Enantioselective total synthesis of (+)-digitoxigenin

Article abstract of DOI:10.1016/j.tetlet.2007.01.024

An enantioselective total synthesis of (+)-digitoxigenin is described. This total synthesis is accomplished in a convergent manner using two chiral fragments prepared via the catalytic asymmetric intramolecular cyclopropanation and baker's yeast mediated reduction developed by us, respectively. This convergent synthesis would be useful for preparing some new derivatives of digitoxigenin for SAR studies and could be applied for the total synthesis of other cardenolides left unprepared.

Full text of DOI:10.1016/j.tetlet.2007.01.024

Tetrahedron Letters 48 (2007) 1541–1544
Enantioselective total synthesis of (+)-digitoxigenin
Masahiro Honma and Masahisa Nakada*
Department of Chemistry, Faculty of Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
Received 22 November 2006; revised 22 December 2006; accepted 4 January 2007
Available online 7 January 2007
Abstract—An enantioselective total synthesis of (+)-digitoxigenin is described. This total synthesis is accomplished in a convergent
manner using two chiral fragments prepared via the catalytic asymmetric intramolecular cyclopropanation and baker’s yeast medi-
ated reduction developed by us, respectively. This convergent synthesis would be useful for preparing some new derivatives of digi-
toxigenin for SAR studies and could be applied for the total synthesis of other cardenolides left unprepared.
Ó 2007 Elsevier Ltd. All rights reserved.
(+)-Digitoxigenin (Fig. 1), produced by Digitalis purpu-
rea and Digitalis lunata, has clinically been used for the
treatment of congestive heart failure.1 Recently, it was
reported that (+)-digitoxigenin and its glycosides
strongly inhibited the proliferation of the HT-1080 cell
line (IC50 values, 54–1600 nM)2 and also exhibited
strong cytotoxic activities against oral human epider-
moid carcinoma (KB), human breast cancer cell (BC),
and human small cell lung cancer (NCI-H187).3 In addi-
tion, the congeners of (+)-digitoxigenin, toad poison
bufadienolides and their derivatives, have been reported
to show potent cytotoxicity toward primary liver carci-
noma cells PLC/PRF/5, too.4
reported;5 however, most of them are partial syntheses
and started from a commercially available steroid com-
pound. Furthermore, an enantioselective total synthesis
of cardenolides has been limited to the total synthesis
of (+)-digitoxigenin reported by Stork’s group.6 For
example, ouabain (Fig. 1),7 which has also been used
for the treatment of congestive heart failure8 and
possesses a highly oxygenated digitoxigenin skeleton,
remains unsynthesized.9
Since modification of cardenolides has been concen-
trated on their sugar moiety,10 we conceived of the con-
vergent synthetic approach to (+)-digitoxigenin for SAR
studies of the structurally divergent cardenolides and
their derivatives that were inaccessible from natural
products, and herein we report the enantioselective total
synthesis of (+)-digitoxigenin in a convergent manner.
(+)-Digitoxigenin has a steroid-like framework; how-
ever, cis A/B and C/D ring junctions, a tertiary 14b-
hydroxyl group, and a l7b-unsaturated lactone are
characteristic structural features different from common
steroids. Consequently, this unique structure as well as
the potent bioactivities have drawn much attention from
synthetic chemists, many synthetic studies have been
Our retrosynthetic analysis is outlined in Scheme 1. We
expected that the advanced intermediate 1, which incor-
porated a furan as a surrogate butenolide at the C17
position, would be prepared via a stereoselective
intramolecular aldol reaction of 2 and subsequent deoxy-
genation. Diketone 2 was expected to be obtained via
the coupling of enone 3 and bromide 4.
O
(+)-digitoxigenin
O
R1=R2=R3=R4=R5=H
(+)-digitoxin
R5
19
R1=R3=R4=R5=H
R2=digoxosyl
R4
17
R1
Enone 3 was expected to be converted from tri-
cyclo[4.4.0.05,7]decene derivative 5 because we have
reported enantioselective preparation of 5 via the
CuOTf-ligand 9 catalyzed asymmetric intramolecular
cyclopropanation of 8 (Scheme 2).11
H
14
(+)-ouabain
H
OH
R1=R3=R4=R5=OH
R2=α-(L)-rhamnosyl
3
R2O
R3
Figure 1.
