Versatile strategy to access tricycles related to quassinoids and triterpenes

Article abstract of DOI:10.1021/ol902711b

[Chemical equaction presented] The reactivity of two new bicyclic cyclohexenones (13 and 27) with several Nazarov reagents is presented. A flexible synthetic strategy is developed and provides access to highly substituted tricycles related to quassinoids

Full text of DOI:10.1021/ol902711b

ORGANIC
LETTERS
2010
Vol. 12, No. 3
508-511
Versatile Strategy to Access Tricycles
Related to Quassinoids and Triterpenes
Pierre-Yves Caron and Pierre Deslongchamps*
Laboratoire de synthe`se organique, Institut de pharmacologie de Sherbrooke,
UniVersite´ de Sherbrooke, Sherbrooke, Que´bec, Canada J1H 5N4
pierre.deslongchamps@usherbrooke.ca
Received November 24, 2009
ABSTRACT
The reactivity of two new bicyclic cyclohexenones (13 and 27) with several Nazarov reagents is presented. A flexible synthetic strategy is
developed and provides access to highly substituted tricycles related to quassinoids and triterpenes.
The stereocontrolled reaction of a cyclohexenone 1 and a
Nazarov reagent 2,1 known as anionic polycyclization, has
Scheme 1
been a major topic of interest in our laboratory for several
years (Scheme 1). The reaction consists of two successive
Michael additions and is analogous to a cycloaddition such
as the Diels-Alder reaction.2
Since its discovery in 1988,3 this synthetic tool was used
to provide a one-step construction of a racemic 13-R-methyl
14-R-hydroxy steroid,4 an optically active 13-ꢀ-methyl 14-
ꢀ-hydroxy steroid,5 a convergent and expedient synthesis of
synthesis of Ouabain,9 a cardioactive glycoside isolated from
the bark of the African ouabio tree (Acokanthera ouabio).10
In the array of possible natural product targets, quassinoids
caught our attention. Quassinoids are a group of terpenoid
natural products mainly isolated from Simaroubaceae spe-
cies,11 the most well-known members of the family being
quassin and bruceantin (Figure 1). The highly oxygenated
pentacyclic framework of bruceantin, coupled with its
steroids using bicyclic Nazarov reagents,6 a convergent route
to access various tricyclic and tetracyclic products related
to sterols,7 and a novel synthesis of highly functionalized
14-ꢀ-hydroxysteroids related to Batrachotoxin.8 This meth-
odology finally proved once again its value in the first total
(1) Nazarov, I. N.; Zauyalou, S. I. Zh. Obshch. Khim. 1953, 23, 1703.
(2) (a) Lee, R. A. Tetrahedron Lett. 1973, 14, 3333. (b) White, K. B.;
Reush, W. Tetrahedron 1978, 34, 2439.
(3) Lavalle´e, J.-F.; Deslongchamps, P. Tetrahedron Lett. 1988, 29, 5117.
(4) Lavalle´e, J.-F.; Deslongchamps, P. Tetrahedron Lett. 1988, 29, 6033.
(5) (a) Ruel, R.; Deslonchamps, P. Tetrahedron Lett. 1990, 31, 3961.
(b) Ruel, R.; Deslongchamps, P. Can. J. Chem. 1992, 70, 1939.
(6) (a) Lepage, O.; Stone, C.; Deslongchamps, P. Org. Lett. 2002, 4,
1091. (b) Lepage, O.; Deslongchamps, P. J. Org. Chem. 2003, 68, 2183.
(7) Guay, B.; Deslongchamps, P. J. Org. Chem. 2003, 68, 6140.
(8) Trudeau, S.; Deslongchamps, P. J. Org. Chem. 2004, 69, 832.
(9) (a) Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew.
Chem., Int. Ed. 2008, 47, 1. (b) Reddy, M. S.; Zhang, H.; Phoenix, S.;
Deslongchamps, P. Chem. Asian J. 2009, 4, 725.
(10) (a) Arnaud, A. C.R. Hebd. Seances Acad. Sci. 1888, 106, 1011.
(b) Arnaud, A. C.R. Hebd. Seances Acad. Sci. 1888, 107, 1062. (c) Fieser,
L. F.; Fieser, M. Steroids; Reinhold: New York 1959:Chapter 20.
(11) (a) Polonsky, J. Fortschr. Chem. Org. Naturst. 1985, 47, 22. (b)
Polonsky, J. Prog. Chem. Org. Nat. Prod. 1973, 30, 101.
10.1021/ol902711b  2010 American Chemical Society
Published on Web 01/07/2010

