
1H NMR (270 MHz, CDCl3): d=7.39 (s, 1H), 6.95 (s, 1H),
6.90 (d, J=7.9 Hz, 1H), 6.87–6.84 (m, 1H), 6.73 (d, J=
7.9 Hz, 1H), 6.69–6.63 (m, 1H), 6.06 (s, 1H), 5.60–5.50 (m,
1H), 5.30 (m, 1H), 3.63 (s, 3H), 3.09 (d, J=7.9 Hz, 1H);
EI-LR-MS: m/z=408 (M+), 390, 376; EI-HR-MS: m/z=
408.0850, calcd for C22H16O8 (M+): 408.0845.
Synthesis of Taiwanin E from6
To a solution of 6 (64 mg, 0.17 mmol) in CH2Cl2 (4.2 mL)
was added mCPBA (8234 mg, 1.4 mmol) at 08C, and the
mixture was stirred at room temperature for 1 h. The mix-
ture was diluted with Et2O. The solution was successively
washed with 10% saturated aqueous Na2S2O3, NaHCO3,
and brine, and dried over Na2SO4. After removal of the sol-
vent, the crude formate was dissolved in MeOH (7 mL), and
K2CO3 (35 mg, 0.25 mmol) was added to the solution. The
mixture was stirred at room temperature for 30 min, and the
mixture was diluted with Et2O, and filtered. The filtrate was
washed with brine, and dried over Na2SO4. After removal of
the solvent, the residue was purified by column chromatog-
raphy on silica gel (CH2Cl2/Et2O=30/1) to give taiwanin E
(yield: 54 mg, 88% from 6) as a colorless solid, whose spec-
tral data were identical with those previously reported by
Iwasaki et al.[12i]
1,3,6,8-Tetrahydro-4-(benzo[d][1,3]dioxol-5-yl)-10-
hydroxymethyl-3-oxo-2,6,8-trioxaindeno
(12)
A
[5,6-f]indene
To a solution of 10 (124 mg, 0.30 mmol) in MeOH/THF
(8 mL/8 mL) was added NaBH4 (59 mg, 1.5 mmol) at 08C,
and the mixture was stirred at room temperature for 4 h. To
the mixture was added again NaBH4 (59 mg, 1.5 mmol) at
08C, and the mixture was stirred at room temperature for
15 h. Then, to the mixture was added again NaBH4 (22 mg,
0.60 mmol) at 08C, and the mixture was stirred at room tem-
perature for 2 h. To the mixture was added 5% aqueous
658
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DEDICATED CLUSTER
FULL PAPERS
Palladium-Catalyzed [2+2+2] Cocyclization of Arynes and Diynes
yield: 272 mg (71%); mp 266–2688C; IR (film): n=2937,
Conversion of Taiwanin E into Taiwanin C via
Triflate 13
1
1767, 1644, 1580, 1504, 1465, 1413 cmÀ1; H NMR (400 MHz,
CDCl3): d=7.26 (s, 1H), 7.14 (s, 1H), 6.51–6.58 (m, 2H),
6.11 (s, 2H), 5.37 (br, 2H), 3.97 (s, 3H), 3.84–3.86 (m, 6H),
3.44–3.52 (m, 6H); EI-LR-MS: m/z=481 (M+), 451, 421,
406, 393; EI-HR-MS: m/z=481.1368, calcd. for C25H23NO9
(M+): 481.1372.
