On reactions of spirostane sapogenins with benzeneseleninic anhydride

Article abstract of DOI:10.1016/j.tet.2010.05.013

Direct dehydrogenation of spirostane sapogenins with benzeneseleninic anhydride/iodoxybenzene afforded the Δ²² derivatives in low yields. The reactions catalyzed by BF₃/Et₂O produced the 23-oxo-sapogenins in addition to th

Full text of DOI:10.1016/j.tet.2010.05.013

Tetrahedron 66 (2010) 5024e5029
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On reactions of spirostane sapogenins with benzeneseleninic anhydride
*
ꢀ
Izabella Jastrze˛bska, Aneta Dobrogowska, Ewa Lutostanska, Jacek W. Morzycki
Institute of Chemistry, University of Białystok, Piłsudskiego 11/4, 15-443 Białystok, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Direct dehydrogenation of spirostane sapogenins with benzeneseleninic anhydride/iodoxybenzene aff-
orded the D22 derivatives in low yields. The reactions catalyzed by BF3/Et2O produced the 23-oxo-sa-
pogenins in addition to their 22-oxo-23-spiro-isomers. The reactions of sapogenins with
benzeneseleninic anhydride carried out in the presence of TiCl4 afforded products chlorinated at C23.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 25 January 2010
Received in revised form 13 April 2010
Accepted 4 May 2010
Available online 8 May 2010
Keywords:
Benzeneseleninic anhydride
Spirostane
Sapogenin
Oxidation
Rearrangement
1. Introduction
easily undergoes ring F cleavage to a reactive enol ether susceptible
to an electrophilic attack at C23. There are several papers dealing
Steroidal saponins are frequently occurring natural products
with diverse biological activity.1 Upon hydrolysis, these compounds
yield sugars and aglycones called sapogenins with cholestane,
furostane or spirostane frameworks. The spirostane sapogenins
(SS) obtained from natural saponins always have an R configuration
with halogenation8 or oxidation9 at this position. However, none of
these are devoted to direct dehydrogenation leading to the 23(24)-
unsaturated SS, potentially useful in various syntheses. The syn-
theses of these compounds have been reported in the literature
only by rather inefficient routes, e.g., dehydrobromination of the
23-bromo-SS,10 denitroamination of the 23-nitroamino-SS,11 the
Shapiro reaction of tosylhydrazones of the SS 23-oxo-derivatives6a
or using lengthy procedures, e.g., phenylselenylation of SS followed
by oxidation of phenylselenide to its selenoxide and subsequent
elimination.12
at the spiro carbon atom. The 21-methyl group is usually
(20S). However, the SS differ in configuration at C25. In compounds
with an equatorial -methyl group (e.g., hecogenin) this stereo-
center has a 25R configuration, while compounds with an axial
-methyl group, such as sarsasapogenin, have the 25S configura-
a-oriented
a
b
tion. Of course, apart from the side chain there are further struc-
tural differences between SS in the type of functionalization and
2. Results and discussion
stereochemistry at the A/B ring junction (5a- and 5b-steroids). The
The spiroketal moiety of SS is sensitive to protic and Lewis acids.
The acids catalyze reversible opening of ring F of SS to form the enol
ether that has been postulated as an intermediate of several re-
actions proceeding at C23. The enol form is also a reactive in-
termediate of various ketone dehydrogenation procedures.
Therefore we thought that it might be possible to carry out direct
dehydrogenation of SS to the 23(24)-unsaturated derivatives in acid
medium. Here we present the results of our study on benzenese-
leninic anhydride (BSA) oxidation of SS under various conditions.
