First synthesis of steroidal 1,2,4-trioxolanes

Article abstract of DOI:10.1134/S1070428014070197

Griesbaum ozonolysis of mixtures of methyl 3-(methoxyimino)-5β-cholan- 24-oate with ketones (cyclohexanone, methyl trifluoromethyl ketone, and phenyl trifluoromethyl ketone) afforded for the first time steroidal 1,2,4-trioxolanes which were isolated as mixtures of stereoisomers.

Full text of DOI:10.1134/S1070428014070197

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 7, pp. 1043–1047. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © E.Yu. Yamansarov, O.B. Kazakova, N.I. Medvedeva, D.V. Kazakov, O.S. Kukovinets, G.A. Tolstikov, 2014, published in Zhurnal
Organicheskoi Khimii, 2014, Vol. 50, No. 7, pp. 1059–1062.
First Synthesis of Steroidal 1,2,4-Trioxolanes
E. Yu. Yamansarov, O. B. Kazakova, N. I. Medvedeva, D. V. Kazakov,
O. S. Kukovinets, and G. A. Tolstikov†
Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: obf@anrb.ru
Received December 31, 2013
Abstract—Griesbaum ozonolysis of mixtures of methyl 3-(methoxyimino)-5β-cholan-24-oate with ketones
(
cyclohexanone, methyl trifluoromethyl ketone, and phenyl trifluoromethyl ketone) afforded for the first time
steroidal 1,2,4-trioxolanes which were isolated as mixtures of stereoisomers.
DOI: 10.1134/S1070428014070197
Interest in the chemistry and pharmacological
properties of natural metabolites possessing a peroxide
fragment [1–3] has increased considerably when
unique antimalarial activity of artemisinin has been
disclosed [4]. Since that time studies related to the
design of antimalarial drugs on the basis of peroxide
compounds develop along three main lines: (1) syn-
thetic transformations of artemisinin [5, 6], (2) elabo-
ration of new methods [7] and synthesis of various
peroxy compounds [8–10], and (3) study of physico-
chemical properties and mechanism of antimalarial
action of 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes
acids are known to exhibit high antimalarial and
antitumor activity [24, 25]. Therefore, synthesis of
1,2,4-trioxolanes based on steroids seems to be topical.
As starting compound we used methyl 3-oxo-5β-
cholan-24-oate (II) which was prepared from commer-
cially available lithocholic acid (I) according to stand-
ard procedures. The reaction of II with a slight excess
of O-methylhydroxylamine hydrochloride in boiling
methanol–pyridine (1 : 1) gave 93% of O-methyl
ketone oxime III which was isolated as a mixture of
two isomers at a ratio of 1:1 (according to the NMR
data; Scheme 1).
Methyl 3-(methoxyimino)-5β-cholan-24-oate (III)
was subjected to ozonolysis in the presence of 2 equiv
of ketones (cyclohexanone, methyl trifluoromethyl
ketone, phenyl trifluoromethyl ketone) at 0°C in a mix-
ture of methylene chloride with cyclohexane (TLC
monitoring). Compounds IV–VI were isolated by
column chromatography in 53–82% yield. According
[
11–17]. Important advances have been achieved in all
these directions. It should be especially emphasized
that some 1,2,4-trioxolane and 1,2,4,5-tetraoxane
derivatives turned out to be superior to artemisinin in
antimalarial activity [18]. One of these, second gen-
eration ozonide OZ439, is now successfully passing
the final step of clinical trials [12, 19].
Compounds with a 1,2,4-trioxolane fragment are
commonly synthesized by ozonolysis of unsaturated
compounds [9, 10, 20], as well as by ozonolysis of
O-methyl ketone oximes in the presence of carbonyl
compounds, which was proposed by Griesbaum [21].
Following the latter approach, several hundred ada-
mantan-2-one-based 1,2,4-trioxolanes have been pre-
pared [22, 23], including OZ277 and OZ439 proposed
for clinical trials. No examples of synthesis of steroidal
Me
H
H
Me
O
O
O
O
O
H
Me
Artemisinin
O
O
O
1
,2,4-trioxolanes according to Griesbaum have been
O
N
reported, though 1,2,4,5-tetraoxanes derived from bile
O
†
Deceased.
