Meldrum's acid-derived thione dienophile in a convergent and stereoselective synthesis of a tetracyclic quassinoid intermediate

Article abstract of DOI:10.1021/ol060892t

An advanced intermediate toward anti-cancer quassinoids has been synthesized using a quadruple diene-transmissive [4+2]-cycloaddition strategy. High convergence is achieved thanks to a regio- and stereoselective hetero-Diels-Alder reaction using a thione. The relative stereochemistry of the final Diels-Alder adduct was controlled by tethered substituents introduced via a highly syn- and γ-selective vinylogous Mukaiyama aldol.

Full text of DOI:10.1021/ol060892t

ORGANIC
LETTERS
2
006
Vol. 8, No. 20
385-4388
Meldrum’s Acid-Derived Thione
Dienophile in a Convergent and
Stereoselective Synthesis of a
Tetracyclic Quassinoid Intermediate
4
St e´ phane Perreault and Claude Spino*
D e´ partement de Chimie, UniVersit e´ de Sherbrooke,
Sherbrooke, Qu e´ bec J1K 2R1, Canada
claude.spino@usherbrooke.ca
Received April 12, 2006
ABSTRACT
An advanced intermediate toward anti-cancer quassinoids has been synthesized using a quadruple diene-transmissive [4
strategy. High convergence is achieved thanks to a regio- and stereoselective hetero-Diels Alder reaction using a thione. The relative
Alder adduct was controlled by tethered substituents introduced via a highly syn- and -selective vinylogous
+2]-cycloaddition
−
stereochemistry of the final Diels
−
γ
Mukaiyama aldol.
Quassinoids, represented by quassin and bruceantin (Figure
), form a large family of naturally occurring and biologically
picrasane framework (Figure 1). Despite the fact that over
3
1
300 quassinoids have been identified since 1960, less than
2
0 completed total syntheses have been reported to date.4
Our basic strategy utilizes three diene-transmissive [4+2]-
cycloadditions taking full advantage of the power of the
Diels-Alder cycloaddition in building up molecular com-
plexity with efficient stereochemical control (Scheme 1).5
,6
(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., Part A 1990, 7, 369-404. (c)
Polonsky, J. Chem. Org. Naturst. 1973, 30, 101-150. (d) Polonsky, J. Chem.
Org. Naturst. 1985, 47, 221-264.
Figure 1. Representative quassinoids.
(
2) Cuendet, M.; Pezzuto, J. M. J. Nat. Prod. 2004, 67, 269-272.
(
3) (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.
(4) For selected syntheses, see: (a) Shing, T. K. M.; Yeung, Y. Y. Angew.
Chem., Int. Ed. 2005, 44, 7981-7984. (b) Grieco, P. A.; Collins, J. L.;
Huffman, J. C. J. Org. Chem. 1998, 63, 9576-9579. (c) Stojanac, H.;
Valenta, Z. Can. J. Chem. 1991, 69, 853-855. (d) Hirota, H.; Yokoyama,
A.; Miyaji, K.; Nakamura, T.; Igarashi, M.; Takahashi, T. J. Org. Chem.
active molecules isolated as bitter principles of subtropical
shrubs and trees of the Simaroubaceae genera. These heavily
1
oxygenated lactones are considered promising therapeutic
agents, thanks to their wide spectrum of biological activi-
ties.1 The majority of these degraded triterpenes possesses
the same carbon skeleton as quassin, the so-called C20
,2
1991, 56, 1119-1127. (e) Kim, M.; Kawada, K.; Gross, R. S.; Watt, D. S.
J. Org. Chem. 1990, 55, 504-511.
1
0.1021/ol060892t CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/29/2006

