The design and synthesis of new steroidal compounds as potential mimics of taxoids

Article abstract of DOI:10.1002/ejoc.200500203

Eight new steroidal compounds bearing the phenylisoserine and benzoate side-chains of docetaxel were synthesised as potential mimics of antitumour taxoids. They were readily obtained either from cholic acid or from 4-androstene-3,17-dione by a reductive T

Full text of DOI:10.1002/ejoc.200500203

FULL PAPER
The Design and Synthesis of New Steroidal Compounds as Potential Mimics of
Taxoids
Fanny Roussi,*[a] Quoc Anh Ngo,[a] Sylviane Thoret,[a] Françoise Guéritte,[a] and
Daniel Guénard[a]
Keywords: Antitumor agents / Asymmetric synthesis / Medicinal chemistry / Steroids
Eight new steroidal compounds bearing the phenylisoserine
and benzoate side-chains of docetaxel were synthesised as
potential mimics of antitumour taxoids. They were readily
obtained either from cholic acid or from 4-androstene-3,17-
dione by a reductive Tsuji–Trost/reduction one-pot reaction.
Two compounds showed an unexpected inhibitory activity of
tubulin assembly.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
shows that a few taxoid analogues, in which a simpler core
replaces the taxane skeleton, have already been elabo-
rated.[11] Some of them are of particular interest. Klar and
co-workers,[11h] for example, have synthesised a new class of
borneol esters 3 which stabilize microtubules much better
than paclitaxel but show reduced cytotoxic activity. On the
other hand, Ojima et al. have elaborated the indolizidinone-
type compounds 4,[11i] which mimic the bioactive confor-
mation of taxoids (Figure 1). They show micromolar level
IC50 values against two human breast-cancer cell-lines but
no activity in promoting the formation of microtubules. Re-
cently, Frejd et al. have designed, by computer modelling,
spirobicyclooctane derivatives, whose first synthesised com-
pound failed to stabilize microtubules.[11j]
Introduction
Paclitaxel (Taxol®, 1a)[1] and docetaxel (Taxotere®, 1b)[2]
are very potent anticancer drugs of the taxoid series (Fig-
ure 1). Paclitaxel has been shown to promote the polymeri-
sation of tubulin to microtubule.[3] This interaction with
microtubules has been strongly correlated with the antitu-
mour properties of taxoids. Since their discovery, structure–
activity relationships have been studied in order to deter-
mine the minimal structural requirements necessary for bio-
logical activity.[4] These studies highlighted the importance
of the C-13 side-chain, the ester groups at C-2 and C-4 and
the rigid core to which these patterns are connected. In ad-
dition, extensive studies have been devoted to the elucida-
tion of the bioactive conformation of the taxoids, namely
those they adopt when bound to microtubules and which
induce the inhibition of depolymerisation in vitro. Recently,
a conformation called “T-shaped”[5] has been proposed as
the active one, using the 3.7-Å structure of the α,β-tubulin
taxol complex obtained by electron crystallography of zinc-
induced tubulin sheets[6] and an analysis of paclitaxel con-
formations with the NAMFIS methodology.[7] Since then,
active constrained analogues mimicking the “T-shaped”
conformation have been synthesised.[8] Despite the strong
antitumour activity of paclitaxel and docetaxel, many tu-
mours show significant resistance to taxoid derivatives[9,10]
which are, in addition, very expensive treatments. Therefore,
it would be highly useful to elaborate synthetic non-taxane
compounds with the same tubulin activity but without the
above-mentioned drawbacks. A survey of the literature
Figure 1. Examples of taxoid analogues.
[a] Institut de Chimie des Substances Naturelles, CNRS,
Avenue de la Terrasse, 91198 Gif sur Yvette Cedex, France
Fax: +33-1-69077247
Our group has been involved in taxoid chemistry for
many years, and more recently in the search for new taxoids
with a locked conformation.[12] We are also interested in
finding compounds with a simpler scaffold that retains
E-mail: roussi@icsn.cnrs-gif.fr
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
3952
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200500203
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New Steroidal Compounds as Potential Mimics of Taxoids
FULL PAPER
most of the three-dimensional features and mimics the
active conformation of taxoids. We thus began searching
for commercially available compounds that fit our require-
ments for a “T-shaped” conformation, in other words prod-
ucts with a rigid structure and two hydroxy groups at about
4 Å from each other on the same side of the molecule. Mol-
ecular dynamic modelling studies (Sybyl 6.9) were per-
formed on pre-selected molecules with the phenylisoserine
and benzoate side-chains of taxoids to determine their con-
formational behaviour. We thus found that cholic acid de-
rivatives 7 (Figure 2) could be good potential mimics of
taxoids as we noticed that these steroidal compounds
greatly overlay T-shaped taxoids (Figure 3).
Results and Discussion
Cholic acid (5) is characterised by two axial hydroxy
groups on C-7 and C-12, an equatorial OH on C-3 and a
long carboxylic acid chain on C-17. The main problem for
the synthesis of our first set of analogues was to function-
alise positions 3 and 7 selectively. For that, we used Davis’
methodology,[16] as shown in Scheme 1, to protect the 12α-
OH as a trifluoroacetate ester as well as the carboxyl acid
as a tert-butyl ester (compound 8). In addition, we elabo-
rated two other starting materials whose acid chain was
protected as a methyl[17] or a benzyl ester (compounds 9
and 10). From these different starting products 8–10, we
wanted to elaborate derivatives with different steric hin-
drance and/or polarity on their northern part, as the tri-
fluoroacetate and the benzyl ester can be easily removed.
From compounds 8–10, the selective esterification of the
more reactive equatorial 3α-OH was cleanly performed to
give the expected compounds 12–14 in good yields. These
reactions were carried out with one equivalent of the pro-
tected docetaxel side-chain 11 [2-(4-methoxyphenyl)-1,3-ox-
azolidine derivative of N-Boc-phenylisoserine],[18] under
Figure 2. Potential mimics of taxoids from cholic acid and 4-andro-
stene-3,17-dione.
Figure 3. Superposition of T-shaped docetaxel (yellow) with a con-
former of cholic-type analogue 7a (left; magenta) and with a con-
former of simplified cholic-type analogue 7b (right; cyan).
Indeed, the rigid cholic-type skeleton presents a cis A-B
ring junction that gives it a U conformation. This curved
conformation is similar to that of docetaxel and is increased
by the presence of cycles C and D, for, in computational
studies, simple decaline systems were found to be much
flatter. Furthermore, the two α-hydroxy groups at C-3Ј and
C-7 in cholic acid 5 are at about 4 Å from each other and
they can be esterified by the acids corresponding to the
side-chains of docetaxel. Two examples of steroids with a
trans A-B ring junction showing a moderate microtubule-
stabilizing activity can also be found in the literature.[13–15]
The synthesis of two sets of analogues was therefore consid-
ered, with and without the lateral chain at C-17, starting
either from cholic acid (5) or from 4-androstene-3,17-dione
(6).
