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ROBERT GREENHOUSE
Syntex, S. A., Division de
Investigation,
Apartado Postal 10-820, Mexico
10,
D.F.
AND
JOSEPH
M. MUCHOWSKI
Syntex Research, Institute of Organic Chemistry,
3401
Hillview Ave., Palo Alto, CA
94304,
U.S.A
Received November 4,1980
:
ROBERT GREENHOUSE and JOSEPH M. MUCHOWSKI. Can. J. Chem.
59,
1025 (1981).
The synthesis of the title compounds was accomplished by (i) boron trifluoride etherate catalysed alkylation of digitoxigenin with
diazoalkanes, (ii) silver tetrafluoroborate assisted solvolysis of
3-desoxy-3a-iododigitoxigen
2d in an alcoholic medium, and (iii)
m-chloroperbenzoic acid induced oxidative solvolytic displacement on the iodo compound 26 in the presence of alcohols. The third
process was the most useful for the preparation of the mono ethers 2e and 2f of ethylene glycol and glycerol, respectively.
ROBERT GREENHOUSE et JOSEPH M. MUCHOWSKI. Can. J. Chem.
59,
1025 (1981).
On a synthetise les composCs mentionnks dans le titre de la fa~on suivante: (i) une alkylation de la digitoxigenine par les
diazoalcanes en presence de l'etherate de trifluorure de bore, (ii) une solvolyse, assistee par le tttrafluoroborate d'argent, du
desoxy-3 iodo-3a digitoxigkne (2d) en milieu alcoolique, et (iii) un deplacement solvolytique oxydant, induit par I'acide m-
chloroperbenzoique, du compose iode 2d en presence d'alcools. Cette trosieme etape est la plus utile dans la preparation, par
exemple, des mono ethers 2e et 2f de I'tthylene glycol et du glycerol. [Traduit par le journal]
Digitoxigenin-3-alkyl ethers were required in
connection with our interest in modified car-
denolides with a therapeutic ratio superior to that
found in the cardiac glycosides currently in use.
Simple 3-alkyl ethers of digitoxigenin have
heretofore not been described in the literature. In-
deed,
3,16-di-0-methylgitoxigenin
lb
,
prepared by
the boron trifluoride etherate catalysed alkylation
of gitoxigenin
la
with diazomethane, appears to be
the only example of a 3-alkoxy cardenolide which
has been reported to date (1).
The conversion of digitoxigenin
2a
into the cor-
responding 3-alkyl ethers, a seemingly simple
chemical operation, could not be accomplished
using the more common methods of effecting such
transformations. For example, the Williamson
ether synthesis with various alkyl halides (methyl
iodide, ally1 bromide, benzyl bromide, or epi-
bromohydrin) in the presence of a variety of bases
(sodium hydride
(2),
barium oxide, sodium hy-
droxide under phase transfer conditions (3), thal-
lium(1) ethoxide (4), proton sponge, 1,5-
diazabicyclo[4.3.0]non-5-ene,
2,6-lutidine, etc.) in
diverse solvents, consistently failed to give the ex-
pected products. In addition, the reaction of'di-
gitoxigenin with a large excess of an alkyl halide
(see above), in the presence of silver tetrafluoro-
borate or mercuric perchlorate, in solvents such as
acetonitrile, dimethylformamide, etc., did not
occur in the desired sense. Of the large number of
methods examined using digitoxigenin as the sub-
strate, only the boron trifluoride etherate catalysed
reaction of diazoalkanes (e.g. diazomethane and
phenyldiazomethane) was successful, but this pro-
cess did not take place with more complicated
diazo compounds such as ethyl diazoacetate.
A
much more useful point of embarkation for the
synthesis of the desired compounds was 3-
desoxy-3a-iododigitoxigenin
2d.
This substance,
which was prepared from digitoxigenin and
triphenylphosphine diiodide
(5),2
gave the methyl
ether
2b,
in 55% yield, when solvolysed in
methanol containing silver tetrafluoroborate.
'Contribution no.
566
from the Syntex Institute of Organic
Chemistry. lThis compound, mp 175-177"C, was first prepared (and fully
characterized) by
E.
Prisbe, Syntex Research, Palo Alto, CA.
0008-404218 1107 1025-03$0 1.00/0
01981 National Research Council of CanadalConseil national de recherches du Canada
Can. J. Chem. Downloaded from www.nrcresearchpress.com by 192.30.84.165 on 01/02/17
For personal use only.
