Synthesis of bicyclic pyrane derivatives via tungsten-mediated [3 + 3] cycloaddition of epoxides with tethered alkynes

Article abstract of DOI:10.1021/jo010698e

Propargyltungsten compounds bearing a tethered epoxide were prepared in short steps from readily available materials. In the presence of various Lewis acids, BF₃·Et₂O catalysts (25 mol %) most effectively promote the [3 + 3] cycloaddition of the epoxide with its tethered propargyltungsten group, delivering bicyclic pyranyltungsten compounds in reasonable yields. This cyclization proceeds highly diastereoselectively with tolerance of various functional groups. The stereochemical outcome indicates that the cycloaddition is initiated by the ring opening of the epoxides via an exo-attack of the propargyltungsten group. The resulting pyranyltungsten organometallics were demetalated to yield various bicyclic pyranyl derivatives using different oxidants. This new method provides a short enantiospecific synthesis of bicyclic oxygen compounds if chiral epoxide is used in the cyclizatlon. A mechanistic model is presented to rationalize the reaction pathway of this [3 + 3] cycloaddition.

Full text of DOI:10.1021/jo010698e

8106
J . Org. Chem. 2001, 66, 8106-8111
Syn th esis of Bicyclic P yr a n e Der iva tives via Tu n gsten -Med ia ted
[3 + 3] Cycloa d d ition of Ep oxid es w ith Teth er ed Alk yn es
Kuo-Hui Shen,† Shie-Fu Lush,‡ Tseng-Li Chen,† and Rai-Shung Liu*,†
Department of Chemistry, National Tsing-Hua University, Hsinchu, 30043 Taiwan, and Department of
Medical Technology, Yuanpei Institute of Science and Technology, Hsinchu, Taiwan, ROC
rsliu@mx.nthu.edu.tw
Received J uly 11, 2001
Propargyltungsten compounds bearing a tethered epoxide were prepared in short steps from readily
available materials. In the presence of various Lewis acids, BF3‚Et2O catalysts (25 mol %) most
effectively promote the [3 + 3] cycloaddition of the epoxide with its tethered propargyltungsten
group, delivering bicyclic pyranyltungsten compounds in reasonable yields. This cyclization proceeds
highly diastereoselectively with tolerance of various functional groups. The stereochemical outcome
indicates that the cycloaddition is initiated by the ring opening of the epoxides via an exo-attack
of the propargyltungsten group. The resulting pyranyltungsten organometallics were demetalated
to yield various bicyclic pyranyl derivatives using different oxidants. This new method provides a
short enantiospecific synthesis of bicyclic oxygen compounds if chiral epoxide is used in the
cyclization. A mechanistic model is presented to rationalize the reaction pathway of this [3 + 3]
cycloaddition.
Sch em e 1
In tr od u ction
The cycloaddition of an epoxide with alkynes and
alkenes is a direct and efficient method for the synthesis
of oxacyclic compounds.1,2 Two types of cycloadditions
have been reported as shown in Scheme 1. Equation 1
shows [3 + 2] cycloaddition of an epoxide with an
electron-deficient alkyne or alkene via cleavage of the
C-C bond of the epoxide;3 this pathway involves a
zwitterionic intermediate produced on thermal or pho-
tolytic activation.3 An alternative route entails use of a
Lewis acid to effect cycloaddition of an epoxide with an
electron-rich alkene;4 this pathway involves cleavage of
the C-O bond of the epoxide to generate the ionic
intermediate B that leads to a furan framework via a
† National Tsing-Hua University.
‡ Yuanpei Institute of Science and Technology.
(1) (a) Gothelf, K. V.; J orgensen, K. A. Chem. Rev. 1998, 98, 863.
(b) Tufariello, J . J . In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A.; Ed.; J ohn Wiley & Sons: Chichester, 1984; Vol. 2, p 83.
(2) (a) Carruthers, W. Cycloaddition in Organic Synthesis; Perga-
mon: Oxford, 1990. (b) Pindur, U.; Lutz, G.; Otto, C. Chem. Rev. 1993,
93, 741. (c) Togni, A.; Venanzi, L. M. Angew. Chem., Int. Ed. Engl.
1994, 33, 497.
(3) Examples for cycloaddition of epoxide or aziridine with olefin
and alkyne ivolving cleavage of the C-C bond: (a) Sisko, J .; Weinreb,
S. M. J . Org. Chem. 1991, 56, 3211. (b) Takano, S.; Iwabuchi, Y.;
Ogasawara, K. J . Am. Chem. Soc. 1987, 109, 5523. (c) DeShong, P.;
Kell, D. A.; Sidler, D. R. J . Org. Chem. 1985, 50, 2309. (d) Metra, P.;
Hemelin, J . J . Chem. Soc., Chem. Commun. 1980, 1038. (e) Gaebert,
C.; Siegner, C.; Mattay J .; Toubartz, M.; Steenken, S. J . Chem. Soc.,
Perkin Trans. 2 1998, 2735. (f) Domingo, L. R. J . Org. Chem. 1999,
64, 3922. (g) Chou, W.-N.; White, J . B. Tetrahedron Lett. 1991, 32,
7637. (h) Gaebert, C.; Mattaay, J . Tetrahedron 1997, 53, 14297. (i)
Palomino, E.; Schaap, A. P.; Heeg, M. J . Tetrahedron Lett. 1989, 30,
6801.