Scheme 2
Figure 1. Examples of quassinoids.
complex stereochemical configuration, makes it an attractive
target in organic synthesis. Since its isolation in 1973,12
several groups came up with synthetic strategies for the
preparation of highly functionalized intermediates.13
A
formal synthesis (relay) has been reported by Takahashi in
199014 and was followed by the first total synthesis in 1993
by the group of Grieco.15
Scheme 3
In our group, previous polycyclization strategies only
involved a monocyclic cyclohexenone structurally similar
to 1 in the double Michael addition key step. Acyclic and
bicyclic Nazarov reagents, on the other hand, have been used
with great success.6 We now wish to report the reactivity of
two new bicyclic cyclohexenones with Nazarov reagents and
their application in a natural product synthetic strategy.
By inspecting the bruceantin stereochemical framework
and based on our double Michael reaction methodology, a
retrosynthetic analysis would lead to the lactone intermediate
4 (Scheme 2). Prior to lactonization, cycloadduct 5 would
be the result of a double Michael addition between bicyclic
cyclohexenone 6 (X ) CHO, CN) and approprietly substi-
tuted Nazarov reagent 7.
The synthesis of bicyclic cyclohexenone 13 is depicted in
Scheme 3. The synthesis started with lactol 8 (obtained by
the Robinson annulation of (-)-dihydrocarvone with ethyl
vinyl ketone)16 which was dehydrated with KOH in MeOH.16
The resulting enone was carefully17 reduced to the equatorial
alcohol under Birch conditions.18 The secondary alcohol was
then protected with a benzyl group to afford coumpound 9.
Having served its diastereomeric control purpose in the
annulation reaction, the isopropenyl group was then dihy-
droxylated by the catalytic action of osmium tetroxide. The
diol was cleaved to the ketone which was then treated with
an excess of m-CPBA to afford the corresponding acetate
10 upon Baeyer-Villiger oxidation. Hydrolysis and PDC
oxidation afforded ketone 11 which was reacted with sodium
hydride and ethyl formate to give rise to ꢀ-keto-aldehyde
12. The insaturation was installed by reacting 12 with phenyl
selenium chloride and pyridine, followed by an oxidative
quench to provide the expected cyclohexenone 13, used
directly for the double Michael addition.19
(12) (a) Kupchan, S. M.; Britton, R. W.; Ziegler, M. F.; Sigel, C. W. J.
Org. Chem. 1973, 38, 178. (b) Kupchan, S. M.; Britton, R. W.; Lacadie,
J. A.; Ziegler, M. F.; Sigel, C. W. J. Org. Chem. 1975, 40, 648.
(13) (a) Kuo, F.; Fuchs, P. L. J. Am. Chem. Soc. 1987, 109, 1122. (b)
Shishido, K.; Saitoh, T.; Fukumoto, K.; Kametani, T. J. Chem. Soc., Chem.
Commun. 1983, 852. (c) Ziegler, F. E.; Klein, S. I.; Pati, U. K.; Wang,
T.-F. J. Am. Chem. Soc. 1985, 107, 2730. (d) Kerwin, S. M.; Paul, A. G.;
Heathcock, C. H. J. Org. Chem. 1987, 52, 1686. (e) Kim, M.; Gross, R. S.;
Sevestre, H.; Dunlap, N. K.; Watt, D. S. J. Org. Chem. 1988, 53, 93. (f)
Darvesh, S.; Grant, A. S.; MaGee, D. I.; Valenta, Z. Can. J. Chem. 1989,
67, 2237.
(14) Sasaki, M.; Murae, T.; Takahashi, T. J. Org. Chem. 1990, 55, 528.
(15) VanderRoest, J. M.; Grieco, P. A. J. Am. Chem. Soc. 1993, 115,
5841.
The next step in our synthesis was to prepare suitably
substituted Nazarov reagents (Scheme 4). Monoprotection
of propanediol followed by Swern oxidation and Wittig
(16) Macias, F. A.; Aguilar, J. M.; Molinillo, J. M. G.; Rodriguez-Luis,
F.; Collado, I. G.; Massanet, G. M.; Fronczek, F. R. Tetrahedron 2000, 56,
3409.
(17) Sequential reduction was necessary to prevent isopropenyl group
reduction.
(19) Liotta, D.; Barnum, C.; Puleo, R.; Zima, G.; Bayer, C.; Kezar III,
H. S. J. Org. Chem. 1981, 46, 2920. Cyclohexenone 13 was unstable and
was prepared freshly prior to use, without any purification.
(18) Hua, D. H.; Venkataraman, S. J. Org. Chem. 1988, 53, 1095.
Org. Lett., Vol. 12, No. 3, 2010
509