To a solution of taiwani E (30 mg, 0.084 mmol) in THF
(4.2 mL) was added LHMDS (1.0M THF solution, 0.13 mL,
0.13 mmol) at À788C, and the mixture was stirred at the
same temperature for 1 h. To the mixture was added Tf2O
(0.028 mL, 0.17 mmol) at À788C, and the mixture was stir-
red at À788C for 1.5 h. The reaction mixture was quenched
with saturated aqueous NaHCO3 solution at À788C, and the
mixture was slowly warmed to room temperature. The solu-
tion was extracted with Et2O, and the organic layer was
washed with brine, dried over Na2SO4. After removal of the
solvent, the residue was purified by column chromatography
on silica gel (CH2Cl2) to give 13 as a colorless solid; yield:
27 mg (66%); mp 165–1668C; IR (film): n=1778, 1468,
Methyl 1-Oxo-5-(3,4,5-trimethoxyphenyl)-1,3-dihydro-
2,7,9-trioxadicyclopenta
late
A
Following the similar procedure for 9, the crude product,
which was prepared from 1bm (263 mg, 0.55 mmol), MeOH
(2.8 mL), and NaH (66 mg, 60% dispersion in mineral oil,
1.6 mmol) in CH2Cl2 (2.8 mL) at room temperature for 24 h,
was purified by column chromatography on silica gel
(hexane/AcOEt=3/1) to give the corresponding lactone as a
colorless solid; yield: 210 mg (85%); mp 287–2898C; IR
1215, 1037 cmÀ1 1H NMR (270 MHz, CDCl3): d=7.44 (s,
;
1H), 7.16 (s, 1H), 6.97 (s, 1H), 6.79–6.75 (m, 2H), 6.16 (s,
2H), 6.09 (d, J=6.5 Hz, 1H), 6.08 (d, J=6.5 Hz, 1H), 5.47
(s, 2H); EI-LR-MS: m/z=496 (M+), 363, 335; EI-HR-MS:
m/z=496.0086, calcd. for C21H11SO9F3: 496.0075.
1
(film): n=2912, 1730, 1580, 1498, 1464, 1410 cmÀ1; H NMR
(400 MHz, CDCl3): d=3.64 (s, 3H), 3.85–3.97 (m, 9H), 3.53
(s, 2H), 6.13 (s, 2H), 6.48 (s, 2H), 6.99 (s, 1H), 8.47 (s, 1H);
13C NMR (68 MHz, CDCl3): d=52.1, 56.2, 61.1, 70.2, 100.2,
102.1, 105.1, 106.5, 119.3, 120.5, 129.0, 130.7, 134.0, 137.6,
145.9, 147.4, 149.0, 151.4, 153.1, 166.4, 171.1; EI-LR-MS: m/
z=452 (M+ÀH), 437, 423, 405, 389, 377; EI-HR-MS m/z=
452.11059 (M+ÀH), calcd. for C24H20O9: 452.11070.
To a solution of 13 (27 mg, 0.054 mmol), Pd(OAc)2
A
(1.0 mg, 4.5 mmol), PPh3 (2.3 mg, 8.7 mmol) in DMF
(1.2 mL) were added triethylamine (0.023 mL, 0.165 mmol)
and formic acid (0.004 mL, 0.106 mmol), and the mixture
was stirred at 608C for 1.5 h. To the mixture was added
brine, and the solution was extracted with Et2O. The organic
layer was washed with brine, dried over Na2SO4. After re-
moval of the solvent, the residue was purified by column
chromatography on silica gel (CH2Cl2/Et2O=40/1) to give 1-Hydroxy-5-(3,4,5-trimethoxy-phenyl)-1,3-dihydro-
taiwanin C; yield: 14 mg (76%).
