Asymmetric synthesis of 4-deoxyverrucarol via two types of ring expansion reactions

Article abstract of DOI:10.1021/jo991430e

Asymmetric synthesis of a trichothecane analogue, 4-deoxyverrucarol (2), was carried out through two types of ring expansion reactions. First, synthesis of the racemate of 2 was investigated. Thus, 1-[1-(tert- butyldimethylsiloxy)-ethyl]-1-methoxycarbonyl-2-hexen-4-one (10), prepared by Diels-Alder reaction, was converted into the cyclopropylidene 15. The cyclobutanone (±)-18 was obtained from 15 via dihydroxylation, followed by successive treatments with SO₂Cl₂ in the presence of imidazole and Florisil. After transformation of (±)-18 into the vinylcyclobutanol (±)-19, the second ring expansion reaction was performed with Pd(OAc)₂ to provide the cyclopentanone (±)-20. The product was converted into the racemate of 4- deoxyverrucarol (2) through the cyclohexenone (±)-22, but the diastereoselectivity during the introduction of the double bond was unsatisfactory. The selectivity was improved in the case of the asymmetric synthesis. The optically active cyclobutanone (+)-18 was prepared via AD reaction of 15 with 73% ee. After the transformation of (+)-18 into the cyclohexanone (-)-30 through the palladium-mediated ring expansion reaction, (-)-30 was subjected to the diastereoselective deprotonation reaction using the chiral amide. The key synthetic intermediate (-)-25 of 4-deoxyverrucarol (2) was synthesized in an optically pure form by taking advantage of a kind of kinetic resolution that occurred during the deprotonation step.

Full text of DOI:10.1021/jo991430e

504
J . Org. Chem. 2000, 65, 504-512
Asym m etr ic Syn th esis of 4-Deoxyver r u ca r ol via Tw o Typ es of Rin g
Exp a n sion Rea ction s
J unji Miyata, Hideo Nemoto,*,† and Masataka Ihara*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University,
Aobayama, Sendai 980-8578, J apan
Received September 10, 1999
Asymmetric synthesis of a trichothecane analogue, 4-deoxyverrucarol (2), was carried out through
two types of ring expansion reactions. First, synthesis of the racemate of 2 was investigated. Thus,
1-[1-(tert-butyldimethylsiloxy)-ethyl]-1-methoxycarbonyl-2-hexen-4-one (10), prepared by Diels-
Alder reaction, was converted into the cyclopropylidene 15. The cyclobutanone (()-18 was obtained
from 15 via dihydroxylation, followed by successive treatments with SO2Cl2 in the presence of
imidazole and Florisil. After transformation of (()-18 into the vinylcyclobutanol (()-19, the second
ring expansion reaction was performed with Pd(OAc)2 to provide the cyclopentanone (()-20. The
product was converted into the racemate of 4-deoxyverrucarol (2) through the cyclohexenone (()-
22, but the diastereoselectivity during the introduction of the double bond was unsatisfactory. The
selectivity was improved in the case of the asymmetric synthesis. The optically active cyclobutanone
(+)-18 was prepared via AD reaction of 15 with 73% ee. After the transformation of (+)-18 into the
cyclohexanone (-)-30 through the palladium-mediated ring expansion reaction, (-)-30 was subjected
to the diastereoselective deprotonation reaction using the chiral amide. The key synthetic
intermediate (-)-25 of 4-deoxyverrucarol (2) was synthesized in an optically pure form by taking
advantage of a kind of kinetic resolution that occurred during the deprotonation step.
In tr od u ction
Trichothecanes are a group of tricyclic sesquiterpenes
isolated from various species of fungi.1 In general, these
compounds comprise an A/B/C ring system and an exo-
epoxy ring as the common features (Figure 1). Members
of this class exhibit significant biological activities such
as antifungal, antiviral, and antibacterial actions, and
also some members of this family inhibit tumor cells.2
Recently, Iida and Tomioka have reported that trichoth-
ecinol A (1) exhibited not only potent inhibitory effect
against the tumor promoter 12-O-tetradecanoylphorbol-
13-acetate (TPA) but also tumor promotion effect in the
absence of TPA.3 Therefore, trichothecanes are expected
to serve as a potential tool in disclosing the mechanism
of carcinogenesis. These biological activities and unique
structural features have stimulated many organic chem-
ists to make significant contributions for the synthesis
of this class of compounds.4
F igu r e 1.
Synthesis of 4-deoxyverrucarol (2) has been carried out
from verrucarol (3) and analogues for studies on the
preparation and development of monoclonal antibodies
for trichothecanes.5 A new route to 4-deoxyverrucarol (2)
via a series of ring expansion reactions6 of small ring
compounds has been planned by us as shown in Scheme
1. The potential intermediate 5 would be synthesized
through palladium-mediated ring expansion reaction of
vinylcyclobutanol, the precursor 6 of which could be
†Present address: Faculty of Pharmaceutical Sciences, Toyama
Medical and Pharmaceutical University, Sugitani 2630, Toyama 930-
0194 J apan.
(4) (a) Schlessinger, R. H.; Nugent, R. A. J . Am. Chem. Soc. 1982,
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Soc. 1984, 106, 383. (c) Roush, W. R.; D’Ambra, T. E. J . Am. Chem.
Soc. 1983, 105, 1058. (d) Koreeda, M.; Ricca, D. J .; Luengo, J . I. J .
Org. Chem. 1988, 53, 5586. (e) White, J . D.; Kim, N.; Hill, D. E.;
Thomas, J . A. Synthesis 1998, 619. (f) Ishihara, J .; Nonaka, R.;
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1987, 35, 906. (k) Tamm, C.; J eker, N. Tetrahedron 1989, 45, 2385.
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Prod. 1984, 47, 514. (b) J arvis, B. B. Report 1985, Order AD-A 165344/
3/GAR; NTIS. Gov. Rep. Announce. Index U.S. 1986, 86, Abstr. 628439.
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mata, H.; Nagamochi, M.; Fukumoto, K. Teterahedron 1995, 51, 5511.
(1) (a) Devon, T. K.; Scott, A. I. Handbook of Naturally Occurring
Compounds, Vol. II, Terpenes; Academic Press: New York, 1972; p 114.
(b) Terpenoids and Steroids; The Chemical Society, London, Vol. 1-12.
(c) ApSimon, J . W.; Blackwell, B. A.; Blais, L.; Fielder, D. A.;
Greenhalgh, R.; Kasitu, G.; Miller, J . D.; Savard, M. Pure Appl. Chem.
1990, 62, 1339. (d) Dewick, P. M. Nat. Prod. Rep. 1997, 111.
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C. Fortschr. Chem. Org. Naturst. 1974, 31, 63. (c) Kupchan, S. M.;
J arvis, B. B.; Dailey, R. G., J r.; Bright, W.; Bryan, R. F.; Shizuri, Y. J .
Am. Chem. Soc. 1976, 98, 7092. (d) Ueno, Y. Trichothecenes-Chemical,
Biological and Toxicological Aspects, Developments in Food Science 4;
American Elsevier: New York, 1983. (e) Dolyle, T. W.; Bradner, W. T.
In Anticancer Agents Based on Natural Product Models; Cassady, J .
M., Douros, J . D., Eds.; Academic Press: New York, 1980; Vol. 6.
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on the Chemistry of Natural Products, Symposium Papers; Sapporo,
J apan, 1997; 157.
10.1021/jo991430e CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/31/1999

Asymmetric Synthesis of 4-Deoxyverrucarol
J . Org. Chem., Vol. 65, No. 2, 2000 505
Sch em e 1
Sch em e 2a
prepared from the cyclopropylidene 7. We would like to
describe an asymmetric synthesis of 2 according to this
strategy.7
Resu lts a n d Discu ssion
Syn th esis of Ra cem ic Com p ou n d s. The synthesis
was first investigated utilizing racemic compounds. The
construction of the contiguous quaternary carbons is one
of the most difficult problems in trichothecane synthesis.
Recently, we reported a synthesis of (()-scirpene (4),8 in
which the A ring was constructed through Birch reduc-
tion and [3,3]-sigmatropic reaction. However, unsatisfac-
tory stereocontrol was observed. To overcome the diffi-
culty, a Diels-Alder reaction was adopted to build up
one of the two quaternary carbons. Thus, the cycloaddi-
tion of the silyloxydiene 89 and the methylenebutyric
ester 910 provided the unsaturated ketone 10 (ratio of
diastereomers 2.6:1) corresponding to the A-ring part of
trichothecanes (Scheme 2). Successive hydrogenation of
10 and acetalization gave the ester 11. Because the
A-ring part of the ester 11 had no chiral center, the
necessity to handle diastereomers was avoided. Next, the
ester 11 was reduced with DIBALH, and the resulting
alcohol was protected as the MOM ether 12. Desilylation
of 12, followed by Swern oxidation of 13, afforded the
ketone 14. Wittig reaction of 14 with cyclopropylidene-
triphenylphosphorane11 afforded the cyclopropylidene 15,
but the reaction proceeded in low yield, presumably as a
result of the bulkiness of the substrate. Treatment of the
cyclopropylidene 15 with m-CPBA gave the correspond-
ing epoxide 16. However, the acidic treatment of the
epoxide 16 did not produce the desired cyclobutanone.
Therefore, 15 was transformed into the diol (()-17, and
its 1,2-rearrangement was investigated under various
conditions. The results are shown in Table 1.
a
Key: (a) 180 °C (96%); (b) H2, Pd-C×b0; (c) ethylene glycol,
PPTS (90%); (d) DIBALH; (e) MOMCl, i-Pr2NEt (96%); (f) TBAF
(97%); (g) (COCl)2, DMSO, Et3N (93%); (h) cyclopropyltriph-
enylphosphonium bromide, NaH (27%; 99% based on recovered
14); (i) m-CPBA, NaHCO3 (96%); (j) OsO4, DABCO, K3Fe(CN)6,
K2CO3, MeSO2NH2 (85%).
