Anionic cyclization approach toward perhydrobenzofuranone: Stereocontrolled synthesis of the hexahydrobenzofuran subunit of avermectin

Article abstract of DOI:10.1021/jo010853p

A facile anionic cyclization approach toward stereocontrolled synthesis of the hexahydrobenzofuran subunit 3 of avermectin is described. As a model study, treatment of iodo compound 7 with n-BuLi at -100°C effected metal-halogen exchange and subsequent anionic cyclization to afford perhydrobenzofuranone 8. For the total synthesis of subunit 3, compound 9 was dihydroxylated to give diol 10. Protection of the hydroxyl groups of diol 10 gave compound 11. Ketone 11 was then converted into the required enone 12 using Saegusa's protocol. On iodination followed by Luche reduction, enone 12 yielded α-iodo allylic alcohol 14, which on alkylation afforded ether 15. Conversion of the ester unit of 15 into a Weinreb amide group followed by anionic cyclization gave enone 17. 1,4-Addition of (MeOCH₂)₂CuCNLi₂ to enone 17 followed by cleavage of the acetal unit afforded ketone 19. Preferential acetylation of the secondary alcoholic function of 19 afforded compound 20. The stereochemistry of 20 is confirmed by single-crystal X-ray analysis. Elimination of HOAc from 20 gave the crucial olefin 21. Hydrolysis of the acetate unit of 21 followed by protection of the resulting alcoholic function yielded tert-butyldimethylsilyl ether 23. Introduction of a hydroxyl group at the ring junction of 23, using Davis's procedure, finally afforded the hexahydrobenzofuran subunit 3.

Full text of DOI:10.1021/jo010853p

J . Org. Chem. 2002, 67, 831-836
831
An ion ic Cycliza tion Ap p r oa ch tow a r d P er h yd r oben zofu r a n on e:
Ster eocon tr olled Syn th esis of th e Hexa h yd r oben zofu r a n Su bu n it
of Aver m ectin
Chin-Kang Sha,* Shih-J ung Huang, and Zhuang-Ping Zhan
Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan, Republic of China
cksha@chem.nthu.edu.tw
Received August 21, 2001
A facile anionic cyclization approach toward stereocontrolled synthesis of the hexahydrobenzofuran
subunit 3 of avermectin is described. As a model study, treatment of iodo compound 7 with n-BuLi
at -100 °C effected metal-halogen exchange and subsequent anionic cyclization to afford
perhydrobenzofuranone 8. For the total synthesis of subunit 3, compound 9 was dihydroxylated to
give diol 10. Protection of the hydroxyl groups of diol 10 gave compound 11. Ketone 11 was then
converted into the required enone 12 using Saegusa’s protocol. On iodination followed by Luche
reduction, enone 12 yielded R-iodo allylic alcohol 14, which on alkylation afforded ether 15.
Conversion of the ester unit of 15 into a Weinreb amide group followed by anionic cyclization gave
enone 17. 1,4-Addition of (MeOCH2)2CuCNLi2 to enone 17 followed by cleavage of the acetal unit
afforded ketone 19. Preferential acetylation of the secondary alcoholic function of 19 afforded
compound 20. The stereochemistry of 20 is confirmed by single-crystal X-ray analysis. Elimination
of HOAc from 20 gave the crucial olefin 21. Hydrolysis of the acetate unit of 21 followed by protection
of the resulting alcoholic function yielded tert-butyldimethylsilyl ether 23. Introduction of a hydroxyl
group at the ring junction of 23, using Davis’s procedure, finally afforded the hexahydrobenzofuran
subunit 3.
Sch em e 1
In tr od u ction
The isolation of avermectin and milbemycin families
of highly functionalized pentacyclic macrolides from
Streptomyces is a significant development in the treat-
ment of parasitic diseases.1 In particular, avermectins
are effective against parasites in two major classes,
nematodes and arthropods. Several synthetic derivatives
of avermectins assumed commercial significance as a
method to control parasitic infection.2 These architectu-
ally challenging natural products coupled with their
potent antiparasitic activity have attracted much atten-
tion among synthetic chemists. Many total syntheses of
avermectins are reported.3 In this complex architecture
of avermectins 1, Scheme 1, the hexahydrobenzofuran
subunit 2 offers a significant synthetic challenge. In
particular, the stability of this component is amazing as
it contains two highly labile functional groups that might
undergo successive â-elimination to give a benzenoid ring.
Furthermore, subsequent enolization of the furanone
moiety might yield a benzofuran system. Nevertheless,
these aromatizations did not occur at all during isolation
of these natural products under highly acidic conditions.
Fraser-Reid and Prashad reported the first enantiose-
lective synthesis of the hexahydrobenzofuran subunit
via an intramolecular nitrile oxide 1,3-dipolar cycload-
dition strategy.4 Hanessian and co-workers subsequently
(1) (a) Fisher, M.; Mrozik, H. In Macrolide Antibiotics; Omura, S.,
Ed.; Academic Press: New York, 1984; Chapter 14,
p 553. (b)
Crimmins, M. T.; Hollis, W. G., J r.; O’Mahony, R. In Studies in Natural
Product Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1988;
Vol. 1, p 435. (c) Blizzard, T.; Fisher, M. H.; Mrozik, H.; Shih, T. L. In
Recent Progress in the Chemical Synthesis of Antibiotics; Lukacs, G.,
Ohno, M., Eds.; Springer-Verlag: New York, 1990; p 65. (d) Davies,
H. G.; Green, R. H. Chem. Soc. Rev. 1991, 20, 211.
(2) For synthetic analogues see: (a) Mrozik, H.; Linn, B. O.; Eskola,
P.; Lusi, A.; Matzuk, A.; Preiser, F. A.; Ostlind, D. A.; Schaeffer, J .
M.; Fisherm, M. H. J . Med. Chem. 1989, 32, 375. (b) Fisher, M. H.
Pure Appl. Chem. 1990, 62, 1231. (c) Blizzard, T. A.; Margiatto, G. M.;
Mrozik, H.; Shoop, W. L.; Frankshun, R. A.; Fisher, M. H. J . Med.
Chem. 1992, 35, 375. (d) Newbold, R. C.; Shih, T. L.; Mrozik, H.; Fisher,
M. H. Tetrahedron Lett. 1993, 34, 3825. (e) Meinke, P. T.; O’Connor,
S. P.; Fisher, M. H.; Mrozik, H. Tetrahedron Lett. 1994, 35, 5343. (f)
Cvetovich, R. J .; Kelly, D. H.; DiMichele, L. M.; Shuman, R. F.;
Grabowski, E. J . J . Org. Chem. 1994, 59, 7704. (g) Cvetovich, R. J .;
Senanayake, C. H.; Amato, J . S.; DiMichele, L. M.; Bill, T. J .; Larsen,
R. D.; Shuman, R. F.; Verhoeven, T. R.; Grabowski, E. J . J . Org. Chem.
1997, 62, 3989. (h) Meinke, P. T.; Arison, B.; Culberson, J . C.; Fisher,
M. H.; Mrozik, H. J . Org. Chem. 1998, 63, 2591.
(3) Total synthesis: (a) Hanessian, S.; Dube´, D.; Hodges, P. J . Am.