BSA13 is a convenient reagent for dehydrogenation of ketones and
possesses certain advantages over the commonly used methods
employing o-iodoxybenzoic acid (IBX),14 dicyanodichloroquinone
(DDQ)15 and other high-potential quinones, bromination/dehy-
drobromination or palladium-catalyzed oxidation of the enol
ethers.16
SS are relatively cheap raw materials for the synthesis of various
medicinally important compounds.2 Among them are steroidal
hormones, which may be obtained by Marker degradation of spi-
rostane side chain into C21 or C19 steroids, followed by further
transformations.3 Functionalization of SS in the side chain was
a matter of many recent reports. Syntheses of some natural prod-
ucts with important biological activity (e.g., cephalostatins),4 spi-
rostanic analogues of brassinosteroids,5 glycospirostanes,6 etc.,
involved modification of the SS side chain. The most common
reactions of SS are transformations at the
a position to the spiro
carbon atom (C23).7 This is so, because the spiroketal system of SS
* Corresponding author. Tel.: þ48 85 7457585; fax: þ48 85 7457581; e-mail
address: morzycki@uwb.edu.pl (J.W. Morzycki).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.013

I. Jastrze˛bska et al. / Tetrahedron 66 (2010) 5024e5029
5025
At the beginning of this study it was checked that SS are resistant
to IBX and iodoxybenzene oxidation (no reaction occurred). How-
ever, without acid catalysis there was no oxidation of tigogenin ac-
etate (1) with BSA (in refluxing benzene, toluene or chlorobenzene)
either. The reactions with BSA in the presence of p-TsOH led to
a complex mixture of several products but none of them was the
desired 23(24)-unsaturated derivative. Unexpectedly, when the re-
action was carried out by a catalytic method17 with only small
amount of BSA and iodoxybenzene (in excess) as a cooxidant in
refluxing toluene in the absence of p-TsOH dehydrogenation to
23-dehydrotigogenin acetate (4) took place, albeit in low yield (7.5%).
Exactly the same result was obtained when catalytic amount of
diphenyl diselenide was used instead of BSA (Scheme 1). The anal-
ogous reaction of epismilagenin acetate (2) also afforded the corre-
sponding 23-dehydrogenated 5 product in a slightly better yield
(10%). Most of the unreacted sapogenin could be recovered, if the
reaction time was not too long. However, attempts to increase yields
by optimizing the reaction conditions failed. The problem is that the
olefinic products (4 and 5) slowly react further and the reactions
become messy over time. Sarsasapogenin acetate (3) containing an
axial methyl group at C25 did not form an olefin at all under these
conditions (23-oxosarsasapogenin acetate was obtained instead in
very low yield).
prevents formation of reduced forms of the anhydride generated in
the elimination step, which may give rise to unwanted secondary
reactions. However, there are also reports18 that during reaction be-
tween Ph2Se2 and PhIO2 some peroxy species (e.g., iii) may be formed
(Scheme 2), responsible for the side reactions of the Beyer/Villiger
oxidation type. It is possible, that apart from the major reaction
product (BSA), iodoxybenzene dibenzeneseleninate (i), iodoso-
benzene dibenzeneseleninate (ii), and peroxybenzeneseleninic an-
hydride (iii) are also formed.
O
O
2 PhSe-SePh + 3 PhIO2
2 PhSe-O-SePh + 3 PhI
BSA
O
O
O
OSePh
OSePh
OSePh
PhI
PhI
O
OSePh
O
iii
OSePh
O
OSePh
O
i
ii
Scheme 2.
Since the blank experiments showed that SS do not react with
BSA or PhIO2 in toluene at reflux, it can be concluded that one of the
above mentioned species formed in situ may play an important role
in dehydrogenation. In view of the known disproportionation of
iodosobenzene into iodobenzene and iodoxybenzene at elevated
temperatures, iodosobenzene dibenzeneseleninate (ii) seems to be
a less likely candidate for a reactive intermediate than compound i.
O
O
O
O
(PhSe)2, PhIO2
PhCH3, reflux 3h
4 (7.5%)
1
AcO
H
O
O
O
A
tentative mechanism of dehydrogenation is shown in
Scheme 3. It is suggested that BSA in refluxing toluene behaves
similarly to anhydrides of carboxylic acids promoting opening of the
ring F. The enol ether formed in this way reacts with oxidizing agent,
such as i. The capability of hypervalent iodine compounds to react
with enols is well documented.19
Considering that a hypervalent iodine moiety, after its electro-
philic attack to enol ether, may undergo syn-elimination similarly
to selenoxides, the reaction with a species like i is an alternative to
the reaction of enol ether with BSA. However, it is not clear why the
latter reaction does not work in this case. Therefore an alternative
mechanism assuming that a hypervalent iodine compound assists
in F-ring opening (serves as a weak Lewis acid) and BSA attacks enol
ether can be also envisaged.
O
O
(PhSe)2, PhIO2
PhCH3, reflux 3h
5 (10%)
2
AcO
AcO
H
H
O
(PhSe)2, PhIO2
No olefin is formed
PhCH3, reflux 24h
3
Scheme 1.
