Catalytic crossed Michael cycloisomerization of thioenoates: total synthesis of (+/-)-ricciocarpin A.

Article abstract of DOI:10.1021/ol030035e

[reaction: see text] Thioenoates are found to participate in highly chemoselective catalytic crossed Michael cycloisomerization with appendant aryl ketone and enoate partners to afford cyclopentene and cyclohexene products. This methodology has enabled a

Full text of DOI:10.1021/ol030035e

ORGANIC
LETTERS
2003
Vol. 5, No. 10
1737-1740
Catalytic Crossed Michael
Cycloisomerization of Thioenoates:
Total Synthesis of (±)-Ricciocarpin A
Kyriacos Agapiou and Michael J. Krische*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Austin,
Austin, Texas 78712
mkrische@mail.utexas.edu
Received March 6, 2003
ABSTRACT
Thioenoates are found to participate in highly chemoselective catalytic crossed Michael cycloisomerization with appendant aryl ketone and
enoate partners to afford cyclopentene and cyclohexene products. This methodology has enabled a concise total synthesis of the potent
molluscicide (±)-ricciocarpin A.
Catalytic cycloisomerizations represent an important class
of atom economical transformation.1 Recently, the present
author and Roush disclosed an intramolecular variant of the
Rauhut-Currier reaction,2 a phosphine-catalyzed “Michael
cycloisomerization” of tethered R,â-unsaturated carbonyl
partners.3 A related study was subsequently reported by
Murphy.4 This transformation enables preparation of sub-
stituted cyclopentene and cyclohexene products under metal-
free conditions. Remarkably, due to the exceptional sensi-
tivity of this organocatalytic transformation with respect to
the electrophilicity of the reacting partners, the highly
chemoselective “crossed” cycloisomerization of nonsym-
metric precursors was demonstrated.3,4 Further extension of
scope is potentially achieved by expanding the repertoire of
reacting partners amenable to crossed cycloisomerization. In
this account, we report the highly chemoselective crossed
Michael cycloisomerization of thioenoates with appendant
aryl ketone and enoate partners to afford cyclopentene and
cyclohexene products. This methodology has enabled a
concise total synthesis of the potent molluscicidal agent (()-
ricciocarpin A.
(1) For reviews, see: (a) Trost, B. M. Science 1991, 256, 1471. (b) Trost,
B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259. (c) Trost, B. M.; Krische,
M. J. Synlett 1998, 1.
Impetus for these studies arose from difficulties encoun-
tered in the attempted Michael cycloisomerization of bis-
(enoates) 1a and 2a. While our initial studies establish
enoates as viable electrophilic partners for Michael cyclo-
isomerization,3a substrates 1a and 2a appear to be inert with
respect to trialkylphosphine addition under a range of
conditions. The low reactivity of 1a and 2a is attributed to
the relatively low reactivity of the â-substituted enoate
moiety, which prohibits conjugate addition of phosphine. As
enoate electrophilicity should parallel the acidity of the parent
(2) For selected examples of the Rauhut-Currier reaction, see: (a)
Rauhut, M. M.; Currier, H. (American Cyanamid Co.). U.S. Patent 3074999
19630122, 1963. (b) McClure, J. D. J. Org. Chem. 1970, 35, 3045. (c)
Basavaiah, D.; Gowriswari, V. V. L.; Bharathi, T. K. Tetrahedron Lett.
1987, 28, 4591. (d) Drewes, S. E.; Emslie, N. D.; Karodia, N. Synth.
Commun. 1990, 20, 1915. (e) Jenner, G. Tetrahedron Lett. 2000, 41, 3091.
(3) (a) Wang, L.-C.; Luis, A.-L.; Agapiou, K.; Jang, H.-Y.; Krische, M.
J. J. Am. Chem. Soc. 2002, 124, 2402. (b) Frank, S. A.; Mergott, D. J.;
Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404.
(4) Brown, P. M.; Kappel, N.; Murphy, P. J. Tetrahedron Lett. 2002,
43, 8707.
10.1021/ol030035e CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/22/2003