Scheme 1. Reaction conditions: (a) 1. TFAA, THF, –35 to –40 °C,
2. tBuOH, 3. NaHCO3, THF, MeOH, 72%; (b) 1. TFAA, THF,
–35 to –40 °C, 2. NaHCO3, THF, MeOH, 40%; (c) concd. HCl,
MeOH, 88%; (d) benzyl alcohol, DCC, DMAP, toluene, 60%; (e)
11, DCC, DMAP, toluene; (f) PhCOBr, DMAP, pyridine, 80 °C;
(g) PTSA, MeOH; (h) NH4OH, THF, MeOH; (i) H2, Pd/C, THF,
98%.
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FULL PAPER
standard conditions (DCC, DMAP in toluene at room tem-
The sequence began with a regiospecific dehydrogenation
perature). More drastic conditions were required for the reaction of compound 6 with tetrachloro-p-benzoquinone
functionalisation of the axial 7α-OH, which is not very re- (4-chloranyl) under acidic conditions,[23] which provided the
active because of a congested environment. Thus, benzoyl dienone 25 in one step and in good yield (73%). The dia-
bromide and DMAP were used in pyridine at 90 °C for 3 h stereoselective epoxidation of the obtained dienone 25 to
to obtain the desired bis-functionalised compounds 15–17 give 6α,7α-oxiranoandrost-4-ene-3,17-dione (26) was per-
in good yields (79–82%). Deprotection of the phenylisoser- formed according to a classical procedure. As already ob-
ine side-chain was then performed in acidic conditions to served,[24] we obtained the desired compound (55%) as well
give compounds 18–20 as the first analogues to be tested. as its regioisomer (8%) as a secondary product. Both com-
The 12α-trifluoroacetates were deprotected[16] selectively pounds could easily be separated. The reductive Tsuji–Trost
and smoothly under basic conditions to provide com- reaction was performed on compound 26 under standard
pounds 21–23. Finally, deprotection of the benzyl ester led conditions, i.e. with Pd2(dba)3 [tris(dibenzylideneacetone)
to the formation of 24. Seven new compounds 18–24 were dipalladium], triphenylphosphane, formic acid, and triethyl-
thus easily elaborated from cholic acid as potential mimics amine. In our case, the regioselectivity of this reaction was
of taxoids.
not important, as the double bond of the expected com-
Furthermore, we investigated the synthesis of a simpli- pounds (homoallylic alcohol 33 and allylic alcohol 34) was
fied “cholic-type” steroid with a carbonyl function at posi- to be reduced at the next stage. Nevertheless, although the
tion 17.[19,20] Indeed, unlike taxoids, the northern part of expected homoallylic alcohol 33 could be isolated, the al-
the former analogues (18–24) is rather lipophilic because of lylic alcohol 34 was never observed. The dienone 25, which
the long acid chain. This chain may cause a steric hindrance was probably formed by dehydration of the unstable allylic
with amino acids of the tubulin active site.[21] In addition, alcohol 34, was isolated instead.
the carbonyl group at C-17 could be useful for further func-
To avoid the formation of compound 25, a survey of the
tionalisation of cycle D. The proposed straightforward reaction solvent was performed as it has been shown by
strategy started from commercially available 4-androstene- Tsuji et al.[25] that it influences the selectivity of the reaction
3,17-dione (6) and required no protection step (Scheme 2). (Table 1 and Scheme 3). Dioxane and THF seemed to be
The main difficulties were to attach a 7-α-OH group in a the best solvents. In some cases, when the reaction was per-
regio- and diastereoselective manner as well as a cis A-B formed under anhydrous conditions, a new product 27 was
ring junction and to allow the selective reduction of the formed by palladium-catalysed reduction of the α,β-unsatu-
ketone to a 3α-OH. The key step of this strategy was a rated ketone 33.[26] This reduction occurs at the β-face of
reductive Tsuji–Trost[22] reaction, which was performed on the steroid by attack of the hydride on the same side of the
the transient 6α,7α-oxirane 26 to form the desired the 7α- molecule as the palladium. Thus, compound 27 possesses
OH group in a regioselective manner.
the desired C-5 configuration, which corresponds to a cis
A-B ring junction. This was confirmed by comparison of
its optical rotation with those described in the literature[20]
of the same compound obtained by another way {[α]D
=
+78 (c = 1.0, CH2Cl2); ref.[20] [α]D = +79 (c = 1.07, CH2-
Cl2)}. In dry dioxane, the formation of 27 was even almost
exclusively and selectively observed from epoxide 26. This
reaction can be performed at room temperature (it was
completed in 16 h), but an increase of temperature allowed
1
the reaction to be completed in five hours. The H NMR
spectrum of the crude mixture was very clean and showed
27 to be the only product formed. The overall yield of the
reaction was moderate, however, perhaps because of the pu-
rification conditions. The lower regioselectivity of the Tsuji–
Trost reaction in non-distilled solvents can be accounted
for by the ability of water to disfavour the more stable σ-
palladium complex by inhibiting the intramolecular coordi-
nation of the hydroxy group, as shown by Tsuji.[25] Never-
theless, the reasons why compound 27 needs dry conditions
to be formed remain unclear.
After esterification of compound 27 with benzoic acid
(83%), a diastereoselective reduction of the C-3 carbonyl
group to its 3α-hydroxy group was performed with lithium
tri-tert-butoxyaluminium hydride.[20] Some over-reduction
at position 17 was observed (about 20% in the crude mate-
rial), but the desired compound 29 could be easily separated
by purification on a chromatography column (52%). This
Scheme 2. Reaction conditions: (a) PTSA, 4-chloranil, tBuOH/tol-
uene, 105 °C, 73%; (b) mCPBA, CHCl3, 55%; (c) Pd2(dba)3, PPh3,
HCOOH, Et3N, dioxane, reflux, 49%; (d) benzoic acid, DCC,
DMAP, toluene 83%; (e) LiAlH(OtBu)3, THF, 52%; (f) 11, DCC,
DMAP, toluene, 88%; (g) PTSA, MeOH, 76%.
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Eur. J. Org. Chem. 2005, 3952–3961

New Steroidal Compounds as Potential Mimics of Taxoids
FULL PAPER
Table 1. Effect of different solvents on the reaction selectivity.
compound 31 in apolar solvents is close to those obtained
by molecular dynamic modelling studies and close to the
“T-shaped” conformation of taxoids, as all these results ac-
count for a folded conformation of the phenylisoserine side-
chain in the direction of the benzoyl group. Broadly speak-
ing, because of their strong structural similarities, the other
final compounds 18–24 should be able to adopt the same
conformation.
[b]
Com-
CH2Cl2 CH2Cl2
Dioxane Dioxane[b] THF THF[b]
pound[a]
25[c]
33[c]
27[c]
68
32
–
traces
35
64
9
91
–
traces
traces
Ͼ95
17
83
–
5
6
89
[a] All reactions were carried out with 0.17 mmol of 29, 0.017 mmol
each of Pd2(dba)3 and PPh3, 0.88 mmol of HCOOH and 0.5 mmol
of NEt3 in 2 mL of solvent. [b] Solvents and reagents distilled prior
1
to use. [c] Proportions calculated by integration of H NMR peak
intensities of the crude mixture.
Figure 4. Observed NOEs for compound 31.
