A novel synthetic method of the (±)-(3aα, 8aα)-ethyl 8β-hydroxy- 6β-methyl-2-oxooctahydro-2H-cyclohepta[b]furan-3α-carboxylate and its chemical transformation

Article abstract of DOI:10.1021/jo971529q

The catalytic hydrogenation of ethyl 8-hydroxy-6-methyl-2-oxo-2H- cyclohepta[b]furan-3-carboxylate (6), which was derived regioselectively from 4-methyltropolone (1) in four steps in 62% overall yield, gave (3aα,8aα)- ethyl 8β-hydroxy-6β-methyl-2-oxooctahydro-2H-cylohepta[b]furan-3α- carboxylate (8b) in 45% yield. It is noteworthy that four asymmetric centers newly introduced on the seven-membered ring of 8b were controlled to be syn- oriented by the single operation. The latter was transformed to (3aα,8aα)- 3α,6β-dimethyl-3,3a,4,5,6,8a-hexahydro-2H-cyclohepta[b]furan -2-one (17a) in 77% overall yield in five steps. Reduction of 17a with LiAlH₄ gave (±)- 7β-(2-hydroxy-1α-methylethyl)-4β-methyl-2-cyclohepten-1β-ol (22), whose enantioselective acetylation was achieved by vinyl acetate in the presence of Lipase PS to give (+)-7β-(2-acetoxy-1α-methylethyl)-4β-methyl-2- cyclohepten-1β-ol (24) in 48% yield (93% ee) or in 52% yield (77% ee) and (- )-22 in 52% yield (70% ee) or 44% yield (89% ee). Oxidation of (+)-24 with MnO₂ gave (-)-7β-(2-acetoxy-1α-methyl ethyl)-4β-methyl-2-cyclohepten-1- one (-)-(25). Similarly, acetylation of (-)-22 followed by oxidation or resulting (-)-24 gave (+)-25.

Full text of DOI:10.1021/jo971529q

920
J . Org. Chem. 1998, 63, 920-929
Articles
A Novel Syn th etic Meth od of th e (()-(3a r,8a r)-Eth yl
8â-Hyd r oxy-6â-m eth yl-2-oxoocta h yd r o-2H-cycloh ep ta [b]fu r a n -3r-
ca r boxyla te a n d Its Ch em ica l Tr a n sfor m a tion to
(()-(3a r,8a r)-3r,6â-Dim eth yl-3,3a ,4,5,6,8a -h exa h yd r o-2H-
cycloh ep ta [b]fu r a n -2-on e, (+)- a n d
(-)-7â-(2-Acetoxy-1r-m eth yleth yl)-4â-m eth yl-2-cycloh ep ten -1â-ol,
a n d (+)- a n d
(-)-7â-(2-Acetoxy-1r-m eth yleth yl)-4â-m eth yl-2-cycloh ep ten -1-on e.
P ossible Com m on Syn th etic In ter m ed ia tes for
P seu d ogu a ia n olid es, 4,5-Secop seu d ogu a ia n olid es, Gu a ia n olid es,
4,5-Secogu a ia n olid es, a n d Octa la ctin s
Fumito Shimoma,† Haruhiko Kusaka,‡ Katsuaki Wada,‡ Hidenori Azami,‡
Masafumi Yasunami,‡ Toshio Suzuki,† Hisahiro Hagiwara,† and Masayoshi Ando*,§
Graduate School of Science and Technology, Niigata University, Ikarashi 2-8050, Niigata 950-21, J apan,
Department of Applied Chemistry, Faculty of Engineering, Niigata University, and Department of
Chemistry, Faculty of Science, Tohoku University, Aobaku, Sendai 980, J apan
Received August 14, 1997
The catalytic hydrogenation of ethyl 8-hydroxy-6-methyl-2-oxo-2H-cyclohepta[b]furan-3-carboxylate
(6), which was derived regioselectively from 4-methyltropolone (1) in four steps in 62% overall yield,
gave (3aR,8aR)-ethyl 8â-hydroxy-6â-methyl-2-oxooctahydro-2H-cyclohepta[b]furan-3R-carboxylate
(8b) in 45% yield. It is noteworthy that four asymmetric centers newly introduced on the seven-
membered ring of 8b were controlled to be syn-oriented by the single operation. The latter was
transformed to (3aR,8aR)-3R,6â-dimethyl-3,3a,4,5,6,8a-hexahydro-2H-cyclohepta[b]furan-2-one (17a )
in 77% overall yield in five steps. Reduction of 17a with LiAlH4 gave (()-7â-(2-hydroxy-1R-
methylethyl)-4â-methyl-2-cyclohepten-1â-ol (22), whose enantioselective acetylation was achieved
by vinyl acetate in the presence of Lipase PS to give (+)-7â-(2-acetoxy-1R-methylethyl)-4â-methyl-
2-cyclohepten-1â-ol (24) in 48% yield (93% ee) or in 52% yield (77% ee) and (-)-22 in 52% yield
(70% ee) or 44% yield (89% ee). Oxidation of (+)-24 with MnO2 gave (-)-7â-(2-acetoxy-1R-methyl
ethyl)-4â-methyl-2-cyclohepten-1-one (-)-(25). Similarly, acetylation of (-)-22 followed by oxidation
of resulting (-)-24 gave (+)-25.
Pseudoguaianolides, 4,5-secopseudoguaianolides, gua-
ceptive,19,20 immunomodulation,21 root-growth stimula-
tory,2,22,23 root-growth and germination inhibitory activi-
ties,2,3,12,13,14,24,25 and preventive or curative activities for
ianolides, and 4,5-secoguaianolides are rapidly expanding
groups of natural products comprising to date ca. 1000
varieties.1 Some of them have been shown to exhibit high
biological activities such as antitumor,2-15 antiulcer,15
cardiotonic,15 antisistosomal,2,16,17 anthelmintic,18 contra-
(8) J olad, S. D.; Wiedhopf, R. M.; Cole, J . D. J . Pharm. Sci. 1974,
63, 1321.
(9) Ogura, M.; Cordell, G. A.; Farnsworth, N. R. Phytochemistry
1978, 17, 957.
* To whom correspondence should be addressed. Phone: +81-25-
262-7326. Fax: +81-25-263-3174 or +81-25-262-0785. E-mail: mando@
eng.niigata-u.ac.jp.
(10) Cassady, J . M.; Suttness, M. Anticancer Agent Based on Natural
Product Models; Cassady, J . M., Douros, J ., Eds.; Academic Press: New
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† Graduate School of Science and Technology, Niigata University.
‡ Tohoku University.
(11) Ando, M.; Kusaka, H.; Ohara, H.; Takase, K.; Yamaoka, H.;
Yanagi, Y. J . Org. Chem. 1989, 54, 1952.
§ Department of Applied Chemistry, Faculty of Engineering, Niigata
University.
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Prod. 1991, 54, 1017.
(1) Connolly, J . D.; Hill, R. A. Dictionary of Terpenoids, Vol. 1;
Chapman and Hall: London, 1991; pp 463-545.
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T. A. Cancer Res. 1971, 31, 1649.
(7) Kupchan, S. M.; Kelsey, J . E.; Maruyama, M.; Cassady, J . M.
Tetrahedron Lett. 1968, 3517.
(13) Ando, M.; Isogai, K.; Azami, H.; Hirata, N.; Yamazaki, H.;
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(14) Ando, M.; Wada, T.; Kusaka, H.; Takase, K.; Hirata, N.; Yanagi,
Y. J . Org. Chem. 1987, 52, 4792.
(15) Robles, M.; Aregullin, M.; West, J .; Rodriguez, E. Planta Med.
1995, 61, 199.
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(17) Garcia, M.; Da Silva, A. J . R.; Baker, P. M.; Gilbert, B.; Rabi,
J . A. Phytochemistry 1976, 15, 331.
(18) Sa´nchez-Viesca, F.; Ramo, J . Tetrahedron 1963, 19, 1285.
(19) Bates, R. B.; Cekan, Z.; Procha´zka, V.; Herout, V. Tetrahedron
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S0022-3263(97)01529-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/03/1998

Synthetic Intermediates for Pseudoguaianolides
J . Org. Chem., Vol. 63, No. 4, 1998 921
crop diseases.3,14 Although the total syntheses of these
natural products were reported by many research
groups,26,27 their efficient and systematic syntheses from
easily available compounds are still very important
because of the diverse biological activities of these
compounds and since they are available from natural
sources often in only small quantities. A large number
of pseudoguaianolides,27 4,5-secopseudoguaianolides, 4,5-
secoguaianolides, and some guaianolides have a cis-fused
R-methylene γ-lactone moiety at the C-6,7 position and
a methyl group at C-10 which is oriented to the same
side of the γ-lactone ring as a common structural feature.
The stereocontrolled introduction of these groups at C-6,7
and C-10 is critical in the syntheses of these compounds.
Recently potent cytotoxic eight-membered lactones,
octalactins A and B, were isolated from natural marine
sources.28 For the syntheses of these compounds, we
envisioned Baeyer-Villiger oxidation of appropriately
functionalized cycloheptanone derivatives mentioned
below.
F igu r e 1. Retrosynthetic analyses and possible synthetic
routes of natural products from common synthetic intermedi-
ates.
In connection with the general synthetic strategy of
these natural products, we envisioned common synthetic
intermediates A, B, and C by the retrosynthetic analyses
(Figure 1). The intermediates may be prepared from
compound II, whose all-cis stereochemistry of substitu-
ents on the seven-membered ring may be introduced by
the catalytic hydrogenation of unsaturated γ-lactone
derivative I. The regioselective synthesis of I may be
achieved by the application of tropolone chemistry29 from
4-methyltropolone (1).30,31
F igu r e 2. Rapid tautomeric mixtures of 4-methyltropolone
(1) and 7-iodo-4-methyltropolone (2).
Sch em e 1
In this paper we report the result of the regio- and
stereoselective syntheses of common synthetic intermedi-
(20) J o¨chel, W. Angew. Chem., Int. Ed. Engl. 1962, 1, 541.
(21) Taniguchi, M.; Kataoka, T.; Suzuki, H.; Uramoto, M.; Ando, M.;
Arao, K.; Magae, J .; Nishimura, T.; Otake, N.; Nagai, K. Biosci. Biotech.
Biochem. 1995, 59, 2064.
(22) Osawa, T.; Suzuki, A.; Tamura, S. Agric. Biol. Chem. 1971, 35,
1966.
(23) Osawa, T.; Taylar, D.; Suzuki, A.; Tamura, S. Tetrahedron Lett.
1977, 1169.
(24) Asakawa, Y.; Takemoto, T. Phytochemistry 1979, 18, 285.
(25) Asakawa, Y.; Matsuda, R.; Takemoto, T. Phytochemistry 1980,
19, 567.