carbonyl compound, bis(thioenoates) were anticipated to be
a more reactive substrate class.5 Indeed, the enhanced
performance of thioenoates in Morita-Baylis-Hillman-type
cyclizations has been noted by Keck.6 To test this hypothesis,
bis(thioenoates) 3a and 4a were prepared through exhaustive
olefination of succinaldehyde and glutaraldehyde, respec-
tively, using previously reported stabilized Wittig reagents.7
Gratifyingly, upon exposure of bis(thioenoates) 3a and 4a
to catalytic trimethylphosphine at 30 °C in tert-butyl alcohol
solvent (0.1 M), cyclization proceeds smoothly to provide
good yields of the corresponding cyclopentene and cyclo-
hexene products 3b and 4b, respectively (Scheme 1).8
furanosesquiterpene lactone ricciocarpin A. Ricciocarpin A,
isolated from the liverwort Ricciocarpos natans, exhibits
potent molluscicidal activity against the water snail Biom-
phalaria glabrata, a vector of schistosomiasis.9 Among
humanparasitic diseases, schistosomiasis (sometimes called
bilharziasis) ranks second behind malaria in terms of
socioeconomic and public health importance in tropical and
subtropical areas, infecting more than 200 million people in
rural agricultural and periurban areas. Three safe, effective
drugs are now available to those infected with schistoso-
miasis: praziquantel, oxamniquine, and metrifonate. How-
ever, the long-term objective is to diminish the population
of the parasite vectors. Accordingly, the compound baylus-
cide (niclosamide) has been developed to kill infected water
snails.10 However, bayluscide is rather nonselective, having
adverse affects on native fish, contaminating their flesh.11
As such, ricciocarpin A has attracted considerable attention
from synthetic chemists, which has resulted in several
racemic syntheses12 and a single enantioselective synthesis.13
Using the methodology herein, and inspired by related
reductive Michael cyclization strategies,12d a concise total
synthesis of ricciocarpin A was envisioned, in accordance
with the retrosynthesis analysis depicted in Scheme 3. Here,
Scheme 1. Catalytic Cycloisomerization of Bis(thioenoates)
3a and 4a
Scheme 3. Retrosynthetic Analysis of Ricciocarpin A
The marked difference in reactivity between enoate and
thioenoate functional groups suggests that mixed monoenoate
monothioenoates 5a and 6a may participate in catalytic
crossed Michael cycloisomerization. Indeed, upon exposure
of 5a to the same conditions employed in the cyclization of
bis(thioenoates) 3a and 4a, cycloisomerization product 5b
is obtained in 89% yield. The isomeric material 5c could
not be detected by 1H NMR analysis. Analysis of the reaction
product by gas chromatography reveals that 5b is obtained
in 98% isomeric purity. Under identical conditions, the
homologous substrate 6a provides cyclohexene 6b in 82%
yield. Again, the isomeric material 6c could not be detected
ricciocarpin A should derive via catalytic Michael cyclo-
isomerization of an unsymmetrical bis(enone), which incor-
porates all carbons of the ricciocarpin skeleton. The indicated
boat conformation of ricciocarpin A has been established
1
by H NMR analysis. Analysis of the reaction product by
gas chromatography reveals that 6b is obtained in 99%
isomeric purity (Scheme 2).
1
through H NMR and NOE difference spectroscopy.14
(6) Keck, G. E.; Welch, D. S. Org. Lett. 2002, 4, 3687.
(7) Keck, G. E.; Boden, E. P.; Mabury, S. A. J. Org. Chem. 1985, 50,
709.
Scheme 2. Catalytic Cycloisomerization of Mixed
Monoenoate Monothioenoates 5a and 6a
(8) Procedure. Trimethylphosphine (20 mol %) was added to a 0.1 M
t
solution of substrate in BuOH under an atmosphere of argon, and the
reaction was allowed to stir at 30 °C until complete. The reaction mixture
was subjected to rotary evaporation, and the crude residue was purified by
silica gel chromatography to give the cyclized product.
(9) (a) Wurzel, G.; Becker, H. Phytochemistry 1990, 29, 2565. (b) Wurzel,
G.; Becker, H.; Eicher, T.; Tiefensee, K. Planta Med. 1990, 56, 444. (c)
Zinsmeister, H. D.; Becker, H.; Eicher, T. Angew. Chem. 1991, 103, 134.
(10) Nabih, I.; Elwasimi, M. T. J. Pharm. Sci. 1968, 57, 1202.
(11) Schreier, T. M.; Dawson, V. K.; Choi, Y.; Spanjers, N. J.; Boogaard,
M. A. J. Agric. Food Chem. 2000, 48, 2212.
(12) For racemic syntheses of ricciocarpin A, see: (a) Eicher, T.;
Massonne, K.; Herrmann, M. Synthesis 1991, 1173. (b) Ihara, M.; Suzuki,
S.; Taniguchi, N.; Fukumoto, K. J. Chem. Soc., Perkin Trans. 1 1993, 2251.
(c) Ihara, M.; Suzuki, S.; Taniguchi, N.; Fukumoto, K. Chem. Commun.
1993, 755. (d) Takeda, K.; Ohkawa, N.; Hori, K.; Koizumi, T.; Yoshii, E.
Heterocycles 1998, 47, 277.
At this point, further methodological refinement was
pursued in the context of a synthetic approach to the
(5) Cronyn, M. W.; Chang, M. P.; Wall, R. A. J. Am. Chem. Soc. 1955,
77, 3031.
(13) For an enantioselective syntheses of ricciocarpin A, see: Held, C.;
Frohlich, R.; Metz, P. Angew. Chem., Int. Ed. 2001, 40, 1058.
1738
Org. Lett., Vol. 5, No. 10, 2003