The activity of compounds 18–24 and 31 in tubulin poly-
merisation and depolymerisation assays, as well as their cy-
totoxicity towards KB, MCF7 and MCF7R cell lines, were
evaluated. The most interesting results are summarised in
Table 2. None of these compounds show appreciable ac-
tivity in inhibiting the disassembly of microtubules in the
standard in vitro tubulin depolymerisation assay. However,
two of them, 23 and 24, show a significant microtubule as-
sembly inhibitory activity (3.8 and 94 µ, respectively).
None of the tested compounds were active against the
MCF7R cell line and compound 22 was the only one to
show a weak activity against the MCF7 cell line. Finally,
compounds 22, 24 and 31 show a significant cytotoxic ac-
tivity on KB cells (IC50 of 2.0, 7.2 and 3.2 µ, respectively),
whereas cholic acid is devoid of cytotoxicity on this cell line.
These results clearly show that the cytotoxic activity of
these compounds results from a different mechanism of ac-
tion than that of paclitaxel and docetaxel, and that a good
structural similarity with taxoids is not sufficient to have
the same tubulin activity.
Scheme 3.
four-step sequence provided an easy and efficient access to
cholic-type compounds. The expected compound 31 was
then obtained in two steps from 29 (esterification of the
3α-hydroxy group with docetaxel-protected lateral chain 11
followed by deprotection under acidic conditions) with
good yields (Scheme 2). Finally, steroid 31 was synthesised
in seven steps from commercial 6.
For all final compounds 18–24 and 31, the 2Ј-H/3Ј-H
coupling constant is small in both apolar (CDCl3) and po-
lar ([D6]DMSO) solvents. In addition, NMR conforma-
tional analysis (NOESY and ROESY) on compounds 18–
24 and 31 in CDCl3 showed an intense NOE between 2Ј-H
and 3Ј-H, characteristic of a gauche interaction between
these two protons. Furthermore, compound 31 is the only
one to present weak NOEs between the benzoate and 3Ј-H
Conclusions
In summary, we have elaborated new cholic-type steroi-
and NH (Figure 4). This means that the conformation of dal compounds possessing a benzoate and a phenylisoserine
Table 2. Biological evaluation of steroidal compounds.
Compound
Microtubule disassembly in- Microtubule assembly inhibitory Cytotoxicity against KB
Cytotoxicity against
MCF7 cell line IC50 []
[a]
[b,c]
[d]
[d]
hibitory activity IC50 [µ]
activity IC50
[µ]
cell line IC50 []
Docetaxel
Cholic acid
0.078
inactive
inactive
inactive
3.8
94
120
1.6 10–10
inactive
2.7 10–6
inactive
7.2 10–6
3.2 10–6
inactive
inactive
10–5
inactive
inactive
inactive
inactive
inactive
inactive
inactive
inactive
22
23
24
31
[a] IC50 is the concentration that inhibits 50% of the rate of microtubule disassembly. [b] IC50 is the concentration that inhibits 50% of
the rate of microtubule assembly. [c] Under the same conditions, the IC50 of vinblastine is 2 µ. [d] IC50 measures the drug concentration
required for the inhibition of 50% cell proliferation after 72 h of incubation.
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F. Roussi, Q. A. Ngo, S. Thoret, F. Guéritte, D. Guénard
FULL PAPER
under reduced pressure and the residue was diluted with Et2O
(50 mL). The organic phase was washed with aqueous HCl (1 ,
10 mL), a saturated solution of NaHCO3 (25 mL) and brine. The
organic layer was dried with MgSO4, filtered and concentrated un-
der reduced pressure. The crude mixture was purified by column
chromatography on silica gel (EtOAc/heptane = 3:7) to afford com-
side-chain in order to mimic taxoid derivatives. They were
readily synthesised in few steps either from cholic acid or
from 4-androstene-3,17-dione. Although they show some
structural similarity, according to molecular dynamic mod-
elling studies, and have the correct conformation of the lat-
eral chains in apolar solvents, these compounds show no
microtubule disassembly inhibitory activity, although three
of them show microtubule assembly inhibitory activity.
These experimental results, as well as those previously pub-
1
pound 10 (588 mg, 60%). H NMR (300 MHz, CDCl3): δ = 0.65
3
(s, 3 H, 18-H), 0.70 (d, J = 6.2 Hz, 3 H, 21-H), 0.79 (s, 3 H, 19-
H), 0.83–2.34 (m, 24 H), 3.31 (m, 1 H, 3-H), 3.76 (s, 1 H, 7-H),
5.05 (d, 2J = 2.0 Hz, 2 H, 24-H), 5.20 (s, 1 H, 12-H), 7.25 (m, 5 H,
lished by other teams, show how challenging it is to find Har) ppm. 13C NMR (75 MHz, CDCl3): δ = 12.0 (C-18), 17. 3 (C-
21), 22.4 (C-19), 22.5 (CH2), 25.3 (CH2), 27.0 (CH2), 27.5 (CH),
30.4 (C), 30.5 (CH2), 30.9 (CH2), 34.4 (CH + 2 CH2), 34.9 (CH2),
38.9 (CH), 39.4 (CH2), 41.2 (CH), 43.3 (CH), 44.9 (C), 47.3 (CH),
66.0 (C-24), 67.5 (C-7), 71.6 (C-3), 80.8 (C-12), 128.1, 128.4, 135.9
synthetic non-taxane compounds that possess a tubulin ac-
tivity similar to that of paclitaxel and docetaxel.
(6 C ), 157.0 (CO), 173.7 (CO) ppm. IR (film): νmax = 3397, 1777,
˜
ar
1737 cm–1. [α]2D0 = +51 (c = 1.12, CH2Cl2). MS (ESI, MeOH): m/z
(%) = 617.3 (100) [M + Na]+. C33H45F3O6 (594.70): calcd. C 66.65,
H 7.63; found C 66.81, H 7.84.
Experimental Section
General Remarks: All chemicals were purchased from Aldrich or
Acros Organics and were used without further purification unless
mentioned otherwise. Solvents were purchased from SDS. Anhy-
drous THF and dioxane were obtained by distillation immediately
prior to use from a dark blue-purple solution of sodium benzophe-
none ketyl. Merk silica gel 60 (230–400 mesh) was used for the
flash chromatographic purification of some compounds. The acid
chain of docetaxel 11 was a gift from Alain Commerçon (Sanofi-
Aventis). Microtubular proteins were purified from mammalian
brain as described previously.[27] Cytotoxicity and microtubule dis-
assembly inhibition were carried out according to established litera-
ture protocols.[28,29] Molecular modelling studies were realized with
the Sybyl software from Tripos with the MMFF94 force field.
