A triple diene-transmissive Diels-Alder strategy to build the quassinoid framework

Article abstract of DOI:10.1021/ol0522236

(Chemical Equation Presented) An advanced intermediate to the highly oxygenated triterpene quassinoids was prepared in 14 steps from tetrahydrofuran. The key steps are three diene-transmissive Diels-Alder cycloadditions. Several features of this synthesis are noteworthy, including a successful Mitsunobu reaction on an allenylic alcohol, a rare [4 + 2] cycloaddition involving an enethiol ether dienophile, and complete control over all 10 chiral centers created.

Full text of DOI:10.1021/ol0522236

ORGANIC
LETTERS
2005
Vol. 7, No. 25
5601-5604
A Triple Diene-Transmissive Diels
Strategy To Build the Quassinoid
Framework
−Alder
Ame´lie Dion, Pascal Dube´, and Claude Spino*
De´partement de Chimie, UniVersite´ de Sherbrooke, 2500 Boul. UniVersite´,
Sherbrooke, QC, Canada J1K 2R1
claude.spino@usherbrooke.ca
Received September 14, 2005
ABSTRACT
An advanced intermediate to the highly oxygenated triterpene quassinoids was prepared in 14 steps from tetrahydrofuran. The key steps are
three diene-transmissive Diels Alder cycloadditions. Several features of this synthesis are noteworthy, including a successful Mitsunobu
−
reaction on an allenylic alcohol, a rare [4
centers created.
+ 2] cycloaddition involving an enethiol ether dienophile, and complete control over all 10 chiral
Quassinoids are degraded triterpenes isolated from the stem
and bark of subtropical shrubs and trees belonging to the
Simaroubacea species.1,2 Their chemical synthesis is proving
inordinately difficult as judged by the small number of
successful syntheses (less than 20)3 that were reported since
the structure of the parent member, quassin (1), was
published in 1960 (Figure 1).4
preparation in the laboratory. Besides the challenge they pose
to synthetic chemists, efforts to prepare these compounds
by synthesis is spurred by the large spectra of biological
activities that many members of this family display (antiviral,
(1) For a review on the isolation and biological activities of quassinoids,
see: (a) Guo, Z.; Vangapandu, S.; Sindelar, R. W.; Walker, L. A.; Sindelar
R. D. Curr. Med. Chem. 2005, 12, 173-190. (b) Okano, M.; Fukamiya,
N.; Lee K. H. Stud. Nat. Prod. Chem. 1990, 7 (pt. A), 369-404. (c)
Polonsky, J. Fortschr. Chem. Org. Naturst. 1973, 30, 101-150. (d)
Polonsky, J. Fortschr. Chem. Org. Naturst. 1985, 47, 221-264.
(2) For a review on the synthesis of quassinoids, see: (a) Kawada, K.;
Kim, M.; Watt, D. S. Org. Prep. Proc. Int. 1989, 21, 521-618. (b) Murae,
T.; Sasaki M. Stud. Nat. Prod. Chem. 1992, 11, 71-111.
(3) For selected syntheses see: (a) Walker, D. P.; Grieco, P. A. J. Am.
Chem. Soc. 1999, 121, 9891-9892. (b) Grieco, P. A.; Collins, J. L.; Huffman
J. C. J. Org. Chem. 1998, 63, 9576-9579. (c) Shing, T. K. M.; Jiang, Q.
J. Org. Chem. 2000, 65, 7059-7069. (d) Hirota, M.; Yokoyama, A.; Miyaji,
K.; Nakamura, H.; Takahashi, T. Tetrahedron Lett. 1987, 28, 435-438.
(e) Stojanac, H.; Valenta, Z. Can. J. Chem. 1991, 69, 853-855. (f) Kim,
M.; Kawada, K.; Gross, R. S.; Watt, D. S. J. Org. Chem. 1990, 55, 504-
511. (g) Shing, T. K. M.; Jiang, Q.; Mak, T. C. W. J. Org. Chem. 1998,
63, 2056-2057. (h) VanderRoest, J. M.; Grieco, P. A. J. Org. Chem. 1996,
61, 5316-5325. (i) Hirota, H.; Yokoyama, A.; Miyaji, K.; Nakamura, T.;
Igarashi, M.; Takahashi, T. J. Org. Chem. 1991, 56, 1119-1127. (j) Kim,
M.; Kawada, K.; Gross, R. S.; Watt, D. S. J. Org. Chem. 1990, 55, 504-
511. For a relay synthesis see: (k) Sasaki, M.; Murae, T.; Takahashi, T. J.
Org. Chem. 1990, 55, 528-540.
Figure 1. Quassinoids having the picrasane framework.
Their highly oxygenated carbon framework, of which
bruceantin (2) is a typical example, and the large number of
stereocenters they contain are the principal obstacles to their
(4) (a) Valenta, Z.; Gray, A. H.; Papadopoulos, S.; Podesva, C.
Tetrahedron Lett. 1960, 1, 25-33. (b) Valenta, Z.; Gray, A. H.; Orr, D. E.;
Papadopoulos, S.; Podesva, C. Tetrahedron 1962, 18, 1433-1441.
10.1021/ol0522236 CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/11/2005