Chem. Soc. 1987, 109, 7063. Hanessian, S.; Ugolini, A.; Dube´, D.;
Andre´, C. J . Am. Chem. Soc. 1986, 108, 2776. (b) Danishefsky, S. J .;
Armistead, D. M.; Wincott, F. E.; Selnick, H. G.; Hungate, R. J . Am.
Chem. Soc. 1989, 111, 2967. (c) Danishefsky, S. J .; Armistead, D. M.;
Wincott, F. E.; Selnick, H. G.; Hungate, R.; J . Am. Chem. Soc. 1987,
109, 8117. (d) White, J . D.; Bolton, G. L. J . Am. Chem. Soc. 1990, 112,
1626. (e) Hirama, M.; Noda, T.; Yasuda, S.; Itoˆ, S. J . Am. Chem. Soc.
1991, 113, 1830. (f) Ley, S. V.; Armstrong, A.; Diez-Martin, D.; Ford,
M. J .; Grice, P.; Knight, J . G.; Kolb, H. C.; Madin, A.; Marby, C. A.;
Mukherjee, S.; Shaw, A. N.; Slawin, A. M. Z.; Vile, S.; White, A. D.;
Williams, D. J .; Woods, M. J . J . Chem. Soc., Perkin Trans. 1 1991,
667. (g) White, J . D.; Bolton, G. L.; Dantanarayana, A. P.; Fox, C. M.
J .; Hiner, R. N.; J ackson, R. W.; Sakuma, K.; Warrier, U. S. J . Am.
Chem. Soc. 1995, 117, 1908.
(4) Prashad, M.; Fraser-Reid, B. J . Org. Chem. 1985, 50, 1566.
10.1021/jo010853p CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/10/2002

832 J . Org. Chem., Vol. 67, No. 3, 2002
Sha et al.
Sch em e 2
Sch em e 4
Sch em e 3
achieved5 a stereoselective synthesis of the same subunit;
they likewise used a chiral starting material toward
preparation of an optically active analogue of hexahy-
drobenzofuran. Hirama and co-workers accomplished a
stereoselective synthesis of the hexahydrobenzofuran
subunit using an aldol-condensation strategy.6 About the
same time, Williams and Klinger developed7 a stereose-
lective approach to the hexahydrobenzofuran subunit via
intramolecular Claisen condensation. Uang et al. pub-
lished8 an enantioselective approach to the subunit using
an asymmetric Diels-Alder reaction. Barrett et al.
reported9 a synthesis of an intermediate closely related
to the hexahydrobenzofuran subunit. Ley et al. pre-
pared10 a hexahydrobenzofuran subunit lacking a crucial
double bond and employed that method for a total
synthesis3f of avermectin B1a. Smith and Fujiwara de-
veloped a preparation of highly demanding hexahy-
drobenzofuran subunit 2 for the total synthesis of aver-
mectins.11 We recently described an anionic cyclization
approach to the synthesis of perhydroindolone 5a , per-
hydroquinolone 5b, and perhydrobenzoazepinone 5c,
Scheme 2, and successfully applied this method to a total
synthesis of (-)-brunsvigine.12 Herein we report our
results on a stereocontrolled synthesis of the hexahy-
drobenzofuran subunit 3 of avermectin using a similar
anionic cyclization approach.
Having established the method for preparation of
perhydrobenzofuranone, we turned our attention to the
application of this method for total synthesis of the
hexahydrobenzofuran subunit of avermectins. Our syn-
thetic plan to prepare allyic alcohol 14 containing the
necessary substituents of hexahydrobenzofuran subunit
3 is outlined in Scheme 4. Dihydroxylation of com-
mercially available 3-methylcyclohex-2-en-1-one (9) with
osmium tetroxide and N-morpholine N-oxide18 afforded
diol 10 in 82% yield. Protection of the diol unit of 10 gave
ketone 11. Ketone 11 was then smoothly converted into
the required enone 12 in 71% yield according to Saegusa’s
protocol.19 Enone 12 was iodinated at the R-position
through J ohnson’s procedure20 to give the corresponding
iodo enone 13. Luche reduction13 of compound 13 gave
allylic alcohol 14 as a single diastereomer in 93% yield.
Once the required allylic alcohol 14 was in hand, it was
smoothly alkylated with ethyl bromoacetate, using NaH
as a base, to give compound 15 in 97% yield. Ester 15
was then transformed into Weinreb amide 16 in 85%
yield.21 Initially we tried anionic cyclization with ester
15, but the yield of product 17 was low (10-20%). When
the same reaction was carried out with Weinreb amide
16, cyclized product 17 was obtained in excellent yield,22
Scheme 5.
Resu lts a n d Discu ssion
Enone 17 was then treated with CuCN and (meth-
oxymethyl)lithium in the presence of TMSCl to afford
compound 18 in 87% yield, Scheme 6; 1,4-addition
occurred stereoselectively at the less hindered R-face.
As a model study, we first applied the anionic cycliza-
tion method to the synthesis of perhydrobenzofuranone
8, Scheme 3. The perhydrobenzofuran skeleton is the core
skeleton of many natural products, such as avermectins,1
milbemycins,13 phyllanthocin,14 burchellin,15 and brey-
nolide.16 On alkylation with ethyl bromoacetate using
NaH as a base, allylic alcohol 617 was converted to ester
7. Treatment of 7 with n-BuLi in the presence of TMSCl
effected metal-halogen exchange and anionic cyclization
to afford perhydrobenzofuranone 8 in 72% yield.
(13) Mishima, M.; Ide, J .; Muramatsu, S.; Ono, M. J . Antibiot. 1983,
36, 980.
(14) Kupchan, S. M.; LaVoie, E. J .; Branfman, A. R.; Fei, B. Y.;
Bright, W. M.; Bryan, R. F. J . Am. Chem. Soc. 1977, 99, 3199.
(15) Engler, T. A.; Wei, D.; Letavic, M. A.; Combrink, K. D.; Reddy,
J . P. J . Org. Chem. 1994, 59, 6588.
(16) (a) Sakai, F.; Ohkuma, H.; Koshiyama, H.; Naito, T.; Kawagu-
chi, H. Chem. Pharm. Bull. 1976, 24, 114. (b) Trost, W. IRCS Med.
Sci. 1986, 14, 905.
(17) Compound 6 was prepared via Luche reduction (Luche, J . L.
J . Am. Chem. Soc. 1978, 100, 2226) of 2-iodo-2-cyclohexen-1-one, which
was obtained from iodination of 2-cyclohexen-1-one according to
J ohnson’s method (ref 20).
(18) Nicolaou, K. C.; Yue, E. W.; La greca, S.; Nadin, A.; Yang, Z.;
Leresche, J . E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F. Chem.sEur. J .
1995, 1, 467.
(5) Hanessian, S.; Beaulieu, P.; Dube´, D. Tetrahedron Lett. 1986,
27, 5071.
(6) Hirama M.; Noda, T.; Itoˆ, S. J . Org. Chem. 1988, 53, 708.
(7) Williams, D. R.; Klinger, F. D. J . Org. Chem. 1988, 53, 2134.
