Stereocontrolled synthesis of bicyclic lactone derivatives via tungsten-mediated [3 + 2] cycloaddition of epoxides with a tethered alkynyl group

Article abstract of DOI:10.1021/jo020669j

In the presence of BF₃·Et₂O, alkynyltungsten complexes underwent [3 + 2] cycloaddition with tethered epoxides to give bicyclic γ-lactones efficiently. Only one diastereomeric product was formed despite the presence of three stereogen

Full text of DOI:10.1021/jo020669j

Ster eocon tr olled Syn th esis of Bicyclic La cton e Der iva tives via
Tu n gsten -Med ia ted [3 + 2] Cycloa d d ition of Ep oxid es w ith a
Teth er ed Alk yn yl Gr ou p
Reniguntala J . Madhushaw,† Chien-Le Li,† Haw-Lih Su,† Chu-Chen Hu,† Shie-Fu Lush,‡ and
Rai-Shung Liu*,†
Department of Chemistry, National Tsing-Hua University, Hsinchu 30043, Taiwan, ROC, and
Department of Medical Technology, Yuanpei Institute of Science and Technology, Hsinchu, Taiwan, ROC
rsliu@mx.nthu.edu.tw
Received October 24, 2002
In the presence of BF3‚Et2O, alkynyltungsten complexes underwent [3 + 2] cycloaddition with
tethered epoxides to give bicyclic γ-lactones efficiently. Only one diastereomeric product was formed
despite the presence of three stereogenic centers. A mechanism is proposed that involves formation
of a tungsten-vinylidenium species via an SN2 attack of the epoxide carbon by an alkynyltungsten
group to give a tungsten-enol ether species via counterattack at the central tungsten-vinylidenium
carbon by the OBF3- terminus. Most of the tungsten enol ether species were too unstable for isolation
and underwent hydrolysis to give only cis-fused γ-bicyclic lactones. This cyclization works for both
cis- and trans-epoxides and tolerates various functional groups. In the case of trans-phenyl epoxide,
the reaction led to an addition product via a 6-endo attack of epoxide by the tungsten fragment.
This method provides a simple enantiospecific synthesis of complex bicyclic lactones if a chiral
epoxide is used in the cyclization. It is also applicable to the one-pot synthesis of bicyclic unsaturated
γ-lactones if a suitable alkynyltungsten functionality is used.
SCHEME 1
In tr od u ction
[3 + 2] Cycloaddition of epoxides with alkynes and
alkenes is a direct and efficient method for the synthesis
of furan derivatives.1,2 This cycloaddition can be achieved
by cleavage of either the C-C bond3 or C-O bond.4 The
former process is performed by either photochemical or
thermal activation to give an oxonium ylide intermediate
that can be trapped by electron-deficient olefins and
alkynes by 1,3-dipolar cycloaddition (Scheme 1, eq 1).3
This pathway proceeds with high diastereoselectivity,
† 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., Intl. Ed. Engl.
1994, 33, 497.
(3) Cycloaddition of aziridine with olefin and alkyne with cleavage
of the C-C bond; see, for example: (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. (b) Gaebert, C.;
Mattaay, J . Tetrahedron 1997, 53, 14297. (h) Palomino, E.; Schaap,
A. P.; Heeg, M. J . Tetrahedron Lett. 1989. 30, 6801.
(4) For 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) Nakagawa, M.;
Kawahara, M. Org. Lett. 2000, 2, 953. (e) Sugita, Y.; Kimura, Y.; Yokoe,
I. Tetrahedron Lett. 1999, 40, 5877.
since rotation of the C-C bond normally follows Wood-
ward-Hoffmann rules. This system has been thoroughly
studied and is useful in organic synthesis. An alternative
method involves the use of a Lewis acid to cleave the
10.1021/jo020669j CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/31/2003
1872
J . Org. Chem. 2003, 68, 1872-1877

Tungsten-Mediated [3 + 2] Cycloaddition of Epoxides
SCHEME 2
SCHEME 3
C-O bond of the epoxide to yield a zwitterionic inter-
mediate (Scheme 1, eq 2).4 This process is not widespread,
and only a few cases of special olefins have been
reported.4 Treatment of epoxides with electron-rich ole-
fins normally gives addition products.5,6 To the best of
our knowledge, the cycloaddition of epoxides with alkynes
has not yet been reported.
Previously, we reported that alkynyltungsten com-
plexes reacted with aldehydes to generate tungsten
vinylidenium intermediate, which undergoes hydrolysis
to give acyltungsten complexes7,8 (Scheme 1, eq 3). The
central carbon of metal vinylidenium species is highly
electrophilic and suitable for [3 + 2] cycloaddition if
epoxides are cleaved with a suitable acid (Scheme 1, eq
4). In this study,9 we report a new [3 + 2] cycloaddition
of alkynyltungsten complexes with epoxides based on this
reaction protocol.
catalytic conversion to tungsten-oxacarbenium C7a and
finally gives cis-fused bicyclic lactone 3 in the presence
of water.