A modular approach to catalytic Michael cycloisomeriza-
tion substrates 8a-10a begins with the aldol condensation
of 3-acetylfuran with 2,2-dimethyl-hex-5-enal to afford
olefinic furyl enone 7. Ozonolytic cleavage of 7, followed
by exposure of the resulting aldehyde to selected stabilized
Wittig reagents, gave the cycloisomerization substrates 8a-
10a, which contain enoate, enal, and thioenoate moieties,
respectively (Scheme 4).
Scheme 5. Phosphine-Catalyzed Michael Cycloisomerization
of Furyl Enone Containing Substrates 8a-10a
Scheme 4. Preparation of Cycloisomerization Substrates
8a-10a
of diastereomers 11a and 11b was corroborated by NOE
difference spectroscopy. In an effort to attenuate over-
reduction, thioester 10b was converted to the corresponding
methyl ester 12. Exposure of 12 to the aforementioned
reduction conditions provides lactones 11a and 11b in 77%
yield as a 3:1 mixture of diastereomers, respectively. The
minor, undesired lactone isomer 11b may be converted to
11a via saponification-Mitsunobu inversion. Conjugate
reduction of the unsaturated lactone 11a using sodium
borohydride in pyridine16 provides (()-ricciocarpin A,
identical in all respects to previously reported material.9,12,13
Notably, the conjugate reduction of 11a to afford ricciocarpin
A is completely stereoselective (Scheme 6).
With compounds 8a-10a in hand, their ability to partici-
pate in phosphine-catalyzed Michael cycloisomerization was
examined. Consistent with the results pertaining to bis-
(enoates) 1a and 2a, exposure of monoenoate monofuryl
enone 8a to tributyl- or trimethylphosphine under a wide
range of conditions gives only trace quantities of the
corresponding cycloisomerization product 8b. The related
monoenal monofuryl enone 9a embodies a more electrophilic
pronucleophile. Upon exposure of 9a to the conditions
employed in the cyclization of thioenoates 3a-6a (Schemes
1 and 2), cycloisomerization product 9b is obtained in 38%
yield, along with products of decomposition. Conducting the
cycloisomerization under more dilute conditions and at higher
catalyst loading affords a 51% yield of the corresponding
cycloisomerization product 9b. Finally, monothioenoate
monofuryl enone 10a was examined. Upon exposure of 10a
to the conditions employed in the cyclization of thioenoates
3a-6a (Schemes 1 and 2), cycloisomerization product 10b
is obtained in 32% yield, along with recovered 10a. The use
of higher reaction temperatures overcomes the apparent lack
of reactivity, providing cycloisomerization product 10b in
81% yield (Scheme 5).
Scheme 6. Reductive Lactonization of 10b and 12a
Ricciocarpin A may be derived from thioester 10b via
reductive lactonization of the keto-ester followed by conju-
gate reduction. Direct concomitant reductive lactonization-
conjugate reduction of 10b or 12 proved to be unsuccessful.
Therefore, reductive lactonization of 10b was attempted.
Exposure of 10b to the reduction conditions described by
Luche15 provides lactones 11a and 11b in 55% yield as a
1:3 mixture of diastereomers, respectively, along with
products of over-reduction. The stereochemical assignment
a Conditions: MeONa, MeOH, 25 °C, 88%. (b) NaBH4,
CeCl3‚7H2O, MeOH, 25 °C. (c) LiOH, THF‚H2O (4:1), 25 °C. (d)
DIAD, Ph3P, CH2Cl2, 25 °C, 80% over two steps. (e) NaBH4,
pyridine, 25 °C, 78%.
In summary, thioenoates participate in highly chemo-
selective catalytic crossed cycloisomerization with appendant
aryl ketone and enoate partners to afford cyclopentene and
(14) Wurzel, G.; Becker, H. Phytochemistry 1990, 29, 2565.
(15) Luche, J.-L.; Gemal, A. L. J. Am. Chem. Soc. 1981, 103, 5454.
(16) Jackson, W. R.; Zuquiyah, A. J. Chem. Soc., Chem. Commun. 1965,
5280.
Org. Lett., Vol. 5, No. 10, 2003
1739

cyclohexene products, enabling a concise synthetic approach
to the furanosesquiterpene lactone ricciocarpin A. Future
studies will be devoted to the discovery of other reacting
partners amenable to crossed cycloisomerization and the
development of enantioselective variants of the catalytic
methodology reported herein.
Petroleum Research Fund, administered by the American
Chemical Society (34974-G1), the Research Corporation
Cottrell Scholar Award (CS0927), the Alfred P. Sloan
Foundation, and Eli Lilly for partial support of this research.
Supporting Information Available: Spectral data for all
new compounds (1H NMR, 13C NMR, IR, HRMS) and
NOESY spectra for 11a and 11b. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Acknowledgment is made to the
Robert A. Welch Foundation (F-1466), the NSF-CAREER
program (CHE0090441), the Herman Frasch Foundation
(535-HF02), the NIH (RO1 GM65149-01), donors of the
OL030035E
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Org. Lett., Vol. 5, No. 10, 2003