An approach toward the Illudin family of sesquiterpenes using the tandem cyclization - Cycloaddition reaction of rhodium carbenoids

Article abstract of DOI:10.1021/jo961574i

The Rh(II)-catalyzed reaction of 1-acetyl-1-(diazoacetyl)cyclopropane with 5,5-dimethylcyclopentenone afforded the product of a 1,3-dipolar cycloaddition in high yield. The reaction involves formation of a rhodium carbenoid and subsequent transannular cyclization of the electrophilic carbon onto the adjacent keto group to generate a five-membered cyclic carbonyl ylide which undergoes a subsequent 1,3-dipolar cycloaddition reaction. The regiochemical results encountered can be rationalized on the basis of FMO considerations. Treatment of the cycloadduct with p-toluene-sulfonic acid results in loss of water followed by a subsequent acid-catalyzed cyclopropyl ketone rearrangement to give dihydrobenzofuran 21. The product distribution derived from the SmI₂-induced reduction of the dipolar cycloadduct was found to depend on the reaction conditions. Under kinetic conditions, the reduction resulted in opening of the cyclopropyl ring adjacent to the carbonyl group. However, under thermodynamic conditions, cleavage of the oxy bridge corresponded to the major pathway. The cycloaddition-reduction protocol provides a rapid assembly of the basic core unit of ptaquilosin having most of the functionality in place. Generation of a carbanion adjacent to the oxy bridge leads to opening of the oxabicyclic ring system in a highly regioselective manner. A short synthesis of (±)-illudin M and the closely related isodehydroilludin M is described in which the key step involves a dipolar cycloaddition using a carbonyl ylide.

Full text of DOI:10.1021/jo961574i

J . Org. Chem. 1997, 62, 1317-1325
1317
An Ap p r oa ch tow a r d th e Illu d in F a m ily of Sesqu iter p en es Usin g
th e Ta n d em Cycliza tion -Cycloa d d ition Rea ction of Rh od iu m
Ca r ben oid s
Albert Padwa,* Erin A. Curtis, and Vincent P. Sandanayaka†
Department of Chemistry, Emory University, Atlanta, Georgia 30322
Received August 13, 1996X
The Rh(II)-catalyzed reaction of 1-acetyl-1-(diazoacetyl)cyclopropane with 5,5-dimethylcyclopen-
tenone afforded the product of a 1,3-dipolar cycloaddition in high yield. The reaction involves
formation of a rhodium carbenoid and subsequent transannular cyclization of the electrophilic carbon
onto the adjacent keto group to generate a five-membered cyclic carbonyl ylide which undergoes a
subsequent 1,3-dipolar cycloaddition reaction. The regiochemical results encountered can be
rationalized on the basis of FMO considerations. Treatment of the cycloadduct with p-toluene-
sulfonic acid results in loss of water followed by a subsequent acid-catalyzed cyclopropyl ketone
rearrangement to give dihydrobenzofuran 21. The product distribution derived from the SmI2-
induced reduction of the dipolar cycloadduct was found to depend on the reaction conditions. Under
kinetic conditions, the reduction resulted in opening of the cyclopropyl ring adjacent to the carbonyl
group. However, under thermodynamic conditions, cleavage of the oxy bridge corresponded to the
major pathway. The cycloaddition-reduction protocol provides a rapid assembly of the basic core
unit of ptaquilosin having most of the functionality in place. Generation of a carbanion adjacent
to the oxy bridge leads to opening of the oxabicyclic ring system in a highly regioselective manner.
A short synthesis of (()-illudin M and the closely related isodehydroilludin M is described in which
the key step involves a dipolar cycloaddition using a carbonyl ylide.
Illudins M (1) and S (2) are extremely toxic sesqui-
terpenes produced by Omphalotus illudens, the jack-o’-
lantern mushroom.1-4 Recently, two new members of
this family (3 and 4) have been isolated from a closely
related fungus.5 The illudins and certain derivatives
have been evaluated for antitumor activity at the NCI
and show selective toxicity for human myelocytic leuke-
mia and other carcinoma cells of various species of
origin.6 Most of the existing illudin analogs in the
literature have been derived from the natural products.7-9
The spirocyclopropane and R,â-unsaturated ketone present
in the illudin skeleton constitutes a bis-electrophile that
is undoubtedly responsible for the DNA damage.10 Some
simpler illudin analogs such as the dehydroilludins M
(5) as well as isodehydroilludin M (6) have recently been
shown to possess high efficacy against a number of
adenocarcinomas.9,10
A number of compounds related to the illudin family
have also been isolated from the bracken fern Pteridium
aquilinium.11 This fern is widely distributed throughout
the world and its lethal properties toward cattle was first
reported in the late 19th century.12 Cattle which con-
sume bracken fern exhibit the syndrome known as “cattle
bracken poisoning”, the features of which include hemor-
rhage, anorexia, extensive intestine damage, ulceration,
and pyrexia.11,12 Epidemiological studies provide evi-
dence that esophageal cancer in J apan is correlated with
the consumption of bracken.13 In 1983 the Yamada group
† Current address: Wyeth-Ayerst Research Lederle Laboratories,
401 N. Middletown Rd., Pearl River, NY 10965.
X Abstract published in Advance ACS Abstracts, December 1, 1996.
(1) Nakanishi, K.; Tada, M.; Yamada, Y.; Ohashi, M.; Komatsu, N.;
Terakawa, H. Nature 1963, 197, 292. French, A. L.; Garrettson, L. K.
Clin. Toxicol. 1988, 26, 81.
(2) McMorris, T. C.; Anchel, M. J . Am. Chem. Soc. 1965, 87, 1594.
(3) Nakanishi, K.; Ohashi, M.; Tada, M.; Yamada, Y. Tetrahedron
1965, 21, 1231.
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U.S.A. 1952, 38, 927.
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Perkin Trans. 1 1991, 733.
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, M. A.; Taetle, R. J . Org. Chem. 1992, 57, 6876.
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S.; Sakan, F. Tetrahedron Lett. 1970, 1171.
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1971, 3489.
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Med. Chem. Lett. 1996, 6, 1029.
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1990, 82, 1562. McMorris, T. C.; Kelner, M. J .; Chadha, R. K.; Siegel,
J . S.; Moon, S.; Moya, M. M. Tetrahedron 1989, 45, 5433. Kelner, M.
J .; McMorris, T. C.; Estes, L.; Starr, R. J .; Rutherford, M.; Montoya,
M.; Samson, K. M.; Taetle, R. Cancer Res. 1995, 55, 4936.
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Plant Origin; Hirono, I.; Ed.; Kodansha-Elsevier: Tokyo, Amsterdam,
1987; pp 87-120.
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Ed.; American Chemical Society: Washington, D.C., 1984; Vol. 2, pp
1171-1204.
(13) Naturally Occurring Carcinogens-Mutagens and Modulators of
Carcinogenesis; Miller, E. C., Ed.; J apan Sci. Soc. Press: Tokyo; pp
359-380.
(14) Niwa, H.; Ojika, M.; Wakamatsu, K.; Yamada, K.; Hirono, I.;
Matsushita, K. Tetrahedron Lett. 1983, 24, 4117.
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K.; Yamada, K. Acta. Crystallogr., Sect. C. 1984, 40, 1877.
S0022-3263(96)01574-5 CCC: $14.00 © 1997 American Chemical Society

1318 J . Org. Chem., Vol. 62, No. 5, 1997
Padwa et al.
Sch em e 1
Sch em e 2
Sch em e 3
isolated a carcinogen ptaquiloside (7) from bracken fern,14
elucidated its structure,15 and established its carcinoge-
nicity.16 The ultimate carcinogen derived from ptaqui-
losine (8), the aglycon of ptaquiloside, is dienone 9 which
acts as a powerful alkylating agent toward amino acids
and nucleic acid bases, and it causes cleavage of DNA.17,18
Ptaquiloside (7) was found to be unstable in both acidic
and basic solution at 25 °C and was converted to pterosin
B (10).18 Yamada and co-workers demonstrated that
ptaquiloside can be readily transformed into dienone 9
by elimination of D-(+)-glucose under basic conditions.14,18
Dienone 9 is rapidly converted to 10 under weakly acidic
conditions (Scheme 1).14,18
As a consequence of their biological activity, it is not
surprising that these compounds have received consider-
able attention as synthetic targets. The total synthesis
of (()-illudin M was first achieved by Matsumoto in
1968.19,20 Kigoshi and co-workers reported the total
synthesis of (-)-ptaquilosin (8) in 1993 in 20 steps (2.9%
overall yield).21 In light of the interest in this class of
antitumor agents, we undertook a study designed to
provide a general means for the synthesis of the core
skeleton of these molecules.22 In addition, because of
their extreme toxicity and consequent low therapeutic
index, it seemed reasonable to us to modify the basic
skeleton so as to reduce cytotoxicity without compromis-
ing antitumor activity.23 Specifically, we envisioned the
use of a dipolar cycloaddition reaction of a cyclic carbonyl
ylide dipole as the key step for the construction of the
illudin/ptaquilosin skeleton.22 This strategy provides for
a rapid assembly of the basic core unit of the target
molecules having most of the functionality in place
(Scheme 2). As shown in the retrosynthetic scheme,
opening of the oxy bridge of the cycloadduct would
ultimately lead to the core structure of the target
molecules in a highly convergent manner. In this paper,
we detail the extension of our tandem cyclization-
cycloaddition chemistry of rhodium carbenoids24 toward
a synthesis of (()-illudin M (1) and the closely related
isodehydroilludin M (6).