This one-pot operation provides an easy and stereo-
controlled synthesis of bicyclic lactones with three ste-
reogenic centers. We prepared the substrates 4-15 to
examine the generality of this new approach. In a typical
procedure, the alkynyltungsten complex was treated with
BF3‚Et2O (25 mol %) in cold CH2Cl2 (-40 °C) for 4-12 h
before water was added. Entries 1 and 2 show cycliza-
tions of trans- and cis-epoxides 4 and 5; the products 16
and 17 have a cis-fused bicyclic ring bearing cis-methyl
and trans-propyl groups (entries 1 and 2), respectively.
The structures of lactones 16 and 17 are determined by
1H NOE effects (see the Supporting Information). This
reaction also works for gem-disubstituted epoxide 6 to
give the corresponding lactone 18 in 83% yield. This
method was successfully extended to the synthesis of cis-
fused γ-lactone 19 and 20 bearing a different pyranyl
group. It is also applicable to functionalized lactone 21,
which contains an acetate group. Entry 7 shows an
additional example for the efficient formation of γ-lactone
fused with a pyrrolidinyl ring. Similarly, cyclization of
functionalized cis- and trans-epoxides 11 and 12 led to
formation of the corresponding cis-fused lactones 23 and
24, which contain trans-methoxymethyl and cis-hy-
droxymethyl groups, respectively. Entry 10 shows the
formation of γ-lactone 25 bearing a piperidinyl group.
Both cis- and trans-fused isomers were obtained and
separated on a silica column. The presence of an ester
functionality in compounds 14 and 15 did not inhibit
cyclization, and bicyclic lactones 26 and 27 were obtained
in good yields.
Resu lts a n d Discu ssion
Cycloaddition of alkynyltungsten species with its tether
epoxide appears to be a direct and efficient synthesis of
bicyclic lactone because the expected cycloadduct-
tungsten enol ethers B are prone to hydrolysis to liberate
bicyclic lactone efficiently. A representative protocol is
shown in Scheme 2. Alkynyltungsten species 2 was
synthesized in 78% yield by metalation with CpW(CO)3Cl
(1.1 equiv) and CuI (3 mol %) in Et2NH.7a Treatment of
complex 2 with BF3‚Et2O (25 mol %) in CH2Cl2 (-40 °C,
8 h) caused the disappearance of complex 2 as shown by
monitoring the reaction chromatographically (SiO2 TLC
plate). Subsequent treatment of this mixture with H2O
gave the lactone 3 in 86% yield. The three stereogenic
protons of lactone 3 are mutually cis to one another
according to proton NOE spectra (see the Experimental
Section). Such a stereochemical outcome suggests that
ring opening of the epoxide is caused by SN2 attack of
the alkynyltungsten fragment to give tungsten-vinylide-
nium intermediate A.7a The enol ether B10 is highly
sensitive to the presence of protons, which accelerate its
The hybridization of epoxide lies between sp2 and sp3,11
and both endo and exo attack in Scheme 3 are likely to
occur. The results in Table 1 indicate that the cyclizations
exclusively follow exo-mode to give [3 + 2] cycloadducts.
(5) For review papers, see: (a) Tanner, D. Angew. Chem., Int. Ed.
Engl. 1994, 33, 599. (b) Yamamoto, Y.; Asao N. Chem. Rev. 1993, 2207.
(6) See, for example: (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) (a) Liang, K.-W.; Li,W.-T.; Lee, G.-H.; Peng, S.-Mi.; Liu, R.-S. J .
Am. Chem. Soc. 1997, 119, 4404. (b) Liang, K.-W.; Chandrasekharam,
M.; Li, C.-L.; Liu, R.-S. J . Org. Chem. 1998, 63, 7289. (c) Li, W.-T.;
Pan, M.-H.; Wu, Y.-R.; Wang, S.-L.; Liao, F.-L.; Liu, R.-S. J . Org. Chem.
2000, 65, 6362. (c) Chen, M.-J .; Lo, C.-Y.; Liu, R.-S. Synlett 2000, 1300.
(8) Li, C.-L.; Liu, R.-S. Chem. Rev. 2000, 100, 3127.
(9) Madhushaw, R.-J .; Li, C.-L.; Shen, K.-H.; Hu, C.-C.; Liu, R.-S.
J . Am. Chem. Soc. 2002, 123, 7427.
(10) McDonald, F. E.; Schults, C. C. J . Am. Chem. Soc. 1994, 169,
9363.
(11) Nicolaou, K. C.; Duggan, M. E.; Huang, C.-K.; Somers, P. K. J .
Chem. Soc., Chem. Commun. 1985, 1359.
J . Org. Chem, Vol. 68, No. 5, 2003 1873

Madhushaw et al.
TABLE 1. Cycloa d d ition of Alk yn yltu n gsten Com p lexes
w ith Teth er ed Ep oxid es
SCHEME 4
derivative 37 (78%), and then to epoxide 38 (84%), and
finally metalated to give alkynyltungsten species 39.
