A facile synthesis of enantiopure tricyclic furanyl and pyranyl derivatives via tungsten-mediated cycloalkenation and Diels-Alder reaction

Article abstract of DOI:10.1021/jo0205208

We report the synthesis of chiral furanyl and pyranyl dienes 1 and 2 based on cycloalkenation of chiral tungsten alkynol complexes. These two dienes bear a chiral 1,3-dioxolane group to control diastereoselective Diels-Alder reactions with electron-deficient olefins. The chiral 1,3-dioxolane substituents of the cycloadducts were degraded into hydrogen atoms to make these molecules possess common furan and pyran rings. Dienes 1 and 2 are good building blocks for enantiopure forms of tricyclic oxygen compounds.

Full text of DOI:10.1021/jo0205208

A F a cile Syn th esis of En a n tiop u r e Tr icyclic F u r a n yl a n d P yr a n yl
Der iva tives via Tu n gsten -Med ia ted Cycloa lk en a tion a n d
Diels-Ald er Rea ction
Heh-Lung Huang and Rai-Shung Liu*
Chemistry Department, National Tsing-Hua University, Hsinchu,Taiwan, Republic of China
rsliu@mx.nthu.edu.tw
Received August 6, 2002
We report the synthesis of chiral furanyl and pyranyl dienes 1 and 2 based on cycloalkenation of
chiral tungsten alkynol complexes. These two dienes bear a chiral 1,3-dioxolane group to control
diastereoselective Diels-Alder reactions with electron-deficient olefins. The chiral 1,3-dioxolane
substituents of the cycloadducts were degraded into hydrogen atoms to make these molecules possess
common furan and pyran rings. Dienes 1 and 2 are good building blocks for enantiopure forms of
tricyclic oxygen compounds.
SCHEME 1
In tr od u ction
Enantiopure tricyclic furanyl and pyranyl derivatives
with the frameworks A and B are often encountered in
many naturally occurring compounds, particularly on
terpenoids.1 Scheme 1 shows several representatives with
interesting biological activities.1 The bicyclic ether frame-
works A and B are also useful building blocks for complex
bioactive molecules.2 Synthesis of these bicyclic ether
derivatives has attracted considerable attention.2,3 The
synthetic methods are quite diversified and lengthy.
Furthermore, most previous studies have focused on the
synthesis of racemic forms.2,3 [4 + 2]-Cycloaddition of
heterocyclic dienes with electron-deficient olefins is a
useful method for synthesis of complex molecules.4 One
example is depicted in eq 3 (Scheme 1) which shows a
facile synthesis of furanyl diene via [3 + 2]-cycloaddition
of tungsten-vinylpropargyl complex with (2S)-2-(benzyl-
oxy)propanal.3e This chiral diene is a good building block
for chiral tricyclic furanyl derivatives through its dia-
(1) For representative examples, see the following: (a) Flegel, M.;
Adam, K.-L.; Becker, H. Phytochemistry 1999, 52, 1633. (b) Finnegan,
R. A.; Djerassi, C. J . Am. Chem. Soc. 1960, 82, 4342. (c) Astudillo, L.;
Gonzalez, A.; Galindo, A.; Mansilla, T. Tetrahedron Lett. 1997, 38, 6737
(d) Hijfte, L. V.; Vandewalle, M. Tetrahedron 1984, 40, 4371. (e) Carda,
M.; Marco, J . A. Tetrahedron 1992, 48, 9789. (f) Talwar, K. K.; Singh,
I. P.; Kalsi, P. S. Phytochemistry 1992, 31, 336. (g) Paquette, L. A.;
Oplinger, J . A. Tetrahedron 1989, 45, 107. (h) Ohloff, G.; Vial, C.; Wolf,
H. R.; J ob, K.; J ejou, E.; Polonsky, J .; Lederer, E. Helv. Chim. Acta.
1980, 63, 205. (i) Maji, S. K.; Mukhopadhyaya, S. K.; Mukherjee, D.;
Dutta, P. C. J . Chem. Soc., Perkin Trans 1 1980, 2511.
(2) (a) Medebielle, M. Tetrahedron Lett. 1996, 37, 5119. (b) Backvall,
J .-E.; Anderson, P. G. J . Am. Chem. Soc. 1992, 114, 6374. (c) Takacs,
J . M.; Weidner, J . J .; Newson, P. W.; Takacs, B. E.; Chidambaram, R.;
Shoemaker, R. J . Org. Chem. 1995, 60, 3473. (d) Trost, B. M.; King, S.
A. J . Am. Chem. Soc. 1995, 60, 3473. (e) Itami, K.; Palmgren, A.;
Backvall, J .-E. Tetrahedron Lett. 1998, 39, 1223.
stereoselective Diels-Alder reaction with dienophile.
Recently, we reported that treatment of alkynyltungsten
compounds with RCH2CHO/BF3‚Et2O complex formed
oxacarbenium salts5 (Scheme 1, eq 4), further yielding
tungsten-furanyl diene5 efficiently. In this report, we
describe a short synthesis of enantiomeric bicyclic ethers
A based on this tungsten-mediated cyclization with the
protocol shown in Scheme 1. The oxacyclic diene is
(3) (a) Breitmaire, E.; Potthoff, B. Chem. Ber. 1986, 119, 3204 (b)
Breitmaire, E.; Reffer, U. Synthesis 1989, 623. 3204. (c) Cornwall, P.;
Dell, C. P.; Knight, D. W. J . Chem. Soc., Perkin Trans. 1 1993, 2395.
