10660
J. Am. Chem. Soc. 1996, 118, 10660-10661
The Total Synthesis of a Natural Cardenolide:
(+)-Digitoxigenin
Gilbert Stork,* Fred West,† Hee Yoon Lee,‡
Richard C. A. Isaacs,§ and Shino Manabe|
Department of Chemistry, Columbia UniVersity
New York, New York 10027
ReceiVed June 26, 1996
It has been said that the active components in the Digitalis
extracts have been “the most ingested drugs in medicine”.1 These
substances, usually called cardenolides, differ from ordinary
steroids in three major respects: the C/D ring system is cis rather
than trans fused, there is a tertiary hydroxyl at C-14, and the
substituent at C-17 (a butenolide) is in the thermodynamically
less stable â orientation.2 As might be expected, many partial
syntheses of cardenolides have been described starting with
readily available steroids.3,4
Figure 1.
using its racemate. Ozonolysis of the trimethylsilyl enol ether
of 3 gave, in a not unprecedented reaction,7 a mixture of
R-hydroxy ketones which was reduced (NaBH4) to the corre-
sponding glycols, followed by cleavage with periodate to the
dialdehyde 4 (71% overall yield from 3). The two aldehyde
groups in 4 now had to be differentially elaborated.
We now report the total synthesis of natural (+)-digitoxigenin
(1), the biologically active cardenolide which, as its trisaccharide
derivative digitoxin, is one of the most frequently used of the
active principles isolated from Digitalis species.
We divided the synthesis, which we carried out both to
racemic and to natural (+)-digitoxigenin, in three parts: syn-
thesis of the tricyclic enone 2; elaboration of the fused
5-membered ring D to produce a tetracyclic system bearing both
a 14-â-hydroxy substituent and a substituent at C-17 capable
of further transformation; and, finally, elaboration of that
substituent to the â-oriented butenolide system.
We chose to approach the construction of the tricyclic enone
2 via an intramolecular [4 + 2] cycloaddition, as schematized
in Figure 1.
Key: (a) NEt3, DMF; 95%; (b) CH2Cl2/MeOH; DMS; 80% ketol; (c)
MeOH, -20 °C to room temp.; (d) CH2Cl2/H2O, 0 °C; 71% from 3;
(e) benzene; 67%.
We found the aldehyde alcohol 5, which was formed (57%)
by the selective reduction of 4 with sodium triacetoxyborohy-
dride, to be useful for that purpose. Its condensation by the
method of Yamamoto8 with the lithio carbanion from (E)-2-
butenyldiphenylphosphine oxide9 cleanly led (77%) to the
desired (E,E)-1,3- pentadienyl substituent,10 which, after Swern
oxidation, gave us the proper enantiomer 6 of the dienyl
aldehyde that we had previously made by a different route in
the dl series (vide supra). A variety of dienophiles could easily
be made from the aldehyde function of 6. However, even
though some obvious candidates (cf., A, Figure 1, E ) CN or
NO2) underwent ready intramolecular [4 + 2] cycloaddition,
we were unable to transform these adducts into the required
enone. Fortunately, the conjugated dithiane 7, easily prepared
by reaction of 6 with the appropriate dithiane phosphonate,11
solved the problem, since it underwent the required cycload-
dition (61%) at 180 °C.12 Two new asymmetric centers are
formed in the cycloaddition process, but the required orientation
shown in 8 was anticipated from the endo transition state 8a
which we expected to be the lowest energy conformation. The
high temperature required for the cycloaddition suggested that
this expectation be viewed with some caution, but the stereo-
chemistry shown in 8 was confirmed by X-ray analysis.13
Conversion of the cyclic ketal at C-3 to a â-hydroxyl group
was performed at this stage: acid hydrolysis to 9, followed by
We initiated the synthesis from the monoketal (-)-3, prepared
by applying to the readily available (S)-enantiomer of the
Wieland Miescher ketone,5 the sequence previously described6
† University of Utah.
‡ Korea Advanced Institute of Science and Technology, Taejon, Korea.
§ Merck, Sharp & Dohme, West Point, PA.
| Tokyo Institute of Technology, Dept. of Pharmacology.
(1) Inter alia: (a) Aronson, J. K. An Account of the FoxgloVe and its
Medicinal Uses 1785-1985; Oxford University Press: London, 1985. (b)
Cardiac Glycosides; Erdmann, E., Greff, K., Skou, J. C., Eds.; International
Boehringer Mannheim Symposia; Springer Verlag: New York, 1986. (c)
Digitalis Glycosides; Smith, Th., Ed.; Grime & Stratton, Inc.: Orlando,
FL, 1986. (d) Gunthert, Th. W.; Linde, H. H. A. Experientia 1977, 33,
697.