Before cyclization, HPLC analysis of the epoxide 38
showed an enantiopurity of ca. 87%. A small decrease in
the ee value is observed for bicyclic lactone 44 (91% ee)
derived form the epoxide 40 (97% ee). The [R] value of
compound 44 is consistent with that of an authentic
sample.14 A considerable decrease in ee value is found
for lactone 45 (65% ee) obtained from chiral gem-
disubstituted epoxide 41 (87% ee), which suggests the
formation of a tertiary carbocation during the opening
of the epoxide. In the cyclization of trans-epoxides 42
(94% ee) and 43 (94% ee), no loss of enantiopurity is
observed for the resulting products 46 (93% ee) and 47
(93% ee).
This new method was also applicable to the synthesis
of various bicyclic unsaturated γ-lactones, and the results
are given in Scheme 5. The starting alkynyltungsten
complexes 52-55 were prepared according to conven-
tional methods. A synthetic protocol for 54 is shown in
Scheme 4. Epoxide 51 was prepared with high enan-
tiopurity via a fructose-based catalytic asymmetric ep-
oxidation15 and each acetate diastereomer showed 90%
ee according to HPLC-analysis. This fructose-based ep-
oxidation was also used to prepare chiral epoxide 55 and
both of the acetate diastereomers showed 94% ee. The
working hypothesis shown in eq 2 involves cleavage of
the OAc- group of the tungsten-enol ether species to
form bicyclic unsaturated tungsten-carbenium, which
gives the desired lactone 56 (61% yield) upon hydrolysis
in air. This approach works well for cis-epoxide 53 to give
an unsaturated lactone 57 bearing a trans-hexyl group.
In the cyclization of chiral epoxides 54 and 55, the
resulting lactones 58 and 59 were produced in reasonable
yields without loss of enantiopurity. The primary product
from alkynyltungsten species 55, being unstable in
reaction medium, was converted to naphthalene deriva-
tive 59 upon subsequent oxidation.
a
W ) CpW(CO)3, BF3‚Et2O (25 mol %), CH2Cl2, -40 °C. b Yields
were reported after purification from preparative silica TLC plates.
To examine the possibility of endo attack to form a six-
membered ring, we prepared various phenyl-substituted
epoxides, which are expected to favor endo-attack with
the formation of a benzyl carbocation upon opening of
the epoxide with BF3‚Et2O. The results in Scheme 3
reveal that cis-epoxide 28 led to the formation of cycload-
duct 31, whereas trans-epoxides 29 and 30 gave six-
membered heterocyclic derivatives 32 and 33 in good
yields. The structure of 33 was confirmed by an X-ray
diffraction study.12 The preferred exo-attack of compound
28 can be explained by steric hindrance as the alkynyl-
tungsten group approaches the phenyl carbon in SN2-
mode. The cis-phenyl group makes it difficult for the
alkynyl to align with the σ*-orbital of the PhC-O bond.
Oxidative demetalation of compound 32 with I2 in MeOH
(0 °C, 8 h) gave trisubstituted pyrane derivative 34 in
96% yield.
We also prepared chiral epoxides allowing for a con-
clusive study of enantiospecific cycloaddition. Epoxides
40, 42, and 43 (>92% ee) were prepared with high
enantiopurity according to Sharpless asymmetric epoxi-
dation,13 and the synthetic procedures are provided in
the Supporting Information. Scheme 4 shows the syn-
thetic protocol of chiral epoxide 39. Asymmetric dihy-
droxylation of enyne 35 produced chiral diol in 86% yield
with 75% ee. Recrystallization of this solid from ether
and hexane increased its enantiopurity to 87% with a
final 56% yield. The diol 36 was transformed to tosylate
In summary, we reported a BF3-promoted intra-
molecular [3 + 2] cycloaddition of alkynyltungsten com-
(12) X-ray diffraction data of compound 33 is provided in the
Supporting Information.
(13) Hanson, R. M.; Sharpless, K. B. J . Org. Chem. 1986, 51, 1922.
(14) Petit, F.; Furstoss, R. Tetrahedron: Asymmetry 1993, 4, 1341.
(15) Wang, Z.-X.; Yong, T.; Frohn, M.; Zhang, J .-R.; Shi, Y. J . Am.
Chem. Soc. 1997, 119, 11224.
1874 J . Org. Chem., Vol. 68, No. 5, 2003

Tungsten-Mediated [3 + 2] Cycloaddition of Epoxides
3.28 (dd, J ) 14.8, 5.2 Hz, 1 H), 2.89-2.88 (m, 2 H), 2.41 (s, 3
H), 2.02 (t, J ) 2.4 Hz, 1 H), 1.29 (d, J ) 5.2 Hz, 3 H); 13C
NMR (100 MHz, CDCl3) δ 143.8, 135.7, 129.5, 127.7, 76.6, 73.9,
57.3, 52.9, 47.9, 37.9, 21.5, 17.0; MS (EI, 75 eV, m/z) 279 (M+).
