A convergent synthesis of the cardenolide skeleton: Intramolecular aldol condensation via reduction of α-bromoketones

Article abstract of DOI:10.1021/jo025612b

Synthesis of the highly biologically valuable cardenolide backbone was achieved via anionic polycyclization. Bromoketone 18, obtained from double-Michael cycloaddition between cyclohexenone 14 and γ,δ-unsaturated β-ketoester 16, was efficiently aldolized under reductive conditions. The highly functionalized tetracyclic compound 52 is an important synthetic intermediate that is potentially amenable to natural cardenolide total synthesis.

Full text of DOI:10.1021/jo025612b

A Con ver gen t Syn th esis of th e Ca r d en olid e Sk eleton :
In tr a m olecu la r Ald ol Con d en sa tion via Red u ction of
r-Br om ok eton es
Daniel Chapdelaine, J ulie Belzile, and Pierre Deslongchamps*
Laboratoire de synthe`se organique, De´partement de chimie, Institut de pharmacologie de Sherbrooke,
Universite´ de Sherbrooke, 3001, 13e Avenue nord, Sherbrooke, Que´bec J 1H 5N4, Canada
pierre.deslongchamps@courrier.usherb.ca
Received February 14, 2002
Synthesis of the highly biologically valuable cardenolide backbone was achieved via anionic
polycyclization. Bromoketone 18, obtained from double-Michael cycloaddition between cyclohexenone
14 and γ,δ-unsaturated â-ketoester 16, was efficiently aldolized under reductive conditions. The
highly functionalized tetracyclic compound 52 is an important synthetic intermediate that is
potentially amenable to natural cardenolide total synthesis.
SCHEME 1a
In tr od u ction
Cardenolides constitute a special subset of the steroid
natural products as their highly oxygenated structure
(e.g., strophantidol 1 and ouabain 2a ) possesses unusual
cis A/B and C/D ring junctions. Moreover, it has been
known for a long time that the digitalis extract, which
contains a mixture of cardenolides, exhibits valuable
clinical improvement for the treatment of certain cardiac
diseases.1 Surprisingly, relatively little work has been
carried out on the total synthesis of cardenolides.2
a
Reagents and conditions: (a) Cs2CO3, CH2Cl2; (b) APTS,
refluxing benzene, 47% (two steps) of 6 from 3; 44% (two steps) of
a 1:1 mixture of 8 and 9 from 7.
the double-Michael adduct 8, along with the tetracyclic
compound 9, in which the R configuration at C-13 and
C-14 is precisely opposite to that found in the naturally
occurring cardenolides.4
Subsequently, we decided to investigate the utility of
Nazarov reagent 10 (Scheme 2), which can only lead to
13â-methyl-14â-hydroxysteroids.5 Thus, in the presence
of cyclohexenone 7 and cesium carbonate, the double-
Michael adduct 11 was isolated, along with a minor
diastereomer6 in 85:15 ratio. Base-catalyzed aldolization
of 11 at higher temperatures or the use of stronger bases
furnished either 12 or 13 in low yields, along with the
recovered starting material. We reasoned that the poor
yields of tetracyclic products obtained are due to the
following factors: (a) poor facial stereoselectivity in the
We have previously reported on the reaction between
cyclohexenones 3 and 7 (Scheme 1) with the symmetric
Nazarov reagent 4 in order to access the tetracyclic
products 6 and 9.3 Under basic conditions, 6 was obtained
as the sole product from cyclohexenone 3 via a cascade
double-Michael-aldol condensation, so-called anionic
polycyclization. Cyclohexenone 7 gave a 1:1 mixture of
(1) Aronson, J . K. An Account of the Foxglove and its Medical Uses,
1785-1985; Oxford University Press: London, UK, 1985.
(2) Recent publications on this subject limited to the following: (a)
The total synthesis of digitoxigenin: Stork, G.; West, F.; Lee, H. Y.;
Isaac, R. C. A.; Manabe, S. J . Am. Chem. Soc. 1996, 118, 10 660. (b)
One synthetic approach toward ouabagenin: Overman, L. E.; Rucker,
P. V. Tetrahedron Lett. 1998, 39, 4643 1998. Overman, L. E.; Nasser,
T.; Rucker, P. V. Tetrahedron Lett. 1998, 39, 4647. Overman, L. E.;
Rucker, P. V. Heterocycles 2000, 52, 1297.
(4) The aldol condensation is the result of a preferred attack of the
double-Michael-issued enolate ion on the pro-S carbonyl of the cyclo-
pentadione unit: Lavalle´e, J .-F.; Deslongchamps, P. Tetrahedron Lett.
1988, 29, 6033.
(3) (a) Lavalle´e, J .-F.; Spino, C.; Ruel, R.; Hogan, K. T.; Deslong-
champs, P. Can. J . Chem. 1992, 70, 1406. (b) Ruel, R.; Deslongchamps,
P. Can. J . Chem. 1992, 70, 1939.
(5) Ruel, R.; Deslongchamps, P. Tetrahedron Lett. 1990, 31, 3961.
(6) The side product (5R,9â,10R-diastereomer of 11) was the result
of a cycloaddition syn to the isopropenyl group of 7.
10.1021/jo025612b CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/27/2002
J . Org. Chem. 2002, 67, 5669-5672
5669

