Cyclobutanone approach to the synthesis of cardenolides

Article abstract of DOI:10.1002/ejoc.200400580

17β-(3′-Oxocyclobutyl)androstane, prepared by the thermal [2 + 2] cycloaddition of dichloroketene to 3β-acetoxypregna-5,20-diene, is the key intermediate in the new, efficient synthesis of steroids bearing the 17β-butenolide fragment that characterizes cardenolides. The six-step synthesis of 3β-tert-butyldimethylsilyloxy-14α-carda-5,20(22)- dienolide was achieved with a total yield of 32%. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400580

FULL PAPER
Cyclobutanone Approach to the Synthesis of Cardenolides[‡]
Krzysztof Błaszczyk,[a] Hanna Koenig,[a] and Zdzisław Paryzek,*[a]
Keywords: Cyclobutanones / Steroids / Cardenolides / Cycloaddition
17β-(3Ј-Oxocyclobutyl)androstane, prepared by the thermal
[2 + 2] cycloaddition of dichloroketene to 3β-acetoxypregna-
5,20-diene, is the key intermediate in the new, efficient syn-
thesis of steroids bearing the 17β-butenolide fragment that
characterizes cardenolides. The six-step synthesis of 3β-tert-
butyldimethylsilyloxy-14α-carda-5,20(22)-dienolide
achieved with a total yield of 32%.
was
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
Cardenolides[1] are plant steroids that occur as glycosides and inversion of the configuration accompanied by func-
and possess powerful cardiotonic activity. They are consid- tionalization of the C-14 atom. In most cases, 21-hydroxy-
ered to be “the most ingested drugs in medicine”.[1a] Since 20-ketones[4,13] with a 17β-oriented side-chain or steroidal
the pioneering studies by Ruzicka et al.[2] and the first syn- 17-ketones[4,14] were selected as substrates. Recently, 17-
thesis of digitoxigenin[3] in 1962, enormous efforts have oxoandrostanes, readily available by chemical or biological
been directed towards the synthesis of cardenolides.[1,4] De- degradation of sitosterol, have also become promising start-
spite the long history of research in this area, the interest ing materials.[4,15,16] Structurally similar, planar steroid lac-
in cardenolides continues. Recently reported work on card- tones with ∆4 or ∆5 unsaturation and/or a 5α,14α configu-
enolides includes the total synthesis of digitoxigenin[1,5] and ration, which lack the 14-OH group, are also of consider-
ouabain,[6] biosynthesis[7] and the search for new, less toxic able biological importance, for example, spironolactone,
digitalis-like compounds with better pharmacological prop- canrenone and others.[1b]
erties for therapeutic use.[8] It has recently been reported
This work is a continuation of our interest in steroidal
that cardenolides have a growth inhibitory effect on cancer cyclobutanones.[17] Since the transformation of pregnane
cell lines[9] and show antiproliferative[10] and cytotoxic[11] derivatives into 17β-butenolide steroids requires a two-car-
activity. New methods for the introduction of the 17β-but- bon side-chain elongation, the [2 + 2] cycloaddition reac-
enolide moiety[4] and synthetic approaches to complex card- tion of the appropriate olefinic substrate with a reactive ke-
enolides have also been reported.[12]
tene to give cyclobutanone appeared to be an attractive ap-
The 17β-butenolide moiety is one of the features of card- proach to the four-carbon side-chain moiety that is charac-
enolides that is crucial for their biological activity. The syn- teristic of cardenolides. Further oxidation of the cyclobut-
thesis of cardenolides with the 14α configuration from com- anone to a lactone followed by dehydrogenation should fur-
mercially available substrates involves the construction of nish the target compound with the side-chain fragment
the β-oriented heterocyclic substituent at the C-17 position characteristic of cardenolides. Cycloaddition of dichloro-
Scheme 1
[‡]
Steroidal Cyclobutanones, 6. Part 5: Ref.[17a]
Faculty of Chemistry, Adam Mickiewicz University,
Grunwaldzka 6, 60-780 Poznan´, Poland
Fax: +48-61-8658008
ketene to the pregn-20-ene derivative appeared to offer a
promising entry to a suitably substituted cyclobutanone
precursor. The main steps in the planned synthetic pathway
to steroid butenolides are shown in Scheme 1.
[a]
E-mail: zparyzek@amu.edu.pl
Eur. J. Org. Chem. 2005, 749–754
DOI: 10.1002/ejoc.200400580
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
749

K. Błaszczyk, H. Koenig, Z. Paryzek
FULL PAPER
butanone 8 as a mixture of four diastereoisomers in 60%
yield.