(26) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.;
White, C. T. The Total Synthesis of Natural products, Vol. 5; ApSimons,
J ., Ed.; Wiley: New York, 1982, and references cited therein.
(27) The pseudoguaianolides which possess the â-oriented secondary
methyl group at C-10 and the cis-fused γ-lactone moiety at the C-6, 7
position are called ambrosanolides. The references of the total syn-
theses of ambrosanolides are shown below: (a) Marshall, J . A.; Snyder,
W. R. J . Org. Chem. 1975, 40, 1656. This paper did not report the
total synthesis of ambrosanolides but described important synthetic
methodology of ambrosanolides. (b) Kretchmer, R. A.; Thompson, W.
J . J . Am. Chem. Soc. 1976, 98, 3379. (c) DeClercq, P.; Vandewalle, M.
J . Org. Chem. 1977, 42, 3447. (d) Kok, P.; DeClercq, P.; Vandewalle,
M. Bull. Soc. Chem. Belg. 1978, 87, 615. (e) Grieco, P. A.; Ohfune, Y.;
Majetich, G. J . Am. Chem. Soc. 1977, 99, 7393. (f) Grieco, P. A.; Oguri,
T.; Burke, S.; Rodriguez, E.; DeTitta, G. T.; Fortier, S. J . Org. Chem.
1978, 43, 4552. (g) Roberts, M. R.; Schlessinger, R. H. J . Am. Chem.
Soc. 1979, 101, 7626. Quallich, G. J .; Schlessinger, R. H. J . Am. Chem.
Soc. 1979, 101, 7627. (h) Demuynck, M.; DeClercq, P.; Vandewalle,
M. J . Org. Chem. 1979, 44, 4863. (i) Heathcock, C. H.; Tice, C. M.;
Germorth, T. C. J . Am. Chem. Soc. 1982, 104, 6081.
(28) Structure: Tapiolas, D. M.; Roman, M.; Fenical, W.; Stout, T.
J .; Clardy, J . J . Am. Chem. Soc. 1991, 113, 4682. Syntheses: (a)
Buszek, K. R.; Sato, N.; J eong, Y. J . Am. Chem. Soc. 1994, 116, 5511.
(b) McWilliams, J . C.; Clardy, J . J . Am. Chem. Soc. 1994, 116, 8378.
(c) Bach, J .; Berenguer, R.; Garcia, J .; Vilarrasa, J . Tetrahedron Lett.
1995, 3425. (d) Buszek, K. R.; J eong, Y. Tetrahedron Lett. 1995, 7189.
(e) Andrus, M. B.; Argade, A. B. Tetrahedron Lett. 1996, 5049. (f)
Kodama, M.; Matsushita, M.; Terada, Y.; Takeuchi, A.; Yoshio, S.;
Fukuyama, Y. Chem. Lett. 1997, 117.
ates A, B, and C. We also report the result of the
syntheses of optically active intermediates B and C by
the enantioselective acetylation of (()-diol B (P ) H) and
subsequent oxidation of B (P ) Ac).
Resu lts a n d Discu ssion
R egioselect ive Syn t h esis of E t h yl 8-Hyd r oxy-6-
m e t h yl-2-oxo-2H -cycloh e p t a [b]fu r a n -3-ca r b oxyl-
a te (6). We chose 4-methyltropolone (1) as a starting
material on the basis of the above-mentioned retrosyn-
thetic analyses and examined the regioselective synthesis
of 6 via 4-methyl-2-(tosyloxy)tropone (4) (Scheme 1). The
attempt of tosylation of 1 gave a 1:1 mixture of 4 and its
regioisomer, 6-methyl-2-(tosyloxy)tropone. The result is
well explained from the fact that 1 exists in a tautomeric
mixture of 1a and 1b (Figure 2).32 The regioselective
tosylation of 1 to 4 was achieved via 7-iodo-4-methyl-
tropolone (2), which was prepared by the treatment of 1
with I2 in the presence of K2CO3 in H2O in 85% yield.
Tosylation of 2 gave 7-iodo-4-methyl-2-(tosyloxy)tropone
(29) Nozoe, T.; Takase, K.; Kato, M.; Nogi, T. Tetrahedron 1971, 27,
6023.
(30) Brady, W. T.; Hieble, J . P. J . Am. Chem. Soc. 1972, 94, 4278.
(31) Brady, W. T. Synthesis 1971, 415.
(32) Dewar, M. J . S. Nature 1945, 155, 50.

922 J . Org. Chem., Vol. 63, No. 4, 1998
Shimoma et al.
Sch em e 2
F igu r e 3. Stereostructure of compounds III, 8a , 8b, 9a , and
9b and the results of their NOE experiments.
(3) exclusively. The result was explained by the approach
of TsCl from the less hindered hydroxyl group of 2a in a
tautomeric mixture of 2a and 2b. Hydrogenolysis of 3
in methanol in the presence of 10% Pd-C under H2 gave
the desired 4-methyl-2-(tosyloxy)tropone (4) in 89% yield.
Condensation of 4 with diethyl malonate in ethanol in
the presence of NaOEt gave 6 regioselectively in 88%
yield.
gave 9a and 9b in 96% and 91% yields, respectively. The
stereochemistry of the ring junction of these compounds
was deduced to be cis from the coupling constant between
C3a-H and C8a-H which was smaller than those of trans-
fused compounds34 and confirmed by the measurement
of the NOE between C3a-H and C8a-H (Figure 3).
Ca ta lytic Hyd r ogen a tion of 6. We investigated the
reduction conditions of 6 to (3aR,8aR)-ethyl 8â-hydroxy-
6â-methyl-2-oxooctahydro-2H-cyclohepta[b]furan-3R-car-
boxylate (8b) (Scheme 2). The best result was given by
catalytic hydrogenation performed at atmospheric pres-
sure in ethanol in the presence of Pt-C catalyst that was
generated in the reaction mixture of 18% PtO2 and 72%
of activated carbon by weight on 6. Under this condition,
6 gave the desired product 8b in 45% yield accompanied
by the minor five products, (3aR,8aR)-ethyl 6R-methyl-
2-oxooctahydro-2H-cyclohepta[b]furan-3R-carboxylate (7a)
in 10% yield, (3aR,8aR)-ethyl 6â-methyl-2-oxooctahydro-
2H-cyclohepta[b]furan-3R-carboxylate (7b) in 19% yield,
(3aR,8aR)-ethyl 8â-hydroxy-6R-methyl-2-oxooctahydro-
2H-cyclohepta[b]furan-3R-carboxylate (8a ) in 9% yield,
(3aR,8aR)-ethyl 6R-methyl-2,6-dioxooctahydro-2H-cyclo-
hepta[b]furan-3R-carboxylate (9a ) in 4% yield, and
(3aR,8aR)-ethyl 6â-methyl-2,6-dioxooctahydro-2H-cyclo-
hepta[b]furan-3R-carboxylate (9b) in 9% yield.
The stereochemistry of the substituent at C-3 of these
compounds was deduced to be R-orientation by the fact
that NOE between C3-H and C3a-H was not observed. The
stereochemistry of the substituent at C-3 could not be
determined by the coupling constant because this value
was largely influenced by the mode of substitution at C-8
and the conformation of seven-membered as well as
γ-lactone rings.34 The stereochemistry of the substituent
at C-3 of 8a and 8b was finally determined by the fact
that the acid (HBr in acetic acid) or base (NaOEt in
EtOH) treatment of 8a and 8b gave the recovery of
starting material intactly. These experimental results
strongly suggested that the compounds 8a and 8b were
thermodynamically more stable than the corresponding
C3-epimers. The inspection of Dreiding model showed
that the compounds possessing the substituent of R-con-
figuration at C-3 were more stable than the correspond-
ing â-epimers which had serious steric interaction be-
tween the C3-substituent and the C3a-C4 bond.
The minor products 7a and 7b were generated by the
hydrogenolysis of C8-OH group under this condition. The
stereoselectivity of the cis γ-lactone moiety at the C-3a,8a
position vs the methyl group at the remote C-6 position
is 2:1 for the 8-deoxy derivatives 7b and 7a , 5:1 for
8-hydroxy derivatives 8b and 8a , and 2:1 for 8-oxo
derivatives 9b and 9a , respectively, and the syn products
were predominantly produced. The ratio of 8-deoxy
derivatives 7a and 7b vs the 8-oxygenated compounds
(8-hydroxy derivatives 8a and 8b plus 8-oxo derivatives
9a and 9b) is 1:2.3. The ratio depended on the pressure
of H2, and the yield of 8-deoxy derivatives (7a and 7b)
was increased to 50% and the yield of 8-oxygenated
derivatives (8a , 8b, 9a , and 9b) was decreased to 32%
at 30 atm.
Although the yield of desired product 8b was moderate
and accompanied by five byproducts, 8b was easily
separated from the mixture by column chromatography
and conveniently functionalized for the syntheses of a
wide variety of natural products possessing seven-
membered ring.33
Ch em ica l Cor r ela tion a n d Ster eoch em istr y of th e
P r od u cts of Ca ta lytic Hyd r ogen a tion of 6. The
stereochemistry of the products was determined by the
following chemical transformation and the analyses of
their NMR spectra. Oxidation of 8a and 8b with PCC
The stereochemistry of the hydroxyl group at C-8 of
8a and 8b was deduced to be the â-configuration from
the values of the coupling constant between C8-H and
C8a-H (J ) 1.5 and 1.9 Hz, respectively) and the result
of NOE experiments.
The stereochemistry of the methyl group at the C-6
position of 9b was deduced to be the â-orientation from
the fact that an NOE was observed between C6-H and
C8a-H. The result of this NOE experiment and the
chemical correlation between 8b and 9b suggested that
the stereochemistry of the C-6 methyl group of 8b was
also the â-orientation. Since two pairs of compounds, (8a ,
8b) and (9a , 9b), are stereoisomeric concerning the
methyl group at C-6 from the result of the analyses of
1H NMR spectra mentioned above, the C-6 methyl groups
of 8a and 9a must be in the R-configuration, opposite to
those of 8b and 9b. The 1H NMR spectrum of III34
resembles closely that of 8a and differs from that of 8b.
This observation as well as the result of NOE experi-
(33) We have already completed the syntheses of two ambrosano-
lides, hymenolin and parthenin from the intermediate C, and the
synthesis of the C-1-C-8 part of octalactins A and B (formal total
syntheses of these compounds) from intermediate B. These results
will appear in the following papers of this series.
(34) Ando, M.; Kataoka, N.; Yasunami, M.; Takase, K.; Hirata, N.;
Yanagi, Y. J . Org. Chem. 1987, 52, 1429.