(4) Cycloaddition of aziridine or epoxide with alkene with cleavage
of the C-X bond, see: (a) Bergmeier, S. C.; Fundy, S. L.; Seth, P. P.
Tetrahedron 1999, 55, 8025. (b) Schneider, M. R.; Mann, A.; Taddei,
M. Tetrahedron Lett. 1996, 37, 8493. (c) Sugita, Y.; Kimura, Y.; Yokoe,
I. Tetrahedron Lett. 1999, 40, 5877. (d) Sugita, Y.; Kimura, Y.; Yokoe,
I. Tetrahedron Lett. 1999, 40, 5877. (e) Nakagawa, M.; Kawahara, M.
Org. Lett. 2000, 2, 953.
counterattack of its oxygen terminus at the carbonium
center. Examples of this cycloaddition are very few and
only limited to alkenes of special types.4 The treatment
of epoxides with a mixture of activated alkenes and Lewis
acid normally produced addition products.5,6 The [3 + 2]
cycloaddition of epoxide or aziridine with an activated
alkyne remained unknown before our study on alkynyl-
(5) For review paper, see: (a) Tanner, D. Angew Chem., Int. Ed.
Engl. 1994, 33, 599. (b) Yamamoto, Y.; Asao N. Chem. Rev. 2000, 100,
2207.
10.1021/jo010698e CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/02/2001

Synthesis of Bicyclic Pyrane Derivatives
J . Org. Chem., Vol. 66, No. 24, 2001 8107
molybdenum, and tungsten CpM(CO)n- (M ) Fe, n ) 2;
M ) Mo, W, n ) 3) fail to react with epoxide in the
absence of Lewis acids. Treatment of this epoxide with
these metal anions NaM (M ) CpFe(CO)2, CpMo(CO)3,
CpW(CO)3) in THF afforded the corresponding pro-
pargyltungsten compounds in 77-87% yields. For these
three propargylmetal complexes, BF3‚Et2O (25 mol %)
effected the cyclization of tungsten and molybdenum
complexes 6a and 6b in cold CH2Cl2 (-40 °C, 6-8 h) to
afford the products 7a and 7b in 67% and 63% yields,
respectively. This reaction failed with the iron species
6c which was recovered in 66% yield. The failure of iron
complex 6c in cyclization is attributed to its lower
reactivity with electrophiles.9 Bicyclic pyranyl structures
were assignable to compounds 7a and 7b on the basis of
their 1H and 13C NMR spectral data. The 13C NMR of
the three W-CO groups of 7a appeared at δ 228.3 and
221.1 ppm at -45 °C and became broad at 23 °C. The
metal fragment of 7a and 7b underwent a 1,2-shift to
become a vinyltungsten group. We investigate this cyclo-
addition with other Lewis acids including Me3SiOTf,
TiCl4, and Zn(OTf)2, which were found less reactive as
compared to BF3‚Et2O. Compound 7a can produce vari-
ous bicyclic pyranyl derivatives upon demetalation with
various oxidants; a protocol is shown in eq 4. Treatment
of this pyranyltungsten complex 7a with I2 (1.2 equiv)
and BnOH (2.0 equiv) in cold CH2Cl2 (-78 °C, 8 h)
resulted in carbonylation10 to afford bicyclic benzyl ester
8a in 82% yield. Hydrodemetalation11 of 7a with Me3NO
(3.0 equiv) in CH3CN (23 °C, 5 h) gave the protonated
product 8b in 65% yield. Oxidation of 7c with m-
chloroperbenzoic acid (m-CPBA) in CH2Cl2 (23 °C, 8 h)
afforded the bicyclic ketone compound 8c in 47% yield
together with the protonated compound 8b (41%). The
cis configuration of the lactone 8c was determined by 1H-
NOE spectra.
Sch em e 2
We also extended this cyclization on various propar-
gyltungsten compounds containing an epoxide. Com-
pounds 9-17 were formed from NaCpW(CO)3 and the
corresponding chloropropargyl derivatives; preparation
of the latter compounds is described in the Supporting
Information. The cyclization followed that of the related
alkynyltungsten compound 6a as described before. In a
typical reaction, the alkynyltungsten complex was treated
with BF3‚Et2O catalyst (25 mol %) in cold CH2Cl2 (-40
°C, 4-10 h) and quenched with a saturated NaHCO3
solution at the end of the reaction. Entries a and b (Table
1) present two instances of formation of pyranyltungsten
compounds 18 and 19 fused with a five-membered carbo-
and azacyclic ring, respectively. The yields of 18 and 19
were 51% and 61%, respectively. I2-promoted oxidative
carbonylation of 18 and 19 afforded the esters 27 and
28 in 91% and 90% yield, respectively. Entries c-e show
[3 + 3] cycloaddition of a tethered cis epoxide comprised
in compounds 11-13; bicyclic pyranyl products 20-22
were obtained as one diastereomer in good yields (69-
72%), with a trans configuration assigned on the basis
of their 1H NMR-NOE spectra.12 This information
indicated that a propargyltungsten group effects ring
tungsten compounds with the protocol shown in eq 3.7
This cycloaddition is synthetically useful because it
provides a one-pot synthesis of bicyclic lactones via a
tungsten enol ether. In the present work, we extend our
investigation to propargyltungsten complexes comprising
a tethered epoxide. Treatment of these tungsten com-
pounds with Lewis acid leads to [3 + 3] cycloaddition
rather than to an expected [3 + 2] pathway as known
for special allylsilane derivatives.4a-d Most propargyl and
allylmetal complexes undergo addition reactions with
epoxides in the presence of a Lewis acid.5,6 We report here
the full scope of this cycloaddition.8
Resu lts a n d Discu ssion
We focus our attention on intramolecular cyclization.