Results and Discussion
Starting olefin 1, 3β-acetoxypregna-5,20-diene,[18] was
obtained from the commercially available 3β-acetoxypregn-
5-en-20-one following the procedure reported earlier.[19] We
found, however, that reduction of this ketone with sodium
borohydride in methanol gave a mixture of the alcohols
(20R)-2[19] and (20S)-3[20] in a 9:1 ratio, as estimated by the
integration of the 1H NMR signals at δ = 0.76 and
0.67 ppm, respectively, arising from the 18-CH3 group. The
mixture of 2 and 3,which gave two distinct spots on TLC
plates, was used without separation in the next step. Mesyl-
ation in pyridine/dichloromethane gave the productasa mix-
ture of chromatographically indistinguishable isomers 4 [δH
= 0.79 (singlet due to the 18-CH3 group) and 3.00 (singlet
due to the CH3SO2 group)][19] and 5 (δH = 0.72 and 2.98).
The mesylates were eliminated by treatment with potassium
tert-butoxide in refluxing toluene to give the diene 1.[19] The
6β-methoxy-3α,5-cyclo-5α-pregn-20-ene 6,[21] with a pro-
tected ∆5 double bond, was then used as the substrate for
the preparation of the cyclobutanone by reaction with a
ketene. Olefin 6 was prepared from 3β-hydroxy-pregna-
5,20-diene following a procedure previously described in the
literature.[21] However, the reaction of 6 with dichloroke-
tene[22] generated from trichloroacetyl chloride and zinc
failed. Likewise, when olefin 1 was treated with dichloroke-
The monodehalogenation step was evidenced by the shift
tene generated by the reaction of dichloroacetyl chloride in the IR absorption of the four-membered ring carbonyl
with triethylamine[23] in hexane or chloroform, the expected moiety from ν
= 1805 cm–1 in dichlorocyclobutanone 7
˜
max
1
cycloaddition product did not form either.
to ν
= 1793 cm–1 in 8. In the H NMR spectrum of 8 a
˜
max
Regioselective [2 + 2] cycloaddition of 1 and dichloroke- new signal at δ = 4.53–4.48 ppm, ascribed to the proton in
tene generated in situ from trichloroacetyl chloride and ac- the CHCl group, was observed. The full dehalogenation of
tivated zinc in diethyl ether gave the best results under son- dichlorocyclobutanone 7 could be effected with activated[22]
ification conditions. In experiments performed without son- zinc in boiling acetic acid. The formation of cyclobutanone
ification the yields of the cycloaddition product were appre- 9 was evidenced by the IR absorption of the carbonyl group
ciably lower.[24] After chromatographic purification the re- at ν
= 1775 cm–1. The yield of the two-step synthesis of
˜
max
action afforded dichlorocyclobutanone 7 in 58% isolated yi- cyclobutanone 9 was about 50%. However, when the crude
eld. We have previously found that purification of the crude cycloaddition product 7 was immediately reduced under the
reaction product on a SiO2 column is usually accompanied above conditions, the two-step synthesis gave cyclobut-
by slow decomposition of the dichlorcyclobutanones.[17b] anone 9 in a much higher yield of 82%. The Baeyer–Villiger
The dichlorocyclobutanone 7 had spectral characteristics oxidation of cyclobutanone 9 with hydrogen peroxide under
1
(IR, H and 13C NMR, MS) in accordance with the pro- basic conditions was accompanied by hydrolysis of the 3-
posed structure. Compound 7 was formed as a mixture of acetate group and afforded 3-hydroxy-17-lactone 12 in 64%
C-20 epimers in an approx. 2:1 ratio, as evidenced by the yield after chromatography. This unsatisfactory yield was
1H NMR spectrum (see Expt. Sect.). It is supposed that the attributed to the oxidation of the A,B ring fragment of the
major diastereoisomer of 7 has a (20R) configuration for steroid as polar impurities were observed on TLC plates.
the following reasons: a) the approach of dichloroketene to The hydroxy lactone 12, an amorphous mixture of C-20
the ∆20 double bond should occur from the rear side of epimers, exhibited an IR absorption at ν
= 1772 cm–1.
˜
max
the steroid skeleton;[8] b) semiempirical calculations (AM1, The H NMR spectrum of 12 showed signals arising from
CAChe, Fujitsu) show that the s-trans rotamer of olefin 1 protons of the 21-CH2 group at δ = 4.47, 4.38, 3.94 and
is lower in energy than the s-cis rotamer by approx. 0.18 3.83 ppm and a two-proton multiplet due to the 22-CH2
kcal/mol. Consequently, the major dichlorocyclobutanone group at δ = 2.65–2.44 ppm. The 3-OH group of 12 was
(20R)-7 should form via a transition state that results from acetylated with acetic anhydride/pyridine to give the crystal-
the approach of dichloroketene to the olefin 1 in s-trans line acetate 13. Since the yield of lactone 12 prepared from
conformation from the side opposite to the 18-CH3 group. 9 could not be improved by changing the reaction condi-
The endocyclic double bond in ring B of 1 was inert tions, at this stage of the synthesis we used a silyl group to
towards dichloroketene under the reaction conditions. Mild protect the 3-OH group before the oxidation step. Thus,
reduction[25] of the dichlorocyclobutanone 7 with zinc in acetate 8 was hydrolyzed under mild basic conditions by
acetic acid at room temperature afforded monochlorocyclo- using potassium carbonate in methanol to afford a quanti-
1
750
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 749–754

Cyclobutanone Approach to the Synthesis of Cardenolides
FULL PAPER
tative yield of alcohol 10. This was silylated by reaction Table 1. 13C NMR chemical shifts of the cyclobutanones 9–11 and
cardenolide 16
with tert-butyldimethylsilyl chloride and imidazole in DMF
to give silyl derivative 11 in 92% yield. The Baeyer–Villiger
oxidation of ketone 11 with 30% H2O2in a basic methanol/
tetrahydrofuran solution resulted in the formation of lac-
tone 14 in 87% yield after short-column chromatography.