Resu lts a n d Discu ssion
Earlier reports from this laboratory have described the
formation of cyclic carbonyl ylides by a process involving
a transannular cyclization of an electrophilic rhodium
carbenoid onto an adjacent carbonyl group.24,25 Five-
membered-ring carbonyl ylides were generated by treat-
ing 1-diazobutanediones with rhodium(II) carboxylates
(Scheme 3).26 However, it was necessary to block the
R-position of the 1-diazobutanedione with two substituent
groups in order for the cycloaddition to occur. When only
a single substituent group was present, the five-mem-
bered dipole was found to undergo proton transfer at a
faster rate than bimolecular dipolar cycloaddition, lead-
ing to furanones of type 13.26 The formation of furanone
13 is not surprising as one of the characteristic reactions
(16) Hirono, I.; Yamada, K.; Niwa, H.; Shizuri, Y.; Ojika, M.; Hosaka,
S.; Yamaji, T.; Wakamatsu K.; Kigoshi, H.; Niiyama, K.; Uosaki, Y.
Cancer Lett. 1984, 21, 239. Hirono, I.; Aiso, S.; Yamaji, T.; Mori, H.;
Yamada, K.; Niwa, H.; Ojika, M.; Wakamatsu, K.; Kigoshi, H.;
Niiyama, K.; Uosaki, Y. Gann 1984, 75, 833. Hirono, I.; Ogino, H.;
Fujimoto, M.; Yamada, K.; Yoshida, Y.; Ikagawa, M.; Okumura, M. J .
Natl. Cancer Inst. 1987, 79, 1143.
(17) Niwa, H.; Ojika, M.; Wakamatsu, K.; Yamada, K.; Ohba, S.;
Saito, Y.; Hirono, I.; Matsushita, K. Tetrahedron Lett. 1983, 24, 5371.
(18) Ojika, M.; Wakamatsu, K.; Niwa, H.; Yamada, K. Tetrahedron
1987, 43, 5261.
(19) Matsumoto, T.; Shirahama, H.; Ichihara, A.; Shin, H.; Kagawa,
S.; Sakan, F.; Matsumoto, S.; Nishida, S. J . Am. Chem. Soc. 1968, 90,
3280. Matsumoto, T.; Shirahama, H.; Ichihara, A.; Shin, H.; Kagawa,
S.; Sakan, F.; Miyano, K. Tetrahedron Lett. 1971, 2049.
(20) Kinder, F. R., J r.; Bair, K. W. J . Org. Chem. 1994, 59, 6965.
(21) Kigoshi, H.; Imamura, Y.; Mizuta, K.; Niwa, H.; Yamada, K. J .
Am. Chem. Soc. 1993, 115, 3056. Kigoshi, H.; Sawada, A.; Nakayama,
Y.; Niwa, H.; Yamada, K. Tetrahedron Lett. 1989, 30, 1983.
(22) For a preliminary report, see: Padwa, A.; Sandanayaka, V. P.;
Curtis, E. A. J . Am. Chem. Soc. 1994, 116, 2667.
(23) McMorris, T. C.; Kelner , M. J .; Wang, W.; Moon, S.; Taetle, R.
Chem. Res. Toxicol. 1990, 3, 574. Kelner, M. J .; McMorris, T. C.; Beck,
W. T.; Zamora, J . M.; Taetle, R. Cancer Res. 1987, 47, 3186.
(24) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223.
(25) Kinder, F. R., J r.; Padwa, A. Tetrahedron Lett. 1990 31, 6835.
Padwa, A.; Kinder, F. R., J r.; Zhi, L. Synlett 1991, 287. Padwa, A.;
Kinder, F. R., J r.; Nadler, W. R.; Zhi, L. Heterocycles 1993, 35, 367.
Padwa, A.; Kinder, F. R., J r. J . Org. Chem. 1993, 58, 21. Padwa, A.;
Fryxell, G. E.; Zhi, L. J . Am. Chem. Soc. 1990, 112, 3100.
(26) Padwa, A.; Chinn, R. L.; Hornbuckle, S. F.; Zhang, Z. J . J . Org.
Chem. 1991, 56, 3271.

Approach toward the Illudin Family of Sesquiterpenes
J . Org. Chem., Vol. 62, No. 5, 1997 1319
Sch em e 4
Sch em e 5
Sch em e 6
of carbonyl ylides derived from the reaction of R-diazoal-
kanes with ketones consists of intramolecular proton
transfer.27-29 During the course of these studies we
discovered that the Rh(II) catalyzed reaction of cyclopro-
pyl substituted R-diazo ketones 15 and 16 resulted in a
smooth cycloaddition to a variety of acyclic and cyclic
alkenes.22 This dipolar cycloaddition strategy was suc-
cessfully applied toward the synthesis of several members
of the pterosin family of sesquiterpenes by converting the
initial cycloadduct 17 (R ) H) to the corresponding
methylene derivative 18, followed by a subsequent acid-
catalyzed cyclopropyl ring opening reaction to give 19
(Scheme 4).30
Having established that the tandem cyclization-cy-
cloaddition reaction of R-diazo ketones 15 and 16 occurred
with ease, we next turned our attention to the oxy-bridge
ring cleavage. Several issues emerged at the outset of
these investigations: (1) what type of reagents work best,
(2) how to control the regioselectivity of the cleavage
reaction and, (3) the possiblity of keeping the labile spiro
cyclopropyl ring intact. Translation of the stereochemical
features present in the oxybicyclic framework of the
dipolar cycloadduct 17 to the stereochemistry of the
illudin/ptalquilosin family of sesquiterpenes was a major
objective of our studies. We therefore initiated an
investigation dealing with the cleavage reaction of several
of the dipolar cycloadducts with various reagents, to
eventually give products belonging to the illudin/
ptalquilosin family.
Our initial studies focused on the acid-catalyzed reac-
tion of spirotricyclodecanone 17. Treatment of 17 with
p-toluenesulfonic acid afforded dihydrobenzofuran 21 in
70% yield. The formation of 21 proceeds by an initial
oxy-bridge ring opening followed by a subsequent dehy-
dration to give 20 as a nonisolable intermediate which
reacts further by an acid-catalyzed cyclopropyl ketone
rearrangement (Scheme 5).31-33 The facility of the pro-
cess is undoubtedly related to the aromaticity gained in
the final step. Interestingly, when 17 was treated with
BF3‚OEt2, the only product isolated (50%) corresponded
to the unexpected carboxylic acid 24 (Scheme 6). More
than likely, this compound is derived by a Lewis acid-
induced C-C bond cleavage to generate the acylium
cation 22 which is converted to dienone 23 and then to
the rearranged acid 24.
Since the acid-induced opening of the dipolar cycload-
duct destroyed the cyclopropyl ring, we opted to study
other reagents capable of cleaving the oxabicyclic ring
system. In recent years, samarium(II) iodide has emerged
as a powerful, yet highly selective, reducing agent.34
Molander has utilized the selective nature of SmI2 to
effect reduction of functionalized vinyloxirane deriva-
tives,35 and these results prompted us to explore the use
of this reagent in the present study. Overwhelming
evidence suggests that free radicals are formed during
SmI2 reductions.34 Consequently, a major concern as-
sociated with the planned illudin/ptaquilosin approach
was that the cyclopropyl ring present in the dipolar
cycloadduct would be cleaved when treated with SmI2.36
Indeed, treatment of cycloadduct 25 with SmI2/THF/
MeOH at -78 °C produced the cyclopropyl ring-opened
(27) Bien, S.; Gillon, A. Tetrahedron Lett. 1974, 3073. Bien, S.;
Gillon, A.; Kohen, S. J . Chem. Soc., Perkin Trans. 1 1976, 489.
(28) Kharasch, M. S.; Rudy, T.; Nudenberg, W.; Buchi, G. J . Org.
Chem. 1953, 18, 1030.
(29) Lottes, A. C.; Landgrebe, J . A.; Larsen, K. Tetrahedron Lett.
1989, 30, 4089.
(30) Curtis, E. A.; Sandanayaka, V. P.; Padwa, A. Tetrahedron Lett.
1995, 36, 1989. Padwa, A.; Curtis, E. A.; Sandanayaka, V. P. J . Org.
Chem. 1996, 61, 73.
(31) Schweizer, E. E.; Kopay, C. M. J . Org. Chem. 1971, 36, 1489.
(32) Danishefsky, S.; Dynak, J . Tetrahedron Lett. 1975, 79.
(33) Saalfrank, R. W.; Gu¨ndel, J .; Rossmann, G.; Hanek, M.; Rost,
W.; Peters, K.; von Schnering, H. G. Chem. Ber. 1990, 123, 1175.
(34) Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307.
Molander, G. A. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 1, pp 251-282.
Soderquist, J . A. Aldrichim. Acta 1991, 24, 15. Holton, R. A.; Williams,
A. D. J . Org. Chem. 1988, 53, 5981.
(35) Molander, G. A.; La Belle, B. E.; Hahn, G. J . Org. Chem. 1986,
51, 5259. For some related reports, see: Otsubo, K.; Inanaga, J .;
Yamaguchi, M. Tetrahedron Lett. 1987, 28, 4437. Matsukawa, M.;
Tabuchi, T.; Inanaga, J .; Yamaguchi, M. Chem. Lett. 1987, 2101. De
Schrijver, J .; De Clercq, P. J . Tetrahedron Lett. 1993, 34, 4369.