1026
CAN.
J.
CHEM.
VOL.
59, 1981
Similarly, the 1-glyceryl ether 2f was obtained in
25%
and
28%
yields when the reaction was effected
in glycerol-tetrahydrofuran-dimethylformamid or
glycerol
-
tert-butanol solutions, respectively. In
all of these reactions an olefinic material, probably
a mixture of the
A3-
and A4-isomers of anhy-
drodigitoxigenin, was formed as the principal by-
product.
The most successful approach to the synthesis of
the title compounds was based on the oxidative
solvolytic displacement of hypervalent iodine
(6)
from the a-iodo compound 2d. Thus, the reaction
of 2d with m-chloroperbenzoic acid in the presence
of methanol, ethylene glycol, or glycerol, at room
temperature, gave the ethers 2b, 2e, and 2f, re-
spectively. Compound 2f was synthesized unam-
biguously, and in much better yield, by the acidic
hydrolysis of the product derived from the oxida-
tive displacement reaction using glycerol
acetonide.
This ether synthesis obviously is of considerable
utility. The mildness of the conditions under which
the reaction is conducted suggest several other
areas where it could be used advantageously.
The cardiotonic activities of the ethers of di-
gitoxigen were evaluated in driven left atria of the
guinea pig
(7).
In this assay compounds 2e and 2f
were equipotent with digitoxigenin whereas the
methyl and benzyl ethers, 2b and 2c, were ca.
0.3
and 0.1 times as active as digitoxigenin. The sep-
aration of cardiotonic activity and toxicity (ar-
rhythmias, negative inotropic effects) was in no
case, however, better than that observed for di-
gitoxigenin.
Experimental
The melting points were determined in a Mel-Temp apparatus
and are corrected. The infrared spectra were measured with a
Perkin-Elmer Model 237 grating infrared spectrophotometer.
The ultraviolet spectra were recorded with a Perkin-Elmer
Model 402 ultraviolet visible spectrophotometer. The nmr
spectra were taken with a Varian T-60 nmr spectrometer and are
expressed as parts per million (6) from internal tetramethyl-
silane. The mass spectra were measured with an Atlas CH-4
spectrometer. The high pressure liquid chromatographic separa-
tions were effected using a Dupont Model 841 apparatus equip-
ped with a Waters Associates refractive index detector.
3~-Methoxy-14~-hydroxy-5~-card-2~22)-enolide
2(b)
(a) From Digitoxigenin and Diazomethane
Ethereal diazomethane (prepared from nitrosomethylurea
(5 g)) was added in portions with stirring at O°C to a solution of
digitoxigenin (0.500g) in dry dichloromethane (80 mL) contain-
ing boron trifluoride etherate (2 drops). If nitrogen evolution did
not begin shortly after the addition of the first portion of the
diazomethane solution an additional one drop of boron
trifluoride etherate was added. When the addition was com-
pleted (ca. 50 min) the solution was stirred at
O°C until the yellow
colour of the diazomethane had disappeared. The solution was
diluted with an equal volume of ether and washed successively
with 10% sodium carbonate solution and water; the organic
phase was dried over sodium sulfate and evaporated in uacuo.
The residue was subjected to thin layer chromatography (tlc) on
silicagel (ethyl acetate
-
hexane, 2:3) to give a crystalline solid
(0.345g, 66%) which had mp 165.5"C after crystallization from
dichloromethane-hexane;
[a],
+24.4" (c 0.242, CHCI,), ir
(CHCI,) v,,,: 3520, 3490, 1792, 1749, 1625 cm-'; uv (MeOH)
A,,,: 223 nm (E 12 600); nmr (CDC1,)S: 0.86 (s, 3H), 0.91 (s, 3H),
1.00-3.00(m, 23H), 3.23 (s, 3H), 3.45 (m, lH), 4.88 (m,2H), 5.83
(m, 1H); ms m/e: 388 (M+). Anal. calcd. for CZ4H3,O4: C 74.19,
H 9.34; found: C 73.90, H 8.96.