Scheme 2 shows an instance for the synthesis of an
organic substrate 5 comprising a tethered epoxide. It was
conveniently prepared from propargylamino tosylate 1
according to conventional methods; the overall yield of 5
was 45%. Transition-metal carbonyl anions of iron,
(6) See the examples: (a) Dubiois, S.; Mehta, A.; Toureet, E.; Dodd,
R. H. J . Org. Chem. 1994, 59, 434. (b) Sato, K.; Kozikowski, A. P.
Tetrahedron Lett. 1989, 30, 4073. (c) Bennani, Y. L.; Zhu, G. D.;
Freeman, J . C. Synlett 1998, 754. (d) Marson, C. M.; McGregor, J .;
Khan, A. J . Org. Chem. 1998, 63, 7833.
(7) Madhushaw, R. J .; Li, C.-L.; Shen, K.-H.; Hu, C.-C.; Liu, R.-S.
J . Am. Chem. Soc. 2001, 123, 7427.
(9) Gilbert, T. M.; Bergman, R. G. J . Am. Chem. Soc. 1985, 107,
3502.
(10) Shieh, S.-J .; Tang, T.-C.; Lee, J .-S.; Lee, G.-H.; Peng, S.-M.; Liu,
R.-S. J . Org. Chem. 1996, 61, 3245.
(11) Li, W.-T.; Pan, M.-H.; Wu, Y.-R.; Wang, S.-L.; Liao, F.-L.; Liu,
R.-S. J . Org. Chem. 2000, 65, 3761.
(8) Part of this paper has appeared in an earlier communication,
see ref 7.
(12) The 1H NMR NOE maps of bicyclic pyranyl compounds 8c, 21,
and 23 were provided in Supporting Information.

8108 J . Org. Chem., Vol. 66, No. 24, 2001
Shen et al.
Ta ble 1. [3 + 3] Cycloa d d ition Rea ction s a n d
Dem eta la tion s (W ) Cp W(CO)3)
Sch em e 3
Sch em e 4
complexes 23-26 were converted smoothly to the corre-
sponding bicyclic benzyl esters 32-35 in 82-90% yields.
This new method provides a short synthesis of chiral
bicyclic pyranyl derivatives. We prepared the chiral
epoxides 38 and 39 (Scheme 3) via fructose-based cata-
lytic asymmetric epoxidation of the chloropropargyl al-
kenes 36 and 37, developed by Shi et al.13 The ee values
of 38 and 39 were 91% and 93%, respectively, on the basis
of HPLC analysis. Cyclization of chiral propargyltungsten
epoxides 40 and 41 using the BF3‚Et2O catalyst (25 mol
%) in cold CH2Cl2 afforded the chiral pyranyltungsten
compounds 42 and 43 in 67% and 62% yields, respec-
tively, further leading to the chiral bicyclic esters 44
(79%) and 45 (82%) after I2-promoted oxidation. The cis
configurations of 42 and 43 were confirmed by 1H-NOE
spectra. HPLC analyses showed the 90% and 93% ee
values for compounds 44 and 45, respectively. These
values were consistent with those of the starting chiral
epoxides 38 and 39. No cycloaddition occurred for a
tethered aziridine such as 47. Treatment of this complex
with BF3‚Et2O (25 mol %) in cold diethyl ether failed to
yield cycloadducts; instead, the starting aziridine was
recovered in 67% yield. Scheme 4 (eq 1) provides a
mechanistic model to rationalize a preference for [3 + 3]
a
b
BF3‚Et2O (25 mol %), CH2Cl2 (-40 °C). Yields were reported
after purification from silica TLC plate. c BnOH (2.0 equiv), I2 (1.1
equiv), CH2Cl2 -40 °C.
opening of epoxide via an intramolecular SN2 attack.
Demetalation of these organometallics by I2/PhCH2OH
in cold CH2Cl2 gave the bicyclic esters 29-31 in 81-92%
yields. In the case of a trans epoxide as in compound 14
(entry f), the BF3-promoted cyclization afforded a 67%
yield of the product 23 that has a cis-substituted config-
1
uration according to the H-NOE effect. Entry g show
an additional example for cyclization of a tethered
ternary epoxide 15, giving the corresponding pyranyl-
tungsten complex 24 in 74% yield. This cycloaddition also
works for cis-functionalized epoxides such as compounds
16 and 17 which gave trans-pyranyl products 25 and 26
in 68% and 62% yields, respectively. Pyranyltungsten
(13) Wang, Z.-X.; Yong, T.; Frohn, M.; Zhang, J .-R.; Shi, Y. J . Am.