(36) For a description of cyclopropyl ring cleavage from the SmI2-
induced ketyl anion generation, see: Molander, G. A.; McKie, J . A. J .
Org. Chem. 1991, 56, 4112.

1320 J . Org. Chem., Vol. 62, No. 5, 1997
Padwa et al.
Sch em e 7
Sch em e 8
Several other SmI2 induced ring-opening reactions
were carried out to further demonstrate the scope and
generality of the oxy bridge cleavage reaction. Thus,
treatment of cycloadducts 30 and 1730 with SmI2 at 50
°C in THF gave the desired ring-opened products 31 and
32 in 62% and 60%, respectively. In both cases, there
product 26 in 61% yield (2:1 mixture of diastereomers)
(Scheme 7). Apparently, the SmI2-MeOH combination
is a sufficiently powerful reducing agent that rapidly
donates an additional electron to the putative ring-
opened carbon-centered radical, thereby generating an
organosamarium intermediate that is irreversibly pro-
tonated.
Cyclopropyl ketyl anions, whose only substituents on
the cyclopropyl ring are alkyl or hydrogen, are known to
undergo a reversible ring-opening reaction.37 This ob-
servation suggested that if the SmI2-promoted cyclopro-
pyl carbinyl ketyl ring opening reaction proceeded under
kinetic control, then cleavage of the oxy bridge might
occur under thermodynamic conditions. Toward this end,
we examined the SmI2-induced reaction of 25 without
MeOH (proton source) at 25 °C. However, the only
product formed corresponded to furanone 27 (5:1 mixture
of diastereomers, 85%). Under these conditions, SmI2
acts as a Lewis acid34 and induces a retro-Claisen-type
fragmentation via a dimethoxy carbenium ion. In sup-
port of this suggestion, the reaction of 25 with 1 equiv of
SnCl2 gave 27 in 79% yield. Realizing that the presence
of the carbethoxy group promotes the retro-Claisen
fragmentation, we turned our attention to cycloadduct
28 wherein the ester functionality is replaced by a
hydrogen. As indicated in Scheme 7, this substrate
underwent efficient oxy bridge ring opening to give 29
(62%) when treated with SmI2 in THF at 40 °C. No signs
of any cyclopropyl ring opened product was detected in
the crude reaction mixture. Under thermodynamic con-
ditions, cleavage of the oxy bridge is followed by a
subsequent elimination of methoxide from the resulting
samarium enolate, producing 29 as the exclusive product.
An alternate explanation, which is also consistent with
the product crossover, assumes that SmI2 is less strongly
solvated in THF and therefore is a more selective
reducing agent with respect to C-O bond cleavage.
Indeed, the reducing power of SmI2 has been shown to
be closely related to the coordinating power of the
reaction medium.38
was no indication of any product(s) derived from reduc-
tion of the five-membered ring. When the dimethylated
cycloadduct 17 was used, a 3:1-mixture of the cis and
trans isomers of 32 was obtained. Assignment of the
stereochemistry was based on 1H-NMR spectral data,
extensive decoupling experiments, and a 2D-NOESY
experiment. Presumably, the Lewis acid character34 of
SmI2 had resulted in the epimerization of the cis-isomer,
although it is not evident why this did not occur with
31.
In an analogous manner, treatment of cycloadducts 33
and 3430 with SmI2 (THF, 50 °C) cleanly afforded
compounds 35 and 36 in 75% and 70% yield, respectively
(Scheme 8). Isolation of the spiro-cyclopropylcarbinyl
alcohol 36 demonstrates the complexity of structures that
can be obtained by this method. Thus, the strategy of a
rhodium(II)-catalyzed cyclization-cycloaddition reaction
followed by reductive cleavage of the resulting cycload-
duct represents an effective method for generating mul-
tiple contiguous stereocenters on polyfunctional fused
ring systems. Further efforts directed toward applying
this method to ptaquilosin (8) are currently underway
in our laboratory.
The generation of a carbanion adjacent to the oxy
bridge has also been found to result in a smooth ring
opening of the 7-oxabicyclo[2.2.1]heptane ring system.
Reaction of cycloadduct 37 with LDA at -78 °C produced
hydroxy-enone 38 in 78% yield as a 3:1 mixture of
diastereomers. Apparently, the initial ring-opened prod-
uct epimerizes under the workup conditions. The Rh-
(II)-catalyzed reaction of diazo ketone 15 with phenyl
vinyl sulfone afforded cycloadduct 39 as an 8:3 mixture
of exo/ endo diastereomers. The thermodynamically more
stable exo-cycloadduct was easily obtained as a crystalline
solid by silica gel chromatography of the mixture. Treat-
ment of 39 with 1 equiv of methylmagnesium bromide
resulted in attack from the less hindered exo-(top) face
(37) Tanko, J . M.; Drumright, R. E. J . Am. Chem. Soc. 1990, 112,
5362.
(38) Molander, G. A.; Harring, L. S. J . Org. Chem. 1990, 55, 6171.
Molander, G. A.; McKie, J . A.; J . Org. Chem. 1992, 57, 3132. Kusuda,
K.; Inanaga, J .; Yamaguchi, M. Tetrahedron Lett. 1989, 30, 2945.
Otsubo, K.; Inanaga, J .; Yamaguchi, M. Tetrahedron Lett. 1986, 27,
5763. Inanaga, J .; Ishikawa, M.; Yamaguchi, M. Chem. Lett. 1987,
1485. Hou, Z.; Kobayashi, K.; Yamazaki, H. Chem. Lett. 1991, 265.
Enholm, E. J .; J iang, S.; Abboud, K. J . Org. Chem. 1993, 58, 4061.
Hasegawa, E.; Curran, D. P. J . Org. Chem. 1993, 58, 5008.

Approach toward the Illudin Family of Sesquiterpenes
J . Org. Chem., Vol. 62, No. 5, 1997 1321
Sch em e 9
Sch em e 10
Sch em e 11
of the oxabicyclic ring leading to a single diastereomer
in 80% yield. Further reaction of 40 with n-BuLi in THF
afforded diol 41 in 70% yield (Scheme 9). This model
study demonstrates that it is possible to effect a base-
induced ring opening of the oxabicyclic ring with high
stereoselectivity. The simplicity of the sequence and the
rapid construction of adjacent stereocenters encouraged
us to examine this pathway as a route to (()-illudin M
(1).
The Rh(II)-catalyzed cycloaddition reaction of R-diazo
ketone 15 with 5,5-dimethylcyclopentenone (42) pro-
ceeded in only 51% yield (Scheme 4), and a significant
amount of unreacted cyclopentenone was recovered.39 We
attribute the low yield to the existence of significant steric
interactions of the dipole with the methyl groups of the
dipolarophile in the transition state for the cycloaddition.
Given the limited success of this reaction, we turned our
attention to a more highly activated cyclopentenone, one
that we expected would undergo the reaction with a
significant rate enhancement. Earlier studies in our
laboratory demonstrated that the bimolecular cycload-
dition of cyclic carbonyl ylides with phenylsulfonyl-
substituted alkenes was a remarkably efficient process.40
MO calculations using the AM1 Hamiltonian reveal a
small energy gap between the HOMO of the dipole and
the LUMO of the phenylsulfonyl-substituted alkene. This
led us to examine 2-(phenylsulfonyl)-5,5-dimethylcyclo-
pentenone (46) as a surrogate for 42, since the sulfonyl
group can easily be removed by reductive desulfonyla-
tion.41 The requisite phenylsulfonyl cyclopentenone 46
was prepared in high yield from the reaction of the
iodonium salt 43 with anhydrous sodium p-toluenesulfi-
nate according to the general procedure of Stang and co-
workers.42 The initially formed alkylidenecarbene 45
undergoes a subsequent intramolecular 1,5-carbon-
hydrogen insertion reaction to give 46 in 73% yield
(Scheme 10).
The preparation and use of the required cycloadduct
47 is detailed in Scheme 11. Treatment of diazo ketone
15 with 46 in the presence of a catalytic amount of Rh2-
(OAc)4 afforded a 2:1-mixture of the exo- and endo
cycloadducts 47 in 98% yield. The two diastereomers
could easily be separated by silica gel chromatography.
Reaction of the exo-cycloadduct 47a with methylmagne-
sium iodide regiospecifically gave alcohol 48 in 90% yield
where attack occurred from the less hindered exo-face of
the oxabicyclo[2.2.1]heptane ring system. Sodium amal-
gam desulfonylation proceeded smoothly to give 49 in
87% yield. We were gratified to find that treatment of
49 with KOH/MeOH led to rapid oxabicyclic ring opening
to afford the desired diol 50 in 80% yield. A related set
of reactions occurred with the corresponding endo-dias-
tereomer 47b which ultimately gave the epimeric diol 53
in 39% overall yield from 47b.