The previous study17 has proved that oxygen atom transfer from
the iodineeoxygen bond into selenium atom is fast and BSA is formed
from diphenyl diselenide and iodoxybenzene. The catalytic ketone
dehydrogenation reactions with Ph2Se2/PhIO2 generally give yields
equal or superior to those obtained by use of the anhydride (BSA) in
stoichiometric amount. This is so, because the catalytic approach
A further study of SS reactions with BSA was performed in the
presence of strong Lewis acids at room temperature. The reaction of
tigogenin acetate (1) with BSA/BF3$Et2O afforded three products in
comparable yields: 23-phenylselenide 6, the 23-oxotigogenin acetate
(7), and its 22-oxo-23-spiro-isomer 8 (Scheme 4). A similar reaction
of sarsasapogenin acetate (3) gave analogous products but in
O
O
O
PhSe
O
PhSe
+
O
O
O
BSA
H
O
AcO
1
H
O
O
i
IPh
O
O
O
H
O-SePh
O
4
Scheme 3.

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I. Jastrze˛bska et al. / Tetrahedron 66 (2010) 5024e5029
O
Partial isomerization of 7 into 8 catalyzed by BF3$Et2O is a known
O
reaction. However, this transformation requires very harsh condi-
tions (reflux 7 days in THF).20a In the present case isomerization of
a selenium species occurred quickly at room temperature. The
equilibration of the isomeric spiro systems in the case of a sarsasa-
pogenin derivative proved to be much more efficient. The minor re-
action products, 23-phenylselenides, were formed as a result of an
enol ether reactionwith reduced forms of BSA. Formation of these by-
products may be suppressed by using BSA in larger excess.
The reaction of SS with BSA carried out in the presence of TiCl4
afforded only chlorinated products. BSA appeared to be a very strong
oxidizing agent in acid medium. It seems that a new hypervalent
iodine species containing chlorine atom21 was generated in situ by
the reaction of BSA with TiCl4. This species was a source of electro-
philic ‘Clþ’, which reacted with enol etherobtained upon treatmentof
SS with TiCl4. Tigogenin acetate (1) afforded two monochlorides (12
and 13) and dichloride 14, while sarsasapogenin acetate (3) yielded
only dichloride 15. In the latter case the second chlorination is
probably faster than the first one (Scheme 6).
O
.
SePh
BSA, BF3 Et2O
O
+
toluene, r.t., 1 h
1
6 (30%)
AcO
H
O
O
O
O
O
+
+
O
7 (31%)
8 (25%)
O
O
O
.
SePh
BSA, BF3 Et2O
O
+
toluene, r.t., 1 h
9 (5%)
3
AcO
H
O
O
O
3. Conclusions
O
O
+
+
O
All reactions of SS with BSA proceed via an enol ether in-
termediate. Direct dehydrogenation of tigogenin acetate at C23 was
achieved using a catalytic method (Ph2Se2/PhIO2) but yield was un-
satisfactory. The reactions of SS with BSA in the presence of BF3$Et2O
afforded 23-ketones in addition to their 22-oxo-23-spiro isomers. In
the case of sarsasapogenin acetate the latter product was obtained in
69% yield. When TiCl4 was used as a Lewis acid in the SS reactions
with BSA only chlorinated at C23 products were formed.
10 (15%)
11 (69%)
Scheme 4.
different yields. The major reaction product (69%)dthe 23-spiro-22-
ketone 11 was accompanied by 23-oxosarsasapogenin acetate
(10;15%) and small amount of 23-phenylselenide 9. A likely mecha-
nism of compound 1 reaction is outlined in Scheme 5. It seems rea-
O
O
-
BF3
O
-
+
F3B-O
.
+
BF3 Et2O
O:
O
-H+
1
AcO
H
-
F3B-O
O
O
SePh
O
SePh
O
OH
O
O
PhSe-O-SePh
O
O
SePh
O
O
O
+
.
+
BF3 Et2O
SePh
O
+
SePh
O
O
-
- BF3OH
-
-
BF3OH
BF3OH
- PhSeH
- PhSeH
O
O
O
O
O
O
7
8
Scheme 5.
sonable to postulate that under the reaction conditions enolization of
the initially formed selenoxide is faster than syn-elimination. Mi-
gration of a hydroxyl group from selenium atom into C23 followed by
elimination of benzeneselenol resulted in formation of 23-ketone 7.