Chem. Soc. 1997, 119, 11224.

Synthesis of Bicyclic Pyrane Derivatives
J . Org. Chem., Vol. 66, No. 24, 2001 8109
the solution was concentrated to ca. 20 mL. The organic layer
was extracted with diethyl ether, concentrated in vacuo, and
eluted through a short silica column (diethyl ether/hexane )
1/1) to afford 2 as a colorless solid (3.70 g, 15.6 mmol, 81%).
IR (Nujol, cm-1): υ(OH) 3380 (vs, br), υ(CtC) 2177 (m). 1H
NMR (400 MHz, CDCl3): δ 7.71 (2H, d, J ) 8.0 Hz), 5.78 (1H,
br), 4.00 (2H, s), 3.72 (2H, s), 2.36 (3H, s). 13C NMR (100 MHz,
CDCl3): δ 143.7, 136.2, 129.6, 127.3, 82.8, 78.8, 50.3, 32.9, 21.4.
HRMS calcd for C11H14O3S, 226.0663; found, 226.0623.
(2) Syn th esis of N-(4-Hyd r oxy-bu t-2-yn yl)-4-m eth yl-N-
(2-m eth yla llyl)-ben zen esu lfon a m id e (3). To a THF solution
of NaH (0.24 g, 10.1 mmol) was added a THF solution of
compound 2 (2.00 g, 8.47 mmol), and the solution was stirred
for 4 h before addition of a THF solution of 3-bromo-2-
methylpropene (1.21 g, 9.00 mmol). The mixtures were re-
fluxed for 8 h, cooled at 23 °C, and quenched with a NH4Cl
solution (3.0 mL). The solution was concentrated and added
with water and diethyl ether. The ether extract was concen-
trated and eluted through a silica column (diethyl ether/
hexane) to afford compound 3 as yellow oil (1.67 g, 5.76 mmol,
68%). IR (Nujol, cm-1): υ(OH) 3380 (vs, br), υ(CtC) 2177 (m),
cycloaddition rather than an expected [3 + 2] cycloaddi-
tion. Special allyl silanes (Scheme 1, eq 2) underwent
cyclization with its tethered epoxide to afford the [3 + 2]
cycloadduct.4a-c In the presence of BF3‚Et2O, the pro-
pargyltungsten group of compound 12 undergoes an exo-
attack at the epoxide to induce ring opening, forming an
η2-tungsten allene cationic intermediate14 in which the
CpW(CO)3 fragment lies opposite to the BF3O- terminus.
The BF3O- terminus of this intermediate attacks the
remoted allene carbon rather than the central carbon,
in contrast to the case of free allenes comprising a similar
alcohol.15 The central carbon of an η2-tungsten allene
cation is generally more reactive than the terminal
carbon, as for the example in cyclocarbonylation (Scheme
4, eq 2). The exact nature of this atypical behavior is
unclear at this stage; we propose that it may be due to
the coordination of CpW(CO)3 to the external dCdC
group to make coordination at the carbon nearly tetra-
hedral. Such an effect disfavors a [3 + 2] cycloaddition
pathway corresponding to 5-endo-trig ring closure. In the
case of cyclocarbonylation, insertion at the central allene
carbon reflects the cis orientation of the tungsten frag-
ment relative to its tethered hydroxy group. Since the
ring opening of the epoxide proceeds via an inversion of
stereochemistry at the epoxide carbon, the cis epoxide
12 is expected to give the product 32 having a trans
configuration.
1
υ(CdC) 1657 (m). H NMR (400 MHz, CDCl3): δ 7.73 (2H, d,
J ) 8.8 Hz), 7.29 (2H, d, J ) 8.4 Hz), 4.98 (1H, s), 4.90 (1H,
s), 4.03 (2H, t, J ) 1.6 Hz), 3.92 (2H, t, J ) 1.6 Hz), 3.70 (3H,
s), 2.41 (3H, s), 1.74 (3H, s). 13C NMR (100 MHz, CDCl3): δ
143.5, 139.1, 136.0, 129.3, 127.8, 115.4, 83.7, 78.2, 52.5, 50.5,
35.7, 21.4, 19.6. HRMS calcd for C15H19NO3S, 293.1085; found,
293.1083.