Lactone 14 was formed as an approx. 1:1 mixture of C-20
epimers, as estimated from the integration of the low-field
signals ascribed to the protons of the 21-CH2 group at δ =
4.47, 4.37 (isomer A) and 3.93, 3.83 ppm (isomer B) in the
1H NMR spectrum. The attempted dehydrogenation of lac-
tone 13 with benzeneseleninic anhydride[26] in boiling chlo-
robenzene failed. This result confirmed the previously re-
ported inertness of γ-lactones under direct dehydrogenation
conditions.[26] Dehydrogenation of lactone 14 was achieved,
however, by using the phenylselenylation–oxidation pro-
cedure.[27] The α-phenylselenyl lactone 15 was isolated in
75% yield from the reaction of lactone 14 with lithium di-
ethylamide and phenylselenylchloride in tetrahydrofuran
at –70 °C. As expected, the α-phenylselenyl lactone 15 was
formed as a mixture of four diastereoisomers. This was evi-
denced by its 1H NMR spectrum which was rather complex
(see Expt. Sect.). However, four signals ascribed to the 18-
CH3 protons at δ = 0.73, 0.71, 0.65, and 0.62 ppm and to
the 19-CH3 group at δ = 1.02, 1.01, 1.00 and 0.98 ppm
could be distinguished in the spectrum.
δ [ppm]
Carbon atom
9
10
11
16
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
C-9
C-10
C-11
C-12
C-13
C-14
C-15
C-16
C-17
C-18
C-19
C-20
C-21
C-22
C-23
37.1
27.8
73.8
38.1
139.6
122.3
31.9
31.9
50.1
36.7
20.8
38.7
42.7
56.1
24.4
27.0
57.1
13.1
19.4
25.3
51.7
52.7
208.0
37.3
31.6
71.6
42.3
140.7
121.4
31.9
31.9
50.1
36.5
20.8
38.8
42.6
56.0
24.4
27.0
57.1
13.1
19.4
25.2
51.7
52.6
208.4
37.5
32.2
72.6
42.9
141.6
121.0
32.0
32.0
50.3
36.7
20.9
38.9
42.7
56.2
24.5
27.1
57.2
13.2
19.5
25.3
51.8
52.8
208.4
37.2
31.6
72.4
42.6
141.7
120.7
31.9
32.0
50.0
36.5
20.2
37.9
44.2
56.5
24.3
25.8
50.7
12.9
19.3
171.4
73.4
116.0
174.2
Si(CH3)2
C(CH3)3
C(CH3)3
CH3CO2
CH3CO2
–4.4
18.4
26.1
–4.7
18.1
25.8
170.3
21.5
portant step in the synthesis is the cycloaddition of dichlo-
roketene to the unsaturated ∆20 steroid. This is another ex-
ample of the synthetic utility of cyclobutanones in the syn-
thesis of biologically significant compounds.[28] The six-step
synthesis of 16 from 1 was achieved with a total yield of
32%. Since the transformation of 14α-card-20(22)-enolide
The final step in the synthesis was the oxidation of com- to ∆14 olefin and 14β-hydroxy derivatives has already been
pound 15 with 30% H2O2 in tetrahydrofuran/acetic acid, reported,[29] this method may be adapted to the synthesis
which gave a crystalline product in 67% yield. The IR ab- of variously substituted or modified cardenolides with 14α
sorptions[13a,13b] at ν
= 1785, 1750 and 1630 cm–1 and and 14βconfigurations. It is also expected that this side-
˜
max
the 1H NMR spectral properties of this product are in chain elongation procedure can be applied to the 5β-steroid
agreement with the cardenolide structure 16. A low-field series as well.
signal at δ = 5.85 ppm arising from the 22-H atom and two
signals of characteristic multiplicity at δ = 4.83 and
4.69 ppm, ascribed to the protons at C-21, were observed.