2,7,9-trioxa-dicyclopenta[a,g]naphthalene-4-carbox-
A
ylic acid methyl ester (14)
Total Synthesis of Dehydroxydesoxypodophyllotoxin;
Synthesis of 3-(N-Methoxy-N-methylcarbamoyl)prop-
2-ynyl 3-(3,4,5-Trimethoxyphenyl)propiolate (3m)
Following the similar procedure for 10, the crude product,
which was prepared from the above lactone (110 mg,
0.24 mmol) and DIBAL-H (1.0M toluene solution, 0.29 mL,
0.29 mmol) in CH2Cl2 (6.0 mL) at À788C for 2 h, was puri-
fied by column chromatography on silica gel (hexane/
AcOEt=2/1) to give 14 (yield: 67 mg, 61%) as a colorless
solid along with the recovered lactone (8 mg, 7%). 14: Mp
208–2108C; IR (film): n=3441, 2940, 1701, 1582, 1508,
Following the similar procedure for 3e, the crude product,
which was prepared from 3-(3,4,5-trimethoxyphenyl)propiol-
ic acid (CAS Registry No. 4698–21–9, 980 mg, 4.1 mmol),
propargylic alcohol 18d (710 mg, 5.0 mmol), PPh3 (1.3 g,
5.0 mmol) and DIAD (1.0 mL, 5.0 mmol) in THF (14 mL)
at 08C for 2 h, was purified by column chromatography on
silica gel (hexane/AcOEt=3/1) to give 3m as a yellowish
oil; yield: 1.2 g (88%); IR (neat): n=2940, 2213, 1717, 1649,
1465 cmÀ1 1H NMR (270 MHz, CDCl3): d=2.93 (m, 1H),
;
3.60 (s, 3H), 3.83 (m, 6H), 3.95 (s, 3H), 5.35 (s, 1H), 5.53–
5.60 (m, 1H), 6.07 (s, 2H), 6.47–6.48 (m, 2H), 6.85–6.89 (m,
1H), 6.98 (s, 1H), 7.40 (s, 1H); 13C NMR (68 MHz, CDCl3):
d=51.9, 56.2 (2H), 61.0, 73.7, 100.3, 101.7, 101.8, 104.8,
106.8, 106.9, 121.3, 127.2, 130.1, 133.6, 134.6, 135.1, 137.3,
142.3, 148.2, 149.6, 152.9, 167.6; EI-LR-MS: m/z=452
(M+À2H), 436, 421, 405; FAB-HR-MS: m/z=452.1117
(M+À2H), calcd. for C24H20O9: 452.1139.
1
1577, 1454, 1414 cmÀ1; H NMR (270 MHz, CDCl3): d=3.24
(br, 3H), 3.79–3.90 (m, 12H), 4.98 (s, 2H), 6.85 (s, 2H); EI-
LR-MS: m/z=361 (M+), 330, 315, 290, 275, 257; EI-HR-
MS: m/z=361.1154, calcd. for C18H19NO7: 361.1161.
[2+2+2] Cocyclization of 3mand 2 ’b Producing 1bm
Pd2
G
P(o-tol)3 (97 mg,
N
9-Hydroxymethyl-5-(3,4,5-trimethoxyphenyl)-8H-
furo[3’,4’:6,7]naphtho
0.32 mmol), and CsF (727 mg, 4.79 mmol) were dissolved in
CH3CN (1.0 mL), and the mixture was stirred at room tem-
perature for 20 min. To the catalyst solution was added a so-
lution of 3m (288 mg, 0.80 mmol) and 2b (821 mg, 2.4 mmol)
in CH3CN (1.8 mL) at 08C, and the mixture was stirred at
room temperature for 40 h. To the mixture was added satu-
rated aqueous NH4Cl solution, and the solution was extract-
ed with AcOEt. The organic layer was washed with brine
and dried over Na2SO4. After removal of the solvent, the
residue was purified by column chromatography on silica
gel (hexane/AcOEt=30/1) to give 1bm as a yellowish solid;
N
A
Following the similar procedure for 12, the crude diol, which
was prepared from 14 (61 mg, 0.13 mmol) and NaBH4
(36 mg, 1.1 mmol) in THF (3.4 mL) and MeOH (3.4 mL) at
08C for 16 h, was treated with 5% HCl at 08C. After the
usual work-up, the residue was purified by column chroma-
tography on silica gel (hexane/AcOEt=1/1) to give the cor-
responding alcohol as a colorless solid; yield: 52 mg (92%);
mp 276–2798C; IR (film): n=3489, 2920, 1747, 1734, 1614,
1582, 1507, 1468, 1410 cmÀ1 1H NMR (270 MHz, DMSO-
;
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659

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Yoshihiro Sato et al.
d6): d=3.77–3.82 (m, 9H), 5.01 (d, J=5.5 Hz, 2H), 5.51 (d,
J=5.5 Hz, 1H), 6.23 (s, 2H), 6.61 (s, 2H), 6.95 (s, 1H), 7.63
(s, 1H); 13C NMR (68 MHz, DMSO-d6): d=56.9, 59.5, 61.0,
69.1, 101.3, 103.1, 103.8, 108.3, 119.0, 130.7, 131.0, 131.6,
132.6, 137.9, 139.0, 139.4, 148.8, 150.7, 153.4, 170.1; EI-LR-
MS: m/z=424 (M+), 409, 393, 381; EI-HR-MS: m/z=
424.1155 (M+), calcd. for C23H20O8: 424.1158.