Ta ble 1
yield
entry
conditions
(%)
Reaction of (()-17 with PPTS resulted in nonproduc-
tive decomposition of the substrate (entry 1). Treatment
with MsCl-pyridine or SOCl2-Et3N gave no desired
product (entries 2 and 3). Therefore, a direct formation
of the cyclic sulfate,12 which was expected to be more
reactive than the cyclic sulfite, was examined. When (()-
1
2
3
4
5
6
PPTS, 80 °C, 1 h
MsCl, pyridine, rt, 48 h
0
0
SOCl2, Et3N, rt, 24 h
0
SO2Cl2, imidazole, rt, 1 h
0
SO2Cl2, imidazole, rt, 1 h then silica gel, rt, 19 h
SO2Cl2, imidazole, rt, 1 h then Florisil, rt, 14 h
88
91
17 was treated with SO2Cl2 and imidazole,13 the con-
sumption of (()-17 resulted in a complicated decompo-
sition of the product (entry 4). However, formation of the
cyclic sulfate, followed by treatment with silica gel,
afforded the cyclobutanone (()-18 in a high yield (entry
5). Furthermore, reaction of (()-17 with SO2Cl2 and
(7) Synthesis of (()-4-deoxyverrucarol was reported as a preliminary
communication; Nemoto, H.; Miyata, J .; Ihara, M. Teterahedron Lett.
1999, 40, 1933.
(8) Nemoto, H.; Takahashi, E.; Ihara, M. Org. Lett. 1999, 1, 517.
(9) Danishefsky, S.; Kitahara, T. J . Am. Chem. Soc. 1974, 96, 7807.
(10) Paquette, L. A.; Bennette, G. D.; Chhatriwalla, A.; Isaac, M.
B. J . Org. Chem. 1997, 62, 3370.
(11) Stafford, J . A.; McMurry, J . E. Tetrahedron Lett. 1988, 29, 2531.
(12) For review about cyclic sulfates, see: Lohray, B. B. Synthesis
1992, 1035-1052.
(13) Tewson, T. J . J . Org. Chem. 1983, 48, 3507-3510.

506 J . Org. Chem., Vol. 65, No. 2, 2000
Miyata et al.
Sch em e 3a
Sch em e 4a
a
Key: (a) CSA, LiBF4 (50%); (b) NBS (67%); (c) m-CPBA,
NaHCO3 (73%); (d) Zn, NH4Cl (85%).
the cis relationship between the hydroxy group at the
C-3 position and the A-ring part permits cyclization to
form the B ring. These two compounds were expected to
be diastereomers at C-6 and C-11 positions. The config-
uration of (()-23 was assigned mainly on the basis of its
conversion into the known compound as shown in Scheme
4. On the other hand, the structure 24 of the diastere-
oisomer was supported by the NOE observation between
the exo-methylene and the methylene of the C-15 posi-
tion. Deprotection of (()-24 failed because of its instabil-
ity under acidic conditions.
a
Key: (a) vinylmagnesium bromide, CeCl3 (97%); (b) Pd(OAc)2
(90%); (c) DIBALH; (d) 10% HCl (92%); (e) TMSCl, Et3N, 100 °C;
(f) Pd(OAc)2 (79%); (g) MeLi; (h) CSA (23, 23%; 24, 30%).
imidazole, followed by addition of Florisil, gave the most
effective outcome (entry 6). These results would suggest
that the role of silica gel and Florisil is to promote the
rearrangement of cyclic sulfate intermediate.
The MOM group of (()-23 was deprotected to give (()-
15-hydroxytrichothec-9,12-diene (25), whose (+)-enanti-
omer had been synthesized by Gilbert with 45% ee.4i The
stereoselective introduction of the exo-epoxy group at the
C-12 and -13 positions was performed by the application
of Schlessinger’s procedure.4a Thus, intramolecular bro-
moetherification with NBS afforded the bromoether (()-
26, which on treatment with m-CPBA stereoselectively
provided the epoxide (()-27. Finally, reductive ring
opening of (()-27 with zinc and NH4Cl17 produced (()-
4-deoxyverrucarol (2). The spectral data of the synthetic
compound were consistent with those reported by Schu-
da.5
Next, the construction of the skeletal structure of
trichothecanes via the ring expansion reaction as the
second key step was performed as shown in Scheme 3.
The cyclobutanone (()-18 was stereoselectively converted
into the vinylcyclobutanol (()-19 by treatment with
vinylmagnesium bromide in the presence of CeCl3.14 The
stereochemistry of (()-19 was determined by the obser-
vation of the definite NOE between the methyl group and
a vinyl hydrogen. The ring expansion reaction of (()-19
was achieved by using a stoichiometric amount of Pd-
(OAc)2 to give the cyclopentanone (()-20 in a high yield.
Reduction of (()-20, followed by treatment with 10% HCl,
provided a 5.2:1 mixture of the hydroxyketones 21. Silyl
enolization15 of (()-21, followed by application of Sae-
gusa’s method,16 furnished enones (()-22 as an insepa-
rable mixture of four diastereoisomers. Analysis of the
1H NMR spectrum of the mixture suggested that the
mixture is composed of stereoisomers at the quaternary
stereogenic center of the cyclohexenone in the ratio of
1.3:1. The mixture thus obtained was treated with MeLi,
and the resulting diols were subjected to cyclization
under acidic conditions to give a 1:1.3 mixture of the
tricyclic compounds (()-23 and (()-24.
Thus, the total synthesis of (()-4-deoxyverrucarol (2)
was accomplished. This route must be efficient, if intro-
duction of the double bond into the A-ring part could be
carried out diastereoselectively. The selectivity was
improved in the case of asymmetric synthesis (vide infra).
Asym m etr ic Syn th esis. Asymmetric dihydroxylation
of 15, followed by 1,2-rearrangement of the resulting 17,
would lead to the optically active cyclobutanone 18. It
was expected that the desired diastereoselective intro-
duction of the double bond into the cyclohexane part
would be performed by deprotonation using chiral base.
The stereochemistry of these tricyclic compounds was
determined as follows. Namely, it is apparent that only
Thus, the asymmetric dihydroxylation of the cyclopro-
pylidene 15 was examined (Scheme 5). (DHQ)2PHAL is
one of the most widely used ligands because of the high
ability for enantioselective dihydroxylation of almost all
(14) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiyama, Y. J . Am. Chem. Soc. 1989, 111, 4392.
(15) House, H. O.; Czuba, L. J .; Gall, M.; Olmstead, H. D. J . Org.
Chem. 1969, 34, 2324.
(16) Ito, Y.; Hirao, T.; Saegusa, T. J . Org. Chem. 1978, 43, 1011.
(17) Corey, E. J .; Danheiser, R. L. Tetrahedron Lett. 1973, 45, 4477.

Asymmetric Synthesis of 4-Deoxyverrucarol
J . Org. Chem., Vol. 65, No. 2, 2000 507
Sch em e 5a
Sch em e 6a
a
Key: (a) OsO4, (DHQ)2PYR, K3Fe(CN)6, K2CO3, MeSO2NH2
(79%): (b) SO2Cl2, imidazole then Florisil, -40 °C (74%; 73% ee);
(c) NaBH4 (87%); (d) BzCl, Et3N, DMAP (95%).
classes of olefins, which include tetrasubstituted olefins.18
However, AD-mix R, including the ligand (DHQ)2PHAL,
did not have any characteristic influence on the reaction
of the cyclopropylidene 15 at all. The ligand would not
be suitable for the tetrasubstituted olefin because the
A-ring part is presumably too hindered to permit access
of OsO4 and (DHQ)2PHAL to the double bond. In contrast,
OsO4 and (DHQ)2PYR, which is known as a better ligand
for oxidation of olefins having bulky alkyl substituents,19
reacted with 15 to afford the optically active diol (+)-17,
whose absolute configuration was predicted on the basis
of theory.18 Conversion of (+)-17 into benzoyl or MTPA
ester was attempted to evaluate the optical purity but
failed.
Compound (+)-17 was subjected to the 1,2-rearrange-
ment through the direct formation of the cyclic sulfate
intermediate. When the reaction was carried out at -40
°C, the enantiomeric purity of (+)-18 was 73% ee. It is
expected that the rearrangement would proceed via the
inversion at the stereogenic center.20
The enantiomeric excess was evaluated after conver-
sion of (+)-18 into the benzoyl ester (-)-29. Namely, the
cyclobutanone was reduced with NaBH4 to afford the cis-
cyclobutanol (-)-28. The stereochemistry of (-)-28 was
established by NOE between the methyl group and the
methine hydrogen on the cyclobutane ring. The benzoyl
ester (-)-29, obtained from (-)-28, was subjected to a
chiral HPLC analysis.
Grignard reaction of (+)-18 provided (-)-19, which was
applied to the palladium-mediated ring expansion reac-
tion (Scheme 6). The enantiomeric excess (73% ee) of the
product (+)-20, determined directly by chiral HPLC,
indicates no loss of the optical purity during the ring
expansion reaction. Successive DIBALH reduction and
deprotection afforded the allyl alcohol (+)-21 as an
inseparable mixture of diastereomers. The major dias-
a
Key; (a) vinylmagnesium bromide, CeCl3 (86%); (b) Pd(OAc)2
(82%, 73% ee); (c) DIBALH; (d) 10% HCl (87%); (e) TMSCl,
imidazole (79%); (f) (S,S)-R,R-bis(phenethyl)amine, BuLi, -98 °C
then TMSCl, Et3N; (g) Pd(OAc)2 (88%); (h) MeLi then 50% HF (49);
(i) 3,5-dinitrobenzoyl chloride, Et3N, DMAP (95%, >98% ee).
tereomer of (+)-21 was isolated as TMS ether (-)-30,
which was then subjected to the deprotonation reaction
using lithium (S,S)-R,R-bis(phenylethyl)amide.21 The re-
action was executed at -98 °C, and the resulting silyl
enol ether was immediately used for the next step after
separation from the chiral amine through Florisil column
chromatography. The Saegusa reaction16 proceeded
smoothly to give the cyclohexenones 31 and 32 as an
inseparable mixture in the ratio of 2:1. When lithium
(R,R)-R,R-bis(phenylethyl)amide was used for the above
transformation, a mixture of 31 and 32 was formed in
the ratio of 1:4. Reaction of the mixture, obtained by the
use of the (S,S)-amine, with MeLi followed by addition
of 50% HF afforded (-)-25. No formation of other dias-
tereoisomers was observed.
