Total synthesis of (+)-cassaine utilizing an anionic polycyclization strategy

Article abstract of DOI:10.1021/ol4030937

A stereoselective total synthesis of (+)-cassaine (1) via an anionic polycyclization methodology is described. Commercially available (+)-carvone (5), the only chiral source, was used to fix the entire stereochemistry of the natural product. Anionic polyc

Full text of DOI:10.1021/ol4030937

ORGANIC
LETTERS
2013
Vol. 15, No. 24
6270–6273
Total Synthesis of (þ)-Cassaine Utilizing
an Anionic Polycyclization Strategy
Kontham Ravindar,† Pierre-Yves Caron,‡ and Pierre Deslongchamps*,†,‡
ꢀ
Departement de Chimie, Faculte des Sciences et de Genie, Pavillon Alexandre-Vachon,
Universite Laval, 1045, avenue de la Medecine, Quebec City, QC G1V 0A6, Canada, and
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Departement de Chimie, Universite de Sherbrooke, Sherbrooke, QC, J1K 2R1 Canada
ꢀ
pierre.deslongchamps@chm.ulaval.ca
Received October 30, 2013
ABSTRACT
A stereoselective total synthesis of (þ)-cassaine (1) via an anionic polycyclization methodology is described. Commercially available (þ)-carvone
(5), the only chiral source, was used to fix the entire stereochemistry of the natural product. Anionic polycyclization of a new substituted
2-(methoxycarbonyl)cyclohex-2-en-1-one (4) with known 1-phenylysulfinyl-3-penten-2-one (3) provided the versatile tricycle (2) with requisite
stereochemistry. A sequence of functional group manipulations of tricycle (2) furnished the natural product 1.
In 1988, we reported a base catalyzed stereocontrolled
synthesis of cis-decalins,1 from a substituted Nazarov re-
agent2 (γ,δ-unsaturated-β-ketoester) and 2-carbomethoxy-
2-cyclohexenone, which is now well recognized as an anionic
polycyclization. This reaction comprises two consecutive
Michael additions and is analogous to the DielsꢀAlder
cycloaddition.3 Subsequently we disclosed the synthesis
of a racemic 13-R-methyl 14-R-hydroxy steroid,4 a novel
synthesis of functionalized optically active 13-β-methyl
14-β-hydroxy steroid,5 and a convergent synthetic ap-
proach to a tetracyclic steroidnucleus using several bicyclic
Nazarov reagents.6 This anionic polycyclization strategy
proved once again its versatility in the first stereoselective
total synthesis of the complex cardioactive steroidal nat-
ural product ouabain.7
€
Most recently, Bruckner and Petrovic reported the
synthesis of densely functionalized octalindiones from
acceptor-substituted benzoquinone monoketals and var-
ious substituted Nazarov reagents using anionic poly-
cyclization.8 We have also reported a versatile synthetic
strategyinvolvinganionicpolycyclizationtoaccessvarious
tricycles related to quassinoids and terpenoids from suitably
substituted 2-(formyl)cyclohex-2-en-1-one and 2-(nitrile)-
cyclohex-2-en-1-one with diverse Nazarov reagents.9 Herein
we report a stereoselective total synthesis of (þ)-cassaine (1)
using this strategy.
The Erythrophleum alkaloid (þ)-cassaine (1), a nonste-
roidal inhibitor of Naþ-Kþ-ATPase, was isolated by the
Dalma group in 1935,10 from the bark of Erythrophleum
guinneese. Structurally, 1 is a N,N-dimethylaminoethyl
ester of monocarboxylic acid of the diterpenoid. Turner
and co-workers reported the structural elucidation of
1,11 and the same group disclosed the first relay total syn-
thesis.12 It is a specific inhibitor of monovalent cation
†
ꢀ
Universite Laval.
‡
ꢀ
Universite de Sherbrooke.
ꢀ
(1) Lavallee, J.-F.; Deslongchamps, P. Tetrahedron Lett. 1988, 29, 5117.
(2) Nazarov, I. N.; Zauyalou, S. I. Zh. Obshch. Khim. 1953, 23, 1703.
(3) (a) Lee, R. A. Tetrahedron Lett. 1973, 14, 3333. (b) White, K. B.;
Reush, W. Tetrahedron 1978, 34, 2439.
ꢀ
(4) Lavallee, J.-F.; Deslongchamps, P. Tetrahedron Lett. 1988, 29, 6033.
(5) (a) Ruel, R.; Deslongchamps, P. Tetrahedron Lett. 1990, 31, 3961.
(b) Ruel, R.; Deslongchamps, P. Can. J. Chem. 1992, 70, 1939. (c) Yang, Z.;
Shannon, D.; Truong, V.; Deslongchamps, P. Org. Lett. 2002, 4, 4693.
(6) (a) Lepage, O.; Stone, C.; Deslongchamps, P. Org. Lett. 2002, 4,
1091. (b) Lepage, O.; Deslongchamps, P. J. Org. Chem. 2003, 68, 2183.
(c) Guay, B.; Deslongchamps, P. J. Org. Chem. 2003, 68, 6140. (d)
Trudeau, S.; Deslongchamps, P. J. Org. Chem. 2004, 69, 832.
(7) (a) Trudeau, S.; Deslongchamps, P. J. Org. Chem. 2004, 69, 832.
(b) Zhang, H.; Reddy, M. S.; Phoenix, S.; Deslongchamps, P. Angew.
Chem., Int. Ed. 2008, 47, 1. (c) Reddy, M. S.; Zhang, H.; Phoenix, S.;
Deslongchamps, P. Chem.;Asian J. 2009, 4, 725.
€
(8) Petrovic, D.; Bruckner, R. Org. Lett. 2011, 13, 6524.
(9) Caron, P. Y.; Deslongchamps, P. Org. Lett. 2010, 12, 508 and
references cited herein.
(10) Dalma, G. Ann. Chim. Appl. 1935, 25, 569.
(11) (a) Turner, R. B.; Herzog, E. G.; Morin, R. B.; Riebel, A.
Tetrahedron Lett. 1959, 1, 7. (b) Gensler, W. J.; Sherman, G. M.
J. Am. Chem. Soc. 1959, 81, 5217.
r
10.1021/ol4030937
Published on Web 12/02/2013
2013 American Chemical Society