OZ439
1
043

1
044
YAMANSAROV et al.
Scheme 1.
2
8
1
Me
Me
Me
22
O
O
2
0
1
Me
24
2
3
1
2
OH
OMe
1
9
11 13
17
16
i
Me
H
Me
H
H
9
14
1
5
1
4
2
3
10
8
7
H
6
H
H
H
5
HO
O
H
I
II
Me
Me
Me
Me
O
O
OMe
OMe
ii
iii
Me
H
Me
H
2
'
H
H
O
H
H
MeO
1'O
3'
O4'
N
5
'
H
H
R1
R2
III
IV–VI
1
2
1
2
1
2
IV, R R = (CH
2
)
5
; V; R = CF
3
, R = Me; VI, R = CF
3
, R = Ph; Reagents and conditions: i: (1) H
2
4
SO –MeOH, 64ºC, 3 h; (2) Jones
1
2
reagent, acetone, 0°C, 1 h; ii: MeONH
2
·HCl, MeOH–C
5
H
5
N, 115ºC, 4 h; iii: R R C=O, O
3
, 0ºC, CH
2
Cl
2
6 12
–cyclo-C H .
Scheme 2.
O
Me
Me
H
Me
H
Me
H
MeO
R1
R2
O3
N
O
O
–
MeONO
MeO
O
O
N
O
H
O
O
O
R1
R2
IV–VI
III
A
B
to the NMR data, peroxide IV was a pure compound
while peroxides V and VI were mixtures of four
possible stereoisomers at ratios of 0.3:0.2:0.3:0.2 (V)
and 0.1:0.2:0.4:0.3 (VI). It was difficult to isolate
pure diastereoisomers of V and VI because of their
similar chromatographic mobilities. Peroxides IV–VI
remained unchanged during the isolation and purifica-
tion procedures, in contrast to trioxolanes derived
from 29-norlupan-20-one O-methyloxime, which were
converted into methyl diacetoxy-29,30-bisnorlupan-
Thus, by joint ozonolysis of methyl 3-(methoxy-
imino)-5β-cholan-24-oate with ketones we have syn-
thesized for the first time steroidal 1,2,4-trioxolanes
which attract interest as potential antimalarial and anti-
tumor agents.
EXPERIMENTAL
1
13
The H and C NMR spectra were recorded on
a Bruker AM-300 spectrometer at 300 and 75.5 MHz,
respectively, using tetramethylsilane as internal refer-
ence. The melting points were determined on a Boetius
micro hot stage. The optical rotations were measured
on a Perkin Elmer 241 MC polarimeter using a 10-cm
tube. Thin-layer chromatography was performed on
Sorbfil plates (Sorbpolimer closed corporation, Russia)
using chloroform–ethyl acetate (40:1) as eluent; spots
were detected by treatment with 10% sulfuric acid,
followed by heating to 100–120°C for 2–3 min. Ozone
was generated with the aid of an Ozon-4K ozonizer.
Lithocholic acid (I), O-methylhydroxylamine hydro-
2
0-oate [26].
In keeping with the mechanism proposed by
Griesbaum [21], the formation of steroidal 1,2,4-tri-
3
oxolanes includes oxidation of the C =NOCH double
3
bond in III with ozone to unstable five-membered
molozonide A which decomposes to give carbonyl
oxide B and cyclization (intramolecular [3+2]-cyclo-
addition of intermediate carbonyl oxide to the carbonyl
group of ketone) to form five-membered 1,2,4-trioxo-
lane ring (Scheme 2).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 7 2014

FIRST SYNTHESIS OF STEROIDAL 1,2,4-TRIOXOLANES
1045
1
12
chloride, cyclohexanone, methyl trifluoromethyl
ketone, and phenyl trifluoromethyl ketone were com-
mercial products (from Aldrich). Neutral alumina
C ), 40.0 and 40.1 (0.5C each, C ), 42.4 and 42.5
1
3
5
(0.5C each, C ), 42.7 and 42.8 (0.5C each, C ), 45.6
1
4
and 45.7 (0.5C each, C ), 47.8 and 47.9 (0.5C each,
9
17
(Reakhim) was used for column chromatography.