The 98% ee enantiomeric purity of the synthetic (-)-
25 was determined by the chiral HPLC analysis of (-)-
33, derived from (-)-25. The enhancement of the optical
purity could be attributed to an enantiomeric enrichment
during the conversion. Recrystallization of (-)-25 gave
the enantiomerically pure compound (>99% ee). The
specific rotation of the synthetic compound 38, [R]D -147
(c 0.42, CHCl3), [45% ee of its antipode, lit.4i [R]D +33 (c
0.3, CHCl3)] supports that its absolute stereochemistry
must be the same as natural trichothecanes. Because (-)-
25 is convertible into 4-deoxyverrucarol (2) as described
as above, its formal asymmetric synthesis has been
achieved.
(18) Morikawa, K.; Park, J .; Andersson, P. G.; Hashiyama, T.;
Sharpless, K. B. J . Am. Chem. Soc. 1993, 115, 8463; for review, see:
Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994,
94, 2483.
(19) Crispino, G. A.; J eong, K.-S.; Kolb, H. C.; Wang, Z.-M.; Xu, D.;
Sharpless, K. B. J . Org. Chem. 1993, 58, 3785.
(20) (a) Nemoto, H.; Ishibashi, H.; Nagamochi, M.; Fukumoto, K. J .
Org. Chem. 1992, 57, 1707. (b) Nemoto, H.; Tanabe, T.; Fukumoto, K.
J . Org. Chem. 1995, 60, 6785. (c) Nemoto, H.; Fukumoto, K. Synlett
1997, 875. (d) Nemoto, H.; Yoshida, M.; Fukumoto, K.; Ihara, M.
Tetrahedon Lett. 1999, 40, 907.
(21) Cousins, R. P. C.; Simpkins, N. S. Tetrahedron Lett. 1989, 30,
7241.

508 J . Org. Chem., Vol. 65, No. 2, 2000
Miyata et al.
a colorless oil: IR (neat) 1100 cm-1; 1H NMR (300 MHz, CDCl3)
δ 0.03 (3H, s), 0.05 (3H, s), 0.89 (9H, s), 1.11 (3H, d, J ) 6.6
Hz), 1.50-1.69 (8H, m), 3.35 (3H, s), 3.46 (1H, d, J ) 9.9 Hz),
3.60 (1H, d, J ) 9.9 Hz), 3.79 (1H, q, J ) 6.6 Hz), 3.94 (4H, s),
4.58 (1H, d, J ) 6.6 Hz), 4.61 (1H, d, J ) 6.6 Hz); 13C NMR
(75 MHz, CDCl3) δ -5.1, -4.0, 18.0, 18.3, 25.9, 26.0, 26.7, 30.6,
40.5, 55.2, 64.2, 67.9, 71.8, 96.9, 109.1; MS m/z 359 (M+ - Me);
HRMS calcd for C18H35O5Si 359.2252, found 359.2293.
Exp er im en ta l Section
Gen er a l P r oced u r e. All reactions were carried out under
a positive atmosphere of nitrogen in dried glassware unless
indicated otherwise. Dehydrated THF, Et2O, and CH2Cl2 were
purchased, and other solvents were distilled prior to use. DME
was freshly distilled from CaH2 and LiAlH4, and DMF, DMSO,
o-dichlorobenzene, toluene, and MeCN were distilled form
CaH2 and stored over 4 Å molecular sieves. Eluants for HPLC
were purchased. Silica gel column chromatography was carried
out by using Merck Kieselgel 60 Art. 7734, Merck Kieselgel
60 Art. 9385, or Cica silica gel 60 (spherical). Reactions and
chromatography fractions were analyzed by employing pre-
coated silica gel 60 F254 plates (Merck). Shimadzu LC-10AD
was employed for HPLC, equipped with Shimadzu SPD-10A
as a UV detector at 254 nm. CHIRAL CEL OJ or OB-H (0.46
cm φ × 25 cm, Daicel Chemical) was used as a HPLC column.
1-[1-(ter t-Bu tyld im eth ylsilyloxy)eth yl]-1-m eth oxyca r -
bon yl-2-h exen -4-on e (10). A solution of 9 (27.2 g, 0.111 mol)
and 8 (25 mL, 0.13 mol) in o-dichlorobenzene (80 mL) was
heated for 14 h at 180 °C. The solvent was distilled off, and
the residue was diluted with Et2O. The mixture was washed
with 10% HCl, saturated NaHCO3, and saturated NaCl. The
residue upon workup was chromatographed on silica gel with
hexane-AcOEt (92:8 v/v) to give the cyclohexenone 10 (33.4
g, 72:28 diastereomers mixture, 96%) as a colorless oil: IR
(neat) 1740, 1690 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.03 (6H,
s), 0.86 (9H, s), 1.12 (2.16H, d, J ) 6.3 Hz), 1.10 (0.84H, d, J
) 6.3 Hz), 1.98-2.14 (1H, m), 2.26-2.38 (1H, m), 2.41-2.57
(2H, m), 3.72 (3H, s), 4.19-4.31 (1H, m), 6.03 (0.28H, d, J )
10.5 Hz), 6.10 (0.72H, d, J ) 10.5 Hz), 6.82 (0.28H, dd, J )
1.5 and 10.5 Hz), 6.97 (0.72H, dd, J ) 1.5 and 10.5 Hz); MS
m/z 297 (M+ - Me). Anal. Calcd for C16H28O4Si: C, 61.50; H,
9.03. Found: C, 61.41; H, 8.86.
1-(1-Hyd r oxyeth yl)-1-(m eth oxym eth oxy)m eth yl-4-cy-
cloh exa n e Eth ylen e Aceta l (13). A mixture of 12 (26.0 g,
69.4 mmol) and a solution of TBAF (150 mL, 1.0 M in THF,
0.15 mol) was stirred for 20 h at 50 °C. The reaction mixture
was cooled, diluted with water, and extracted with AcOEt. The
combined extracts were washed with saturated NaCl. The
residue upon workup was chromatographed on silica gel with
hexane-AcOEt (70:30 v/v) to give the alcohol 13 (17.6 g, 97%)
as a colorless oil: IR (neat) 3500 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 0.83 (3H, d, J ) 6.6 Hz), 1.13-1.50 (8H, m), 2.84-
2.91 (1H, m), 3.01 (3H, s), 3.18 (1H, d, J ) 9.9 Hz), 3.30 (1H,
d, J ) 9.9 Hz), 3.35-3.44 (1H, m), 3.58 (4H, s), 4.27 (2H, s);
13C NMR (75 MHz, CDCl3) δ 17.1, 26.0, 26.4, 29.6, 29.7, 38.7,
54.5, 63.5, 69.2, 71.3, 96.0, 108.1; MS m/ z 260 (M+). Anal.
Calcd for C13H24O5: C, 59.98; H, 9.29. Found: C, 59.91; H,
9.20.
1-Ace t yl-1-(m e t h oxym e t h oxy)m e t h yl-4-cycloh e xa -
n on e Eth ylen e Aceta l (14). To a stirred solution of DMSO
(5.8 mL, 82 mmol) in CH2Cl2 (330 mL) was added oxalyl
chloride (5.8 mL, 66 mmol) dropwise at -78 °C. After 10 min,
a solution of 13 (7.09 g, 27.2 mmol) in CH2Cl2 (20 mL) was
added, and the stirring was continued for 30 min at the same
temperature. Et3N (22 mL, 0.16 mol) was added, and the
temperature was raised to 0 °C over 20 min. The reaction
mixture was quenched with 10% NaOH (100 mL) and ex-
tracted with AcOEt. The combined extracts were washed with
saturated NaCl. The residue upon workup was chromato-
graphed on silica gel with hexane-AcOEt (70:30 v/v) to give
1-[1-(ter t-Bu tyld im eth ylsiloxy)eth yl]-1-m eth oxyca r bo-
n yl-4-cycloh exa n on e Eth ylen e Aceta l (11). To a solution
of 10 (30.0 g, 96.0 mmol) in MeOH (400 mL) was added 10%
Pd-C (300 mg). The suspension was stirred under H2 for 13
h at room temperature and filtered through Celite. The filtrate
was concentrated under reduced pressure. The residue was
dissolved in benzene (300 mL), and ethylene glycol (20 mL,
0.36 mol) and PPTS (0.40 g, 1.6 mmol) were added. The
mixture was refluxed for 5 h with removal of water. The
resulting mixture was cooled, diluted with water, and ex-
tracted with Et2O, and the combined extracts were washed
with saturated NaHCO3 and saturated NaCl. The residue upon
workup was chromatographed on silica gel with hexane-
AcOEt (85:15 v/v) to give the ketal 11 (31.0 g, 90%) as a
colorless oil: IR (neat) 1720 cm-1; 1H NMR (300 MHz, CDCl3)
δ 0.01 (3H, s), 0.02 (3H, s), 0.86 (9H, s), 1.07 (3H, d, J ) 6.3
Hz), 1.51-1.70 (6H, m), 1.99-2.08 (1H, m), 2.09-2.18 (1H,
m), 3.66 (3H, s), 3.80 (1H, q, J ) 6.3 Hz), 3.91 (4H, br s); 13C
NMR (75 MHz, CDCl3) δ -5.2, -4.1, 17.8, 19.0, 25.7, 27.2, 27.4,
the ketone 14 (6.53 g, 93%) as a colorless oil: IR 1700 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.51-1.74 (6H, m), 2.06-2.21
(2H, m), 2.21 (3H, s), 3.31 (3H, s), 3.57 (2H, s), 3.93 (4H, s),
4.56 (2H, s); 13C NMR (75 MHz, CDCl3) δ 25.9, 27.9, 31.3, 51.5,
55.3, 64.3, 73.1, 96.6, 108.5, 211.6; MS m/z 258 (M+); HRMS
calcd for C13H22O5 258.1466, found 258.1499.