Scheme 1. Synthetic Analysis of (þ)-Cassaine (1)
Scheme 2. Synthesis of β-Keto Ester 4
transport and of the Naþ-Kþ-ATPase, and known to
possess remarkable pharmacological action similar to that
ofthe digitalisglycosidessuchasdigitoxin, eventhoughthe
chemical structures are quite different.13 Impressed by the
interesting biological profile of 1, we previously reported
the stereoselective total synthesis using our own protocol
of the transannular DielsꢀAlder reaction.14
the annulation reaction, the isopropenyl group of 8 was
subjected to OsO4 mediated dihydroxylation, followed
by silica gel supported-NaIO417 cleavage to give ketone 9
(Scheme 2).
BaeyerꢀVilliger oxidation of ketone 9, followed by
saponification and PDC oxidation, afforded the ketone
10. Carbomethoxylation18 of ketone 10, and subsequent
phenylselenation and dehydroselenation, gave the desired
substituted 2-(methoxycarbonyl)cyclohex-2-en-1-one 4,19
which was used as a key fragment in the anionic poly-
cyclization reaction (Scheme 2).
Anionic polycyclization of the new substituted 2--
(carbomethoxy)-R,β-unsaturated ketone 4 and known9
1-phenyl-sulfinyl-3-pent-2-one (3) with cesium carbonate
in EtOAc at room temperature furnished the diastereo-
merically pure tricycle 2 in 62% yield, possessing the
desired axially oriented C14 methyl group, which is very
difficult toobtain by other methods.14 The stereochemistry
of the tricycle 2 was assigned based on comparison of the
spectral data with our recently reported analogous tri-
cycles.9 As we observed in our earlier studies, the stereo-
chemical outcome at C8 and C14 of 2 is directly influenced
by the C10 angular methyl group of 4, which forces the
Nazarov reagent 3 to enter from the R-face in an endo
approach.9,20 Base (NaOEt in EtOH) induced decarbo-
methoxylation of 2 with concomitant olefin migration
afforded enone intermediate 11 in 90% yield (Scheme 3).
Selective reduction of the C12 ketone functionality of 11
with NaBH4 at ꢀ78 °C provided the C12 R-alcohol 12,
which was protected as its TBS ether 13 in 96% yield.
Palladium (Pd/C, 15 psi of H2, 24 h) catalyzed selective
hydrogenation of benzyl ether 13 gave the alcohol 14 in 90%
yield, without affecting the enone functionality (Scheme 3).
In our continuing quest for new applications of anionic
polycyclization reactions, and in combination with the
very interesting cardiotonic properties of (þ)-cassaine,
we examined the efficacy of this reaction in a stereo-
controlled total synthesis of (þ)-cassaine.
Our synthetic strategy is illustrated in Scheme 1, which
was based on the initial construction of suitably function-
alized tricycle 2, which contains, in principle, all the
functionalities required for the construction of natural
product 1. Tricycle 2 would be readily prepared from the
new substituted 2-(methoxycarbonyl)cyclohex-2-en-1-one
4 and 1-phenylysulfinyl-3-penten-2-one (3) using Cs2CO3
mediated anionic polycyclization reaction. β-Keto ester 4
could be readily prepared from (þ)-carvone (5) using our
previously reported analogous synthetic route.9
The preliminary steps in the synthesis of the β-keto ester
4 drawn from our previous studies on the synthesis of
analogous trans-decalins were successful.9 Thus, the syn-
thesis of 4 started with enone 6 (obtained by the Birch
reduction followed by Robinson annulation of (þ)-car-
vone (5) and ethyl vinyl ketone),9,15 which was subjected to
reductive methylation (Li, liquid NH3, CH3I) followed by
highly stereocontrolled reduction of the C3 ketone func-
tionality (steroid numbering) with NaBH4 providing the
β-alcohol 7.16 Benzyl protection of alcohol 7 using stan-
dardreaction conditions affordedthe benzylether 8 in 95%
yield. Having served its diastereomeric control purpose in
(12) Turner, R. B.; Buchardt, O.; Herzoy, E.; Morin, R. B.; Riebel,
A.; Sanders, J. M. J. Am. Chem. Soc. 1966, 88, 1766.
(13) De Munari, S.; Barassi, P.; Cerri, A.; Fedrizzi, G.; Gobbini, M.;
Mabilia, M.; Melloni, P. J. Med. Chem. 1998, 41, 3033.
(14) Phoenix, S.; Reddy, M. S.; Deslongchamps, P. J. Am. Chem.
Soc. 2008, 130, 13989.
(15) Macias, F. A.; Aguilar, J. M.; Molinillo, J. M. G.; Rodriguez-Luis,
F.; Collado, I. G.; Massanet, G. M.; Froncazek, F. R. Tetrahedron 2000, 56,
3409.
(17) Zhong, Y.-L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622.
(18) Ruest, L.; Blouin, G.; Deslongchamps, P. Synth. Commun. 1976,
6, 169.
(19) Liotta, D.; Barnum, C.; Puleo, R.; Zima, G.; Bayer, C.; Kezar,
H. S., III. J. Org. Chem. 1981, 46, 2920.
(16) Hagiwara, H.; Uda, H. J. Org. Chem. 1988, 53, 2308.
(20) Spino, C.; Deslongchamps, P. Tetrahedron Lett. 1990, 31, 3969.
Org. Lett., Vol. 15, No. 24, 2013
6271