C ), 51.0 and 51.1 (0.5C each, C ), 56.4 and 56.5
(
0.5C each, OCH ), 60.8 and 60.9 (0.5C each,
3
Methyl 3-oxo-5β-cholan-24-oate (II). A solution
3
=
NOCH ), 161.0 and 161.2 (0.5C each, C ), 174.7
3
of 0.76 g (2 mmol) of lithocholic acid (I) in 60 mL of
2
4
(
C ). Found, %: C 74.76; H 10.39; N 3.36.
anhydrous methanol containing 0.3 mL of 98% H SO
2
4
C H NO . Calculated, %: C 74.78; H 10.38; N 3.35.
2
6
43
3
was heated for 3 h under reflux. The mixture was
poured into 300 mL of cold water, and the precipitate
was filtered off, washed with water, and dried. Yield of
lithocholic acid methyl ester 0.74 g (95%). The result-
ing ester, 0.39 g (1 mmol), was dispersed in 50 mL of
acetone, the suspension was cooled to 0°C, and 2.6 mL
of freshly prepared Jones reagent was added. The mix-
ture was stirred for 1 h and poured into 150 mL of cold
water, and the precipitate was filtered off, washed with
water, and dried. Yield 0.36 g (93%), mp 185–187°C,
Methyl 5β-dispiro[cholane-3,3′-[1,2,4]trioxolane-
5′,1″-cyclohexan]-24-oate (IV). A solution of 0.42 g
(1 mmol) of compound III and 0.2 mL (2 mmol) of
cyclohexanone in 30 mL of methylene chloride–cyclo-
hexane (1:1) was cooled to 0°C, and ozone was passed
through the solution until the initial compound disap-
peared (TLC). The mixture was evaporated under
reduced pressure, and the residue was subjected to
column chromatography on alumina using hexane as
eluent. Yield 0.27 g (53%), amorphous substance,
2
0
1
[
α] = +38° (c = 0.10, CHCl ). H NMR spectrum
D
3
19
20
D
1
(
CDCl ), δ, ppm: 0.65 s (3H, C H ), 0.93 d (3H,
[α]
= +18° (c = 0.10, CHCl
3
). H NMR spectrum
3
3
1
8
21
19
C H , J = 6.0 Hz), 1.15 s (3H, C H ), 1.17–2.40 m
(CDCl
3
), δ, ppm: 0.73 s (3H, C H
3
), 0.83 s (3H,
3
3
1
3
18
21
(
28H, CH , CH), 3.65 s (3H, OCH ). C NMR spec-
C H
(38H, CH
trum (CDCl
(CH ), 22.6 (CH
24.9 (C ), 25.9 (C ), 26.5 (C ), 28.1 (C ), 29.5 (C ),
3
), 0.95 d (3H, C H
3
, J = 7.8 Hz), 1.05–2.45 m
2
3
1
9
18
13
trum (CDCl ), δ , ppm: 12.1 (C ), 18.3 (C ), 21.2
2
, CH), 3.66 s (3H, OCH
3
). C NMR spec-
3
C
2
1
11
2
15
16
19 18
(
(
(
(
(
C ), 22.6 (C ), 24.2 (C ), 25.8 (C ), 26.6 (C ), 28.1
3
), δ , ppm: 12.0 (C ), 18.2 (C ), 21.1
C
6
10
23
22
7
21 11
C ), 30.9 (C ), 31.1 (C ), 34.9 (C ), 35.3 (C ), 35.5
2
2
), 22.9 (CH
2
), 23.8 (C ), 24.1 (C ),
4
20
8
1
12
2
15
22
16
6
10
20
C ), 37.0 (C ), 37.2 (C ), 40.0 (C ), 40.7 (C ), 42.4
1
3
5
9
17
14
23
7
4
C ), 42.8 (C ), 44.3 (C ), 51.5 (C ), 55.9 (C ), 56.4
29.6 (C ), 30.0 (C ), 31.0 (C ), 34.3 (C ), 34.5 (C ),
2
4
3
8
1
OCH ), 174.7 (C ), 213.3 (C ). Found, %: C 77.26;
34.7 (CH
2
), 34.9 (C ), 35.4 (C ), 35.5 (CH ), 39.7
2
3
1
2
13
5
14
9
H 10.35. C H O . Calculated, %: C 77.27; H 10.38.