(d) Arrayas, R. G.; Liebeskind, L. S. J . Am. Chem. Soc. 2001, 123, 6185.
(e) Pei, C. C.; Liu, R. S. Org. Lett. 2001, 3, 1295.
(4) Review article of Diels-Alder reaction, see: Roush, W. R. In
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, 1991; Vol. 5, p 513.
(5) (a) Liang, K.-W.; Li, W.-T.; Lee, G.-H.; Peng, S.-M.; Liu, R.-S. J .
Am. Chem. Soc. 1997, 119, 4404. (b) Li, W.-T.; Lai, F.-C.; Lee, G.-H.;
Peng, S.-M.; Liu, R.-S. J . Am. Chem. Soc. 1998, 120, 4520.
10.1021/jo0205208 CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/10/2002
J . Org. Chem. 2003, 68, 805-810
805

Huang and Liu
SCHEME 2
SCHEME 3 a
a
Conditions: (i) Swern oxidation, (ii) (EtO)3PCH2CO2Et, (iii)
Dibal-H, (iv) AD-mix â, MeSO2NH2, BuOH/H2O, (v) Me2C(OMe)2,
p-TSA/acetone, (vi) CpW(CO)3Cl, CuI, Et2NH, (v) MeCHO,
BF3‚Et2O, Et3N, (vi) Me3NO, CH3CN.
designed to bear a chiral dioxolane group. This substitu-
ent has roles in synthetic applications: (1) it controls the
diastereoselectivity of [4 + 2]-cycloaddition and (2) it is
easily degradable into a common functionality after
cycloaddition.
Compound 12 was smoothly converted to chiral diene 2,
using tungsten-mediated cycloalkenation as mentioned
above.
Resu lts a n d Discu ssion
Table 1 shows the Diels-Alder reaction of oxacyclic
diene 1 with various reactive dienophiles. The dioxolane
group of diene 1 effects diastereoselective Diels-Alder
reaction under ambient conditions; the results are shown
in Scheme 3. The reaction of diene 1 with maleic
anhydride, maleic imide, and N-phenyl maleimide pro-
ceeded smoothly at 23 °C to give only one diastereomeric
product 14-16 (dr > 20, entries 1-3). Crystallization
from diethyl ether/hexane afforded the cycloadducts 14-
16 in yields of 84-87%. This stereoselectivity is remark-
able, because four isomers are likely to occur. Elucidation
of the structures of cycloadduct 14 relies on the proton
NOE map, which reveals that the H3 proton is cis to the
H2 and H4 protons but trans to the H1-proton (Chart 1).
This infers that the olefin approaches the diene in endo
mode and opposite the chiral dioxolane group. In the
presence of Zn(OTf)2 (3.0 equiv), 1,4-benzoquinone and
1,4-naphthoquinone reacted with diene 1 at 23 °C to give
cycloadducts in 8.2:1 and 13.1:1 diastereomeric mixtures,
respectively, and finally gave pure 17 and 18 in respec-
tive yields of 76% and 79% after crystallization. It is
fruitless to determine stereochemistry of the minor
diastereomer of 17 and 18, because their NMR reso-
nances are largely overlapped with those of its major
isomer. BF3‚Et2O also effected cycloaddition of 1 with
ethyl glyoxalate to give pure cycloadduct 19 in 85% yield
Scheme 2 shows the synthesis of chiral tungsten-
alkynol 6 for the cyclization. The starting chiral diol 3
was prepared in two steps from L(+)-diethyl tartrate as
described in the literature.6 This diol was subsequently
transformed into chiral alkynyl alcohol 5 according to
method reported by Wu,7 and the protocol is shown in
Scheme 2. Treatment of alkynol 5 with CpW(CO)3Cl (1.1
equiv) and CuI catalyst (11.0 mol %) in Et2NH effected
metalation,5 yielding tungsten-alkynol species 6 in 71%
yield. Treatment of complex 6 with excess acetaldehyde
in the presence of BF3‚Et2O (1.5 equiv) in cold diethyl
ether (-40 °C) produced a yellow oil, presumably a
tungsten-oxacarbenium salt B.5 Subsequent treatment
of this salt with Et3N (2.0 equiv) afforded tungsten-
furanyl diene 7 in an overall yield of 64%. Hydrodemeta-
lation of dienyl complex 7 with Me3NO3e in CH3CN gave
the desired chiral diene 1 in 60% yield.
Scheme 3 shows a protocol for the synthesis of chiral
tungsten-alkynol species 2. Carbon elongation of 4-pen-
tyn-1-ol was achieved by conventional methods including
Swern oxidation, Wittig reaction, and Dibal reduction.