antimalarial, antineoplastic, and antifeedant properties).1
Recently reported biological activities suggest bruceantin
should be reinvestigated for clinical efficacy against hema-
tological malignancies, which has revived interest in this
family of natural products with the hope that it will lead to
a new therapeutic drug.5
Herein we report a highly efficient and stereoselective
preparation of an advanced pentacyclic intermediate 3
possessing 18 of the 20 carbons of the so-called picrasane
framework. The sequence encompasses three diene-transmis-
sive Diels-Alder cycloadditions (5 f 4 and 4 f 3 in Figure
2), each occurring with exquisite stereochemical control. This
to arise from a completely stereoselective addition of the
organolithium 10 to R-chloroketone 9 following the Felkin-
Anh model of nucleophilic addition to carbonyls.8
Propargylic epoxide 11 was opened by a stereospecific
SN2′ displacement using a higher order alkenylcyanocuprate
prepared from propenyllithium to give the unstable vinyla-
llene 12 (Scheme 2).9
Scheme 2. Preparation of Diene-Transmissive Precursor 4
Figure 2. Retrosynthetic strategy to the picrasane framework.
strategy constitutes a significant improvement over a previous
strategy, which involved only two diene-transmissive
[4 + 2] cycloadditions, and importantly, the previous
approach had failed to incorporate the C-10 methyl group
(cf. Figure 1).6
The synthesis starts with the conversion of tetrahydrofuran
to the protected iodobutanol 6, which was used to alkylate
the anion of tert-butylacetoacetate 7 to give 8 (Scheme 1).
Its stereochemistry was inferred from the stereochemistry
of a later intermediate (vide infra). Vinylallene 12 was
submitted to the Mitsunobu reaction condition with thioacetic
acid, giving the thioacetate 13 in 74% yield for the last two
steps. To the best of our knowledge, only one Mitsunobu
reaction on an allenic alcohol has been reported in the
literature,10 and it did not involve the use of a sulfur
nucleophile.
Scheme 1. Preparation of Propargylic Epoxide 11
The deprotection of the thiol in 13 was achieved in an
unusual way using hydrazine hydrate,11 and all attempts to
isolate the corresponding thiol were unsuccessful. Conse-
quently, coupling with methyl propiolate was performed
without isolating the thiol, and the cycloaddition product 14a
was directly obtained in 83% yield for the overall conversion.
The stereochemistry was assigned by analysis of the NOESY
spectrum of a very close analogue (see 14b in Supporting
(7) R-Chloroketones have been prepared in nonracemic form by the
alkylation of chiral R-chloro imidates and offers the possibility of an
asymmetric version of our synthesis. See: (a) Pridgen, L. N.; De Brosse,
C. J. Org. Chem. 1997, 62, 216-220. (b) Evans, D. A.; Sjogren, E. B.;
Weber, A. E.; Conn, R. E. Tetrahedron Lett. 1987, 28, 39-42.
(8) Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191-1223.
(9) For recent discussions on the mechanism of SN2′ cuprate displace-
ments, see: (a) Yamanaka, M.; Kato, S.; Nakamura, E. J. Am. Chem. Soc.
2004, 126, 6287-6293. (b) Karlstrom, A.; Sofia, E.; Ba¨ckvall, J.-E. Chem.
Eur. J. 2001, 7, 1981-1989. For selected examples involving alkylnyl
epoxides, see: (c) Dieter, R. K.; Chen, N.; Yu, H.; Nice, L. E.; Gore, V.
K. J. Org. Chem. 2005, 70, 2109-2119. (d) Ferna´ndez de la Pradilla, R.;
Viso, A.; Castro, S.; Ferna´ndez, J.; Manzano, P.; Tortosa, M. Tetrahedron
2004, 60, 8171-8180.
Chlorination of 8 followed by decarboxylation gave a
racemic mixture of R-chloroketone 9.7 Addition of alkynyl-
lithium 10 afforded a single diastereomer of epoxide 11 in
96% yield. The formation of the single isomer 11 is thought
(5) Cuendet, M.; Pezzuto, J. M. J. Nat. Prod. 2004, 67, 269-272.
(6) (a) Spino, C.; Hill, B.; Dube´, P.; Gingras, S. Can. J. Chem 2003, 81,
81-108. (b) Spino, C.; Liu, G.; Tu, N.; Girard, S. J. Org. Chem. 1994, 59,
5596-5608.
(10) Ma, S.; Yu, F.; Gao, W. J. Org. Chem. 2003, 68, 5943-5949.
(11) Endo, A.; Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama,
T. J. Am. Chem. Soc. 2002, 124, 6552-6554.
5602
Org. Lett., Vol. 7, No. 25, 2005