(8) Lee, K.-C.; Wu, J . C. C.; Yen, K.-F.; Uang, B.-J . Tetrahedron Lett.
1990, 31, 3563.
(9) Barrett, A. G. M.; Barta, T. E.; Flygare, J . A.; Sabat, M.; Spilling,
C. D. J . Org. Chem. 1990, 55, 2409.
(10) Armstrong, A.; Ley, S. V. Synlett 1990, 323.
(11) Fujiwara, S.; Smith, A. B., III. Tetrahedron Lett. 1992, 33, 1185.
(12) (a) Sha, C.-K.; Huang, S.-J .; Huang, C.-M.; Hong, A.-W.; J eng,
T.-H. Pure Appl. Chem. 2000, 72, 1773. (b) Sha, C.-K.; Hong, A.-W.;
Huang, C.-M. Org. Lett. 2001, 3, 2177.
(19) Ito, Y.; Hirato, T.; Saegusa, T. J . Org. Chem. 1978, 43, 1011.
(20) J ohnson, C. R.; Adams, J . P.; Braun, M. P.; Senanayake, C. B.
W.; Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron Lett. 1992, 33,
917.
(21) Evans, D. A.; Kaldor, S. W.; J ones, T. K.; Clardy, J .; Stout, T.
J . J . Am. Chem. Soc. 1990, 112, 7001.
(22) Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 129.

Cyclization Approach toward Perhydrobenzofuranone
J . Org. Chem., Vol. 67, No. 3, 2002 833
Sch em e 5
target compound 3 in 82% yield (based on 41% conver-
sion), Scheme 6.
In conclusion, we have developed a general and ef-
ficient method to synthesize the perhydrobenzofuranone
skeleton using the anionic cyclization as a key step, and
successfully applied this method toward total synthesis
of the hexahydrobenzofuran subunit of avermectins. This
anionic cyclization approach is potentially useful for the
synthesis of other natural products containing the per-
hydobenzofuran skeleton.
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR spectra were recorded in
CDCl3 solution at 400, 500, or 600 MHz. 13C NMR spectra were
recorded at 100, 125, or 150 MHz. Mass spectra were recorded
by electron impact (70 eV) or FAB ionization. IR spectra were
recorded on a spectrometer. Melting points were determined
with an open capillary tube and are uncorrected.
Sch em e 6
2-Iod o-2-cycloh exen -1-ol (6). To a solution of R-iodocy-
clohexenone (693 mg, 3.12 mmol) in dry methanol (10 mL) at
o
0 C was added CeCl3·7H2O (769 mg, 3.12 mmol); the reaction
mixture was stirred for 10 min. NaBH4 (141 mg, 3.74 mmol)
was added, and the reaction mixture was warmed to room
temperature and stirred for 1 h; excess NaBH4 was then
quenched with water (10 mL). The resulting mixture was
extracted with diethyl ether (3 × 30 mL). The combined
organic layer was washed with brine (20 mL) and dried
(MgSO4). Removal of solvent followed by column chromatog-
raphy (silica gel, EtOAc/n-hexane, 1:3) afforded compound 6
(650 mg, 93%) as a colorless solid: IR (neat) 3370, 3028, 1625,
1
1426, 1161, 1078 cm-1; H NMR (400 MHz, CDCl3) δ 6.42 (t,
1 H, J ) 4.0 Hz), 4.11 (s, 1 H), 2.65 (s, 1 H), 2.10-1.52 (m, 6
H); 13C NMR (100 MHz, CDCl3) δ 140.42 (CH), 103.20 (C),
71.34 (CH), 31.82 (CH2), 28.97 (CH2), 17.24 (CH2); MS (EI) m/z
224 (M+, 3), 97 (100); HRMS (EI) m/z calcd for C6H9IO
223.9698, found 223.9694.
Eth yl 2-[(2-Iodo-2-cycloh exen yl)oxy]acetate (7). To NaH
(78 mg, 80% in mineral oil, 2.61 mmol) washed with dry
benzene (3 × 1 mL) was added dry DMF (0.5 mL). The mixture
was cooled to 0 °C. A solution of alcohol 6 (195 mg, 0.87 mmol)
in dry DMF (2 mL) was added. The reaction mixture was
stirred at 0 °C for 30 min. Ethyl bromoacetate (436 mg, 2.61
mmol) was added, and the reaction mixture was warmed to
room temperature and stirred for 6 h. Excess NaH was
quenched with H2O (5 mL). The reaction mixture was ex-
tracted with diethyl ether (3 × 10 mL). The organic layer was
washed with brine (15 mL) and dried (MgSO4). Removal of
solvent followed by column chromatography (silica gel, EtOAc/
n-hexane, 1:4) afforded compound 7 (195 mg, 72%) as a yellow
oil: IR (neat) 2929, 1746, 1627, 1441, 1375, 1280, 1203, 1120,
Cleavage of the acetal unit with HCl produced diol 19,
which on preferential acetylation of the secondary alcohol
unit with acetic anhydride and DMAP at room temper-
ature yielded tertiary alcohol 20. The stereochemistry of
compound 20 was confirmed by a single-crystal X-ray
analysis.23 Heating of 20 with p-TSA in refluxing benzene
gave the desired product 21 along with two olefin isomers
as the minor products. The ratio of the major isomer 21
to the two minor isomers together was 4.5:1. Recrystal-
lization from CH2Cl2/n-hexane (10:1) afforded the pure
major product 21 in 60% yield. The minor products were
difficult to separate and were not fully characterized.
Compound 21 was then carefully hydrolyzed with NaOMe
in methanol at room temperature to give alcohol 22 in
88% yield. Protection of the secondary alcohol of 22 using
TBSOTf afforded compound 23 in 77% yield. Introduction
of the required hydroxyl group at the ring junction was
finally carried out according to Davis’s procedure.24
Treatment of compound 23 with LDA at -78 to -20 °C
in THF followed by reaction with Davis’s reagent afforded
1
1030 cm-1; H NMR (400 MHz, C6D6) δ 6.23 (t, 1 H, J ) 3.6
Hz), 4.08 and 4.04 (AB q, 2 H, J ) 16.0 Hz), 3.91 (q, 2 H, J )
7.1 Hz), 3.72 (dd, 1 H, J ) 3.8 and 3.8 Hz), 1.85-1.77 (m, 1
H), 1.65-1.44 (m, 4 H), 1.25-1.16 (m, 1 H), 0.93 (t, J ) 7.1
Hz, 3 H); 13C NMR (100 MHz, C6D6) δ 170.1 (C), 142.2 (CH),
98.6 (C), 80.5 (CH), 68.0 (CH2), 60.4 (CH2), 29.9 (CH2), 29.4
(CH2), 17.4 (CH2), 14.2 (CH3); MS (EI) m/z 183 ([M - I]+ 100),
105 (43); HRMS (FAB) m/z calcd for C10H16IO3 [M + H]
311.0146, found 311.0146.
2,3,5,6,7,7a -Hexa h yd r oben zo[b]fu r a n -3-on e (8). To a
stirred solution of substrate 7 (100 mg, 0.32 mmol) in dry THF
(6.5 mL) at -100 °C was added TMSCl (52 mg, 0.48 mmol). A
solution of n-BuLi in n-hexane (2.0 M, 0.2 mL, 0.39 mmol) was
slowly added at -100 °C, and the reaction mixture was
maintained at -70 oC for 20 min. The cooling bath was
removed; the reaction mixture was stirred for 10 min and
quenched at 0 °C with a saturated solution of NH4Cl (10 mL).