Experimental Section
Full assignment of the signals in the 13C NMR spectra of
General Remarks: M.p. values were determined on a Kofler hot-
cardenolide 16 and of the three 17β-cyclobutyl-androstane
stage apparatus and are uncorrected. IR spectra were determined
derivatives 9–11 is shown in Table 1. Deprotection of the
with a FT-IR Bruker FS 113V spectrometer for solutions inchloro-
TBDMS ether 16 afforded the known 3β-hydroxycardenol-
ide 17.[13a,13b] The 1H NMR spectrum of compound 17 was
in perfect agreement with the literature data.[13a,13b]
form. 1H and 13C NMR spectra were recorded with a Varian Gem-
ini 300 VT spectrometer (300 and 75.5 MHz, respectively) op-
erating in the Fourier transform mode using solutions in deuterioc-
hloroform. Chemical shifts (δ) are expressed in ppm relative to
tetramethylsilane as the internal standard. The DEPT technique
was used to assign the multiplicity of the carbon signals in the
13C NMR spectra. The additivity rules and comparison with data
reported for compounds of similar structure were helpful for signal
assignment. Electron-impact mass spectra were recorded with an
Conclusions
The sequence of reactions that leads to the butenolide
fragment of cardenolides from readily available 3β-acetoxy-
pregna-5,20-diene is relatively simple and efficient. An im- AMD 402 spectrometer using ionization energy of 70 eV. Optical
Eur. J. Org. Chem. 2005, 749–754
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K. Błaszczyk, H. Koenig, Z. Paryzek
FULL PAPER
rotations were recorded with a Perkin–Elmer 243 B polarimeter.
Solvents were dried and distilled according to the standard pro-
cedures. Reaction progress and the purity of compounds were mon-
itored by TLC using precoated aluminium-backed silica plates (E.
Merck, no. 5554). Silica gel 60 (Merck 70–230 mesh, no. 7734) was
used for flash chromatography.
acid (100 mL) and activated zinc dust (2000 mg, 30 mmol) was
added. The mixture was stirred at 100 °C for 1 h. Then an ad-
ditional portion of activated zinc (1000 mg, 15 mmol) was added
and stirring was continued at 100 °C for 1 h. The mixture was then
filtered and the filtrate poured into water. The usual workup gave
a crude product which was purified by column chromatography on
silica gel with benzene/ethyl acetate (50:1) as eluent to give com-
pound 9 (1.847 g, total yield of 82% for the two steps). M.p. 130–
6β-Methoxy-3α,5-cyclo-5α-pregn-20-ene (6): Compound 6 was pre-
pared according to the literature procedure.[21] M.p. 65–70 °C
(Et2O). 1H NMR: δ = 5.72–5.83 (m, 1 H, 20-H), 4.99 (d, J =
1.1 Hz, 1 H, 21-H), 4.93–4.96 (m, 1 H, 21-H), 3.33 (s, 3 H, OCH3),
2.78 (t, J = 3.0 Hz, 1 H, 6-H), 1.031 (s, 3 H, 19-CH3), 0.648 (s, 3
H, 18-CH3), 0.42–0.46 (m, 1 H, 4-H) ppm.
132 °C (methanol). [α]D = –60.3 (c = 1, CHCl ). IR: ν = 1775, 1725,
˜
3
1250, 1030, 680 cm–1. H NMR: δ = 5.38 (br. d, J = 5.1 Hz, 1 H,
1
6-H), 4.60 (m, 1 H, 3α-H), 3.14–3.00 (m, 2 H, CH2CO), 2.87–2.70
(m, 2 H, H2CO), 2.03 (s, 3 H, CH3CO2), 1.03 (s, 3 H, 19-CH3),
0.70 (s, 3 H, 18-CH3) ppm. MS: m/z (%) = 384 (1) [M+], 324 (100),
309 (11), 282 (14), 145 (12), 105 (15), 93 (16). C25H36O3 (384.56):
calcd. C 78.08, H 9.44; found C 77.87, H 9.55.
3β-Acetoxy-21,21-dichloro-21,23-cyclo-24-nor-20ξ-chol-5-en-23-one
(7): A solution of trichloroacetyl chloride (213 mg, 1.16 mmol) in
anhydrous diethyl ether (7.5 mL) was added dropwise over 2 h to
3β-Hydroxy-24-nor-21,23-cyclochol-5-en-23-one (10): A saturated
methanolic solution of potassium carbonate (40 mL) was added to
a solution of compound 9 (1.340 g, 3.48 mmol) in methanol
(130 mL). The reaction mixture was stirred at room temperature
for 4 h. The usual workup gave chromatographically pure com-
a
suspension of 3β-acetoxypregna-5,20-diene (1)[19] (200 mg,
0.58 mmol) and zinc dust (114 mg, 1.74 mmol) in anhydrous diethyl
ether (7.5 mL) under argon. During the addition of trichloroacetyl
chloride, the reaction mixture was irradiated in the water bath of
a sonicator at a bath temperature of 25–30 °C. The sonication was
continued for an additional 2 h after the addition of trichloroacetyl
chloride was completed. Then the reaction mixture was kept under
argon at room temperature for 18 h. Thereafter the mixture was
filtered, the solution diluted with benzene and then washed with
water and 5% aqueous sodium hydrogen carbonate. The organic
layer was dried with magnesium sulfate and the solvent was re-
moved in vacuo. The residue was purified by chromatography on
silica gel with benzene as eluent to give compound 7 (156 mg, 58%,
slowly decomposed[17b] on silica gel) as an oil; two diastereoisomers
were formed in a 2:1 ratio, as estimated from the integration of the
pound 10 (1.174 g, 98%). M.p. 175–176 °C (methanol). [α]D
=
–70.8 (c = 0.25, CHCl ). IR: ν = 3610, 3470, 1775, 1230, 1040 cm–1.
