A stereoselective synthesis of digitoxin and digitoxigen mono- and bisdigitoxoside from digitoxigenin via a palladium-catalyzed glycosylation

Article abstract of DOI:10.1021/ol061683b

(Chemical Equation Presented) A convergent and stereocontrolled route to trisaccharide natural product digitoxin has been developed. The route is amenable to the preparation of both the digitoxigen mono- and bisdigitoxoside. This route featured the iterative application of the palladium-catalyzed glycosylation reaction, reductive 1,3-transposition, diastereoselective dihydroxylation, and regioselective protection. The natural product digitoxin was fashioned in 15 steps starting from digitoxigenin 2 and pyranone 8a or 18 steps from achiral acylfuran.

Full text of DOI:10.1021/ol061683b

ORGANIC
LETTERS
2006
Vol. 8, No. 19
4339-4342
A Stereoselective Synthesis of Digitoxin
and Digitoxigen Mono- and
Bisdigitoxoside from Digitoxigenin via a
Palladium-Catalyzed Glycosylation
Maoquan Zhou and George A. O’Doherty*
Department of Chemistry, West Virginia UniVersity, Morgantown, West Virginia 26506
george.odoherty@mail.wVu.edu
Received July 8, 2006
ABSTRACT
A convergent and stereocontrolled route to trisaccharide natural product digitoxin has been developed. The route is amenable to the preparation
of both the digitoxigen mono- and bisdigitoxoside. This route featured the iterative application of the palladium-catalyzed glycosylation reaction,
reductive 1,3-transposition, diastereoselective dihydroxylation, and regioselective protection. The natural product digitoxin was fashioned in
15 steps starting from digitoxigenin 2 and pyranone 8a or 18 steps from achiral acylfuran.
Oligosaccharides bearing deoxysugars have played a pivotal
role in many pharmacologically important antibiotics, vac-
cines, and antitumor agents.1 The cardiac glycoside digitoxin
(1) (Figure 1), which possesses both potent cardiac2 and
digoxose (3).5 Recently, Thorson has constructed a neogly-
coside library of digitoxin analogues with improved anti-
cancer activity yet lower cardiotoxicity.6 To delineate the
(1) (a) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503-1531. (b)
Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996, 35,
1380-1419. (c) Kirschning, A.; Bechthold, A. F.-W.; Rohr, J. Top. Curr.
Chem. 1997, 188, 1-84. (d) Marzabadi, C. H.; Frank, R. W. Tetrahedron
2000, 56, 8385-8417. (e) Kirschning, A.; Jesberger, M.; Schoning, K. U.
Synthesis 2001, 507-540. (f) Nicolaou, K. C.; Mitchell, H. J. Angew. Chem.,
Int. Ed. 2001, 40, 1576-1624. (g) He, X.; Liu, H.-W. Annu. ReV. Biochem.
2002, 71, 701-754.
(2) Digitoxin has been used to treat congestive heart failure and cardiac
arrhythmia for over 200 years. However, extensive care must be taken when
treated with digitoxin because the typical therapeutic dose (14-26 ng mL-1
is dangerously close to the toxic dose (>35 ng mL-1).
)
(3) Greeff, K. Cardiac Glycosides, Part 1: Experimental Pharmacology.
In Handbook of Experimental Pharmacology; Springer-Verlag; Berlin; New
York, 1981; Vol. 56.
(4) For the synthesis of digitoxigenin, see: (a) Danieli, N.; Mazur, Y.;
Sondheimer, F. J. Am. Chem. Soc. 1962, 84, 875-876. (b) Donovan, S. F.;
Avery, M. A.; McMurry, J. E. Tetrahedron Lett. 1979, 35, 3287-90. (c)
Tsai, T. Y. R.; Minta, A.; Wiesner, K. Heterocycles 1979, 12, 1397-1402.
(d) Marini-Bettolo, R.; Flecker, P.; Tsai, T. Y. R.; Wiesner, K. Can. J.
Chem. 1981, 59, 1403-1410. (e) Kabat, M. M. J. Org. Chem. 1995, 60,
1823-1827. (f) Stork, G.; West, F.; Lee, H. Y.; Isaacs, R. C. A.; Manabe,
S. J. Am. Chem. Soc. 1996, 118, 10660-10661. (g) Almirante, N.; Cerri,
A. J. Org. Chem. 1997, 62, 3402-3404. (f) Bocknack, B. M.; Wang, L.-
C.; Krische, M. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5421-5424.
Figure 1. Digitoxin, digitoxigenin, and digoxose.
anticancer activities,3 is the combination of two natural
products, the aglycon digitoxigenin (2)4 and the trisaccharide
10.1021/ol061683b CCC: $33.50
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Published on Web 08/18/2006

