An efficient approach toward the synthesis of the A/B rings of ouabain

Article abstract of DOI:10.1016/j.tetlet.2006.08.047

The synthesis of the highly functionalized A/B ring related to ouabain has been accomplished efficiently from commercially available α-tetralone. A key Birch reductive alkylation allows the building of an angularly substituted decalone that was adequately

Full text of DOI:10.1016/j.tetlet.2006.08.047

Tetrahedron Letters 47 (2006) 7447–7449
An efficient approach toward the synthesis
of the A/B rings of ouabain
Mar ´ı a Fernanda Plano, Guillermo R. Labadie, Manuel Gonzalez Sierra
and Raquel M. Cravero*
Instituto de Qu ı´ mica, Org a´ nica de S ı´ ntesis, Departamento de Qu ´ı mica Org a´ nica, Facultad de Ciencias Bioqu ı´ micas y Farmac e´ uticas,
Universidad Nacional de Rosario-Suipacha 531, S2002LRK Rosario, Argentina
Received 4 July 2006; revised 10 August 2006; accepted 14 August 2006
Available online 1 September 2006
Abstract—The synthesis of the highly functionalized A/B ring related to ouabain has been accomplished efficiently from commer-
cially available a-tetralone. A key Birch reductive alkylation allows the building of an angularly substituted decalone that was
adequately functionalized to produce the intermediate 2c.
Ó 2006 Elsevier Ltd. All rights reserved.
The cardiotonic steroid ouabain 1 isolated in 1888 from
the bark and roots of the ouabaio tree by Arnaud, has
larly functionalized substituent. After that, by a series of
stereoselective reactions, the final product would be pre-
pared. The advantage of our approach relays on the
additional functionalization over C-5 of the intermedi-
ate 2c which would allow future C/D rings construction.
1
been utilized for centuries in the treatment of congestive
heart failure. Structurally, this cardenolide possesses A/
B and C/D cis fused rings that together with substituents
on C-14, C-17 and C-19, make it different to most com-
mon steroids. Also, its high degree of oxidation has
made its synthesis extremely difficult, without any
reported total synthesis up to date. Different efforts have
been reported on the construction of Ouabain inter-
Our initial approach was an exploratory study using a
methyl group as alkylating agent, to optimize the
sequence after the BAR. First, to prepare the epoxy-
alcohol intermediate, the proposed synthesis involves
the dienone epoxidation and ketone reduction in that
2
mediates and related compounds. Between them, Jung
3
4a
and Piizzi recently reported the first synthesis of a fully
order. Following our reported procedure, the enone
functionalized all cis-decalin tetralol 3a corresponding
to the A/B ring system of that cardenolide. On that
approach, the synthesis was achieved using a Robinson
annelation to construct the decalin mainframe (Fig. 1).