The intermediate cation may rearrange to the more thermodynam-
ically stable isomeric spiro system before hydrolysis to a ketone.20
4. Experimental section
4.1. General
Melting points were determined on a Kofler apparatus of the
Boetius type. NMR spectra were recorded with a Bruker Avance II

I. Jastrze˛bska et al. / Tetrahedron 66 (2010) 5024e5029
5027
O
4.73 (m, 1H), 4.54 (m, 1H), 3.70 (ddd, J1¼10.9 Hz, J2¼6.3 Hz,
J1¼1.3 Hz, 1H), 3.49 (t, J¼10.9 Hz, 1H), 2.37 (m, 1H), 2.04 (s, 3H) 0.96
(s, 3H), 0.94 (d, J¼7.0 Hz, 3H), 0.90 (d, J¼7.2 Hz, 3H), 0.81 (s, 3H); 13C
O
O
BSA, TiCl4
Cl
O
+
NMR d (ppm): 170.6 (C), 136.8 (CH), 126.8 (CH), 107.2 (C), 81.9 (CH),
toluene, r.t., 1 day
74.3 (CH), 65.4 (CH2), 62.4 (CH), 56.3 (CH), 41.9 (CH), 41.8 (CH), 40.8
(C), 40.5 (CH), 40.2 (CH2), 35.4 (C), 35.0 (CH), 34.7 (CH2), 32.2 (CH2),
31.8 (CH2), 29.7 (CH2), 29.1 (CH), 26.9 (CH2), 26.6 (CH2), 23.3 (CH3),
21.5 (CH3), 20.6 (CH2), 16.4 (CH3), 15.7 (CH3), 14.4 (CH3); ESI-MS,
m/z: 479 [(MþNa)þ, 100%]; HRMS calcd for C29H44NaO4: 479.3137,
found: 479.3153.
AcO
1
12 (25%)
H
Cl
O
Cl
O
l
C
O
O
+
+
13 (20%)
14 (42%)
4.3. Reaction of tigogenin acetate (1) with BSA in the presence
of BF3$Et2O
O
Cl
O
To a solution of tigogenin acetate (1, 50 mg, 0.1 mmol) in dry
toluene (10 mL) BSA (41 mg, 1.2 equiv) and BF3$Et2O (0.082 mL,
6 equiv) were added. The reaction mixture was stirred at room
temperature. The reaction progress was monitored by TLC. After 1 h
the reaction mixture was poured into brine and extracted ex-
haustively with dichloromethane. Combined organic extracts were
dried over Na2SO4 and evaporated in vacuo. Column chromatog-
raphy with ethyl acetate/hexane 5:95 elution gave pure (22R,25R)-
O
Cl
BSA, TiCl4
O
toluene, r.t., 1 day
15 (70%)
3
AcO
H
Scheme 6.
400 MHz spectrometer in CDCl3 as a solvent with TMS as internal
standard (only selected signals in the 1H NMR spectra are reported).
Infrared spectra were recorded on a Nicolet series II Magna-IR 550
FT-IR spectrometer in chloroform solutions. Mass spectra were
obtained at 70 eV with an AMD-604 spectrometer. The reaction
products were isolated by column chromatography performed on
70e230 mesh silica gel (Baker). The TLC silica gel 60 F254 sheets
(Merck) were used.
23-phenylseleno-5
followed by (25R)-3
Further elution with acetate/hexane 15:85 afforded (23R,25R)-3
a
b
-spirostan-3
b
-ol acetate (6, 20 mg, 30%)
-acetoxy-5a-spirostan-23-one (7, 16 mg, 31%).
b
-
acetoxy-16b,23:23,26-diepoxy-5a-cholestan-22-one (8, 13 mg,
25%).
4.3.1. (22R,25R)-23-Phenylseleno-5a-spirostan-3b-ol acetate (6).