pharmalogical role the tris-2-deoxy sugar plays in the
biological activity of digitoxin, synthetic access to digitoxin
and its bis- and mono-saccharide analogues are desired.
There have been two syntheses of digitoxin (1), a
carbohydrate approach by Wiesner (∼20 steps from a
protected 2-deoxy sugar) and a de novo approach by
McDonald (20 steps from TMS-acetylene).7 We planned to
prepare digitoxin (1) via a de novo strategy, which could
also be used to prepare various digitoxin analogues. Our goal
was to design a more efficient route in terms of number of
steps and stereocontrol than the previous approaches.8
The stereocontrolled synthesis of 2-deoxy sugars is not a
problem readily solved by traditional carbohydrate methods.9
The deoxymonosaccharides are not naturally abundant or
readily available. They are usually prepared from common
sugar in multiple steps. The control of anomeric stereochem-
istry in the installation of 2-deoxyglycosides is also chal-
lenging. Due to the missing control element at the 2-position,
it is particularly difficult to synthesize â-2-deoxy-glyco-
sides.10 This problem was evident in the previous syntheses
of digitoxin.8,11 Herein we describe our successful de novo
approach to address the 2-deoxy-â-glycosides using a dia-
stereoselective palladium-catalyzed glycosylation reaction12
and its application to syntheses of â-1,4-linked oligosaccha-
ride natural product digitoxin (1). Our strategy (Scheme 1)
features the iterative use of a â-selective palladium-catalyzed
glycosylation reaction, followed by diastereoselective instal-
lation of the C-3/C-4 hydroxy groups and regioselective C-3
protection.
Scheme 1. Digitoxin Retrosynthetic Analysis
∼50% yields after chromatographic separation. If the Boc-
protection is performed at elevated temperature ((Boc)2O/
NaOAc in benzene at 80 °C), the pyranones can be prepared
as a diastereomeric mixture at the anomeric center (Scheme
2). The ratio of â-pyranones to R-pyranones at these higher
Scheme 2. Pyranone Synthesis
Previously, we have shown that acylfurans 9a/b can be
enantioselectively reduced (Noyori, >95% ee)13 and dia-
stereoselectively converted into the R-Boc-pyranones 10a/
b.14 Alternatively, the â-pyranones 8a/b can be isolated in a
(5) The attempts at the selective hydrolysis of digitoxin (1) to form
digoxose (3) have been futile; only the monosaccharide digitoxose was
isolated. Surprisingly, 3 can be isolated from the dried twigs of Orthenthera
Viminea; see: Tiwari, K. N.; Khare, N. K.; Khare, A.; Khare, M. P.
Carbohydr. Res. 1984, 129, 179-187.
(6) 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.
(7) (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.
(8) In both the Wiesner and McDonald syntheses of digitoxin at least
one of the three glycosidic bonds was assembled with poor stereoselectivity;
see ref 7.
(9) (a) Roush, W. R.; Bennett, C. E. J. Am. Chem. Soc. 1999, 121, 3541-
3542. (b) Sherry, B. D.; Loy, R. N.; Toste, F. D. J. Am. Chem. Soc. 2004,
126, 4510-4511.
(10) (a)Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503-1531. (b)
Roush, W. R.; Lin, X.-F. J. Am. Chem. Soc. 1995, 117, 2236-2250.
(11) In contrast, McDonald is able to use his methodology to prepare an
all-R-analogue of digitoxin with high stereocontrol; see: McDonald, F. E.;
Wu, M. Org. Lett. 2002, 4, 3979-3981.
(12) (a)Babu, R. S.; O’Doherty, G. A. J. Am. Chem. Soc. 2003, 125,
12406-12407. (b) Comely, A. C.; Eelkema, R.; Minnaard, A. J.; Feringa,
B. L. J. Am. Chem. Soc. 2003, 125, 8714-8715. (c) Kim, H.; Men, H.;
Lee, C. J. Am. Chem. Soc. 2004, 126, 1336-1337. For its application in
the de novo synthesis of R-linked 1,4- and 1,6-oligosaccharides, see: (d)
Babu, R. S.; Zhou, M.; O’Doherty, G. A. J. Am. Chem. Soc. 2004, 126,
3428-3429.
(13) (a) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1996, 118, 2521-2522. (b) Li, M.; Scott, J. G.;
O’Doherty, G. A. Tetrahedron Lett. 2004, 45, 1005-1009. (c) Li, M.;
O’Doherty, G. A. Tetrahedron Lett. 2004, 45, 6407-6411.
temperatures can be as high as 1.3:1. Fortunately, once the
R-pyranones 10 and â-pyranones 8 have been separated they
can be converted via palladium(0) catalysis into their
corresponding mixed acetal pyranones with complete reten-
tion of stereochemistry (i.e., 10 to 11 and 8 to 12). By means
of a palladium-catalyzed glycosylation,12a the R-pyranones
can be oligomerized and subsequently transformed into
R-linked oligosaccharides.12d Encouraged by these results,
we decided to investigate the use of the â-isomers 8a/b for
the synthesis of â-linked oligosaccharides (e.g., digitoxin 1).
Our initial effort toward the preparation of 2-deoxysugars
commenced with the synthesis of the 2-deoxy-L-allose. Thus,
using only 5 mol % palladium, the â-pyranone ent-8b14 was
coupled with benzyl alcohol providing â-benzyloxy pyranone
13 in 84% yield (Scheme 3). A reduction of pyranone 13
under Luche conditions15 gave a mixture allylic alcohols
14a/b in 88% yield with the diastereomeric ratio of ca. 1.5:
1. The diastereomeric ratio of alcohols could be improved
(14) (a) Babu, R. S.; O’Doherty, G. A. J. Carbohydr. Chem. 2005, 24,
169-177. (b) Guo, H.; O’Doherty, G. A. Org. Lett. 2005, 7, 3921-3924.
(15) For reduction of â-pyranones, the CeCl3 is necessary to avoid 1,4-
reduction products. For the Luche reduction, see: (a) Luche, J. L. J. Am.
Chem. Soc. 1978, 100, 2226-2227. (b) Haukaas, M. H.; O’Doherty, G. A.
Org. Lett. 2001, 3, 401-404.
4340
Org. Lett., Vol. 8, No. 19, 2006