Bromide 4 was envisioned to be derived from alkene 6
via Suzuki–Miyaura coupling reaction and subsequent
hydroxyl-directed stereoselective hydrogenation. Alkene
*
Corresponding author. Tel.: +81 3 5286 3240; fax: +81 3 3286
3240; e-mail: mnakada@waseda.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.024

1542
M. Honma, M. Nakada / Tetrahedron Letters 48 (2007) 1541–1544
thiophenoxide, followed by the subsequent removal of
O
the phenylthio group and the phenylsulfonyl group with
lithium naphthalenide (60%).13 Stereoselective reduction
of 10 with the readily available reducing reagent14 gave
an undesired product; however, the reduction of 10 with
L-Selectride provided the desired isomer stereoselec-
tively (94%, dr = 5/1), which was protected as a TBDPS
ether 11 (98%). Allylic oxidation at the C7 position of 11
was widely surveyed, and the reagent reported by Ochiai
et al. successfully furnished the desired ketone 3 in a
good yield (63%).15
(+)-digitoxigenin
H
H
OH
HO
1
H
O
Br
O
O
+
O
4
Synthesis of another fragment 4 was started from 7
(Scheme 4).12 Although 7 contained a small amount of
the regioisomeric hydroxyl ketone which was derived
from the baker’s yeast reduction of the corresponding
1,3-dione, the ethylene ketal prepared from 7 was suc-
cessfully separated by silica gel chromatography as a
O
TBDPSO
O
H
TBDPSO
2
O
H
5
3
O
I
TBDPSO
4
HO
O
TBSO
1) ethylene glycol, CH(OEt)3
TsOH, reflux, 84%
O
6
7
O
Scheme 1. Retrosynthetic analysis of (+)-digitoxigenin.
HO
2) TBSCl, imidazole
DMAP, DMF, 60 oC, 97%
TBSO
7
>99% ee
12
CuOTf
(10 mol %)
toluene, rt
H
1) O3, MeOH, -78 oC
then, NaBH4, 0 oC
2) TBDPSCl, imidazole
O
N2
TBDPSO
1) H2NNH2, TEA
EtOH, 100 oC
O
O
DMAP, CH2Cl2, DMF, rt
SO2Ph
PhO2S
H
O
O
8
5
TBSO
13
91%, 92% ee
N
N
2) I2, DBU, Et2O
0 oC to rt
93% (2 steps)
3) TsOH, acetone, H2O
50 oC, 81% (3 steps)
9
i
-Pr
i
-Pr
(15 mol %)
O
1)
Pd(PPh3)4
Cs2CO3
DMF
Scheme 2. Catalytic asymmetric intramolecular cyclopropanation of 8.
O
O
B
O
I
TBDPSO
50 oC
HO
6 was anticipated to be obtained from previously
prepared 7 by baker’s yeast mediated reduction of the
corresponding 1,3-cyclopentanedione derivative.12
100%
TBSO
2) TBAF, THF, 50 oC
100%
HO
6
14
As shown in Scheme 3, we commenced the synthesis of 3
starting with the conversion of 5 to the previously re-
ported 1011a by the improved one-pot procedure, which
is a cyclopropane-ring opening reaction with lithium
1) TBSCl, imidazole
DMAP, CH2Cl2
DMF, rt
O
H2
[Ir(COD)Py(PCy3)]PF6
HO
2) Dess-Martin
periodinane
CH2Cl2, rt
CH2Cl2, rt, 100%
HO
15
1) L-Selectride
THF, -78 oC
PhSLi, THF
50 oC
O
O
1) TBAF, THF, rt
dr=5/1, 94%
5
TBSO
Br
O
>99% ee
recryst
then,
2) CBr4, PPh3, CH2Cl2
0 oC to rt
2) TBDPSCl
imidazole
rt, 98%
H
10
Li, naphthalene
THF, -78 oC, 60%
O
78% (4 steps)
O
16
17
t
-BuOO
I
O
ethylene glycol
O
Br
O
O
4
CH(OEt)3, TsOH
3
7
3
7
O
TBDPSO
O
TBDPSO
CH2Cl2, reflux
91% (86% conv)
H
H
K2CO3
C6H6, rt
11
3
63%
Scheme 3. Synthesis of 3 from 5.
Scheme 4. Synthesis of 4 from 7.