(3) Syn t h esis of N-(4-Ch lor o-bu t -2-yn yl)-4-m et h yl-N-
(2-m eth yla llyl)-ben zen esu lfon a m id e (4). To a diethyl ether
solution (15 mL) of compound 3 (1.20 g, 4.13 mmol) was added
HMPA (0.68 mmol, 3.93 mmol), and the mixture was cooled
at 0 °C and added with SOCl2 (0.36 mL, 4.96 mmol). The
solution was stirred for an additional 5 h and quenched with
a saturated NaHCO3 solution. The organic layer was extracted
with diethyl ether, concentrated, and eluted through a silica
column to afford compound 4 as yellow oil (1.17 g, 3.80 mmol,
92%). IR (Nujol, cm-1): υ(OH) 3380 (vs, br), υ(CtC) 2167 (m),
In summary, we reported a BF3-catalyzed intra-
molecular [3 + 3] cycloaddition of propargyltungsten
complexes and epoxide. This cycloaddition proceeds with
high diastereoselectivity to afford, in reasonable yields,
bicyclic pyranyltungsten complexes which can be de-
metalated to various bicyclic pyranes with diverse oxi-
dants. This new method provides a short enantiospecific
synthesis of bicyclic pyrane derivatives.16 A mechanistic
model is presented to rationalize this cycloaddition via
altering the coordination of carbon in the allene group.
1
υ(CdC) 1654 (m). H NMR (400 MHz, CDCl3): δ 7.70 (2H, d,
J ) 8.0 Hz), 7.28 (2H, d, J ) 8.0 Hz), 4.93 (1H, s), 4.87 (1H,
s), 4.04 (2H, t, J ) 1.6 Hz), 3.78 (2H, t, J ) 1.6 Hz), 3.67 (2H,
s), 2.43 (3H, s), 1.76 (3H, s).13C NMR (100 MHz, CDCl3): δ
143.5, 139.0, 135.8, 129.4 (CH), 127.7, 115.5, 80.2, 79.2, 52.6,
35.6, 29.7, 21.4, 19.5. HRMS calcd for C15H18ClNO2S, 311.0746;
found, 311.0748.
Exp er im en ta l Section
(4) Syn t h esis of N-(4-Ch lor o-bu t -2-yn yl)-4-m et h yl-N-
(2-m eth y-oxir a n ylm eth yl)-ben zen esu lfon a m id e (5). To a
CH2Cl2 solution (10 mL) of compound 4 was added m-CPBA
(0.78 g, 2.10 mmol) at 23 °C, and the mixtures were stirred
for 5 h. The solution was concentrated, and the remaining
white residues were chromatographed through a short basic
alumina column (diethyl ether/hexane ) 1/1) to yield the
epoxide 5 (0.92 g, 2.82 mmol, 87%). IR (neat, cm-1): υ(CtC)
Unless otherwise noted, all reactions were carried out under
a nitrogen atmosphere in oven-dried glassware using a stand-
ard syringe, cannula, and septa apparatus. Benzene, diethyl
ether, tetrahydrofuran, and hexane were dried with sodium
benzophenone and distilled before use. Dichloromethane was
dried over CaH2 and distilled before use. W(CO)6, BF3‚Et2O,
dicyclopentadiene, propargyl bromide, benzyl alcohol, I2, and
sodium were obtained commercially and used without purifi-
cation. Mass data of tungsten compounds were reported
according to 184W. NaCpW(CO)3 was prepared by reduction of
[CpW(CO)3]2 with Na/Hg in THF.17 Spectral data of compounds
6b and 6c, 9-35, 37, 39, 41, 43, 45-47 in repetitive experi-
ments are provided in the Supporting Information.
(1) Syn th esis of N-(4-Hyd r oxy-bu t-2-yn yl)-4-m eth yl-
ben zen esu lfon a m id e (2). To a THF solution (80 mL) of
propargylamino tosylate (4.0 g, 19.2 mmol) was added BuLi
(16.9 mL, 2.5 M in THF) at -78 °C, and the solution was
stirred for 4 h before addition of paraformaldehyde powder
(0.69 g, 23.0 mmol). The solution was stirred for 2 h at -78
°C and slowly warmed to 23 °C in a period of 6 h. To this
solution was added a saturated NH4Cl solution (20 mL), and
1
2167 (m). H NMR (400 MHz, CDCl3): δ 7.70 (2H, d, J ) 8.0
Hz), 7.29 (2H, d, J ) 8.0 Hz), 4.23 (2H, s), 3.77 (2H, t, J ) 1.2
Hz), 3.26 (2H, ABq, J ) 14.4 Hz), 2.68 (1H, d, J ) 4.4 Hz),
2.61 (1H, d, J ) 4.4 Hz), 2.38 (3H, s), 1.36 (3H, s). 13C NMR
(100 MHz, CDCl3): δ 143.7, 135.7, 129.5, 127.6, 80.3, 79.2,
55.5, 51.3, 51.0, 37.9, 29.7, 21.4, 18.7. HRMS calcd for C15H18
ClNO3S, 327.0695; found, 327.0692.