Chapdelaine et al.
SCHEME 2a
SCHEME 4a
a
Reagents and conditions: (a) Ph3PdC(Br)CO2Me, refluxing
benzene, 81% (Z:E ) 4:1); (b) DIBAL-H, CH2Cl2, -78 to 0 °C, 74%;
(c) Dess-Martin periodinane, CH2Cl2, 79% for 24 and 83% for 15;
(d) Zn, BrCH2CO2t-Bu, THF, 76%.
a
Reagents and conditions: (a) Cs2CO3, CH2Cl2; (b) APTS,
refluxing benzene, 60%; (c) KHMDS, THF, 25% of 12; (d) Cs2CO3,
refluxing CH3CN, 32% of 13 from either 11 or 12.
Resu lts a n d Discu ssion
Synthesis of brominated Nazarov reagent 15 (Scheme
4) was initiated by olefination of the known aldehyde 214
with a stabilized phosphorane reagent9 to yield ester 2210
as a separable (4:1) Z/E mixture. Following an overre-
duction-reoxidation sequence (via triol 23) into aldehyde
24, addition of the Reformatsky reagent derived from tert-
butyl bromoacetate furnished alcohol 25. Further oxida-
tion with Dess-Martin periodinane11 offered the γ,δ-
unsaturated â-ketoester 15.
SCHEME 3
Enantiopure Nazarov reagent 16 was prepared (Scheme
5) with the chiral borneol 27.12 Transesterification of
commercial â-ketoester 26 followed by selective dehy-
drogenation via phenylselenide13 provided chiral enoate
29. Highly diastereoselective addition of the higher order
cuprate,14 derived from 3-bromofuran, yielded adduct 30,
from which 27 was recovered via methanolysis. Com-
pound 31 was then methylated, followed by dealkoxy-
carbonylation15 of â-ketoester 32 to yield methyl ketone
33, which was subjected to a regioselective Michael
addition16 with ethyl acrylate. As expected, the stereo-
chemical outcome of the former three steps is well-
controlled by 1,2-induction (from 7 to 10:1) provided by
the furan group. Ketoester 34 was then reduced (a two-
step sequence via diol 35) into aldehyde 36, from which
16 was elaborated via the same sequence used for 15.
Cyclohexenone 14 was prepared by desymmetrization
of the known 4-silanoxycyclohexanone 41 (Scheme 6).17
Following the addition of dimethyl carbonate to the
racemic enolate of 41 (generated by sodium/potassium
hydride),18 an equimolar mixture of enantiomeric â-ke-
toesters 42 and 43 (enol forms shown) was produced.19
Alternatively, enantioselective deprotonation could be
first coupling step (double-Michael cycloaddition), and (b)
competitive retroaldol and degradation reactions during
the second step (aldolization).
To circumvent the first of these two shortcomings, we
developed the cyclohexenone 14 (Scheme 3), which is
known to afford excellent levels of facial diastereocontrol
in conjunction with various Nazarov reagents.7 An al-
ternative strategy for the C ring formation was to
synthesize precursors for regiospecific enolization at the
pro-8 position (steroid numbering) of the tricyclic double-
Michael adduct. Interestingly, it was known that bro-
moacetates of ω-hydroxyaldehydes (and ketones) cleanly
undergo intramolecular Reformatsky condensation using
samarium(II) as the reducing agent to furnish â-hydroxy-
lactones.8 This prompted us to initiate the synthesis of
brominated Nazarov reagent 15, as well as 16 (which
contains a â-furyl substituent at the pro-17 position), to
study their condensation with cyclohexenones 3 and 14.
The resulting tricyclic R-bromoketones 17 and 18 have
been found to be excellent precursors of enolates 19 and
20 (via chemical reduction), both of which undergo
intramolecular aldolization in high yields. We wish to
report on the results of this latter approach herein.
(9) Maerkl, G. Chem. Ber. 1961, 94, 2996.
(10) All new compounds in this publication were characterized by
1H and 13C NMR, IR, and HRMS. [R]D and mp were also recorded when
pertinent. See Supporting Information.
(11) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4156.
(12) Urban, E.; Knu¨lh, G.; Helmchen, G. Tetrahedron 1996, 52, 971.
(13) Liotta, D.; Bornum, C.; Puleo, R.; Zima, G.; Bayer, C.; Kezar,
H. S. J . Org. Chem. 1981, 46, 2920.
(14) Lipshultz, B. H.; Koerner, M.; Parker, D. A. Tetrahedron Lett.
1987, 28, 945.
(15) Elsinger, F. Org. Synth. 1973, 5, 76.
(16) House, H. O.; Roelofs, W.; Trost, B. M. J . Org. Chem. 1966, 31,
646.
(17) Nagao, Y.; Goto, M.; Ochiai, M. Chem. Lett. 1990, 9, 1507.
(18) Ruest, L.; Blouin, G.; Deslongchamps, P. Synth. Commun. 1976,
6 (3), 169.
(7) Belzile, J . M.Sc. Thesis, Universite´ de Sherbrooke, 1999.
(8) Molander, G. A.; Etter, J . B. J . Am. Chem. Soc. 1987, 109, 6556.
Tabuchi, T.; Kawamura, K.; Inanaga, J .; Yamaguchi, M. Tetrahedron
Lett. 1986, 27, 3889.
5670 J . Org. Chem., Vol. 67, No. 16, 2002