(6) By the Silver TetrafIuoroborate Assisted Solvolysis of 2d in
Methanol
Silver tetrafluoroborate (0.025 g) was added to a stirred solu-
tion of the 3a-iodo compound 2d (0.050g) in dry methanol
(7mL). After 40min at room temperature the mixture was di-
luted with ether, the ether phase was washed with 5% sodium
bicarbonate solution, dried, and evaporated. Thin-layer
chromatographic analysis (silica gel, ethyl acetate
-
hexane, 3:7)
of the residue showed that starting material was still present and
therefore the mixture was resubmitted to the solvolysis condi-
tions described above. After 2 h, the usual work-up gave a
mixture which was subjected to tlc on silicagel using the above
solvent system. A less polar product (0.018g, presumably a
mixture of A-3 and A-4 anhydrodigitoxigenin) and the more
polar ether (0.023g, 55%) were obtained. After crystallization
from dichloromethane-hexane, it has mp 165-165.5"C, unde-
pressed on admixture with a sample synthesized by method (a).
(c) By Oxidative Solvolysis of 2d
meta-Chloroperbenzoic acid (0.183 g) was added, in one por-
tion, to a solution of the 3a-iodo compound 2d (O.200g) in
anhydrous methanol (15 mL) containing dry dichloromethane
(5 mL). After 1 h at room temperature, the mixture was poured
into ether (175 mL), the solution was washed with 5% sodium
bicarbonate solution, dried, and evaporated in uacuo. The re-
sidue was filtered through a short column of silica gel using ether
as the solvent. The mixture thus obtained was separated by high
pressure liquid chromatography (hplc) on a 50cm
x
i
in. Li-
chrosorb column using ethyl acetate
-
hexane (1:3) as the de-
veloping solvent (flow rate 9 mL/min at 1100psig). The major
product (0.072g, 45%) had a retention time of 26.5 min and was
identical to the methyl ether obtained by methods (a) or (b).
3~-Benzyloxy-14~-hydroxy-5~-card-2~22)-enolide
2e
A solution of phenyldiazomethane, prepared from N(N1-
nitrosobenzylaminomethyl)benzamide
(3.80g) according to the
method of Sekiya et al. (8), in dry dichloromethane (15 mL) was
added in portions (0.5 mL) at O°C, to a stirred solution of di-
gitoxigenin (0.500g) in dry dichloromethane (30 mL) containing
boron trifluoride etherate solution (5 drops, prepared from
boron trifluoride etherate (1mL) and anhydrous
dichloromethane (9mL)). When the addition was completed,
stirring was continued for an additional 10 min and the solution
was diluted with dichloromethane. The mixture was washed
with water, dried, and evaporated in uacuo. The oily residue
was subjected to tlc on silica gel (ethyl acetate
-
hexane, 3:2) to
give a solid (0.356g, 57%). Crystallization of this material from
hexane-dichloromethane followed by hexane-acetone gave the
analytical specimen mp 145.5-146'C;
[aID
+24.6" (c 0.245,
CHCI,); ir (KBr) v,,,: 3530, 1785, 1755, 1740sh, 1720sh,
1627cm-I; uv (MeOH)
A,,:
219nm (E 15 100); nmr (CDCI,)
6:
0.86(s, 3H),0.93(s,3H),
1.00-3.00(m,23H),3.68(m,
lH), 4.44
(s, 2H), 4.84 (m, 2H), 5.81
(s,
IH), 7.26 (s, 5H); ms m/e:
464
(M+). Anal. calcd. for C30H4004: C 77.55, H 8.68; found: C
77.24. H 8.49.
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GREENHOUSE
AND
MUCHOWSKI
1027
3P-(2-Hydroxyethoxy)-I4P-hydroxy-5P-
card-2q22)-enolide 2e
meta-Chloroperbenzoic acid (0.177g) was added, in one por-
tion, to a stirred solution of the iodo compound (0.196g) in
'
dioxan (9 mL) to which ethylene glycol (6 mL) had been added.
,
After 1.5 h the reaction mixture was poured into water and the
product was extracted with ether. The extract was washed
,
successively with water and 5% sodium bicarbonate solution,
1
dried over sodium sulfate, and evaporated in uacuo. The residue
was subjected to tlc (hexane-acetone, 7:3) to give the major
product (0.093g, 55%) as a crystalline solid. Crystallization of
this material from a small volume of ethyl acetategave a powder,
mp 174.5-182.S0C. On occasion, a solid, mp 165-166"C, was
obtained, but the higher melting modification was the more
stable one; [aID +2S0 (c 0.145, CHCI,); ir (CHCI,) v,,,: 3625,
3490, 1791, 1749, 1723cm-I, uv (MeOH) h,,,: 219nm (E 14500);
nmr (CDCI,) 5: 0.90 (s, 3H), 0.94 (s, 3H), 1.15-2.96 (m, 24H),
3.40-3.80 (m, 5H), 4.90 (s, 2H), 5.87 (s, 1H). Anal. calcd. for
,
CZ5H3805: C 71.74, H 9.15; found: C 71.74, H 9.20.