Information) where a NOE enhancement was observed
between the C13 methyl group and the C11 proton (cf.
Scheme 2). The stereochemistry of 14 is in line with the
stereochemistry observed in other similarly prepared com-
pounds.6a,12 It arises from an endo transition state in which
the enethiol-ester adopts the E geometry (Figure 3). It is
approach of ethylvinyl ether from the less hindered bottom
face of oxadiene 4, as expected (Figure 4, top).6 Heating 15
Figure 3. Transition states of the intramolecular cycloaddition
giving 14.
Figure 4. Transition states of the cycloadditions of 4 and 15.
probable that the addition of the thiol to the propiolate ester
is reversible but that the (E)-enethiol undergoes a faster
cycloaddition. The enethiol intermediate was never detected
during the reaction. The temperature at which this Diels-
Alder reaction occurs is remarkably low (25 °C) thanks to
an early transition state in which the severe steric interactions
of the final product (between the vinylic methyl and CH2-
OR groups) are not yet present.13
to 250 °C for 17 h resulted in the formation of only one
pentacyclic adduct 3 in 50% yield. Careful analysis of the
NOESY spectrum of 3 allowed us to unambiguously
establish its stereochemistry, which was later confirmed by
a single-crystal X-ray diffraction analysis of the sulfone
derivative 16 (Figure 5), thus confirming the earlier stere-
Deprotection and oxidation with IBX14 of both alcohols
in 14a gave a dialdehyde, which underwent a chemoselective
olefination using the Horners-Wadsworth-Emmons condi-
tions to afford compound 4 (Scheme 2). Only a trace of the
diolefination product was detected under the conditions used,
though exposure of the dialdehyde to an excess of the
phosphonate reagent did result in higher amounts of this
unwanted product being isolated.
The hetero-Diels-Alder cycloaddition of 4 and ethylvinyl
ether (EVE) proceeded in very good yield (76%) and
cycloadduct 15 was obtained as a single diastereomer
(Scheme 3). The stereochemistry of 15 results from an endo
Figure 5. Oxidation of compound 3 and ORTEP diagram of the
resulting sulfone 16.
Scheme 3. Two Diels-Alder Cycloadditions for the
Preparation of 3
ochemical assignment of compounds 11 and 14. We have
not yet fully investigated the use of Lewis acids to lower
the temperature at which the final cycloaddition takes place.
The stereochemistry of 3 results from an endo chairlike
transition state (Figure 4, bottom). It is interesting to note
that when the C10 methyl group and sulfur linkage are
absent, similar cycloadditions occur at 25 °C.6
The survival of the sulfide functionality to the reaction
conditions of the hetero- and the intramolecular Diels-Alder
reactions was welcome but somewhat unexpected in view
of the fact that analogous oxygen functionalities do not
(12) Dube´, P. Ph.D. Thesis, Universite´ de Sherbrooke, 2005.
(13) Spino, C.; Thibault, C.; Gingras, S. J. Org. Chem. 1998, 63, 5283-
5287.
(14) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001-3003.
Org. Lett., Vol. 7, No. 25, 2005
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withstand such conditions.6a,12 The main decomposition
pathway for these compounds is depicted in Figure 6. The
simple starting material and with complete control over the
stereochemistry of all 10 stereogenic centers. The enethiol
connector for the first Diels-Alder (13 f 14a) is a corner-
stone of the synthesis in that the sulfur linkage controls the
stereochemical outcome of both the first and third [4 + 2]
cycloadditions. Efforts toward the total synthesis of natural
quassinoids are continuing and will be reported in due course.
Acknowledgment. We thank the Natural Sciences and
Engineering Council of Canada and the Universite´ de
Sherbrooke for financial support.
Figure 6. Decomposition pathway of oxygen analogues of 15.
Supporting Information Available: Experimental pro-
cedures, characterization data, H NMR spectra for all new
1
compounds, and single-crystal X-ray analysis data for 16.
This material is available free of charge via the Internet at
http://pubs.acs.org.
presence of the sulfur atom in 3 will undoubtedly be useful
to introduce the C8-carbon and further elaborate ring A.
In conclusion, the synthesis of the advanced pentacyclic
intermediate 3 was achieved in only 14 steps from a very
OL0522236
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Org. Lett., Vol. 7, No. 25, 2005