Asymmetric dihydroxylation of alcohol 9 with AD-mix-
â8 afforded chiral triol 10 in 72% yield with 91% ee. Triol
10 is present as a solid form, and crystallization from
ether/hexane increased its ee value to 96% with a yield
of 61%. Treatment of triol 10 with Me2C(OMe)2 and
p-TSA catalyst (3.0 mol %) gave the dioxolane derivative
11, which was converted to chiral tungsten-alkynol 12
by CpW(CO)3Cl, Et2NH, and CuI catalyst (11 mol %).
1
after crystallization. The H NOE map of compound 19
is shown in Supporting Information. Although the ee
value of pyranyl diene 2 is 96%, its Diels-Alder cyclo-
adducts 20-24 have ee values exceeding 98% (Merck,
chiralsphere column) because of purification by crystal-
lization.
Table 1 also shows the results for the cycloaddition of
chiral pyranyl diene 2 with the same olefins. Using the
same approach, the cycloadducts 20-22 were obtained
in yields of 82-83% after crystallization (entries 7-9).
Again, the chiral dioxolane group of diene 2 has a
pronounced effect on diastereoselectivity. In the presence
of Zn(OTf)2, pure 1,4-benzoquinone and 1,4-naphtho-
quinone adducts 23-24 were obtained in 8.1:1 and 11.1:1
(6) (a) Palomo, C.; Oiarbide, M.; Landa, A.; Esnal, A.; Linden, A. J .
Org. Chem. 2001, 66, 4180. (b) Inouye, M.; Fujimoto, K.; Furusyo, M.;
Nakazumi, H. J . Am. Chem. Soc. 1999, 121, 1452.
(7) Wu, W.-L.; Yao. Z.-J .; Li, J . C.; Xia, Y.; Wu, Y.-L. J . Org. Chem.
1995, 60, 3257.
(8) (a) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl.
1996, 35, 5. 448. (b) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.;
Crispimo, G. A.; Hartung, J .; J eong, K. S.; Kwong, H.; Morikawa, K.;
Wang, Z.; Xu, D.; Zhang, X. J . Org. Chem. 1992, 57, 2786. (c) Crispimo,
G. A.; J eong, K. S.; Kolb, H. C.; Wang, Z.; Xu, D.; Sharpless, K. B. J .
Org. Chem. 1993, 58, 3785.
806 J . Org. Chem., Vol. 68, No. 3, 2003

Tricyclic Furanyl and Pyranyl Derivatives
TABLE 1. Cycloa d d ition of Ch ir a l Dien es 1-2 w ith
Olefin s
SCHEME 4
SCHEME 5
20 shown in Chart 1. Again, the observed stereoselec-
tivities are attributed to endo-facial cycloaddition and the
steric effect of a chiral dioxolane group.
This new approach is applicable to the intramolecular
Diels-Alder reaction,4 as shown in Scheme 4. Sequential
treatment of chiral tungsten-alkynol 6 with aldehyde
25 and BF3‚Et2O (1.5 equiv) in cold diethyl ether (-40
°C), followed by the addition of Et3N, gave chiral tung-
sten-furanyl species 26 in 56% yield. Hydrodemetalation
of complex 26 with Me3NO in CH3CN gave chiral oxacy-
clic diene 27 in 51% yield. Heating diene 27 at 60 °C in
toluene for 24 h gave tricyclic furan 28 (dr > 20) in 91%
yield. The structure of furan 28 was elucidated based on
proton NMR NOE spectra. The trans-annulated config-
uration is consistent with those expected from the
literature.4,9,10
a
The yields were reported after purification from crystallization
from ether/hexane.
CHART 1
Scheme 5 shows a convenient method for degradation
of the dioxolane group of cycloadducts into a hydrogen
atom to make these chiral molecules possess a common
structure. Hydrolysis of compounds 14-16 with HCl (3.0
N)/MeOH mixtures at 0 °C for 4 h led to formation of
the corresponding diols, which were subsequently oxi-
datively cleaved by NaIO4/silica11 to afford aldehyde
derivatives 29-31 in yields of 62-65% after purification
(9) (a) Brown, F. K.; Houk, K. N. Tetrahedron Lett. 1985, 26, 2297.
(b) Wu, T. C.; Houk, K. N. Tetrahedron Lett. 1985, 26, 2293. (c) Rousch,
W. R.; Essenfeld, A. P.; Warmus, J . S. Tetrahedron Lett. 1987, 28, 2447.
(10) (a) Ichihara, A.; Miki, M.; Tazaki, H.; Sakamura, S. Tetrahedron
Lett. 1987, 28, 1175. (b) Burke, S. D.; Piscopio, A. D.; Buchana, J . L.