1-(1-Cyclop r op ylid en eeth yl)-1-(m eth oxym eth oxy)m e-
th yl-4-cycloh exa n on e Eth ylen e Aceta l (15). A suspension
of cyclopropyltriphenylphosphonium bromide (9.9 g, 26 mmol)
and NaH (0.84 g, 60% oil suspension, 21 mmol) in DME (80
mL) was stirred for 9 h at 56 °C. A solution of 14 (2.66 g, 10.3
mmol) in DME (20 mL) was added dropwise at the same
temperature, and the stirring was continued for 12 h at 95 °C
(bath temperature). The reaction mixture was quenched with
water and extracted with AcOEt. The combined extracts were
washed with saturated NaCl. The residue upon workup was
chromatographed on silica gel with hexane-AcOEt (96:4 v/v)
to give the cyclopropylidene derivative 15 (0.797 g, 27%) as a
colorless oil. Further elution with hexane-AcOEt (85:15 v/v)
gave the recovered substrate 14 (1.92 g, 72%). 15: IR (neat)
1160, 1100 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.88 (2H, dd, J
) 5.7 and 8.7 Hz), 1.23 (2H, ddd, J ) 1.5, 5.7, and 8.7 Hz),
1.49-1.73 (6H, m), 1.85 (3H, t, J ) 1.5 Hz), 2.01-2.13 (2H,
m), 3.29 (3H, s), 3.36 (2H, s), 3.88-3.98 (4H, m), 4.54 (2H, s);
13C NMR (75 MHz, CDCl3) δ 0.2, 6.1, 18.5, 29.0, 31.4, 43.1,
54.9, 64.2, 64.3, 74.6, 96.6, 109.2, 119.0, 124.7; MS m/z 282
(M+); HRMS calcd for C16H26O4 282.1803, found 282.1815.
1-(2-Meth yl-1-oxa sp ir op en t-2-yl)-1-(m eth oxym eth oxy)-
m eth th yl-4-cycloh exa n on e Eth ylen e Aceta l (16). To a
stirred solution of 15 (38.0 mg, 0.135 mmol) in CH2Cl2 (3 mL)
was added NaHCO3 (0.12 g, 1.4 mmol) and m-CPBA (35 mg,
0.16 mmol) at room temperature,and the mixture was stirred
for 2 h at the same temperature. The reaction mixture was
quenched with aqueous 10% Na2S2O3 (5 mL) and further
stirred for 1 h. The resulting mixture was extracted with Et2O,
and the extract was washed with saturated NaCl. The residue
upon workup was chromatographed on silica gel with hexane-
AcOEt (85:15 v/v) to give the epoxide 16 (38.7 mg, 96%) as a
32.1, 52.5, 52.6, 64.2, 73.6, 108.7, 175.3; MS m/z 343 (M+
-
Me); HRMS calcd for C17H31O5Si 343.1939, found 343.1921.
1-[1-(ter t-Bu tyld im eth ylsiloxy)eth yl]-1-(m eth oxym eth -
oxy)m eth yl-4-cycloh exa n on e Eth ylen e Aceta l (12). To a
stirred solution of 11 (25.8 g, 72.0 mmol) in CH2Cl2 (400 mL)
was added a solution of DIBALH (170 mL, 0.96 M solution in
hexane, 0.17 mol) dropwise over 30 min at -78 °C. The
reaction mixture was stirred for 1.5 h at the same temperature.
The reaction mixture was quenched with MeOH (10 mL), and
the temperature was raised to room temperature. To the
resulting solution was added aqueous 10% NaOH (200 mL),
and the stirring was continued for 1 h at the same tempera-
ture. The resulting mixture was extracted with Et2O, and the
organic layer was washed with saturated NaCl. The combined
extracts were evaporated, and the residue was dissolved in
CH2Cl2 (350 mL). i-Pr2NEt (28 mL, 0.16 mol) and MOMCl (11
mL, 0.14 mol) were added at 0 °C, and the stirring was
continued for 12 h at room temperature. The reaction mixture
was quenched with water and extracted with Et2O. The
combined extracts were washed with saturated NaCl. The
residue upon workup was chromatographed on silica gel with
hexane-AcOEt (93:7 v/v) to give the ether 12 (26.0 g, 96%) as
1
colorless oil: IR (neat) 1150, 1100, 1040 cm-1; H NMR (300

Asymmetric Synthesis of 4-Deoxyverrucarol
J . Org. Chem., Vol. 65, No. 2, 2000 509
MHz, CDCl3) δ 0.68-0.86 (2H, m), 1.06-1.17 (1H, m), 1.18-
1.29 (1H, m), 1.45 (3H, s), 1.53-1.95 (8H, m), 3.30 (3H, s), 3.49
(1H, d, J ) 9.6 Hz), 3.61 (1H, d, J ) 9.6 Hz), 3.93 (4H, s), 4.57
(2H, s); 13C NMR (75 MHz, CDCl3) δ 1.1, 6.2, 18.4, 25.3, 27.0,
30.7, 30.8, 39.7, 55.2, 61.8, 64.3, 67.1, 69.5, 96.8, 108.7; MS
m/z 298 (M+); HRMS calcd for C16H26O5 298.1779, found
298.1766.
40.4, 51.6, 56.0, 64.2, 67.0, 82.0, 96.9, 108.4, 112.1, 142.7; MS
m/z 326 (M+); HRMS calcd for C18H30O5 326.2092, found
326.3071.
(()-1-(1-Meth yl-2-m eth ylen e-3-oxocyclopr opyl)-1-(m eth -
oxym et h oxy)m et h yl-4-cycloh exa n on e E t h ylen e Acet a l
(20). To a stirred solution of (()-19 (1.28 g, 3.92 mmol) in THF
(150 mL) under Ar was added Pd(OAc)2 (1.3 g, 5.8 mmol) at
room temperature, and the stirring was continued for 8 h at
the same temperature. The reaction mixture was passed
through a short pad of silica gel with Et2O as eluant. The
filtrate was concentrated under reduced pressure, and the
residue was chromatographed on silica gel with hexane-
AcOEt (90:10 v/v) to give (()-20 (1.15 g, 90%) as colorless
prisms: mp 53-54 °C (petroleum ether); IR (CHCl3) 1720
(()-1-[1-Hydroxy-1-(1-hydroxycyclopropyl)ethyl]-1-(meth-
oxym eth oxy)m eth yl-4-cycloh exa n on e Eth ylen e Aceta l
(17). To a well stirred solution of 15 (324 mg, 1.15 mmol),
DABCO (7 mg, 0.06 mmol), K3Fe(CN)6 (1.1 g, 3.5 mmol), and
K2CO3 (0.47 g, 3.5 mmol) in t-BuOH-water (1:1 v/v, 12 mL)
was added OsO4 (aqueous 2% w/v, 0.15 mL, 0.012 mmol) at
room temperature, and the stirring was continued for 20 h at
the same temperature. To the reaction mixture was added 10%
Na2S2O3 (10 mL), and stirring was continued for 1 h. The
resulting mixture was extracted with AcOEt, and the combined
extracts were succesively washed with 10% NaOH and satu-
rated NaCl. The residue upon workup was chromatographed
on silica gel with hexane-AcOEt (70:30 v/v) to give (()-17 (309
mg, 85%) as a colorless oil: IR (neat) 3420 cm-1; 1H NMR (300
MHz, CDCl3) δ 0.42-0.53 (1H, m), 0.68-0.78 (2H, m), 0.97-
1.10 (1H, m), 1.31 (3H, s), 1.57-1.71 (4H, m), 1.79-1.95 (4H,
m), 2.52 (1H, br s), 3.40 (3H, s), 3.47 (1H, br s), 3.84 (1H, d, J
) 10.5 Hz), 3.89 (1H, d, J ) 10.5 Hz), 3.95 (4H, s), 4.67 (2H,
s); 13C NMR (75 MHz, CDCl3) δ 9.6, 12.6, 20.8, 24.6, 26.4, 30.4,
30.7, 43.2, 56.0, 60.7, 64.2, 67.6, 76.3, 96.8, 108.5; MS m/z 298
(M+ - H2O); HRMS calcd for C16H26O5 298.1779, found
298.1786.
cm-1 1H NMR (300 MHz, CDCl3) δ 1.27 (3H, s), 1.44-1.80
;
(9H, m), 2.28-2.36 (2H, m), 2.37-2.54 (1H, m), 3.34 (3H, s),
3.51 (1H, d, J ) 10.8 Hz), 3.66 (1H, d, J ) 10.8 Hz), 3.93 (4H,
br s), 4.52 (1H, d, J ) 6.6 Hz), 4.55 (1H, d, J ) 6.6 Hz), 5.27
(1H, d, J ) 0.9 Hz), 6.13 (1H, d, J ) 0.9 Hz); 13C NMR (75
MHz, CDCl3) δ 25.1, 25.4, 26.2, 30.4, 30.6, 30.8, 36.0, 40.9,
48.7, 55.7, 64.2, 67.7, 96.9, 108.4, 119.4, 153.0, 208.6; MS m/z
324 (M+). Anal. Calcd for C18H28O5: C, 66.64; H, 8.70. Found
66.63; H, 8.67.