At this stage of the synthesis, we felt that it would be
prudent to carry out the above sequence of reactions
using a mixture of cycloadducts 47. This would allow
quicker assembly of (()-illudin M (1) and its analogs and
would also be more amenable to scale-up. The final
elaboration of 50/53 into illudin M (1) consisted of a
Swern oxidation to give dione 54 (5:3 mixture of diaster-
eomers) (Scheme 12). Curiously, this compound was
resistant to introduction of the double bond in the five-
membered ring. The difficulty in the oxidation of 54 is
presumably a result of the crowded environment about
the ring juncture. Screening of a series of oxidants
showed that DDQ was capable of effecting the desired
(39) The Rh(II)-catalyzed reaction of 15 with 5,5-dimethylcyclopent-
2-en-1-one produced cycloadduct 17 in 80% yield when less than 0.5 g
of starting material was employed. However, attempts to scale up the
procedure to produce 17 in quantities greater than 1 g always resulted
in a lower yield of the cycloadduct (i.e. 51%). An alternative method
that was also investigated involved the cycloaddition of 15 with
cyclopent-2-en-1-one followed by dimethylation of the resulting cy-
cloadduct. However, the overall yield of this two-step sequence was
only 54%.
(40) Padwa, A. Acc. Chem. Res. 1991, 24, 22.
(41) Smith, A. B., III; Hale, K. J .; McCauley, J . P., J r. Tetrahedron
Lett. 1989, 30, 5579.
(42) Williamson, B. L.; Stang, P. J .; Arif, A. M. J . Am. Chem. Soc.
1993, 115, 2590.

1322 J . Org. Chem., Vol. 62, No. 5, 1997
Padwa et al.
38.6, 39.5, 40.2, 47.6, 56.2, 85.4, 87.8, 212.3, and 219.3. Anal.
Calcd for C14H18O3: C, 71.77; H, 7.74. Found: C, 71.75; H,
7.71.
Sch em e 12
Acid In d u ced Rea r r a n gem en t of Sp ir o[1,4,4-tr im eth yl-
10-oxa t r icyclo-[5.2.1.02,6]d e ca -3,8-d ion e -9,1′-cyclop r o-
p a n e] (17). A solution containing 0.1 g (0.43 mmol) of R-diazo
ketone 17 in 5 mL of CH2Cl2 was treated with a 10-fold excess
of p-toluenesulfonic acid, and the resultant mixture was heated
at reflux for 10 h. The reaction was quenched by the addition
of water, the mixture was extracted with ether, and the
extracts were dried over anhydrous MgSO4. The solvent was
removed under reduced pressure, and the residue was purified
by silica gel chromatography to give 0.07 g (70%) of 4,6,6-
trimethyl-2,3,6,7-tetrahydro-1-oxaindacen-5-one (21) as a white
solid: mp 98-99 °C; IR (CDCl3) 3146, 1680, 1595, 1467, 1310,
and 1090 cm-1; 1H-NMR (300 MHz, CDCl3) δ 1.16 (s, 6H), 2.52
(s, 3H), 2.82 (s, 2H), 3.11 (t, 2H, J ) 8.4 Hz), 4.65 (t, 2H, J )
8.4 Hz), and 6.55 (s, 1H); 13C-NMR (75 MHz, CDCl3) δ 15.0,
25.6, 27.4, 42.4, 45.9, 72.4, 126.1, 127.2, 136.2, 148.6, 156.0,
165.4, and 210.3. Anal. Calcd for C14H16O2: C, 77.75; H, 7.46.
Found: C, 77.69; H, 7.51.
A rearrangement of R-diazo ketone 17 was also carried out
using BF3‚OEt2. To a solution containing 0.23 g (0.90 mmol)
of 17 in 10 mL of dry CH2Cl2 was added 0.36 mL (2.9 mmol)
of BF3‚OEt2, and the resulting mixture was stirred at rt for 1
h. The reaction was quenched by the addition of 10 mL of
water, extracted with CH2Cl2, and dried over MgSO4, and the
solvent was removed under reduced pressure. The product
was purified by silica gel chromatography followed by recrys-
tallization to give 0.12 g (50%) of 3-(methyl-2,3-dihydroben-
zofuran-6-yl)propionic acid (24) as a white solid: mp 101-102
1
°C; IR (neat) 3452, 1695, 1261, and 990 cm-1; H-NMR (300
MHz, CDCl3) δ 1.20 (s, 6H), 2.21 (s, 3H), 2.81 (s, 2H), 3.08 (t,
2H, J ) 9.0 Hz), 4.55 (t, 2H, J ) 9.0 Hz), 6.45 (s, 1H), and
6.47 (s, 1H); 13C-NMR (75 MHz, CDCl3) δ 18.9, 24.7, 28.5, 43.3,
45.8, 71.0, 108.6, 123.4, 124.1, 133.9, 137.6, 159.7, and 183.7.
Anal. Calcd for C14H18O3: C, 71.77; H, 7.74. Found: C, 71.84;
H, 7.79.
Gen er a l P r oced u r e for Sa m a r iu m (II) Diiod id e Red u c-
tion s. To a solution containing 25 mL (2.5 mmol) of 0.1 M
samarium(II) diiodide in THF was added a solution containing
0.13 g (0.46 mmol) of the appropriate cycloadduct in 2 mL of
THF followed by 0.5 mL (12 mmol) of MeOH at -78 °C. The
reaction mixture was stirred for 15 min under argon until the
blue color disappeared, and then the reaction was quenched
with water and extracted with ether. After removal of the
solvent, the residue was purified by silica gel chromatography
to give the ring opened product.
transformation to dione 55 but only in 14% yield. Since
dehydroilludin (M) 55 had previously been converted to
(()-illudin M,20 its formation from 54 constitutes a formal
synthesis of this unique sesquiterpene. The major prod-
uct (56%) isolated from the DDQ oxidation of 54 cor-
responded to the isodehydroilludin M analog 6.
In summary, the Rh(II)-catalyzed cyclization-cycload-
dition methodology is amenable to the synthesis of (()-
illudin M together with the novel antitumor analog
isodehydroilludin M. We are currently investigating
further application of the method outlined here to related
sesquiterpenes.
Exp er im en ta l Section
Red u ction of Eth yl 6,6-Dim eth yl-5,8-ep oxy-8-m eth yl-
4-oxosp ir o[2.5]octa n e-5-ca r boxyla te (25). A 0.13 g (0.46
mmol) of cycloadduct 2530 was reduced according to the general
procedure to give 0.08 g (61%) of an inseparable 2:1 mixture
of the diastereoisomers of ethyl 2,2-dimethoxy-5-ethyl-4-meth-
yl-6-oxo-7-oxabicyclo[2.2.1]heptane-1-carboxylate (26): IR (neat)
1773, 1730, 1289, and 876 cm-1; 1H-NMR (300 MHz, CDCl3) δ
1.06 (t, 3H, J ) 7.5 Hz), 1.26-1.39 (m, 1H), 1.29 (t, 3H, J )
7.5 Hz), 1.57 (s, 3H), 1.65-1.77 (m, 1H), 2.00-2.03 (m, 3H),
3.20 (s, 3H), 3.33 (s, 3H), and 4.29 (m, 2H); 13C-NMR (75 MHz,
CDCl3) δ 12.6, 13.9, 20.8, 21.8, 43.8, 49.7, 50.8, 57.1, 61.8, 83.7,
93.7, 110.3, 163.1, and 203.6; HRMS Calcd for C14H22O6:
286.1416. Found: 286.1422.
Sa m a r iu m (II) Diiod id e-In d u ced Rin g-Op en in g of Eth -
yl 6,6-Dim eth yl-5,8-epoxy-8-m eth yl-4-oxospir o[2.5]octan e-
5-ca r boxyla te (25). A 0.2 g (0.7 mmol) sample of cycloadduct
2530 was reduced according to the general procedure but
without added MeOH to give 0.16 g (85%) of an inseparable
4:1 mixture of the diastereomers of ethyl 4-[(methoxycarbonyl)-
methyl]-4-methyl-7-oxo-5-oxaspiro[2.4]heptane-6-carboxy-
late (27): IR (neat) 1731, 1323, 1197, 1092, and 835 cm-1; 1H-
NMR (300 MHz, CDCl3) major isomer: δ 0.94 (m, 1H), 1.08-
1.26 (m, 6H), 1.35 (s, 3H), 2.47 (d, 1H, J ) 16.2 Hz), 2.68 (d,
1H, J ) 16.2 Hz), 3.59 (s, 3H), 4.18 (m, 2H), and 4.79 (s, 1H);
1H-NMR (300 MHz, CDCl3) minor isomer: δ 0.94 (m, 1H),
1.08-1.26 (m, 6H), 1.35 (s, 3H), 2.71 (m, 2H), 3.59 (s, 3H), 4.18
(m, 2H), and 4.68 (s, 1H); 13C-NMR (75 MHz, CDCl3) δ 14.1,
14.7, 16.3, 17.4, 18.9, 25.5, 26.4, 35.7, 44.7, 51.6, 61.9, 79.2,
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed in flame-dried glassware under
an atmosphere of dry nitrogen. Solutions were evaporated
under reduced pressure with a rotary evaporator, and the
residue was chromatographed on a silica gel column using an
ethyl acetate-hexane mixture as the eluent unless specified
otherwise.