Tetrahedron Lett. 1988, 29, 2757. (c) Marshall, J . A.; Audia, J . E.; Crote,
J . J . Am. Chem. Soc. 1988, 110, 1290.
diastereomeric mixtures (entries 10-11). Crystallization
of these mixtures gave pure 23 and 24 in respective yields
of 75% and 77%. Determination of the stereochemistry
relies on the NOE map of the maleic anhydride adduct
J . Org. Chem, Vol. 68, No. 3, 2003 807

Huang and Liu
Syn th esis of 1-(5-Ben zyloxym eth yl-2, 2-d im eth yl-[1,
3]-dioxolan -4-yl)-bu t-3-yn -1-ol (5). To a mixed solvent (Et2O-
DMF, 1:1, 40 mL) of compound 4 (3.93 mmol, 15.7 mmol) and
propargyl bromide (3.71 g, 31.4 mmol) was added zinc powder
(3.01 g, 47.1 mmol) at 23 °C. The mixture was stirred for 10 h
at 25 °C and combined with diethyl ether (150 mL), and the
resulting solution filtered. The filtrate was washed with
saturated ammonium chloride. The organic layer was dried
with MgSO4, concentrated, and chromatograghed over a silica
column to give compound 5 as a pale gray oil (3.92 g, 13.5
on a silica column. Column chromatography of these
samples also led to epimization of the aldehyde carbon
to form two diastereomers (ca. 3:1 ratio). Treatment of
compounds 29-31 with RhCl(PPh3)3 catalyst (1.0 equiv)12
in CH2Cl2 (23 °C) led to decarbonylation and the efficient
formation of tricyclic furan derivatives 32-34 efficiently.
This degradation method can be also applicable to related
pyran derivatives 20-22. Aldehydes 35-37and their
decarbonylation products 38-40 were obtained in rea-
sonable yields via HCl hydrolysis, followed by catalytic
decarbonylation using RhCl(PPh3)3 catalyst.
In summary, we report a short synthesis of chiral
furanyl and pyranyl dienes 1 and 2 based on organo-
tungsten chemistry. Synthesis of related oxacyclic dienes
in the literature reports requires a lengthy procedure
even for their racemic forms. The dienes bear a chiral
1,3-dioxolane group to effect diastereoselective Diels-
Alder reaction. The chiral 1,3-dioxolane groups of the
cycloadducts were easily degradable into hydrogen atoms.
Dienes 1 and 2 are good building blocks for enantiopure
forms of tricyclic oxygen compounds.
mmol, 86%). IR (neat, cm-1): 3280(br,vs), 1620(w). [R]23
)
D
-5.7 (c 0.7, CHCl3). 1H NMR(CDCl3, 400 MHz): δ 7.32 (m,
5H), 4.55 (m, 2H), 4.09 (q, J ) 6.0 Hz, 1H), 3.57-3.77 (m, 4H),
3.08 (br, 1H), 2.41-2.62 (m, 2H), 2.02 (t, J ) 3.2 Hz, 1H), 1.38
(m, 6H). 13C NMR(CDCl3, 100 MHz): δ 137.3, 128.4, 128.4,
127.8, 127.8, 127.6, 109.4, 80.5, 80.3, 78.3, 73.7, 70.6, 70.1, 64.8,
26.8, 26.8, 24.0. HRMS (70 eV): calcd for C17H22O4, 290.1514;
found, 290.1517.
Syn th esis of Tu n gsten Alk yn ol Com p ou n d (6). To an
Et2NH solution (15 mL) of CpW(CO)3Cl (5.48 g, 14.8 mmol)
and CuI (0.28 g, 1.49 mmol) was added compound 5 (3.92 g,
13.5 mmol). The mixture was stirred for 4 h, concentrated,
and chromatographed over a silica column to afford compound
6 as an orange oil (5.97 g, 9.59 mmol, 71%). IR (neat, cm-1):
3380 (br,vs), 1978 (s), 1945 (s), 1618 (w). [R]23 ) -4.5 (c 1.0,
D
1
Exp er im en ta l Section s
CHCl3). H NMR (CDCl3, 400 MHz): δ 7.36 (m, 5H), 5.57 (s,
5H), 4.60 (m, 2H), 4.22 (m, 1H), 3.83 (t, J ) 7.6 Hz, 1H), 3.60-
3.75 (m, 4H), 2.72 (t, J ) 4.8 Hz, 1H), 2.56 (m, 1H), 1.40 (m,
6H). 13C NMR (CDCl3, 100 MHz): δ 229.1, 212.0, 212.0, 137.9,
128.0, 128.0, 127.4, 127.4, 127.3, 122.4, 109.1, 91.2, 78.7, 78.1,
73.3, 71.0, 70.5, 61.3, 27.6, 26.8, 26.8. HRMS (70 eV): calcd
for C25H26O7W, 622.1237; found, 622.1243.
Unless otherwise noted, all reactions were carried out under
a nitrogen atmosphere in oven-dried glassware using standard
syringe, cannula, and septa apparatus. Toluene, diethyl ether,
tetrahydrofuran, and hexane were dried with sodium benzo-
phenone and distilled before use. Dichloromethane was dried
over CaH2 and distilled before use. W(CO)6, BF3‚Et2O, L(+)-
diethyl tartrate, AD-mix-â, maleic anhydride, maleic imide,
N-phenyl maleimide, 1,4-benzoquinone, and 1,4-naphthoquino-
ne were obtained commercially and used without purification.