The reaction mixture was extracted with diethyl ether (3 ×
10 mL). The organic layer was washed with NaHCO3 (15 mL)
and brine (15 mL) and dried (MgSO4). Removal of solvent
followed by column chromatography (silica gel, EtOAc/n-
hexane, 1:4) afforded pure compound 8 (32 mg, 72%) as a
(23) The X-ray data and the crystal structure of compound 20 are
in the Supporting Information.
(24) Davis, F. A.; Vishwakarma, L. C.; Billmers, J . M.; Finn, J . J .
Org. Chem. 1984, 49, 3241.

834 J . Org. Chem., Vol. 67, No. 3, 2002
Sha et al.
colorless oil: IR (neat) 2918, 1703, 1617, 1436, 1181, 1054
cm-1; 1H NMR (400 MHz, CDCl3) δ 6.75-6.71 (m, 1 H), 4.52-
4.45 (m, 1 H), 4.04 and 3.95 (AB q, 2 H, J ) 16.4 Hz), 2.38-
2.18 (m, 3 H), 1.96-1.87 (m, 1 H), 1.61-1.48 (m, 1 H), 1.41-
1.29 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 202.3 (C), 137.1
(C), 134.1 (CH), 79.7 (CH), 71.8 (CH2), 28.3 (CH2), 25.5 (CH2),
18.8 (CH2); MS (EI) m/z 138 (M+, 11), 110 (37), 108 (29), 80
(40), 79 (100); HRMS (EI) m/z calcd for C8H10O2 138.0681,
found 138.0681.
(3a R*,7a R*)-5-Iod o-2,2,7a -tr im eth yl-3a ,4,7,7a -tetr a h y-
d r o-1,3-ben zod ioxol-4-on e (13). To a solution of enone 12
(278 mg, 1.53 mmol) in CH2Cl2 (8 mL) were added pyridine
(3.7 mL) and iodine (1.55 g, 6.12 mmol) at 0 °C. The reaction
mixture was stirred at room temperature for 2 h and diluted
with diethyl ether (80 mL). The reaction mixture was washed
with 1 N Na2S2O3 solution (50 mL) and brine (40 mL) and dried
over MgSO4. Concentration and column chromatography (silica
gel, EtOAc/n-hexane, 1:4) gave iodo enone 13 (414 mg, 88%)
as a yellow solid. The solid was recrystallized from 1:10 CH2-
Cl2/n-hexane to afford 13 as yellow crystals: mp 74-75 °C;
IR (neat) 2986, 2934, 1688, 1601, 1453, 1377, 1333, 1224, 1093,
1057 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.57 (dd, apparent t,
1 H, J ) 4.5, 4.5 Hz), 4.15 (s, 1 H), 2.83 (dd, 1 H, J ) 19.1, 4.5
Hz), 2.56 (dd, 1 H, J ) 19.1, 4.5 Hz), 1.38 (s, 3 H), 1.37 (s, 3
H), 1.17 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 189.6 (C), 156.4
(CH), 110.3 (C), 101.2 (C), 80.8 (C), 79.9 (CH), 39.6 (CH2), 28.1
(CH3), 27.9 (CH3), 26.4 (CH3); MS (EI) m/z 308 (M+, 65), 293
([M - CH3]+, 33), 265 (54), 181 ([M - I]+, 38); HRMS (EI) m/z
calcd for C10H13IO13 307.9911, found 307.9908.
(2R*,3R*)-2,3-Dih ydr oxy-3-m eth ylcycloh exan -1-on e (10).
To a solution of enone 9 (1.47 g, 13.3 mmol) in THF (25 mL)
were added N-methylmorpholine N-oxide (1.87 g, 16.0 mmol),
tert-butyl alcohol (12 mL), water (2 mL), and then OsO4 (13.3
mL, 0.67 mmol, 0.05 M in tert-butyl alcohol) at room temper-
ature. The reaction mixture was stirred for 24 h, then
quenched with solid Na2SO3 (4.00 g, 32 mmol), and stirred at
room temperature for 15 min. Florisil (4.00 g) was added. The
mixture was stirred for 15 min and then filtered through
Celite. Concentration and column chromatography (silica gel,
EtOAc/n-hexane,1:1) gave diol 10 (1.57 g, 82%) as a colorless
oil. Recrystallization from 1:8 diethyl ether/benzene afforded
10 as white crystals: mp 46.5-48.5 °C; IR (neat) 3387, 2933,
1716, 1455, 1375, 1315, 1228, 1111 cm-1; 1H NMR (400 MHz,
CDCl3) δ 3.94 (s, 1 H), 2.57-2.50 (m, 1 H), 2.39-2.23 (m, 1
H), 2.11-1.95 (m, 2 H), 1.92-1.75 (m, 2 H), 1.38 (s, 3 H); 13C
NMR (100 MHz, CDCl3) δ 209.8 (C), 80.2 (CH), 76.5 (C), 38.4
(CH2), 35.4 (CH2), 26.8 (CH3), 21.3 (CH2); MS (EI) m/z 144 (M+,
6), 127 (100); HRMS (EI) m/z calcd for C7H12O3 144.0786, found
144.0786.
(3a S*,4R *,7a R *)-5-Iod o-2,2,7a -t r im et h yl-3a ,4,7,7a -t et -
r a h yd r o-1,3-b en zod ioxol -4-ol (14). To a cooled (-78 °C)
solution of R-iodo enone 13 (973 mg, 3.16 mmol) was added
CeCl3‚7H2O (1.24 g, 3.32 mmol) in methanol (32 mL) and
sodium borohydride (126 mg, 3.32 mmol). The reaction mixture
was stirred for 40 min and then quenched with water (40 mL).
The resulting mixture was extracted with diethyl ether (3 ×
40 mL). The combined organic layer was washed with brine
(50 mL) and dried MgSO4. Concentration and column chro-
matography (silica gel, CH2Cl2) gave iodo alcohol 14 (914 mg,
93%) as a yellow solid. The solid was recrystallized from 1:10
CH2Cl2/n-hexane to afford 14 as white crystals: mp 75.5-77.5
°C; IR (neat) 3440, 2984, 2931, 1631, 1376, 1229, 1138, 1079,
(3aR*,7aR*)-2,2,7a-Tr im eth ylper h ydr o-1,3-ben zodioxol-
4-on e (11). To a solution of diol 10 (1.55 g, 10.8 mmol) and
pyridinium p-toluenesulfonate (136 mg, 0.541 mmol) in CH2-
Cl2 (150 mL) at 0 °C was added 2-methoxypropene (3.89 g,
54.1 mmol). The reaction mixture was allowed to warm to room
temperature and stirred for 12 h. The reaction mixture was
diluted with CH2Cl2 (50 mL) and washed with saturated
NaHCO3 solution (80 mL) and brine (80 mL). The organic layer
was dried over MgSO4. Concentration and column chroma-
tography (silica gel, EtOAc/n-hexane, 1:8) gave acetonide 11
(1.77 g, 89%) as a colorless oil: IR (neat) ν 2951, 1725, 1455,
1
1057 cm-1; H NMR (400 MHz, CDCl3) δ 6.42-6.38 (m, 1 H),
4.24 (d, 1 H, J ) 3.6 Hz), 3.93-3.86 (m, 1 H), 2.94 (d, 1 H, J
) 8.8 Hz), 2.29 (dd, 1 H, J ) 16.2, 6.6 Hz), 1.82 (dm, 1 H, J )
16.2 Hz), 1.33 (s, 3 H), 1.30 (s, 3 H), 1.27 (s, 3 H); 13C NMR
(100 MHz, CDCl3) δ 135.3 (CH), 109.2 (C), 103.8 (C), 83.1 (CH),
80.1 (C), 69.3 (CH), 39.4 (CH2), 27.3 (CH3), 27.1 (CH3), 27.0
(CH3); MS (EI) m/z 310 (M+, 7), 295 (14), 281 (12), 207 (36),
114 (48), 89 (100); HRMS (EI) m/z calcd for C10H15IO3 310.0068,
found 310.0053.