General Procedure for the Esterification Reaction of Cholic Esters
with Protected Side-Chain 11: 1,3-Dicyclohexylcarbodiimide
(1.1 equiv.), 4-(dimethylamino)pyridine (1.0 equiv.) and protected
side-chain 11 (1.1 equiv.) were added to a solution of cholic esters
in toluene. The reaction mixture was stirred at 80 °C for 16 h, co-
oled and filtered. Toluene was evaporated under reduced pressure
and the residue was diluted with EtOAc. The organic layer was
washed with aqueous HCl (1 ), a saturated solution of NaHCO3
and brine, dried with MgSO4, filtered and concentrated. The crude
mixture was purified by column chromatography on silica gel
(EtOAc/heptane = 3:7) to afford the desired compound.
tert-Butyl 3α,7α-Dihydroxy-12α-trifluoroacetoxy-5β-cholan-24-oate
(8): This compound, prepared as reported previously,[16] gave the
expected spectral and analytical data.
tert-Butyl 3α-[N-Boc-N,O-(4-methoxybenzylidene)-β-phenylisoseri-
noyl]-7α-hydroxy-12α-trifluoroacetoxy-5β-cholan-24-oate (12): The
reaction was carried out with 0.71 mmol (396 mg) of compound 8
and 0.78 mmol (311 mg) of 11 in toluene (15 mL) to give, after
Methyl
(9): Four drops of concentrated HCl were added to a solution of
3α,7α-dihydroxy-12α-trifluoroacetoxy-5β-cholan-24-oic
acid[16]
3α,7α-Dihydroxy-12α-trifluoroacetoxy-5β-cholan-24-oate
1
purification, the expected compound 12 (527 mg, 79%). H NMR
3
(300 MHz, CDCl3): δ = 0.78 (s, 3 H, 18-Me), 0.81 (d, J = 6.0 Hz,
3 H, 21-Me), 0.89 (s, 3 H, 19-Me), 1.06 (s, 9 H, Boc), 1.44 (s, 9 H,
(176 mg, 0.35 mmol) in refluxing MeOH (6 mL). The reaction mix-
ture was then cooled to room temperature and neutralised with a
saturated solution of Na2CO3. MeOH was evaporated under re-
duced pressure and the aqueous solution was extracted with EtOAc
(3×10 mL). The combined organic layers were dried with MgSO4,
filtered and concentrated to give the desired product (160 mg, 88%)
as a white powder which could be used without further purifica-
tBu), 0.97–2.35 (m, 24 H), 3.81 (s, 3 H, OMe), 3.87 (s, 1 H, 7-H),
3
4.50 (m, 1 H, 3-H), 4.52 (d, J = 4.4 Hz, 1 H, 2Ј-H), 5.30 (m, 2 H,
12-H, 3Ј-H), 6.35 (bs, 1 H, 4Ј-H), 6.86–7.39 (m, 9 H, Har) ppm.
13C NMR (75 MHz, CDCl3): δ = 12.2 (C-18), 17.5 (C-21), 22.4 (C-
19), 22.8 (CH2), 25.3 (CH2), 26.0 (CH2), 27.2 (CH2), 27.5 (CH),
27.8 (3CH3 of Boc), 28.1 (3CH3 of tBu), 30.7 (CH2), 32.2 (CH2),
34.3 (CH2), 34.4 (CH + CH2), 34.5 (C), 34.9 (CH2), 39.1 (CH),
41.0 (CH), 43.3 (CH), 45.1 (C), 47.5 (CH), 55.3 (OCH3), 63.4 (C-
3Ј), 67.6 (C-7), 75.6 (C-3), 80.0 (C), 80.5 (C), 80.8 (C-12), 83.4 (C-
2Ј), 92.0 (C-4Ј), 113.6, 126.3, 127.8, 128.5, 128.7 (12Car), 157.2
1
tion. H NMR (300 MHz, CDCl3): δ = 0.82 (s, 3 H, 18-Me), 0.84
3
(d, J = 6.0 Hz, 3 H, 21-Me), 0.95 (s, 3 H, 19-Me), 0.95–2.37 (m,
24 H), 3.44 (m, 1 H, 3-H), 3.68 (s, 3 H, OMe), 3.89 (s, 1 H, 7-H),
5.34 (s, 1 H, 12-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 12.0 (C-
18), 17. 3 (C-21), 22.4 (C-19), 22.5 (CH2), 25.2 (CH2), 27.0 (CH2),
27.5 (CH), 30.3 (CH2), 30.5 (CH2), 34.4 (CH + 2 CH2), 34.8 (CH2),
37.5 (C), 38.9 (CH), 39.4 (CH2), 41.2 (CH), 43.2 (CH), 44.9 (C),
47.2 (CH), 51.4 (CH3), 67.5 (C-7), 71.6 (C-3), 80.8 (C-12), 157.2
(CO), 160.1 (CO), 169.2 (CO), 173.4 (CO) ppm. IR (film): ν
=
˜
max
3530, 1777, 1721, 1709 cm–1. [α]2D0 = +58 (c = 1.03, CH2Cl2). MS
(ESI, MeOH): m/z (%) = 964.5 (100) [M + Na]+. C52H70F3NO11
(942.11): calcd. C 66.29, H 7.49, N 1.49; found C 66.41, H 7.74, N
1.61.
(CO), 174. 3 (CO) ppm. IR (film): ν
= 3401, 1776, 1735 cm–1.
˜
max
[α]2D0 = +50 (c = 1.05, CH2Cl2). MS (ESI, MeOH): m/z = 541.3.
C27H41F3O6 (518.61): calcd. C 62.53, H 7.97; found C 62.56, H
8.21.
Methyl
3α-[N-Boc-N,O-(4-methoxybenzylidene)-β-phenylisoseri-
noyl]-7α-hydroxy-12α-trifluoroacetoxy-5β-cholan-24-oate (13): The
reaction was carried out with 0.64 mmol (332 mg) of compound
9 and 0.70 mmol (281 mg) of 11 in toluene (8 mL) to give, after
purification, the desired compound 13 (471 mg, 82%). 1H NMR
Benzyl
3α,7α-Dihydroxy-12α-trifluoroacetoxy-5β-cholan-24-oate
(10): 1,3-Dicyclohexylcarbodiimide (307 mg, 1.49 mmol) and 4-(di-
methylamino)pyridine (121 mg, 0.99 mmol) were added to a solu-
tion of 3α,7α-dihydroxy-12α-trifluoroacetoxy-5β-cholan-24-oic
acid[16] (500 mg, 0.99 mmol) and benzyl alcohol (103 µL,
1.49 mmol) in toluene (10 mL). The reaction mixture was stirred at
room temperature for 1.5 h and filtered. Toluene was evaporated
3
(300 MHz, CDCl3): δ = 0.80 (s, 3 H, 18-Me), 0.81 (d, J = 6.5 Hz,
3 H, 21-Me), 0.85 (s, 3 H, 19-Me), 1.06 (s, 9 H, Boc), 0.92–1.82
(m, 14 H), 1.93–2.08 (m, 6 H), 2.09–2.39 (m, 4 H), 3.66 (s, 3 H,
OMe), 3.80 (s, 3 H, OMe), 3.87 (s, 1 H, 7-H), 4.45 (m, 1 H, 3-H),
4.51 (d, 3J = 4 Hz, 1 H, 2Ј-H), 5.30 (m, 2 H, 12-H, 3Ј-H), 6.34 (bs,
3956
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 3952–3961

New Steroidal Compounds as Potential Mimics of Taxoids
FULL PAPER
1 H, 4Ј-H), 6.87–7.38 (m, 9 H, Har) ppm. 13C NMR (75 MHz,
128.3, 128.7, 129.4, 130.3, 133.2 (18 Car), 156.9 (CO), 160.1 (CO),
CDCl3): δ = 12.2 (C-18), 17.5 (C-21), 22.4 (C-19), 22.7 (CH2), 25.3 165.3 (CO), 168.9 (CO), 173.3 (CO) ppm. IR (film): ν
= 1779,
˜
max
(CH2), 26.0 (CH2), 27.1 (CH2), 27.5 (CH), 27.8 (3 CH3 of Boc), 1750, 1713 cm–1. [α]2D0 = +61 (c = 0.9, CH2Cl2). MS (ESI, MeOH):
30.6 (CH2), 34.3 (CH2), 34.4 (CH2), 34.5 (CH + CH2), 34.9 (CH2), m/z (%) = 1068.8 (100) [M + Na]+. C59H74F3NO12 (1046.2): calcd.