Proton NOE-spectra were measured on the basis of spatial
(through-space) effect. The measurement follows the procedure
described in the literature.13 Mass data of tungsten compounds
were reported according to 184W. Chiral diol 3 was prepared
by the method as described in the literature.7
Syn th esis of 5-Ben zyloxym eth yl-2,2-d im eth yl-[1,3]-d i-
oxola n e-4-ca r ba ld eh yd e (4). To a THF solution of sodium
hydride (n-hexane, prewashed, 1.30 g, 60%, 32.4 mmol) was
added compound 3 (5.00 g, 30.9 mmol) at 0 °C, and the mixture
was stirred for 1 h before addition of benzyl bromide (4.98 g,
29.3 mmol). The resulting solution was stirred for 12 h at room
temperature and then quenched with a saturated NH4Cl
solution. The organic layer was extracted with diethyl ether,
dried with MgSO4, concentrated, and purified by flash chro-
matography to afford a benzyl ether derivative (4.67 g, 18.5
mmol, 60%) as a colorless oil.
Syn th esis of Tu n gsten F u r a n yl Dien e (7). To a diethyl
ether solution (15 mL) of compound 6 (1.50 g, 2.41 mmol) at
-78 °C was added acetaldehyde (3.0 mL) and BF3‚OEt2 (0.29
mL, 2.89 mmol), and the solution was stirred for 5 h. The
solution was dried in vacuo, redissolved in CH2Cl2 (12 mL),
and treated with Et3N (1.5 mL). The mixture was stirred for
30 min at 23 °C, concentrated, and filtered over a basic
aluminum oxide bed to give compound 7 as an orange oil (1.00
g, 1.54 mmol, 64%). IR (neat, cm-1): 2002 (s), 1945 (s), 1621
(w). [R]23 ) -16.4 (c ) 1.0, CHCl3). 1H NMR (CDCl3, 400
D
MHz): δ 7.31 (m, 5H), 6.29 (dd, J ) 10.8 Hz, J ) 17.8 Hz,
1H), 5.21 (s, 5H), 4.78 (d, J ) 12.0 Hz, 1H), 4.64 (d, J ) 15.8
Hz, 1H), 4.54 (s, 2H), 4.50 (m, 1H), 4.11 (m, 1H), 3.72 (t, J )
8.2 Hz, 1H), 3.66 (m, 1H), 3.53 (m, 2H), 2.74 (m, 1H), 1.37-
1.43 (m, 6 H). 13C NMR (CDCl3, 100 MHz): δ 227.0, 215.3,
215.3, 150.2, 138.0, 134.1, 130.1, 128.2, 128.2, 127.6, 127.6,
127.4, 109.0, 107.4, 91.4, 82.5, 79.1, 78.7, 73.3, 70.9, 33.9, 27.1,
27.0. HRMS (70 eV): calcd for C27H28O7W, 648.1322; found,
648.1223.
To a CH2Cl2 solution of oxalyl chloride (3.1 g, 24.6 mmol)
at -78 °C was added dropwise DMSO (3.60 g, 46.3 mmol) at
-60 °C for 30 min, and to this mixture was added benzyl ether.
The mixture was stirred for 30 min before addition of Et3N.
The resulting solution was stirred for 30 min at -60 °C and
then warmed to 25°C for 2 h. It was washed with brine several
times and concentrated at reduced pressure to afford the
compound 4 as a pale yellow colored oil (3.93 g, 15.7 mmol,
Syn th esis of 4-Ben zyloxym eth yl-2,2-d im eth yl-5-(vin yl-
2,3-d ih yd r o-fu r a n -2-yl)-[1,3]-d ioxola n e (1). To an aceto-
nitrile solution (20 mL) of compound 7 (1.00 g, 1.54 mmol) at
23 °C was added anhydrous Me3NO (0.60 g). The mixture was
stirred for 4 h, filtered through MgSO4, concentrated, and
chromatographed over a silica column to give compound 1 as
a colorless oil (0.29 g, 0.93 mmol, 60%). IR (neat, cm-1): 1621-
(w). [R]23 ) +32.0 (c ) 1.0, CHCl3). 1H NMR (CDCl3, 400
D
85%). IR (neat, cm-1): 1720 (s), 1620 (w). [R]23 ) +16.8 (c )
D
MHz): δ 7.33 (m, 5H), 6.42 (dd, J ) 10.8 Hz, J ) 17.2 Hz,
1H), 6.34 (s, 1H), 4.87 (d, J ) 10.8 Hz, 1H), 4.81 (d, J )17.2
Hz, 1H), 4.58 (m, 2H), 4.09 (m, 1H), 3.94 (t, J ) 6.8 Hz, 1H),
3.65 (m, 1 H), 3.58 (m, 2 H), 2.66-2.84 (m, 2 H), 1.43 (m, 6
H). 13C NMR (CDCl3, 100 MHz): δ 144.2, 138.0, 128.5, 128.3,
128.3, 127.7, 127.7, 127.6, 116.4, 110.4, 109.8, 82.6, 78.6, 78.6,
73.5, 70.7, 31.1, 27.1, 27.1. HRMS (70 eV): calcd for C19H24O4,
316.1732; found, 316.1714.
