Synthesis of digitoxigenin from 3β-[(tert-butyldimethylsilyl)oxy]-17α-iodo-5β-androstan-14β-ol via 17β stereoselective free-radical introduction of γ-butyrolactone moiety

Full text of DOI:10.1021/jo962237c

3402
J . Org. Chem. 1997, 62, 3402-3404
Notes
cyano group was easily and selectively accomplished from
Syn th esis of Digitoxigen in fr om
a 14â-hydroxy-17R-iodo derivative via an SN2-type free-
radical reaction with tert-butyl isocyanide without the
protection of the 14â-hydroxy function. This strategy
resulted in a new and highly stereospecific method for
the 17â functionalization of a cis C/D ring steroid.
However, the four-step process leading to the butenolide
ring from the 17â-cyano group was troublesome and low
yielding (10% yield).
3â-[(ter t-Bu tyld im eth ylsilyl)oxy]-17r-iod o-
5â-a n d r osta n -14â-ol via 17â Ster eoselective
F r ee-Ra d ica l In tr od u ction of
γ-Bu tyr ola cton e Moiety
Nicoletta Almirante* and Alberto Cerri
Prassis Istituto di Ricerche Sigma-Tau, Via Forlanini 3,
20019 Settimo Milanese (MI), Italy
In order to find a more efficient process, we decided to
investigate whether the high â stereoselectivity shown
by the carbon radical generated at the 17 position in the
attack to tert-butyl isocyanide could be preserved as a
peculiarity of the structure, in the reaction with other
suitable functionalized reagents. Actually, in the litera-
ture, simple cyclopentyl radicals or cyclic radicals from
sugars with substituents at the R position are reported
to yield preeminently the trans-substituted product.6
Since 2-buten-1,4-olide and its derivatives were reported
to be unreactive as radical acceptors by Daniewski,4 we
directed our attention to a similar but handier and more
reactive compound, conveniently designed for further
synthetic manipulation. We chose maleic anhydride, a
most frequently used radical acceptor in free-radical
chemistry, which had two important requirements: it
allowed us to achieve the desired five-membered ring in
the â configuration in one step and the intermediate
adduct could undergo a polar intramolecular reaction
with the already present 14â-hydroxyl to discriminate
the two carbonyl functions.
Received December 3, 1996
Digitalis cardiac glycosides, such as digoxin, digitoxin,
and ouabain, are naturally occurring inotropic drugs
clinically used for the treatment of congestive heart
failure,1 although their low therapeutic index makes their
use not completely safe. The search for less toxic agents
prompted a lot of work on natural compounds.2 Recently,
the identification of endogenous digitalis-like factors that
may be responsible for essential hypertension2 has
opened a new field in the study of digitalis compounds.
The genins of these molecules (cardenolides), e.g.,
digitoxigenin 8 (Scheme 1), are steroids with three
peculiar structural characteristics, all of them of utmost
importance for the pharmacological action: the cis C/D
ring junction, the 17â-butenolide moiety, and the 14â-
hydroxyl function.
As a part of our work aimed at searching new digitalis-
like compounds with a better pharmacological profile, we
wish to report an improvement to a known synthetic
approach to digitoxigenin.
Scheme 1 illustrates the synthetic pathway. The
starting iodide 1 was obtained from 3â,14â-dihydroxy-
5â-androstan-17one5 via elaboration of the corresponding
17-hydrazono compound to the 17-iodo-16-dehydro de-
rivative and then hydrogenation of the double bond with
diimide (55% overall yield) following a reported proce-
dure.5 The 3â-hydroxy group of 1 was protected as the
TBDMS ether 2 to prevent reaction with maleic anhy-
dride. The free-radical reaction was performed with tris-
(trimethylsilyl)silane7 (TTMSS) and AIBN in toluene at
90 °C with 2 equiv of maleic anhydride, since TTMSS is
known to react with it. Following the reaction by TLC,
we could spot the formation of an intermediate that
slowly evolved to a new more polar pruduct during the
reaction. We found that the best workup for the reaction
was a basic treatment (DBU/Et2O)8 that allowed the
complete conversion of the first intermediate to the more
polar product and prevented the dehydration of the acid-
labile 14â-hydroxy function. The structure of the polar
product was identified with the 17â-functionalized com-
pound 5 (70% yield from the iodide 2). In principle,
lactone 5 could derive from iodide 2 through two different
intermediates (Scheme 1): the 14â-O-maleate derivative
3 or the anhydride 4. We can affirm that the unisolated
intermediate of the reaction is the anhydride 4 because,
even if the high stereoselectivity shown by the free-
radical reaction might be ascribed to an intramolecular
The synthesis of cardenolides starting from more
readily available steroids, i.e., with a trans-fused C/D ring
system, is still the aim of several research groups, and
17-oxoandrostane derivatives have been widely used as
cardenolide precursors.3 In most of the published syn-
theses, the 14â-hydroxylation step follows the introduc-
tion of a 17â substituent. Actually, if the 14â-hydroxyl
group is added before the elaboration of the ketone at
the 17 position, due to the cis C/D ring junction, only the
isomer possessing the thermodynamically more stable
17R residue is obtained, either directly by nucleophilic
attack to the 17-keto group or by hydrogenation of the
16(17)
∆
or ∆17(20) double bond.3
However, we needed to construct the 17â-butenolide
moiety starting from steroidal compounds with a cis C/D
ring junction.