(C ), 40.2 (C ), 40.8 (C ), 42.7 (C ), 51.4 (C ), 56.0
2
5
40
3
1
7
3
5′
(
(
C ), 56.5 (OCH ), 108.5 (C ), 109.9 (C ), 174.7
3
Methyl 3-(methoxyimino)-5β-cholan-24-oate
III). O-Methylhydroxylamine hydrochloride, 0.1 g
2 mmol), was added to a solution of 0.38 g (1 mmol)
24
C ). Found, %: C 74.07; H 10.04. C H O . Calcu-
31
50
5
(
(
lated, %: C 74.06; H 10.02.
of compound II in 30 mL of a 1:1 mixture of anhy-
drous methanol and pyridine, and the mixture was
heated for 4 h under reflux. The mixture was poured
into 150 mL of 5% aqueous HCl, and the precipitate
was filtered off, washed with water, and dried. Yield
Methyl 5′-methyl-5′-trifluoromethyl-5β-spiro-
[cholane-3,3′-[1,2,4]trioxolan]-24-oate (V) was syn-
thesized in a similar way from 0.42 g (1 mmol) of
compound III and 0.20 mL (2 mmol) of methyl tri-
2
0
fluoromethyl ketone. Yield 0.42 g (82%), [α] = +18°
D
2
0
1
0
0
0
.39 g (93%), amorphous substance, [α] = +14° (c =
(c = 0.30, CHCl
3
). H NMR spectrum (CDCl
3
), δ,
D
1
19
18
.10, CHCl ). H NMR spectrum (CDCl ), δ, ppm:
ppm: 0.60 s (3H, C H ), 0.90 d (3H, C H , J =
3
3
3
3
1
9
18
21
.70 s (3H, C H ), 0.80 s (3H, C H ), 0.90 d (3H,
6.0 Hz), 0.98 s (3H, C H ), 1.00–2.35 m (31H, CH ,
3
3
3
2
2
1
13
C H , J = 19.5 Hz), 1.00–2.40 m (28H, CH , CH),
CH), 3.63 s (3H, OCH ). C NMR spectrum (CDCl ),
3
2
3
3
1
9
18
3
=
.65 s (3H, OCH ), 3.80 s and 3.81 s (1.5H each,
δ , ppm: 11.9 (C ), 17.0 (CH ), 18.0 (C ), 28.1 (0.3C,
3
C
3
1
3
21 21 21
NOCH ). C NMR spectrum (CDCl ), δ , ppm: 11.2
C ), 28.2 (0.2C, C ), 28.3 (0.3C, C ), 28.4 (0.2C,
3
3
C
1
9
18
21 11 11
and 11.3 (0.5C each, C ), 18.2 (C ), 20.4 and 20.5
C ), 30.7 (0.3C, C ), 30.8 (0.2C, C ), 30.9 (0.3C,
11 11 2 15 16
2
1
11
(
0.5C each, C ), 21.0 and 21.1 (0.5C each, C ), 21.5
C ), 31.0 (0.2C, C ), 32.0 (C ), 33.1 (C ), 33.7 (C ),
6 10 23 22
2
and 21.6 (0.5C each, C ), 23.0 and 23.1 (0.5C each,
34.1 (C ), 34.6 (C ), 35.3 (C ), 35.4 (0.3C, C ), 35.5
22 22 22
1
5
16
C ), 24.1 and 24.12 (0.5C each, C ), 25.6 and 25.7
(0.2C, C ), 35.5 (0.3C, C ), 35.6 (0.2C, C ), 35.7
7 4 20 8
6
10
(
0.5C each, C ), 26.3 and 26.4 (0.5C each, C ), 26.5
(C ), 36.8 (C ), 37.7 (C ), 37.8 (0.3C, C ), 39.9 (0.3C,
8 8 8 1
2
3