M. Honma, M. Nakada / Tetrahedron Letters 48 (2007) 1541–1544
1543
pure form (84%), which was converted to a TBS ether 12
O
(97%). Ozonolysis of the terminal alkene in 12 with a
reductive workup using NaBH4, followed by a TBDPS
ether formation of the primary alcohol and selective
deprotection of the ketone as an ethylene ketal under
acidic conditions to afford 13 (81%, three steps). The
reaction of 13 with hydrazine, and then with I2 and
DBU,16 provided iodide 6 (93%, two steps). Suzuki–
Miyaura coupling reaction of 6 with 3-(4,4,5,5-tetra-
t
-BuLi, Et2O, THF, -78 oC
then, (2-Th)Cu(CN)Li
-78 to -10 oC, again -78 oC
4
O
then 3, warm up to -30 oC
O
91%
TBDPSO
O
H
18
methyl-1,3,2-dioxaborolan-2-yl)furan17
successfully
O
afforded the desired coupled product (100%), which
was globally deprotected with TBAF to afford diol 14
(100%). The hydroxyl group-directed hydrogenation of
14 with Crabtree’s catalyst18 successfully provided 15
(100%). Selective conversion of the primary alcohol of
15 to the corresponding halide failed because the cis diol
system of 15 was easily converted to a THF ring. Fur-
thermore, selective oxidation of the secondary alcohol
was fruitless. Consequently, the primary alcohol of 15
was protected as a TBS ether and the remaining second-
ary alcohol was oxidized by Dess–Martin oxidation to
afford ketone 16, followed by the deprotection of the
TBS group with TBAF and subsequent reaction of the
resulting alcohol with CBr4 and PPh3 to provide bro-
mide 17 (78%, four steps). Finally, the ethylene ketal
formation of bromide 17 under conventional conditions
furnished 4 (91%, 86% conv).
TsOH, acetone, H2O
reflux
99%
O
TBDPSO
TBDPSO
O
H
2
O
Cs2CO3, CH3CN
H
reflux
H
OH
O
82% (40% conv)
H
19
1) DIBAL-H, CH2Cl2, -78 oC, 100%
2) KH, CS2, MeI, THF, rt
O
3)
n
-Bu3SnH, AIBN, benzene
H
With 3 and 4 in hand, we examined the coupling reac-
tion of these fragments (Scheme 5) and found that the
higher order cuprate derived from 4 by the use of tert-
BuLi and lithium 2-thienylcyanocuprate19 was effective
for this 1,4-addition reaction, providing the desired
product 18 as a single diastereomer (91%). The ethylene
ketal in 18 was cleanly removed under the acidic condi-
tions to afford the corresponding diketone 2 (99%),
which was subjected to the intramolecular aldol reac-
tion. Although most of the bases generated a mixture
of 19 and its dehydrated product, the use of Cs2CO3
in CH3CN20 afforded the desired product 19 as a single
product (82%, 40% conv). All attempts in the direct
deoxygenation reaction of ketone 19 failed to afford
the corresponding methylene compound; hence, this
deoxygenation reaction was carried out via the conven-
tional three steps; that is, DIBAL-H reduction (100%) of
19, a methyl xantate formation, and tin-hydride reduc-
tion (73%, two steps). The TBDPS group in the product
was removed by TBAF to provide 1 (98%), which was
reacted with singlet oxygen in the presence of DIPEA
under photo-irradiation conditions using Rose bengal
as a sensitizer,21 followed by the reduction of the result-
ing hemiacetal with NaBH4 to furnish (+)-digitoxigenin
(61%, two steps). Synthetic (+)-digitoxigenin proved to
be identical in all respects to the natural product, indi-
cating that we succeeded in the enantioselective total
synthesis of (+)-digitoxigenin.
reflux, 73% (2 steps)
H
OH
4) TBAF, THF, reflux, 98%
HO
1
H
1) hν, O2, Rose bengal
CH2Cl2, DIPEA, -78 oC
(+)-digitoxigenin
2) NaBH4, CH2Cl2, H2O, rt
61% (2 steps)
Scheme 5. Enantioselective total synthesis of (+)-digitoxigenin.
could be applied for the total synthesis of other cardeno-
lides left unprepared.
Acknowledgments
This work was financially supported in part by a Wase-
da University Grant for Special Research Projects and a
Grant-in-Aid for Scientific Research on Priority Areas
(Creation of Biologically Functional Molecules (No.
17035082)) from The Ministry of Education, Culture,
Sports, Science, and Technology, Japan. We are also
indebted to 21COE ‘Practical Nano-Chemistry’. The
fellowship for young scientists to M.H. from JSPS is
also gratefully acknowledged.