A Convergent Synthesis of the Cardenolide Skeleton
SCHEME 5a
SCHEME 6a
a
Reagents and conditions: (a) NaH, KH (cat.), (MeO)2CO, THF,
90% of 42 and 43 in 1:1 ratio; (b) 44 or 45, n-BuLi, THF, -78 °C
then CNCO2Me, 79% of 42 and 43 in 1:4 ratio; (c) 46 neat, 55-
60% of 47 and 48 in the same proportions as 42 and 43, resolved
by flash chromatography; (d) H2SO4(aq) 3 M, THF, 91%; (e)
PhSeCl, pyridine, CH2Cl2; (f) H2O2(aq) 30%, CH2Cl2, 90% (2 steps).
SCHEME 7a
a
Reagents and conditions: (a) DMAP, refluxing toluene, 96%;
(b) PhSeCl, pyridine, CH2Cl2 then H2O2, 98%; (c) i. 3-bromofuran,
n-BuLi, THF, -78 °C. ii. 2-ThCuCNLi. iii. 29, 70%; (d) MeOH,
150 °C, 93% for 31 and 100% for 27; (e) KH, MeI, THF-DMF, 86%;
(f) LiI∼2H2O, refluxing collidine, 89%; (g) t-BuOK, ethyl acrylate,
t-BuOH, 65%; (h) DIBAL-H, THF; (i) Swern oxidation, 60% for 2
steps; (j) Ph3PdC(Br)CO2Me, refluxing benzene, 71% (Z:E ) 4:1);
(k) DIBAL-H, CH2Cl2, -78 to 0 °C, 80%; (l) Dess-Martin perio-
dinane, CH2Cl2, 86% of 39 and 85% of 16; (m) Zn, BrCH2CO2-
t-Bu, THF, 99%.
effected with the chiral lithium amide derived from either
amine 44 or 45,20 but the overall process involving
carbomethoxylation with methyl cyanoformate21 yielded
43 as the major enantiomer in a rather poor 50% ee.
Enantiomeric purity was increased to 80%, however,
through condensation of the â-ketoesters mixture with
(S)-2-aminobutanol 46, followed by chromatographic
separation of diastereomeric enamines 47 and 48 and
further hydrolysis under acidic conditions. The usual
sequential selenylation-oxidation finally led to chiral 14.
The Nazarov reagent 15, when reacted with cyclohex-
enone 3, furnished tricyclic intermediate 17 (mixture of
epimers at the pro-8 position) via double-Michael cy-
cloaddition. Reduction with samarium(II) iodide22 gave
the tetracyclic aldol product 49 (Scheme 7), for which the
three-dimensional structure was ascertained by single-
a
Reagents and conditions: (a) Cs2CO3, CH2Cl2; (b) APTS,
refluxing benzene, 65% of 17 for 2 steps and 56% of 18; (c) SmI2,
THF, -78 °C, 84% of 49 from 17; for reduction of 18, see Table 1;
(d) HCl anhyd., CH2Cl2, 90%.
crystal X-ray diffraction analysis.23 It is noteworthy that
the 13R-methyl, 14R-hydroxy configuration of 49 is the
result of aldolization at the pro-S carbonyl of the cyclo-
pentanedione unit of 17, as observed previously.4 Tricyclic
bromoketone 18 was obtained from the coupling between
optically active cyclohexenone 14 and Nazarov reagent
16. Upon reduction of the C-Br bond with samarium-
(II), the expected enolate 20 was produced nearly quan-
titatively, as only the reduced compound 50 was isolated
after quenching at -78 °C (see Table 1). Warming up the
reaction mixture allowed the aldolization to take place,
and tetracyclic compounds 51 and 52 were obtained in
varying ratios depending on the temperature and reac-
tion time. At -20 °C, nearly only kinetic aldol product
(19) Compounds 42 and 43 have been found (1H NMR analysis) to
exist as a mixture of ketoesters and enol forms.
(20) (a) Majewski, M.; Lasny, R. J . Org. Chem. 1995, 60, 5825. (b)
Bunn, B. J .; Cox, P. J .; Simpkins, N. Tetrahedron 1993, 49, 207.
(21) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425.
(22) SmI2 was freshly prepared following the known procedure:
Girard, P.; Namy, J . L.; Kagan, H. B. J . Am. Chem. Soc. 1980, 102,
2693.
(23) We wish to thank M. Drouin (Universite´ de Sherbrooke) for
the crystallographic analysis.
J . Org. Chem, Vol. 67, No. 16, 2002 5671