˜
3
1H NMR: δ = 5.35 (br. d, J = 5.2 Hz, 1 H, 6-H), 3.52 (m, 1 H, 3α-
H), 3.14–3.00 (m, 2 H, CH2CO), 2.87–2.70 (m, 2 H, CH2CO), 1.02
(s, 3 H, 19-CH3), 0.70 (s, 3 H, 18-CH3) ppm. MS: m/z (%) = 342
(100) [M+], 300 (47), 267 (57), 231 (42), 213 (42), 159 (39), 145 (60),
133 (42), 105 (80), 91 (54), 41 (58). C23H34O2 (342.52): calcd. C
80.64, H 10.01; found C 80.42, H 10.09.
3-(tert-Butyldimethylsilyloxy)-24-nor-21,23-cyclochol-5-en-23-one
(11): A solution of compound 10 (1.000 g, 2.92 mmol), tert-butyldi-
methylchlorosilane (1.100 g, 7.30 mmol) and imidazole (1000 mg,
14.6 mmol) in anhydrous dimethylformamide (10 mL) was stirred
at room temperature for 1 h. The solution was then poured into
1
signals at δ = 0.78 and 0.72 ppm in the H NMR spectrum of the
1
crude product. IR: ν = 1805, 1725, 1250, 1025, 810, 680 cm–1. H
˜
NMR: δ = 5.38 (br. d, J = 4.9 Hz, 1 H, 6-H), 4.60 (m, 1 H, 3α-H),
3.22–3.03 (m, 2 H, CH2CO), 2.03 (s, 3 H, CH3CO2), 1.03 and 1.02 water and extracted with diethyl ether. The organic layer was
(two s, 3 H, 19-CH3), 0.78 and 0.72 (two s, 3 H, 18-CH3) ppm. 13C
washed with water, dried with magnesium sulfate and the solvent
NMR: δ = 192.3 and 191.8 (C=O), 170.3 (CH3COO), 139.7 and removed in vacuo. The residue was purified by column chromatog-
139.5 (C-5), 122.2 (C-6), 90.1 and 88.2 (CCl2), 73.86 and 73.80 (C- raphy on silica gel with benzene as eluent to yield compound 11
3) ppm. MS: m/z (%) = 410 (2) [M+ – ketene], 394 (98), 392 (100), (1.222 g, 92%). M.p. 149–150 °C (methanol/acetone). [α]D = –43 (c
352 (70), 350 (96), 213 (54), 145 (53), 44 (93). C25H34Cl2O3
(453.45): calcd. C 66.22, H 7.56; found C 66.17, H 7.56.
= 1, CHCl ). IR: ν = 1775, 1250, 1075, 885, 870, 835 cm–1. 1H
˜
3
NMR: δ = 5.32 (br. d, J = 5.2 Hz, 1 H, 6-H), 3.48 (m, 1 H, 3α-H),
3.14–3.00 (m, 2 H, CH2CO), 2.87–2.70 (m, 2 H, CH2CO), 1.01 (s,
3 H, 19-CH3), 0.89 [s, 9 H, C(CH3)3], 0.70 (s, 3 H, 18-CH3), 0.06
[s, 6 H, Si(CH3)2] ppm. MS: m/z (%) = 456 (1) [M+], 399 (100), 357
(10), 323 (16), 171 (17), 159 (25), 145 (40), 119 (25), 105 (32), 93
(35), 75 (99). C29H48O2Si (456.78): calcd. C 76.25, H 10.59; found
C 76.45, H 10.79.
3β-Acetoxy-21-chloro-21,23-cyclo-24-nor-20ξ,21ξ-chol-5-en-23-one
(8): Zinc dust (750 mg, 11.5 mmol) was added in portions to the
crude product obtained from the reaction of compound 1 (1.000 g,
2.92 mmol) with dichloroketene stirred in acetic acid (50 mL) at
room temperature. The mixture was stirred at room temperature
for 1 h. Then the reaction mixture was filtered, and the filtrate was
poured into water. After workup, the crude product was purified
by chromatography on silica gel (30 g) with benzene as the eluent
to give compound 8 (730 mg, total yield of 60% for the two steps)
Crystallization of 11 from MeOH gave the dimethyl acetal of 11.