1
1376, 1217, 1062 cm-1; H NMR (400 MHz, CDCl3) δ 3.94 (s,
1 H), 2.62-2.54 (m, 1 H), 2.28-2.20 (m, 1 H), 2.05-1.94 (m, 2
H), 1.75-1.55 (m, 2 H), 1.41 (s, 3 H), 1.40 (s, 6 H); 13C NMR
(100 MHz, CDCl3) δ 208.8 (C), 110.3 (C), 84.3 (CH), 84.0 (C),
38.2 (CH2), 35.2 (CH2), 27.7 (CH3), 27.4 (CH3), 26.8 (CH3), 19.2
(CH2); MS (EI) m/z 184 (M+, 0.71), 169 (21), 127 (14); HRMS
(EI) m/z calcd for C10H16O3 184.1099, found 184.1099.
Eth yl 2-{[(3aS*,4R*,7aR*)-5-Iodo-2,2,7a-tr im eth yl-3a,4,7,-
7a -tetr a h yd r o-1,3-ben zod ioxol-4-yl]oxy}a ceta te (15). So-
dium hydride (178 mg, 80% in mineral oil, 5.94 mmol) was
washed with anhydrous benzene (3 × 1.5 mL). THF (2 mL)
was added. The suspension was cooled to 0 °C. A solution of
14 (613 mg, 1.98 mmol) in THF (10 mL) was added to the NaH
suspension dropwise. After the resulting mixture was stirred
for 30 min, ethyl bromoacetate (992 mg, 5.94 mmol) was added
at 0 °C. The reaction mixture was warmed to room tempera-
ture, stirred for 3 h, and then quenched with water (15 mL).
The mixture was extracted with diethyl ether (3 × 30 mL).
The organic layer was washed with brine (40 mL) and dried
over MgSO4. Concentration and column chromatography (silica
gel, CH2Cl2) gave iodo ester 15 (760 mg, 97%) as a yellow oil:
(3a R*,7a R*)-2,2,7a -Tr im eth yl-3a ,4,7,7a -tetr a h yd r o-1,3-
ben zod ioxol-4-on e (12). A solution of acetonide 11 (921 mg,
5.00 mmol) and triethylamine (759 mg, 7.50 mmol) in dry
benzene (25 mL) was treated with trimethylsilyl trifluo-
romethanesulfonate (1.22 g, 5.50 mmol) at room temperature.
The reaction mixture was stirred at room temperature for 4
h, quenched with saturated NaHCO3 solution (30 mL), and
extracted with diethyl ether (3 × 20 mL). The combined
organic layer was washed with brine (40 mL) and dried
(MgSO4). Concentration gave a crude oil. The crude oil was
dissolved in acetonitrile (50 mL) and treated with palladium
acetate (1.46 g, 6.50 mmol). The mixture was stirred at room
temperature for 24 h, diluted with diethyl ether (50 mL),
filtered through Celite, and concentrated to give a crude oil.
Column chromatography (silica gel, EtOAc/n-hexane, 1:8 to
1:4) gave recovered ketone 11 (82 mg, 9%) and product 12 (648
mg, 71%) as a colorless oil. Data for 12: IR (neat) 2988, 2936,
1682, 1453, 1380, 1228, 1094, 1055 cm-1; 1H NMR (400 MHz,
CDCl3) δ 6.90 (dt, 1 H, J ) 10.2, 4.3 Hz), 6.16 (dt, 1 H, J )
10.2, 2.0 Hz), 4.01 (s, 1 H), 2.82 (ddd, 1 H, J ) 19.0, 4.3, 2.0
Hz), 2.51 (ddd, 1 H, J ) 19.0, 4.3, 2.0 Hz), 1.44 (s, 3 H), 1.43
(s, 3 H), 1.32 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 195.6 (C),
148.3 (CH), 128.0 (CH), 109.6 (C), 80.6 (CH), 80.5 (C), 36.1
(CH2), 28.0 (CH3), 27.7 (CH3), 26.3 (CH3); MS (EI) m/z 167 ([M
- CH3]+, 34), 125 (42), 114 (82), 99 (64), 97 (46), 96 (67), 95
(72); HRMS (EI) m/z calcd for C10H14O3 182.0943, found
182.0946.
1
IR (neat) 2940, 1744, 1612, 1445, 1377, 1191, 1038 cm-1; H
NMR (400 MHz, CDCl3) δ 6.54-6.50 (m, 1 H), 4.55 (d, 1 H, J
) 2.8 Hz), 4.44 and 4.29 (AB q, 2 H, J ) 16.8 Hz), 4.24-4.15
(m, 2 H), 3.87-3.84 (m, 1 H), 2.35 (dd, 1 H, J ) 16.4, 6.8 Hz),
1.81 (dm, 1 H, J ) 16.4 Hz), 1.40 (s, 3 H), 1.36 (s, 3 H), 1.35
(s, 3 H), 1.27 (t, 3 H, J ) 7.4 Hz); 13C NMR (100 MHz, CDCl3)
δ 170.1 (C), 136.1 (CH), 109.3 (C), 98.4 (C), 83.3 (CH), 80.3
(C), 77.4 (CH), 67.9 (CH2), 60.7 (CH2), 39.9 (CH2), 27.1 (CH3),
26.9 (CH3), 26.8 (CH3), 14.0 (CH3); MS (EI) m/z 381 ([M -
CH3]+, 20), 339 (89), 194 (33), 114 (100); HRMS (EI) m/z calcd
for C14H21IO5 396.0435, found 396.0431.
