Total synthesis of the sesquiterpene (+/-)-illudin C via an intramolecular nitrile oxide cycloaddition.

Article abstract of DOI:10.1021/ol016314o

[reaction: see text] A convergent total synthesis of illudin C is described. The tricyclic ring system of the natural product was quickly assembled from cyclopropane and cyclopentene precursors via a novel oxime dianion coupling reaction and a subsequent intramolecular nitrile oxide-olefin cycloaddition.

Full text of DOI:10.1021/ol016314o

ORGANIC
LETTERS
2001
Vol. 3, No. 16
2611-2613
Total Synthesis of the Sesquiterpene
(±)-Illudin C via an Intramolecular Nitrile
Oxide Cycloaddition
Ronald A. Aungst, Jr., Collin Chan, and Raymond L. Funk*
Department of Chemistry, PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
rlf@chem.psu.edu
Received June 21, 2001
ABSTRACT
A convergent total synthesis of illudin C is described. The tricyclic ring system of the natural product was quickly assembled from cyclopropane
and cyclopentene precursors via a novel oxime dianion coupling reaction and a subsequent intramolecular nitrile oxide−olefin cycloaddition.
The illudins are an intriguing class of sesquiterpenes isolated
from several fungi.1 Their varied substitution patterns are
suggestive of nature’s attempts to optimize their cytotoxic
properties. These natural products can be structurally cat-
egorized according to the degree and position of unsaturation
in the unusual tricyclic ring system and the site of tertiary
hydroxyl substituents. Three different types of illudins result
from this analysis (Figure 1). Thus, illudin M/S embody a
conjugated C(4)-C(5)-C(9)-C(8) diene and C(2) tertiary
hydroxyl, whereas an unconjugated C(5)-C(9), C(2)-C(10)
diene and C(4) tertiary hydroxyl are found in the illudin C/C2/
C3 and illudinic acid group. Illudin A/B share features
common to both of the aforementioned groups, namely, C(2)
and C(4) tertiary hydroxyl substituents and C(5), C(9) sp2-
hybridized carbon atoms.
adduct has yet to be isolated since illudin S does not
spontaneously bind to DNA. It has been proposed that illudin
S is bioactivated, perhaps by conjugate addition of an
endogenous nucleophile (glutathione/NADH)2b to the enone
moiety. The resultant labile cyclohexadienol intermediate
then undergoes facile nucleophilic attack by DNA (or other
The cytotoxicity and anticancer activity of illudin S has
been most extensively investigated.2 The target of the
compound is believed to be DNA, although an illudin-DNA
(1) (a) Matsumoto, T.; Shirahama, H.; Ichihara, A.; Fukuoka, Y.;
Takahashi, Y.; Mori, Y.; Watanabe, M. Tetrahedron 1965, 21, 2671. (b)
Arnone, A.; Cardillo, R.; Nasini, G.; de Pava, O. V. J. Chem. Soc., Perkin
Trans. 1 1991, 733. (c) Arnone, A.; Cardillo, R.; Modugno, V.; Nasin, G.
Gazz. Chim. Ital. 1991, 121, 345. (d) Lee, I.-K.; Jeong, C. Y.; Cho, S. M.;
Yun, B. S.; Kim, Y. S.; Yu, S. H.; Koshino, H.; Yoo, I. D. J. Antibiot.
1996, 49, 821. (e) Dufresne, C.; Young, K.; Pelaez, F.; Gonzalez, A.;
Valentino, D.; Graham, A.; Platas, F.; Bernard, A.; Zink, D. J. Nat. Prod.
1997, 60, 188.
Figure 1.