Synthetic Intermediates for Pseudoguaianolides
J . Org. Chem., Vol. 63, No. 4, 1998 923
Sch em e 3
F igu r e 4. NOESY experiment of 15 at 500 MHz.
Sch em e 4
ments suggests that the conformation of the seven-
membered ring of 8a is the chair form, the same as III,
and that of 8b is the boat form as depicted in Figure 3.
The stereochemistries of 7a and 7b were determined
by chemical correlation with 8a and 8b (Scheme 3).
Hydrolysis of an inseparable mixture of 7a and 7b (1:2)
with a 1 M aqueous solution of KOH in ethanol followed
by treatment with Et2NH and 35% formalin in acetic acid
gave R-methylene γ-lactones 11a and 11b in 23% and
48% yields. Reduction of 11a with NaBH4 gave an
epimeric mixture of R-methyl γ-lactones, 12a and 12b,
in 17% and 57% yields, respectively. Since the treatment
of 12b with 1 M NaOMe in MeOH gave a 9.1:1 mixture
of 12a and 12b, the former was found to be the thermo-
dynamically more stable 3R-methyl γ-lactone derivative.
Analogously, reduction of 11b with NaBH4 in MeOH
gave 13b as the sole isolated product in 89% yield. Since
the treatment of 13b with 1 M NaOMe in MeOH gave a
14.2:1 mixture of 13a and 13b, it was found that 13a
was the thermodynamically more stable 3R-isomer and
13b was the thermodynamically less stable 3â-isomer.
Catalytic hydrogenation of 17b in a solution of benzene
and ethanol in the presence of (Ph3P)3RhCl gave 13b.
From this chemical correlation, the stereochemistry of
the methyl group at C-6 of 7a and 7b was assigned to be
the R- and â-orientation, respectively.
Syn th eses of th e Com m on Syn th etic In ter m ed i-
a tes of Typ es A, B, a n d C fr om 8b. Treatment of 8b
with 2.8 molar equiv of NaH in THF in the presence of
0.03 molar equiv of imidazole followed by 5 molar equiv
of CS2 and CH3I resulted in concomitant introduction of
the methyl group at C-3 and transformation of the C-8
hydroxyl group into a (methylthio)(thiocarbonyl)oxy group
to give xanthate ester 14 (Scheme 4) in 91% yield.35 The
stereochemistry of the newly introduced methyl group
at C-3 was deduced to be the R-configuration by the
consideration that the reagent approached from the less
hindered convex R-face of the enolate anion of the
substrate and finally confirmed by an NOESY experi-
ment (Figure 4).
The pyrolysis of 14 at 200 °C under reduced pressure
gave the desired 7,8-unsaturated γ-lactone 15 regiose-
lectively in 94% yield. Hydrolysis of 15 with a 1 M
aqueous solution of KOH in ethanol and successive
thermal decarboxylation of the carboxylic acid 16 under
reduced pressure gave a mixture of stereoisomers con-
cerning C-3, 17a and 17b, in 34% and 57% yields,
respectively. Since the treatment of 17b with 1 M
NaOMe in methanol gave an 8.8:1 mixture of 17a and
17b, it was found that 17a was the thermodynamically
more stable 3R-methyl γ-lactone and 17b was the ther-
modynamically less stable 3â-methyl γ-lactone.
Reduction of 17b with LiAlH4 in ether gave the diol
18 in 98% yield (Scheme 5). Acetylation of 18 with Ac2O
and pyridine gave the desired monoacetate 20 in 58%
yield accompanied by the undesired diacetate 19 in 23%
yield. Since the latter was hydrolyzed with 1 M KOH in
ethanol to give 18 in a quantitative yield, the undesired
diacetate 19 could be recycled to 20. Oxidation of 20 with
MnO2 in CHCl3 gave the enone 21 in 95% yield. No
change in configuration was observed in these three
steps, and the stereochemistry at C-1′ of 18, 19, 20, and
21 is the â-configuration.
Analogously reduction of 17a with LiAlH4 in ether gave
the diol 22 in 92% yield. Acetylation of 22 with Ac2O
and pyridine gave the desired monoacetate 24 in 66%
yield accompanied by the undesired diacetate 23 in 32%
yield. The latter was recycled to 24 by hydrolysis and
subsequent acetylation of resulting 22. Oxidation of 24
with MnO2 in CHCl3 gave the enone 25 in 98% yield. The
stereochemistry at C-1′ of 22, 23, 24, and 25 is the
R-configuration and opposite to that of the corresponding
18, 19, 20, and 21.
Then we attempted the selective silylation of the
primary hydroxyl group of 22. Silylation of 22 with
t-BuMe2SiCl in DMF in the presence of imidazole gave
(35) Barton, D. H. R.; McCombie, S. W. J . Chem. Soc., Perkin Trans.
1 1975, 1574.

924 J . Org. Chem., Vol. 63, No. 4, 1998
Shimoma et al.
Sch em e 5
Sch em e 6
more stable Eu(fod)3 complex than those of the (S)-(-)-
MTPA ester of (1′R)-carbinol, (-)-29.37 From the chemi-
cal shift and integration values of -OMe signals of (S,R)
and (S,S) Mosher’s esters, the stereochemistry of C-1′ and
the enantiomeric excess of (-)-22 were determined to be
R and 89% ee. Since the relative stereochemistry of (()-
22 has already been determined, the absolute configura-
tions of (+)- and (-)-22 were established as depicted in
Scheme 6. This conclusion was also supported by the
observed positive sign of the CD curve of p-bromoben-
zoate of (+)-24, which is in agreement with the expected
sign from the exiton chirality rule applied to cyclic allylic
alcohols.38
the desired monosilyl ether 27 in 91% yield accompanied
by disilyl ether 26 in 8% yield. Oxidation of 27 with
MnO2 in CHCl3 gave the desired enone 28 in a quantita-
tive yield.
The acetate, (+)-24 ([R]25 +38.0), was hydrolyzed by
Syn th eses of th e Op tica lly Active Com p ou n d s
(+)- a n d (-)-22, (+)- a n d (-)-24, a n d (+)- a n d (-)-25.
The optical resolution of (()-22 was achieved by enzy-
matic acetylation (Scheme 6). The most promising
results were obtained with Lipase PS in an alcohol-
lipase-sieves ratio (3.7:1.2:1) in vinyl acetate solution.
The resolution was carried out at 23 °C, and the diol-
monoacetate ratio was monitored by GC. The enantio-
meric excess (ee) of the diol 22 and the monoacetate 24
in the reaction course was determined after the separa-
tion of a part of the reaction mixture by HPLC. The
D
a 1 M aqueous solution of KOH to give (+)-22 ([R]25
D
+15.6), which was converted to the corresponding (S)-
(-)-MTPA ester, (-)-30. By the analogous method
mentioned above, the stereochemistry of C-1′ and the
enantiomeric excess of (+)-24 were determined to be S
and 77% ee.
Oxidation of (+)-24, which was obtained by the above-
mentioned enzymatic acetylation, with MnO2 in CHCl3
gave (-)-25 ([R]20 -108.4) in 91% yield (Scheme 7).
D
Analogously, acetylation of (-)-22, which was obtained
by the enzymatic acetylation mentioned above as the
recovered diol, and subsequent oxidation of the resulting
monoacetate (+)-24 ([R]25 +46.1, 93% ee) and the diol
D
(-)-22 ([R]25 -13.0, 70% ee) were obtained in 48% and
D
monoacetate (-)-24 ([R]25 -45.3) with MnO2 in CHCl3
52% yields, respectively, after 4.5 h. If we desired higher
optical purity of diol (-)-22, we could get the desired (-)-
22 ([R]25D -16.5, 89% ee) in 44% yield by the prolongation
of the reaction time accompanied by monoacetate (+)-24
D
gave (+)-25 ([R]20 +129.6) in 55% overall yield.
D
Biologica l Activities. 1. Cell Gr ow th In h ibitor y
Activity of Com p ou n d s to P -388 Lym p h ocytic Leu -
k em ia .39 The compounds 11a and 11b showed signifi-
([R]25 +38.0, 77% ee) in 52% yield. The absolute
D
configuration and the optical yield were determined as
follows.
(37) (a) Yasuhara, F.; Yamaguchi, S. Tetrahedron Lett. 1977, 4085.
(b) Yamaguchi, S. Asymmetric Synthesis, Vol. 1; Morrison, J . D., Ed.;
Academic Press: 1983, pp 125-152. (c) Sugimoto, Y.; Sakita, T.,
Moriyama, Y.; Murae, T.; Tsuyuki, T.; Takahashi, T. Tetrahedron Lett.
1978, 4285. (d) Sugimoto, Y.; Sakita, T.; Ikeda, T.; Moriyama, Y.;
Murae, T.; Tsuyuki, T.; Takahashi, T. Bull. Chem. Soc. J pn. 1979, 52,
3027. (e) Sugimoto, Y.; Tsuyuki, T.; Moriyama, Y.; Takahashi, T. Bull.
Chem. Soc. J pn. 1980, 52, 3027.
(38) (a) Harada, N.; Iwabuchi, J .; Yokota, Y.; Uda, H.; Nakanishi,
K. J . Am. Chem. Soc. 1981, 103, 5590. (b) Nakanishi, K.; Berova, N.
Circular Dichroism, Principles and Applications, Chapter 10; Nakan-
ishi, K., Berova, N., Woody, R. W., Eds.; VCP Publishers: Cambridge,
U.K., 1994, and references cited therein.
(-)-22 ([R]25 -16.5) was converted to the correspond-
D
ing (S)-(-)-MTPA ester, (-)-29, according to Mosher’s
method36 (Scheme 6). In the NMR spectra, the magni-
tude of lanthanide induced shift by Eu(fod)3 for the OMe
group of the (S)-(-)-MTPA ester of (1′S)-carbinol is
expected to be larger than that of (1′R)-carbinol, since
the (S)-(-)-MTPA ester of (1′S)-carbinol, (-)-30, forms a
(36) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512.

Synthetic Intermediates for Pseudoguaianolides
J . Org. Chem., Vol. 63, No. 4, 1998 925
codes are as follows: A, 30 × 2 cm i.d. stainless column packed
with 15-25 µm silica gel; B, 25 × 0.8 cm i.d. stainless column
packed with 10 µm silica gel; C, 30 × 1 cm i.d. glass column
packed with 10 µm silica gel; D, 25 × 0.4 cm i.d. stainless
column packed with 10 µm silica gel. Silica gel (230-400
mesh) was employed for flash chromatography, and 70-230
mesh silica gel was employed for column chromatography. To
describe the conditions of column and flash chromatographies,
the weight of silica gel, column i.d., and solvent are designated
in this order.