1
1.1, CHCl3). H NMR (CDCl3, 400 MHz): δ 9.67 (s, 1H), 7.25
(m, 5H), 4.51 (s, 2H), 4.15 (m, 2H), 3.57 (t, J ) 4.0 Hz, 2H),
1.40 (s, 3H), 1.33 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 200.6,
137.6, 128.4, 128.4, 127.7, 127.6, 127.6, 111.6, 82.0, 76.1, 73.6,
69.8, 26.8, 26.1. HRMS (70 eV): calcd for C14H18O4, 250.1387;
found, 250.1384.
(11) Cambie, R. C.; Hayard, R. C.; Roberts, J . L.; Rutledge, P. S. J .
Chem. Soc., Perkin Trans. 1 1974, 1858.
(12) Ohno, K.; Tsuji, J . J . Am. Chem. Soc. 1968, 90, 99.
(13) Sanders, J . K.; Hunter, B. K. In Modern NMR Spectroscopy,
2nd ed.; Oxford University Press: Oxford, 1993.
Syn th esis of Hep t-2-en -6-yon ic Acid Eth yl Ester (8).
To a THF (250 mL) solution of oxalyl chloride (6.65 g, 51.6
mmol) was added dropwise DMSO (4.10 mL, 4.51 g, 57.8 mmol)
at -78 °C, and the mixtures were stirred at -78 °C for 20
808 J . Org. Chem., Vol. 68, No. 3, 2003

Tricyclic Furanyl and Pyranyl Derivatives
min. To this resulting white suspension was added a THF (10
mL) solution of 4-pentyl-1-ol (2.0 g, 23.8 mmol), and the
mixtures were stirred at -78 °C for 1 h before treatment with
triethylamine (18.0 mL, 13.1 g, 0.129 mol). The reaction was
stirred at -60 °C for 45 min, warmed to 23 °C, and stirred for
an additional 1 h. The mixtures were filtered, the filtercake
was washed with THF, and the filtrate was stored under
nitrogen at 0 °C.
Crystallization from ether/hexane afforded a colorless crystal-
line solid (110 mg, 0.28 mmol, 87%). [R]23 ) -25.8 (c ) 1.0,
D
CHCl3). IR (neat, cm-1): 1778 (s), 1642 (w), 1620 (w). 1H NMR
(CDCl3, 400 MHz): δ 7.29 (m, 5H), 5.54 (s, 1H), 4.56 (m, 2H),
4.47 (m, 1H), 4.34 (m, 1H), 3.97 (d, J ) 2.0 Hz, 2H), 3.56-
3.68 (m, 2H), 3.47 (m, 1H), 2.71 (m, 1H), 2.62 (d, J ) 7.2 Hz,
2H), 2.41 (m, 2H), 1.39 (m, 6H). 13C NMR(CDCl3, 100 MHz):
δ 171.9, 169.4, 138.0, 137.6, 135.6, 128.3, 127.8, 127.8, 127.6,
118.4, 109.8, 79.5, 79.5, 78.7, 73.5, 73.5, 70.7, 44.1, 41.8, 32.7,
27.1, 27.0, 26.7. HRMS (70 eV): calcd for C23H26O7, 414.1744;
found, 414.1771.
A suspension of sodium hydride (hexane-prewashed, 54.2
mmol) in THF (70 mL) was cooled to 0 °C, and neat triethyl
phosphonoacetate (12.4 g, 55.4 mmol) was added dropwise over
5 min. The solution was stirred at 0 °C for 45 min and then
added to the filtrate described above. The solution was stirred
at 0 °C for 1 h, combined with ethyl ether (150 mL), washed
with ammonium chloride and then with 1 N HCl, and finally
washed with sodium bicarbonate. The organic layer was dried
with MgSO4, filtered, concentrated, and chromatographed over
a silica column to afford 8 as a yellow oil (3.37 g, 22.1 mmol,
(11) Syn th esis of 8-(2,2-Dim eth yl-[1,3]-d ioxola n -4-yl)-
2-p h en yl-4,6,7,8,9a ,9b-h exa h yd r o-3a H-9-oxa -2-a za -cyclo-
p en ta [a ]n a p h th a len e-1, 3-d ion e (22). To a CH2Cl2 solution
(1.0 mL) of compound 2 (60 mg, 0.29 mmol) was added
N-phenyl maleimide (50 mg, 0.31 mmol), and the solution was
stirred at room temperature for 12 h. The mixture was
concentrated and chromatographed with a silica column to
afford compound 22 as a white solid. Crystallization from
ether/hexane gave a crystalline solid (90 mg, 0.23 mmol, 82%).
[R]23D ) +4.5 (c ) 1.0, CHCl3). IR (neat, cm-1): 1720 (s), 1640-
(w), 1622 (w); 1H NMR(CDCl3, 400 MHz): δ 7.16-7.42 (m, 5H),
5.59 (s, 1H), 4.66 (d, J ) 7.2 Hz, 1H), 4.16 (m, 1H), 3.96 (m,
3H), 3.52 (t, J ) 8.8 Hz, 1H), 3.17 (t, J ) 7.2 Hz, 1H), 2.77
(dd, J ) 15.6, 6.8 Hz, 1H), 2.46 (dt, J ) 15.2, 5.2 Hz, 1H), 2.29
(dt, J ) 12.4, 3.2 Hz, 1H), 2.15 (m, 1H), 1.78 (m, 1H), 1.64 (m,
1H), 1.38-1.43 (m, 6H). 13C NMR (CDCl3, 100 MHz): δ 178.6,
175.5, 139.0, 132.3, 129.2, 129.1, 128.7, 126.5, 126.5, 118.4,
109.6, 78.1, 73.1, 69.9, 65.8, 44.9, 39.1, 28.4, 28.4, 26.6, 25.4,
23.6. HRMS (70 eV): calcd for C22H25NO5, 383.1742; found,
383.1773.
