A concise total synthesis of Dysidiolide through application of a dioxolenium-mediated diels - Alder reaction [1]

Full text of DOI:10.1021/ja9740428

J. Am. Chem. Soc. 1998, 120, 1615-1616
1615
Communications to the Editor
A Concise Total Synthesis of Dysidiolide through
Application of a Dioxolenium-Mediated Diels-Alder
Reaction
Steven R. Magnuson,† Laura Sepp-Lorenzino,‡
Neal Rosen,‡ and Samuel J. Danishefsky*,†,§
Department of Chemistry, Columbia UniVersity
HaVemeyer Hall, New York, New York, 10027
Laboratories for Bioorganic Chemistry
and Molecular Oncogenesis
Sloan-Kettering Institute for Cancer Research
1275 York AVenue, Box 106, New York, New York 10021
ReceiVed December 1, 1997
A variety of structurally fascinating and biologically active
natural products can be obtained from marine sources. The
isolation, structural formulation, and biological evaluation of
natural products from the aquatic biomass constitutes a frontier
of growing importance in chemistry. In some instances, where
the structures are especially novel or the biological profiles of
action hold particular promise, a program in total synthesis may
be appropriate. We felt that such a situation pertained in the case
of dysidiolide (1), a sesterterpene isolated from the marine sponge
Dysidea etheria de Laubenfels.1 From a biogenetic point of view,
structure 1 corresponds to a novel cyclization mode of an acyclic
C25 isoprenoid precursor. Moreover, the difficultly available
dysidiolide is a potent inhibitor of the human cdc25A protein
phosphatase.2,3 Since this class of enzymes (cdc25A, B and C)
is involved in dephosphorylation of cyclin-dependent kinases, it
has been proposed that inhibitors could produce specific cell cycle
arrest. Early results have shown that dysidiolide inhibits growth
of lung carcinoma and murine leukemia cell lines.1
Figure 1.
Scheme 1a
We approached the total synthesis problem from the perspective
of testing a dioxolenium (Gassman) type of activated dienophile
(Figure 1).4,5 We hoped to study a Diels-Alder reaction of the
type 2 + 4, wherein the presumed mechanistically active
intermediate (3) would undergo cycloaddition in the regiosense
indicated, and with tight diastereoface governance based on
differing demands of R1 and R2. Most interesting was the matter
of endo/exo selectivity. To reach 5, it would be necessary for
the dioxolenium function of 3 to direct endo in the Diels-Alder
a Reagents and conditions: (a) Me2CuLi, Et2O, -45 °C; ICH2CO2Et,
HMPA, -55 °C to rt (30-55%). (b) Superhydride, THF, -78 to -20
°C; imidazole, TBDPSCl, -20 °C to rt (68%). (c) i. LAH, Et2O; ii. TsCl,
pyridine, 0 °C; iii. NaI, acetone, ∆ (92% overall). (d) DME, HMPA,
-55 °C to rt (49%). (e) Tf2O, 2,6-di-tert-butyl-4-methylpyridine, CH2Cl2
(87%). (f) CH2dCHSnBu3, Pd(PPh3)4, LiCl, THF, ∆ (80%).
step.4,5a,6 The realization of this line of thinking is described below
in the context of a total synthesis of 1.
† Columbia University.
‡ Laboratory for Molecular Oncogenesis, Sloan-Kettering Institute for
Cancer Research.
The specific version of 2 which was selected to serve as the
operative dienophile was acetal 8. The synthesis of this com-
pound was accomplished starting with known dioxolane 6
(Scheme 1).7 Addition of lithium dimethylcuprate to 6, followed
by trapping with ethyl iodoacetate under the conditions indicated,8
afforded olefin 7. The ester function was converted to a protected
two-carbon alcohol residue, as shown, to provide dienophile 8.
The specific version of 4 selected as the operative diene was
structure 14. The synthesis of 14 commenced with the com-
mercially available unsaturated ester 9. The latter was converted
§ Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer
Research.
(1) Gunasekera, S. P.; McCarthy, P. J.; Kelly-Borges, M.; Lobkovsky, E.;
Clardy, J. J. Am. Chem. Soc. 1996, 118, 8759.