and 26.6 (0.5C each, C ), 26.7 and 26.8 (0.5C each,
C ), 39.9 (0.3C, C ), 40.0 (0.3C, C ), 40.5 (C ), 40.6
12 13 5 5
2
2
7
C ), 28.6 and 28.7 (0.5C each, C ), 30.9 and 31.00
(
(C ), 40.7 (C ), 40.8 (0.3C, C ), 40.9 (0.2C, C ), 41.1
5 5 9 17
4
20
0.5C each, C ), 32.2 and 32.3 (0.5C each, C ), 35.2
(0.3C, C ), 41.2 (0.2C, C ), 42.6 (C ), 43.6 (C ), 51.4
14 3 3
8
and 35.3 (0.5C each, C ), 36.1 and 36.2 (0.5C each,
(C ), 56.4 (OCH ), 102.4 (0.3C, C ), 102.6 (0.2C, C ),
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 7 2014

1
046
YAMANSAROV et al.
3
3
5′
1
1
1
02.7 (0.3C, C ), 102.8 (0.2C, C ), 109.8 (0.3C, C ),
7. Terent’ev, A.O., Kutkin, A.V., Starikova, Z.A., Anti-
5
′
5′
5′
pin, M.Yu., Ogibin, Yu.N., and Nikishin, G.I., Synthesis,
09.9 (0.2C, C ), 110.6 (0.3C, C ), 110.9 (0.2C, C ),
13.1 (0.3C, CF ), 113.2 (0.2C, CF ), 120.6 (0.3C,
2
004, no. 14, p. 2356.
3
3
2
4
8
. Jefford, C.W., Curr. Top. Med. Chem., 2012, vol. 12,
p. 373.
CF ), 122.8 (0.2C, CF ), 174.7 (C ). Found, %:
3
3
C 65.12; H 8.37; F 11.07. C H F O . Calculated, %:
2
8
43
3
5
9
. Kazakova, O.B., Kazakov, D.V., Yamansarov, E.Yu.,
Medvedeva, N.I., Tolstikov, G.A., Suponitsky, K.Yu.,
and Arkhipov, D.E., Tetrahedron Lett., 2011, vol. 52,
p. 976.
C 65.10; H 8.39; F 11.05.
Methyl 5′-phenyl-5′-trifluoromethyl-5β-spiro-
[
cholane-3,3′-[1,2,4]trioxolan]-24-oate (VI) was syn-
thesized in a similar way from 0.42 g (1 mmol) of
1
0. Kazakova, O.B., Smirnova, I.E., Do Tkhi Tkhu, H.,
Tkhankh Tra Nguen, Apryshko, G.N., Zhukova, O.S.,
Medvedeva, N.I., Nazyrov, T.I., Tret’yakova, E.V., Chu-
dov, I.V., Ismagilova, A.F., Suponitsky, K.Yu., Kaza-
kov, D.V., Safarov, F.E., and Tolstikov, G.A., Russ. J.
Bioorg. Chem., 2013, vol. 39, no. 2, p. 202.
compound III and 0.29 mL (2 mmol) of phenyl tri-
2
0
fluoromethyl ketone. Yield 0.44 g (76%), [α] = +15°
D
1
(
c = 0.10, CHCl ). H NMR spectrum (CDCl ), δ,
3
3
1
9
18
ppm: 0.65 s (3H, C H ), 0.73 s (3H, C H ), 0.98 d
3
3
2
1
(
3
3H, C H , J = 6.8 Hz), 1.00–2.50 m (28H, CH , CH),
3
2
1
1. Kazakov, D.V., Kazakova, O.B., Ishmuratov, G.Yu.,
.58 s (3H, OCH ), 7.20 s (1H, Ph), 7.41–7.50 m (2H,
3
13
Terent’ev, A.O., Nikishin, G.I., and Tolstikov, G.A.,
Doklady Chem., 2011, vol. 436, no. 2, p. 34.