38.9 (C), 39.1 (CH), 41.0 (CH), 43.2 (CH), 45.0 (C), 47.3 (CH), C 67.73, H 7.13, N 1.34; found C 67.91, H 7.49, N 1.39.
51.4 (OCH3), 55.3 (OCH3), 63.4 (C-3Ј), 67.6 (C-7), 75.6 (C-3), 80.5
Methyl 7α-Benzoyloxy-3α-[N-Boc-N,O-(4-methoxybenzylidene)-β-
(C), 80.7 (C-12), 83.3 (C-2Ј), 92.0 (C-4Ј), 113.6, 126.3, 127.8, 128.6,
phenylisoserinoyl]-12α-trifluoroacetoxy-5β-cholan-24-oate (16): The
128.7 (12 Car), 157.2 (CO), 160.1 (CO), 169.2 (CO), 174.4 (CO)
reaction was carried out with 0.52 mmol (471 mg) of compound 13
ppm. IR (film): νmax = 3531, 1776, 1733, 1701 cm–1. [α]2D0 = +63 (c
˜
and 5.23 mmol (620 µL) of benzoyl bromide in dry pyridine (8 mL)
= 1.23, CH2Cl2). MS (ESI, MeOH): m/z (%) = 923.4 (100) [M +
to give, after purification, the expected compound 16 (426 mg,
Na]+. C49H64F3NO10 (884.03): calcd. C 65.39, H 7.17; found C
82%). 1H NMR (300 MHz, CDCl3): δ = 0.81 (s, 3 H, 18-Me), 0.84
65.68, H 7.41.
(d, 3J = 6.0 Hz, 3 H, 21-Me), 0.90 (s, 3 H, 19-Me), 1.06 (s, 9 H,
Boc), 0.90–2.50 (m, 24 H), 3.62 (s, 3 H, OMe), 3.79 (s, 3 H, OMe),
4.40 (d, J = 2.5 Hz, 1 H, 2Ј-H), 4.43 (m, 1 H, 3-H), 5.19 (m, 2 H,
Benzyl
3α-[N-Boc-N,O-(4-methoxybenzylidene)-β-phenylisoseri-
3
noyl]-7α-hydroxy-12α-trifluoroacetoxy-5β-cholan-24-oate (14): The
reaction was carried out with 0.75 mmol (445 mg) of compound 10
and 0.82 mmol (328 mg) of 11 in toluene (10 mL) to give, after
purification, the expected compound 14 (490 mg, 67%) as white
crystals. 1H NMR (300 MHz, CDCl3): δ = 0.74 (s, 3 H, 18-Me),
7-H, 3Ј-H), 5.40 (s, 1 H, 12-H), 6.32 (bs, 1 H, 4Ј-H), 6.76–8.06 (m,
14 H, Har) ppm. 13C NMR (75 MHz, CDCl3): δ = 11.8 (C-18), 17.4
(C-21), 22.2 (C-19), 22.6 (CH2), 25.0 (CH2), 26.0 (CH2), 26.8
(CH2), 27.8 (3 CH3 of Boc), 28.4 (CH), 30.4 (2 CH2), 31.1 (CH2),
34.2 (CH + CH2), 34.4 (CH2 + C), 38.0 (CH), 40.4 (CH), 42.8
(CH), 44.9 (C), 47.2 (CH), 51.4 (OCH3), 55.1 (OCH3), 63.0 (C-3Ј),
70.8 (C-7), 75.2 (C-3), 80.4 (C), 80.8 (C-12), 83.2 (C-2Ј), 91.6 (C-
4Ј), 113.4, 126.0, 126.2, 127.7, 128.2, 128.5, 129.3, 130.0, 130.2,
133.2, 133.4, 133.5 (18 Car), 156.1 (CO), 160.0 (CO), 165.2 (CO),
3
0.81 (d, J = 6.0 Hz, 3 H, 21-Me), 0.85 (s, 3 H, 19-Me), 1.05 (s, 9
H, Boc), 0.88–2.40 (m, 24 H), 3.77 (s, 3 H, OMe), 3.82 (s, 1 H, 7-
H), 4.48 (m, 2 H, 2Ј-H, 3-H), 5.09 (s, 2 H, 24-H), 5.29 (m, 2 H, 12-
H, 3Ј-H), 6.36 (bs, 1 H, 4Ј-H), 6.86–7.39 (m, 14 H, Har) ppm. 13C
NMR (75 MHz, CDCl3): δ = 11.9 (C-18), 17.2 (C-21), 22.3 (C-19),
22.5 (CH2), 25.2 (CH2), 25.9 (CH2), 27.0 (CH2), 27.3 (CH), 27.8 (3
CH3 of Boc), 30.4 (CH2), 30.7 (CH2), 34.3 (CH2), 34.3 (CH2 + C),
34.4 (CH), 34.7 (CH2), 38.9 (CH), 40.9 (CH), 43.1 (CH), 44.9 (C),
47.3 (CH), 55.0 (OCH3), 63.2 (C-3Ј), 66.0 (C-24), 67.2 (C-7), 75.5
(C-3), 80.3 (C), 80.7 (C-12), 83.2 (C-2Ј), 91.8 (C-4Ј), 113.4, 126.2,
127.7, 128.3, 128.5, 135.8 (18 Car), 157.2 (CO), 159.9 (CO), 169.0
168.7 (CO), 174.2 (CO) ppm. IR (film): ν
= 1779, 1735,
˜
max
1712 cm–1. [α]2D0 = +64 (c = 1.04, CH2Cl2). MS (ESI, MeOH): m/z
(%) = 1026.6 (100) [M + Na]+. C56H68F3NO12 (1004.1): calcd. C
66.98, H 6.83, N 1.39; found C 67.24, H 6.67, N 1.56.
Benzyl 7α-Benzoyloxy-3α-[N-Boc-N,O-(4-methoxybenzylidene)-β-
phenylisoserinoyl]-12α-trifluoroacetoxy-5β-cholan-24-oate (17): The
reaction was carried out with 0.45 mmol (440 mg) of compound 14
and 4.50 mmol (530 µL) of benzoyl bromide in dry pyridine (6 mL)
to give, after purification, the expected compound 17 (390 mg,
(CO), 173.6 (CO) ppm. IR (film): ν
= 3440, 1775, 1730,
˜
max
1700 cm–1. [α]2D0 = +54 (c = 1.0, CH2Cl2). MS (ESI, MeOH): m/z
(%) = 998.5 (100) [M + Na]+. C55H68F3NO11 (976.12): calcd. C
67.67, H 7.02, N 1.43; found C 67.83, H 7.07, N 1.26. M.p. 86–
88 °C.