20
Mp 168e170 ꢀC (CH2Cl2-hexane); Rf (15% AcOEt/hexane) 0.35; [
a]
ꢁ20.1 (c 1.0, CHCl3); IR nmax (cmꢁ1): 1724, 1579, 1262, 1024, 943; 1DH
NMR
d (ppm): 7.55 (m, 2H), 7.27 (t, m, 3H), 4.69 (m, 1H), 4.39 (m,
4.2. Reaction of tigogenin acetate (1) with Ph2Se2 and PhIO2
1H), 3.48 (dd, J1¼10.8, J2¼4.6 Hz, 1H), 3.41 (t, J¼10.9 Hz, 1H), 3.28
(dd, J1¼12.6, J2¼4.8 Hz, 1H), 2.84 (m, 1H), 2.03 (s, 1H), 0.93 (d,
J¼6.8 Hz, 3H), 0.92 (s, 3H), 0.85 (s, 3H), 0.77 (d, J¼6.5 Hz, 3H); 13C
To a solution of Ph2Se2 (11 mg, 0.03 mmol) in dry toluene
(20 ml), PhIO2 (135 mg, 0.68 mmol) was added. The reaction mix-
ture was stirred and refluxed until the yellow color disappeared
(about 10 min). Then tigogenin acetate (1, 80 mg, 0.17 mmol) was
added. After 24 h the reaction mixture was poured into water and
extracted with dichloromethane. Combined organic extracts were
dried over Na2SO4 and evaporated in vacuo. Silica gel column
chromatography with ethyl acetate/hexane 10:90 elution afforded
the unreacted substrate (1, 42 mg) and the more polar product 4
(6 mg, 7.5%).
NMR
d
(ppm): 170.7 (C), 133.9 (CHꢂ2), 130.5 (C), 129.0 (CHꢂ2),
127.1 (CHꢂ2), 110.6 (C), 81.4 (CH), 73.6 (CH), 66.1 (CH2), 61.4 (CH),
56.0 (CH), 54.2 (CH), 45.6 (CH), 44.6 (CH), 41.2 (C), 40.3 (CH2), 38.84
(CH2), 38.76 (CH), 36.7 (CH2), 35.6 (C), 34.8 (CH), 34.0 (CH2), 32.7
(CH), 32.2 (CH2), 31.5 (CH2), 28.5 (CH2), 27.4 (CH2), 21.4 (CH3), 21.0
(CH2), 17.1 (CH3), 16.6 (CH3), 14.2 (CH3), 12.2 (CH3); ESI-MS, m/z: 457
(MꢁC6H5SeH)þ, 615 [M(80Se)þH]þ. Elemental analysis, found C,
68.15; H, 8.15. C35H50O4Se requires C, 68.50; H, 8.21%.
Compounds 77d,22 and 820 proved identical in all respects with
the same compounds described in the literature.
4.2.1. (25R)-5
a
-Spirost-23-en-3
b
-ol acetate (4). Mp 198e200 ꢀC
20
(CH2Cl2-hexane); Rf (15% AcOEt/hexane) 0.33; [
a
]
ꢁ51.1 (c 0.75,
D
4.4. Reaction of sarsasapogenin acetate (3) with BSA in the
presence of BF3$Et2O
CHCl3); IR nmax (cmꢁ1): 1724, 1654, 1255, 981; 1H NMR
n (ppm):
5.86 (dd, J1¼10.0, J2¼1.5 Hz, 1H), 5.57 (dd, J1¼10.0, J2¼2.6 Hz, 1H),
4.69 (m, 1H), 4.57 (m, 1H), 3.69 (ddd, J1¼10.9, J2¼5.6, J3¼1.3 Hz, 1H),
3.49 (t, J¼10.9 Hz, 1H), 2.37 (m, 1H), 2.03 (s, 3H), 0.93 (d, J¼7.0 Hz,
To a solution of sarsasapogenin acetate (3, 50 mg, 0.1 mmol) in
dry toluene (10 mL) BSA (41 mg, 1.2 equiv) and BF3$Et2O (0.082 mL,
6 equiv) were added. The reaction mixture was stirred one hour at
room temperature, poured into brine and extracted exhaustively
with dichloromethane. Combined organic extracts were dried over
Na2SO4, evaporated in vacuo and the products were separated by
silica gel column chromatography. Elution with ethyl acetate/hexane
3H), 0.89 (d, J¼7.2 Hz, 3H), 0.85 (s, 3H), 0.81 (s, 3H); 13C NMR
d
(ppm): 170.7 (C), 136.8 (CH), 126.8 (CH), 107.2 (C), 81.9 (CH), 73.6
(CH), 65.4 (CH2), 62.4 (CH), 56.2 (CH), 54.2 (CH), 44.6 (CH), 41.9
(CH), 40.7 (C), 39.9 (CH2), 36.7 (CH2), 35.6 (C), 35.0 (CH), 34.0 (CH2),
32.1 (CH2), 31.7 (CH2), 29.1 (CH), 28.4 (CH2), 27.4 (CH2), 21.4 (CH3),
21.0 (CH2), 16.5 (CH3), 15.7 (CH3), 14.4 (CH3), 12.2 (CH3); EIMS, m/z
456 (Mþ, 4%); HRMS calcd for C29H44O4: 456.3240, found:
456.3255.