N-Met h oxy-N-m et h yl-2-{[(3a S*,4R*,7a R*)-5-iod o-2,2,-
7a -tr im eth yl-3a ,4,7,7a -tetr a h yd r o-1,3-ben zod ioxol-4-yl]-
oxy}a cet a m id e (16). To a suspension of N,O-dimethyl-
hydroxylamine in CH2Cl2 (6 mL) at 0 °C was added trimethyl-
aluminum (1.91 mL 1.6 M in n-hexane, 3.05 mmol) dropwise
(caution: vigorous evolution of gas occurred). After the addi-
tion, the cooling bath was removed. The clear solution was
stirred at room temperature for 30 min and then cooled to -10

Cyclization Approach toward Perhydrobenzofuranone
J . Org. Chem., Vol. 67, No. 3, 2002 835
°C. A solution of 15 (485 mg, 1.22 mmol) in CH2Cl2 (4 mL)
was added. The reaction mixture was stirred at -10 °C for 2
h and at 0 °C for another 1 h and then quenched with HCl
solution (1 N, 10 mL) slowly (caution: vigorous evolution of
gas occurred) at 0 °C. The resulting mixture was extracted
with CH2Cl2 (3 × 12 mL). The combined organic layer was
washed with saturated NaHCO3 solution (25 mL) and dried
over MgSO4. Concentration and column chromatography (silica
gel, EtOAc/n-hexane, 1:1) gave amide 16 (428 mg, 85%) as a
yellow solid. The solid was recrystallized from CH2Cl2/n-
hexane (1:10) to afford 16 as white crystals: mp 89-90 °C; IR
(neat) 2950, 1673, 1444, 1377, 1255, 1103, 1042 cm-1; 1H NMR
(400 MHz, CDCl3) δ 6.52-6.48 (m, 1 H), 4.73-4.65 (m, 2 H),
4.47 (d, 1 H, J ) 16.8 Hz), 3.91-3.89 (m, 1 H), 3.68 (s, 3 H),
3.17 (s, 3 H), 2.32 (dd, 1 H, J ) 16.4, 6.8 Hz), 1.78 (dm, 1 H,
J ) 16.4 Hz), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.34 (s, 3 H); 13C
NMR (100 MHz, CDCl3) δ 170.8 (C), 135.7 (CH), 109.1 (C),
99.3 (C), 83.6 (CH), 80.4 (C), 77.2 (CH), 67.9 (CH2), 61.3 (CH3),
39.9 (CH2), 32.0 (CH3), 27.2 (CH3), 26.9 (CH3), 26.8 (CH3); MS
a solution of 18 (104 mg, 0.38 mmol) in THF (2 mL) was added
HCl (2 N, 2 mL). The reaction mixture was heated at 80 °C
for 8 h, cooled to room temperature, and extracted with CH2-
Cl2 (6 × 8 mL). The combined organic layer was dried over
MgSO4. Concentration and column chromatography (silica gel,
EtOAc) gave diol 19 (68 mg, 77%) as a colorless oil: IR (neat)
3380, 2903, 1755, 1643, 1386, 1260, 1181, 1077 cm-1; 1H NMR
(400 MHz, CDCl3) δ 4.36 (t, 1 H, J ) 4.0 Hz), 4.23 (d, 1 H, J
) 16.8 Hz), 3.80 (d, 1 H, J ) 16.8 Hz), 3.50 (dd, 1 H, J ) 8.8,
4.0 Hz), 3.39 (dd, 1 H, J ) 9.4, 4.8 Hz), 3.35 (dd, 1 H, J ) 9.4,
3.2 Hz), 3.29 (s, 3 H), 3.22 (br s, 2 H), 2.42 (dd, 1 H, J ) 11.2,
4.0 Hz), 1.99-1.85 (m, 2 H), 1.53 (t, 1 H, J ) 13.2 Hz), 1.24 (s,
3 H); 13C NMR (100 MHz, CDCl3) δ 213.1 (C), 80.8 (CH), 72.2
(CH), 72.1 (CH2), 71.8 (C), 70.8 (CH2), 58.9 (CH3), 47.2 (CH),
40.2 (CH2), 29.2 (CH), 26.0 (CH3); MS (EI) m/z 230 (M+, 15),
213 ([M - OH]+, 100); HRMS (EI) m/z calcd for C11H18O5
230.1154, found 230.1153.
(3aS*,4R*,6R*,7S*,7aS*)-6-Hydr oxy-4-(m eth oxym eth yl)-
6-m eth yl-3-oxop er h yd r oben zo[b]fu r a n -7-yl Aceta te (20).
To a solution of diol 19 (57.0 mg, 0.248 mmol) and 4-(dim-
ethylamino)pyridine (45.0 mg, 0.371 mmol) in CH2Cl2 (3 mL)
was added acetic anhydride (30.0 mg, 0.296 mmol) at room
temperature. The reaction mixture was stirred for 1 h and then
quenched with HCl (1 N, 6 mL). The aqueous layer was
extracted with CH2Cl2 (3 × 8 mL). The combined organic layer
was washed with saturated NaHCO3 solution (10 mL) and
brine and dried over MgSO4. Concentration and column
chromatography (silica gel, EtOAc/n-hexane, 1:1) gave alcohol
20 (54.7 mg, 81%) as a colorless solid. Recrystallization from
CH2Cl2/n-hexane (1:8) afforded 20 as white crystals: mp 110-
111 °C; IR (neat) 3502, 2909, 1743, 1378, 1242, 1103, 1044
(EI) m/z 411 (M+, 7), 354 (100); HRMS (EI) m/z calcd for C13H19
INO5 (M - CH3) 396.0310, found 396.0305. Anal. Calcd for
14H22INO5: C, 40.89; H, 5.39; N, 3.41. Found: C, 40.72; H,
-
C
5.36; N, 3.42.
(3aR*,8aS*,8bS*)-2,2,3a-Tr im eth yl-3a,4,6,7,8a,8b-h exah y-
d r ofu r o-[2′,3′:3,4]ben zo[d ][1,3]d ioxol-6-on e (17). To a solu-
tion of amide 16 (101 mg, 0.246 mmol) in THF (5 mL) at -100
°C was added n-BuLi (0.15 mL, 2.0 M in n-hexane, 0.30 mmol)
over 5 min. The reaction mixture was stirred at -70 °C for 30
min. The solution was quenched by HCl (1.0 N, 5 mL) at 0 °C
and stirred for 5 min. The resulting mixture was extracted
with diethyl ether (3 × 10 mL). The combined organic layer
was washed with brine (15 mL) and dried over MgSO4.
Concentration and column chromatography (silica gel, EtOAc/
n-hexane, 1:2) gave enone 17 (46 mg, 82%) as a white solid:
mp 56-58 °C; IR (neat) 2935, 1725, 1658, 1443, 1376, 1159
cm-1; 1H NMR (400 MHz, CDCl3) δ 6.95-6.91 (m, 1 H), 4.70-
4.66 (m, 1 H), 4.49 (d, 1 H, J ) 3.6 Hz), 4.33 and 4.23 (AB q,
2 H, J ) 16.8 Hz), 2.73 (dd, 1 H, J ) 17.2, 6.8 Hz), 1.91 (dt, 1
H, J ) 17.2, 3.0 Hz), 1.49 (s, 3 H), 1.37 (s, 3 H), 1.23 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 200.4 (C), 134.5 (C), 132.8 (CH),
109.4 (C), 82.1 (CH), 81.1 (C), 78.6 (CH), 73.8 (CH2), 38.6 (CH2),
27.8 (CH3), 26.7 (CH3), 26.4 (CH3); MS (EI) m/z 224 (M+, 13),
209 (24), 195 (47), 167 (35); HRMS (EI) m/z calcd for C12H16O4
224.1049, found 224.1043.