Chapdelaine et al.
SCHEME 8a
TABLE 1. Red u ction P r od u cts fr om Tr ea tm en t of 18
w ith Sm I2
isolated yield (%)
conditions
(T, t)
50
51
52
53
-78 °C, 0.5 h
-20 °C, 16 h
0 °C, 1.5 h
78
0
0
0
63
50
0
0
7
16
28
0
25
34
70
20 °C, 1 h
0
51 was obtained. In contrast, at room temperature, the
more stable 52 was the only tetracyclic compound ob-
served; however, it was accompanied by a larger amount
of 53 resulting from a base-catalyzed fragmentation
(retro-Michael) reaction from 50-52.24 Nevertheless,
tetracyclic products were isolated in 70% (combined) yield
by maintaining the reaction temperature between -20
and 0 °C. Moreover, substrate 52, which has the correct
stereochemistry for the synthesis of natural cardenolides,
can be obtained by epimerization of 51 under acidic
conditions in excellent yield.
In an effort to ascertain the structure of 52 by X-ray
crystallography, chemical derivatization was focused on
the deprotection of the silyl ether functionality. Upon
treatment of 52 with tris(dimethylamino)sulfonium dif-
luorotrimethylsilicate (TASF, Scheme 8), the intermedi-
ate alkoxide 54 underwent a retro-Dieckmann rearrange-
ment to yield γ-lactone 55.25 The furan unit was in turn
oxidized, presumably by atmospheric oxygen during
workup or storage, into butenolide 56. Single-crystal
X-ray diffraction analysis of 56 confirmed the absolute
configuration of chiral centers at positions 4, 5, 8, 9, 13,
14, and 17 (Scheme 8).
a
Reagents and conditions: (a) TASF, THF; (b) atmospheric
oxygen, 70% for 2 steps.
tion of the AB fused ring unit. Completion of the anionic
polycyclization triad via aldol condensation and ring C
formation required selective enolization at the pro-8
position. R-Bromoketone as a regiospecific precursor of
the ∆7,8 enolate fulfilled this latter requirement, and as
such, highly valuable tetracyclic aldol products 51 and
52 were obtained with this strategy. Stereochemical
control at C-8 was then achieved by thermodynamic
epimerization.
The convergence of the overall process demonstrates
the power of the anionic polycyclization strategy for the
total synthesis of complex natural cardenolides. Applica-
tions of this attractive method for the total synthesis of
this important subset of naturally occurring steroids are
currently underway in our laboratory.
Ack n ow led gm en t. Financial support provided by
BioChem Pharma Inc. (Basic Research Chair to P.
Deslongchamps), Fonds FCAR, and NSERCC (for schol-
arships to D. Chapdelaine) is gratefully acknowledged.
Con clu sion
Cardenolides are an important class of naturally
occurring steroids, not only from the standpoint of their
cardiotonic activity but also because of the synthetic
challenge they represent for the organic chemist. The
double-Michael cycloaddition permitted rapid construc-
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for all new compounds; 1H
NMR spectra for all compounds, 13C NMR spectra for 47 and
48, and ORTEP representations for 49 and 56. This material
is available free of charge via the Internet at http://pubs.ac-
s.org. The following crystal structures have been deposited at
the Cambridge Crystallographic Data Centre: 49 (CCDC
179214) and 56 (CCDC 179215).
(24) The degradation cascade may be driven by efficient negative
charge stabilization in the â-ketoester functionality of 53, together with
steric decompression of the tetracyclic (tricyclic) structures of 51 and
52 (50).
(25) This side reaction has already been observed in our laboratory
with similar systems (Chapdelaine, D., Ph.D. Thesis, Universite´ de
Sherbrooke, 2001).
J O025612B
5672 J . Org. Chem., Vol. 67, No. 16, 2002