1
M.p.161–164 °C. IR: no carbonyl absorption. H NMR: δ = 5.32
(br. d, J= 5.2 Hz, 1 H, 6-H), 3.47 (m, 1 H, 3α-H), 3.16 (s, 3 H,
OCH3), 3.12 (s, 3 H, OCH3), 0.99 (s, 3 H, 19-CH3), 0.89 [s, 9 H,
C(CH3)3], 0.61 (s, 3 H, 18-CH3), 0.06 [s, 6 H, Si(CH3)2] ppm.
as a mixture of four diastereoisomers. M.p. 135–145 °C. IR: ν =
˜
1
1793, 1725, 1254 cm–1. H NMR: δ = 5.38 (br. d, J = 4.9 Hz, 1 H,
6-H), 4.66–4.54 (m, 1 H, 3α-H), 4.53–4.48 (m, 1 H, CHCl), 3.17–
3.06 (m, 1 H, CH2CO), 2.82–2.73 (m, 1 H, CH2CO), 2.04 (s, 3 H,
CH3CO2), 1.04 and 1.03 (two s, 3 H, 19-CH3), 0.79 and 0.72 (two
s, 3 H, 18-CH3) ppm. 13C NMR: δ = 199.06 and 198.89 (C=O),
170.27(CH3CO2), 139.56 and 139.47 (C-5), 122.20 (C-6), 73.76 (C-
3), 66.17 and 65.08 (CHCl) ppm. MS: m/z (%) = 388 (4), 336 (100),
304 (16), 296(43). C25H35ClO3 (419.00): calcd. C 71.66, H 8.42;
found C 71.47, H 8.61.
3β-Hydroxy-14α,20ξ-card-5-enolide (12): A solution of NaOH in
CH3OH (0.5 m, 5 mL) and H2O2 (30%, 1.5 mL) was added to a
solution of cyclobutanone 9 (645 mg, 1.68 mmol) in CH3OH/THF
(1:1, 50 mL) and the mixture was stirred overnight at room temp.
The solution was acidified with HCl (0.1 n), benzene and H2O were
added and the organic layer was washed with brine, dried with
MgSO4, filtered and the solvent evaporated to give the crude pro-
duct (726 mg). This was purified by chromatography on a silica-gel
column with benzene/hexane mixtures as eluent to give pure lac-
3β-Acetoxy-24-nor-21,23-cyclochol-5-en-23-one (9): The crude pro-
duct obtained from the reaction of 3β-acetoxypregna-5,20-diene 1
(2.000 g, 5.84 mmol) with dichloroketene was dissolved in acetic
tone 12 (382 mg, 64%). M.p. 245–247 °C (MeOH). IR: ν = 3606,
˜
1
3015, 2942, 1772 (C=O), 1380, 1088 cm–1. H NMR: δ = 5.35 (br.
752
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 749–754

Cyclobutanone Approach to the Synthesis of Cardenolides
FULL PAPER
d, J = 5.2 Hz, 1 H, 6-H), 4.47 (t, J = 8.5 Hz, 1 H, 21-H, isomer
A), 4.38 (dd, J = 8.5, 7.9 Hz, 1 H, 21-H, isomer B), 3.94 (dd, J=
vacuo and the reaction products were separated by column chro-
matography. Elution with benzene gave fraction A (two diastereo-
8.7, 9.6 Hz, 1 H, 21-H, isomer A), 3.83 (dd, J = 9.8, 8.7 Hz, 1 H, isomers of 15) and fraction B (two further diastereoisomers of 15)
21-H, isomer B), 3.58–3.48 (m, 1 H, 3α-H), 2.65–2.44 (m, 2 H, 22-
H), 1.02 (s, 3 H, 19-CH3), 0.59 (s, 3 H, 18-CH3) ppm. MS: m/z (%)
= 358 [M+] (12), 339 (100), 324 (29). HRMS: calcd. for C23H34O3:
358.25079; found 358.25146.
as yellow oils. The total yield of 15 was 99.5 mg (75% yield). IR
(KBr): ν = 1770, 1752, 1250, 1185, 1177, 1092, 887, 870, 836,
˜
776 cm–1.