(3a R*,5R*,5a S*,8a S*,8bS*)-5-(Meth oxym eth yl)-2,2,3a -
t r im et h ylp er h yd r ofu r o[2′,3′:3,4]b en zo[d ][1,3]d ioxol-6-
on e (18). To a solution of MeOCH2SnBu3 (382 mg, 1.14 mmol)
in THF (5 mL) at -78 °C was added n-BuLi (0.57 mL, 2.0 M
in n-hexane, 1.14 mmol). The reaction mixture was stirred for
15 min. CuCN (55 mg, 0.62 mmol) was added. The mixture
was warmed to -60 °C, stirred for 1 h, and then cooled to -78
°C. A solution of enone 17 (99 mg, 0.44 mmol) and chlorotri-
methylsilane (143 mg, 1.32 mmol) in THF (3 mL) was added
dropwise. The reaction mixture was allowed to warm to room
temperature slowly over 5 h, then quenched with HCl (0.5 M,
8 mL), and stirred for 15 min at 0 °C. The resulting mixture
was extracted with EtOAc (3 × 10 mL). The combined organic
layer was washed with saturated NaHCO3 (15 mL) and brine
(15 mL) and dried over MgSO4. Concentration and column
chromatography (silica gel, EtOAc/n-hexane, 1:2) gave product
18 (104 mg, 87%) as a colorless oil: IR (neat) 2928, 1756, 1640,
1450, 1377, 1120, 1111, 1051 cm-1; 1H NMR (400 MHz, CDCl3)
δ 4.45 (dd, 1 H, J ) 9.3, 2.8 Hz), 4.20 (d, 1 H, J ) 2.8 Hz),
4.11 and 3.99 (AB q, 2 H, J ) 16.6 Hz), 3.50 (dd, 1 H, J ) 9.2,
4.8 Hz), 3.41 (dd, 1 H, J ) 9.2, 3.2 Hz), 3.31 (s, 3 H), 2.65 (dd,
1 H, J ) 9.3, 9.3 Hz), 2.30-2.20 (m, 1 H), 1.55 (dd, 1 H, J )
14.0, 2.8 Hz), 1.33 (s, 3 H), 1.32 (s, 3 H), 1.30 (s, 3 H), 1.21
(dd, 1 H, J ) 14.0, 14.0 Hz); 13C NMR (100 MHz, CDCl3) δ
215.6 (C), 108.3 (C), 81.8 (CH), 80.0 (C), 76.7 (CH), 75.1 (CH2),
70.6 (CH2), 58.9 (CH3), 43.6 (CH), 37.4 (CH2), 31.2 (CH), 27.4
(CH3), 26.5 (CH3), 25.6 (CH3); MS (EI) m/z 270 (M+, 56), 255
(61), 213 (100); HRMS (EI) m/z calcd for C14H22O5 270.1467,
found 270.1474.
1
cm-1; H NMR (400 MHz, CDCl3) δ 4.89 (d, 1 H, J ) 4.0 Hz),
4.46 (t, 1 H, J ) 4.0 Hz), 4.28 (d, 1 H, J ) 17.2 Hz), 3.81 (d, 1
H, J ) 17.2 Hz), 3.56 (s, 1 H), 3.45 (dd, 1 H, J ) 9.3, 5.2 Hz),
3.37 (dd, 1 H, J ) 9.3, 3.0 Hz), 3.32 (s, 3 H), 2.53 (dd, 1 H, J
) 11.2, 4.0 Hz), 2.19 (s, 3 H), 2.12-2.00 (m, 1 H), 1.93 (dd, 1
H, J ) 13.6, 3.6 Hz), 1.66 (t, 1 H, J ) 13.6 Hz), 1.18 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 212.3 (C), 170.5 (C), 78.7 (CH),
73.3 (CH), 71.7 (CH2), 71.0 (C), 70.9 (CH2), 58.9 (CH3), 47.3
(CH), 40.9 (CH2), 29.4 (CH), 25.9 (CH3), 20.8 (CH3); MS (EI)
m/z 213 ([M - OAc]+, 100); HRMS (EI) m/z calcd for C13H20O6
272.1260, found 272.1252. A single-crystal X-ray analysis of
20 was performed.23
(3aS*,4R*,7R*,7aS*)-4-(Meth oxym eth yl)-6-m eth yl-3-oxo-
2,3,3a ,4,7,7a ,-h exa h yd r oben zo[b]fu r a n -7-yl Aceta te (21).
To a solution of alcohol 20 (72.8 mg, 0.267 mmol) was added
PTSA·H2O (5.0 mg, 0.027 mmol) in benzene (8 mL). The
mixture was heated at reflux for 9 h and cooled to room
temperature. Concentration and column chromatography (silica
gel, EtOAc/n-hexane, 1:1) gave a white solid, consisting of
major product 21 and two minor olefin isomers according to
1H NMR analysis. The ratio of the major isomer 21 to the two
minor isomers together was 4.5:1. Recrystallization from CH2-
Cl2/n-hexane (1:10) afforded 21 as white crystals (102 mg,
60%): mp 94-95 °C; IR (neat) 2905, 1747, 1442, 1374, 1235,
1
1120, 1059, 1018 cm-1; H NMR (400 MHz, CDCl3) δ 5.60-
5.56 (m, 1 H), 5.39 (d, 1 H, J ) 3.6 Hz), 4.65 (dd, 1 H, J ) 9.6,
3.6 Hz), 4.10 and 4.05 (AB q, 2 H, J ) 16.8 Hz), 3.45 (dd, 1 H,
J ) 8.8, 5.2 Hz), 3.41 (dd, 1 H, J ) 8.8, 5.2 Hz), 3.36 (s, 3 H),
2.99-2.83 (m, 1 H), 2.72 (dd, 1 H, J ) 9.6, 4.4 Hz), 2.01 (s, 3
H), 1.81 (br s, 3 H); 13C NMR (100 MHz, CDCl3) δ 214.4 (C),
170.0 (C), 132.9 (C), 128.1 (CH), 76.7 (CH), 75.1 (CH2), 72.0
(CH), 70.9 (CH2), 59.0 (CH3), 43.7 (CH), 34.9 (CH), 21.2 (CH3),
20.9 (CH3); MS (EI) m/z 254 (M+, 9), 195 (90), 163 (100); HRMS
(EI) m/z calcd for C13H18O5 254.1154, found 254.1149. The
minor products were not purified and fully characterized.
(3a S*,4R*,7R*,7a S*)-7-Hyd r oxy-4-(m eth oxym eth yl)-6-
m eth yl-2,3,3a ,4,7,7a -h exa h yd r oben zo[b]fu r a n -3-on e (22).
To a solution of 21 (85 mg, 0.335 mmol) in methanol (5 mL)
was added NaOCH3 (73 mg, 1.35 mmol) at 0 °C. The reaction
mixture was allowed to warm to room temperature, stirred
for 1 h, and then quenched with water. The mixture was
extracted with EtOAc (3 × 10 mL). The combined organic layer
was washed with brine (15 mL) and dried over Na2SO4.