1
93%). IR (neat, cm-1): 2221 (m), 1700 (s), 1620 (w). H NMR
(CDCl3, 400 MHz): δ 6.93 (dt, J ) 16.0, 6.8 Hz, 1H), 5.85 (d,
J ) 15.6 Hz, 1H), 4.18 (q, J ) 6.0 Hz, 2H), 2.36-2.42 (m, 2H),
2.31-2.33 (m, 1H), 1.97 (m,1H), 1.24 (t, J ) 7.2 Hz, 3H). 13C
NMR (CDCl3, 100 MHz): δ 166.3, 146.2, 122.4, 82.6, 69.3, 60.2,
30.9,17.3, 14.2. HRMS (70 eV): calcd for C9H12O2, 152.0843;
found, 152.0821.
Syn th esis of Hep t-2-en -6-yn -1-ol (9). A THF (100 mL)
solution of compound 8 (3.20 g, 21.0 mmol) was stirred at 0
°C, and to this solution was added diisobutylaluminum hydride
(1.0 M in hexane, 46.6 mL, 46.6 mmol) over a period of 30 min.
The mixture was stirred at 0 °C for 2 h, quenched by
ammonium chloride, extracted with EtOAc, concentrated, and
purified by flash chromatography to give 9 as a pale yellow
oil (2.07 g, 18.8 mmol, 85%). IR (neat, cm-1): 2221 (m), 1650
(w). 1H NMR (CDCl3, 400 MHz): δ 5.68 (m, 2H), 4.05 (m, 2H),
2.23 (m, 4H), 1.93 (d, J ) 1.2 Hz, 1H). 13C NMR (CDCl3, 100
MHz): δ 130.7, 84.0, 69.0, 63.6, 31.3, 18.7. HRMS (70 eV):
calcd for C7H10O, 110.0795; found, 110.0643.
(12) Syn th esis of 1,3-Dioxo-2-p h en yl-1,2,3,3a ,4,6,7,8,9a ,-
9b-d eca h yd r o-9-oxa -2-a za -cyclop en ta [a ]n a p h th a len e-8-
ca r ba ld eh yd e (37). To a methanol solution (2.0 mL) of
compound 22 (90 mg, 0.23 mmol) was added dropwise 3 N HCl
(50 mL) at 0 °C, and the solution was warmed to 23 °C. The
solution was quenched with 20% NaOH solution, extracted
with EtOAc, and chromatographed over a silica column to
afford a diol derivative as a white solid (50 mg, 0.15 mmol).
NaIO4 (2.57 g, 12 mmol) was dissolved in H2O (5 mL) and
mixed with SiO2 (10 g), and this slurry was dried in vacuo for
12 h at 23 °C. To a CH2Cl2 solution (5 mL) of the diol derivative
prepared above was added this NaIO4/silica gel mixture (1.0
g) at 0 °C, the slurry was stirred for 1 h and filtered, and the
silica cake was washed with diethyl ether. The combined
filtrate was concentrated and chromatographed with a silica
column to afford compound 37 as a white solid (50 mg, 0.15
Syn th esis of Hep t-1,2,3-tr iol (10). To a mixed (t-BuOH
and water, 1:1, 50 mL) solvent of compound 9 (2.07 g, 18.8
mmol) at 0 °C was added AD-mix-â (26.4 g) and benzene-
sulfonamide (1.79 g), and the mixture was stirred at 0 °C for
27 h. The solution was quenched with sodium sulfite, extracted
with EtOAc, and concentrated to afford 10 as a white solid
(1.95 g, 13.6 mmol, 72%). IR (neat, cm-1): 3467 (br, vs), 2310
1
(m). H NMR (CDCl3, 400 MHz): δ 4.10-4.58 (br, 3H), 3.46-
3.67 (m, 4H), 2.26 (m, 2H), 2.10 (t, J ) 2.4 Hz, 1H), 1.64 (m,
2H). 13C NMR (CDCl3, 100 MHz): δ 84.0, 74.0, 70.5, 63.9, 43.1,
31.9, 14.7. HRMS (70 eV): calcd for C7H12O3, 144.0842; found,
144.0846.
mmol, 66%). [R]23 ) -18.5 (c ) 1.0, CHCl3). IR (neat, cm-1):
D
1720 (s), 1640 (w), 1622 (w). 1H NMR (CDCl3, 400 MHz): δ
9.87 (s, 1H), 7.21-7.45 (m, 5H), 5.62 (m, 1H), 4.50 (d, J ) 7.6
Hz, 1H), 4.39 (t, J ) 6.4 Hz, 1H), 3.58 (t, J ) 8.0 Hz, 1H), 3.43
(m, 1H), 3.22 (t, J ) 7.6 Hz, 1H), 2.86 (dd, J ) 16.8, 6.0 Hz,
1H), 2.25 (m, 2H), 2.02 (m, 1H), 1.93 (m, 1H). 13C NMR(CDCl3,
100 MHz): δ 203.4, 177.8, 175.0, 135.5, 132.0, 129.1, 129.1,
128.5, 126.4, 126.4, 119.6, 79.1, 69.1, 44.0, 37.9, 27.4, 24.4, 21.7.