was epoxidized obtaining a mixture of inseparable a/b
epoxides (2.7:1) completely selective toward the C4a–
C5 double bond, as we have shown before. Then, the
epoxide mixture 8 was reduced with sodium borohy-
dride, producing a mixture of 3 epoxy-alcohols 9, a-
epoxy-a-ol, and a mixture of b-epoxy-b-ol, a-epoxy-b-
ol, on 1:1.6 ratio (b-epoxy ketone gave only b-ol but
from a-epoxy ketone, a mixture 1:1 of both alcohols
were obtained). Alternatively, the enone was generated
by protection of the b-alcohol as benzoate using stan-
dard procedure followed by oxidation with PDC/t-
BuOOH as have been reported before, obtaining the die-
none 10 in good yield. When this dienone was submitted
to classical enone epoxidation conditions with H O /
As part of our studies on highly functionalized decalin
systems, we became familiar with the very useful inter-
mediaries obtained from the Birch-alkylation reaction
4
(
BAR) performed on benzylic ketones. When this reac-
tion is performed over a-tetralones it produces very ver-
satile, angularly substituted, bicyclic 1,4-dienes that are
perfect precursors of substituted decalins. Based on
Jung’s approach we envisioned that epoxy-alcohol 2a,
prepared on that work, could be synthesized starting
from a-tetralone through a BAR to introduce the angu-
2
2
NaOH, instead of getting the expected epoxide, the alde-
hyde 11 was found. The formation of that product can
be explained by the hydrolysis of the benzoate and the
subsequent rearomatization to produce the phenyl-
butyraldehyde 11. Finally, the alcohol 6 was epoxidized
*
Corresponding author. Tel./fax: +54 341 4370477; e-mail:
cravero@iquios.gov.ar
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.047

7448
M. F. Plano et al. / Tetrahedron Letters 47 (2006) 7447–7449
O
O
R1
R2
R2
O
HO
HO
R1
O
HO
C
H
O
D
H
O
O
O
A
B
OH
α-Tetralone
O
HO
3a R1=OH R2=H
3b R =OH R =OBz
2a R1=CH2OH R2=H
2b R =Me R =OBz
O
HO
Ouabain 1
Me
1
2
1
2
2c R =CH OCH R =OBz
1
2
3
2
HO OH
Figure 1.
under the conditions mentioned before,4a to induce the
attack of the peracid over the beta face. This reaction
produces the epoxy alcohol 9 as a a/b mixture 1.5:1,
being the best selectivity obtained over all. Both diaste-
reomers were easily separated by flash chromatography
and relative stereochemistry of the products was estab-
butyl hydroperoxide/Celite in benzene, a cleaner trans-
8
9
formation was observed obtaining the epoxy-enone in
91% yield (Scheme 1).
With all that in mind, we decided to move to the
oxidized angular substituent. From the possible
different alkylating reagents (MOMCl, BOMCl, CH @
CHCH Br), MOMCl was chosen based on our previous
5
lished straightforward by NMR. Then, the alcohol 9
2
was esterified with PhCOCl, DMAP in pyridine at room
2
6
4a
temperature producing the benzoyl ester 12 in 92%
experience. Starting from a-tetralone as before, under
yield. Allylic oxidation of 12 was first attempted using
BAR conditions, dienone 13 was produced in high yield.
Then, the ketone was reduced with sodium borohydride,
obtaining exclusively the beta alcohol 14 as for the
methyl derivative. The alcohol was then epoxidized
7
3
,5-dimethylpyrazole–CrO complex producing the de-
3
sired a,b-unsaturated ketones 2b in 80–85% yields. To
our satisfaction, by using pyridinium dichromate/tert-
O
O
O
OH
OH
OBz
OBz
OBz
OBz
OH
g
a
b
c
d
O
4
5
6
7
10
e
e
CHO
11
b
e
f
O
O
8
O
9
O
O
12
2b
Scheme 1. Reagents and conditions: (a) 1. NH
3
, K, Et
2
O, t-BuOH, ꢀ78 °C; 2. LiBr, 3. MeI, ꢀ78 °C to rt; (b) NaBH
4
, MeOH, ꢀ78 °C, 30 min, 90%;
(c) PhCOCl, Py, DMAP, 0 °C, 2 h, 92%; (d) PDC, t-BuOOH, DCM; (e) m-CPBA, CH
2
Cl , 0.5 M NaHCO , 4 °C, overnight, 71%; (f) PDC, t-
2
3
BuOOH, Celite, benzene, room temperature, overnight, 91%; (g) H
2
O
2
, 1 M NaOH, THF, 94%.
O
MeO
MeO
O
OH
a
b
4
13
14
MeO
MeO
MeO
OBz
OH
OBz
c
d
e
O
O
O
16
O
2c
15
Scheme 2. Reagents and conditions: (a) 1. NH
78 °C, 30 min, 98%; (c) m-CPBA, CH Cl , 0.5 M NaHCO
Celite, benzene, room temperature, 48 h, 66%.