(()-1-(3-Hyd r oxy-1-m eth yl-2-m eth ylen ecyclop en tyl)-1-
(m eth oxym eth oxy)m eth yl-4-cycloh exa n e (21). To a stirred
solution of (()-20 (375 mg, 1.16 mmol) in THF (30 mL) was
dropwise added a solution of DIBALH (1.8 mL, 0.94 M in
hexane, 1.7 mmol) at -78 °C, and the mixture was stirred for
2 h at the same temperature. The reaction mixture was
quenched with MeOH (2 mL) and the temperature was raised
to room temperature. To the mixture was added 10% HCl (10
mL), and stirring was continued for 2.5 h at the same
temperature. The reaction mixture was quenched with 10%
NaOH (20 mL) and extracted with AcOEt. The combined
extracts were washed with saturated NaCl. The residue upon
workup was chromatographed on silica gel with hexane-
AcOEt (60:40 v/v) to give (()-21 (cis:trans ) 84:16, 300 mg,
(()-1-(Met h oxym et h oxy)m et h yl-1-(1-m et h yl-2-oxocy-
clobu tyl)-4-cycloh exa n on e Eth ylen e Aceta l (18). (entry 6;
Table 1) To a stirred solution of (()-17 (72.2 mg, 0.228 mmol)
and imidazole (0.18 g, 2.6 mmol) in CH2Cl2 (20 mL) was added
SO2Cl2 (0.050 mL, 0.69 mmol) at 0 °C, and the mixture was
stirred for 1 h at the same temperature. Florisil (1.0 g) was
added at room temperature, and the stirring was further
continued for 14 h at the same temperature. The reaction
mixture was filtered through silica gel in vacuo, and the filtrate
was evaporated under reduced pressure. The residue was
chromatographed on silica gel with hexane-AcOEt (85:15 v/v)
to give (()-18 (61.7 mg, 91%) as a colorless oil: IR (neat) 1770
1
92%) as a colorless oil: IR (neat) 3450, 1720 cm-1; H NMR
(300 MHz, CDCl3) δ 1.14 (2.52H, s), 1.21 (0.48H, s), 1.37-1.47
(1H, m), 1.67-1.86 (2.16H, m), 1.88-2.13 (3.84H, m), 2.25-
2.64 (7H, m), 3.38 (0.48H, s), 3.39 (2.52H, s), 3.66 (0.16H, d, J
) 10.5 Hz), 3.74 (0.16H, d, J ) 10.5 Hz), 3.79 (0.84H, d, J )
10.5 Hz), 3.86 (0.84H, d, J ) 10.5 Hz), 4.62 (0.32H, s), 4.63
(1.68H, s), 5.03 (0.16H, d, J ) 2.7 Hz), 5.10 (0.84H, s), 5.22
cm-1 1H NMR (300 MHz, CDCl3) δ 1.26 (3H, s), 1.43-1.74
;
(7H, m), 1.80-1.99 (2H, m), 2.37 (1H, ddd, J ) 6.9, 10.5 and
12.3 Hz), 2.82 (1H, ddd, J ) 6.0, 10.5 and 18.0 Hz), 2.99 (1H,
ddd, J ) 6.9, 10.2 and 18.0 Hz), 3.36 (3H, s), 3.57 (1H, d, J )
10.5 Hz), 3.68 (1H, d, J ) 10.5 Hz), 3.93 (4H, br s), 4.57 (1H,
d, J ) 6.6 Hz), 4.60 (1H, d, J ) 6.6 Hz); 13C NMR (75 MHz,
CDCl3) δ 18.9, 22.2, 25.5, 26.0, 30.5, 38.9, 42.3, 55.4, 64.2, 67.8,
70.4, 96.8, 108.4, 215.7; MS m/z 298 (M+). Anal. Calcd for
(0.16H, d, J ) 2.7 Hz), 5.35 (0.84H, s); MS m/z 282 (M+
-
MeOH); HRMS calcd for C15H22O3 250.1568, found 250.1577.
(()-1-(3-Hyd r oxy-1-m eth yl-2-m eth ylen ecyclop r op yl)-1-
(m eth oxym eth oxy)m eth yl-2-cycloh exen -4-on e Eth ylen e
Aceta l (22). To a stirred solution of (()-21 (98.9 mg, 0.350
mmol) and Et3N (2 mL, 14 mmol) in DMF (15 mL) was added
TMSCl (1 m, 0.8 mmol) at room temperature, and the stirring
was continued for 5 h at 100 °C. The reaction mixture was
quenched with saturated NaHCO3 and extracted with hexane.
The combined extracts were washed with saturated NaCl. The
residue upon workup was dissolved in MeCN (15 mL). Pd-
(OAc)2 (0.12 g, 0.53 mmol) was added at room temperature,
and the mixture was stirred for 24 h at the same temperature
under Ar. The reaction mixture was passed through a short
pad of Florisil with hexane-AcOEt (70:30 v/v) as elueant. The
filtrate was concentrated under reduced pressure, and the
residue was chromatographed on silica gel with hexane-
AcOEt (50:50 v/v) to give (()-22 (77.6 mg, diastereoisomeric
ratio 47:37:8:8, 79%) as a colorless oil: IR (neat) 3400, 1670
cm-1; 1H NMR (300 MHz, CDCl3) δ 1.14 (0.37H, s), 1.20 (2.47H,
s), 1.25 (0.16H, s), 1.38-1.57 (2H, m), 1.67-1.81 (1H, m), 1.81-
2.51 (4H, m), 2.61-2.77 (1H, m), 3.33 (0.08H, s), 3.34 (0.08H,
s), 3.35 (2.47H, s), 3.36 (0.37H, s), 3.60-3.85 (2H, m), 4.29-
4.43 (0.53H, m), 4.44-4.50 (0.47H, m), 4.53-4.64 (2H, m), 5.03
(0.08H, d, J ) 2.4 Hz), 5.21 (0.37H, s), 5.29 (0.08H, d, J ) 2.4
Hz), 5.21 (0.47H, s), 5.29 (0.08H, d, J ) 2.4 Hz), 5.30 (0.08H,
d, J ) 2.4 Hz), 5.36 (0.47H, s), 5.41 (0.37H, s), 6.06-6.15 (1H,
m), 6.69 (0.08H, dd, J ) 1.2 and 10.2 Hz), 6.84 (0.08H, dd, J
) 1.2 and 10.2 Hz), 6.92 (0.37H, dd, J ) 1.2 and 10.5 Hz),
6.97 (0.47H, dd, J ) 1.5 and 10.5 Hz); MS m/z 279 (M+ - H);
HRMS calcd for C16H23O4 279.1595, found 279.1567.
C
16H26O5: C, 64.41; H, 8.78. Found: C, 64.41; H, 8.78.
(()-(1S*,2R*)-2-{8-(Meth oxym eth oxy)m eth yl-1,4-d ioxa -
sp ir o[4.5]d ec-8-yl}-2-m eth yl-1-vin ylcyclobu ta n ol (19). To
a stirred suspension of CeCl3 (2.2 g, 8.8 mmol) in THF (170
mL) was added a solution of vinylmagnesium bromide (23 mL,
0.80 M in THF, 18 mmol) at -78 °C. After 1 h of stirring, a
solution of (()-18 (1.32 g, 4.42 mmol) in THF (30 mL) was
added dropwise to the reaction mixture at the same temper-
ature, and the temperature was then raised to room temper-
ature in 30 min. The reaction mixture was quenched with
saturated NH4Cl (1 mL) followed by addition of saturated
NaHCO3 (1 mL) and MgSO4 (3 g). The resulting mixture was
filtered through Celite, and the filtrate was concentrated under
reduced pressure. The residue was chromatographed on silica
gel with hexane-AcOEt (85:15 v/v) to give (()-19 (1.40 g, 97%)
as a colorless oil: IR (neat) 3430 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 1.06 (3H, s), 1.24-1.35 (1H, m), 1.38-1.47 (1H, m),
1.48-1.70 (5H, m), 1.75-1.86 (1H, m), 1.87-2.03 (1H, m),
2.16-2.28 (1H, m), 2.34-2.51 (2H, m), 3.39 (3H, s), 3.40 (1H,
d, J ) 10.2 Hz), 3.78 (1H, d, J ) 10.2 Hz), 3.85-3.90 (4H, m),
4.19 (1H, s), 4.62 (1H, d, J ) 7.2 Hz), 4.65 (1H, d, J ) 7.2 Hz),
5.04 (1H, dd, J ) 1.8 and 10.5 Hz), 5.16 (1H, dd, J ) 1.8 and
17.4 Hz), 6.08 (1H, dd, J ) 10.5 and 17.4 Hz); 13C NMR (75
MHz, CDCl3) δ 21.5, 24.8, 26.4, 27.3, 29.3, 30.7, 30.9, 31.2,

510 J . Org. Chem., Vol. 65, No. 2, 2000
Miyata et al.
(()-(2R*,5S*,6S*,11S*)-15-(Met h oxym et h oxy)m et h yl-
tr ich oth ec-9,12-d ien e (24) a n d (()-(2R*,5S*,6R*,11R*)-15-
(Meth oxym eth oxy)m eth yltr ich oth ec-9,12-d ien e (23). To
a stirred solution of (()-22 (77.6 mg, 0.277 mmol) in THF (30
mL) was added a solution of MeLi (3 mL, 1.04 M in Et2O, 3.1
mmol) at -78 °C, and the stirring was continued for 1 h at
the same temperature. The reaction mixture was quenched
with MeOH (1 mL) and water. The mixture was extracted with
AcOEt. The residue upon workup was dissolved in CH2Cl2 (30
mL) and stirred. To the solution was added CSA (40 mg, 0.17
mmol) at room temperature, and the stirring was continued
for 2 h at the same temperature. The reaction mixture was
quenched with saturated aqueous NaHCO3 and extracted with
Et2O. The combined extracts were washed with saturated
aqueous NaCl. The residue upon workup was chromato-
graphed on silica gel with hexane-AcOEt (97:3 v/v) to suc-
cessively give (()-24 (23.2 mg, 30%) and (()-23 (17.9 mg, 23%)
as colorless oil.