10:90 gave consecutively: (22R,25S)-23-phenylseleno-5
-ol acetate (9, 5.5 mg, 5%), (25S)-3 -acetoxy-5 -spirostan-23-one
(10, 13 mg, 15%), and (23R,25S)-3 -acetoxy-16 ,23:23,26-diepoxy-
-cholestan-22-one (11, 57 mg, 69%).
b-spirostan-
3b
a
a
a
b
Analogous reaction of epismilagenin acetate (2) with Ph2Se2 and
5a
PhIO2 afforded (25R)-5b-spirost-23-en-3a-ol acetate (5) in 10% yield.
4.4.1. (22R,25S)-23-Phenylseleno-5
b
-spirostan-3
b
-ol acetate (9). An
20
4.2.2. (25R)-5
b
-Spirost-23-en-3
a
-ol acetate (5). Mp 159e162 ꢀC
oil; Rf (15% AcOEt/hexane) 0.35; [
a]
ꢁ32.2 (c 0.5, CHCl3); IR,
D
(CH2Cl2-methanol); Rf (15% AcOEt/hexane) 0.36; [
a
]
20 ꢁ28.2 (c 0.5,
nmax (cmꢁ1): 1724, 1264, 1024, 948; 1H NMR (CDCl3)
d (ppm): 7.52
D
CHCl3); IR nmax (cmꢁ1): 1721,1663, 1261, 980; 1H NMR
d
(ppm): 5.87
(m, 2H), 7.26 (m, 3H), 5.08 (br s, 1H), 4.42 (m, 1H), 3.99 (dd,
(dd, J1¼10.0 Hz, J2¼1.5 Hz, 1H), 5.57 (dd, J1¼10.0 Hz, J2¼2.6 Hz, 1H),
J1¼11.0 Hz, J2¼2.6 Hz, 1H), 3.51 (dd, J1¼13.1 Hz, J2¼5.0 Hz, 1H), 3.31

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I. Jastrze˛bska et al. / Tetrahedron 66 (2010) 5024e5029
(d, J¼11.0 Hz, 1H), 2.78 (m, 1H), 2.37 (m, 1H), 2.06 (s, 3H), 1.07
(d, J¼7.1 Hz, 3H), 1.00 (s, 3H), 0.97 (d, J¼6.9 Hz, 3H), 0.92 (s, 3H); 13C
(CH3); ESI-MS, m/z: 515 [M(35Cl)þNa]þ; HRMS (ESI): [M(35Cl)þNa]þ,
found 515.2920. C29H45ClNaO4 requires 515.2904.
NMR (CDCl3)
d
(ppm): 170.7 (C), 133.5 (CHꢂ2), 130.6 (C), 129.0
(CHꢂ2), 127.0 (CH), 111.2 (C), 81.6 (CH), 70.7 (CH), 64.5 (CH2), 61.4
(CH), 56.2 (CH), 41.5 (CH), 41.3 (C), 40.5 (CH2), 40.0 (CH), 39.2 (CH),
37.3 (CH2), 36.3 (CH2), 35.1 (CH), 35.0 (C), 31.5 (CH2), 30.7 (CH2),
30.6 (CH2), 30.0 (CH), 26.5 (CH2), 26.4 (CH2), 25.0 (CH2), 23.8 (CH3),
21.5 (CH3), 20.9 (CH2), 17.0 (CH3), 16.1 (CH3), 14.1 (CH3); ESI-MS, m/
z: 637 [M(80Se)þNa]þ; HRMS (ESI): [M(80Se)þNa]þ, found 637.2797.
C35H50NaO4Se requires 637.2772.
4.6. Reaction of sarsasapogenin acetate (3) with BSA in the
presence of TiCl4
To a solution of sarsasapogenin acetate (3, 110 mg, 0.24 mmol) in
dry toluene (8 mL) BSA (86 mg,1 equiv) and TiCl4 (0.03 mL,1.1 equiv)
were added. The reaction mixture was stirred 20 h at room tem-
perature, poured into saturated aqueous solution of NaCl and
extracted exhaustively with dichloromethane. Combined organic
extracts were dried over Na2SO4 and evaporated in vacuo. Column
chromatography with ethyl acetate/hexane 5:95 elution afforded
pure 23,23-dichlorosarsasapogenin acetate (15, 75 mg, 70%).