3
, K, Et
2
O, t-BuOH, ꢀ78 °C; 2. LiBr; 3. MOMCl, benzene, ꢀ78 °C to rt, 91%; (b) NaBH
4
, MeOH,
ꢀ
2
2
3
, 4 °C, overnight, 71%; (d) PhCOCl, Py, DMAP, 0 °C, 2 h, 95%; (e) PDC, t-BuOOH,

M. F. Plano et al. / Tetrahedron Letters 47 (2006) 7447–7449
7449
under conditions mentioned above obtaining the
epoxy-alcohols 15 in 1:9.2 a/b ratio. As can be seen,
the presence of methoxy-methyl group produces an
enhancement on the selectivity to the b-face increasing
almost 14 times over the reaction on the methyl deriva-
tive 6. This can also be seen when the methyl and the
methoxy-methyl series were compared. In fact, the epox-
idation a/b ratio goes from 2.3:1 to 1.5:1 from the
ketone compared to the b-ol. On the mom-series, a/b
ratio goes from 2.3:1 for the ketone to 1:9.2 for the
epoxidation of the beta-alcohol. The synthesis is com-
pleted by the epoxide separation, and alcohol protection
as benzoate producing the benzoate protected alcohol
4. (a) Labadie, G. R.; Cravero, R. M.; Gonzalez Sierra, M.
Synth. Commun. 2000, 30, 4065; (b) Labadie, G. R.;
Cravero, R. M.; Gonzalez Sierra, M. Synthesis 2001, 5,
7
08; (c) Labadie, G. R.; Estiu, G. L.; Cravero, R. M.;
Gonzalez Sierra, M. Theochem 2003, 635, 173; (d) Laba-
die, G. R.; Luna, L. E.; Gonzalez Sierra, M.; Cravero, R.
M. Eur. J. Org. Chem. 2003, 3429.
5
. Cravero, R. M.; Labadie, G. R.; Gonzalez Sierra, M. Can.
J. Chem. 2002, 80, 774.
6. Ley, S.; Sternfeld, F.; Taylor, S. Tetrahedron Lett. 1987,
28, 225–226.
7. (a) Salmond, W. G.; Barta, M. A.; Havens, J. L. J. Org.
Chem. 1978, 43, 2057; (b) Ananda, G.; Bertranne-Dela-
haye, M.; Maurs, M.; Azerad, R. Tetrahedron Lett. 1997,
3
8, 815.
1
6. Finally, by allylic oxidation with PDC, t-BuOOH,
8
9
. Chimdanbaran, N.; Chandrasekaran, S. J. Org. Chem.
Celite in benzene, the final product 2c was obtained in
1
987, 52, 5049; Guo, Z.; Schultz, A. G. Org. Lett. 2001, 3,
1
0
6
6% yield (Scheme 2).
1
177.
. (1aR,4aS,5S,8aR)-4ab-(Methyl)-2-oxo-2,4a,5,6,7,8-hexa-
hydro-1aH-naphtho[1,8a-b]oxiren-5b-yl benzoate (2b):
Colorless oil (hexane–EtOAc 85:15, 20.5 mg, 92%). IR
(film) 2953, 1715, 1688, 1620, 1448, 1372, 1189, 1097, 980,
In conclusion we have developed a simple procedure for
preparing the decalin 2c in five steps starting from a-
tetralone with BAR as a key step. This intermediate,
has provided a compound with adequate functionalities
that can be transformed on Jung’s intermediate having
additional functionalities and protections that would
allow future work on a most advanced intermediate.