1.2 Hz), 4.01 (1H, dd, J ) 2.7 and 8.7 Hz), 4.25 (1H, dd, J )
1.5 and 8.7 Hz), 4.49 (1H, d, J ) 4.5 Hz), 4.62 (1H, s), 5.02
(1H, s); 13C NMR (75 MHz, CDCl3) δ 15.7, 18.3, 24.2, 27.6, 27.9,
31.6, 40.4, 45.0, 55.7, 67.0, 68.0, 73.2, 80.6, 103.6, 153.3; MS
m/z 312 (M+); HRMS calcd for C15H21O2Br 312.0724, found
312.0724.
(()-(1S*,2S*,5R*,7S*,8S*,9S*,14R*)-8-Bromo-14,14-(epoxy-
methano)-2,9-dimethyl-6,10-dioxatetracyclo[7.2.2.01,7.02,5]tetra-
d eca n e (27). To a stirred solution of (()-26 (11.6 mg, 0.0370
mmol) in CH2Cl2 (2 mL) were added NaHCO3 (80 mg, 0.96
mmol) and m-CPBA (40 mg, 80% active, 0.185 mmol) at room
temperature, and the stirring was continued for 16 h at the
same temperature. The reaction mixture was quenched with
10% Na2S2O3 (5 mL) and extracted with Et2O. The combined
extracts were washed with saturated NaCl. The residue upon
workup was chromatographed on silica gel with hexane-
AcOEt (95:5 v/v) to give (()-27 (8.9 mg, 73%) as colorless
prisms: mp 62-63 °C (hexane-AcOEt); IR (CHCl3) 1100 cm-1
;
1
(()-23: IR (neat) 1040 cm-1; H NMR (300 MHz, CDCl3) δ
1H NMR (300 MHz, CDCl3) δ 0.69 (3H, s), 1.29 (3H, s), 1.47-
1.64 (2H, m), 1.68-1.82 (1H, m), 1.86-2.14 (4H, m), 2.23 (1H,
dd, J ) 10.2 and 13.8 Hz), 2.85 (1H, d, J ) 3.9 Hz), 3.18 (1H,
d, J ) 3.9 Hz), 3.68 (1H, dd, J ) 2.4 and 9.3 Hz), 3.71 (1H, dd,
J ) 2.4 and 9.3 Hz), 3.87 (1H, d, J ) 4.5 Hz), 3.99 (1H, dd, J
) 2.4 and 8.7 Hz), 4.29 (1H, dd, J ) 1.8 and 8.7 Hz); 13C NMR
(75 MHz, CDCl3) δ 11.0, 18.9, 24.4, 26.4, 28.0, 30.8, 40.7, 42.6,
48.8, 55.1, 65.8, 66.8, 68.1, 73.7, 80.9; MS m/ z 328 (M+); HRMS
calcd for C15H21O3Br 328.0673, found 328.0668.
1.15 (3H, s), 1.38 (1H, ddd, J ) 5.4, 12.7 and 1.35 Hz), 1.55-
1.64 (1H, m), 1.69 (3H, br s), 1.71-2.00 (5H, m), 2.39 (1H, ddd,
J ) 4.5, 9.3 and 13.5 Hz), 3.28 (1H, d, J ) 10.5 Hz), 3.36 (3H,
s), 3.53 (1H, d, J ) 10.5 Hz), 3.77 (1H, br d, J ) 5.4 Hz), 4.30
(1H, d, J ) 4.5 Hz), 4.55 (1H, d, J ) 6.6 Hz), 4.58 (1H, d, J )
6.6 Hz), 4.61 (1H, s), 4.96 (1H, s), 5.40 (1H, br d, J ) 5.4 Hz);
13C NMR (75 MHz, CDCl3) δ 17.6, 20.2, 23.4, 27.3, 28.4, 32.8,
43.4, 47.8, 55.6, 67.0, 68.3, 80.0, 97.2, 102.9, 120.0, 140.3, 155.7;
MS m/z 278 (M+); HRMS calcd for C16H26O3 278.1880, found
278.1909.
(()-4-Deoxyver r u ca r ol (2). To a stirred solution of (()-
27 (4.2 mg, 0.013 mmol) in THF (5 mL) and EtOH (1 mL) were
added Zn powder (100 mg, 1.5 mmol) and NH4Cl (70 mg, 1.3
mmol), and the mixture was heated at 60 °C for 9 h with
vigorous stirring. The reaction mixture was cooled, diluted
with Et2O, and filtered through Celite. The filtrate was
concentrated under reduced pressure. The residue upon
evaporation was chromatographed on silica gel with hexane-
AcOEt (90:10 v/v) to give (()-4-deoxyverrucarol (2) (2.7 mg,
85%) as colorless prisms: mp 111-112 °C (hexane-AcOEt);
IR (CHCl3) 3450 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.93 (3H,
s), 1.20-1.32 (1H, m), 1.57-1.72 (1H, m), 1.73 (3H, s), 1.74-
2.13 (6H, m), 2.24 (1H, ddd, J ) 4.2, 9.3, and 13.8 Hz), 2.90
(1H, d, J ) 3.9 Hz), 3.17 (1H, d, J ) 3.9 Hz), 3.49 (1H, d, J )
12.0 Hz), 3.64-3.76 (3H, m), 5.41-5.48 (1H, m); 13C NMR (75
MHz, CDCl3) δ 12.4, 20.7, 23.3, 26.2, 28.6, 32.0, 44.1, 45.3,
49.5, 63.0, 66.5, 66.9, 80.1, 119.5, 141.1; MS m/z 250 (M+).
Anal. Calcd for C15H22O3: C, 71.97; H, 8.86. Found: C, 71.77;
H, 8.88.
1
(()-24: IR (neat) 1050 cm-1; H NMR (300 MHz, CDCl3) δ
1.19 (3H, s), 1.20-1.31 (1H, m), 1.48-1.61 (1H, m), 1.65-1.84
(3H, m), 1.70 (3H, br s), 1.84-2.05 (3H, m), 2.31 (1H, ddd, J
) 4, 8, 9.6 and 13.8 Hz), 3.10 (1H, d, J ) 10.5 Hz), 3.34 (1H,
d, J ) 10.5 Hz), 3.36 (3H, s), 4.37 (1H, d, J ) 3.0 Hz), 4.53
(1H, d, J ) 6.6 Hz), 4.56 (1H, d, J ) 6.6 Hz), 4.85 (1H, s), 5.02
(1H, s), 5.36-5.41 (1H, dr d, J ) 3.0 Hz); 13C NMR (75 MHz,
CDCl3) δ 19.6, 21.7, 23.6, 28.1, 31.5, 32.2, 46.0, 46.3, 56.0, 68.3,
69.0, 80.4, 97.3, 105.0, 121.3, 139.0, 155.3; MS m/z 247 (M+
-
MeO); HRMS calcd for C16H23O2 247.1697, found 247.1649.
(()-(2R*,5S*,6R*,11R*)-15-Hyd r oxytr ich oth ec-9,12-d i-
en e (25). To a stirred solution of (()-23 (30.0 mg, 0.108 mmol)
in 10% MeOH (5.5 mL) was added CSA (30 mg, 0.13 mmol),
and the reaction mixture was refluxed for 3.5 h. CSA (30 mg,
0.13 mmol) was added again, and the solution was refluxed
for 6.5 h. After addition of LiBF4 (60 mg, 0.64 mmol), the
mixture was refluxed for 4 h. The reaction mixture was
quenched with saturated NaHCO3. MeOH was evaporated off,
and the resulting mixture was diluted with water and ex-
tracted with Et2O. The residue upon workup was chromato-
graphed on silica gel with hexane-AcOEt (97:3 v/v) to give
(()-25 (12.7 mg, 50%) as colorless needles: mp 61-62 °C
(+)-(S)-1-[1-Hyd r oxy-1-(1-h yd r oxycylop r op yl)eth yl]-1-
(m eth oxym eth oxy)m eth yl-4-cycloh exan on e Eth ylen e Ac-
eta l (17). To a well stirred solution of 15 (154 mg, 0.545 mmol),
(DHQ)2PYR (24 mg, 0.027 mmol), K3Fe(CN)6 (0.53 g, 1.6
mmol), K2CO3 (0.22 g, 1.6 mmol), and MeSO2NH2 (0.15 g, 1.6
mmol) in t-BuOH-water (1:1 v/v; 6 mL) was added OsO4
(aqueous 2% w/v, 0.07 mL, 0.005 mmol) at 0 °C, and stirring
was continued for 8 h at the same temperature. To the reaction
mixture was added 10% Na2S2O3 (15 mL), and the stirring was
continued for 1 h. The reaction mixture was extracted with
AcOEt, and the combined extracts were washed with 10%
NaOH and saturated NaCl. The residue upon workup was
chromatographed on silica gel with hexane-AcOEt (70:30 v/v)
1
(hexane-AcOEt); IR (CHCl3) 3430 cm-1; H NMR (300 MHz,
CDCl3) δ 1.18 (3H, s), 1.41 (1H, ddd, J ) 5.4, 12.6, and 13.5
Hz), 1.55-1.67 (2H, m), 1.70 (3H, br s), 1.71-1.94 (3H, m),
1.99-2.07 (2H, m), 2.30 (1H, ddd, J ) 4.8, 9.0, and 13.5 Hz),
3.49 (1H, d, J ) 12.0 Hz), 3.70 (1H, br d, J ) 5.4 Hz), 3.73
(1H, d, J ) 12.0 Hz), 4.30 (1H, d, J ) 4.8 Hz), 4.62 (1H, s),
4.97 (1H, s), 5.42 (1H, br d, J ) 5.4 Hz); 13C NMR (75 MHz,
CDCl3) δ 17.8, 19.9, 23.4, 27.3, 28.7, 32.7, 44.2, 47.8, 63.2, 66.9,
79.9, 103.1, 119.9, 140.7, 155.6; MS m/z 234 (M+); HRMS calcd
for C15H22O2 234.1619, found 234.1613.
to give (+)-17 (137 mg, 79%) as a colorless oil: [R]24 +9.92 (c
D
2.24, CHCl3). Spectral data were consistent with those of the
corresponding racemate.