Quite recently, Daniewsi4 and Wicha5 reported that
14â-hydroxy-17â-cyanoandrostane derivatives were good
starting materials for the synthesis of digitoxigenin and
its 9(11)-dehydro derivative. The introduction of the 17â-
(1) Hoffmann, B. F.; Bigger, J . T., J r. In The Pharmacological Basis
of Therapeutics; Goodman Gilman, A., Goodman, L. S., Rall, T. W.,
Murad, F., Eds.; MacMillan Publishing Company: New York, 1985; p
716.
(2) Thomas, R.; Gray, P.; Andrews, J . Adv. Drug Res. 1990, 19, 312-
562.
(3) Recent leading reference: Kabat, M. J . Org. Chem. 1995, 60,
1823.
(4) Daniewski, A. R.; Kabat, M. M.; Masnyk, M.; Wicha, J .;
Wojciechowska, W.; Duddeck, H. J . Org. Chem. 1988, 53, 4855.
(5) Daniewski, A. R.; Kabat, M. M.; Masnyk, M.; Wojciechowska,
W.; Wicha, J . Collect. Czech. Chem. Commun. 1991, 56, 1064.
(6) Giese, B.; Harnisch, H.; Lu¨ning, U. Chem. Ber. 1985, 118, 1345.
(7) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188.
(8) Modification of Curran procedure without treatment with io-
dine: Curran, D. P.; Chang, C.-T. J . Org. Chem. 1989, 54, 3140.
S0022-3263(96)02237-2 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 10, 1997 3403
Sch em e 1a
a
Reagents and conditions: (a) TBDMSCl, imidazole, DMF, rt, 20 h; (b) maleic anhydride, PhCH3, 90 °C, 4 h; (c) (i) maleic anhydride,
TTMSS, AIBN, PhCH3, 90 °C, 1.5 h; (ii) DBU, Et2O, rt, 20 h; (d) (i) NaBH4, MeOH, THF, reflux, 1.5 h; (ii) HCl (aq), Et2O, rt, 20 h; (e) (i)
LDA, THF, -30 to 0 °C; (ii) PhSeCl, -70 °C, 3 h; (f) AcOH, H2O2, THF, -10 °C to rt, 1.5 h; (g) 0.2 N H2SO4(aq), MeOH, reflux, 1 h.
addition, as in the case of derivative 3, an ester adduct
between 14â-OH and maleic anhydride was never ob-
served. In fact, the two reactants were recovered un-
changed after prolonged heating in the absence of the
radical initiator (besides, it is known that a 14â-ester
derivative is not easily prepared).9
nylselenyl) derivative, following a general method.11
Subsequent acid removal of the silyl group gave digitoxi-
genin 8, in 95% yield, whose analytical and spectral data
were in full agreement with those of an authentic sample.
In conclusion, this reaction sequence provides an
efficient method for the stereoselective introduction of a
γ-butyrolactone moiety at the 17â-position of 14â-hydroxy
steroids through an advanced precursor such as 5, which
offers the advantage of presenting differently manageable
functionalities in the desired lactone skeleton that permit
an easy and efficient transformation into the desired
butenolide ring.
The isolation of lactone 5 confirmed both of our
hypotheses: an advanced precursor of the butanolide ring
could be selectively introduced at position 17â in one step,
and the 14â-OH allowed the discrimination between the
two carbonyl functions of the intermediate anhydride.
Further, the presence of the lactone in compound 5 was
a confirmation of the â-stereoselective pathway of the
radical reaction.
Exp er im en ta l Section
Compound 5 could be easily transformed into the
cardanolide derivative 6 by a chemoselective reduction
of the lactone ring with NaBH4-MeOH in refluxing
THF.10 After a careful workup, compound 6 was isolated
in 80% yield as a diastereoisomeric mixture. Lactone 6
was transformed into the unsaturated lactone 7 (60%
yield) through the oxidation of the corresponding R-(phe-
Melting points were determined by the capillary method on
an electrothermal apparatus and are uncorrected. NMR spectra
were recorded at 300.13 MHz (1H NMR) or at 75.48 MHz (13
C
NMR) in CDCl3 solution with Me4Si as the internal standard; J
values are in Hz. Mass spectral data were obtained with an
electron-impact ionization technique at 70 eV using the direct
exposure probe (DEP). Flash chromatography was carried out
on silica gel (70-230 mesh). After workup, organic solvents were
dried over anhydrous Na2SO4 and then filtered, and the solvent
was evaporated under reduced pressure on a rotary evaporator.