accomplish the final cycloaddition (Scheme 1, path a), the
dienophile tether Z in 8 would have to be cleaved at C2
and/or C11.
Scheme 1. Diene-Transmissive Diels-Alder Cycloaddition
Strategy and Decarboxylation Pathway to Form Diene 5
We report herein the successful realization of this strategy
involving four diene-transmissive Diels-Alder cycloaddi-
tions. The key feature of our approach is a remarkable regio-
and stereoselective hetero-Diels-Alder reaction involving
8
a Meldrum’s acid-derived thione dienophile.
We began with the synthesis of 1,3-dienes 7a,b. The
addition of the alkynyllithium derived from 9 to trans-
crotonaldehyde gave an allylic alcohol that was oxidized and
reacted with the anion of 1,3-dithiane to give 11 after
acetylation of the tertiary alcohol (Scheme 3). Deprotection
Scheme 3. Stereoselective Synthesis of 1,3-Dienes 7a and 7b
We have already demonstrated that, using a sulfur atom as
a connector (Z ) S in 2), all three Diels-Alder reactions
7
occur to give pentacyclic intermediate 3 (path a). An
interesting opportunity arose when a lactone (Z ) O
2
3
2
C in
) was used as a connector. The desired tetracyclic compound
was not formed, but we instead detected product 5, which
5
b
came from the decomposition of 2 according to path b.
At first glance, the decomposition of 2 into diene 5 seems
like an unfortunate event. However, we imagined that it could
be, in fact, a blessing in disguise. If this decomposition
process could be optimized to give, for example, diene 7
(Scheme 2) and if yet another [4+2]-cycloaddition could be
Scheme 2. Retrosynthetic Analysis
N
of the primary alcohol followed by an S 2′ displacement of
the acetate with a higher-order methylcuprate reagent led to
effected on diene 7, it would bring in a large fragment of
the molecule in a very convergent way while retransmitting
the original diene unit found in compound 2. Moreover, the
sequence involves no extra step because the decomposition
of 6 was effected during its formation (vide infra). To
vinylallene 12, with no byproduct resulting from the addition
9
on the double bond.
Fumaric acid monoethyl ester or 4-oxo-2-pentenoic acid10
was separately tethered to the primary alcohol using DCC
in benzene. There was no need to isolate 13a or 13b because
simply warming the reaction mixtures to 80 °C triggered a
stereoselective intramolecular Diels-Alder cycloaddition
yielding exclusively 14a or 14b, respectively. Both of these
(
5) (a) Spino, C. Synlett 2006, 23-32. (b) Spino, C.; Hill, B.; Dub e´ , P.;
Gringras, S. Can. J. Chem. 2003, 81, 81-108.
6) For reviews on the synthetic application of the Diels-Alder cycload-
(
dition, see: (a) Carruthers, W. In Cycloaddition Reactions in Organic
Synthesis; Pergamon Press: Oxford, U.K., 1990. (b) Nicolaou, K. C.;
Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int.
Ed. 2002, 41, 1668-1698. For reviews on an intramolecular Diels-Alder
cycloaddition, see: (c) Takao, K.; Munakata, R.; Tadano, K. Chem. ReV.
(8) For selected discussions of thiocarbonyl compounds as dienophiles,
see: (a) Vedejs, E.; Galante, R. J.; Goekjian, P. G. J. Am. Chem. Soc. 1998,
120, 3613-3622. (b) Rohr, U.; Schatz, J.; Sauer, J. Eur. J. Org. Chem.
1998, 2875, 5-2883.
(9) (a) Yamanaka, M.; Kato, S.; Nakamura, E. J. Am. Chem. Soc. 2004,
126, 6287-6293. (b) Karlstrom, A.; Sofia, E.; B a¨ ckvall, J.-E. Chem.-Eur.
J. 2001, 7, 1981-1989.
(10) Porter, N. A.; Scott, D. M.; Rosenstein, I. J.; Giese, B.; Veit, A.;
Zeitz, H. G. J. Am. Chem. Soc. 1991, 113, 1791-1799.
2
4
005, 105, 4779-4807. (d) Fallis, A. G. Acc. Chem. Res. 1999, 32, 364-
74. For reviews on a hetero-Diels-Alder cycloaddition, see: (e) Tietze,
L. F.; Kettschau, G. Top. Curr. Chem. 1997, 189, 1-120. (f) Boger, D. L.;
Weinreb, S. N. In Hetero-Diels-Alder Methodology; Wassermann, H., Ed.;
Acedemic Press: New York, 1987; Vol. 47. (g) Weinreb, S. N.; Staib, R.
S. Tetrahedron 1982, 38, 3087-3128.
(7) Dion, A.; Dub e´ , P.; Spino, C. Org. Lett. 2005, 7, 5601-5604.
4386
Org. Lett., Vol. 8, No. 20, 2006