Ph), 7.63–7.70 m (2H, Ph). C NMR spectrum
1
9
18
21
(
CDCl ), δ , ppm: 19.0 (C ), 21.0 (C ), 22.8 (C ),
3
C
11
2
15
16
12. Charman, S.A., Arbe-Barnes, S., Bathurst, I.C.,
Brun, R., Campbell, M., Charman, W.N., Chiu, F.C.K.,
Chollet, J., Craft, J.C., Creek, D.J., Dong, Y., Matile, H.,
Maurer, M., Morizzi, J., Nguyen, T., Papastogian-
nidis, P., Scheurer, C., Shackleford, D.M., Sriragha-
van, K., Stingelin, L., Tang, Y., Urwyler, H., Wang, X.,
White, K.L., Wittlin, S., Zhou, L., and Venner-
strom, J.L., Proc. Natl. Acad. Sci. USA, 2011, vol. 108,
p. 4400.
3. Garah, F., Wong, M., Amewu, R.K., Muangnoicha-
roen, S., Maggs, J.L., Stigliani, J.-L., Park, B.K., Chad-
wick, J., Ward, S.A., and O’Neill, P.M., J. Med. Chem.,
2011, vol. 54, p. 6443.
2
2.9 (C ), 24.1 (C ), 25.7 (C ), 26.3 (0.1C, C ), 26.4
16 16 16
(
0.2C, C ), 26.5 (0.4C, C ), 26.6 (0.3C, C ), 27.3
6 10 23 23
(
C ), 28.1 (C ), 28.6 (0.1C, C ), 28.7 (0.2C, C ),
2
3
23
22
2
8.8 (0.4C, C ), 28.9 (0.3C, C ), 30.9 (C ), 32.2
7 4 20 20
(
C ), 33.4 (C ), 34.0 (0.1C, C ), 34.1 (0.2C, C ), 34.2
20 20 8 1
(
0.4C, C ), 34.3 (0.3C, C ), 34.5 (C ), 35.3 (C ), 39.8
12 13 5 9
(
C ), 40.0 (C ), 40.1 (C ), 41.0 (C ), 42.7 (OCH ),
3
1
7
14
14
5
1.3 (C ), 55.6 (0.1C, C ), 55.7 (0.2C, C ), 55.8
14 14 3
1
(
(
0.4C, C ), 55.9 (0.3C, C ), 103.5 (0.1C, C ), 104.0
3 3 3
0.2C, C ), 104.2 (0.4C, C ), 104.5 (0.3C, C ), 107.6
5
′
5′
5′
(
0.1C, C ), 108.3 (0.2C, C ), 109.4 (0.4C, C ), 109.5
5
′
(
0.3C, C ), 119.76 and 123.6 (CF ), 126.5 (C ),
3
arom
), 132.1
1
4. Kazakov, D.V., Timerbaev, A.R., Safarov, F.E., Nazi-
rov, T.I., Kazakova, O.B., Ishmuratov, G.Yu., Terent’-
ev, A.O., Borisov, D.A., Tolstikov, A.G., Tolstikov, G.A.,
and Adam, W., Roy. Soc. Chem., Advances, 2012, no. 2,
p. 107.
1
26.6 (C
arom
), 128.2 (C
), 132.2 (C
), 130.2 (C
), 174.6 (C ). Found, %:
arom
arom
arom
2
4
(
C
arom
C 68.51; H 7.80; F 9.83. C H F O . Calculated, %:
3
3
45
3
5
C 68.49; H 7.84; F 9.85.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 09-03-00831) and by the President of the Russian
Federation (program for state support of young
Russian scientists, project no. MD-3852.2009.3.).
15. Perry, Ch.S., Charman, S.A., Prankerd, R.J.,
Chiu, F.C.K., Dong, Y., Vennerstrom, J.L., and Char-
man, W.N., J. Pharm. Sci., 2006, vol. 95, p. 737.
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