Sch em e 7
7-Iod o-4-m eth yltr op olon e (2). Into a stirred solution of
4-methyltropolone (50 g, 0.367 mol) and K2CO3 (104.7 g, 0.754
mol) in H2O (750 mL) was slowly added a solution of I2 (95.3
g, 0.376 mol) and KI (102.8 g, 0.616 mol) in H2O (300 mL) at
0 °C. The mixture was stirred at rt for 20 h and filtered. The
crystalline material separated by filtration was dissolved in
CHCl3 (500 mL) and stirred for 1 h with a mixture of NaHSO3
(3.5 g, 19.7 mmol), 6 M H2SO4 (290 mL), and H2O (80 mL).
The chloroform layer was dried (Na2SO4) and concentrated.
The residue was dissolved in MeOH (200 mL) and treated with
activated carbon (10 g) at the refluxing temperature. The
mixture was filtered and concentrated to give spectroscopically
pure 2 (46.0 g, 48%).
cant cell growth inhibitory activity against murine
lymphocytic leukemia (P-388) in vitro. The growth
inhibition ratios of 11a and 11b are 50% and 69% at a
concentration of 1 µg/mL, respectively.
2. Con tr ol of Cr op Disea ses.40 The preventive and
curative activities in controlling crop diseases were
examined by pot test. The R-methylene γ-lactones 11a
and 11b showed significant preventive activities in
controlling damping-off of cucumber caused by Pythium
aphanidermatum. The evaluation of disease control is
70-80% for 11a and 100% for 11b at 500 ppm.
3. Her bicid e Test.41 The R-methylene γ-lactone 11b
showed significant growth inhibitory activity against
Echinochloa flumentacea (J apanese millet) and Avena
sativa (oat) in field. The evaluation of the growth
inhibition was 100% for E. flumentacea and 70-80% for
A. sativa at a concentration of 8 g per 100 m2 by
posttreatment.
The aqueous layer was also treated with a mixture of
NaHSO3 (10.0 g, 56.2 mmol) and 6 M H2SO4 (200 mL) at pH
1-2 and extracted with CHCl3. The extracts were treated in
the above-mentioned manner to give additional 2 (35.8 g, 37%)
as a spectroscopically pure crystalline material.
The analytical sample of 2 was obtained by recrystallization
from Et2O as pale brown prisms: mp 118-120 °C; IR (CHCl3)
1
3012, 1612 cm-1; H NMR δ 2.45 (3 H, s, C4-Me), 6.59 (1 H,
dd, J ) 10.6, 1.0 Hz, C5-H), 7.26 (1 H, br s, C3-H), 8.32 (1 H,
d, J ) 10.6 Hz, C6-H); 13C NMR δ 14.7 (q, C4-Me), 106.5 (s,
C-7), 121.5 (d, C-3), 127.8 (d, C-5), 147.9 (d, C-6), 150.1 (s, C-4),
161.6 (s, C-2), 172.2 (s, C-1). Anal. Calcd for C8H7O2I: C,
36.67; H, 2.69. Found: C, 36.86; H, 2.69.
7-Iod o-4-m eth yl-2-(tosyloxy)tr op on e (3). Into a stirred
solution of 2 (90.0 g, 0.343 mol) in pyridine (850 mL) was added
TsCl (115.5 g, 0.515 mol) at 0 °C. The solution was stirred at
0 °C for 3 h and then at rt for 11 h and poured into cold water
(10 L) under vigorous stirring. The pale brown crystalline
material was collected by filtration under reduced pressure
and dried in a desiccator under reduced pressure to give
spectroscopically pure 3 (136.2 g, 0.327 mol, 95%) as a
crystalline material. A part of this crystalline material was
recrystallized from Et2O to give pale brown microcrystals: mp
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r e. All melting points
are uncorrected. 1H NMR spectra were recorded at 200 MHz
and 13C NMR spectra at 50 MHz in CDCl3 unless otherwise
stated. The assignments of 1H NMR spectra were determined
by decoupling and H-H COSY experiments. The assignments
of 13C NMR spectra were determined by DEPT, C-H COSY,
HMQC, and HMBC experiments. Reactions were run under
an atmosphere of N2 or Ar. THF and ether were distilled from
sodium benzophenone ketyl. CHCl3 was dried over CaCl2 and
distilled. Benzene was dried over CaCl2, distilled, and stored
in a bottle with Na wire equipped with a mercury seal.
CH2Cl2, DMF, and pyridine were distilled from CaH2. MeOH
and EtOH were distilled from Mg(OMe)2 and Mg(OEt)2,
respectively. To describe HPLC conditions, the column,
solvent, and flow rate are designated in this order. The column
1
140-142 °C; IR (KBr) 1604, 1380, 1360, 1182 cm-1; H NMR
δ 2.36 (3 H, s, C4-Me), 2.46 (3 H, s, Ts-Me), 6.60 (1 H, dd, J )
9.6, 1.3 Hz, C5-H), 7.36 (2 H, d, J ) 8.4 Hz, m-Hs of Ph), 7.44
(1 H, d, J ) 1.3 Hz, C3-H), 7.94 (2 H, d, J ) 8.4 Hz, o-Hs of
Ph), 8.38 (1 H, d, J ) 9.6 Hz, C6-H); 13C NMR δ 21.8 (q, Ts-
Me), 26.2 (q, C4-Me), 122.9 (s, C-7), 128.7 (d, C-2′ of Ph), 129.7
(d, C-3′ of Ph), 131.6 (d, C-5), 132.9 (s, C-1′ of Ph), 133.1 (d,
C-3), 143.2 (s, C-4), 145.7 (s, C-4′ of Ph), 146.9 (d, C-6), 147.1
(s, C-2), 174.6 (s, C-1). Anal. Calcd for C15H13O4SI: C, 43.28;
H, 3.14. Found: C, 43.55; H, 3.26.
4-Meth yl-2-(tosyloxy)tr op on e (4). A mixture of 3 (50.0
g, 0.120 mol), 10% Pd-C (5.0 g), NaOAc (15.1 g, 0.180 mol),
and MeOH (1.5 L) was stirred vigorously under 1 atm of H2.
Hydrogen uptake (3.2 L, 0.14 mol) was ceased after 80 min,
and the mixture was filtered through Celite. The filtrate was
concentrated to 300 mL and poured into water (1.3 L). The
crystalline material was filtered under reduced pressure to
give spectroscopically pure 4 (31.1 g, 89%) as a pale brown
crystalline material, a part of which was recrystallized from
Et2O to give pale brown microcrystals: mp 110 °C; IR (KBr)
(39) Murine lymphocytic leukemia cells (p388) were incubated with
compounds at 37 °C in a humidified atmosphere of 5% CO2 for 48 h.
After incubation, the cell number was counted with a Coulter counter,
and the cell growth inhibition ratio (%) was calculated according to
T - C0
C - C0
cell growth inhibition ratio ) 1 -
× 100
(
)
where T ) cell count after culture with compound, C ) cell count after
culture without compound, and C0 ) cell count at the start of culture.
(40) Test samples, which were formulated as emulsifiable in water,
were applied by spraying to the plants or drenching to soil before or
after incubation. The plants were inoculated with spores or hypa of
fungal pathogens. After incubation, disease severity of test plants was
observed under desirable conditions for 4-15 days. The tested crop
diseases are as follows; blast of rice, sheath blight of rice, powdery
mildew of wheat, damping off of cucumber, dawny mildew of grape,
late blight of tomato, scab of apple.
1636, 1602, 1584, 1366, 1192 cm-1 1H NMR δ 2.39 (3 H, s,
;
C4-Me), 2.45 (3 H, s, Ts-Me), 6.94 (1 H, ddd, J ) 8.0, 2.8, 1.4
Hz, C5-H), 7.02 (1 H, dd, J ) 12.0, 2.8 Hz, C7-H), 7.11 (1 H, d,
J ) 12.0, 8.0 Hz, C6-H), 7.36 (2 H, d, J ) 8.4 Hz, m-Hs of Ph),
7.39 (1 H, d, J ) 1.4 Hz, C3-H), 7.95 (2 H, d, J ) 8.4 Hz, o-Hs
of Ph); 13C NMR δ 21.8 (q, Ts-Me), 26.5 (q, C4-Me), 128.6 (d,
C-2′ of Ph), 129.6 (d, C-3′ of Ph), 133.0 (d, C-5), 133.5 (s, C-1′
of Ph), 133.8 (d, C-3), 136.6 (d, C-7), 138.8 (d, C-6), 142.3 (s,
(41) In 8-10 days after sowing, test samples, which were formulated
as emulsifiable in water, were applied by spraying to the plants and
the degree of the growth inhibition of plants was observed.

926 J . Org. Chem., Vol. 63, No. 4, 1998
Shimoma et al.
C-4), 145.4 (s, C-4′ of Ph), 153.8 (s, C-2), 178.8 (s, C-1). Anal.
Calcd for C15H14O4S: C, 62.05; H, 4.86. Found: C, 61.91; H,
4.86.
53.5 (d, C-3), 62.3 (t, Et-CH2), 71.5 (d, C-8), 85.5 (d, C-8a), 167.9
(s), 171.8 (s). Anal. Calcd for C13H20O5: C, 60.92; H, 7.87.
Found: C, 60.68; H, 8.21.
Eth yl 6-Meth yl-2-oxo-2H-cycloh ep ta [b]fu r a n -3-ca r box-
yla te (5) a n d Eth yl 8-Hyd r oxy-6-m eth yl-2-oxo-2H-cyclo-
h ep ta [b]fu r a n -3-ca r boxyla te (6). To a stirred solution of
4 (44.0 g, 0.152 mol) and diethyl malonate (45.3 mL, 0.300
mol) in EtOH (200 mL) was added a 1 M solution of NaOEt in
EtOH (300 mL, 0.300 mol). The solution was stirred at 0 °C
for 20 min, stored in a refrigerator overnight, poured into
water (2 L), and extracted with benzene. The combined
extracts were washed with a saturated aqueous solution of
NaCl, dried (Na2SO4), and concentrated to 50 mL. The residue
was diluted with ether to give spectroscopically pure 5 (1.50
g, 4%). A part of 5 was recrystallized from MeOH to give
yellow prisms: mp 144 °C. Anal. Calcd for C13H12O4: C,
67.23; H, 5.21. Found: C, 67.29; H, 5.29.
