J. Am. Chem. Soc. 1999, 121, 5087-5088
5087
The acylfulvene class of compounds can function as alkylating
agents, and this ability has been attributed to their potent
cytotoxicity. For instance, McMorris et al. have shown that, at
an optimum pH of 5.6-6.1, illudin S reacts spontaneously with
sulfur nucleophiles such as glutathione (Scheme 1).1a Glutathione
adds in a Michael type fashion to the R,â-unsaturated ketone 4
to give the very reactive cyclohexadiene intermediate 5 which is
rapidly converted to the stable aromatic species 6 via a Julia type
fragmentation. It has been suggested that the nucleophiles may
range from water to cellular DNA to proteins.7b However, in an
extensive study to determine the mechanism of action of HMAF,
neither interstrand cross-links nor DNA-protein cross-links were
detected in cellular DNA.7a
The HMAF (3) used in these studies is obtained semisyntheti-
cally from the natural product illudin S (2). Illudin S is produced
in cultures of Omphalotus illudens (Jack o’Lantern mushroom),
and treatment of the illudin S with formaldehyde in 1 N H2SO4
solution gives HMAF (Scheme 2) via a reverse Prins reaction to
afford the intermediate acylfulvene which then undergoes an ene
reaction with formaldehyde.1b
A Short Synthesis of the Potent Antitumor Agent
(()-Hydroxymethylacylfulvene Using an Allenic
Pauson-Khand Type Cycloaddition
Kay M. Brummond* and Jianliang Lu
Department of Chemistry, West Virginia UniVersity,
Morgantown, West Virginia 26506-6045
ReceiVed February 10, 1999
The naturally occurring sesquiterpenes, illudin M (1) and S
(2), have been shown to possess potent antitumor activity, but
when tested in vivo were found to have a poor therapeutic index.1
Subsequently, illudin analogues have been prepared that show
greatly improved efficacy when compared with the parent
compounds.2 One analogue in particular, hydroxymethylacyl-
fulvene (3) (HMAF, also called MGI 114), has generated a
significant amount of excitement since it has proven effective
against breast, lung, and colon tumors in animal models while
exhibiting dramatically reduced toxicity.3 Furthermore, HMAF
is effective against the MDR phenotype.4
McMorris and co-workers8 have reported the only synthesis
of HMAF that features a Padwa type carbonyl ylide 1,3-dipolar
cycloaddition9 to arrive at the basic illudin skeleton. We would
like to report a shorter synthesis of HMAF utilizing an intra-
molecular [2 + 2 + 1] cycloaddition strategy developed in our
group which should also permit the preparation of new analogues
of the illudane class of compounds.10
The 3,6-dimethyl[4.3.0]nona-1,3,5-triene substructure embodied
in the skeleton is unique, and it was anticipated to be easily
accessible by application of an allenic variant of the Pauson-Khand
(P-K) type cycloaddition (Scheme 3). On the basis of our previous
investigations, we expected that a suitably functionalized alkynyl
allene 8 would cyclize to afford only 9 and none of the
R-methylene cyclopentenone 7 when subjected to our standard
cyclization protocol.10a,b The cycloadduct 9 could then be
methylated and dehydrated to afford the key ring system 10.
To that end, the readily available 1,1-diacetylcyclopropane
(11),11 was treated with the lithio derivative of the tert-butyl-
dimethylsilyl ether of 3-trimethylsilylpropyn-1-ol 12 (Scheme 4)
to afford ketone 13 as a 1.3:1 mixture of diastereomers in 57%
yield. These diastereomers were advanced through the synthetic
sequence in two ways. First, they were separated by column
chromatography and converted to acylfulvene 19 independently,
and second, they were taken on as a mixture to the final product,
HMAF. Next, addition of ethynylmagnesium bromide to ketone
13 in the presence of cerium(III) chloride gave the desired
propargyl alcohol 14a in 97% yield.12 Independent conversion
of the diastereomers of ketone 13 to the propargylic alcohol 14a
showed the major isomer affording a 9.2:1 mixture of inseparable
diastereomers and the minor isomer affording only one dia-
stereomer. Next, selective formation of the propargylic acetate
of the less-hindered tertiary alcohol gave diyne 14b in 98% yield.