Concentration and column chromatography (silica gel, EtOAc/
(3a S*,4R*,6R*,7S*,7a S*)-6,7-Dih yd r oxy-4-(m et h oxy-
m eth yl)-6-m eth ylp er h yd r oben zo[b]fu r a n -3-on e (19). To

836 J . Org. Chem., Vol. 67, No. 3, 2002
Sha et al.
n-hexane, 1:1) gave product 22 (62 mg, 87%) as a white solid.
This solid was recrystallized from CH2Cl2/n-hexane (1:8) to
afford 22 as white crystals: mp 79-80 °C; IR (neat) 3432,
2881, 1758, 1448, 1380, 1192, 1117, 1064 cm-1; 1H NMR (400
MHz, CDCl3) δ 5.45-5.48 (m, 1 H), 4.55 (dd, 1 H, J ) 8.6, 4.0
Hz), 4.21 (d, 1 H, J ) 3.6 Hz), 4.17, 4.05 (AB q, 2 H, J ) 16.4
Hz), 3.37 (d, 2H, J ) 5.2 Hz), 3.32 (s, 3 H), 2.85-2.80 (m, 1
H), 2.65(ddd, 1 H, J ) 8.7, 3.6, 1.2 Hz), 1.80 (br s, 3 H); 13C
NMR (100 MHz, CDCl3) δ 214.6 (C), 135.6 (C), 125.3 (CH),
78.3 (CH), 75.2 (CH2), 70.8 (CH2), 69.9 (CH), 58.9 (CH3), 43.9
(CH), 34.6 (CH), 21.1 (CH3); MS (FAB) m/z 213 (M + H+, 100),
195 (35), 163 (41); HRMS (FAB, M + H+) m/z calcd for
NH (0.025 mL, 0.18 mmol) in THF (2 mL) was added n-BuLi
(2.3 M in hexane, 0.078 mL, 0.18 mmol) dropwise at 0 °C. After
being stirred for 0.5 h at 0 °C, the mixture was cooled to -78
°C; compound 23 (17 mg, 0.052 mmol) in THF (0.5 mL) was
added dropwise. The mixture was stirred for 0.5 h at -78 °C
and then allowed to warm to -20 °C over 1 h. The mixture
was cooled to -78 °C again; 2-sulfonyloxaziridine (23 mg, 0.088
mmol) in THF (0.25 mL) was added dropwise. The mixture
was stirred at -78 °C for 1.2 h and quenched at -78 °C with
saturated NH4Cl solution (0.5 mL). The mixture was extracted
with EtOAc (3 × 10 mL). The combined organic layer was
washed with brine (15 mL) and dried over Na2SO4. Concentra-
tion and column chromatography (silica gel, EtOAc/n-hexane,
1:3) gave product 3 (6 mg, 34%, 82% yield based on 41%
conversion) as a colorless oil and recovered starting material
23 (10 mg, 59%). Data for compound 3: IR (neat) 3431, 2929,
1770, 1472, 1386, 1253, 1110, 1074 cm-1; 1H NMR (500 MHz,
CDCl3) δ 5.30 (br s, 1 H), 4.43 (br s, 1 H), 4.33, 4.09 (AB q, 2
H, J ) 17.0 Hz), 4.02 (d, 1 H, J ) 4.5 Hz), 3.67 (dd, 1 H, J )
10.0, 4.0 Hz), 3.56 (dd, 1 H, J ) 10.0, 6.0 Hz), 3.37 (s, 3 H),
2.66-2.69 (m, 1 H), 1.81 (br s, 3 H), 0.89 (s, 9 H), 0.11 (s, 3 H),
0.10 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 213.2 (C), 136.5
(C), 121.5 (CH), 82.3 (CH), 78.1 (C), 72.3 (CH2), 70.1 (CH2),
69.2 (CH), 59.2 (CH3), 35.4 (CH), 25.8 (CH3), 20.3 (CH3), 18.3
(C), -4.8 (CH3), -4.6 (CH3); MS (FAB) 343 (M + H+, 9), 325
(20), 285 (7), 73(100); HRMS (FAB, M + H+) m/z calcd for
C
11H17O4 213.1127, found 213.1127.
(3a S*,4R*,7R*,7a S*)-7-[(ter t-Bu tyld im eth ylsilyl)oxy]-4-
(m eth oxym eth yl)-6-m eth yl-2,3,3a ,4,7,7a -h exa h yd r oben -
zo[b]fu r a n -3-on e (23). To a solution of 22 (38 mg, 0.18 mmol)
and 2,6-lutidine (44 mg, 0.41 mmol) in dry THF (2 mL) was
added TBSOTf (0.061 mL, 0.27 mmol) dropwise at 0 °C. The
mixture was stirred for 3 h at 0 °C, then quenched with water,
and extracted with CH2Cl2 (3 × 10 mL). The combined organic
layer was washed with saturated NaHCO3 solution (15 mL)
and brine (15 mL) and dried over Na2SO4. Concentration and
column chromatography (silica gel, EtOAc/n-hexane, 1:5) gave
product 23 (45 mg, 77%) as a colorless oil: IR (neat) 2930,
1760, 1473, 1362, 1253, 1197, 1122, 1075 cm-1; 1H NMR (600
MHz, CDCl3) δ 5.49 (br s, 1 H), 4.38 (dd, 1 H, J ) 9.7, 2.9 Hz),
4.20, 4.06 (AB q, 2 H, J ) 16.1 Hz), 4.19(d, 1 H, J ) 4.5 Hz),
3.51 (dd, 1 H, J ) 9.0, 4.6 Hz), 3.42 (dd, 1 H, J ) 9.0, 5.5 Hz),
3.35 (s, 3 H), 2.87-2.90 (m, 1 H), 2.55 (ddd, 1H, J ) 9.7, 5.4,
1.4 Hz), 1.76 (br s, 3 H), 0.79(s, 9 H), 0.06 (s, 3 H), 0.02 (s, 3
H); 13C NMR (125 MHz, CDCl3) δ 215.4 (C), 135.8 (C), 127.6
(CH), 79.9 (CH), 75.4 (CH2), 73.0 (CH), 71.5 (CH2), 59.1 (CH3),
42.6 (CH), 35.2 (CH), 25.6 (CH3), 21.6 (CH3), 17.9 (C), -4.5
(CH3), -4.9 (CH3); MS (FAB) 327 ([M + H]+, 35), 269(78), 73-
(100); HRMS (FAB, M + H+) m/z calcd for C17H31O4Si
327.1992, found 327.1997.
C
17H31O5Si 343.1941, found 343.1949.
Ack n ow led gm en t. We thank the National Science
Council of the Republic of China for financial support
(Grant NSC 90-2113-m-007-025).
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra of compounds 6-8, 10-23, and 3 and the X-ray
crystal structure and data of compound 20. This material is
available free of charge via the Internet at http://pubs.acs.org.
(3a R*,4S*,7R*,7a R*)-7-[(ter t-Bu t yld im et h ylsilyl)oxy]-
3a -h yd r oxy-4-(m et h oxym et h yl)-6-m et h yl-2,3,3a ,4,7,7a -
h exa h yd r oben zo[b]fu r a n -3-on e (3). To a solution of i-Pr2-
J O010853P