1H NMR: fraction A: δ = 7.71–7.67 (m, 2 H, C6H5), 7.40–7.25 (m,
3 H, C6H5), 5.30 (br. d, J = 5.0 Hz, 1 H, 6-H), 4.27–4.00 (m, 2 H,
21-H), 3.75 (d, J= 3.8 Hz, 0.5 H, 22-H),3.58 (d, J= 5.4 Hz, 0.5 H,
22-H), 3.47 (m, 1 H, 3α-H), 2.45 (m, 1 H, 20-H), 1.00 and 0.98 (s,
3 H, 19-CH3), 0.890 and 0.885 [s, 9 H, C(CH3)3], 0.65 and 0.62 (s,
3 H, 18-CH3), 0.058 and 0.053 [s, 6 H, Si(CH3)2] ppm; fraction B:
δ = 7.71–7.65 (m, 2 H, C6H5), 7.40–7.25 (m, 3 H, C6H5), 5.33 (br.
d, J = 5.3 Hz, 1 H, 6-H), 4.38–3.84 (m, 2 H, 21-H), 3.84 (d, J =
5.7 Hz, 0.5 H, 22-H), 3.70 (d, J = 6.5 Hz, 0.5 H, 22-H), 3.49 (m, 1
H, 3α-H), 1.017 and 1.006 (s, 3 H, 19-CH3), 0.89 [s, 9 H, C(CH3)3],
0.73 and 0.71 (s, 3 H, 18-CH3), 0.065 and 0.063 [s, 6 H, Si(CH3)2]
ppm. MS: m/z (%) = 628 [M+] (74), 569 (36), 493 (32), 337 (27),
199 (33), 158 (100). HRMS: calcd. for C35H53O3SiSe: 629.29291;
found 629.29204.
3β-Acetoxy-14α,20ξ-card-5-enolide (13): Acetic anhydride (1 mL)
was added to a solution of compound 12 (129 mg, 6 mmol) in pyri-
dine (1 mL) and the mixture was stirred for 2 h at room temp. It
was then poured into ice/H2O and extracted with benzene. The
organic layer was washed with HCl (0.1 n), NaHCO3 (0.1 n) and
brine, dried with MgSO4 and the solvent evaporated to give 13
(115 mg, 80% yield) as a mixture of C-20 epimers. M.p. 197–202 °C
(Me CO). IR: ν = 3016, 2947, 1773 (lactone C=O), 1725 (acetate),
˜
2
1375, 1366, 1254, 1087, 1028, 626 cm–1. H NMR: δ = 5.38 (br. d,
1
J = 4.9 Hz, 1 H, 6-H), 4.55–4.66 (m, 1 H, 3α-H), 4.47 (dd, J = 8,2,
8.5 Hz, 1 H, 21-H, isomer A), 4.38 (dd, J = 7.9, 8.2 Hz, 1 H, 21-
H, isomer B), 3.93 (dd, J= 9.0, 9.6 Hz, 1 H, 21-H, isomer A), 3.84
(dd, J = 9.8, 8.7 Hz, 1 H, 21-H, isomer B), 2.63–2.47 (m, 2 H, 22-
H), 2.01 (s, 3 H, CH3CO), 1.02 (s, 3 H, 19-CH3), 0.707 (s, 3 H, 18-
CH3, isomer A), 0.69 (s, 3 H, 18-CH3, isomer B) ppm. MS: m/z
3β-(tert-Butyldimethylsilyloxy)-14α-carda-5,20(22)-dienolide (16):
Acetic acid (0.1 mL) and a 30% solution of hydrogen peroxide
(0.3 mL, 2.5 mmol) were added to a solution of compound 15
(60 mg, 0.1 mmol) in tetrahydrofuran (3 mL). The reaction mixture
was stirred at 0 °C for 15 min. After warming to room temp., stir-
ring was continued for 45 min. Then the mixture was poured into
water and extracted with diethyl ether. The usual workup gave a
crude product, which was purified on a silica-gel column with ben-
zene/ethyl acetate (20:1) as eluent to yield compound 16 (33.5 mg,
67%). M.p. 183–185 °C (heptane). [α]D = –40 (c = 0.25, CHCl3).
(%) = 340 [M+ – AcOH] (100). HRMS: calcd. for C23H32O2 [M+
AcOH]: 340.24023; found 340.24114.
–
3β-(tert-Butyldimethylsilyloxy)-14α,20ξ-card-5-enolide (14): A 0.5 m
methanolic solution of sodium hydroxide (2.5 mL, 1.25 mmol) and
a 30% solution of hydrogen peroxide (0.5 mL, 4 mmol) were added
to a solution of compound 11 (500 mg, 1.1 mmol) in methanol
(50 mL) and tetrahydrofuran (50 mL). The reaction mixture was
stirred at room temperature for 10 min, then poured into water and
extracted with diethyl ether. The organic layer was washed with
water and dried with magnesium sulfate. After evaporation of the
solvent, the residue dissolved in benzene was passed through silica
gel to give compound 14 (448 mg, 87%) as a mixture of two diaster-
eoisomers in a 1:1 ratio, as estimated from the integration of the
IR: ν = 1785, 1750, 1630, 1255, 1090, 888, 870, 837 cm–1. 1H NMR:
˜
δ = 5.85 (d, J = 1.6 Hz, 1 H, 22-H), 5.32 (br. d, J= 5.2 Hz, 1 H, 6-
H), 4.83 (dd, J = 17.6, 1.6 Hz, 1 H, 21-H), 4.69 (dd, J = 17.6,
1.6 Hz, 1 H, 21-H), 3.48 (m, 1 H, 3α-H), 1.00 (s, 3 H, 19-CH3),
0.89 [s, 9 H, C(CH3)3], 0.64 (s, 3 H, 18-CH3), 0.06 [s, 6 H, Si(CH3)2]
ppm. FAB-MS: m/z (%) = 471 [M+ + H] (100), 412 (7), 338 (17).