HMAF (3) is currently in Phase II clinical trials which are being
supported by the National Cancer Institute (NCI)5 and MGI
Pharma, Inc.6 This series of Phase II trials will ultimately include
studies in breast, colon, renal, ovarian, nonsmall-cell lung, and
cervical cancers. The NCI is also conducting a Phase I study in
pediatric cancer patients with solid tumors. MGI Pharma, Inc.
has also started to enroll patients in a Phase II study in prostate,
pancreatic, and ovarian cancers. The ovarian cancer study involves
women with tumors that are no longer responding or did not
respond to a chemotherapy regimen that includes Taxol and
platinum-based reagents. The mechanism by which illudins
selectively kill cancer cells is not well understood. Illudins bind
covalently to DNA, but damage induced by these agents appears
to differ from that produced by other known toxins.7
* Corresponding author: (tel.) 304-293-3435 x4445; (fax) 304-293-4904;
(e-mail) kbrummon@wvu.edu.
(1) (a) McMorris, T. C.; Kelner, M. J.; Wang, W.; Diaz, M. A.; Estes, L.
A.; Taetle, R. Experientia 1996, 52, 75. (b) McMorris, T. C.; Kelner, M. J.;
Wang, W.; Yu, J.; Estes, L. A.; Taetle, R. J. Nat. Prod. 1996, 59, 896. For
previous syntheses of illudin M, see the following: Kinder, F. R., Jr.; Blair,
K. W. J. Org. Chem. 1994, 59, 6965; Matsumoto, T.; Shirahama, H.; Ichihara,
A.; Shin, H.; Kagawa, S.; Sakan, F.; Matsumoto, S.; Nishida, S. J. Am. Chem.
Soc. 1968, 90, 3280.
13
Treatment of propargylic acetate 14b with [CuH(PPh3)]6 gave
(2) (a) McMorris, T. C.; Yu, J.; Hu, Y.; Estes, L. A.; Kelner, M. J. J. Org.
Chem. 1997, 62, 3015. (b) McMorris, T. C.; Kelner, M. J.; Wang, W.; Estes,
L. A.; Montoya, M. A.; Taetle, R. J. Org. Chem. 1992, 57, 6876.
(3) (a) 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. (b) Kelner, M. J.; McMorris, T. C.; Estes, L. A.; Wang,
W.; Samson, K. M.; Taetle, R. InVestigational New Drugs 1996, 14, 161.
(4) Kelner, M. J.; McMorris, T. C.; Estes, L.; Samson, K. M.; Bagnell, R.
D.; Taetle, R. Eur. J. Cancer 1998, 34, 908.
NCI_CANCER_TRIALS/index.html. Search NCI’s Trials Database (PDQ).
product/mgi114abs.htm
the allene 15a in 54% yield. Finally, the trimethylsilyl moiety
was removed from the alkyne terminus using a standard protocol
(8) McMorris, T. C.; Hu, Y.; Yu, J.; Kelner, M. J. Chem. Commun. 1997,
315.
(9) Padwa, A.; Curtis, E. A.; Sandanayaka, V. P. J. Org. Chem. 1996, 61,
73.
(10) (a) Brummond, K. M.; Wan, H.; Kent, J. L. J. Org. Chem. 1998, 63,
6535. (b) Brummond, K. M.; Wan, H. Tetrahedron Lett. 1998, 39, 931. (c)
Kent, J. L.; Wan, H.; Brummond, K. M. Tetrahedron Lett. 1995, 36, 2407.
(11) Ogoshi, H.; Kikuchi, Y.; Yamaguchi, T.; Toi, H.; Aoyama, Y.
Organometallics 1987, 6, 2175. 1,1-Diacetylcyclopropane was prepared from
2,4-pentanedione, 1,2-dibromoethane, and potassium carbonate in DMF.
(12) Hayashi, Y.; Nishizawa, M.; Sakan, T. Tetrahedron 1977, 33, 2513.
(13) Daeuble, J. F.; McGettigan, C.; Stryker, J. M. Tetrahedron Lett. 1990,
31, 2397.
(7) (a) Woynarowski, J. N.; Napier, C.; Koester, S. K.; Chen, S.-F.; Troyer,
D.; Chapman, W.; MacDonald, J. R. Biochem. Pharmacol. 1997, 54, 1181.
(b) McMorris, T. C.; Yu, J.; Estes, L. A.; Kelner, J. Tetrahedron 1997, 53,
14579.
10.1021/ja990426h CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/14/1999