In summary, enantioselective total synthesis of (+)-digi-
toxigenin was achieved by effectively utilizing chiral
building blocks prepared via the catalytic asymmetric
intramolecular cyclopropanation developed by us. This
convergent synthesis would be useful for preparing some
new derivatives of digitoxigenin for SAR studies and
References and notes
1. Hoffmann, B. F.; Bigger, J. T., Jr. In The Pharmacological
Basis of Therapeutics; Goodman Gilman, A., Goodman,
L. S., Rall, T. W., Murad, F., Eds.; MacMillan: New
York, 1985; p 716.

1544
M. Honma, M. Nakada / Tetrahedron Letters 48 (2007) 1541–1544
2. Ueda, J.; Tezuka, Y.; Banskota, A. H.; Tran, Q. L.; Tran,
9. For synthetic studies on ouabain, see: (a) Hynes, J., Jr.;
Overman, L. E.; Nasser, T.; Rucker, P. V. Tetrahedron
Lett. 1998, 39, 4647–4650; (b) Larry, E.; Overman, L. E.;
Rucker, P. V. Tetrahedron Lett. 1998, 39, 4643–4646;
(c) Overman, L. E.; Rucker, P. V. Heterocycles 2000, 52,
1297–1314; (d) Jung, M. E.; Davidov, P. Angew. Chem.,
Int. Ed. 2002, 41, 4125–4128; (e) Chapdelaine, D.;
Belzile, J.; Deslongchamps, P. J. Org. Chem. 2002, 67,
5669–5672; (f) Jung, M. E.; Piizzi, G. Org. Lett. 2003, 5,
137–140; (g) Jung, M. E.; Piizzi, G. J. Org. Chem. 2003, 68,
2572–2582; (h) Plano, M. F.; Labadie, G. R.; Sierra, M. G.;
Cravero, R. M. Tetrahedron Lett. 2006, 47, 7447–7449.
10. (a) Wiesner, K.; Tsai, T. Y. R.; Jin, H. Helv. Chim. Acta
1985, 68, 300–314; (b) Wiesner, K.; Tsai, T. Y. R. Pure
Appl. Chem. 1986, 58, 799–810; (c) McDonald, F. E.;
Reddy, K. S.; Diaz, Y. J. Am. Chem. Soc. 2000, 122, 4304–
4309; (d) McDonald, F. E.; Reddy, K. S. Angew. Chem.,
Int. Ed. 2001, 40, 3653–3655; (e) McDonald, F. E.; Wu, M.
Org. Lett. 2002, 4, 3979–3981; (f) Langenhan, J. M.;
Peters, N. R.; Guzei, I. A.; Hoffmann, F. M.; Thorson, J.
S. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 12305–12310;
(g) Zhou, M.; O’Doherty, G. A. Org. Lett. 2006, 8, 4339–
4342.
Q. K.; Saiki, I.; Kadota, S. J. Nat. Prod. 2003, 66, 1427–
1433.
3. Laphookhieo, S.; Cheenpracha, S.; Karalai, C.; Chant-
rapromma, S.; Rat-a-pa, Y.; Ponglimanont, C.; Chant-
rapromma, K. Phytochemistry 2004, 65, 507–510.
4. Kamano, Y.; Kotake, A.; Hashima, H.; Inoue, M.;
Morita, H.; Takeya, K.; Itokawa, H.; Nandachi, N.;
Segawa, T.; Yukita, A.; Saitou, K.; Katsuyama, M.; Pettit,
G. R. Bioorg. Med. Chem. 1998, 6, 1103–1115.
5. (a) Danieli, N.; Mazur, Y.; Sondheimer, F. J. Am. Chem.
Soc. 1962, 84, 875–876; (b) Sondheimer, F. Chem. Br.
1965, 1, 454–464; (c) Danieli, N.; Mazur, Y.; Sondheimer,
F. Tetrahedron 1966, 22, 3189–3193; (d) Bach, G.;
Capitaine, J.; Engel, C. R. Can. J. Chem. 1968, 46, 733–
749, and references cited therein; (e) Fritsch, W.; Haede,
W.; Radscheit, K.; Ruschig, H. Liebigs Ann. Chem. 1969,
721, 168–185; (f) Pettit, G. R.; Houghton, L. E.; Knight, I.