10.1021/ol016314o CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/06/2001

biological targets) on the cyclopropane ring to produce a
stable aromatic compound.3 The low therapeutic index of
illudin S has precluded its development as a chemothera-
peutic agent. However, the semisynthetic illudin analogue,
6-(hydroxymethyl)acylfulvene (HMAF),4 shows outstanding
activity against breast, colon, lung, pancreas, prostate, and
skin cancers and is now in various Phase I, II, and III clinical
trials.5
Scheme 1
1d
Illudin C,1c C21d, and C3 and illudinic acid1e have only
recently been isolated, and the latter three have been shown
to possess antimicrobial activity against methicillin-resistant
Staphylococcus aureus (MRSA).1d,e The anticancer activity
of these compounds has not been reported, although cyto-
toxicity in a mammalian cell culture system has been
demonstrated.1e Although the total synthesis of the illudin
S/M type of natural products has been extensively investi-
gated,6 no synthetic entry to the illudin C variant is presently
available. In view of the successful analogue breakthrough
in the illudin S/M series, an efficient synthetic entry to the
illudin C type of natural products is highly desirable in order
to more fully investigate the cytotoxic properties of these
compounds and congeners. Herein we describe a flexible,
convergent strategy for the preparation of the illudin C class
of compounds that features a two-step elaboration of the fully
functionalized tricyclic ring system from appropriately
substituted cyclopentene and cyclopropane precursors.
Our retrosynthetic analysis for the synthesis of illudin C
(1) is outlined in Scheme 1. On the basis of the pioneering
investigations of Curran and Kozikowski,7 it was envisaged
that the R-methylene ketone functionality of illudin C could
be introduced via dehydration of the corresponding â-hy-
droxy ketone, in turn available from the hydrogenolysis-
hydrolysis reaction of isoxazoline 2. The conformationally
restricted alkenyl nitrile oxide 3 was anticipated to be an
excellent substrate for an intramolecular dipolar cycloaddition
to furnish isoxazoline 2 and could be generated by the
standard protocol, namely, oxidation of oxime 4. While the
obvious route to oxime 4 was from the corresponding
aldehyde, this would have necessitated prior protection of
the aldehyde moiety in order to effect a planned vinyl anion
coupling with cyclopropyl ketone 6. Instead, we were
intrigued by the possibility of employing dianion 5, prepared
by metalation of the corresponding â-halo unsaturated oxime,
in a more direct synthesis of oxime 4. Little in the way of
precedent for this transformation could be found in the
literature, although the preparation and alkylation of the
dilithium derivatives of saturated ketoximes (R-Li, O-Li)8
offered some encouragement to pursue this especially
convergent approach.
(2) (a) Kelner, M. J.; McMorris, T. C.; Estes, L.; Rutherford, M.;
Montoya, M.; Goldstein, J.; Samson, K.; Starr, R.; Taetle, R. Biochem.
Pharmacol. 1994, 48, 403. (b) Tanaka, K.; Inoue, T.; Tezuka, Y.; Kikuchi,
T. Chem. Pharm. Bull. 1996, 44, 273. (c) McMorris, T. C.; Kelner, M. J.;
Wang, W.; Moon, S.; Taetle, R. Chem. Res. Toxicol. 1990, 3, 574.
(3) Moreover, the damage produced by illudin S appears to differ from
that of other known cytotoxic agents since ERCC2 and ERCC3 (excision
repair cross complementing) helicases are required for repair.2a These
helicases, as opposed to ERCC1, are not upregulated in drug-resistant
tumors, which may be the underlying basis for the increased sensitivity of
certain MDR cell lines to the illudins.2a
To that end, we considered the preparation of cyclopen-
tenecarboxaldehyde 8 using a Vilsmeier-Haack procedure
(Scheme 2). Several examples in the literature suggested that
(4) (a) Weinreb, S. M.; McMorris, T. C.; Anchel, M. Tetrahedron Lett.
1971, 12, 3489. (b) McMorris, T. C.; Kelner, M. J.; Wang, W.; Diaz, M.
A.; Estes, L. A.; Taetle, R. Experientia 1996, 52, 75. (c) McMorris, T. C.;
Kelner, M. J.; Wang, W.; Yu, J.; Estes, L. A.; Taetle, R. J. Nat. Prod.
1996, 59, 896. (d) McMorris, T. C.; Yu, J.; Gantzel, P. K.; Istes, L. A.;
Kelner, M. J. Tetrahedron Lett. 1997, 38, 1687. (e) MacDonald, J. R.;
Muscoplat, C. C.; Dexter, D. L.; Mangold, G. L.; Chen, S. F.; Kelner, M.