1
80%). H NMR (300 MHz, CDCl3): δ = 0.77 (s, 3 H, 18-Me), 0.82
(d, 3J = 6.0 Hz, 3 H, 21-Me), 0.99 (s, 3 H, 19-Me), 1.06 (s, 9 H,
Boc), 0.90–2.40 (m, 24 H), 3.80 (s, 3 H, OMe), 4.38 (d, 3J = 4.0 Hz,
General Procedure for the Esterification Reaction of Cholic Esters
with Benzoyl Bromide: Benzoyl bromide (10 equiv.) was added
dropwise, under argon, at 0 °C, to a solution of ester and 4-(di-
methylamino)pyridine (1 equiv.) in dry pyridine. The reaction mix-
ture was stirred at 90 °C for 3 h. The cooled mixture was diluted
with Et2O. The organic layer was washed with aqueous HCl (1 ),
a saturated solution of NaHCO3 and brine, dried with MgSO4,
filtered and concentrated. The crude mixture was purified by col-
umn chromatography on silica gel (CH2Cl2, then CH2Cl2 with an
increasing amount of 1–5% of MeOH) to afford the desired com-
pound.
2
1 H, 2Ј-H), 4.42 (m, 1 H, 3-H), 5.08 (d, J = 2.1 Hz, 2 H, 24-H),
5.18 (m, 2 H, 7-H, 3Ј-H), 5.38 (s, 1 H, 12-H), 6.31 (bs, 1 H, 4Ј-H),
6.79–8.05 (m, 19 H, Har) ppm. 13C NMR (75 MHz, CDCl3): δ =
11.5 (C-18), 17.1 (C-21), 21.9 (C-19), 22.4 (CH2), 24.7 (CH2), 25.7
(CH2), 26.6 (CH2), 27.5 (3 CH3 of Boc), 28.1 (CH), 30.1 (CH2),
30.5 (CH2), 30.9 (CH2), 33.9 (CH + CH2), 34.2 (CH2 + C), 37.8
(CH), 40.2 (CH), 42.6 (CH), 44.6 (C), 47.1 (CH), 51.8 (OCH3),
62.8 (C-3Ј), 65.7 (C-24), 70.6 (C-7), 75.0 (C-3), 80.0 (C), 80.3 (C-
12), 83.0 (C-2Ј), 91.4 (C-4Ј), 113.4, 125.8, 127.4, 127.8, 127.9, 128.0,
128.1, 128.3, 129.0, 129.9, 132.9, 135.6 (24 Car), 156.1 (CO), 160.0
(CO), 164.8 (CO), 168.3 (CO), 173.1 (CO) ppm. IR (film): ν
=
˜
max
1778, 1709 cm–1. [α]2D0 = +59 (c = 0.99, CH2Cl2). MS (ESI, MeOH):
m/z (%) = 1102.5 (100) [M + Na]+. C62H72F3NO12 (1080.2): calcd.
C 68.94, H 6.72, N 1.30; found C 68.96, H 6.72, N 1.12.
tert-Butyl 7α-Benzoyloxy-3α-[N-Boc-N,O-(4-methoxybenzylidene)-
β-phenylisoserinoyl]-12α-trifluoroacetoxy-5β-cholan-24-oate
The reaction was carried out with 0.25 mmol (236 mg) of com-
pound 12 and 2.50 mmol (295 µL) of benzoyl bromide in dry pyri-
dine (1 mL) to give, after purification, the expected compound 15
(15):
General Procedure for the Deprotection of the Phenylisoserine Side-
Chain: PTSA (3 equiv.) was added to an MeOH solution of the
ester. The reaction mixture was stirred at room temperature for 3 h
and then quenched with an excess of ethyl acetate. The organic
layer was washed with a saturated solution of NaHCO3 and brine,
dried with MgSO4, filtered and concentrated. The crude mixture
was purified by column chromatography on silica gel (CH2Cl2, then
CH2Cl2 with an increasing amount of 1–5% MeOH) to afford the
desired compound.
1
(205 mg, 79%). H NMR (300 MHz, CDCl3): δ = 0.80 (s, 3 H, 18-
Me), 0.82 (d, 3J = 6.0 Hz, 3 H, 21-Me), 0.98 (s, 3 H, 19-Me), 0.96–
1.92 (m, 18 H), 1.06 (s, 9 H, Boc), 1.40 (s, 9 H, tBu), 1.99–2.35 (m,
6 H), 3.79 (s, 3 H, OMe), 4.38 (d, 3J = 4.4 Hz, 1 H, 2Ј-H), 4.41 (m,
1 H, 3-H), 5.18 (m, 2 H, 7-H, 3Ј-H), 5.39 (s, 1 H, 12-H), 6.31 (bs,
1 H, 4Ј-H), 6.20–8.05 (m, 14 H, Har) ppm. 13C NMR (75 MHz,
CDCl3): δ = 12.0 (C-18), 17.6 (C-21), 22.3 (C-19), 22.7 (CH2), 25.1
(CH2), 26.1 (CH2), 27.0 (CH2), 27.9 (3 CH3 of Boc), 28.1 (3 CH3
of tBu), 28.5 (CH), 30.7 (CH2), 31.3 (CH2), 32.1 (CH2), 34.3 (CH tert-Butyl 7α-Benzoyloxy-3α-(N-Boc-β-phenylisoserinoyl)-12α-tri-
+ C), 34.5 (2 CH2), 38.2 (CH), 40.6 (CH), 42.9 (CH), 45.0 (C), 47.5 fluoroacetoxy-5β-cholan-24-oate (18): The reaction was carried out
(CH), 55.3 (OCH3), 63.1 (C-3Ј), 71.0 (C-7), 75.4 (C-3), 80.0 (C), with 0.12 mmol (125 mg) of compound 15 in MeOH (3 mL) to give,
80.5 (C), 80.7 (C-12), 83.3 (C-2Ј), 92.0 (C-4Ј), 113.6, 126.2, 127.8,
after purification, the expected compound 18 (85 mg, 77%). 1H
Eur. J. Org. Chem. 2005, 3952–3961
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3957

F. Roussi, Q. A. Ngo, S. Thoret, F. Guéritte, D. Guénard
NMR (300 MHz, CDCl3): δ = 0.82 (s, 3 H, 18-Me), 0.83 (d, J = w/w). After 1 h, the reaction mixture was partitioned between Et2O
FULL PAPER
3
6.0 Hz, 3 H, 21-Me), 0.90–1.95 (m, 16 H), 1.02 (s, 3 H, 19-Me),
1.37 (bs, 9 H, Boc), 1.41 (s, 9 H, tBu), 2.03–2.37 (m, 8 H), 3.20 (s,
and aqueous phosphate buffer (pH = 7; 1 ). The organic layer
was dried (MgSO4) and concentrated in vacuo. The crude mixture
1 H, OH), 4.30 (s, 1 H, 2Ј-H), 4.60 (m, 1 H, 3-H), 4.84 (d, 3J = was then purified to give the desired 12α-hydroxy compounds.