(2) See: Fieser, L. F.; Fieser, M. Steroids; Reinhold Publishing Corp.:
New York, 1959; Chapter 20.
(3) (a) Danieli, N.; Mazur, Y.; Sondheimer, F. J. Am. Chem. Soc. 1962,
84, 875. (b) For a review of early work, see: Sondheimer, F. Chem. Br.
1965, 1, 454. (c) Bach, G.; Capitaine, J.; Engel, C. R. Can. J. Chem. 1968,
46, 733 and references therein. (d) Fritsch, W.; Haede, W.; Radscheit, K.;
Stache, U.; Ruschig, H. Liebigs Ann. Chem. 1974, 621. (e) Yoshii, E.;
Koizumi, T.; Ikeshima, H.; Uzaki, K.; Hayashi, I. Chem. Pharm. Bull. 1975,
23, 2496. (f) Donovan, S. F.; Avery, M. A.; McMurry, J. E. Tetrahedron
Lett. 1979, 3287. (g) Marini-Bettolo, R.; Flecker, P.; Tsai, T. Y. R.; Wiesner,
K. Can. J. Chem. 1981, 59, 1403. (h) Kocovsky, P.; Cerny, V. Coll. Czech.
Commun. 1981, 46, 446. (i) Welzel, P.; Stein, H.; Milkova, T. Liebigs Ann.
Chem. 1982, 2119. (j) Wicha, J.; Kabat, M. M. J. Chem. Soc., Chem.
Commun. 1983, 985. (k) Wicha, J.; Kabat, M. M. J. Chem. Soc., Perkin
Trans. 1 1985, 50, 1990. (l) Wiesner, K.; Tsai, T. Y. R. Pure Appl. Chem.
1986, 58, 799. (m) Kutney, J. P.; Piotrowska, K.; Somerville, J.; Huang, S.
P.; Rettig, S. J. Can. J. Chem. 1989, 67, 580. (n) Groszek, G.; Kurek-
Tyrlik, A.; Wicha, J. Tetrahedron 1989, 45, 2223. (o) Kocovsky, P.;
Stieborova, I. Tetrahedron Lett. 1989, 30, 4295.
(6) (a) Corey, E. J.; Ohno, M.; Mitra, R. B.; Vatakencherry, P. A. J.
Am. Chem. Soc. 1964, 86, 478. (b) McMurry, J. J. Am. Chem. Soc. 1968,
90, 6821. (c) Camps, P.; Ortuno, R. M.; Serratosa, F. Tetrahedron Lett.
1978, 3159.
(7) (a) Clark, R. D.; Heathcock, C. H. Tetrahedron Lett. 1974, 2027. (b)
Zhou, W. S.; Jiang, B.; Pan, X. F. J. Chem. Soc., Chem. Commun. 1988,
791.
(8) Ikeda, Y.; Ukai, J.; Ikeda, N.; Yamamoto, H. Tetrahedron 1987, 43,
723.
(4) For some total synthesis contributions, see: (a) Stryker, J. M. Diss.
Abstr. Int. B 1984, 24, 2432. (b) Daniewski, A. R.; Kabat, M. M.; Masnyk,
M.; Wicha, J.; Wojciechowska, W. J. Org. Chem. 1988, 53, 4855 (for an
interesting total synthesis of the 9,11-dehydro relative of a digitoxigenin
derivative). (c) Ruel, R.; Deslongchamps, P. Tetrahedron Lett. 1990, 31,
3961 (d) Laschat, S.; Narjes, F.; Overman, L. E. Tetrahedron 1994, 50,
347.
(5) Buchschacher, P.; Furst, A.; Gutzwiller, J. Organic Syntheses;
Wiley: New York, 1990; Collect. Vol. VII, 368. Gutzwiller, J.; Buch-
schacher, P.; Furst, A. Synthesis 1977, 167.
(9) Lythgoe, B.; Moran, T. A.; Nambudiry, M. E. N.; Ruston, S. J. Chem.
Soc., Perkin Trans. 1 1976, 2386.
(10) In contrast, the use of the corresponding phosphonate gave a 4:1
E,E and Z,E mixture of dienes.
(11) Mlotkowska, B.; Gross, H.; Costisella, B.; Mikolajczyk, M.;
Grzejszczak, S.; Zatorski, A. J. Prakt. Chem. 1977, 319, 17.
(12) Dr. J. Stelmach, in these laboratories, has recently found that a
closely related intramolecular addition takes place in essentially quantitative
yield at a sand bath temperature of ∼280 °C (internal temperature ∼200
°C).
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