J.; McMorris, T. C.; Von Hoff, D. D. Cancer Res. 1997, 57, 279. (f)
McMorris, T. C.; Yu, J.; Ngo, H.-T.; Wang, H.; Kelner, M. J. J. Med. Chem.
2000, 43, 3577.
Scheme 2
(5) These studies are being undertaken by MGI Pharma. For an extensive
compilation of relevant literature references, see: http://www.mgipharma-
.com/Products_in_Development/MGI_114/body_mgi_114.html.
(6) For previous synthetic effort, see: (a) Matsumoto, T.; Shirahama,
H.; Ichihara, A.; Shin, H.; Kawawa, S.; Sakan, F.; Matsumoto, S.; Nishida,
S. J. Am. Chem. Soc. 1968, 90, 3280. (b) Matsumoto, T.; Shirahama, H.;
Ichihara, A.; Shin, H.; Kagawa, S.; Sakan, F.; Miyano, K. Tetrahedron Lett.
1971, 12, 2049. (c) Kigoshi, H.; Imamura, Y.; Mizuta, K.; Niwa, H.;
Yamada, K. J. Am. Chem. Soc. 1993, 115, 3056. (d) Kinder, F. R., Jr.;
Bair, D. W. J. Org. Chem. 1994, 59, 6965. (e) Padwa, A.; Curtis, E. A.;
Sandanayaka, V. P. J. Org. Chem. 1997, 62, 1317. (f) McMorris, T.; Hu,
Y.; Yu, J.; Kelner, M. J. J. Chem. Soc., Chem. Commun. 1997, 315. (g)
Pirrung, M. C.; Kaliappan, K. P. Org. Lett. 2000, 2, 353. (h) Brummond,
K. M.; Lu, J. L.; Petersen, J. J. Am. Chem. Soc. 2000, 122, 4915. (i) Armone,
A.; Merlini, L.; Nasini, G.; de Pava, O. V.; Zunino, F. J. Chem. Soc. Perkin
Trans. 1 2001, 610.
this compound could be obtained from 3,3-dimethylcyclo-
pentan-1-one by regioselective attack of the bromo(dimethyl-
amino)methyl cation on the less encumbered enol (7, TES
2612
Org. Lett., Vol. 3, No. 16, 2001

) H).9 However, a nearly equal mixture of aldehyde 8 and
the regioisomeric product (2-bromo-5,5-dimethylcyclopent-
1-enecarboxaldehyde, 1.1:1) was obtained using PBr3/DMF
in methylene chloride. Consequently, we turned to the known
silyl enol ether 7,10 but unfortunately treatment with PBr3/
DMF afforded the same mixture of regioisomers, presumably
through initial hydrolysis of the silyl enol ether. To our
delight, if POBr3/DMF in methylene chloride was employed,
then only the aldehyde 8 regioisomer was formed in 64%
yield.11 Aldehyde 8 was then converted to the E-oxime 9
using the standard protocol in 82% yield.
Scheme 3
The preparation of the electrophilic component for the
pending coupling reaction, ketone 6 (Scheme 2), was more
straightforward and was initiated by bisalkylation of 2,4-
pentanedione with 1,2-dibromoethane to provide the known
cyclopropane 10.12 Monoreduction of diketone 10 to keto
alcohol 11 could be accomplished with Li(O-t-Bu)3AlH
(58%) and was accompanied by only minor amounts of the
corresponding diol. Although dehydration of the alcohol 11
to the olefin 6 took place upon treatment with the Burgess
reagent, this transformation was best performed by initial
conversion to the unstable iodide (82%) followed by distil-
lation from neat DBU to afford the volatile ketone 6 in 58%
yield.