-
(5) Syn th esis of P r op a r gyltu n gsten Com p ou n d 6a . To
a THF solution (10 mL) of Na/Hg (10.0 g, 3 wt %) was added
[CpW(CO)3]2 (0.86 g, 1.29 mmol), and the mixtures were stirred
for 8 h to yield a light yellow color. This solution was
transferred to another flask containing compound 5 (0.60 g,
1.85 mmol), and the mixture was stirred for 6 h to yield a dark
yellow solution. The solution was concentrated and chromato-
graphed through
a short basic alumina column to yield
compound 6a (0.84 g, 1.35 mmol, 73%). IR (neat, cm-1): υ(CO)
2001 (s), 1903 (s), υ(CtC) 2167 (m). 1H NMR (400 MHz,
CDCl3): δ 7.69 (2H, d, J ) 8.4 Hz), 7.27 (2H, d, J ) 8.4 Hz),
5.33 (5H, s), 4.23 (2H, d, J ) 2.2 Hz), 3.32 (2H, ABq, J ) 14.4
Hz), 2.65 (1H, ABq, J ) 4.8 Hz), 2.38 (1H, d, J ) 4.8 Hz), 1.65
(2H, t, J ) 2.2 Hz), 1.35 (3H, s). 13C NMR (100 MHz, CDCl3):
δ 228.3, 216.5, 216.4, 143.2, 136.3, 129.4, 127.6, 95.4, 92.3, 71.5,
(14) Chen, C.-C.; Fan, J .-S.; Shieh, S.-J .; Lee, G.-H.; Peng, S.-M.;
Wang, S.-L.; Liu, R.-S. J . Am. Chem. Soc. 1996, 118, 9279.
(15) Schuster, H. F.; Coppola, G. M. Allene in Organic Synthesis;
J ohn Wiley & Sons: Chichester, 1985; p 79.
(16) Marco-Contelles, J . Tetrahedron Lett. 1994, 35, 5059.
(17) Behrens, U.; Edelman, F. J . Organomet. Chem. 1984, 263,
179.

8110 J . Org. Chem., Vol. 66, No. 24, 2001
Shen et al.
55.5, 51.4, 50.6, 38.5, 21.4, 18.4, -33.3. IR (neat, cm-1): 1719
(s). MS (EI, 75 eV) m/e (relative intensities, %): 613 (M+, 11),
585 (96), 557 (92), 529 (44). Anal. Calcd for WC23H24NO6S: C,
44.08; H, 3.86; N, 2.24. Found: C, 43.78; H, 3.77; N, 2.20.
(6) Cycliza tion of P r op a r gyltu n gsten Com p ou n d 6a .
To a CH2Cl2 solution (10 mL) of compound 6a (0.30 g, 0.48
mmol) was added BF3‚Et2O (0.12 mmol) at -40 °C, and the
solution was slowly warmed to 23 °C in a period of 6 h. To
this dark yellow suspension was added a saturated NaHCO3
solution, and the organic layer was extracted with diethyl
ether, dried over MgSO4, concentrated, and chromatographed
through a silica column to afford compound 6a as a yellow solid
7a (201 mg, 0.33 mmol, 67%). IR (neat, cm-1): υ(CO) 2001
(10) Syn th esis of (2R,3R)-2-[(4-Br om o-2-bu tyn yl(2S,3R)-
3-m eth yl-oxir a n -2-yl Eth er (38). The chiral ketone derived
from fructose was prepared according to the method in the
literature. A buffer solution (pH 9-10) was prepared from
Na2B4O7‚10H2O (1.907 g), Na2EDTA (1 mL, 0.1 M), and water
(99 mL). This buffer solution (20 mL) was added with CH3CN
(30 mL), propargyl bromide 36 (0.60 g, 2.96 mmol), chiral
fructose-derived ketone (0.46 g, 0.60 mmol), and Bu4NHSO4
(0.030 g). To this mixture were added an aqueous K2CO3
solution (2.00 g, 13 mL of water) and a Na2EDTA solution (4
× 10-4 M, 18 mL) of oxone (2.52 g) in a period of 2 h. The
mixtures were stirred at 0 °C for an additional 3 h before
quenching with pentane (50 mL) and water (30 mL). The
organic layer was extracted with pentane, dried over MgSO4,
and chromatographed through a Et3N-pretreated silica column
to afford 38 (0.52 g, 2.40 mmol, 81%) as a colorless oil. [R]D
-63.7° (c 0.45, CHCl3). IR (Nujol, cm-1): υ(CtC) 2177 (m).
1H NMR (400 MHz, CDCl3): δ 4.23 (2H, m), 3.89 (2H, t, J )
1
(s), 1903 (s). H NMR (400 MHz, CDCl3): δ 7.67 (2H, d, J )
8.4 Hz), 7.27 (2H, d, J ) 8.4 Hz), 5.46 (5H, s), 3.94 (2H, ABq,
J ) 15.4 Hz), 3.78 (1H, d, J ) 14.4 Hz), 3.69 (1H, d, J ) 10.4
Hz), 3.49 (1H, d, J ) 14.4 Hz), 3.26 (1H, d, J ) 8.8 Hz), 3.09
(1H, d, J ) 10.4 Hz), 2.56 (1H, d, J ) 8.8 Hz), 2.38 (3H, s),
1.08 (3H, s). 13C NMR (100 MHz, CDCl3): δ 146.1, 143.3, 133.1,
129.6, 127.5, 115.0, 91.2, 77.8, 72.0, 57.2, 54.5, 44.3, 22.4, 21.4.
MS (EI, 75 eV) m/e (relative intensities, %): 613 (M+, 13), 585
(86), 557 (92), 529 (26). Anal. Calcd for WC23H25NO6S: C,
44.08; H, 3.86; N, 2.24. Found: C, 43.97; H, 3.97; N, 2.30.