The aqueous layer was adjusted at pH 3 with 6 M HCl (90
mL) to form a yellow crystalline material, which was separated
by filtration, washed with water, and dried to give spectro-
scopically pure 6 (32.9 g, 88%), a part of which was recrystal-
lized from EtOH to give yellow microcrystals: mp 186 °C; IR
(KBr) 3460, 1745, 1734, 1684 cm-1; 1H NMR (DMSO-d6) δ 1.29
(3 H, t, J ) 7.1 Hz, Et-CH3), 2.50 (3 H, s, C6-Me), 4.23 (2 H, q,
J ) 7.1 Hz, Et-CH2), 7.48 (1 H, br s, C7-H), 7.55 (1 H, d, J )
11.4 Hz, C5-H), 8.62 (1 H, d, J ) 11.4 Hz, C4-H); 13C NMR
(DMSO-d6) δ 14.3 (q, Et-CH3), 26.8 (q, C6-Me), 59.0 (t, Et-CH2),
88.8 (s, C-8a), 129.3 (d, C-4), 130.4 (d, C-7), 138.9 (d, C-5), 141.9
(s), 146.2 (s, C-6), 148.7 (s), 150.7 (s), 163.6 (s), 164.1 (s). Anal.
Calcd for C13H12O5: C, 62.90; H, 4.87. Found: C, 63.10; H,
4.94.
(()-(3a r,8a r)-E t h yl 8â-((Met h ylt h io)(t h ioca r b on yl)-
oxy)-3r,6â-d im eth yl-2-oxoocta h yd r o-2H-cycloh ep ta [b]fu -
r a n -3â-ca r boxyla te (14). A solution of 8b (930 mg, 3.63
mmol) in THF (45 mL) containing imidazole (7.6 mg, 0.11
mmol) was slowly added to NaH [prepared from 55% NaH
dispersion in mineral oil (455 mg, 1.02 mmol) by being washed
with pentane] and stirred at 40 °C for 2.5 h. Then CS2 (1.11
mL, 18.3 mmol) was added into the mixture, and the solution
was stirred at 50 °C for 30 min. Finally MeI (1.14 mL, 18.2
mmol) was added into the mixture, and the solution was
stirred at 50 °C for 30 min. After cooling, the reaction was
quenched by the addition of AcOH (0.6 mL). The mixture was
worked up as usual to give an oily crude product (1.43 g), which
was chromatographed over silica gel [45 g; 3.1 cm i.d.; EtOAc-
hexane (3:7)] to give 14 (1.19 g, 91%) as colorless prisms
(ether-hexane): mp 107-108 °C; IR (CHCl3) 1790, 1734 cm-1
;
1H NMR δ 0.97 (3 H, d, J ) 6.5 Hz, C6-Me), 1.32 (3 H, t, J )
7.2 Hz, Et-CH3), 1.63 (3 H, s, C3-Me), 1.89 (1 H, m, C7-H), 2.08
(1 H, m, C7-H), 2.58 (3 H, s, OCS2CH3), 2.63 (1 H, m, C3a-H),
4.25 (1 H, dq, J ) 11.7, 7.2 Hz, Et-CH2), 4.29 (1 H, dq, J )
11.7, 7.2 Hz, Et-CH2), 4.99 (1 H, br d, J ) 6.7 Hz, C8a-H), 5.95
(1 H, dd, J ) 11.4, 1.7 Hz, C8-H); 13C NMR δ 14.0 (q, Et-CH3),
18.9 (q, C3-Me), 21.5 (q, C6-Me), 22.7 (q, OCS2CH3), 27.2 (t),
31.6 (t), 33.1 (d, C-6), 35.1 (t), 47.2 (d, C-3a), 55.0 (s, C-3), 61.8
(t, Et-CH2), 80.9 (d), 81.4 (d), 169.1 (s, CO2Et), 174.8 (s, C-2),
215.2 (s, OCS2CH3). Anal. Calcd for C16H24O5S2: C, 53.31;
H, 6.71. Found: C, 53.76; H, 6.92.
(()-(3a r,8a r) Eth yl 3r,6â-Dim eth yl-2-oxo-3,3a ,4,5,6,8a -
h exa h yd r o-2H-cycloh ep t a [b]fu r a n -3â-ca r b oxyla t e (15).
Xanthate 14 (2.14 g, 5.94 mmol) in Ku¨gelrohr distillation
apparatus was heated at 200 °C for 10 h under reduced
pressure (40 Torr) and then distilled at this temperature at 2
Torr to give a pale yellow oil, which was purified by flash
chromatography [15 g; 2.2 cm i.d.; EtOAc-hexane (1:9)] to give
a crystalline material, which was recrystallized from a mixture
of EtOAc-hexane to give 15 (1.41 g, 94%) as colorless
needles: mp 53-54 °C; IR (CHCl3) 1775, 1742 cm-1; 1H NMR
δ 1.06 (3 H, d, J ) 6.8 Hz, C6-Me), 1.27 (3 H, t, J ) 7.2 Hz,
Et-CH3), 1.48 (3H, s, C3-Me), 2.37 (1 H, m, C6-H), 2.41 (1 H,
ddd, J ) 13.0, 9.2, 4.0 Hz, C3a-H), 4.14 (1 H, dq, J ) 11.0, 7.2
Hz, Et-CH2), 4.21 (1 H, dq, J ) 11.0, 7.2 Hz, Et-CH2), 5.34 (1
H, ddd, J ) 10.5, 5.5, 3.0 Hz, C7-H), 5.40 (1 H, dddd, J ) 9.2,
3.0, 3.0, 1.4 Hz, C8a-H), 5.64 (1 H, ddd, J ) 10.5, 3.3, 2.2 Hz,
C8-H); 13C NMR δ 14.0 (q, Et-CH3), 20.6 (q, C3-Me), 21.4 (q,
C6-Me), 22.8 (t), 29.2 (t), 31.3 (d, C-6), 47.3 (d, C-3a), 54.1 (s,
C-3), 61.7 (t, Et-CH2), 78.5 (d, C-8a), 127.2 (d, C-8), 132.8 (d,
C-7), 169.5 (s, CO2Et), 176.1 (s, C-2). Anal. Calcd for
Ca ta lytic Hyd r ogen a tion of 6. A mixture of 6 (10.0 g,
40.3 mmol), PtO2 (1.8 g), and activated carbon (7.2 g) in EtOH
(590 mL) was stirred vigorously under 1 atm of hydrogen.
Hydrogen uptake (6.5 L) ceased after 2 h and 50 min, and the
mixture was filtered. The filtrate was concentrated under
reduced pressure to give an oily crude product (ca. 12 g), which
was subsequently chromatographed over silica gel [350 g; 6.5
cm i.d.; EtOAc-hexane (2:8)].
The first fraction gave an inseparable 1:2 mixture of (()-
(3aR,8aR)-ethyl 6R-methyl-2-oxooctahydro-2H-cyclohepta[b]fu-
ran-3R-carboxylate (7a ) and (()-(3aR,8aR)-ethyl 6â-methyl-2-
oxooctahydro-2H-cyclohepta[b]furan-3R-carboxylate (7b) (2.8
g, 29%) as a colorless oil. The elemental analysis of the
mixture was performed instead of those of pure 7a and 7b.
Anal. Calcd for C13H20O4: C, 64.98; H, 8.39. Found: C, 64.77;
H, 8.62.
The second fraction gave spectroscopically pure (()-(3aR,8aR)-
ethyl 8â-hydroxy-6R-methyl-2-oxooctahydro-2H-cyclohepta[b]-
furan-3R-carboxylate (8a ) (970 mg, 9%) as
a crystalline
material, which was recrystallized from a mixture of EtOAc-
hexane to give colorless needles: mp 78-80 °C. Anal. Calcd
for C13H20O5: C, 60.92; H, 7.87. Found: C, 60.80; H, 8.16.
The third fraction gave a 1:2 mixture of (()-(3aR,8aR)-ethyl
6R-methyl-2,8-dioxooctahydro-2H-cyclohepta[b]furan-3R-car-
boxylate (9a ) and (()-(3aR,8aR)-ethyl 6â-methyl-2,8-dioxooc-
tahydro-2H-cyclohepta[b]furan-3R-carboxylate (9b) (1.33 g,
13%) as a crystalline material. The repeated separation of this
mixture by HPLC [column D; EtOAc-hexane (3:7); 3.0 mL/
min] gave pure 9b (faster running) and 9a (slower running).
9a : colorless prisms (CHCl3): mp 55-57 °C. Anal. Calcd for
C
14H20O4: C, 66.64; H, 7.99. Found: C, 66.68; H, 8.13.
(()-(3a r,8a r)-3r,6â-Dim eth yl-2-oxo-3,3a ,4,5,6,8a -h exa -
h yd r o-2H-cycloh ep ta [b]fu r a n -3â-ca r boxylic Acid (16). A
solution of 15 (3.52 g, 14.0 mmol) and a 1 M aqueous solution
of KOH (28 mL) in ethanol (55 mL) was stirred at rt for 4 h,
poured into a mixture of 2 M aqueous solution of HCl (28 mL)
and a saturated aqueous solution of NaCl (250 mL), and
extracted with EtOAc. The combined extracts were treated
in the usual manner to give 16 (3.11 g, 99%) as colorless
needles (CHCl3): mp 109-111 °C; IR (KBr) 3500-2300, 1775,
1715 cm-1; 1H NMR δ 1.07 (3 H, d, J ) 6.8 Hz, C6-Me), 1.44 (3
H, s, C3-Me), 2.45 (1 H, m, C6-H), 3.02 (1 H, ddd, J ) 10.5,
7.8, 4.9 Hz, C3a-H), 5.40-5.62 (3 H, C7-, C8-, and C8a-Hs), 8.91
(1 H, br s, CO2H); 13C NMR δ 16.5 (q, C3-Me), 20.9 (t), 21.2 (q,
C6-Me), 30.0 (t), 31.1 (d, C-6), 44.2 (d, C-3a), 54.3 (s, C-3), 80.1
(d, C-8a), 125.0 (d, C-8), 135.0 (d, C-7), 175.3 (s), 176.1 (s). Anal.
Calcd for C12H16O4: C, 64.27; H, 7.19. Found: C, 64.00; H,
7.35.
C
13H18O5: C, 61.41; H, 7.13. Found: C, 61.11; H, 7.11. 9b:
colorless needles (EtOAc-hexane): mp 71-72 °C. Anal.
Calcd for C13H18O5: C, 61.41; H, 7.13. Found: C, 61.13; H,
7.09.