ꢀ1 1
941, 861, 820, 750, 689 cm . H NMR: d 7.94 (m, 2H, H-
0
0
0
2
), 7.63 (m, 3H, H-3 and H-4 ), 6.40 (d, 1H, J = 12 Hz,
H-4), 5.73 (dd, 1H, J = 2 and 14.0 Hz, H-3), 4.70 (dd, 1H,
J = 6.0 and 10.5 Hz, H-5), 3.31 (s, 1H, H-1), 2.32–2.15 (dt,
2
1
H, J = 14 and 4 Hz, H-7), 1.97–1.78 (m, 2H, H-6), 1.79–
13
.65 (m, 2H, H-8), 1.21 (s, 3H, CH
3
). C NMR 194.7
0
(
(
C@O), 151.3 (OC(O)Ph), 148.7 (C-4), 136.6 (C-1 ), 134.0
C-4 ), 129.3 (C-2 ), 127.6 (C-3 ), 123.4 (C-3), 81.6 (C-5),
6.3 (C-8a), 60.8 (C-1), 43.3 (C-4a), 27.7 (C-8), 27.4 (C-6),
Acknowledgements
0
0
0
6
We thank CONICET Argentina, Fundaci o´ n Antorchas
and ANPCYT-Argentina for financial support. G.R.L.
and R.M.C. are members of the scientific staff of Coni-
cet, Argentina.
20.8 (C-7), 19.1 (CH ). MS: m/z (%) = 227 (30), 177
3
+
(M ꢀbenzoate, 100), 147 (20), 91 (38), 77 (25).
10. (1aR,4aS,5S,8aR)-4ab-(Methoxymethyl)-2-oxo-2,4a,5,6,7,
8
-hexahydro-1aH-naphtho[1,8a-b]oxiren-5b-yl benzoate
(
2c): Oily solid (hexane–EtOAc 75:25, 167.8 mg, 85%).
ꢀ1 1
IR (film) 2942, 1732, 1659, 1450, 1070, 986, 758 cm . H
0
0
0
NMR: d 8.00 (m, 2H, H-2 ), 7.59 (m, 3H, H-3 , H-4 ), 6.41
d, 1H, J = 10.7 Hz, H-4), 5.77 (dd, 1H, J = 1.3 and
.8 Hz, H-3), 4.73 (dd, 1H, J = 5.2 and 10.4 Hz, H-5), 3.76
d, J = 9.3 Hz, 1H, CH OCH ), 3.50 (d, J = 9.4 Hz, 1H,
), 3.34 (s, 3H, OCH ), 3.20 (br s, 1H, H-1), 2.22–
References and notes
(
9
(
1
2
. Arnaud, M. Compt. Rend. Acad. 1888, 107, 1011.
. (a) Overman, L. E.; Rucker, P. V. Heterocycles 2000, 52,
2
3
CH
2
OCH
3
3
1
297–1314; (b) Chapdelaine, D.; Belzile, J.; Deslong-
13
1
1
1
.78 (m, 6H, H-6, H-7 and H-8). C NMR 194.3 (C@O),
50.7 (OC(O)Ph), 148.3 (C-4), 133.6 (C-1 ), 133.7 (C-4 ),
champs, P. J. Org. Chem. 2002, 67, 5669–5672; (c) Jung,
M. E.; Davidov, P. Angew. Chem., Int. Ed. 2002, 41, 4125–
0
0
0
0
28.9 (C-2 ), 127.3 (C-3 ), 123.5 (C-3), 81.2 (C-5), 65.8
OCH ), 64.6 (C-8a), 60.5 (C-1), 58.8 (OCH ), 42.9
C-4a), 27.3 (C-6), 27.2 (C-8), 20.4 (C-7). ESI-HRMS
4128; (d) Jung, M. E.; Piizzi, G. J. Org. Chem. 2003, 68,
2572; (e) Trudeau, S.; Deslonchamps, P. J. Org. Chem.
2004, 69.
(
(
CH
2
3
3
+
Calcd for (M +Na) C H O Na 351.1208; found
1
9
20
5
3
. Jung, M. E.; Piizzi, G. Org. Lett. 2003, 5, 137.
3
51.1208.