(2) Syn th esis of WCp (CO)3[η1-(2R*,3R*)-3-m eth yl-2-[[(4-
m e t h ylp h e n yl)(2-p r op yn yl)su lfon a m id o]m e t h yl]oxi-
r a n e] (2). To a Et2NH solution (15.0 mL) of alkynyltungsten
complex 1 (0.50 g, 1.79 mmol) were added CpW(CO)3Cl (0.66
g, 1.79 mmol) and CuI (34 mg, 0.179 mmol), and the solution
was stirred for 3 h to yield a dark yellow solution. The solution
was concentrated to ca. 3 mL and eluted through a Et3N-
pretreated silica column to give compound 2 (0.77 g, 1.26
mmol, 70%) as a viscous solid: IR (neat, cm-1) 2016 (s), 1914
SCHEME 5
1
(vs); H NMR (300 MHz, CDCl3) δ 7.69 (d, J ) 8.4 Hz, 2 H),
7.25 (d, J ) 8.4 Hz, 2 H), 5.42 (s, 5 H), 4.30 (ABq, J ) 18 Hz,
2 H), 3.42 (dd, J ) 14.8, 4.8 Hz, 1 H), 3.25 (dd, J ) 14.4, 5.6
Hz, 1 H), 2.89∼2.86 (m, 2 H), 2.40 (s, 3 H), 1.28 (d, J ) 5.6
Hz, 3 H); 13C NMR (75 MHz, CDCl3): δ 228.8, 211.6, 143.0,
136.4, 129.4, 127.7, 120.3, 91.3, 67.5, 57.3, 53.5, 47.4, 40.7, 21.4,
17.1; MS (75 eV, m/z) 611 (M+). Anal. Calcd for C22H22O6-
NWS: C, 43.15; H, 3.62; N, 2.29. Found: C, 43.11; H, 3.44; N,
2.11.
(3) Syn th esis of (3S*,3a R*,6a S*)-3-Meth yl-5-[(4-m eth -
ylp h en yl)su lfon yl]p er h yd r ofu r o[3,4-c]p yr r ol-1-on e (3).
To a CH2Cl2 solution (3.0 mL) of alkynyltungsten complex 2
(0.50 g, 0.81 mmol) was added BF3‚Et2O at -40 °C, and the
mixtures were stirred for 8 h before addition of water (2.0 mL).
The solution was stirred for 6 h, and the organic layer was
extracted with diethyl ether. Flash chromatography over a
silica bed afforded 3 as a colorless solid (0.21 g, 0.70 mmol,
86%): IR (neat, cm-1) 1774 (vs); 1H NMR (300 MHz, CDCl3) δ
7.65 (d, J ) 8.2 Hz, 2 H), 7.31 (d, J ) 8.2 Hz, 2 H), 4.68 (dt, J
) 12.8, 6.5 Hz, 1 H), 3.59 (dd, J ) 10, 1.8 Hz, 1 H), 3.69-3.30
(m, 1H), 3.25-3.11 (m, 3 H), 3.05-2.98 (m, 1 H), 2.40 (s, 3 H,
CH3), 1.34 (d, J ) 6.5 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ
176.5, 144.2, 132.1, 129.9, 127.8, 76.3, 50.0, 47.2, 46.0, 42.7,
21.5, 16.2; MS (EI, 75 eV, m/z) 295(M+); HRMS calcd for
plexes with tethered epoxides. This cycloaddition tolerat-
ing various functionalities proceeds with high dia-
stereoselectivity to afford, in reasonable yields, bicyclic
γ-lactones. The stereochemical outcome of the products
suggests that ring-opening of epoxide is initiated by SN-2
attack of alkynyltungsten group. In most cases, 5-exo
mode for the attack at epoxide carbon is more preferable
than 6-endo mode. This new method provides a short
enantiospecific synthesis of bicyclic saturated or unsat-
utated γ-lactones if suitable epoxides are used.
C
14H17NO4S 295.3642, found 295.3646.
Exp er im en ta l Section
Unless otherwise noted, all reactions were carried out under
a nitrogen atmosphere in oven-dried glassware using standard
syringe, cannula, and septa apparatus. Benzene, diethyl ether,
tetrahydrofuran, and hexane were dried with sodium ben-
zophenone and distilled before use. Dichloromethane was dried
over CaH2 and distilled before use. W(CO)6, BF3‚Et2O, dicy-
clopentadiene, 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. ClCpW(CO)3 were prepared by procedures
described in the literature.16 Spectral data of compounds 4-30,
33, 35, 40-48, and 55-57 in repetitive experiments are
provided in the Supporting Information.
(1) Syn t h esis of (2R*,3R*)-3-Met h yl-2-[[(4-m et h yl-
p h en yl)(2-p r op yn yl)Su lfon a m id o]m et h yl]oxir a n e (1).