C.; Bruschweiler, F. J. Org. Chem. 1970, 35, 2895–2898;
(g) Valcavi, U.; Innocenti, S. El. Farmaco Ed. Sci. 1974,
29, 194–203; (h) Fritsch, W.; Haede, W.; Radscheit, K.;
Stache, U.; Ruschig, H. Liebigs Ann. Chem. 1974, 621–
629; (i) Yoshii, E.; Koizumi, T.; Ikeshima, H.; Uzaki, K.;
Hayashi, I. Chem. Pharm. Bull. 1975, 23, 2496–2506; (j)
Lenz, G. R.; Schulz, J. A. J. Org. Chem. 1978, 43, 2334–
2339; (k) Donovan, S. F.; Avery, M. A.; McMurry, J. E.
Tetrahedron Lett. 1979, 3287–3290; (l) Kocovsky, P.
Collect. Czech. Chem. Commun. 1980, 45, 2998–3007;
(m) Nickisch, K.; Kose, W.; Bohlmann, F. Chem. Ber.
1980, 113, 2038–2039; (n) Marini-Bettolo, R.; Flecker, P.;
Tsai, T. Y. R.; Wiesner, K. Can. J. Chem. 1981, 59, 1403–
1404; (o) Kocovsky, P.; Cerny, V. Collect. Czech. Com-
mun. 1981, 46, 446–451; (p) Welzel, P.; Stein, H.; Milkova,
T. Liebigs Ann. Chem. 1982, 2119–2134; (q) Wicha, J.;
Kabat, M. M. J. Chem. Soc., Chem. Commun. 1983, 985–
987; (r) Wicha, J.; Kabat, M. M. J. Chem. Soc., Perkin
Trans. 1 1985, 1601–1605; (s) Wiesner, K.; Tsai, T. Y. R.
Pure Appl. Chem. 1986, 58, 799–810; (t) Kutney, J. P.;
Piotrowska, K.; Somerville, J.; Huang, S. P.; Rettig, S. J.
Can. J. Chem. 1989, 67, 580–589; (u) Groszek, G.; Kurek-
Tyrlik, A.; Wicha, J. Tetrahedron 1989, 45, 2223–2226; (v)
Kocovsky, P.; Stieborova, I. Tetrahedron Lett. 1989, 30,
4295–4298; For reviews of partial syntheses, see: (w)
Hanson, J. R. Nat. Prod. Rep. 1993, 10, 313–325.
6. Stork, G.; West, F.; Lee, Y. H.; Isaacs, R. C.; Manabe, S.
J. Am. Chem. Soc. 1996, 118, 10660–10661.
11. Yield of 5 was improved to 91% from 78% (Ref. 11a). (a)
Honma, M.; Sawada, T.; Fujisawa, Y.; Utsugi, M.;
Watanabe, H.; Umino, A.; Matsumura, T.; Hagihara,
T.; Takano, M.; Nakada, M. J. Am. Chem. Soc. 2003, 125,
2860–2861; (b) Honma, M.; Nakada, M. Tetrahedron Lett.
2003, 44, 9007–9011.
12. Brooks, D. W.; Mazdiyasni, H.; Grothaus, P. G. J. Org.
Chem. 1987, 52, 3223–3232.
13. Yield of 10 from 3 by the previous method using sodium
amalgam10a was 45%.
14. For example, the reduction of 10 with NaBH4 afforded the
undesired isomer preferentially (86%, dr = 1/3).
15. Ochiai, M.; Ito, T.; Takahashi, H.; Nakanishi, A.;
Toyonari, M.; Sueda, T.; Goto, S.; Shiro, M. J. Am.
Chem. Soc. 1996, 118, 7716–7730.
16. Barton, D. H. R.; Bashiardes, G.; Fourrey, J. L. Tetra-
hedron 1988, 44, 147–162.
17. Commercially available.
18. Crabtree, R. H.; Morris, G. E. J. Organomet. Chem. 1977,
135, 395–403.
19. Lipshutz, B. H.; Koerner, M.; Parker, D. A. Tetrahedron
Lett. 1987, 28, 945–948.
20. Rue1, R.; Deslongchamps, P. Tetrahedron Lett. 1990, 31,
3961–3964.
7. Arnaud, M. C.R. Acad. 1888, 107, 1011.
8. Bigelow, N. M.; Jacobs, W. A. J. Biol. Chem. 1932, 96,
647–658.
21. Kernan, M. R.; Faulkner, D. J. J. Org. Chem. 1988, 53,
2773–2776.