(9) Acetylation of the 14â-hydroxy group was accomplished with
acetic anhydride in pyridine in the presence of DMAP after 6 days at
room temperature; see: Lindig, C.; Repke, K. R. H. J . Prakt. Chem.
1987, 329(5), 841.
(11) Urones, J . G.; Basabe, P.; Marcos, I. S.; D´ıez Mart´ın, D.;
Sexmero, M. J .; Peral, M. H.; Broughton, H. B. Tetrahedron 1992, 48,
10389.
(10) Soai, K.; Oyamada, H. Synthesis 1984, 605.

3404 J . Org. Chem., Vol. 62, No. 10, 1997
Notes
Yields refer to homogeneous products (TLC). Elemental analy-
ses were performed by Redox, Cologno Monzese, Italy.
of 3.2-3.5. After addition of Et2O, the mixture was acidified to
pH 1.4 with 3 N HCl and stirred overnight. Then EtOAc was
added and the mixture extracted. After evaporation, the residue
was purified by flash chromatography (CH2Cl2/EtOAc 95:5) to
yield 6 (192 mg, 80%) as a white solid, 1:1 diastereoisomeric
mixture: 1H NMR δ 0.022 (s, 12H), 0.89 (s, 18H), 0.93 (s, 6H),
0.95 (s, 3H), 0.97 (s, 3H), 2.18 (dd, J ) 17, 10, 1H), 2.38 (dd, J
) 18, 10, 1H), 2.57 (dd, J ) 18, 10, 1H), 2.70 (dd, J ) 17, 10,
1H), 2.88 (m , 2H), 3.88 (t, J ) 9, 1H), 4.05 (m, 3H), 4.42 (t, J )
8, 1H), 4.51 (t, J ) 9, 1H); MS m/ z (rel intensity) 475 (M+ - 15,
2), 433 (100). Anal. Calcd for C29H50O4Si: C, 70.97; H, 10.27.
Found: C, 70.61; H, 10.39.
Digitoxigen in 3-ter t-Bu tyld im eth ylsilyl Eth er (7). To a
solution of lactone 6 (152 mg, 0.31 mmol) in dry THF (3 mL)
cooled to -30 °C, under a nitrogen atmosphere, was slowly added
a 2 M commercial solution of LDA in THF/heptane/ethylbenzene
(0.93 mL, 1.86 mmol). The temperature was slowly raised to 0
°C during 1 h. The solution was then cooled to -70 °C, and a
solution of PhSeCl (370 mg, 1.92 mmol) in THF (3 mL) was
slowly added. The mixture was stirred for 3 h and then poured
into 5% aqueous NaH2PO4 (10 mL) previously brought to pH 3
with 3 N HCl; additional 3 N HCl was added during the
quenching to keep the pH in the range of 3.2-3.5. The mixture
was extracted with EtOAc, the organic phase dried, and the
solvent evaporated. The residue was dissolved in THF (5 mL),
and AcOH (0.1 mL) was added. The resulting solution was
cooled to -10 °C, and 30% H2O2 (0.34 mL, 3 mmol) was slowly
added. After 0.5 h, the yellow solution was brought to room
temperature and stirred for 1 h. The resulting pale yellow
solution was quenched with aqueous NaHCO3 and the mixture
extracted with EtOAc. The residue was purified by flash
chromatography (CH2Cl2/EtOAc 95:5) to yield 7 (90 mg, 60%)
as a white solid. An analytical sample was obtained by crystal-
lization from CHCl3/n-hexane: mp 228-232 °C; 1H NMR δ 0.023
(s, 6H), 0.98 (s, 9H), 0.88 (s, 3H), 0.93 (s, 3H), 2.14 (m, 2H), 2.80
(m, 1H), 4.05 (m, 1H), 4.81 (d, J ) 18, 1H), 5.01 (d, J ) 18, 1H),
5.90 (m, 1H); MS m/ z (rel intensity) 473 (M+ - 15, 2), 431 (100).
Anal. Calcd for C29H48O4Si: C, 71.27; H, 9.90. Found: C, 70.88;
H, 9.90.
3â-[(ter t-Bu tyld im eth ylsilyl)oxy]-17r-iod o-5â-a n d r osta n -
14â-ol (2). A solution of compound 15 (737 mg, 1.6 mmol),
TBDMSCl (583 mg, 3.9 mmol), and imidazole (526 mg, 7.7 mmol)
in DMF (10 mL) was stirred at room temperature overnight.