Sp ir o[1,4,4-tr im eth yl-10-oxa tr icyclo[5.2.1.02,6]d eca n e-
3,8-d ion e-9,1′-cyclop r op a n e] (17). To a solution containing
0.4 g (1.9 mmol) of spiro[1-methyl-10-oxatricyclo[5.2.1.02,6]deca-
3,8-dione-9,1′-cyclopropane] (30)30 in 10 mL of dry THF was
added 0.35 mL (5.7 mmol) of potassium hexamethyldisilazide
at -78 °C, and the reaction mixture was stirred at this
temperature for 30 min. To this mixture was added 0.35 mL
(5.7 mmol) of iodomethane in one portion, and the resulting
solution was stirred at -78 °C for 1 h. The reaction was
allowed to slowly warm to rt, quenched with water, extracted
with ether, dried over MgSO4, and concentrated under reduced
pressure. The crude residue was purified by silica gel chro-
matography to give 0.23 g (48%) of 17 as a white solid: mp
120-121 °C; IR (neat) 1754, 1732, 1381, and 980 cm-1 1H-
;
NMR (300 MHz, CDCl3) δ 0.66 (m, 1H), 0.93-1.14 (m, 2H),
0.99 (s, 3H), 1.03 (s, 3H), 1.26 (s, 3H), 1.28 (m, 1H), 1.76 (dd,
1H, J ) 13.2 and 7.8 Hz), 2.11 (dd, 1H, J ) 13.2 and 9.0 Hz),
2.65 (d, 1H, J ) 8.4 Hz), 2.82 (q, 1H, J ) 8.4 Hz), and 4.23 (s,
1H); 13C-NMR (75 MHz, CDCl3) δ 11.8, 13.5, 14.4, 22.5, 25.8,

Approach toward the Illudin Family of Sesquiterpenes
J . Org. Chem., Vol. 62, No. 5, 1997 1323
80.4, 81.7, 167.0, 170.4, and 206.9; HRMS Calcd for C13H18O6:
270.1103. Found: 270.1104.
2.06 (m, 1H), 2.29-2.41 (m, 1H), and 2.47-2.54 (m, 1H); 13C-
NMR (75 MHz, CDCl3) δ 6.8, 17.2, 20.5, 25.4, 26.6, 28.8, 32.7,
39.3, 39.4, 42.1, 72.8, and 210.6; HRMS Calcd for C12H18O2:
194.1307. Found: 194.1316.
R ed u ct ion of 6,6-Dim et h oxy-5,8-ep oxy-8-m et h yl-4-
oxa sp ir o[2.5]octa n e (28). A 0.1 g (0.47 mmol) sample of 2830
was reduced according to the general procedure to give 0.05 g
(62%) of 8-hydroxy-6-methoxy-8-methylspiro[2.5]oct-5-en-4-one
(29): IR (neat) 1623, 1445, 1190, and 816 cm-1; 1H-NMR (300
MHz, CDCl3) δ 0.81 (m, 1H), 1.00-1.10 (m, 2H), 1.18 (m, 1H),
1.21 (s, 3H), 1.70 (s, 1H), 2.57 (d, 1H, J ) 16.8 Hz), 2.66 (d,
1H, J ) 16.8 Hz), 3.70 (s, 3H), and 5.45 (s, 1H); 13C-NMR (75
MHz, CDCl3) δ 11.6, 11.8, 25.6, 35.4, 43.0, 55.8, 70.6, 101.4,
174.9 and 197.9; HRMS Calcd for C10H14O3: 182.0943.
Found: 182.0948.
Dim et h yl 4-H yd r oxy-4-m et h yl-8-oxosp ir o[2.5]oct -6-
en e-5,6-d ica r boxyla te (38). To a solution containing 0.34
mL (2.4 mmol) of diisopropylamine in 5 mL of THF was added
0.9 mL (2.2 mmol) of n-BuLi at -78 °C, and the mixture was
stirred at this temperature for 15 min under argon. A solution
containing 0.5 g (1.9 mmol) of dimethyl 4,7-epoxy-4-methyl-
8-oxospiro[2.5]octane-5,6-dicarboxylate (37)30 in 5 mL of THF
was slowly added, and the mixture was allowed to stir for 10
min. The solution was quenched with a saturated aqueous
NH4Cl solution and extracted with ether. The organic layer
was dried over MgSO4, the solvent was removed under reduced
pressure, and the crude residue was purified by silica gel
chromatography to give 0.38 g (78%) of a 8:3 mixture of the
diastereomers of 38: major isomer: IR (neat) 1726, 1663, 1158,
and 779 cm-1; 1H-NMR (300 MHz, CDCl3) δ 0.90-0.97 (m, 1H),
1.08-1.22 (m, 2H), 1.19 (s, 3H), 1.26-1.34 (m, 1H), 2.29 (brs,
1H), 3.71 (s, 3H), 3.81 (s, 3H), 3.92 (s, 1H), and 6.87 (s, 1H);
13C-NMR (75 MHz, CDCl3) δ 12.4, 15.2, 23.3, 36.2, 52.5, 52.7,
53.6, 72.5, 133.3, 141.8, 166.3, 169.8, and 197.8; HRMS Calcd
for C13H16O6: 268.0947. Found: 268.0960.
Red u ction of Sp ir o[1-m eth yl-10-oxa tr icyclo-[5.2.1.02,6]-
d eca -3,8-d ion e-9,1′-cyclop r op a n e] (30). A 0.32 g (1.6 mmol)
of cycloadduct 3030 was reduced according to the general
procedure to give spiro[7-hydroxy-7-methylhexahydro-indene-
1,5-dione-6,1′-cyclopropane] (31) (62%) as a yellow oil: IR
(neat) 1752, 1446, 1382, and 991 cm-1 1H-NMR (300 MHz,
;
CDCl3) δ 0.85-0.95 (m, 2H), 1.05-1.25 (m, 1H), 1.20-1.35 (m,
1H), 1.25 (s, 3H), 1.80-1.95 (m, 1H), 2.10-2.25 (m, 1H), 2.40-
2.55 (m, 3H), 2.60-2.75 (m, 2H), 2.90-3.05 (m, 1H), and 4.18
(s, 1H, exchanged with D2O); 13C-NMR (75 MHz, CDCl3) δ 10.0,
14.7, 26.7, 27.6, 32.6, 36.7, 37.6, 41.6, 56.7, 71.9, 209.0, and
220.8; HRMS Calcd for C12H16O3: 208.1099. Found: 208.1099.
R ed u ct ion of Sp ir o[1,4,4-t r im et h yl-10-oxa -t r icyclo-
[5.2.1.02,6]decan e-3,8-dion e-9,1′-cyclopr opan e] (17). A 0.15
g (0.6 mmol) sample of cycloadduct 17 was reduced according
to the general procedure and was subsquently purified by silica
gel chromatography. The first fraction isolated from the
column contained 0.07 g (45%) of cis-spiro[7-hydroxy-2,2,7-
t r im et h ylh exa h ydr oin den e-1,5-dion e-6,1′-cyclopr opa n e]
(32a ): mp 110-111 °C; IR (CDCl3) 1718, 1675, 1374, and 1102
cm-1; 1H-NMR (300 MHz, CDCl3) δ 0.87-0.98 (m, 2H), 1.03-
1.10 (m, 1H), 1.09 (s, 3H), 1.11 (s, 3H), 1.19-1.28 (m, 1H), 1.37
(s, 3H),1.58 (dd, 1H, J ) 13.5 and 7.2 Hz), 2.12 (dd, 1H, J )
13.5 and 8.1 Hz), 2.53 (dd, 1H, J ) 16.8 and 6.6 Hz), 2.78 (dd,
1H, J ) 15.9 and 6.9 Hz), 2.82 (d, 1H, J ) 10.5 Hz), 2.94 (m,
1H), and 4.30 (s, 1H); 13C-NMR (75 MHz, CDCl3) δ 12.4, 15.8,
23.9, 26.0, 27.9, 28.5, 37.8, 42.6, 44.3, 46.0, 53.0, 71.9, 209.9,
and 225.4. Anal. Calcd for C14H20O3: C, 71.16; H, 8.53.
Found: C, 71.07; H, 8.52.
The second fraction isolated from the column contained 0.02
g (15%) of trans-spiro[7-hydroxy-2,2,7-trimethylhexahydroin-
dene-1,5-dione-6,1′-cyclopropane] (32b); mp 108-109 °C; IR
(CDCl3) 1718, 1675, 1374, and 1102 cm-1; 1H-NMR (300 MHz,
CDCl3) δ 0.89-0.96 (m, 1H), 0.99-1.15 (m, 2H), 1.08 (s, 3H),
1.10 (s, 3H), 1.26 (s, 3H), 1.34-1.40 (m, 1H), 1.53 (dd, 1H, J )
13.2 and 10.5 Hz), 2.22 (dd, 1H, J ) 13.8 and 6.6 Hz), 2.32
(dd, 1H, J ) 19.8 and 11.4 Hz), 2.80 (d, 1H, J ) 10.5), 2.85
-2.95 (m, 2H), and 3.29 (s, 1H); 13C-NMR (75 MHz, CDCl3) δ
13.6, 16.8, 22.5, 24.8, 25.7, 26.9, 38.8, 42.6, 46.5, 46.9, 53.8,
70.9, 209.8 and 225.4. Anal. Calcd for C14H20O3: C, 71.16;
H, 8.53. Found: C, 71.07; H, 8.52.
Min or isom er : IR (neat) 1723, 1666, 1012, and 777 cm-1
;
1H-NMR (300 MHz, CDCl3) δ 0.81-0.88 (m, 1H), 0.96-1.03
(m, 1H), 1.12-1.18 (m, 1H), 1.35 (s, 3H), 1.40-1.46 (m, 1H),
3.70 (s, 3H), 3.85 (s, 3H), 3.91 (s, 1H), 4.12 (s, 1H), and 5.03
(s, 1H); 13C-NMR (75 MHz, CDCl3) δ 9.1, 17.9, 27.8, 36.1, 50.8,
52.9, 53.0, 71.0, 133.6, 141.9, 166.0, 171.1, and 198.9; HRMS
Calcd for C13H16O6: 268.0947. Found: 268.0941.