To a CH2Cl2 solution (10.0 mL) of enyne (0.50 g, 2.5 mmol)
was added m-CPBA (0.79 g, 3.75 mmol) at 23 °C, and the
mixtures were stirred for 36 h. The solution was concentrated,
and the remaining white residues were chromatographed
through a short basic alumina column (diethyl ether/hexane
) 1/1, Rf ) 0.4) to afford epoxide 1 as a colorless oil (0.55 g,
2.0 mmol, 80%): IR (neat, cm-1) 3310 (vs); 1H NMR (400 MHz,
CDCl3) δ 7.72 (d, J ) 8.0 Hz, 2 H), 7.29 (d, J ) 8.0 Hz, 2 H),
4.20 (ABq, J ) 5.6 Hz, 2 H), 3.41 (dd, J ) 14.8, 4.0 Hz, 1 H),
(4) Syn th esis of (3S*,3a R*,6a S*)-3-P h en ylp er h yd r o-
fu r o[3,4-c]fu r a n -1-on e (31). To a CH2Cl2 solution (3.0 mL)
of alkynyltungsten complex 28 (0.50 g, 0.96 mmol) was added
BF3‚Et2O at -40 °C, and the mixtures were stirred for 8 h
before addition of water (2.0 mL). The solution was stirred for
6 h, and the organic layer was extracted with diethyl ether.
Flash chromatography over a silica bed afforded 31 as colorless
oil (0.15 g, 0.71 mmol, 74%): IR (neat, cm-1) 1776 (vs); 1H NMR
(400 MHz, CDCl3) δ 7.41-7.27 (m, 5 H), 5.23 (d, J ) 5.4 Hz,
1 H), 4.38 (dd, J ) 9.6, 2.0 Hz, 1 H), 4.14 (dd, J ) 9.6, 2.0 Hz,
1 H), 3.85-3.80 (m, 2 H), 3.66-3.41 (m, 1 H), 3.13-3.08 (m, 1
H); 13C NMR (100 MHz, CDCl3) δ 177.9, 139.8, 129.0, 128.7,
125.1, 85.9, 74.2, 71.6, 49.2, 46.0; MS (75 eV, m/z) 204 (M+);
HRMS calcd for C12H12O3 204.2231, found 204.2230.
(5) Syn th esis of WCp (CO)3(η1-3-Ca r bon yl-5-h yd r oxy-
4-p h en yltetr a h yd r op yr a n ) (32). To a CH2Cl2 solution (3.0
mL) of alkynyltungsten complex 29 (0.50 g, 0.96 mmol) was
added BF3‚Et2O at -40 °C, and the mixture was stirred for 8
h before addition of water (2.0 mL). The solution was stirred
for 4 h, and the organic layer was extracted with diethyl ether.
(16) Dub, M. Organometallic Compounds, 2nd ed.; Springer-Ver-
lag: Berlin, 1966; Vol. 1.
Flash chromatography over
a Et3N-pretreated silica bed
J . Org. Chem, Vol. 68, No. 5, 2003 1875

Madhushaw et al.
afforded 32 as yellow solid (0.41 g, 0.76 mmol, 79%): IR (neat,
cm-1) 2017 (vs), 1939 (vs), 1913 (s); 1H NMR (300 MHz, CDCl3)
δ 7.34-7.17 (m, 5 H), 5.22 (s, 5 H, Cp), 4.81-4.72 (m, 1 H),
4.21 (d, J ) 12.1 Hz, 1 H), 4.13 (dd, J ) 10.8, 5.2 Hz, 1 H),
4.01-3.98 (m, 1 H), 3.48 (dd, J ) 12.2, 3.6 Hz, 1 H), 3.08 (dd,
J ) 10.8, 10.0 Hz, 1 H), 2.68 (dd, J ) 10.1, 4.6 Hz, 1 H), 1.75
(bs, 1 H); 13C NMR (75 MHz, CDCl3) δ 242.1, 226.4, 219.9,
219.2, 139.1, 129.0, 128.5, 126.8, 93.6, 75.8, 72.2, 66.8, 64.6,
52.7; MS (75 eV, m/e) 538 (M+). Anal. Calcd for C20H18O6W:
C, 44.63; H, 3.37. Found: C, 44.61; H, 3.29.
(6) Syn th esis of 5-Hyd r oxy-4-p h en yltetr a h yd r op yr a n -
3-ca r boxylic Acid Meth yl Ester (34). To a CH2Cl2 solution
containing I2 (46 mg, 0.185 mmol) wrere added compound 32
(100 mg, 0.185 mmol) and MeOH (2.0 mL) at 0 °C, and the
mixture was stirred for 8 h. The reaction mixture was treated
with a saturated Na2S2O3 solution, and the organic layer was
extracted with diethyl ether, dried over MgSO4, and concen-
Hz, 2 H), 2.74 (d, J ) 4.4 Hz, 1 H), 2.60 (d, J ) 4.4 Hz, 1 H),
2.39 (s, 3H), 1.94 (t, J ) 2.8 Hz, 1 H), 1.37 (3H, s); 13C NMR
(75 MHz, CDCl3) δ 143.6, 135.8, 129.4, 127.6, 76.3, 73.9, 55.5,
51.4, 50.8, 37.6, 21.4, 18.7; MS (75 eV, m/e) 279 (M+); HRMS
calcd for C14H17NSO3 279.0929, found 279.0923.
(10) Syn th esis of WCp (CO)3[η1-4-Meth yl-N-(2-m eth yl-
oxir an ylm eth yl)-N-pr op-2-yn ylben zen esu lfon am ide] (39).