Compounds 1020c,22 and 1120 proved identical in all respects
with the same compounds described in the literature.
4.5. Reaction of tigogenin acetate (1) with BSA in the presence
of TiCl4
4.6.1. 23,23-Dichlorosarsasapogenin acetate (15). Mp 282e284 ꢀC
To a solution of tigogenin acetate (1, 154 mg, 0.3 mmol) in
dry toluene (8 mL) BSA (121 mg, 1 equiv) and TiCl4 (0.11 mL,
3 equiv) were added. The reaction mixture was stirred for 24 h
at room temperature, poured into saturated aqueous solution of
NaCl and extracted exhaustively with dichloromethane. Com-
bined organic extracts were dried over Na2SO4 and evaporated
in vacuo. Column chromatography gave pure 23,23-dichloro-
tigogenin acetate (14, 74 mg, 42%), (23R)-23-chlorotigogenin
acetate (13, 34 mg, 20%), and (23S)-23-chlorotigogenin acetate
(12, 42 mg, 25%) eluted consecutively with ethyl acetate/ben-
zene 0.1:99.9.
20
(CH2Cl2-hexane); Rf (15% AcOEt/hexane) 0.40; [
a
]
ꢁ152.1 (c 1.0,
D
CHCl3); IR nmax (cmꢁ1): 1724, 1263, 1026, 988, 924, 845; 1H NMR
d
(ppm): 5.07 (m, 1H), 4.43 (m,1H), 4.24 (dd, J1¼11.3, J2¼3.8 Hz, 1H),
3.39 (dd, J1¼11.2, J2¼1.4 Hz, 1H), 2.91 (dd, J1¼14.5, J2¼6.3 Hz, 1H),
2.79 (m, 1H), 2.39 (dt, J1¼14.4, J2¼1.8 Hz, 1H), 2.06 (s, 3H), 1.35 (d,
J¼7.5 Hz, 3H), 1.26 (d, J¼6.8 Hz, 3H), 1.00 (s, 3H), 0.96 (s, 3H); 13C
NMR
d (ppm): 170.7 (C), 110.2 (C), 89.2 (C), 81.5 (CH), 70.7 (CH),
63.79 (CH), 63.77 (CH2), 56.3 (CH), 47.0 (CH2), 41.8 (C), 40.2 (CH2),
40.0 (CH), 38.5 (CH), 37.3 (CH), 35.2 (CH), 35.0 (C), 31.7 (CH2), 30.7
(CH2), 30.6 (CH2), 29.7 (CH), 26.43 (CH2), 26.39 (CH2), 25.0 (CH2),
23.8 (CH3), 21.5 (CH3), 20.8 (CH2), 19.4 (CH3), 17.6 (CH3), 16.3 (CH3);
ESI-MS, m/z: 549 [M(35Cl)þNa]þ; HRMS (ESI): [M(35Cl)þNa]þ,
found 549.2528. C29H44Cl2NaO4 requires 549.2514.
4.5.1. 23,23-Dichlorotigogenin acetate (14). Mp 175e177 ꢀC (CH2Cl2-
hexane); Rf (1.5% AcOEt/benzene) 0.33; [
a
]
20 ꢁ68.2 (c 1.0, CHCl3); IR
D
nmax (cmꢁ1): 1723, 1264, 1027, 906, 811; 1H NMR
d (ppm): 4.69 (m,
Acknowledgements
1H), 4.4 (q, J¼7.4 Hz, 1H), 3.54 (dd, J1¼11.1 Hz, J2¼4.9 Hz, 1H), 3.47 (t,
J¼11.1 Hz, 1H), 2.78 (m, 1H), 2.39 (m, 2H), 2.32 (m, 1H), 2.03 (s, 3H),
1.22 (d, J¼6.8 Hz, 3H), 0.94 (s, 3H), 0.85 (s, 3H), 0.84 (d, J¼6.2 Hz, 3H);
The authors thank Mrs. J. Maj for skillful technical assistance and
Dr. L. Siergiejczyk for performing NMR spectra. Financial support
from the University of Bia1ystok within the project BST-124 is
gratefully acknowledged.