The fourth fraction gave spectroscopically pure (()-(3aR,8aR)-
ethyl 8â-hydroxy-6â-methyl-2-oxooctahydro-2H-cyclohepta[b]-
furan-3R-carboxylate (8b) (4.61 g, 45%) as colorless plates
(EtOAc-hexane): mp 58-60 °C; IR (CHCl3) 3500, 1782, 1736
(()-(3a r,8a r)-3r,6â-Dim eth yl-3,3a ,4,5,6,8a -h exa h yd r o-
2H-cycloh ep ta [b]fu r a n -2-on e (17a ) a n d (()-(3a r,8a r)-
3â,6â-Dim et h yl-3,3a ,4,5,6,8a -h exa h yd r o-2H -cycloh ep t a -
[b]fu r a n -2-on e (17b). The carboxylic acid 16 (517 mg, 2.31
mmol) was heated in a Ku¨gelrohr distillation apparatus at 145
°C (90 Torr). After evolution of CO2 ceased in 35 min, the
residue was distilled under reduced pressure (1 Torr) at 145
1
cm-1; H NMR δ 0.99 (3 H, d, J ) 6.1 Hz, C6-Me), 1.32 (3 H,
t, J ) 7.2 Hz, Et-CH3), 3.16 (1 H, dddd, J ) 8.5, 6.1, 6.1, 4.7
Hz, C3a-H), 3.46 (1 H, d, J ) 6.1 Hz, C3-H), 4.06 (1 H, br d, J
) 8.6 Hz, C8-H), 4.26 (2 H, q, J ) 7.2 Hz, Et-CH2), 4.95 (1 H,
dd, J ) 8.5, 1.9 Hz, C8a-H); 13C NMR δ 14.1 (q, Et-CH3), 22.9
(q, C6-Me), 27.7 (t), 31.7 (t), 32.3 (d, C-6), 39.4 (t), 39.8 (d, C-3a),

Synthetic Intermediates for Pseudoguaianolides
J . Org. Chem., Vol. 63, No. 4, 1998 927
°C to give a 1:1.7 mixture of 17a and 17b (513 mg), which
was separated by HPLC [column A; EtOAc-hexane (1:9); 28.5
mL/min].
Hyd r olysis of (()-19. A solution of 19 (126 mg, 0.468
mmol) and a 1 M aqueous solution of KOH (0.8 mL) in ethanol
(2 mL) was stirred at 21 °C for 1 h and worked up as usual to
give 18 (86 mg, 100%) as colorless prisms.
The first peak (tR 7.4 min) gave 17a (141 mg, 34%) as
colorless oil: IR (CHCl3) 3028, 1772, 1668 cm-1 1H NMR δ
;
(()-7â-(2-Acet oxy-1â-m et h ylet h yl)-4â-m et h yl-2-cyclo-
h ep ten -1-on e (21). A mixture of 20 (226 mg, 1.00 mmol),
MnO2 (1.15 g), and CHCl3 (11 mL) was stirred for 23 h and
filtered through Celite under reduced pressure. The filtrate
was concentrated to give spectroscopically pure 21 (214 mg,
95%) as a colorless oil: IR (CHCl3) 1730, 1678 cm-1; 1H NMR
(90 MHz) δ 0.97 (3 H, J ) 6.6 Hz, C1′-Me), 1.17 (3 H, d, J )
7.4 Hz, C4-Me), 2.02 (3 H, s, Ac), 2.50 (3 H, m, C1′-, C7-, and
C4-Hs), 4.03 (2 H, d, J ) 5.6 Hz, C2′-H), 5.91 (1 H, dd, J )
12.0, 2.6 Hz, C2-H), 6.61 (1 H, dd, J ) 12.0, 3.2 Hz, C3-H);
EIMS m/e (relative intensity) 224 (M+, 2.4), 165 (12.6), 124
(100).
1.07 (3 H, d, J ) 7.0 Hz, C6-Me), 1.24 (3 H, d, J ) 6.9 Hz,
C3-Me), 2.25-2.38 (2 H, C3-, and C3a-Hs), 2.40 (1 H, m, C6-H),
5.32 (1 H, ddd, J ) 8.0, 4.3, 2.8 Hz, C8a-H), 5.41 (1 H, ddd, J
) 11.0, 4.3, 2.3 Hz, C7-H), 5.53 (1 H, ddd, J ) 11.0, 2.8, 1.8
Hz, C8-H); 13C NMR δ 14.3 (q, C3-Me), 21.8 (q, C6-Me), 26.5
(t), 29.8 (t), 32.6 (d, C-6), 40.6 (d), 44.6 (d), 79.4 (d, C-8a), 126.4
(d, C-8), 135.0 (d, C-7), 179.3 (s, C-2). Anal. Calcd for
C
11H16O2: C, 73.30; H, 8.95. Found: C, 73.15; H, 9.14.
The second peak (tR 12.0 min) gave spectroscopically pure
17b (238 mg, 57%) as a colorless crystalline material, which
was recrystallized from EtOAc-hexane to give colorless
needles: mp 32.5-33.0 °C; IR (KBr) 3050, 1768 cm-1; 1H NMR
δ 1.04 (3 H, d, J ) 6.8 Hz, C6-Me), 1.18 (3 H, d, J ) 7.3 Hz,
C3-Me), 2.49 (1 H, m, C6-H), 2.65 (1 H, m, C3a-H), 2.86 (1 H,
dq, J ) 7.3, 7.3 Hz, C3-H), 5.24 (1 H, br dd, J ) 6.0, 2.0 Hz,
(()-7â-(2-Hyd r oxy-1r-m eth yleth yl)-4â-m eth yl-2-cyclo-
h ep ten -1â-ol (22). A solution of 17a (1.24 g, 6.88 mmol) in
ether (10 mL) was added into a mixture of LiAlH4 (261 mg,
6.88 mmol) and ether (30 mL). The mixture was refluxed
under stirring for 1 h and worked up as usual to give a crude
crystalline material (1.3 g), which was separated by column
chromatography [15 g; 2.3 cm i.d.; EtOAc-hexane (3:7)] to give
22 (1.16 g, 92%) as colorless needles (CHCl3): mp 74-76 °C;
C
8a-H), 5.47 (1 H, ddd, J ) 11,2, 5.2, 2.0 Hz, C7-H), 5.60 (1 H,
ddd, J ) 11.2, 2.0, 2.0 Hz, C8-H); 13C NMR δ 10.7 (q, C3-Me),
19.5 (t), 21.1 (q, C6-Me), 30.2 (d, C-6), 31.6 (t), 39.5 (d), 40.8
(d), 81.1 (d, C-8a), 124.6 (d, C-8), 135.8 (d, C-7), 178.6 (s, C-2).
Anal. Calcd for C11H16O2: C, 73.30; H, 8.95. Found: C, 72.93;
H, 8.94.
1
IR (KBr) 3250 (br) cm-1; H NMR δ 0.93 (3 H, d, J ) 6.8 Hz,
C1′-Me), 1.04 (3 H, d, J ) 7.1 Hz, C4-Me), 2.27 (1 H, m, C4-H),
3.45 (1 H, dd, J ) 11.4, 5.2 Hz, C2′-H), 3.80 (1 H, dd, J ) 11.4,
3.1 Hz, C2′-H), 4.62 (1 H, m, C1-H), 5.44 (1 H, ddd, J ) 11.2,
3.7, 2.0 Hz, C3-H), 5.65 (1 H, dddd, J ) 11.2, 4.5, 2.5, 1.0 Hz,
C2-H); 13C NMR δ 16.6 (q, C1′-Me), 23.3 (q, C4-Me), 30.0 (t),
30.6 (t), 33.9 (d), 34.2 (d), 44.4 (d, C-7), 67.2 (t, C-2′), 74.0 (d,
C-1), 134.5 (d, C-2), 136.6 (d, C-3). Anal. Calcd for C11H20O2:
C, 71.69; H, 10.94. Found: C, 71.89; H, 11.00.
Isom er iza tion of (()-17b. A solution of 17b (2.82 g, 15.7
mmol) in 1 M NaOMe/MeOH (50 mL) was stirred at rt for 4 h
and poured into a mixture of 2 M HCl (30 mL) and a saturated
aqueous solution of NaCl (70 mL). The mixture was worked
up as usual to give an oily crude product (2.80 g), which was
separated by HPLC [column A; EtOAc-hexane (1:9); 28.5 mL/
min].
Acetyla tion of (()-22. A solution of 22 (63.2 mg, 0.343
mmol) and acetic anhydride (43.4 µL, 0.446 mmol) in pyridine
(2 mL) was stirred for 29 h. Since recovered diol 22 was
detected by TLC, acetic anhydride (10 µL, 0.103 mmol) was
added into the reaction mixture, which was stirred for a
further 12 h. The reaction mixture was worked up as usual
to give a colorless oil (88 mg), which was separated by flash
chromatography (7.5 g; 1.6 cm i.d.).
The first peak (tR 6.6 min) gave 17a (2.49 g, 88%).
The second peak (tR 13.8 min) gave 17b (294 mg, 10%).
Con ver sion of (()-17b to (()-13b. The solution of 17b
(55.7 mg, 0.309 mmol), (Ph3P)3RhCl (14 mg, 0.015 mmol) in
benzene (2 mL), and EtOH (2 mL) was stirred under an H2
atmosphere. H2 uptake (12 mL) ceased after 5.4 h. The
reaction mixture was filtered, passed through short column
of silica gel (0.3 g), and purified by HPLC [column B; EtOAc-
hexane (1:9); 3.1 mL/min; tR 6.2 min] to give 13b (49.1 mg,
87%).
The faster running [EtOAc-hexane (1:9)] gave diacetate 23
(29.9 mg, 32%) as a colorless oil. Anal. Calcd for C15H24O4:
C, 67.14; H, 9.02. Found: C, 67.25; H, 9.14.
(()-7â-(2-Hyd r oxy-1â-m eth yleth yl)-4â-m eth yl-2-cyclo-
h ep ten -1â-ol (18). A solution of 17b (215 mg, 1.19 mmol) in
ether (2 mL) was added into a mixture of LiAlH4 (32 mg, 0.84
mmol) and ether (3 mL). The mixture was refluxed for 45 min
under stirring and worked up as usual to give a crude product,
which was purified by column chromatography [15 g; 2.0 cm
i.d.; EtOAc-hexane (1:1)] to give 18 (218 mg, 98%) as colorless
The slower running [EtOAc-hexane (3:7)] gave monoacetate
24 (50.9 mg, 66%) as a colorless oil: IR (CHCl3) 3620, 1730,
1
1250 cm-1; H NMR δ 0.96 (3 H, d, J ) 6.7 Hz, C1′-Me), 1.05
(3 H, d, J ) 7.2 Hz, C4-Me), 2.06 (3 H, s, Ac), 2.29 (1 H, m,
C4-H), 4.01 (1 H, dd, J ) 11.0, 7.1 Hz, C2′-H), 4.32 (1 H, dd, J
) 11.0, 4.3 Hz, C2′-H), 4.58 (1 H, br d, J ) 3.9 Hz, C1-H),
5.50 (1 H, ddd, J ) 11.2, 3.5, 1.6 Hz, C3-H), 5.68 (1 H, ddd, J
) 11.2, 4.9, 2.5 Hz, C2-H); 13C NMR δ 15.8 (q, C1′-Me), 21.0 (q,
Ac-CH3), 23.2 (q, C4-Me), 28.5 (t), 30.7 (t), 32.4 (d, C-1′), 33.8
(d, C-4), 43.4 (d, C-7), 68.6 (t, C-2′), 73.8 (d, C-1), 133.3 (d, C-2),
137.6 (d, C-3), 171.3 (s, Ac-CO); HREIMS m/e calcd for
prisms (EtOAc-hexane): mp 41-43 °C; IR (CHCl3) 3400 cm-1
;
1H NMR (90 MHz) δ 0.96 (3 H, d, J ) 7.1 Hz, C1′-Me), 1.07 (3
H, d, J ) 7.4 Hz, C4-Me), 2.32 (1 H, m, Wh/2 ) 18 Hz, C4-H),
3.42 (1 H, dd, J ) 11.4, 4.8 Hz, C2′-H), 3.61 (1 H, dd, J ) 11.4,
7.5 Hz, C2′-H), 4.35 (1 H, br d, J ) 4.2 Hz, C1-H), 5.60 (1 H,
dd, J ) 14.4, 2.7, C3-H), 5.77 (1 H, ddd, J ) 14.4, 4.2, 2.3 Hz,
C2-H). Anal. Calcd for C11H20O2: C, 71.69; H, 10.94. Found:
C, 71.57; H, 10.94.