5,8-Ep oxy-4-h yd r oxy-4,8-d im eth yl-7-(p h en ylsu lfon yl)-
sp ir o[2.5]octa n e (40). To a solution containing 0.35 g (2.1
mmol) of phenyl vinyl sulfone in 5 mL of benzene was added
a solution containing 0.32 g (2.1 mmol) of 1-acetyl-1-(diazoace-
tyl)cyclopropane (15),30 and the mixture was stirred in the
presence of 2 mg of rhodium(II) acetate. After stirring for 6 h
at rt, the solvent was removed under reduced pressure, and
the residue was purified by silica gel chromatography to give
0.48 g (79%) of a 8:3-mixture of the diastereomers of 5,8-epoxy-
8-methyl-4-oxo-7-(phenylsulfonyl)spiro[2.5]octane (39): major
isomer: mp 170-171 °C; IR (CDCl3) 1749, 1436, 1372, and
1145 cm-1; 1H-NMR (300 MHz, CDCl3) δ 0.81(m, 1H), 1.04 (m,
1H), 1.12 (m, 1H), 1.38 (m, 1H), 1.65 (s, 3H), 1.83 (dd, 1H, J )
13.8 and 8.7 Hz), 2.34 (m, 1H), 3.50 (dd, 1H, J ) 8.7 and 6.0
Hz), 4.53 (d, 1H, J ) 6.3 Hz), 7.51-7.65 (m, 3H), and 7.85 (m,
2H); 13C-NMR (75 MHz, CDCl3) δ 12.2, 14.9, 31.3, 40.3, 66.8,
79.4, 87.1, 128.3, 129.4, 133.9, 139.0, and 210.6. Anal. Calcd
for C15H16O4S: C, 61.63; H, 5.52. Found: C, 61.55; H, 5.51.
To a solution containing 0.2 g (0.7 mmol) of 39 in 8 mL of
THF was added 0.2 mL (0.7 mmol) of a solution of methyl-
magnesium iodide (3 M in hexane) at 0 °C. The mixture was
stirred for 4 h, quenched with a saturated NH4Cl solution and
extracted with ether. The solvent was removed under reduced
pressure, and the residue was purified by silica gel chroma-
tography to give 0.17 g (80%) of 40: mp 183-184 °C; IR
(CDCl3) 3502, 1296, 1139, and 1075 cm-1; 1H-NMR (300 MHz,
CDCl3) δ 0.25 (m, 1H), 0.54 (m, 1H), 0.65 (m, 1H), 0.85 (m,
1H), 1.15 (s, 3H), 1.20 (s, 1H), 1.43 (s, 3H), 1.98 (m, 1H), 2.36
(dd, 1H, J ) 12.9 and 9.0 Hz), 3.51 (dd, 1H, J ) 9.0 and 6.3
Hz), 4.18 (d, 1H, J ) 5.4 Hz), 7.49-7.62 (m, 3H), and 7.83 (d,
2H, J ) 6.9 Hz); 13C-NMR (75 MHz, CDCl3) δ 6.1, 8.3, 15.2,
26.2, 30.2, 40.5, 67.4, 76.9, 83.3, 88.6, 128.3, 129.2, 133.5, and
139.3. Anal. Calcd for C16H20O4S: C, 62.32; H, 6.54. Found:
C, 62.29; H, 6.50.
Red u ction of Sp ir o[5,8-ep oxy-1,4-m eth a n o-8-m eth yl-
6-oxoocta h yd r on a p h th a len e-7,1′-cyclop r op a n e] (33). A
0.01 g (0.5 mmol) of cycloadduct 3330 was reduced according
to the general procedure to give 0.07 g (75%) of spiro[8-
hydroxy-1,4-methano-8-methyl-6-oxooctahydronaphthalene-
7,1′-cyclopropane] (35): mp 106-107 °C; IR (CDCl3) 1682, 1367
1
and 1310 cm-1; H-NMR (300 MHz, CDCl3) δ 0.72-0.79 (m,
1H), 0.92-0.96 (m, 3H), 1.02 (s, 3H), 1.08 (m, 1H), 1.15-1.23
(m, 2H), 1.28-1.35 (m, 1H), 1.53-1.58 (m, 3H), 1.90-1.98 (m,
3H), 2.30-2.37 (m, 2H), and 2.72 (dd, 1H, J ) 14.7 and 13.5
Hz); 13C-NMR (75 MHz, CDCl3) δ 11.2, 17.6, 25.1, 29.0, 30.9,
34.2, 37.1, 38.4, 41.2, 41.3, 42.2, 51.4, 73.5, and 212.8. Anal.
Calcd for C14H20O2: C, 76.33; H, 9.15. Found: C, 76.25; H,
9.14.
4,8-Dim eth yl-7-(p h en ylsu lfon yl)sp ir o[2.5]oct-7-en e-4,5-
d iol (41). To a solution of containing 0.1 g (0.3 mmol) of 40
in 4 mL of THF was added 0.5 mL of a solution of n-
butyllithium (2.5 M in hexane) and the resultant mixture was
stirred for 3 h at rt. The reaction mixture was quenched by
the addition of a saturated aqueous NH4Cl solution and was
then extracted with ether. After removal of the solvent, the
residue was purified by silica gel chromatography to give 0.07
g (70%) of 41: mp 178-179 °C; IR (CDCl3) 1727, 1372, 1294,
Red u ction of Sp ir o[6,8a -ep oxy-7-oxo-octa h yd r on a p h -
th a len e-8,1′-cyclop r op a n e] (34). A 0.10 g (0.52 mmol)
sample of cycloadduct 3430 was reduced according to the
general procedure to give 0.07 g (70%) of spiro[8a-hydroxy-7-
oxooctahydronaphthalene-8,1′-cyclopropane] (36) as a thick
oil: IR (CDCl3) 3467, 1687, and 1449 cm-1; 1H-NMR (300 MHz,
CDCl3) δ 0.58-0.64 (m, 1H), 0.76-0.82 (m, 1H), 0.92-0.98 (m,
1H), 1.04-1.11 (m, 1H), 1.20 (m, 2H), 1.33-1.80 (m, 9H), 1.92-
and 1131 cm-1
;
1H-NMR (300 MHz, CDCl3) δ 0.58 (m, 1H),
0.86 (m, 1H), 0.98 (m, 1H), 1.03 (s, 3H), 1.15 (m, 1H), 1.76 (s,

1324 J . Org. Chem., Vol. 62, No. 5, 1997
Padwa et al.
3H), 2.23-2.24 (m, 2H), 3.00 (dd, 1H, J ) 17.4 and 6.3 Hz),
3.77 (dd, 1H, J ) 9.9 and 6.3 Hz), 7.50-7.61 (m, 3H), and 7.83
(d, 2H, J ) 7.5 Hz); 13C-NMR (75 MHz, CDCl3) δ 7.1, 10.4,
14.4, 18.9, 32.1, 33.7, 71.2, 71.8, 126.9, 129.1, 130.3, 133.0,
141.7, and 150.2. Anal. Calcd for C16H20O4S: C, 62.32; H,
6.54. Found: C, 62.06; H, 6.70.
extracted with ether, and dried over anhydrous MgSO4. After
removal of the solvent, the residue was purified by silica gel
chromatography to give 0.34 g (87%) of 49 as a white solid:
mp 91-92 °C; IR (neat) 3487, 1730, 1452, and 1374 cm-1; 1H-
NMR (300 MHz, CDCl3) δ 0.03 (m, 1H), 0.40 (m, 1H), 0.54 (m,
1H), 0.71 (m, 1H), 0.87 (s, 3H), 0.91 (s, 3H), 0.98 (s, 3H), 1.07
(s, 3H), 1.44 (m, 1H), 1.90 (m, 1H), 2.37 (m, 1H), 2.45 (d, 1H,
J ) 7.0 Hz), 3.22 (dd, 1H, J ) 7.0 and 6.0 Hz), and 3.80 (s,
1H); 13C-NMR (75 MHz, CDCl3) δ 5.9, 7.7, 14.0, 22.6, 26.1, 26.3,
36.5, 39.8, 40.9, 46.8, 56.3, 76.5, 89.3, 89.4, and 222.4. Anal.
Calcd for C15H22O3: C, 71.97; H, 8.86. Found: C, 71.68; H,
8.69.
Sp ir o[4,5-d ih yd r oxy-2,2,5,7-tetr a m eth yl-2,3,3a r,4,5,6-
h exa h yd r oin d en -1-on e-6,1′-cyclop r op a n e] (50). A solu-
tion containing 0.25 g (1.0 mmol) of 49 and 10 mL of 10% KOH
in MeOH was heated at reflux for 5 h. The reaction mixture
was cooled, neutralized with 1 N HCl, and extracted with
ether. The organic layer was dried over anhydrous MgSO4,
and the crude residue obtained after removal of the solvent
was purified by silica gel chromatography to give 0.2 g (80%)
of 50 as a white solid: mp 134-135 °C; IR (neat) 3459, 1687,
1609, 1450, and 1367 cm-1; 1H-NMR (300 MHz, CDCl3) δ 0.98
(m, 4H), 1.04 (s, 3H), 1.07 (s, 6H), 1.69-1.73 (m, 3H), 1.84 (d,
3H, J ) 2.1 Hz), 3.33 (m, 2H), and 3.63 (d, 1H, J ) 3.6 Hz);
13C-NMR (75 MHz, CDCl3) δ 6.6, 11.8, 13.8, 22.9, 24.5, 24.7,
29.1, 36.0, 36.2, 45.9, 73.3, 73.8, 128.2, 149.5, and 209.9. Anal.