(2) Millar, J. B. A.; Russell, P. Cell 1992, 68, 407.
(3) Baratte, B.; Meijer, L.; Galaktionov, K.; Beach, D. Anticancer Res.
1992, 12, 873.
(4) For examples of Diels-Alder reactions using allylic acetals as the
dienophile, see: (a) Gassman, P. G.; Singleton, D. A.; Wilwerding, J. J.;
Chavan, S. P. J. Am. Chem. Soc. 1987, 109, 2182. (b) Sammakia, T.; Berliner,
M. A. J. Org. Chem. 1994, 59, 6890.
(5) For examples of Diels-Alder reactions using vinyl oxolenium ions
derived from different dienophiles, see: (a) Gassman, P. G.; Chavan, S. P. J.
Org. Chem. 1988, 53, 2392. (b) Gassman, P. G.; Chavan, S. P. Tetrahedron
Lett. 1988, 29, 3407. (c) Gassman, P. G.; Chavan, S. P. J. Chem. Soc., Chem.
Commun. 1989, 837. (d) Hashimoto, Y.; Saigo, K.; Machida, S.; Hasegawa,
M. Tetrahedron Lett. 1990, 39, 5625. (e) Hashimoto, Y.; Nagashima, T.;
Hasegawa, M.; Saigo, K. Chem. Lett. 1992, 1353. (f) Sipf, P.; Xu, W.
Tetrahedron 1995, 51, 4551.
(6) For an example of a Diels-Alder reaction with a similar diene giving
exo selectivity, see: Yoon, T.; Danishefsky, S. J.; de Gala, S. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 85.
(7) (a) Giusti, G. Bull. Chim. Soc. Fr. 1972, 753. (b) Le Coq, A.; Gorgues,
A. Organic Syntheses; Wiley: New York, 1988; Collect. Vol. 6, p 954.
(8) Alexakis, A.; Commercon, A.; Coulentianos, C.; Normant, J. F.
Tetrahedron 1984, 40, 715.
S0002-7863(97)04042-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/05/1998

1616 J. Am. Chem. Soc., Vol. 120, No. 7, 1998
Communications to the Editor
Scheme 2a
a 77% yield of dysidiolide identical in all respects with the natural
product by chromatographic and high-field NMR criteria.1 As
is the case with the natural product, dysidiolide, in solution, exists
as a mixture of C25 diastereomers. Upon crystallization, this
carbon emerges in the relative configuration shown.1
The power of the Gassman dioxolenium dienophile method is
underscored by the fact that trisubstituted analogues of 8, bearing
ester dienophiles instead of the acetal, were ineffective in the
Diels-Alder reaction. We also note that high selectivity for endo
addition was observed when a dioxane acetal of (Z)-2-methyl-
2-butenal was used as the dienophile in a Diels-Alder reaction
with diene 14. The adduct from this reaction was elaborated,
leading to “dysidiolides” stereoisomeric with 1 at carbons 6 and
7. The synthesis and evaluation of these stereo analogues will
be the subject of future disclosures.
With dysidiolide available to us through a concise total
synthesis (albeit for the moment as the racemate), we have begun
to investigate its biological profile. Indeed, within 24 h, dsyidi-
olide (2-50 µM) caused growth arrest on four human cancer cell
lines. In PC3, TSU-Pr1, and DU145 prostate cancer cells, growth
arrest was accompanied by massive apoptosis. In the MCF7
breast cancer cell line, the drug caused loss of the G2/M peak
and accumulation of cells in G1. These data are consistent with
the induction by dysidiolide of cell cycle specific growth arrest
followed by apoptosissa form of programmed cell deathsin
human cancer cells. At the chemical level, we are now attempting
to obtain ketone 12, or a functionally equivalent congener, in
optically pure form, in a straightforward manner so as to pave
the way for the synthesis of enantiomerically pure dysidiolide.