HRMS (70 eV): calcd for C18H17NO4, 311.1231; found, 311.1232
Syn th esis of 1-(2,2-Dim eth yl-[1,3]-d ioxola n -4-yl)-p en t-
4-yn -1-ol (11). To an anhydrous acetone solution (40 mL) of
compound 10 (1.95 g, 13.6 mmol) was added p-toluenesulfonic
acid (80 mg, 0.41 mmol), and the solution was cooled to -60
°C and combined with 2,2-dimethoxypropane. The solution was
stirred for 4 h, quenched by saturated sodium carbonate, and
extracted with diethyl ether. The etherate solution was dried
over MgSO4, concentrated, and purified by flash chromatog-
raphy to afford 9 as a pale yellow oil (2.12 g, 11.5 mmol, 85%).
IR (neat, cm-1): 2221 (m), 1648 (w). 1H NMR (CDCl3, 400
MHz): δ 4.03 (m, 2H), 3.77 (m, 1H), 3.66 (m, 1H), 2.39 (m,
2H), 1.96 (t, J ) 2.8 Hz, 1H), 1.62 (m, 2H), 1.44 (s, 3H), 1.37
(s, 3H). 13C NMR (CDCl3, 100 MHz): δ 109.5, 83.8, 78.7, 70.7,
68.8, 66.0, 32.5, 26.6, 25.2, 14.7. HRMS (70 eV): calcd for
(13) Syn th esis of 2-P h en yl-4,6,7,8,9a ,9b-h exa h yd r o-
3aH-9-oxa-2-aza-cyclopen ta[a ]n aph th alen e-1, 3-dion e (40).
To a CH2Cl2 solution (2.0 mL) of the compound 37 (50 mg,
0.16 mmol) was added RhCl(PPh)3 (112 mg, 0.16 mmol), and
the mixture was stirred at 23 °C for 24 h. The color of the
solution turned from red to yellow. The solution was concen-
trated and chromatographed on a silica column to afford
compound 40 as a white solid (39.1 mg, 0.14 mmol, 86%). To
a CH2Cl2 solution of the compound 37 (0.05 g, 0.16 mmol, 1.0
equiv) was added Wilkinson’s catalyst RhCl(PPh)3 (148 mg,
0.2 mmol), and the mixture was stirred at room temperature
for 24 h. The color of the solution turned from red to yellow.
The solution was concentrated at and chromatographed on a
silica column to afford compound 40 as a white solid (39.13
C
10H16O3, 184.1121; found, 184.1193.
Syn th esis of 2-(5-Ben zyloxym eth yl-2,2-d im eth yl-[1,3]-
d ioxola n -4-yl)-2,3,5,5a ,8a ,8b-h exa h yd r o-1,7-d ioxa -a s-in -
d a cen e-6,8-d ion e (14). To a toluene solution (0.5 mL) of
compound 1 (100 mg, 0.32 mmol) was added maleic anhydride
(30 mg, 0.35 mmol), and the solution was stirred at 60 °C for
1 h. The mixture was concentrated and chromatographed with
a silica column to afford compound 14 as a white solid.
mg, 0.14 mmol, 86%). [R]23 ) -12.35 (c ) 1.0, CHCl3). IR
D
(neat, cm-1): 1728 (s), 1651 (w), 1620 (w). 1H NMR (CDCl3,
J . Org. Chem, Vol. 68, No. 3, 2003 809

Huang and Liu
400 MHz): δ 7.15-7.44 (m, 5H), 5.58 (m, 1H), 4.65 (s, 1H),
4.51 (t, J ) 7.6 Hz, 1H), 3.77 (q, J ) 6.2 Hz, 1H), 3.52 (m,
1H), 3.22 (m, 1H), 2.78 (m, 1H), 2.45 (dd, J ) 12.6, 4.2 Hz,
1H), 2.20 (m, 2H), 1.91 (m, 1H), 1.78 (m, 1H). 13C NMR (CDCl3,
100 MHz): δ 178.7, 175.5, 138.1, 132.3, 129.2, 129.2, 129.1,
127.1, 127.1, 118.0, 73.1, 69.9, 41.7, 34.9, 32.1, 26.4, 23.6.
HRMS (70 eV): calcd for C17H17NO3, 283.1293; found, 283.1281.
Su p p or tin g In for m a tion Ava ila ble: Spectral data of
compounds 2, 12-13, 15-21, 23-36, and 38-39 in repetitive
1
experiments and H and 13C NMR spectra of compounds 1-40.
This material is available free of charge via the Internet at
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J O0205208
810 J . Org. Chem., Vol. 68, No. 3, 2003