Calcd for C15H22O3: C, 71.97; H, 8.86. Found: C, 71.95; H,
8.85 .
2-(p-Tolylsu lfon yl)-5,5-d im eth ylcyclop en ten on e (46). A
mixture containing 0.91 g (2.0 mmol) of (trimethylacetyl)-
[phenyl[[(trifluoromethyl)sulfonyl]oxy]iodo]acetylene (43)42 and
0.36 g (2.02 mmol) of anhydrous sodium p-toluenesulfinate in
30 mL of CH2Cl2 was allowed to stir for 30 min at rt. At the
end of this time, 20 mL of H2O was added and the two phases
were separated. The organic layer was dried over MgSO4, and
the solvent was removed under reduced pressure to give 0.39
g (73%) of 46 as a white solid: mp 125-126 °C; IR (KBr) 2930,
2870, 1722, 1706, and 1085 cm-1; 1H-NMR (CDCl3, 300 MHz)
δ 1.04 (s, 6H), 2.38 (s, 3H), 2.60 (d, 2H), 7.28 (d, 2H), 7.89 (d,
2H) and 8.33 (t, 1H); 13C-NMR (CDCl3, 75 MHz) δ 21.6, 24.6,
43.1, 45.8, 128.5, 129.7, 136.0, 144.6, 145.0, 167.3 and 203.7.
Anal. Calcd for C14H16O3S: C, 63.61; H, 6.10. Found: C,
63.54; H, 5.98.
Spir o[1,4,4-tr im eth yl-2-(p-tolylsu lfon yl)-10-oxatr icyclo-
[5.2.1.02,6]d eca -3,8-d ion e-9,1′-cyclop r op a n e] (47). To a
solution containing 0.83 g (6.5 mmol) of 1-acetyl-1-(diazoace-
tyl)cyclopropane (15)30 and 1.7 g (6.5 mmol) of 46 in 50 mL
dry CH2Cl2 was added 2 mg of rhodium(II) acetate, and the
reaction mixture was stirred at rt for 1 h. The solvent was
removed under reduced pressure, and the residue was purified
by silica gel chromatography to give 2.5 g (100%) of 47 as a
2:1 mixture of exo- and endo-isomers. The exo isomer exhibited
the following spectral properties: mp 222-223 °C; IR (neat)
1751, 1723, 1310, and 1147 cm-1; 1H-NMR (300 MHz, CDCl3)
δ 1.00 (m, 2H), 1.06 (s, 6H), 1.38 (m, 1H), 1.49 (s, 3H), 1.70
(m, 1H), 1.86 (m, 2H), 2.41 (s, 3H), 3.38 (m, 1H), 4.44 (s, 1H),
7.31 (d, 2H, J ) 8.1 Hz), and 7.65 (d, 2H, J ) 8.1 Hz); 13C-
NMR (75 MHz, CDCl3) δ 14.3, 15.8, 16.7, 21.6, 26.2, 38, 40.4,
44.7, 47.5, 86.4, 88.4, 92.7, 129.3, 129.8, 130.5, 136.1, 145.7,
210.0, and 214.3. Anal. Calcd for C21H24O5S: C, 64.93; H,
6.23; S, 8.25. Found: C, 65.03; H, 6.27; S, 8.30.
Spir o[8-h ydr oxy-1,4,4,8-tetr am eth yl-2â-(p-tolylsu lfon yl)-
10-oxa t r icyclo[5.2.1.02,6]d e ca -3,8-d ion e -9,1′-cyclop r o-
p a n e] (51). To a solution containing 1.0 g (2.6 mmol) of 47b
in 45 mL of THF at 0 °C was added 3 mL (3.1 mmol) of 3 M
methylmagnesium bromide solution, and the resulting mixture
was stirred at 0 °C for 5 h. The reaction mixture was quenched
by the addition of a saturated NH4Cl solution, extracted with
ether, and dried over anhydrous MgSO4, and the solvent was
removed under reduced pressure. The solvent was removed
under reduced pressure, and the residue was purified by silica
gel chromatography to give 0.84 g (80%) of 51 as a white
solid: mp 93-94 °C: IR (KBr) 3470, 1725, 1460, 1290, and
The endo isomer exhibited the following spectral proper-
ties: mp 168-169 °C; IR (neat) 1744, 1730, 1310, and 1139
cm-1; 1H-NMR (300 MHz, CDCl3) δ 0.72 (m, 2H), 0.95 (s, 3H),
1.15 (s, 3H), 1.23 (d, 2H, J ) 7.0 Hz), 1.44 (s, 3H), 1.70 (m,
1H), 2.15 (m, 1H), 2.37 (s, 3H), 4.09 (m, 1H), 4.50 (d, 1H, J )
6.0 Hz), 7.27 (d, 2H, J ) 8.1 Hz), and 7.62 (d, 2H, J ) 8.1 Hz);
13C-NMR (75 MHz, CDCl3) δ 14.1, 15.6, 15.7, 21.7, 27.1, 29.5,
33.5, 39.4, 45.9, 51.0, 83.4, 86.4, 88.9, 129.3, 131.1, 134.1, 145.5,
210.5, and 213.3. Anal. Calcd for C21H24O5S: C, 64.93; H,
6.23; S, 8.25. Found: C, 65.04; H, 6.25; S, 8.33.
1
1140 cm-1; H-NMR (300 MHz, CDCl3) δ 0.30-0.35 (m, 2H),
0.60-1.00 (m, 3H), 1.20 (s, 3H), 1.30 (s, 3H), 1.35 (s, 3H), 1.36
(s, 3H), 2.05 (m, 1H), 2.41 (s, 3H), 3.00 (dd, 1H, J ) 14.1 and
3.6 Hz), 4.03 (m, 1H), 4.17 (d, 1H, J ) 6.3 Hz), 7.26 (d, 2H, J
) 8.4 Hz), and 7.62 (d, 2H, J ) 8.4 Hz); 13C-NMR (75 MHz,
CDCl3) δ 6.5, 9.8, 16.9, 21.6, 26.9, 30.1, 31.0, 32.8, 37.4, 47.3,
52.0, 79.3, 83.4, 89.9, 91.5, 128.9, 131.2, 134.8, 144.8, and
215.9. Anal. Calcd for C22H28O5S: C, 65.32; H, 6.98. Found:
C, 65.23; H, 6.99.
Spir o[8-h ydr oxy-1,4,4,8-tetr am eth yl-2r-(p-tolylsu lfon yl)-
10-oxa t r icyclo[5.2.1.02,6]d e ca -3,8-d ion e -9,1′-cyclop r o-
p a n e] (48). To a solution containing 0.5 g (1.3 mmol) of 47
in 15 mL of THF at 0 °C was added 0.56 mL (1.7 mmol) of a
solution containing 3 M methylmagnesium iodide, and the
resulting mixture was stirred at rt for 4 h. The solution was
quenched by the addition of a saturated NH4Cl solution and
was extracted with ether. The combined organic layers were
washed with a 5% aqueous Na2S2O3 solution and dried over
anhydrous MgSO4, and the solvent was removed under
reduced pressure. The crude residue was purified by silica
gel chromatography to give 0.47 g (90%) of 48 as a white
solid: mp 119-120 °C: IR (neat) 3480, 1730, 1452, 1296, and
1139 cm-1; 1H-NMR (300 MHz, CDCl3) δ 0.04 (s, 3H), 0.65 (m,
1H), 0.57 (m, 1H), 0.99 (s, 3H), 1.01 (m, 1H), 1.15 (s, 3H), 1.25
(s, 3H), 1.32 (m, 1H), 1.66 (m, 1H), 1.79 (m, 1H), 2.38 (s, 3H),
3.82 (m, 1H), 4.13 (s, 1H), 4.18 (s, 1H), 7.28 (d, 2H, J ) 8.1
Hz), and 7.66 (d, 2H, J ) 8.1 Hz); 13C-NMR (75 MHz, CDCl3)
δ 8.6, 9.4, 15.3, 21.6, 25.7, 26.3, 26.4, 37.1, 41.2, 41.7, 47.1,
76.8, 86.9, 94.1, 94.5, 129.8, 130.6, 136.1, 145.6, and 215.6;
HRMS Calcd for C22H28O5S: 404.1657. Found: 404.1656.