Scheme 3. Synthesis of Tricycle 14
Scheme 5. Synthesis of Vinyl Triflate 24
due tothe stepwise reduction of the enone double bond, via
steric hindrance promoted inversion at C8 (or) initial
reduction to give B/C cis ring junction followed by Pd/C
facilitated epimerization at the active C8 position. The
structure of the tricycle 15 was rigorously confirmed by
single crystal X-ray diffraction analysis.21 MOM Protec-
tion of alcohol 15 followed by stereoselective NaBH4
reduction gave the alcohol 16 in 90% yield. Alcohol 16
can also be prepared from enone 14 in an alternative route
(Route B), in which conversion of 14 into its MOM ether
17 followed by highly stereoselective Birch reduction (Li,
liquid NH3, tBuOH-THF) of the enone functionality of 17
furnished the alcohol 16 in 90% yield (Scheme 4).22
PMB protection of alcohol 16 using standard reaction
conditions gave the PMB ether 18 in 85% yield. Deprotec-
tion of TBS ether 18 with TBAF in THF gave the cor-
responding alcohol, which was oxidized to ketone 19 with
PDC in anhydrous DMF (Scheme 4).
Scheme 4. Synthesis of Ketone Intermediate 19
After successful synthesis of ketone 19 having trans-
antitrans (TAT) stereochemistry, we turned our attention
toward a crucial manipulation, introduction of the C13
exocyclic olefinic functionality by taking advantage of the
C12 ketone functional group. Carbomethoxylation17 of
ketone 19 followed by chemoselective reduction of the
β-keto ester using NaBH4 furnished the β-hydroxy ester 20
in 80% yield (two steps), which was treated with SOCl2
in pyridine to afford the R,β-unsaturated ester 21.23
Magnesium in the methanol reduction of R,β-unsaturated
ester 21 furnished the corresponding saturated ester 22
(as a diastereomeric mixture at C13) in 96% yield.24
Our next aim was to convert tricycle 14 into ketone 19
via trans-antitrans (TAT) tricycle 16 having the desired
stereochemistry of (þ)-cassaine (1). Pd/C catalyzed hydro-
genation (H2, 20 psi, 48 h) of enone 14 furnished ketone 15
(Route A). To our delight, we obtained only the desired
ketone 15 with the B/C trans ring junction, which might be
(21) See the Supporting Information for crystallographic data.
(22) Alt, G. H.; Barton, D. H. R. J. Chem. Soc. 1954, 1356.
(23) Katoh, T.; Mizumoto, S.; Fudesaka, M.; Takeo, M.; Kajimoto,
T.; Node, M. Tetrahedron: Asymmetry 2006, 17, 1655.
6272
Org. Lett., Vol. 15, No. 24, 2013