We were now in the position to examine the two-step
merger of the cyclopropane and cyclopentene sectors of
illudin C (Scheme 3). Indeed, the dianion 5 could be prepared
by addition of t-BuLi (3 equiv) at -78 °C to bromo oxime
9. To minimize self-condensation products, the cyclopropyl
ketone 6 was diluted with THF and added slowly via syringe
pump (1 h) to the dianion 5 to afford the desired oxime 4 in
68% yield. We were pleased to discover that the final bond
of the tricyclic system formed readily upon treatment of the
oxime 4 with chloramine-T (EtOH, 40 °C, 6 h)13 to deliver
the isoxazoline 2 as a single diastereomer (99%). The cis
stereochemical relationship of the C(4) methyl substituent
and C(2) hydrogen atom in the resultant tetracycle was
assigned using NOE experiments. The diastereoselectivity
is a consequence of preferential cycloaddition of the nitrile
oxide through conformer 3 wherein the smaller C(4) hydroxyl
substituent, vis-a-vis the C(4) methyl substituent, occupies
an equatorial position bisecting the cyclopropane ring.
Transformation of the nitrile oxide-olefin cycloadduct 2
to illudin C (1) was uneventful (Scheme 3). Thus, Raney-
Ni-catalyzed hydrogenation of the N-O bond followed by
in situ hydrolysis of the resulting â-hydroxyimine according
to the Curran protocol (H2O, B(OH)3)14 furnished the formal
aldol adduct 12 in 72% yield. Finally, the one-pot dehydra-
tion of the primary alcohol functionality of diol 12 could be
accomplished by standard conversion to the mesylate (MesCl,
NEt3) followed by addition of DBU to provide racemic
illudin C (1, 73%) identical in all respects with published
spectra.1c
In summary, we have completed the first total synthesis
of illudin C in 10 steps and 8.2% overall yield starting from
allyl alcohol and isobutyraldehyde.10 In the course of the
synthesis we have demonstrated that silyl enol ethers can
be used in regiospecific Vilsmeier-Haack-type reactions,
that â-halo unsaturated oximes permit halogen metal ex-
change, and that an intramolecular nitrile oxide-olefin
cycloaddition facilitates an exceptionally concise route to the
illudin tricyclic ring system. The preparation of illudin C
analogues, as well as the extension of this synthetic sequence
to the construction of other ring systems embodied in
biologically active natural products, is underway in our
laboratories.
(7) (a) Curran, D. P. J. Am. Chem. Soc. 1982, 104, 4024. (b) Kozikowski,
A. P.; Stein, P. D. J. Am. Chem. Soc. 1982, 104, 4023. (c) Kozikowski, A.
P. Acc. Chem. Res. 1984, 17, 410. (d) Curran, D. P. AdV. Cycloadd. 1988,
1, 129.
(8) (a) Henoch, F. E.; Hampton, K. G.; Hauser, C. R. J. Am. Chem. Soc.
1969, 91, 676. (b) Jung, M. E.; Blair, P. A.; Lowe, J. A. Tetrahedron Lett.
1976, 17, 1439. (c) Kofron, W. G.; Yeh, M.-K. J. Org. Chem. 1976, 41,
439.
(9) (a) Iwata, C.; Ida, Y.; Miyashita, K.; Nakanishi, T.; Yamada, M.
Chem. Pharm. Bull. 1982, 30, 2738. (b) Karlsson, J. O.; Frejd, T. J. Org.
Chem. 1983, 48, 1921. (c) Coates, R. M.; Muskopf, J. W.; Senter, P. A. J.
Org. Chem. 1985, 50, 3541.
(10) (a) Magnus, P. D.; Nobbs, M. S. Synth. Commun. 1980, 10, 273.
(b) Exon, C.; Nobbs, M. S.; Magnus, P. D. Tetrahedron 1981, 37, 4515.
(11) To the best of our knowledge, this is the first example of a
regiospecific Vilsmeier-Haack haloformylation of a silyl enol ether. For
the chloroformylation of a silyl enol ether derived from a symmetrical ketone
(cyclohexanone), see: Reddy, D. P.; Tanimoto, S. Synthesis 1987, 575.
(12) Podder, R. K.; Sarkar, R. K.; Ray, S. C. Indian J. Chem. 1988,
27B, 530.
Acknowledgment. We appreciate the financial support
provided by the National Institutes of Health (GM28553).
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL016314O
(13) Hassner, A.; Rai, K. M. L. Synthesis 1989, 57.
(14) Curran, D. P. J. Am. Chem. Soc. 1983, 105, 5826.
Org. Lett., Vol. 3, No. 16, 2001
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