Scheme 3. Synthesis of 2-Deoxy-L-allose
Scheme 5. Synthesis of Digitoxigen Bisdigitoxoside
with the use of DibalH (dr ) 6:1), albeit in slightly lower
yields. Fortunately, we were able to use both diastereomers
of 14a/b in the subsequent reaction, which allowed us to
use the operational simpler NaBH4 procedure. Thus, exposing
the mixture of allylic alcohols 14a/b to the Myers’ reductive
rearrangement conditions16 (NBSH, PPh3/DEAD, NMM,
-30 °C to rt) provided olefin 15 in 71% yield. Dihydrox-
ylation of 15 using the Upjohn conditions17 (OsO4/NMO)
gave exclusively the diol 16 in 91% yield. While this seven-
step sequence to 2-deoxy-â-allose from acylfuran 9b incor-
porates two nonselective steps, all of the post-glycosylation
steps (13 to 16) lead to a single diastereomeric product.
â-pyranone 8a (Schemes 4-6). Our initial concern about
the compatibilities of the tertiary alcohol and furan formation
of lactone in the aglycon proved to be superfluous. Thus,
both the palladium catalyzed glycosylation and Luche
reduction occurred with complete chemoselectivity (i.e. the
tertiary alcohol and the butenolide ring of the aglycon were
left untouched).
Scheme 4. Synthesis of Digitoxigen Monodigitoxoside
Scheme 6. Synthesis of Digitoxin (1)
With the promising results of the synthesis of 2-deoxy-
allo-sugar 16, we next investigated the synthesis of digitoxin
using the same strategy starting from the digitoxigenin and
(16) (a) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492-
4493. (b) Myers, A. G.; Zheng, B. Tetrahedron Lett. 1996, 37, 4841-
4844. (c) Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997,
62, 7507. (d) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2002, 4, 1771-
1774.
(17) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
17, 1973-1976.
In practice, palladium-catalyzed glycosylation of digitoxi-
genin 2 with the pyranone 8a gave the â-glycoside 17 as a
Org. Lett., Vol. 8, No. 19, 2006
4341