(()-(1S*,2S*,5R*,7S*,8S*,9S*)-8-Br om o-2,9-d im et h yl-
14-m e t h y le n e -6,10-d io x a t e t r a c y c lo [7.2.2.01,7.12,5]t e t -
r a d eca n e (26). To a stirred solution of (()-25 (12.7 mg,
0.05442 mmol) in acetone (2 mL) was added NBS (14 mg, 0.081
mmol) at 0 °C ,and stirring was continued for 30 min. NBS
(14 mg, 0.081 mmol) was added again, and the stirring was
continued for 1 h at the same temperature. The reaction
mixture was diluted with Et2O and washed with saturated
NaCl. The residue upon workup was chromatographed on
silica gel with hexane-AcOEt (96:4 v/v) to give (()-26 (11.6
mg, 67%) as colorless needles: mp 74-75 °C (hexane-
AcOEt): IR (CHCl3) 1090 cm-1; 1H NMR (300 MHz, CDCl3) δ
0.93 (3H, s), 1.27 (3H, s), 1.25-1.42 (2H, m), 1.64-1.88 (3H,
m), 1.89-2.00 (2H, m), 2.05-2.23 (2H, m), 3.70 (1H, d, J )
(+)-(R)-1-(Meth oxym eth oxy)m eth yl-1-(1-m eth yl-2-oxo-
cyclobu tyl)-4-cycloh exa n on e Eth ylen e Aceta l (18). To a
stirred solution of (+)-17 (310 mg, 0.980 mmol) and imidazole
(0.68 g, 10 mmol) in CH2Cl2 (20 mL) was added SO2Cl2 (0.15
mL, 2.0 mmol) at 0 °C, and the stirring was continued for 20
min at the same temperature. Florisil (4.4 g) was added at
-78 °C, and the mixture was stirred for 1.5 h at the same
temperature. The temperature was raised to -40 °C ,and the
stirring was continued for 12 h. The reaction mixture was
warmed to room temperature and further stirred for 4.5 h.
The resulting mixture was quenched with MeOH (0.5 mL) and
Et3N (0.5 mL) and filtered through Florisil. The filtrate was

Asymmetric Synthesis of 4-Deoxyverrucarol
J . Org. Chem., Vol. 65, No. 2, 2000 511
evaporated under reduced pressure. The residue was chro-
(+)-20 was applied on HPLC equipped with CHIRALCEL
OJ (hexane-i-PrOH 9:1 v/v, 0.5 mL/min). The enantiomeric
excess was calculated as 73% ee from the chromatogram; tR of
(+)-20, 37 min; tR of (-)-20, 46 min.
matographed on silica gel with hexane-AcOEt (85:15 v/v) to
give (+)-18 (216 mg, 73% ee, 74%) as a colorless oil: [R]24
D
+19.5 (c 1.36, CHCl3). Spectral data were consistent with those
of the corresponding racemate.
(+)-1-(3-Hyd r oxy-1-m eth yl-2-m eth ylen ecyclop en tyl)-1-
(m eth oxym eth oxy)m eth yl-4-cycloh exa n on e (21). To a
stirred solution of (+)-20 (390 mg, 1.20 mmol) in THF (30 mL)
was added a solution of DIBALH (3.8 mL, 0.94 M in hexane,
3.6 mmol) dropwise at -78 °C, and the stirring was continued
for 1.5 h at the same temperature. The reaction mixture was
quenched with MeOH (4 mL), and the temperature was raised
to room temperature. To the mixture was added 10% HCl (10
mL), and the stirring was continued for 2.5 h at the same
temperature. The resulting mixture was quenched with 10%
NaOH (20 mL) and extracted with AcOEt. The combined
extracts were washed with saturated NaCl. The residue upon
workup was chromatographed on silica gel with hexane-
AcOEt (60:40 v/v) to give (+)-21 (cis:trans ) 84:16, 294 mg,
(-)-(1R,2R)-1-Ben zoyloxy-2-{8-(m eth oxym eth oxy)m e-
th yl-1,4-dioxaspir o[4.5]dec-8-yl}-2-m eth ylcyclobu tan e (29).
To a stirred solution of (+)-18 (56.1 mg, 0.188 mmol) in MeOH
(4 mL) was added NaBH4 (50 mg, 1.3 mmol), and the stirring
was continued for 1 h. Addition of the same amount of NaBH4
and the same treatment was further repeated twice. The
solvent was evaporated before addition of water. The mixture
was extracted with AcOEt, and the extract was washed with
saturated NaCl. The residue upon workup was chromato-
graphed on silica gel with hexane-AcOEt (85:15 v/v) to give
(-)-28 (49.4 mg, 87%) as a colorless oil: [R]26 -2.53 (c 1.35,
D
CHCl3); IR (neat) 3430 cm-1
;
1H NMR (300 MHz, CDCl3) δ
1.14 (3H, s), 1.24-1.36 (1H, m), 1.37-1.80 (7H, m), 1.81-1.98
(1H, m), 2.10-2.34 (3H, m), 3.40 (3H, s), 3.56 (1H, d, J ) 9.9
Hz), 3.83 (1H, d, J ) 9.9 Hz), 3.91-3.98 (4H, m), 4.47 (2H, d,
J ) 2.7 Hz), 4.68 (2H, s); MS m/z 272 (M+); HRMS calcd for
87%) as a colorless oil: [R]25 +8.09 (c 1.11, CHCl3). Spectral
D
data were consistent with those of the corresponding racemate.
(-)-(1R,3S)-3-[1-(Meth oxym eth oxy)m eth yl-4-oxocyclo-
h exyl]-3-m et h yl-2-m et h ylen e-1-t r im et h ylsilyloxycyclo-
p en ta n e (30). To a stirred solution of (+)-21 (294 mg, 1.04
mmol) and imidazole (0.35 g, 5.2 mmol) in DMF (10 mL) was
added TMSCl (0.27 mL, 2.1 mmol) at 0 °C ,and the stirring
was continued for 15 min at the same temperature. Saturated
NaHCO3 was added, and the mixture was extracted with Et2O.
The extract was washed with saturated NaCl. The residue
upon workup was chromatographed on silica gel with hexane-
AcOEt-NEt3 (96:1:3 v/v) to give (-)-30 (291 mg, 79%) as a
C
16H28O5 272.1624, found 272.1645.
To a stirred solution of (-)-28 (13.1 mg, 0.0436 mmol), Et3N
(0.60 mL, 4.3 mmol), and DMAP (15 mg, 0.12 mmol) in CH2-
Cl2 (5 mL) was added benzoyl chloride (0.10 mL, 0.86 mmol),
and the reaction mixture was refluxed for 33 h. To the mixture
was added 10% NaOH at 0 °C, and the resulting mixture was
extracted with Et2O. The extract was washed with 10% HCl,
saturated NaHCO3, and saturated NaCl. The residue upon
workup was chromatographed on silica gel with hexane-
AcOEt (90:10 v/v) to give (-)-29 (16.8 mg, 95%) as colorless
colorless oil: [R]26 -6.87 (c 1.28, DME); IR (neat) 1710 cm-1
;
D
prisms: mp 88-89 °C (petroleum ether); [R]24 -15.3 (c 1.68,
1H NMR (300 MHz, CDCl3) δ 0.16 (9H, s), 1.09 (3H, s), 1.20-
1.30 (1H, m), 1.42-1.63 (2H, m), 1.77-2.02 (4H, m), 2.26-
2.43 (2H, m), 2.52 (1H, ddd, J ) 6.6, 11.4 and 16.2 Hz), 3.19
(3H, s), 3.60 (1H, d, J ) 10.5 Hz), 3.64 (1H, d, J ) 10.5 Hz),
4.26 (1H, br d, J ) 3.9 Hz), 4.46 (1H, d, J ) 6.3 Hz), 4.48 (1H,
d, J ) 6.3 Hz), 4.94 (1H, s), 5.14 (1H, s); 13C NMR (75 MHz,
C6D6) δ 0.0, 25.9, 27.8, 28.2, 32.7, 35.0, 37.9, 40.4, 50.4, 55.1,
71.9, 78.6, 97.0, 112.5, 161.1, 210.8; MS m/z 354 (M+). Anal.
Calcd for C19H34O4Si: C, 64.36; H, 9.67. Found: 64.25; H, 9.57.