(7) Syn th esis of 3a -Meth yl-2-(tolu en e-4-su lfon yl)-1,2,3,
3a ,4,6-h exa h yd r op yr a n o[3,4-c]p yr r ole-7-ca r boxylic Acid
Ben zyl Ester (8a ). To a CH2Cl2 solution (2.0 mL) of compound
7a (0.154 g, 0.24 mmol) was added benzyl alcohol (0.48 mmol)
and I2 (94 mg, 0.38 mmol) at -78 °C, and the mixture was
stirred for 30 min and slowly warmed to 23 °C. To this solution
was added water (3.5 mL) containing Na2S2O3 (50 mg), and
the mixture was extracted with CH2Cl2, dried over MgSO4,
and chromatographed on a small silica column to afford the
ester 8a (88 mg, 0.20 mmol, 82%). IR (neat, cm-1): υ(CO) 1714
(s). 1H NMR (400 MHz, CDCl3): δ 7.65 (2H, d, J ) 4.0 Hz),
7.29-7.42 (5H, m), 7.29 (2H, d, J ) 4.0 Hz), 5.15 (2H, ABq, J
) 6.0 Hz), 4.36 (2H, ABq, J ) 7.2 Hz), 4.14 (2H, ABq, J ) 4.0
Hz), 3.77 (1H, d, J ) 10.0 Hz), 3.43 (1H, d, J ) 8.8 Hz), 3.07
(1H, d, J ) 10.0 Hz), 2.54 (1H, d, J ) 8.8 Hz), 2.44 (3H, s),
1.27 (3H, s). 13C NMR (100 MHz, CDCl3): δ 164.0, 153.3, 143.7,
135.5, 133.0, 129.8, 128.7, 128.5, 128.4, 127.7, 120.1, 70.7, 66.4,
64.0, 55.8, 51.1, 42.3, 23.1, 21. HRMS calcd for C24H27NO5S,
427.1453; found, 427.1455.
(8) Syn th esis of 3a -Meth yl-2-(tolu en e-4-su lfon yl)-1,2,3,
3a ,4,6-h exa h yd r op yr a n o[3,4-c]-p yr r ole (8b). To a CH3CN
solution (5 mL) of compound 7a (200 mg, 0.32 mmol) was
added trimethylamine oxide (97 mg, 1.28 mmol) at 0 °C, and
the mixtures were stirred for 12 h. To this solution was added
water (3 mL), and the CH2Cl2 layer was separated, dried over
MgSO4, concentrated, and eluted through a silica column to
afford compound 8b as a colorless solid (73 mg, 0.24 mmol,
78%). IR (neat, cm-1): υ(CO) 1704 (s), 1672 (w). 1H NMR (400
MHz, CDCl3): δ 7.70 (2H, d, J ) 8.0 Hz), 7.31 (2H, d, J ) 8.0
Hz), 5.40 (1H, s), 4.11 (1H, m), 4.00 (2H, m), 3.72-3.95 (2H,
m), 3.31 (1H, d, J ) 9.2 Hz), 3.09 (1H, d, J ) 10.4 Hz), 2.73
(1H, d, J ) 9.2 Hz), 2.42 (3H, s), 1.06 (3H, s). 13C NMR (100
MHz, CDCl3): δ 143.5, 134.7, 133.9, 129.6, 127.5, 118.4, 67.2,
65.4, 55.6, 51.3, 43.7, 23.2, 21.4. HRMS calcd for C15H19NO3S,
293.1085; found, 293.1083.
2.0 Hz), 3.68 (1H, dd, J 1 ) 11.2, 3.2 Hz), 3.44 (1H, dd, J 1
)
11.2, 5.6 Hz), 2.81-2.89 (2H, m), 1.26 (3H, d, J ) 7.6 Hz). 13C
NMR (100 MHz, CDCl3): δ 82.4, 81.6, 69.9, 58.5, 57.3, 52.0,
17.1, 14.0. HRMS calcd for C8H11BrO2, 219.9942; found,
219.9948.
(9) Syn th esis of Ch ir a l P r op a r gyltu n gsten Com p ou n d
40. To a THF solution of chiral bromopropargyl epoxide 38
(0.50 g, 2.28 mmol) was added NaCpW(CO)3 (2.30 mmol), and
the mixture was stirred for 8 h. The solution was concentrated
and eluted through
a silica column to afford the chiral
propargyltungsten compound 40 as a yellow solid (0.79 g, 1.66
mmol, 73%). [R]25D -34.2 (c 2.5, CHCl3). IR (neat, cm-1): υ(CO)
2001 (s), 1903 (s), 1713 (s). 1H NMR (400 MHz, CDCl3): δ 5.42
(5H, s), 4.13 (2H, d, J ) 3.0 Hz), 3.68 (1H, dt, J ) 11.2, 2.8
Hz), 3.38-3.46 (1H, m), 2.78-2.86 (2H, m), 1.89 (2H, t, J )
3.0 Hz), 1.22 (3H, d, J ) 7.8 Hz). 13C NMR (100 MHz, CDCl3):
δ 228.7, 216.5, 96.3, 92.4, 75.3, 69.1, 59.1, 57.4, 51.8, 17.1,
-33.1. MS (EI, 75 eV) m/e (relative intensities, %): 472 (M+,
10), 444 (98), 416 (90), 388 (53). Anal. Calcd for WC16H16O5:
C, 40.59; H, 3.62. Found: C, 40.77; H, 3.78.