13C NMR
d (ppm): 170.7 (C), 109.8 (C), 90.3 (C), 81.3 (CH), 73.6 (CH),
65.4 (CH2), 63.7 (CH), 56.1 (CH), 54.2 (CH), 49.5 (CH2), 44.6 (CH), 41.7
(C), 39.9 (CH2), 37.9 (CH), 36.7 (CH2), 35.5 (C), 34.9 (CH), 34.0 (CH2),
32.1 (CH2), 31.7 (CH2), 29.2 (CH), 28.4 (CH2), 27.4 (CH2), 21.4 (CH3),
20.9 (CH2), 17.5 (CH3), 16.4 (CH3), 15.6 (CH3), 12.2 (CH3); ESI-MS, m/z:
549 [M(35Cl)þNa]þ; HRMS (ESI): [M(35Cl)þNa]þ, found 549.2527.
C29H44Cl2NaO4 requires 549.2514.
References and notes
1. (a) Hostettmann, K.; Marston, A. Saponins; University: Cambridge, UK, 1995; (b)
Fieser, L.; Fieser, M. Sapogenins In Steroids; Reinhold: New York, NY, 1959.
2. (a) Torgov, I. V. Chemistry of spirostanols (in Russian); Nauka: Moscow, 1986; (b)
Lazurievski, G. V., Ed. Stroenie i biologiczeskaya aktivnost steroidnych glikozydov
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Reactions in Steroid Chemistry; van Nostrand Reinhold: New York, NY, 1972; Vol.
II, Chapter 11.
4.5.2. (23R)-23-Chlorotigogenin acetate (13). Mp 160e164 ꢀC
(CH2Cl2-hexane); Rf (1.5% AcOEt/benzene) 0.31; [
a
]
20 ꢁ52.3 (c 0.5,
D
CHCl3); IR nmax (cmꢁ1): 1723, 1263, 1022, 983; 1H NMR
d (ppm):
4.69 (m, 1H), 4.48 (m,1H), 4.01 (t, J¼2.9 Hz, 1H), 3.57 (m, 1H), 3.46
(t, J¼11.4 Hz, 1H), 2.22 (m,1H), 2.03 (s, 3H), 1.17 (d, J¼6.9 Hz, 3H),
0.85 (s, 3H), 0.81 (d, J¼6.7 Hz, 3H), 0.79 (s, 3H); 13C NMR
d (ppm):
170.7 (C), 107.6 (C), 81.7 (CH), 73.6 (CH), 66.6 (CH2), 64.7 (CH),
60.5 (CH), 56.3 (CH), 54.2 (CH), 44.6 (CH), 41.7 (CH), 41.1 (C), 39.4
(CH2), 37.4 (CH2), 36.7 (CH2), 35.6 (C), 35.3 (CH), 34.0 (CH2), 32.08
(CH2), 32.06 (CH2), 28.5 (CH2), 27.4 (CH2), 23.8 (CH), 21.4 (CH3),
20.8 (CH2), 17.1 (CH3), 16.3 (CH3), 16.1 (CH3), 12.2 (CH3); ESI-MS,
m/z: 515 [M(35Cl)þNa]þ, 1007 [2M(35Cl)þNa]þ; HRMS (ESI):
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4.5.3. (23S)-23-Chlorotigogenin acetate (12). Mp 235e238 ꢀC
20
(CH2Cl2/hexane); Rf (1.5% AcOEt/benzene) 0.29; [
a
]
ꢁ48.1 (c 0.5,
D
CHCl3); IR nmax (cmꢁ1): 1723, 1262, 1054, 919, 870; 1H NMR
d (ppm):
4.69 (m, 1H), 4.41 (m, 1H), 3.93 (m, 1H), 3.44 (m, 2H), 2.59 (m, 1H),
2.03 (s, 3H), 0.95 (d, J¼7.0 Hz, 3H), 0.87 (s, 3H), 0.85 (s, 3H), 0.84 (d,
J¼6.3 Hz, 3H); 13C NMR
d (ppm): 170.7 (C), 109.3 (C), 81.4 (CH), 73.7
(CH), 65.6 (CH2), 61.4 (CH), 56.9 (CH), 56.1 (CH), 54.2 (CH), 44.6 (CH),
41.2 (C), 40.2 (CH2), 39.3 (CH2), 36.8 (CH), 36.7 (CH2), 35.6 (C), 34.9
(CH), 34.0 (CH2), 32.5 (CH), 32.2 (CH2), 31.5 (CH2), 28.5 (CH2), 27.4
(CH2), 21.4 (CH3), 21.0 (CH2), 16.5 (CH3), 16.3 (CH3), 14.0 (CH3), 12.2

I. Jastrze˛bska et al. / Tetrahedron 66 (2010) 5024e5029
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