structures were confirmed by single-crystal X-ray diffraction
Diethyl thiomalonate 16 reacted at room temperature to
afford a 1:2 mixture of cycloadducts 19a and 20a. Both
compounds arise from an attack of the dienophile on the
less-hindered R-face of the diene. The observed regioselec-
tivity is not easily explained by FMO theory. In any case,
we believed that steric effects could reverse this selectivity.
We thus investigated bulkier thiones. As hoped, substitution
of both ethyl esters for tert-butyl esters on the thione (17)
led to the preferred formation of the desired regioisomer in
a 2:1 ratio. Ultimately, thione 18, derived from Meldrum’s
acid, led to a 14:1 ratio of the cycloadducts 19c and 20c.
Although the fixed (O)-E conformation of the esters in 18
probably affects the electronics of the thione, steric effects
are likely prominent in controlling the regiochemistry of this
cycloaddition. The rigid structure of 18 may increase its steric
demand, which would destabilize transition state TS II more
effectively (Scheme 4).
1
1
analysis. We believe the stereoselectivity of this unique
cycloaddition comes from conformational constraints. The
endo orientation of the internal carbonyl of the dienophile
imparts quite a bit of conformational strain to the system.
1
2
Unmasking of R,â-unsaturated aldehydes 15a,b was
followed by a second, endo-selective [4+2]-cycloaddition
involving ethylvinyl ether (EVE) and Yb(fod)
3
as the catalyst
13
(
Scheme 3). Cycloadducts 6a or 6b can be isolated as single
11
diastereomers if the reaction is run at 25 °C. However, and
gratifyingly, both compounds underwent the desired decar-
boxylation reaction when the reaction was run in refluxing
benzene to give directly 7a,b from 15a,b (cf. Scheme 1).
The result of the next Diels-Alder cycloaddition would
decide the fate of our strategy. We were looking for a
carbon-heteroatom dienophile because the resulting cy-
cloadduct would then contain two cleavable C-Z bonds (cf.
Scheme 2). It seemed to us that a thiocarbonyl compound
was a good choice because of the ease with which carbon-
sulfur bonds can be manipulated (e.g., desulfurization,
elimination, or Pummerer rearrangement).14 We also con-
sidered carbonyl compounds as dienophiles and tested several
without success (none would undergo the cycloaddition). In
general, thiocarbonyls are more reactive than the correspond-
ing carbonyls and react with 1,3-dienes at exceptionally low
Scheme 4. Transition States for the HDAC of 7a and 18
6g
temperatures. This increased reactivity originates from their
weaker π-bond and lower LUMO orbital.1
5,16
We prepared three thiones according to the methodology
16
developed by Albelman (Table 1). Treatment of bromo-
We repeated the cycloaddition of 18 with 7b with similar
results. In addition, using the method of Capozzi and co-
workers to generate 18, we were able to perform the
cycloaddition at -10 °C to yield 21 and 22 in a 30:1 ratio.17
The structure of 21 was confirmed by single-crystal X-ray
Table 1. Cycloadditions between 7a,b and 16-18
1
1
diffraction analysis.
Concomitant methanolysis and decarboxylation of 21 were
accomplished using a catalytic amount of Ni(acac) (Scheme
). Desulfurization to 23 and complete reduction of the
ester and ketone to the corresponding diol followed by a
2
1
8
5
1
9
double oxidation led to aldehyde 24. The dienophile
necessary for the final intramolecular cycloaddition was
(
11) Details of crystal structure analyses are provided as Supporting
Information. CCDC 600917 (14a), CCDC 600922 (14b), CCDC 600615
6a), CCDC 600923 (6b), CCDC 600918 (19a), CCDC 600926 (20a),
(
1
,3-diene
thione
T (°C)
yield (%)
ratio
CCDC 600919 (19c), CCDC 600925 (20c), and CCDC 600924 (21) contain
the supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
6a
rt
60
82
81
92
80
63
1:2 (19a/20a)
b
c
1
17
1
a
7a
2:1 (19b/20b)
14:1 (19c/20c)
8a
b
(12) Langille, N. F.; Dakin, L. A.; Panek, J. S. Org. Lett. 2003, 5, 575-
78.
5
d
b
7b
18
-10
30:1 (21 /22)
(
24.
13) Danishefsky, S. J.; Bednarski, M. Tetrahedron Lett. 1984, 25, 721-
7
a
Generated by Albelman’s methodology.16 See ref 11. c Structure of
b
(
14) Bur, S. K.; Padwa, A. Chem. ReV. 2004, 104, 2401-2432 and
references therein.
15) (a) Vedejs, E.; Eberlein, T. H.; Mazur, D. J.; McClure, C. K.; Perry,
2
0b was confirmed by desulfurization to the vinylic gem-dimethyl
compound. Generated by Capozzi’s methodology.
d
17
(
D. A.; Ruggeri, R.; Schwartz, E.; Stults, J. S.; Varie, D. L.; Wilde, R. G.;
Wittenberger, S. J. Org. Chem. 1986, 51, 1556-1562. (b) Vedejs, E.; Perry,
D. A. J. Am. Chem. Soc. 1983, 105, 6999-7001.
malonates with sulfur powder and triethylamine led, via a
simple addition-elimination sequence, to the corresponding
thiones 16-18 which reacted in situ with dienes. Table 1
summarizes the results of their cycloaddition with 1,3-diene
(
16) Albelman, M. M. Tetrahedron Lett. 1991, 32, 7389-7392.
(17) Capozzi, G.; Menichetti, S.; Nativi, C.; Rosi, A.; Valle, G.
Tetrahedron 1992, 48, 9023-9032.
(18) All acidic conditions tried gave decomposition products. Ni(acac)2
gave the best results.
7a.
(19) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001-3003.
Org. Lett., Vol. 8, No. 20, 2006
4387