Sp ir o[8-h yd r oxy-1,4,4,8-t et r a m et h yl-10-oxa t r icyclo-
[5.2.1.02,6]d eca -3,8-d ion e-9,1′-cyclop r op a n e] (49). To a
solution containing 0.63 g (1.56 mmol) of 48 in 10 mL of a 5:1
THF:MeOH mixture was added 0.82 g of 6% Na(Hg), and the
resulting mixture was stirred for 12 h at rt. The mixture was
quenched with water, washed with a 1 N HCl solution,
Sp ir o[8-h yd r oxy-1,4,4,8-t et r a m et h yl-10-oxa t r icyclo-
[5.2.1.02,6]d eca -3,8-d ion e-9,1′-cyclop r op a n e] (52). To a
solution containing 0.42 g (1.04 mmol) of 51 in 10 mL of a 5:1
THF:MeOH mixture was added 0.6 g of 6% Na(Hg), and the
resulting mixture was stirred for 12 h at rt. The reaction was
quenched by the addition of water, washed with a 1 N HCl
solution, extracted with ether, and dried over anhydrous
MgSO4. The solvent was removed under reduced pressure,
and the residue was purified by silica gel chromatography to
give 0.18 g (70%) of 52 as a white solid: mp 119-120 °C; IR
1
(neat) 3459, 1716, 1460, 1374, and 1146 cm-1; H-NMR (300
MHz, CDCl3) δ 0.29 (m, 1H), 0.45-0.53 (m, 1H), 0.57 (m, 2H),
1.01 (s, 3H), 1.06 (s, 3H), 1.22 (s, 3H), 1.26 (s, 3H), 1.68 (dd,
2H, J ) 13.2 and 9.6 Hz), 2.93 (d, 1H, J ) 12.0 Hz), 3.11 (dd,
1H, J ) 13.2 and 8.7 Hz), 3.24 (m, 1H), and 4.05 (d, 1H, J )
5.4 Hz); 13C-NMR (75 MHz, CDCl3) δ 5.2, 6.0, 19.3, 23.0, 27.1,
29.9, 35.1, 35.3, 42.6, 52.5, 62.1, 79.8, 84.8, 87.3, and 220.4.
Anal. Calcd for C15H22O3: C, 71.97; H, 8.86. Found: C, 71.77;
H, 8.91.
Sp ir o[4,5-d ih yd r oxy-2,2,5,7-t et r a m et h yl-2,3,3a â,4,5,6-
h exa h yd r oin d en e-1-on e-6,1′-cyclop r op a n e] (53). A solu-
tion containing 0.1 g (0.4 mmol) of 52 and 0.5 mL of 1.7 M
t-BuLi in 4 mL (0.8 mmol) of isopropyl ether was heated at
reflux for 2 h. The reaction mixture was cooled, quenched with
water and extracted with ether. The solvent was removed
under reduced pressure, and the residue was purified by silica
gel chromatography to give 0.07 g (70%) of 53 as a white

Approach toward the Illudin Family of Sesquiterpenes
J . Org. Chem., Vol. 62, No. 5, 1997 1325
solid: mp 104-105 °C; IR (CDCl3) 3445, 1687, 1595, 1374, and
of 54, 0.11 g (0.5 mmol) of DDQ, and 10 mg (0.05 mmol) of
p-TsOH.H2O in 20 mL of benzene was heated at reflux for 12
h. The reaction mixture was filtered, the solvent was removed
under reduced pressure, and the residue was purified by silica
gel chromatography to give a 1:4 mixture of spiro[5-hydroxy-
2,2,5,7-tetramethyl-5,6-dihydro-2H-indene-1,4-dione-6,1′-cyclo-
propane] (55)20 and spiro[5-hydroxy-2,2,5-trimethyl-7-methylene-
3,5,6,7-tetrahydro-2H-indene-1,4-dione-6,1′-cyclopropane] (6)
in 70% yield. The minor product 55 was a white solid: mp
1
1075 cm-1; H-NMR (300 MHz, CDCl3) δ 0.67 (m, 1H), 0.90-
1.10 (m, 3H), 1.04 (s, 3H), 1.06 (s, 3H), 1.17 (s, 3H), 1.36 (t,
1H, J ) 11.7 Hz), 1.80 (d, 3H, J ) 2.1 Hz), 2.15 (dd, 1H, J )
12.0 and 6.6 Hz), 2.68 (m, 3H), and 3.43 (d, 1H, J ) 9.0 Hz);
13C-NMR (75 MHz, CDCl3) δ 7.8, 11.2, 12.2, 20.4, 24.5, 24.7,
32.9, 40.9, 41.3, 46.2, 72.4, 77.9, 129.5, 151.2, and 209.9. Anal.
Calcd for C15H22O3: C, 71.97; H, 8.86. Found: C, 71.70; H,
8.82.
1
Sp ir o[5-h yd r oxy-2,2,5,7-t et r a m et h yl-3,3a ,5,6-t et r a h y-
d r o-2H-in d en e-1,4-d ion e-6,1′-cyclop r op a n e] (54). To a
solution containing 0.1 mL (1.1 mmol) of oxalyl chloride in 2
mL of CH2Cl2 was added a solution containing 0.15 mL (2.2
mmol) of dimethyl sulfoxide in 2 mL of CH2Cl2 at -78 °C. The
resulting mixture was stirred for 15 min at -78 °C, and a
solution containing 0.2 g (0.80 mmol) of a 5:3 mixture of
compounds 50/53 derived from cycloadduct 47 in 4 mL of CH2-
Cl2 was added. After stirring for 1 h, 0.4 mL of triethylamine
was added, and the mixture was allowed to warm to rt during
a period of 15 min. The reaction mixture was quenched with
water and extracted with ether. The combined organic layers
were washed with small amount of 1 N HCl solution and dried
over anhydrous MgSO4. The solvent was removed under
reduced pressure, and the residue was purified by silica gel
chromatography to give 0.15 g (75%) of 54 as a 5:3 mixture of
diasteromers; IR (CDCl3) 3473, 1694, 1609, 1452, and 1104
cm-1; major isomer: 1H-NMR (300 MHz, CDCl3) δ 0.62 (m,
1H), 1.00 (m, 1H), 1.08-1.20 (m, 2H), 1.10 (s, 3H), 1.11 (s, 3H),
1.51 (s, 3H), 1.80 (m, 1H), 1.89 (d, 3H, J ) 2.7 Hz), 2.01 (m,
1H), 3.68 (s, 1H), and 3.86 (m, 1H); minor isomer: 1H-NMR
(300 MHz, CDCl3) δ 0.50 (m, 1H), 0.94 (m, 1H), 1.01-1.20 (m,
2H), 1.06 (s, 3H), 1.12 (s, 3H), 1.21 (s, 3H), 1.63 (t, 1H, J )
12.0 Hz), 2.08 (d, 3H, J ) 3.0 Hz), 2.28 (m, 1H), 3.23 (s, 1H),
and 3.47 (m, 1H); 13C-NMR (75 MHz, CDCl3) δ 5.6, 8.4, 9.8,
11.1, 12.5, 14.6, 24.1, 24.2, 24.4, 24.5, 25.4, 32.4, 35.6, 37.1,
38.6, 43.9, 45.1, 45.8, 46.9, 73.7, 75.0, 128.1, 129.4, 151.1, 152.6,
207.3, 207.8, 210.1, and 214.8; HRMS Calcd for C15H20O3:
248.1412. Found: 248.1416.
66-67 °C; IR (CDCl3) 3488, 1703, 1618, and 1165 cm-1; H-
NMR (300 MHz, CDCl3) δ 0.59 (m, 1H), 1.05-1.17 (m, 2H),
1.19 (s, 3H), 1.24 (s, 3H), 1.33 (m, 1H), 1.34 (s, 3H), 2.04 (s,
3H), 3.61 (s, 1H), and 6.83 (s, 1H); 13C-NMR (75 MHz, CDCl3)
δ 11.7,12.8, 22.9, 23.0, 25.1, 33.8, 51.5, 75.6, 129.5, 134.8, 141.7,
151.2, 199.0, and 206.8. Anal. Calcd for C15H18O3:C, 73.15;
H, 7.37. Found: C, 73.19 ; H, 7.22.
The major product 6 was a yellow solid: mp 63-64 °C; IR
(CDCl3) 3491, 1700, 1672, and 1232 cm-1; 1H-NMR (300 MHz,
CDCl3) δ 0.21 (m, 1H), 0.93-1.06 (m, 3H), 1.19 (s, 3H), 1.20
(s, 3H), 1.34 (s, 3H), 2.52 (d, 1H, J ) 19.5 Hz), 2.73 (d, 1H, J
) 19.5 Hz), 3.30 (s, 1H), 5.29 (s, 1H), and 6.38 (s, 1H); 13C-
NMR (75 MHz, CDCl3) δ 4.2, 12.6, 24.8, 25.1, 25.4, 31.8, 38.8,
45.8, 75.5, 115.8, 138.6, 144.6, 151.8, 202.5 and 212.0. Anal.
Calcd for C15H18O3:C, 73.15; H, 7.37. Found: C, 73.24 ; H,
7.44.
Ack n ow led gm en t. We gratefully acknowledge the
National Cancer Institute (CA-26751), DHEW, for gen-
erous support of this work. Use of a high-field NMR
spectrometer used in these studies was made possible
through equipment grants from the NIH and NSF.
Su p p or tin g In for m a tion Ava ila ble: 1H-NMR and 13C-
NMR spectra for new compounds lacking analyses (9 pages).
This material is contained in libraries on microfiche, im-
mediately 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.
Oxid a t ion of Sp ir o[5-h yd r oxy-2,2,5,7-t et r a m et h yl-
3,3a ,5,6-t et r a h yd r o-2H -in d en e-1,4-d ion e-6,1′-cyclop r o-
p a n e] (54) w ith DDQ. A solution containing 0.1 g (0.4 mmol)
J O961574I