To a Et2NH (10 mL) solution of epoxide 38 (1.00 g, 3.77 mmol)
were added CpW(CO)3Cl (1.38 g, 3.77 mmol) and CuI (71 mg,
0.37 mmol), and the solution was stirred for 3 h. The solution
was concentrated to 3 mL and eluted through an Et3N-
pretreated silical gel column to give compound 39 as a yellow
solid (1.66 g, 2.70 mmol, 76%): [R]D ) -24.7 (CHCl3, c ) 5.0);
IR (neat, cm-1) 2047 (s), 1931 (s); 1H NMR (400 MHz, CDCl3)
δ 7.70 (2 H, d, J ) 8.0 Hz); 7.26 (2 H, d, J ) 8.0 Hz), 5.41(s,
5 H), 4.41 (2 H, dd, J ) 16.0, 1.0 Hz), 4.23 (1 H, dd, J ) 18,
0.8 Hz), 3.45 (d, J ) 14.4 Hz, 1 H), 3.21 (d, J ) 14.4 Hz, 1 H),
2.79 (dd, J ) 4.8 Hz, 2H), 2.60 (d, J ) 4.8 Hz, 1 H), 2.41 (s, 3
H), 1.39 (3 H, s); 13C NMR (75 MHz, CDCl3) δ 228.8, 211.6,
211.6, 142.9, 136.5, 129.3, 127.6, 120.2, 91.2, 67.4, 55.4, 52.1,
50.3, 40.4, 21.4, 19.0; MS (75 eV, m/e) 611 (M+). Anal. Calcd
for C22H21WSNO6: C, 43.22; H, 3.46; N, 2.29. Found: C, 43.01;
H, 3.40; N, 2.00.
(11) Gen er a l P r oced u r es for Syn th esis of En yn e Al-
coh ol (49). To a THF solution (40 mL) of trimethylsilylethyne
(6.0 mL, 42.48 mmol) was added n-BuLi (42.5 mmol) at -78
°C, and the solution was stirred for 1 h. To this solution was
added slowly aldehyde 48 (5.95 g, 42.5 mmol), and the solution
was warmed to 23 °C in a period of 5 h. To this mixture was
added a saturated ammonium chloride solution, and the
organic layer was extracted with diethyl ether, concentrated,
and eluted through a silica column to afford a colorless oil (10.2
g, 39.1 mmol, 92%). This oil was treated with a THF solution
of TBAF (1 M, 40 mL) at 23 °C, and the mixture was stirred
for 1 h. The solution was concentrated and eluted through a
silica column to give compound 49 as a colorless oil (5.90 g,
35.6 mmol, 91%): 1H NMR (400 MHz, CDCl3) δ 5.35-5.33 (m,
2 H), 4.35-4.31 (m, 1 H), 2.4 (s, 1 H), 2.0 -1.84 (m, 4 H), 1.64-
1.62 (m, 2 H), 1.45-1.42 (m, 2 H), 1.38-1.22 (m, 2 H), 0.823
(t, J ) 7.6 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 130.9, 129.9,
85.5, 72.6, 53.3, 37.3, 34.8, 32.3, 25.2, 22.8, 14.11; MS (75 eV,
m/e) 166.14 (M+); HRMS calcd for C11H18O 166.1358, found
166.1355.
(12) Gen er a l P r oced u r es for Syn th esis of Eth yn yl
Aceta te Com p ou n d (50). To a CH2Cl2 (20 mL) of compound
49 (5.50 g, 33.10 mmol) were added dry pyridine (20 mL),
acetic anhydride (51.1 mL, 49.7 mmol), and DMAP (360 mg).
The solution was washed with 100 mL of 1 N HCl and
extracted with ether. The ether extract was concentrated and
eluted through a silica column to give compound 50 as a
colorless oil (5.78 g, 27.8 mmol, 84%): 1H NMR (400 MHz,
CDCl3) δ 5.39-5.32 (m, 3 H), 2.43 (d, J ) 2.4 Hz, 1 H), 2.06 (3
H, s), 1.93-2.02 (m, 4 H), 1.72∼1.76 (m, 2 H), 1.50-1.48 (m,
2 H), 1.37-1.31 (m, 2 H), 0.844 (t, J ) 7.6 Hz, 3 H); 13C NMR
(100 MHz, CDCl3) δ 170.3, 131.3, 129.6, 81.4, 73.6, 63.9, 34.7,
34.2, 32.1, 25.0, 22.8, 21.1, 13.8. MS (75 eV, m/e) 208 (M+);
HRMS calcd for C13H20O2 208.1463, found 208.1456.