On the basis of previous results,20 it is known that a
ꢀ-keto-sulfoxide Nazarov reagent can reverse the C14
stereochemistry. With both Nazarov reagents 21 and 2220
in hand, cyclization with cyclohexenone 13 was undertaken
(Scheme 6).
Scheme 4
Scheme 6
reaction afforded ester 15. DIBAL-H reduction, addition of
the allyl acetate anion produced by LDA, and Dess-Martin
oxidation of the resulting alcohol gave Nazarov reagent 17.
We then explored the reaction of our bicyclic cyclohexenone
13 with ꢀ-keto-ester Nazarov reagent 17.
Reaction of cyclohexenone 13 and Nazarov reagent 17
(R ) CH2CH2OTBS) with cesium carbonate in THF gave
the corresponding diastereomer 18 exclusively in a fair yield
of 65% (Scheme 5). The stereochemistry at C9 (steroid
Cyclization of Nazarov reagent 21 proceeded with the
same ease, and the corresponding tricycle was obtained in
65% yield. Upon decarboxylation, tricycle 23 delivered
crystalline material which could be analyzed by single-crystal
X-ray diffraction analysis to assign C14 stereochemistry to
be the one represented (and expected). On the other hand,
ꢀ-keto-sulfoxide Nazarov 22 gave product 24 coming from
deformylation of the aldehyde group upon cyclization.
Stereochemistry was later confirmed based on other results.
Investigation of a new electron-withdrawing group was our
next concern.
Scheme 5
Having ꢀ-keto-aldehyde 12 in hand, the access to a ꢀ-keto-
cyano enone was straightforward (Scheme 7). Condensation
Scheme 7
numbering) is directly influenced by the angular methyl
group at C10 (1,2-induction). This angular methyl group
forces the Nazarov reagent to attack on the R face of the
cyclohexenone ring, sterically directing the stereochemical
outcome (C9 hydrogen and C8 substituent cis to C10
methyl).
Stereochemistry at C14 results from the exclusive exo
approach of the Nazarov reagent. Further decarboxylation
and removal of the benzyl group provided tricycle 20. Due
to the lack of crystallinity of compounds 18, 19, and 20, we
next looked at reducing the size of the Nazarov R group to
assign C14 stereochemistry.
of 12 with hydroxylamine HCl salt gave a 9:1 mixture of
isoxazole isomers 25 and 26.21 The major isomer was then
(20) Spino, C.; Deslongchamps, P. Tetrahedron Lett. 1990, 31, 3969.
Org. Lett., Vol. 12, No. 3, 2010
510

opened to the R-cyano ketone before completing the forma-
tion of the conjugated system by refluxing with DDQ in
benzene.21 The reactivity of this new bicyclic cyclohexenone
27 was then studied with Nazarov reagents 21 and 22.
The double Michael addition between enone 27 and
Nazarov reagent 21 afforded the corresponding cycloadduct
28 in an excellent 82% yield (Scheme 8). Stereochemistry
stereochemistry resulted from an exclusive endo approach
of Nazarov reagent 22.
With compounds 28 and 29 in hand, we have obtained
highly functionalized tricycles bearing many synthetic levers
to push forward quassinoids or triterpenes total synthesis.
In one double Michael cyclization step, the formation of a
new cycle is accompanied by the control over the formation
of three contiguous stereocenters. The cyclohexenone angular
methyl group (C10) directs the formation of stereocenters 8
and 9. C14 stereochemistry is determined by the approach
of the Nazarov reagent, modulated by the Nazarov ꢀ group
(ester versus sulfoxide, exo versus endo). Tricycle 29
possesses the right stereochemical pattern for quassinoids,
and tricycles 18 and 28 are well suited for the synthesis of
pentacyclic triterpenes or steroids analogues.
Scheme 8
We have demonstrated the reactivity of two new bicyclic
cyclohexenones 13 and 27 with three Nazarov reagents.
Highly functionalized cycloadducts have been obtained and,
with proper substitutions, are appropriate for the total
synthesis of many natural products (quassinoid, triterpene,
steroid). Further developments on this approach and studies
toward total synthesis are now being pursued in our labora-
tory and will be reported in due course.
Acknowledgment. We thank NSERC for fundings, Yves
´
Dory and Eric Marsault (Universite´ de Sherbrooke) for help
was assigned based on previous results obtained with enone
13. Moreover, ꢀ-keto-sulfoxide reagent 22 reacted with enone
27 to give cycloadduct 29 in 68% yield. Upon cyclization,
the sulfoxide group suffered a Cope elimination to provide
the corresponding enone. Fortunately, this newly formed
tricycle crystallized readily, and the stereochemistry was
assigned by single-crystal X-ray diffraction analysis. The C14
with editing this manuscript, and Andreas Decken (University
of New Brunswick) and Daniel Fortin (Universite´ de
Sherbrooke) for crystallographic analysis.
Supporting Information Available: Experimental sec-
tion, physical and spectral data for all new compounds, and
crystallographic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
(21) Honda, Y.; Honda, T.; Roy, S; Gribble, G. W. J. Org. Chem. 2003,
68, 4991.
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