Completion of the synthesis of (þ)-cassaine (1) is de-
scribed in Scheme 6. PMB deprotection followed by Dess-
Martin periodinane oxidation of 24 gave the ketone 25.
Pd(II) catalyzed carboalkoxylation of vinyl triflate 25
using K2CO3, N,N-dimethylamino ethanol, carbon mon-
oxide (100 psi), and 1-methyl-2-pyrrolidinone (NMP)
furnished the known OMOM-cassaine 26.14 Ultimately,
deprotection of the MOM ether was accomplished with
LiBF4 in aqueous acetonitrile to give (þ)-cassaine (1) in
75% yield. The spectroscopic data of OMOM-cassaine 26
and (þ)-cassaine (1) were in full accordance with those
reported in the literature in all respects.14,26
Scheme 6. Synthesis of (þ)-Cassaine (1)
In conclusion, an efficient stereocontrolled total synthe-
sis of (þ)-cassaine (1) has been achieved via a Cs2CO3
mediated anionic polycyclization strategy. (þ)-Carvone
(5) was used as the only chiral source to fix the entire
stereochemistry of the natural product. Further develop-
ments on this anionic polycyclization approach and
studies toward the synthesis of quassinoids (bruceantin
and quassin) are now being pursued in our laboratory and
will be reported in due course.
DIBALH reduction of ester 22 gave the alcohol, and sub-
sequent oxidation with Dess-Martin periodinane provided
the aldehyde 23. After several experiments, it was realized
that aldehyde 23 could be converted into the E-vinyl triflate
24 with KHMDS and Comins reagent (N-(5-chloro-2-
pyridyl)triflimide) (Scheme 5).25
Acknowledgment. We thank the NSERC Canada for
financial support.
Supporting Information Available. Experimental de-
tails, physical and NMR spectral data for all new com-
pounds; X-ray crystallographic data for 15. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(24) Hudlicky, T.; Sinai-Zingde, G.; Natchus, M. G. Tetrahedron
Lett. 1987, 28, 5287.
(25) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(26) (a) Hauth, H.; Stauffacher, D.; Niklaus, P.; Melera, A. Helv.
Chim. Acta 1965, 48, 1087. (b) Qu, J.; Hu, Y.-C.; Yu, S.-S.; Chen, X.-G.;
Li, Y. Planta Med. 2006, 72, 442. (c) Abad, A.; Agullo, C.; Arno, M.;
Domingo, L. R.; Zaragoza, R. J. Tetrahedron Lett. 1986, 27, 3289.
The authors declare no competing financial interest.
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