3P-(2.3-Dihydroxypropoxy)-I4P-hydroxy
5P-card- 2q22)-
enolide 2f
meta-Chloroperbenzoic acid (0.900g) was added, all at once,
to a stirred solution of the iodo compound 2d (1.00g) in dry
I
dichloromethane (25 mL) and glycerol acetonide (25 mL). After
1
1 h, methanol (100 mL) and 0.1
N
sulfuric acid (50 mL) were
added and the mixture was stirred for 3.25 h. The mixture was
made neutral by the addition of solid sodium bicarbonate and
was then concentrated in uacuo to remove most of the
,
methanol. The mixture thus obtained was partitioned between
1
water and ethyl acetate. The organic phase was washed with
water, dried over sodium sulfate, and evaporated in uacuo. The
residue (1.31 g) was taken up in dichloromethane (25 mL) and
applied to a column of silica gel (50g). Elution with ether
(500mL) removed nonpolar material and elution with ethyl
acetate (500mL) removed the partially purified product. This
material was purified by hplc in the manner described above
using ethyl acetate
-
hexane (8: 1) as the eluting solvent at a flow
rate of 12 mllmin at 1500psig. The pure material (0.310g, 36%),
presumably a mixture of stereolsomers, on crystallization from
ethyl acetate had mp 197°C; [all, +22.3 (c 0.274, CHCI,); ir(KBr)
v,,,: 3420, 1775, 1747, 1615cm-I; uv (MeOH) h,,,: 220nm (E
14800); nmr (CDCI,)F: 0.88 (s, 3H), 0.93 (s, 3H), 1.00-3.00 (m,
25H), 3.66 (m, 6H), 4.88 (m, 2H), 5.85 (s, 1H); ms mle: 430 (M+
-
H20). Anal. calcd. for C2,H,,06: C 69.61, H 8.99; found: C
69.47. H 8.96.
Acknowledgements
We thank Mr.
E.
Prisbe, Syntex Research, In-
stitute of Organic Chemistry, for providing us with
the experimental details for the preparation of the
a-iodo compound
2d.
We also thank Dr.
A.
Stros-
berg, Institute of Pharmacology, for the evaluation
of the cardiotonic activities of the title compounds.
1. C. LINDIG, H.
J.
SCHMIDT, and
K.
REPKE. East German
Patent No. 100,263 (1974).
2.
U.
E. DINER,
F.
SWEET, and R. K. BROWN. Can.
J.
Chem.
44,
1591 (1966); B. A. STOOCHNOFF and N. L. BENOITIN.
Tetrahedron Lett. 21 (1973); C. A. BROWN and
D.
BARTON.
Synthesis, 434(1974).
3. A. MENZ. Angew. Chem. Int. Ed. Engl. 12,846 (1973); H.
H. FREEDMAN and R. A. DUBOIS. Tetrahedron Lett. 3251
(1975).
4. H. KALINOWSKI, D. SEEBACH, and
G.
CRASS. Angew.
Chem. Int. Ed. Engl. 14, 1379 (1975).
5. E.
J.
PRISBE,
J.
SMEJKAL,
J.
P. H. VERHEYDEN, and
J.
G.
MOFFAT.
J.
Org. Chem. 41, 1836(1976).
6. H.
J.
REICH and S. L. PEAKE.
J.
Am. Chem. Soc. 100,4888
(1978); R. C. CAMBIE, B.
G.
LINDSAY, P. S. RUTLEDGE,
and P.
D.
WOODGATE.
J.
Chem. Soc. Chem. Commun. 919
(1978); R. C. CAMBIE, D. CHAMBERS, B.
G.
LINDSAY, P. S.
RUTLEDGE, and P. D. WOODGATE.
J.
Chem. Soc. Perkin
Trans. I, 822 (1980). .
7. R. THOMAS,
J.
BOUTAGY, and A. GELBART.
J.
Pharrnacol.
Exp. Ther. 191,219(1974).
8. M. SEKIYA,
Y.
OHASHI,
Y.
TERAO, and
R.
ITO. Chem.
Pharm. Bull. 24,369 (1976).
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