7.1 Hz, 1 H, 3Ј-H), 5.20 (d, 3J = 7.1 Hz, 1 H, NH), 5.21 (s, 1 H, 7-
tert-Butyl 7α-Benzoyloxy-3α-(N-Boc-β-phenylisoserinoyl)-12α-hy-
H), 5.41 (m, 1 H, 12-H), 7.10–8.11 (m, 10 H, Har) ppm. 13C NMR
droxy-5β-cholan-24-oate (21): The reaction was carried out with
(75 MHz, CDCl3): δ = 12.0 (C-18), 17.6 (C-21), 22.3 (C-19), 22.7
(CH2), 25.1 (CH2), 26.4 (CH2), 27.0 (CH2), 27.2 (3 CH3 of Boc),
28.0 (3 CH3 of tBu), 28.5 (CH), 30.6 (CH2), 31.2 (CH2), 32.1 (C),
34.2 (CH2), 34.3 (CH), 34.4 (2 CH2), 38.2 (CH), 40.7 (CH), 43.0
(CH), 45.0 (C), 47.5 (CH), 56.5 (C-3Ј), 70.9 (C-7), 73.8 (C-2Ј), 75.3
(C-3), 79.7 (C), 80.0 (C), 80.7 (C-12), 126.6, 127.6, 128.3, 128.5,
128.6, 129.5, 130.5, 133.1, 138.9, 129.4, 130.3, 133.2 (12 Car), 154.9
(CO), 156.8 (CO), 165.2 (CO), 172.1 (CO), 173.3 (CO) ppm. IR
0.044 mmol (41 mg) of compound 18 and aqueous ammonia
(600 µL) in a mixture of MeOH and THF (1.8 mL) to give, after
purification by preparative TLC (CH2Cl2/3% MeOH), compound
1
21 (19 mg, 52%). H NMR (300 MHz, CDCl3): δ = 0.64 (s, 3 H,
18-Me), 0.91 (m, 6 H, 19-Me, 21-Me), 1.26 (bs, 9 H, Boc), 1.34 (s,
9 H, tBu), 0.69–2.44 (m, 24 H), 3.42 (bs, 1 H, OH), 3.56 (s, 1 H,
OH), 3.97 (s, 1 H, 12-H), 4.25 (s, 1 H, 2Ј-H), 4.56 (m, 1 H, 3-H),
4.82 (m, 1 H, 3Ј-H), 5.14 (m, 2 H, 7-H + NH), 7.10–8.03 (m, 10
H, Har) ppm. 13C NMR (75 MHz, CDCl3): δ = 12.5 (C-18), 17.5
(C-21), 22.0 (C-19), 22.5 (CH2), 23.9 (CH2), 24.6 (CH2), 25.6
(CH2), 26.2 (CH2), 27.0 (3 CH3 of Boc), 27.2 (3 CH3 of tBu), 27.4
(CH2), 30.3 (CH), 31.4 (CH2), 32.9 (CH2), 33.4 (CH2), 33.7 (C),
33.9 (CH), 37.6 (CH), 39.9 (CH), 42.1 (CH), 45.7 (C), 47.3 (CH),
51.5 (C-3Ј), 71.4 (C-7), 72.7 (C-12), 73.9 (C-2Ј), 76.5 (C-3), 77.6
(C), 79.0 (C), 125.7, 126.6, 127.4, 127.5, 128.7, 129.8, 131.9 (12
Car), 153.9 (CO), 164.7 (CO), 171.0 (CO), 172.5 (CO) ppm. IR
(film): νmax = 3448, 1779, 1719 cm–1. [α]2D0 = +38 (c = 1.1, CH2Cl2).
˜
MS (ESI, MeOH): m/z (%) = 950.4 (100) [M + Na]+. HRMS: calcd.
for C51H68F3NNaO11 950.4642; found 950.4642.
Methyl 7α-Benzoyloxy-3α-(N-Boc-N,O-β-phenylisoserinoyl)-12α-tri-
fluoroacetoxy-5β-cholan-24-oate (19): The reaction was carried out
with 0.08 mmol (80 mg) of compound 16 in MeOH (2 mL) to give,
after purification by preparative TLC (CH2Cl2/MeOH 1%), the ex-
1
pected compound 19 (48 mg, 68%). H NMR (300 MHz, CDCl3):
(film): νmax = 3400, 2940, 1713 cm–1. [α]2D0 = +11 (c = 0.95, CHCl3).
˜
3
δ = 0.75 (s, 3 H, 18-Me), 0.78 (d, J = 6.0 Hz, 3 H, 21-Me), 0.94
MS (ESI, MeOH): m/z (%) = 854.4 (100) [M + Na]+. HRMS: calcd.
(s, 3 H, 19-Me), 1.29 (bs, 9 H, Boc), 1.02–2.45 (m, 24 H), 3.56 (s,
for C49H69NNaO10 854.4819; found 854.4851.
3
3 H, OMe), 4.42 (s, 1 H, 2Ј-H), 4.52 (m, 1 H, 3-H), 4.76 (d, J =
Methyl 7α-Benzoyloxy-3α-(N-Boc-N,O-β-phenylisoserinoyl)-12α-hy-
droxy-5β-cholan-24-oate (22): The reaction was carried out with
0.12 mmol (104 mg) of compound 19 and aqueous ammonia
(600 µL) in a mixture of MeOH and THF (3 mL) to give, after
purification by preparative TLC (CH2Cl2/2% MeOH), compound
8.1 Hz, 1 H, 3Ј-H), 5.08 (m, 1 H, NH), 5.13 (s, 1 H, 7-H), 5.33 (m,
1 H, 12-H), 6.03–8.03 (m, 10 H, Har) ppm. 13C NMR (75 MHz,
CDCl3): δ = 11.9 (C-18), 17.5 (C-21), 22.2 (C-19), 22.7 (CH2), 25.0
(CH2), 26.3 (CH2), 26.9 (CH2), 28.1 (3 CH3 of Boc), 28.4 (CH),
30.4 (CH2), 30.5 (CH2), 31.2 (CH2), 34.1 (CH2), 34.2 (C + CH2),
34.6 (CH), 38.1 (CH), 40.6 (CH), 42.9 (CH), 44.9 (C), 47.3 (CH),
51.4 (OCH3), 56.5 (C-3Ј), 70.8 (C-7), 73.7 (C-2Ј), 75.8 (C-3), 79.5
(C), 80.5 (C-12), 126.6, 127.5, 128.3, 128.5, 128.6, 129.5, 130.5,
132.9 (12 Car), 154.9 (CO), 156.7 (CO), 165.2 (CO), 172.0 (CO),
1
22 (44 mg, 47%). H NMR (300 MHz, CDCl3): δ = 0.71 (s, 3 H,
18-Me), 0.96 (d, 3J = 6.1 Hz, 3 H, 21-Me), 0.98 (s, 3 H, 19-Me),
1.11–2.47 (m, 24 H), 1.33 (bs, 9 H, Boc), 3.26 (s, 1 H, OH), 3.62
(s, 3 H, OMe), 4.03 (s, 1 H, 12-H), 4.31 (s, 1 H, 2Ј-H), 4.61 (m, 1
3
H, 3-H), 4.88 (d, J = 8.1 Hz, 1 H, 3Ј-H), 5.20 (s, 1 H, 7-H), 5.24
174.2 (CO) ppm. IR (film): ν
= 3447, 2953, 1779, 1734,
˜
max
1718 cm–1. [α]2D0 = +48 (c = 1.0, CH2Cl2). MS (ESI, MeOH): m/z
(%) = 908.4 (100) [M + Na]+. C48H62F3NO11 (886.00): calcd. C
65.07, H 7.05, N 1.58; found C 65.07, H 7.33, N 1.52.