Acetyla tion of (()-18. A solution of 18 (93 mg, 0.50 mmol)
and acetic anhydride (71 µL, 0.75 mmol) in pyridine (3 mL)
was stirred at rt for 18 h and worked up as usual to give an
oily crude product (109 mg), which was separated by prepara-
tive HPLC [column A; EtOAc-hexane (1:9); 28.5 mL/min].
The first peak (tR 5.2 min) gave diacetate 19 (31 mg, 23%)
as a colorless oil.
C
13H22O3 226.1569, found 226.1578.
Hyd r olysis of (()-23. A solution of 23 (10.3 mg, 0.0384
mmol) and a 1 M aqueous solution of KOH (77 µL) in ethanol
(0.2 mL) was stirred at rt for 2.3 h and worked up as usual to
give a crude oil (8.5 mg), which was purified by flash chroma-
tography to give 22 (6.6 mg, 93%).
(()-7â-(2-Acet oxy-1r-m et h ylet h yl)-4â-m et h yl-2-cyclo-
h ep ten -1-on e (25). A mixture of 24 (46 mg, 0.203 mmol),
MnO2 (265 mg, 3.1 mmol), and CHCl3 (2.5 mL) was stirred
for 9 h. The mixture was worked up as usual to give a crude
oil (50 mg), which was purified by flash chromatography [2.5
g; 1.2 cm i.d.; EtOAc-hexane (1:9)] to give 25 (44.4 mg, 98%)
as a colorless oil: IR (CHCl3) 1734, 1668, 1252 cm-1; 1H NMR
(500 MHz) δ 0.91 (3 H, d, J ) 6.8 Hz, C1′-Me), 1.17 (3 H, d, J
) 7.3 Hz, C4-Me), 2.04 (3 H, s, Ac), 2.52 (1 H, m, C1′-H), 2.56-
2.62 (2 H, C4-, and C7-Hs), 3.95 (1 H, dd, J ) 12.4, 6.5 Hz,
C2′-H), 3.97 (1 H, dd, J ) 12.4, 6.5 Hz, C2′-H), 5.96 (1 H, dd, J
) 12.0, 2.7 Hz, C2-H), 6.33 (1 H, ddd, J ) 12.0, 3.4, 0.5 Hz,
C3-H); 13C NMR (125 MHz) δ 13.3 (q, C1′-Me), 20.9 (q, Ac-CH3),
22.0 (q, C4-Me), 23.2 (t), 32.7 (d, C-1′), 33.2 (t), 33.7 (d, C-4),
The second peak (tR 10.2 min) gave monoacetate 20 (66 mg,
58%) as colorless needles (EtOAc-hexane): mp 46-47 °C; IR
1
(KBr) 3460, 1710 cm-1; H NMR δ 1.06 (3 H, d, J ) 7.4 Hz,
C4-Me), 1.08 (3 H, d, J ) 6.8 Hz, C1′-Me), 2.04 (3 H, s, Ac),
2.30 (1 H, m, Wh/2 ) 23 Hz, C4-H), 3.91 (1 H, dd, J ) 11.0, 6.2
Hz, C2′-H), 4.16 (1 H, dd, J ) 11.0, 4.4 Hz, C2′-H), 4.51 (1 H,
br d, J ) 4.8 Hz, C1-H), 5.51 (1 H, dd, J ) 11.6, 2.6 Hz, C3-H),
5.71 (1 H, ddd, J ) 11.6, 4.8, 1.7 Hz, C2-H). Anal. Calcd for
C
13H22O3: C, 68.99; H, 9.80. Found: C, 68.59; H, 9.75.

928 J . Org. Chem., Vol. 63, No. 4, 1998
Shimoma et al.
52.1 (d, C-7), 67.4 (t, C-2′), 131.7 (d, C-2), 151.0 (d, C-3), 171.1
(s, Ac-CO), 205.1 (s, C-1). Anal. Calcd for C13H20O3: C, 69.61;
H, 8.99. Found: C, 69.37; H, 9.11.
(()-7â-[2-((ter t-Bu tyldim eth ylsilyl)oxy)-1r-m eth yleth yl]-
4â-m eth yl-2-cycloh ep ten -1â-ol (27). A solution of diol 22
(1.85 g, 10.0 mmol), TBDMSCl (1.66 g, 11.0 mmol), and
imidazole (3.47 g, 50.0 mmol) in DMF (7.5 mL) was stirred at
rt for 80 min and worked up as usual to give a crude oil (3.2
g), which was separated by flash chromatography (150 g; 4.5
cm i.d.).
The second peak (tR 32.2 min) gave (-)-22 (88.9 mg, 44%)
as a colorless oil: [R]25 -16.5 (c 1.42, CHCl3), whose IR and
D
1H and 13C NMR were identical with those of (()-22.
F or m a tion of (S)-(-)-MTP A Ester , (-)-(29), fr om (-)-
22 a n d (S)-(-)-MTP ACl. A solution of (-)-22 (7.3 mg, 0.04
mmol), DMAP (2.4 mg, 0.02 mmol), and (S)-(-)-MTPACl (11
µL, 0.06 mmol) in pyridine (0.15 mL) was stirred for 1.5 h.
The reaction mixture was treated as usual to give a pale yellow
oil (33 mg), which was separated by flash chromatography (2
g; 1.2 cm i.d.).
The fraction which was eluted by hexane gave disilyl ether
26 (335 mg, 8%) as a colorless oil. Anal. Calcd for C23H48O2-
Si2: C, 66.92; H, 11.72. Found: C, 66.80; H, 11.71.
The fraction which was eluted by a mixture of EtOAc-
hexane (5:95) gave 27 (2.71 g, 91%) as a colorless oil: IR
(CHCl3) 3396, 3028 cm-1; 1H NMR δ 0.09 (6 H, s, Si-Me), 0.89
(3 H, d, J ) 5.6 Hz, C1′-Me), 0.91 (9 H, s, TBDMS/t-Bu), 1.03
(3 H, d, J ) 7.1 Hz, C4-Me), 2.27 (1 H, m, C4-H), 3.53 (1 H, dd,
J ) 10.5, 5.1 Hz, C2′-H), 3.81 (1 H, dd, J ) 10.5, 3.1 Hz, C2′-
H), 4.50 (1 H, br s, Wh/2 ) 7.0 Hz, C1-H), 5.40 (1 H, br dd, J )
11.3, 3.6 Hz, C3-H), 5.67 (1 H, ddd, J ) 11.3, 5.0, 2.3 Hz, C2-
H); 13C NMR δ -5.5 (q, Si-Me), -5.4 (q, Si-Me), 16.7 (q, C1′-
Me), 18.3 [s, SiC(CH3)3], 23.3 (q, C4-Me), 25.8 [q, SiC(CH3)3],
30.4 (t), 30.5 (t), 33.9 (d), 34.1 (d), 45.0 (d, C-7), 68.0 (t, C-2′),
73.4 (d, C-1), 135.6 (d, C-2), 135.8 (d, C-3). Anal. Calcd for
The eluent by EtOAc-hexane (5:95) gave di-MTPA ester of
(-)-22 (6.4 mg, 26%) as a colorless oil.
The eluent by a mixture of EtOAc-hexane (1:9) gave mono-
MTPA ester (-)-29 (11.0 mg, 69%) as a colorless oil: [R]20
D
-63.5 (c 0.64, CHCl3); 1H NMR δ 0.96 (3 H, d, J ) 6.8 Hz,
C1′-Me), 1.04 (3 H, d, J ) 7.2 Hz, C4-Me), 1.94 (1 H, m, C6-H),
2.05-2.35 (2 H, C1′-, and C4-Hs) 3.56 (3 H, br s, -OMe), 4.4-
4.5 (2 H, C2′-Hs), 4.56 (1 H, br s, Wh/2 ) 7.0 Hz, C1-H), 5.48 (1
H, ddd, J ) 11.3, 3.5, 1.7 Hz, C3-H), 5.63 (1 H, ddd, J ) 11.3,
4.7, 2.5 Hz, C2-H), 7.36-7.45 (3 H, Ph), 7.45-7.58 (2 H, Ph).
From the analysis of the magnitude of shift induced by
Eu(fod)3 and the integration values for OMe of (-)-29, the
absolute configuration (1′R) and the enantiomeric excess of (-)-
22 (89% ee) were determined (see text). Since (-)-22 of 89%
ee showed [R]25 -16.5 (c 1.42, CHCl3), the [R]25 of enantio-
D
D
C
17H34O2Si: C, 68.39; H, 11.48. Found: C, 67.98; H, 11.50.
merically pure (-)-22 was estimated as -18.5.
Desilyla tion of Disilyl Eth er (()-26. A solution of disilyl
Hyd r olysis of (+)-24 w ith a 1 M Aqu eou s Solu tion of
KOH. A solution of (+)-24 (19.7 mg, 0.087 mmol) and a 1 M
aqueous solution of KOH (174 µL) in EtOH (0.4 mL) was
stirred at rt for 2.5 h and poured into a mixture of a 2 M
aqueous solution of HCl (0.2 mL) and a saturated aqueous
solution of NaCl (1 mL). The mixture was worked up as usual
to give a crude oily product (16 mg), which was purified by
flash chromatography [2.5 g; 1.2 cm i.d.; EtOAc-hexane (2:
8)] to give (+)-22 (13.2 mg, 82%): [R]25D +15.6 (c 0.89, CHCl3).