(10) Cycliza tion of Ch ir a l P r op a r gyltu n gsten Ep oxid e
40. Following the preceding procedure, the reaction of BF3‚Et2O
(0.16 g, 1.33 mmol) and chiral propargyltungsten epoxide 40
(0.70 g, 1.48 mmol) in CH2Cl2 afforded the chiral cycloadduct
42 (0.47 g, 0.99 mmol, 67%). [R]25 +67.9 (c 0.8, CHCl3). IR
D
(neat, cm-1): υ(CO) 2000 (s), 1913 (s). 1H NMR (400 MHz,
CDCl3): δ 5.54 (5H, s), 3.33 (1H, d, J ) 3.6 Hz), 3.96-4.16
(4H, m), 3.15-3.24 (2H, m), 2.59 (1H, dt, J ) 12.3, 1.6 Hz),
1.16 (3H, d, J ) 2.8 Hz). 13C NMR (100 MHz, CDCl3): δ 146.0,
111.9, 91.0, 78.7, 73.7, 72.0, 70.4, 49.8, 20.7. MS (EI, 75 eV)
m/e (relative intensities, %): 472 (M+, 10), 444 (91), 416 (88),
388 (66). Anal. Calcd for WC16H16O5: C, 40.62; H, 3.52.
Found: C, 40.44; H, 3.77.
(9) Syn th esis of 3a -Meth yl-2-(tolu en e-4-su lfon yl)-1,2,3,
3a ,4,6-h exa h yd r op yr a n o[3,4-c]-p yr r ol-7-on e (8c). To a
CH2Cl2 solution (5.0 mL) of compound 7a (6 mg, 0.090 mmol)
was added m-CPBA (71 mg, 0.19 mmol) at -78 °C, and the
solution was warmed to 23 °C for 12 h. The solution was
filtered over a short basic alumina bed, concentrated, and
eluted through a silica column to afford compounds 8b and
8c in 47% and 41% yields, respectively. Spectral data for 8c,
IR (neat, cm-1): υ(CO) 1712 (s), 1683 (w). 1H NMR (400 MHz,
CDCl3): δ 7.68 (2H, d, J ) 8.0 Hz), 7.31 (2H, d, J ) 8.0 Hz),
3.90 (2H, ABq, J ) 9.6 Hz), 3.73 (1H, dd, J ) 10.6, 3.9 Hz),
3.58 (2H, ABq, J ) 5.6 Hz), 3.47 (1H, dd, J ) 10.6, 8.2 Hz),
3.12 (2H, ABq, J ) 9.6 Hz), 2.47 (1H, dd, J ) 8.2, 3.9 Hz),
2.47 (1H, dd, J ) 10.6, 3.9 Hz), 2.42 (3H, s). 13C NMR (100
MHz, CDCl3): δ 210.2, 143.5, 134.7, 133.2, 129.4, 127.5, 81.0,
77.1, 53.5, 48.9, 36.3, 31.4, 15.1. HRMS calcd for C15H19NO4S,
309.1034; found, 309.1044.
(11) Syn th esis of Ben zyl(7R,7a S)-7-m eth yl-1,3,5,6,7,7a -
h exa h yd r o-4-isoben zo-fu r a n ca r boxyla te (44). This com-
pound was prepared similarly from a CH2Cl2 solution of I2 (140
mg, 0.41 mmol), benzyl alcohol (60 mg, 0.55 mmol), and

Synthesis of Bicyclic Pyrane Derivatives
J . Org. Chem., Vol. 66, No. 24, 2001 8111
compound 42 (130 mg, 0.28 mmol). The yield of compound 44
Ack n ow led gm en t. The authors wish to thank the
National Science Council, Taiwan, for financial support
of this work.
was 79% (61 mg, 0.22 mmol). [R]25 +81.3 (c 0.80, CHCl3). IR
D
1
(neat, cm-1): υ(CO) 1718 (s), υ(CdC) 1621 (w). H NMR (400
MHz, CDCl3): δ 7.25-7.39 (5H, m), 5.18 (2H, d, J ) 1.2 Hz),
4.72 (2H, ABg, J ) 2.8 Hz), 4.40 (2H, ABg, J ) 8.4 Hz), 4.15
(1H, t, J ) 8.0 Hz), 3.18-3.26 (2H, m), 2.63 (1H, bs), 1.28 (3H,
d, J ) 5.6 Hz). 13C NMR (100 MHz, CDCl3): δ 164.2, 154.3,
135.6, 128.6, 128.5, 128.3, 119.0, 71.3, 71.2, 69.1, 66.2,
64.6, 47.3, 20.5. HRMS calcd for C10H18O4, 202.1205; found,
202.1222.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data of compounds 6b and 6c, 9-35, 37,
39, 41, 43, 45, 46, 47 in repetitive experiments; 1H and 13C
NMR of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O010698E