(13) Syn th esis of 1,3-[(2R,3R)-3-Oxir a n -2-yl]p r op yl-4-
p en tyn yl Aceta te (51). A buffer solution (pH 9-10) was
prepared from Na2B4O7‚10H2O (1.097 g), Na2EDTA (1.0 mL,
0.10 M), and water (99 mL). This buffer solution (20 mL) was
added with CH3CN (30 mL), the enyne 50 (0.416 g, 2.0 mmol),
chiral fructose-derived ketone (0.31 g, 1.20 mmol), and Bu4-
NHSO4 (0.03 g). To this mixture was added an aqueous K2-
CO3 solution (1.6 g, 13.0 mL water) and a Na2EDTA solution
(4 × 10-4 M, 13.0 mL) of oxone (1.70 g, 2.76 mmol) in a period
of 2 h. The mixtures were stirred at 0 °C for an additional 3 h
before treatment with pentane (50 mL), dried over MgSO4, and
chromatographed through a Et3N-pretreated silica column to
afford compound 51 (0.39 g, 1.74, mmol, 87%) as a colorless
oil. HPLC analysis showed a 1:1 diastereomeric mixture
product with each one having 90% ee: [R]D ) +18.9 (CHCl3, c
trated. The residue was eluted through
a silica column
(hexane/ether ) 1:2) to give compound 34 as a colorless solid
(42.0 mg, 0.178 mmol, 96%): IR (neat, cm-1) 2923 (s), 1937
1
(vs), 1688 (w); H NMR (500 MHz, CDCl3) δ 7.34 -7.22 (m, 5
H), 4.82-4.78 (m, 1 H), 4.20-4.16 (m, 1 H), 3.75 (dd, J ) 12.0,
3.5 Hz, 1 H), 3.50 (s, 3 H, OCH3), 3.26 (dd, J ) 11.0, 8.5 Hz,
1 H), 3.0-2.98 (m, 1 H), 2.94 (dd, J ) 9.5, 5.0 Hz, 1 H), 1.72
(bs, 1 H, OH); 13C NMR (75 MHz, CDCl3) δ 172.1, 138.4, 128.7,
128.5, 127.3, 71.8, 69.3, 64.7, 51.5, 50.6, 47.4; MS (75 eV, m/e)
236 (M+); HRMS calcd for C13H16O4 236.1037, found 236.1035.
(7) Syn t h esis of 1-[(2R)-2,2-Dih yd r oxy-2-m et h yl-
p r op yl]-1-(2-p r op yn yl)-4-m et h yl-1-b en zen su lfon a m id e
(36). To a mixture of water (8.6 mL) and tert-butyl alcohol (8.6
mL) were added methyl sulfonamide (0.18 g, 1.89 mmol), â-AD-
mix (2.27 g), and compound 35 (0.50 g, 1.89 mmol), and the
mixture was stirred at 0 °C for 27 h before quenching with a
saturated Na2S2O3 solution. The organic layer was extracted
with ethyl acetate and dried over MgSO4. The solution was
concentrated and chromatographed on a silica column to afford
the diol 36 as a solid form (0.48 g, 1.62 mmol, 86%, 75% ee).
Recrystallization from a saturated diethyl ether/hexane gave
a sample with 87% ee: [R]D ) +4.25 (CHCl3, c ) 2.0); 1H NMR
(400 MHz, CDCl3) δ 7.70 (2 H, d, J ) 11.2 Hz); 7.27 (2 H, d, J
) 11.2 Hz), 4.34 (2 H, s), 3.56 (2 H, m), 3.23 (2H, ABq, J )
11.2 Hz), 3.03 (2H, s), 2.30(3H, s), 1.94 (1H, t, J ) 3.2 Hz); 13
C
NMR (75 MHz, CDCl3) δ 143.4, 136.0, 129.3, 127.7, 126.8, 90.1,
76.3, 67.2, 52.3, 39.4, 23.4, 21.6; MS (75 eV, m/e) 297 (M+);
HRMS calcd for C14H19NSO4 297.1035, found 297.1038.
(8) Syn th esis of Tolu en e-4-su lfon ic Acid 2-Hyd r oxy-
2-m e t h y l-3-[p r o p -2-y n y l(t o lu e n e -4-s u lfo n y l)a m in o ]-
p r op yl E st er (37). To a pyridine solution (5.0 mL) of
compound 36 (0.42 g, 1.21 mmol) was added p-toluenesulfonyl
chloride (0.30 g, 1.41 mmol), and the mixture was stirred for
4 h. To this mixture was added cold water, and the organic
layer was extracted with ether. The solution was concentrated
and eluted through a silica column to give compound 37 as a
colorless solid (0.42 g, 0.94 mmol, 78%): [R]D ) +17.1 (CHCl3,
c ) 2.0); 1H NMR (400 MHz, CDCl3) δ 7.79 (2H, d, J ) 8.4
Hz); 7.31 (2H, d, J ) 8.4 Hz), 7.27 (2H, d, J ) 8.4 Hz), 4.34
(ABq, J ) 11.2 Hz, 2 H), 3.94 (2H, d, J ) 1.6), 3.23 (ABq, J )
11.2 Hz, 2H), 2.41 (3H, s), 1.96 (1H, t, J ) 3.2 Hz); 13C NMR
(75 MHz, CDCl3) δ 143.4, 136.0, 129.3, 127.7, 126.8, 90.1, 76.3,
67.2, 52.3, 39.4, 23.4, 21.6; MS (75 eV, m/e) 451 (M+); HRMS
calcd for C21H25NS2O6 451.1123, found 451.1122.