single diastereomer and in good yield (86%). Luche reduction
of 17 provided a mixture of allylic alcohols 18a/b (90%),
which were inseparable (Scheme 4). Reductive rearrangement
of the diastereomeric mixture of allylic alcohols 18a/b
provided olefin 19 in 80% yield. Dihydroxylation of 19 using
the Upjohn conditions (OsO4/NMO) gave exclusively the
digitoxigen monodigitoxoside 20 in 93% yield.18,19
Subjecting the alcohol 27 and pyranone 8a to our typical
Pd(0)-catalyzed glycosylation stereoselectively installed the
final pyran ring to fashion the 1,4-linked trisaccharides 28
in 90% yield (Scheme 6). A diastereomeric mixture of allylic
alcohols 29a/b was obtained in 98% yield when enone 28
underwent Luche reduction. Upon exposure to the Myers
reductive rearrangement conditions, both allylic alcohols in
29a/b reductively rearranged to corresponding olefin 30 in
89% yield. The digitoxose trisaccharide 31 was prepared with
high yield and complete stereocontrol by dihydroxylation of
olefin in 30. Finally the natural product digitoxin (1) was
prepared by deprotection of the two acetate-protecting groups
in 31, which gave synthetic material 1 (83%) with identical
physical and spectral data to that of the commercially
available natural product 121 (1H NMR, 13C NMR, optical
rotation, and melting point).
In conclusion, a straightforward and stereocontrolled 15-
step route to digitoxin (1) from digitoxigenin (2) as well as
corresponding mono- and disaccharides (20 and 26) has been
developed. This new route featured the iterative use of the
palladium catalyzed â-glycosylation reaction, Myers’ reduc-
tive rearrangement, diastereoselective dihydroxylation and
regioselective protection. This work not only shows the
assembly of the nine stereocenters of the trisaccharide from
an achiral starting material, it also demonstrates the functional
group compatibility of this approach (e.g., the tertiary alcohol
and both the double bond and carbonyl group of the
butenolide). This unique application of our Pd-catalyzed
glycosylation efficiently prepares a challenging and important
2-deoxy-â-glycoside target. This approach is mild and
equally amenable to the preparation of various digitoxin
analogues. The uses of this strategy for the synthesis of
various analogues are ongoing.
As with all the other post-glycosylation transformation the
regioselective acylation of diol 20 proved to be compatible
with the aglycon functionality as well as the glycosidic bond.
We found that simply applying an ortho ester formation/
hydrolysis protocol to diol 20 provided the monoprotected
sugar 21 (98% yield), which is ready for subsequent
glycosylation (21 to 22, Scheme 5).20
We next explored the glycosylation of the C-4 secondary
alcohol in 21 for the synthesis of disaccharide 26. Thus,
subjecting the alcohol 21 and pyranone 8a to the typical
palladium catalyzed glycosylation conditions afforded the
C-4 glycosylated disaccharide 22 in 80% yield with complete
stereocontrol at the anomeric center (Scheme 5). Similarly,
Luche reduction of the keto-group in pyranone 22 provided
a 1.6:1 mixture of allylic alcohols 23a/b, which when
exposed to the Myers’ reductive 1,3-allylic transposition
conditions provided olefin 24 in 82% yield. Once again,
dihydroxylation of 24 gave exclusively the diol 25 in 91%
yield. The digitoxigen bisdigitoxoside 26 was fashioned by
deprotection of the acyl-protecting group in 25 (82% yield).
The installation of the final sugar occurred with the same
efficiency and high degree of stereocontrol as seen in the
conversion of aglycon 2 to monosaccharide 20 and monosac-
charide 21 to disaccharide 26 (Schemes 4 and 5). Once again,
this effort began with a regioselective protection of axial
alcohol in diol 25, which provided 27 in excellent yield
(99%).
Acknowledgment. We thank the NIH (GM63150) and
NSF (CHE-0415469) for their generous support of our
research program. Funding for a 600 MHz NMR and an
LTQ-FT Mass Spectrometer by the NSF-EPSCoR (No.
0314742) is also gratefully acknowledged.
(18) Mono- and bis-digtoxosides has been prepared by gradual degrada-
tion of digitoxin, see: (a) Satoh, D., Aoyama, K. Chem. Pharm. Bull. 1970,
18, 94-98. (b) Templeton, F. J.; Setiloane, P.; Kumar, V. P. S.; Yan, Y.;
Zeglam, H. T.; LaBella, F. S. J. Med. Chem. 1991, 34, 2778-2782. Our
synthetic material 20 and 26 have identical physical and spectral data with
degraded products in the terms of 1H NMR, 13C NMR, optical rotation,
and melting point.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) The nomenclature of compounds 20 and 26 was used according to
ref 18.
(20) Acetate protecting group was demonstrated to provide significant
stabilization effect for the acid-sensitive glycosides. (a) Kunz, H.; Unverzagt,
C. Angew. Chem., Int. Ed. Engl. 1988, 27, 1697-1699. (b) Unverzagt, C.;
Kunz, H. Bioorg. Med. Chem. 1994, 2, 1189-1201. (c) McDonald, F. E.;
Danishefsky, S. J. J. Org. Chem. 1992, 57, 7001-7002.
OL061683B
(21) Digitoxin purchased from Acros was used to do the comparison.
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