(1R,3S)-3-[(1S)-1-(Met h oxym et h oxy)m et h yl-4-oxocy-
cloh exyl]-3-m et h yl-2-m et h ylen e-1-t r im et h ylsilyloxycy-
clopen tan e (31) an d (1S,3R)-3-[(1R)-1-(Meth oxym eth oxy)-
m e t h y l-4-o x o c y c lo h e x y l]-3-m e t h y l-2-m e t h y le n e -1-
tr im eth ylsilyloxycyclop en ta n e (32). To a stirred solution
of (S,S)-R,R-bis(phenylethyl)amine (0.37 g, 1.4 mmol) in THF
(30 mL) was added BuLi (0.91 mL, 1.5 M in hexane, 0.91
mmol) at -98 °C, and the stirred reaction mixture was warmed
to room temperature and recooled to -98 °C. TMSCl (0.91 mL,
7.2 mmol) and a solution of (-)-30 (128 mg, 0.361 mmol) in
THF (2 mL) were added to the mixture at the same temper-
ature. After 30 min of stirring, Et3N (4 mL) and then saturated
NaHCO3 were added. The mixture was warmed to room
temperature and extracted with hexane. The extract was
washed with saturated NaCl. The residue upon workup was
chromatographed on Florisil with hexanes-Et2O (98:2 v/v) to
give crude silyl enol ether. The enol ether was immediately
dissolved in MeCN (30 mL), and Pd(OAc)2 (0.12 g, 0.54 mmol)
was added. The mixture was stirred for 9 h under Ar. The
solvent was evaporated, and the resulting residue was chro-
matographed on silica gel with hexane-AcOEt-NEt3 (94:3:3
v/v) to give an inseparable mixture of 31 and 32 (66:34, 112
D
CHCl3); IR (neat) 1710 cm-1
;
1H NMR (300 MHz, CDCl3) δ
1.34 (3H, s), 1.38-1.51 (1H, m), 1.58-1.78 (4H, m), 1.79-2.02
(4H, m), 2.06-2.21 (1H, m), 2.39-2.52 (2H, m), 3.27 (3H, s),
3.58 (1H, d, J ) 10.2 Hz), 3.64 (1H, d, J ) 10.2 Hz), 3.84-
3.98 (4H, m), 4.51 (2H, s), 5.23 (1H, t, J ) 6.0 Hz), 7.45 (2H,
t, J ) 7.5 Hz), 7.56 (1H, tt, J ) 1.5 and 7.5 Hz), 8.20 (2H, dd,
J ) 1.5 and 7.5 Hz); 13C NMR (75 MHz, CDCl3) δ 25.6, 25.8,
25.9, 26.1, 26.5, 30.9, 39.4, 51.0, 55.4, 64.1, 64.2, 68.6, 79.3,
97.0, 108.9, 128.4, 130.2, 130.8, 132.9, 166.4; MS m/z 404 (M+).
Anal. Calcd for C23H32O6: C, 68.29; H, 7.94. Found 68.31; H,
7.86.
The benzoate was applied on HPLC equipped with CHIRAL-
CEL OJ (hexane-i-PrOH 9:1 v/v, 0.5 mL/min). The enantio-
meric excess was determined as 73% ee from the chromato-
gram; tR of (-)-29,17 min; tR of (+)-29, 22 min.
(-)-(1S,2R)-2-{8-(Met h oxym et h oxy)m et h yl-1,4-d ioxa -
sp ir o[4.5]d ec-8-yl}-2-m eth yl-1-vin ylcyclobu ta n ol (19).
To a stirred suspension of CeCl3 (1.5 g, 6.0 mmol) in THF
(50 mL) was added a solution of vinylmagnesium bromide
(19 mL, 0.62 M in THF, 12 mmol) at -78 °C. After 1
h
of stirring, a solution of (+)-18 (607 mg, 2.03 mmol)
in THF (30 mL) was added dropwise to the reaction mixture
at the same temperature, and the temperature was then
raised to room temperature in 30 min. The reaction mixture
was quenched with saturated NH4Cl (1 mL), and MgSO4
(1.5 g) was added. The resulting mixture was filtered
through Celite, and the filtrate was concentrated under
reduced pressure. The residue was chromatographed on
silica gel with hexane-AcOEt (85:15 v/v) to give (-)-19
(569 mg, 86%) as a colorless oil: [R]25 -17.7 (c 0.97, CHCl3).
D
Spectral data were consistent with those of the corres-
ponding racemate.
mg, 88%) as a colorless oil: [R]26 +30.0 (c 1.12, DME); IR
D
(neat) 1680 cm-1; H NMR (300 MHz, CDCl3) δ 0.11 (9H, s),
1
(+)-(R)-1-(1-Meth yl-2-m eth ylen e-3-oxocyclop r op yl)-1-
(m eth oxym eth oxy)m eth yl-4-cycloh exan on e Eth ylen e Ac-
eta l (20). The following reaction was carried out under Ar.
To a stirred solution of (-)-19 (472 mg, 1.45 mmol) in THF
(200 mL) was added Pd(OAc)2 (0.52 g, 2.3 mmol) at room
temperature, and the stirring was continued for 8 h at the
same temperature. The reaction mixture was passed through
a short pad of silica gel with Et2O as eluant. The filtrate was
concentrated under reduced pressure, and the residue was
chromatographed on silica gel with hexane-AcOEt (90:10 v/v)
to give (+)-20 (386 mg, 82%) as a colorless oil.
1.14 (1.98H, s), 1.18 (1.02H, s), 1.38-1.48 (1H, m), 1.57-1.65
(2H, m), 2.08-2.31 (3H, m), 2.34-2.53 (1H, m), 2.58-2.86 (1H,
m), 3.32 (1.98H, s), 3.35 (1.02H, s), 3.65 (0.66H, d, J ) 10.2
Hz), 3.69 (0.34H, d, J ) 10.2 Hz), 3.73 (0.34H, d, J ) 10.2
Hz), 3.80 (0.66H, d, J ) 10.2 Hz), 4.33-4.36 (0.66H, m), 4.36-
4.40 (0.34H, m), 4.53-4.63 (2H, m), 4.62 (0.34H, s), 5.03
(0.34H, s), 5.10 (0.66H, s), 5.21 (0.66H, s), 5.23 (0.34H, s); 6.07
(0.66H, d, J ) 10.2 Hz), 6.08 (0.34H, d, J ) 10.2 Hz), 6.96
(0.66H, dd, J ) 2.1 and 10.2 Hz), 7.02 (0.34H, d, J ) 10.2 Hz);
MS m/z 352 (M+); HRMS calcd for C19H32O4Si 352.2068, found
352.2065.

512 J . Org. Chem., Vol. 65, No. 2, 2000
Miyata et al.
1
(-)-(2R,5S,6R,11R)-15-H yd r oxyt r ich ot h ec-9,12-d ien e
(25). To a stirred solution of the mixture of 31 and 32 (96.0
mg, 0.272 mmol) in THF (12 mL) was added MeLi (1.0 mL,
1.0 M in Et2O, 1.0 mmol) at -78 °C, and the stirring was
continued for 30 min. A 50% solution of HF (0.60 mL, 15 mmol)
was slowly added to the reaction mixture, and the temperature
was raised to room temperature. The mixture was stirred for
48 h at the same temperature. The reaction mixture was
quenched with saturated aqueous NaHCO3 and extracted with
Et2O. The residue upon workup was chromatographed on silica
gel with hexane-AcOEt (97:3 v/v) to give (-)-25 (31.0 mg, 98%
ee, 49%) as a colorless solid, which was recrystallized from
petroleum ether-AcOEt to give colorless prisms, mp 103-104
1540, 1320 cm-1; H NMR (300 MHz, CDCl3) δ 1.22 (3H, s),
1.46-1.55 (3H, m), 1.70 (3H, s), 1.75-2.15 (4H, m), 2.25 (1H,
ddd, J ) 4.8, 9.0, and 13.8 Hz), 3.84 (1H, d, J ) 4.8 Hz), 4.30
(1H, d, J ) 12.0 Hz), 4.37 (1H, d, J ) 4.2 Hz), 4.47 (1H, d, J
) 12.0 Hz), 4.73 (1H, s), 5.06 (1H, s), 5.47 (1H, br d, J ) 5.1
Hz), 9.12 (2H, br s), 9.25 (1H, br s); MS m/z 428 (M+); HRMS
calcd for C22H24N2O7 428.1582, found 428.1582.
(-)-33 was subjected to HPLC equipped with CHIRALCEL
OJ (hexanes-EtOH 7:3 v/v, 1.0 mL/min). The chromatogram
showed >99% ee; tR of (-)-33, 17 min; tR of (+)-33, 36 min.
Ack n ow led gm en t. This work was partly supported
by a Grant-in-Aid for Scientific Research on Priority
Areas (11119206 and 11147202) from the Ministry of
Education, Science, Sports and Culture, J apan. J .M.
acknowledges a support from the Research Fellowship
of the J apan Society for the Promotion of Science for
Young Scientists.
°C: [R]25 -147 (c 0.42, CHCl3) [lit.4i (+)-25 (45% ee), oil, [R]D
D
+33 (c 0.3, CHCl3)]. Spectral data were consistent with those
of the racemate.
(-)-(2R,5S,6R,11R)-15-(3,5-Din itr oben zoyl)oxytr ich oth -
ec-9,12-d ien e (33). To a stirred mixture of (-)-25 (2.7 mg,
0.012 mmol), Et3N (0.050 mL, 0.36 mmol), and DMAP (5 mg,
0.04 mmol) in CH2Cl2 (2 mL) was added 3,5-dinitrobenzoyl
chloride (15 mg, 0.065 mmol) at room temperature, and the
stirring was continued for 30 min at the same temperature.
After addition of 10% HCl, the mixture was extracted with
Et2O. The extract was washed with saturated NaHCO3. The
residue upon workup was chromatographed on silica gel with
hexane-AcOEt (95:5 v/v) to give (-)-33 (4.9 mg, 95%) as a
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra
(300 MHz) for compounds, 2, 11, 12, 14-17, 19, 21-28, 31 +
32, and 33. This material is available free of charge via the
Internet at http://pubs.acs.org.
colorless oil: [R]25 -136 (c 0.26, CHCl3); IR (CHCl3) 1710,
J O991430E
D