The relative stereochemistries in 28a and 28b were
unambiguously determined by 2D-NMR analysis. This result
means that cycloaddition of 27a occurred exclusively via
an R-endo TS to yield tetracyclic compound 28a, whereas
Scheme 5. Synthesis of Tetracyclic Intermediates 28a,b
2
7b also underwent a stereoselective cycloaddition to give
2
8b via a â-endo TS (Scheme 6). These two TSs are lower
Scheme 6. Proposed Transition States for the IMDAC of 27a,b
in energy because of the pseudoequatorial orientation of the
methyl and silyloxy groups. Tetracycle 28a contains suf-
ficient synthetic levers around its carbon skeleton to be used
in the completion of the synthesis of several natural quassi-
noids.
In conclusion, the convergent and stereoselective synthesis
of tetracycle 28a was efficiently achieved in 18 steps from
propargyl alcohol using a quadruple diene-transmissive
Diels-Alder cycloaddition strategy. The dienophilic carbon
chain was brought about in a very convergent manner using
a regio- and stereoselective hetero-Diels-Alder reaction with
Meldrum’s acid-derived thione 18. The syntheses of several
natural quassinoids using this synthetic strategy are now
underway and will be reported in due course.
introduced by performing a syn- and γ-selective vinylogous
Mukaiyama aldol reaction with ketene acetal 25.20 Because
aldehyde 24 is racemic and 25 is achiral at this stage, both
syn diastereomers 26a and 26b were formed in 1:1 ratio as
an inseparable mixture. An asymmetric version of this
21
vinylogous aldol exists and will be used with a nonracemic
aldehyde 24 that is being prepared using chemistry previously
2
2
published. The free secondary alcohols in 26a,b were then
Acknowledgment. We thank the Natural Sciences and
Engineering Council of Canada and the Universit e´ de
Sherbrooke for financial support.
protected as their silyl ethers. Heating the 1:1 mixture of
2
7a and 27b to 295 °C for 2 h resulted in the exclusive
formation of two separable tetracyclic compounds 28a,b in
8% yield.
Supporting Information Available: Experimental pro-
6
1
cedures, characterization data, H NMR spectra for all new
compounds, and single-crystal X-ray analyses data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(
20) Hassfeld, J.; Christmann, M.; Kalesse, M. Org. Lett. 2001, 3, 3561-
3
564.
(
21) Schlessinger, R. H.; Li, Y.-J.; Von Langen, D. J. J. Org. Chem.
1
996, 61, 3226-3227.
(22) Spino, C.; Fr e´ chette, S. Tetrahedron Lett. 2000, 41, 8033-8036.
OL060892T
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Org. Lett., Vol. 8, No. 20, 2006