HRMS: calcd. for C29H47O3Si: 471.32944; found 471.33029.
1
signals at δ = 4.47, 4.37 and 3.93, 3.83 ppm in the H NMR spec-
trum. M.p. 201–205 °C. IR: ν = 1775, 1250, 1175, 1085, 1025, 885,
˜
870, 835 cm–1. 1H NMR: δ = 5.33 (br. d, J = 5.2 Hz, 1 H, 6-H),
4.47 (dd, J = 8.2, 8.5 Hz, 1 H, 21-H, isomer A), 4.37 (dd, J = 8.2,
7.9 Hz, 1 H, 21-H, isomer A), 3.93 (dd, J = 9.0, 9.3 Hz, 1 H, 21-
H, isomer B), 3.83 (dd, J = 9.0, 9.6 Hz, 1 H, 21-H, isomer B), 3.48
(m, 1 H, 3α-H), 2.65–2.48 (m, 2 H, 22-H), 1.00 (s, 3 H, 19-CH3),
0.89 [9 H, s, C(CH3)3], 0.70 and 0.69 (s, 3 H, 18-CH3), 0.06 [s, 6
H, Si(CH3)2] ppm. 13C NMR: δ = 177.29 and 176.66 (C-23), 141.37
(C-5), 120.73 (C-6), 73.10 and 72.76 (C-21), 72.48 (C-3) ppm. MS:
m/z (%) = 472 (1) [M+], 457 (12), 416 (100), 339 (22), 159 (39), 75
(99). C29H48O3Si (472.78): calcd. C 73.67, H 10.23; found C 73.72,
H 10.54.
3β-Hydroxy-14α-carda-5,20(22)-dienolide (17): A solution of silyl
ether 16 (20 mg, 0.04 mmol) in acetic acid/tetrahydrofuran/water
(3:1:1, 4 mL) was stirred at 90–95 °C for 1 h. Then the reaction
mixture was poured into water and extracted with diethyl ether.
After evaporation of the solvent, the residue dissolved in benzene/
ethyl acetate (2:1) was passed through a pad of silica gel to give
compound 17 (14.5 mg, 95%). M.p. 244–247 °C (Me2CO) (ref.[13a]
m.p. 240–245 °C, ref.[13b] m.p. 235–240 °C). [α]D = –44.0 (c = 0.215,
1
dioxane) [ref.[13c] [α]D = –46.6 (dioxane)]. H NMR: δ = 5.85 (d, J
= 1.3 Hz, 1 H, 22-H), 5.37 (d, J= 5.2 Hz, 1 H, 6-H), 4.83 (dd, J =
17.5, 1.9 Hz, 1 H, 21-HA), 4.69 (d, J = 17.3 Hz, 1 H, 21-HB), 3.53
(m, 1 H, 3β-H), 1.01 (s, 3 H, 19-CH3), 0.64 (s, 3 H, 18-CH3) ppm.
3β-(tert-Butyldimethylsilyloxy)-22ξ-(phenylseleno)-14α,20ξ-card-5-
enolide (15): A 2 m solution of lithium diisopropylamide in tetrahy-
drofuran/heptane/ethylbenzene (Aldrich) (0.63 mL, 1.26 mmol) at
–30 °C was added to
a solution of compound 14 (100 mg,
Acknowledgments
0.21 mmol) in anhydrous tetrahydrofuran (3 mL) under argon. The
reaction mixture was stirred at –30 °C for 30 min and then slowly
warmed to 0 °C within 0.5 h. The solution was then cooled to
–70 °C and a solution of phenylselenyl chloride (241 mg, 1.26 mmol)
in tetrahydrofuran (3 mL) was added dropwise. The mixture was
stirred at –70 °C for 2 h and for a further 1 h at –30 °C. Then a
saturated aqueous ammonium chloride solution (5 mL) was added
and the mixture was left to warm to room temperature. Diethyl
ether was then added and the organic layer was washed with water
and dried with magnesium sulfate. The solvent was evaporated in
Financial support of the work by the Polish State Committee for
Scientific Research (project No. 7 T09A 110 21) is gratefully ac-
knowledged.
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Eur. J. Org. Chem. 2005, 749–754
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753

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Received: August 16, 2004
754
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Eur. J. Org. Chem. 2005, 749–754