The solution was then diluted with water, extracted with Et2O,
and dried. After evaporation, the crude product was purified
by flash chromatography (n-hexane/EtOAc 90:10) to afford 2 (825
mg, 88%) as a white solid: 1H NMR δ 0.025 (s, 6H), 0.89 (s,
9H), 0.940 (s, 3H), 0.946 (s, 3H), 2.04 (m, 1H), 2.19 (m, 1H), 2.44
(m, 1H), 4.04 (m, 1H), 4.44 (t, J ) 9.0, 1H); MS m/ z (rel
intensity) 532 (M+, 1), 475 (23), 255 (100). An analytical sample
was obtained by crystallization from EtOH/water: mp 177-179
°C. Anal. Calcd for C25H45IO2Si: C, 56.38; H, 8.52; I, 23.83.
Found: C, 56.46; H, 8.61; I, 23.66.
(20RS)-3â-[(ter t-Bu t yld im et h ylsilyl)oxy]-14â-h yd r oxy-
5â,24-n or ch ola n e-21,23-d ioic Acid 14,21-La cton e (5). To a
solution of iodo derivative 2 (600 mg, 1.12 mmol) and maleic
anhydride (222 mg, 2.26 mmol) in toluene (10 mL) heated at 90
°C under a nitrogen atmosphere was added a solution of TTMSS
(0.72 mL, 2.38 mmol) and AIBN (19 mg, 0.12 mmol) in toluene
(4 mL) dropwise over 1 h. After an additional 0.5 h at 90 °C,
the reaction was cooled to 0 °C and a mixture of DBU (0.34 mL,
2.24 mmol) in Et2O (6 mL) was added dropwise. After being
stirred at room temperature overnight, the mixture was poured
into 5% aqueous NaH2PO4 (30 mL) previously brought to pH 3
with 3 N HCl; additional 3 N HCl was added during the
quenching to keep the pH in the range of 3.2-3.5. The mixture
was extracted with EtOAc and the organic phase dried and
evaporated. The residue was purified by flash chromatography
(n-hexane/acetone/CHCl3 60:20:20) to yield 5 (390 mg, 70%) as
a white solid, 1:1 diastereoisomeric mixture. The product was
essentially pure by TLC and 1H NMR analysis and was used
for the next step without further purification: 1H NMR of the
1:1 diastereoisomeric mixture δ 0.024 (s, 12H), 0.89 (s, 18H),
0.97 (s, 3H), 0.98 (s, 3H), 1.01 (s, 3H), 1.13 (s, 3H), 2.42 (dd, J )
16, 7, 1H), 2.58 (dd, J ) 13, 9, 1H), 2.90-3.20 (m, 3H), 3.36 (m,
1H), 4.05 (m, 2H); 13C NMR δ 175.5, 175.2, 174.8 174.3, 95.8
and 95.2 (C-14), 44.6 and 45.0 (C-13), 15.7 and 14.5 (C-18); MS
m/ z (rel intensity) 489 (M+ - 15, 1), 447 (77), 371 (100). An
analytical sample, unchanged in diastereoisomeric ratio, was
obtained by crystallization from CHCl3/n-hexane. Anal. Calcd
for C29H48O5Si: C, 69.00; H, 9.58. Found: C, 68.81; H, 9.61.
(20RS)-14â-H yd r oxy-3â-[(ter t-b u t yld im et h ylsilyl)oxy]-
5â-ca r d a n olid e (6). To a solution of acid 5 (250 mg, 0.49 mmol)
in THF (5 mL) was added NaBH4 (129 mg, 3.4 mmol), and the
mixture was refluxed while MeOH (1.1 mL) was slowly added
dropwise over 1 h. During the reduction a vigorous gas evolution
took place. After being refluxed for an additional 0.5 h, the
mixture was cooled and dropped into 5% aqueous NaH2PO4 (10
mL) previously brought to pH 3 with 3 N HCl; additional 3 N
HCl was added during the quenching to keep the pH in the range
Digitoxigen in (8). A mixture of silyl ether 7 (60 mg, 0.12
mmol), MeOH (2 mL), and 0.2 N H2SO4 (0.27 mL) was refluxed
for 1 h. After cooling, the solution was poured into 5% aqueous
NaH2PO4 and extracted with EtOAc. The residue was purified
by flash chromatography (n-hexane/EtOAc 70:30), yielding 8 (44
1
mg, 95%) as a white solid, pure by TLC and H NMR: mp 240-
245 °C (from EtOAc; identical to melting points of a commercial
sample, Fluka, and of a mixed sample).
Ack n ow led gm en t. We thank Dr. S. De Munari and
Mr. G. Marazzi for spectral determinations and useful
discussions.
J O962237C