Acknowledgements
This work was financially supported by Grant-in-Aid for Sci-
entific Research (C) (No. 17590001) from the Japan Society
for the Promotion of Sciences (JSPS), and by the Naito
Foundation, which are gratefully acknowledged.
8-Oxo-9-(3,4,5-trimethoxy-phenyl)-6,8-dihydrofuro-
[3’,4’:6,7]naphtho
(15)
A
G
References
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Following the similar procedure for 6, the crude product,
which was prepared from the above alcohol (33 mg,
0.24 mmol), PCC (50 mg, 0.23 mmol), and MS 4 Š (150 mg)
in CH2Cl2 (3.8 mL) at 08C for 2 h, was purified by column
chromatography on silica gel (hexane/AcOEt=1/2) to give
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;
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3.98 (s, 3H), 5.71 (s, 2H), 6.18 (s, 2H), 6.52 (s, 1 2), 7.21 (s,
1H), 8.16 (s, 1H), 10.94 (s, 1H); 13C NMR (68 MHz,
CDCl3): d=56.2, 61.0, 69.9, 98.5, 102.5, 104.9, 106.9, 119.2,
122.8, 129.5, 131.6, 134.0, 138.3, 144.7, 146.4, 148.7, 152.3,
153.1, 168.5, 189.1; EI-LR-MS: m/z=422 (M+), 422, 407,
391, 347; EI-HR-MS: m/z=422.1008, calcd. for C23H18O8:
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8-Oxo-9-(3,4,5-trimethoxyphenyl)-6,8-dihydrofuro-
[3’,4’:6,7]naphtho
methanesulfonate (16)
G
N
Following the similar procedure for conversion of 6 to 13,
the crude alcohol was obtained through Bayer–Villiger oxi-
dation of 15 (16 mg, 0.037 mmol) using mCPBA (51 mg,
0.29 mmol) in CH2Cl2 (0.9 mL) at 08C for 2 h followed by
hydrolysis using K2CO3 (7.6 mg, 0.55 mmol) in MeOH
(1.2 mL) at room temperature for 4 h. Then the crude alco-
hol was treated with LHMDS (1.0M THF solution, 0.05 mL,
0.05 mmol) and Tf2O (8.4 mL, 0.05 mmol) in THF (1.8 mL)
at À788C. After the usual work-up, the residue was purified
by column chromatography on silica gel (hexane/AcOEt=
1/1) to give 16 as a colorless solid; yield: 9 mg (46%, 3
steps); mp 221–224 8C; IR (film): n=2924,1766 cmÀ1
;
1H NMR (270 MHz, CDCl3): d=3.85 (s, 6H), 3.97 (s, 3H),
5.48 (s, 2H), 6.16 (s, 2H), 6.53 (s, 2H), 7.16 (s, 1H), 7.45 (s,
1H); EI-LR-MS: m/z=542 (M+), 409, 350; EI-HR-MS:
m/z=542.0489, calcd. for C23H17F3O10S: 542.0494.
Dehydrodesoxypodophyllotoxin
To a solution of 16 (7 mg, 0.013 mmol), Pd(OAc)2 (0.2 mg,
G
0.001 mmol), PPh3 (0.6 mg, 0.002 mmol) in DMF (0.3 mL)
were added triethylamine (0.006 mL, 0.043 mmol) and
formic acid (0.001 mL, 0.03 mmol), and the mixture was stir-
red at 608C for 1.5 h. To the mixture was added brine, and
the solution was extracted with Et2O. The organic layer was
washed with brine, dried over Na2SO4. After removal of the
solvent, the residue was purified by column chromatography
on silica gel (hexane/AcOEt=4/1) to give dehydrodesoxy-
podophyllotoxin (yield: 4 mg, 80%) as a colorless solid,
whose spectral data were identical with those previously re-
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Ed. 2004, 43, 2346.
660
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www.asc.wiley-vch.de
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