F or m a tion of (S)-(-)-MTP A Ester of (+)-22. A solution
of (+)-22 (11.5 mg, 0.062 mmol) and DMAP (3.9 mg, 0.03
mmol) in pyridine (0.2 mL) was stirred for 2 min, and then
(S)-(-)-MTPACl (17.0 µL, 0.094 mmol) was added. The
mixture was stirred at rt for 1 h, and then additional (S)-(-
)-MTPACl (5.7 µL, 0.031 mmol) was added. After 40 min,
additional (S)-(-)-MTPACl (5.7 µL, 0.031 mmol) was added.
Stirring for a further 50 min completed the reaction, and the
reaction mixture was worked up as usual to give an oily crude
product (71 mg), which was separated by flash chromatography
(2.5 g; 1.2 cm i.d.).
ether 26 (2.11 g, 5.11 mmol) and n-Bu4NF (1 M in THF, 15.3
mL) in THF (30 mL) was stirred at rt for 18.5 h, poured into
a saturated aqueous solution of NH4Cl (100 mL), and worked
up as usual to give a pale yellow oil (4.0 g), which was purified
by flash chromatography [52 g; 3 cm i.d.; EtOAc-hexane (3:
7)] to give diol 22 (937 mg, 100%) as colorless needles.
(()-7â-[2-((ter t-Bu tyldim eth ylsilyl)oxy)-1r-m eth yleth yl]-
4â-m eth yl-2-cycloh ep ten -1-on e (28). A mixture of allylic
alcohol 27 (2.39 g, 8.01 mmol), MnO2 (13.9 g, 160 mmol), and
CHCl3 (70 mL) was stirred at rt for 48 h. The mixture was
worked up as usual to give 28 (2.34 g, 99%) as a colorless oil:
1
IR (neat) 3080, 1674 cm-1; H NMR δ 0.02 (3 H, s, Si-Me),
0.03 (3 H, s, Si-Me), 0.83 (3 H, d, J ) 7.0 Hz, C1′-Me), 0.87 (9
H, s, TBDMS/t-Bu), 1.16 (3 H, d, J ) 7.2 Hz, C4-Me), 2.33 (1
H, m, C1′-H), 2.59 (1 H, m, C4-H), 2.74 (1 H, m, C7-H), 3.41 (1
H, dd, J ) 9.9, 6.6 Hz, C2′-H), 3.49 (1 H, dd, J ) 9.9, 5.8 Hz,
C2′-H), 5.95 (1 H, dd, J ) 12.0, 2.6 Hz, C2-H), 6.29 (1 H, dd, J
) 12.0, 3.2 Hz, C3-H); 13C NMR δ -5.50 (q, Si-Me), -5.45 (q,
Si-Me), 13.0 (q, C1′-Me), 18.2 [s, SiC(CH3)3], 22.1 (q, C4-Me),
22.8 (t), 25.9 [q, SiC(CH3)3], 33.3 (t), 33.7 (d), 35.4 (d), 51.4 (d,
C-7), 65.9 (t, C-2′), 132.0 (d, C-2), 150.4 (d, C-3), 206.3 (s, C-1).
Anal. Calcd for C17H32O2Si: C, 68.86; H, 10.88. Found: C,
69.18; H, 11.07.
The eluent by EtOAc-hexane (5:95) gave di-MTPA ester
(14.2 mg, 37%) as a colorless oil.
The eluent by EtOAc-hexane (1:9) gave the desired mono-
MTPA ester, (-)-30 (15.6 mg, 63%), as a colorless oil: [R]20
D
Op tica l Resolu tion of (()-22 by En zym a tic Acetyla -
tion . 1. A mixture of (()-22 (91.9 mg, 0.499 mmol), Amano
Lipase PS (30.1 mg), powdered molecular sieves 4A (25.2 mg),
and vinyl acetate (5 mL) was stirred at rt. The reaction was
monitored by GC analysis. After 4.5 h, the ratio of diol/
monoacetate became ca. 1:1, and the reaction mixture was
filtered through Celite and concentrated to give a crude
mixture. The mixture was separated by HPLC [column C;
EtOAc-hexane (3:7); 3.0 mL/min].
-5.2 (c 1.06, CHCl3); 1H NMR δ 0.92 (3 H, d, J ) 6.9 Hz, C1′-
Me), 1.04 (3 H, d, J ) 7.1 Hz, C4-Me), 3.45 (3 H, br s, -OMe),
4.32 (1 H, dd, J ) 10.9, 6.1 Hz, C2′-H), 4.58 (1 H, dd, J ) 10.9,
3.9 Hz, C2′-H), 4.59 (1 H, m, C1-H), 5.50 (1 H, ddd, J ) 11.3,
3.6, 1.7 Hz, C3-H), 5.66 (1 H, ddd, J ) 11.3, 4.7, 2.2 Hz, C2-H),
7.36-7.46 (3 H, Ph), 7.46-7.58 (2 H, Ph).
From the analysis of the magnitude of the shift induced by
Eu(fod)3 of (-)-30, the absolute configuration (1′S) and enan-
tiomeric excess (% ee) of (+)-24 (77% ee) were determined (see
The first peak (tR 14.4 min) gave (+)-24 (53.6 mg, 48%) as
text). Since (+)-24 of 77% ee showed [R]25 +38.0 (c 1.11,
D
a colorless oil, [R]25 +46.1 (c 3.96, CHCl3), whose IR and 1H
CHCl3), the [R]25 of enantiomerically pure (+)-24 was esti-
D
D
and 13C NMR were identical with those of (()-24.
mated as +49.4.
The second peak (tR 32.2 min) gave (-)-22 (47.4 mg, 52%)
(1′S)-(-)-7â-(2-Acet oxy-1r-m et h ylet h yl)-4â-m et h yl-2-
as a colorless oil, [R]25 -13.0 (c 3.65, CHCl3), whose IR and
cycloh ep ten -1-on e (-)-(25). A mixture of (+)-24 ([R]25
D
D
1H and 13C NMR were identical with those of (()-22.
Op tica l Resolu tion of (()-22 by En zym a tic Acetyla -
tion . 2. A mixture of (()-22 (201 mg, 1.09 mmol), Amano
Lipase PS (59 mg), powdered molecular sieves 4A (101 mg),
and vinyl acetate (10 mL) was stirred at rt for 8.5 h. The
reaction mixture was treated as usual to give a crude mixture,
which was separated by HPLC by the conditions mentioned
above.
+38.0, 77% ee, 17.9 mg, 0.079 mmol), MnO2 (104 mg, 1.19
mmol), and CHCl3 (1.5 mL) was stirred for 9 h. The mixture
was worked up as usual to give a pale yellow crude oil (17.8
mg) which was purified by flash chromatography [2.5 g; 1.2
cm i.d.; EtOAc-hexane (1:9)] to give enone (-)-25 (16.1 mg,
91%) as a colorless oil, [R]20 -108.4 (c 1.02, CHCl3), which
D
was identical with (()-25 in IR and 1H NMR.
(1′R)-(+)-7r-(2-Acet oxy-1â-m et h ylet h yl)-4r-m et h yl-2-
The first peak (tR 14.4 min) gave (+)-24 (127.9 mg, 52%) as
cycloh ep ten -1-on e (+)-(25). A solution of (-)-22 ([R]25
D
1
a colorless oil: [R]25 +38.0 (c 1.11, CHCl3), whose IR and H
-16.5, 89% ee, 32.6 mg, 0.18 mmol) and Ac2O (22.4 µL, 0.23
D
and 13C NMR were identical with those of (()-24.
mmol) in pyridine (1 mL) was stirred at rt for 31.5 h.

Synthetic Intermediates for Pseudoguaianolides
J . Org. Chem., Vol. 63, No. 4, 1998 929
Additional Ac2O (5.0 µL, 0.05 mmol) was added into the
reaction mixture, and the solution was stirred for a further 2
h. The reaction mixture was worked up as usual to give an
oily crude product (41 mg), which was separated by flash
chromatography (7.5 g; 1.6 cm i.d).
“Amano Lipase PS”, and also express our thanks to
Chuo-Denki-Kogyo Co., Ltd., in Niigata for the donation
of active MnO2 for our experiments. We also express
our thanks to Y. Yanagi of Sumitomo Pharmaceuticals
Co., Ltd., for bioassay of cell growth inhibitory activity
of compounds to P-388 and to H. Yamazaki of Sumitomo
Chemical Co., Ltd., for bioassay of compounds in con-
trolling crop disease and herbicide test.
The first running which was eluted with a mixture of
EtOAc-hexane (1:9) gave optically active diacetate (-)-23
(11.9 mg, 25%), [R]20 -37.9 (c 0.88, CHCl3), which was
D
identical with (()-23 in IR and 1H NMR.
The second running which was eluted with a mixture of
EtOAc-hexane (3:7) gave optically active monoacetate (-)-
Su p p or tin g In for m a tion Ava ila ble: Table of the com-
24 (24.3 mg, 61%), [R]25 -45.3 (c 1.32, CHCl3), which was
D
1
parison of H NMR spectral data of 8a , 8b, 9a , 9b, and III;
identical with (()-24 in IR and 1H NMR.
data table of the time progress of kinetic resolution of (()-22
by vinyl acetate in the presence of Lipase PS (Amano); 1H NMR
charts and stereostructures of (S)-(-)-MTPA esters of (-)-22
and (+)-22 for determination of absolute configuration and
enantiomeric excess by the lanthanide-induced shift by Eu-
(fod)3 for the -OMe group; CD curve of p-bromobenzoate and
the stereostructure of p-bromobenzoate of (+)-24; spectral data
of 5, 7a and 7b, 8a , 9a , 9b, 19, 23, 26, di-MTPA ester of (+)-
and (-)-22 and Experimental Section for the preparation of
9a and 9b, 10a and 10b, 11a and 11b, 12a and 12b, 13b, and
isomerization of 12b and 13b (11 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
A mixture of (-)-24 ([R]25 -45.3, 24.3 mg, 0.107 mmol),
D
MnO2 (140 mg, 1.61 mmol), and CHCl3 (1.5 mL) was stirred
for 12 h. The mixture was worked up as usual to give a crude
oil (23.2 mg), which was purified by flash chromatography [2.5
g; 1.2 cm i.d.; EtOAc-hexane (1:9)] to give enone (+)-25 (21.5
mg, 90%) as a colorless oil, [R]20D +129.6 (c 1.27, CHCl3), which
was identical with (()-25 in IR and 1H NMR.
Ack n ow led gm en t. We express our thanks to Dr. M.
Ueno (1H NMR, 600 MHz), Mr. T. Sato (HREIMS), and
Mrs. H. Ando (microanalyses) of the Instrumental
Analysis Center for Chemistry, Tohoku University. We
also thank Mr. J . Sakai of our department for the
measurement of 1H NMR at 500 MHz and 13C NMR at
125 MHz. We express our thanks to Amano Pharma-
ceutical Co., Ltd., in Nagoya for the kind donation of
J O971529Q