(9) Syn th esis of 4-Meth yl-N-(2-m eth yloxir a n ylm eth yl)-
N-p r op -2-yn ylben zen esu lfon a m id e (38). To a methanol
solution (10 mL) of alcohol 37 (1.00 g, 2.21 mmol) was added
potassium carbonate (0.65 g, 4.46 mmol), and the mixtures
were stirred for 6 h. To this mixture was added cold water,
and the organic layer was extracted with diethyl ether. The
solution was concentrated and eluted through a silica column
to give compound 38 as a solid (0.52 g, 1.85 mmol, 84%): [R]D
) -24.7 (CHCl3, c ) 5.0); IR (neat, cm-1) 2047 (s), 1934(s); 1H
NMR (400 MHz, CDCl3) δ 7.70 (2H, d, J ) 8 Hz), 7.25 (2 H, d,
J ) 8.0 Hz), 4.21 (ABq, J ) 2.8 Hz, 2 H), 3.35 (ABq, J ) 14
1876 J . Org. Chem., Vol. 68, No. 5, 2003

Tungsten-Mediated [3 + 2] Cycloaddition of Epoxides
) 0.32); 1H NMR (400 MHz, CDCl3) δ 5.38-5.30 (m, 1 H), 2.65
(m, 2 H), 2.44 (1 H, d, J ) 2.0 Hz), 2.07 (s, 3 H), 1.40-1.86 (m,
8 H), 0.948 (t, J ) 4.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ
170.1, 81.1, 73.8, 63.7, 58.7, 58.5, 34.5, 34.3, 31.4, 21.7, 21.1,
19.5, 14.3; MS (75 eV, m/e) 224.14 (M+); HRMS calcd for
added BF3‚OEt2 at -78 °C (0.10 mL, 0.43 mmol), and the
mixture was stirred for 4 h. To this solution was added water
(5.0 mL), and the resulting solution was extracted with diethyl
ether and dried over MgSO4. The solution was concentrated
and eluted on silica to give compound 58 as colorless oil (50.3
mg, 0.279 mmol, 65%): [R]D ) +69.6 (CHCl3, c ) 0.6); IR (neat,
C
13H20O3 224.1424, found 224.1423.
(14) Syn t h esis of WCp (CO)3[η1-1,3-[(2R,3R)-3-p r op yl-
1
cm-1) 1759 (vs), 2015 (vs); H NMR (400 MHz, CDCl3) δ 6.83
oxir a n -2-yl]p r op yl-4-p en tyn yl a ceta te] (54). To a Et3N (4.0
mL) solution of epoxide 51 (0.20 g, 0.89 mmol) were added
CpW(CO)3Cl (0.50 g, 1.36 mmol) and CuI (15 mg, 0.37 mmol),
and the solution was stirred for 3 h. The solution was
concentrated to 3 mL and eluted through a Et3N-pretreated
silica gel column to give the compound as a yellow solid (0.44
g, 0.80 mmol, 70%): [R]D) +7.32 (CHCl3, c ) 4.5); IR (neat,
(m, 1 H), 4.66 (dt, J ) 9.2, 3.2 Hz, 1 H), 3.1-3.00 (m, 1 H),
2.40-2.32 (m, 1 H), 2.24-2.12 (m, 1 H), 2.00-1.83 (m, 2 H),
1.60-1.20 (m, 6 H), 0.92 (t, J ) 6.8 Hz, 3 H); 13C NMR (100
MHz, CDCl3) δ 170.3, 136.3, 129.8, 81.7, 39.9, 34.0, 25.3, 22.7,
21.3, 18.8, 13.9; HRMS calcd for C16H18O3 180.1150, found
180.1148.
1
cm-1) 1919 (vs), 2015 (vs); H NMR (400 MHz, CDCl3) δ 5.46
Ack n ow led gm en t. We thank the National Science
Council, Taiwan, for financial support of this work.
(s, 5 H), 5.30 (t, J ) 6.4 Hz, 1 H), 2.50 (d, J ) 2 Hz, 2 H), 1.87
(s, 3 H), 1.20-1.60 (m, 10 H), 0.80 (t, J ) 6.8 Hz, 3 H); 13C
NMR (100 MHz, CDCl3): δ 229.0, 212.0, 212.1, 170.1, 125.4,
91.7, 66.2, 58.5, 35.6, 34.2, 31.6, 22.6, 21.8, 21.4, 19.3, 14.0;
MS (EI, 75 eV, m/z) 555 (M+). Anal. Calcd for C21H23O6W: C,
45.43; H 4.18. Found: C, 45.33; H, 4.30.
(15) Syn th esis of (3R,3aR)-3-P r opyl-1,3,3a,4,5,6-h exah y-
d r o-1-isoben zofu r a n on e (58). To a diethyl ether (5.0 mL)
solution of tungsten complex 54 (238 mg, 0.43 mmol) was
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data of compounds 4-30, 33, 35, 40-
48, and 55-57 in repetitive experiments. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O020669J
J . Org. Chem, Vol. 68, No. 5, 2003 1877