Also, studies are currently in progress to ascertain the specificity
of the biological target of dysidiolide and to pin down its effects
on cell cycle progression and cytotoxicity in detail. Results in
both areas will be described in due course.
a Reagents and conditions: (a) TMSOTf, CH2Cl2, -90 °C (67%). (b)
Montmorillonite K 10, CH2Cl2 (89%). (c) H2NNH2, KOtBu, n-butanol,
sealed tube, 150 °C (74%). (d) TPAP, NMO, ms, CH2Cl2 (90%). (e)
3-Lithiofuran, THF, -78 °C (34% + 56% C4 epimer). (f) i. p-
Nitrobenzoic acid, Ph3P, DEAD, benzene; ii. DIBAL, CH2Cl2, 0 °C (81%
overall). (g) O2, Rose Bengal, DIPEA, CH2Cl2, hν, -78 °C (77%).
to known iodide 10 as described.9 This compound served as an
alklylating agent with respect to the lithium enolate of 2-meth-
ylcyclohexanone (11)10 giving rise, albeit thus far in modest yield,
to ketone 12.11 This substance was converted to vinyl triflate
1312 and then, by a Stille cross coupling,13 to diene 14.
Diels-Alder reaction between 8 and 14 was conducted under
catalysis by TMSOTf4b as shown (Scheme 2). There was thus
obtained a 67% yield of adduct 15.14 In addition, ca. 5% of a
stereoisomer (structure not yet determined) was obtained. From
adduct 15, we advanced to dysidiolide in the manner shown.
Cleavage of the ketal15 in 15 was followed by Wolff-Kishner
reduction of the aldehyde function in 16 to produce, upon con-
comitant desilylation, alcohol 17. Following oxidation, aldehyde
18 was in hand. Addition of 3-lithiofuran16 to this compound,
under the conditions shown, gave rise to 19 and its C4 stereoi-
somer.17 Photooxidation of 19 with singlet oxygen16,18 provided
Acknowledgment. We dedicate this paper to the memory of Professor
Paul Gassman and to his many contributions to science. This work was
supported by the National Institutes of Health [grant nos. HL25848
(S.J.D.) and P50CA68425-02, Breast Cancer Spore Grant (N.R.)]. S.R.M.
gratefully acknowledges an NSERC (Canada) Postdoctoral Fellowship
(188211). The authors thank Dr. Sarath Gunasekara of the Harbor Branch
Oceanographic Institution for providing a sample of natural dysidiolide
and Mr. Tony Hascall of Columbia University for his help in obtaining
a key confirmatory X-ray crystal structure.14 We are grateful to Vinka
Parmakovich and Barbara Sporer of the Columbia University Mass
Spectral Facility.
(9) (a) Ansell, M. F.; Thomas, D. A. J. Chem. Soc. 1961, 539. (b)
Mazzocchi, P. H.; Wilson, P.; Khachik, F.; Klinger, L.; Minamikawa, S. J.
Org. Chem. 1983, 48, 2981.
(10) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979.
(11) Spijker-Assink, M. B.; Robijn, G. W.; Ippel, J. H.; Lutenburg, J. Recl.
TraV. Chim. Pays-Bas 1992, 111, 29.
Note Added in Proof. Recently, the total synthesis of
dysidiolide has been announced, see: Corey, E. J.; Roberts, B.
E. J. Am. Chem. Soc. 1997, 119, 12425.
JA9740428
(12) Stang, P. J.; Treptow, W. Synthesis 1980, 283.
(13) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033.
(14) The relative stereochemistry of adduct 15 was confirmed by X-ray
crystallographic analysis of the lactol produced by removal of the silyl and
acetal protecting groups.
(17) The undesired C4 epimer of 19 may be recycled, via oxidation to the
ketone and subsequent reduction, to the desired stereoisomer. The reduction
gives a mixture of C4 diastereomers that is processed. Alternatively, the
undesired C4 epimer of 19 may be converted into the desired compound (81%
yield) using a Mitsunobu inversion with p-nitrobenzoic acid and reduction of
the resulting ester. See: Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991,
32, 3017.
(15) Gautier, E. C. L.; Graham, A. E.; Makillop, A.; Standen, S. P.; Taylor,
R. J. K. Tetrahedron Lett. 1997, 38, 1881.
(16) Hagiwara, H.; Inome, K.; Uda, K. J. Chem. Soc., Perkin Trans. 1
1995, 757.
(18) Kernan, M. R.; Faulkner, D. J. J. Org. Chem. 1988, 53, 2773.