(m, 1 H, NH), 7.16–8.10 (m, 10 H, H ). IR (film): ν
= 3433,
˜
ar
max
1714 cm–1. [α]2D0 = +9 (c = 1.0, CH2Cl2). MS (ESI, MeOH): m/z
(%) = 812.4 (100) [M + Na]+. C46H63NO10 (789.99): calcd. C 69.94,
H 8.04, N 1.77; found C 70.03, H 8.21, N 1.54.
Benzyl 7α-Benzoyloxy-3α-(N-Boc-β-phenylisoserinoyl)-12α-trifluo-
roacetoxy-5β-cholan-24-oate (20): The reaction was carried out with
0.35 mmol (383 mg) of compound 17 in MeOH (12 mL) to give,
after purification, the expected compound 20 (293 mg, 86%). 1H
NMR (300 MHz, CDCl3): δ = 0.81 (m, 6 H, 18-Me, 21-Me), 1.0
(s, 3 H, 19-Me), 1.35 (bs, 9 H, Boc), 1.03–1.55 (m, 14 H), 1.67–
1.91 (m, 4 H), 2.06–2.40 (m, 6 H), 3.28 (s, 1 H, OH), 4.28 (s, 1 H,
Benzyl 7α-Benzoyloxy-3α-(N-Boc-β-phenylisoserinoyl)-12α-hydroxy-
5β-cholan-24-oate (23): The reaction was carried out with
0.14 mmol (134 mg) of compound 20 and aqueous ammonia
(700 µL) in a mixture of MeOH and THF (3 mL) to give, after
purification by column chromatography on silica gel (CH2Cl2, then
CH2Cl2/1% MeOH), compound 23 (82 mg, 68%). 1H NMR
3
(300 MHz, CDCl3): δ = 0.70 (s, 3 H, 18-Me), 0.97 (d, J = 6.1 Hz,
3
2Ј-H), 4.58 (m, 1 H, 3-H), 4.82 (d, J = 8 Hz, 1 H, 3Ј-H), 5.08 (d,
3 H, 21-Me), 1.0 (s, 3 H, 19-Me), 1.36 (bs, 9 H, Boc), 0.75–2.50
(m, 24 H), 4.04 (s, 1 H, 12-H), 4.33 (s, 1 H, 2Ј-H), 4.63 (m, 1 H,
2J = 2.1 Hz, 2 H, 24-H), 5.20 (m, 2 H, 7-H + NH), 5.39 (m, 1 H,
12-H), 7.09–8.10 (m, 15 H, Har) ppm. 13C NMR (75 MHz, CDCl3):
δ = 11.9 (C-18), 17.5 (C-21), 22.3 (C-19), 22.7 (CH2), 25.0 (CH2),
26.4 (CH2), 26.8 (CH2), 28.1 (3 CH3 of Boc), 28.4 (CH), 30.4
(CH2), 30.8 (CH2), 31.1 (C), 34.2 (2 CH2), 34.3 (CH), 34.4 (CH2),
38.1 (CH), 40.6 (CH), 42.8 (CH), 44.9 (C), 47.4 (CH), 56.4 (C-3Ј),
60.3 (C-24), 70.8 (C-7), 73.7 (C-2Ј), 75.8 (C-3), 79.6 (C), 80.6 (C-
12), 126.4, 126.6, 127.5, 128.2, 128.3, 128.4, 128.6, 129.4, 129.6,
130.4, 133.1, 135.9, 138.9 (18 Car), 154.9 (CO), 156.8 (CO), 165.2
3
2
3-H), 4.90 (d, J = 8.2 Hz, 1 H, 3Ј-H), 5.09 (d, J = 2.0 Hz, 2 H,
24-H), 5.22 (s, 1 H, 7-H), 5.31 (m, 1 H, NH), 7.18–8.12 (m, 15 H,
Har) ppm. 13C NMR (75 MHz, CDCl3): δ = 12.4 (C-18), 17.2 (C-
21), 22.4 (C-19), 22.9 (CH2), 25.5 (CH2), 26.5 (CH2), 27.1 (CH2),
28.1 (3 CH3 of Boc), 28.4 (CH2), 30.2 (CH), 30.7 (CH2), 31.2 (C),
31.4 (CH2), 34.2 (CH2), 34.6 (CH2), 34.8 (CH), 38.4 (CH), 40.8
(CH), 42.0 (CH), 46.5 (C), 47.2 (CH), 56.5 (C-3Ј),60.3 (C-24), 71.3
(C-7), 72.6 (C-12), 73.7 (C-3), 76.4 (C-2Ј), 79.6 (C), 125.4, 126.6,
127.4, 128.1, 128.4, 129.6, 130.6, 132.8, 135.9 (18 Car), 154.9 (CO),
(CO), 171.2 (CO), 173.3 (CO) ppm. IR (film): ν
= 3440, 1778,
˜
max
1718 cm–1. [α]2D0 = +47 (c = 1.0, CH2Cl2). MS (ESI, MeOH): m/z
(%) = 984.5 (100) [M + Na]+. C54H66F3NO11 (962.10): calcd. C
67.40, H 6.91, N 1.46; found C 67.03, H 6.98, N 1.15.
165.7 (CO), 171.9 (CO), 173.8 (CO) ppm. IR (film): ν
= 3509,
˜
max
3432, 1777, 1714 cm–1. [α]2D0 = +16 (c = 1.0, CH2Cl2). MS (ESI,
MeOH): m/z (%) = 888.4 (100) [M + Na]+. HRMS (APCI): calcd.
for C52H67NNaO10 888.4663; found 888.4645.
General Procedure for the Deprotection of the Trifluoroacetoxy
Group: Aqueous ammonia (35%, w/w) was added to a stirred solu-
tion of the trifluoroacetate in a mixture of MeOH and THF (1:1,
7α-Benzoyloxy-3α-(N-Boc-β-phenylisoserinoyl)-12α-hydroxy-5β-cho-
lan-24-oic Acid (24): A catalytic amount of 10% Pd/C (5 mg, 4.72
3958
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 3952–3961

New Steroidal Compounds as Potential Mimics of Taxoids
FULL PAPER
10–3 mmol) was added to a solution of compound 23 (34 mg,
0.039 mmol) in THF (1.5 mL). The resulting mixture was stirred
under 1 atm of hydrogen for 1.5 h. The catalyst was removed by
filtration through a pad of Celite and the filtrate was concentrated
in vacuo to give the pure compound, which crystallised slowly un-
(film): νmax = 3449, 1738, 1694 cm–1. [α]2D3 = +78 (c = 1.0, CH2Cl2).
˜
MS (ESI, MeOH): m/z = 327.5 [MNa]+. C19H28O3 (304.42): calcd.
C 74.76, H 9.27; found C 74.81, H 9.05.
7α-Hydroxyandrost-4-ene-3,17-dione (33): Formic acid (85 µL,
2.20 mmol) and triethylamine (125 µL, 0.87 mmol) were added, un-
der argon, to a suspension of Pd2(dba)3 (26 mg, 0.025 mmol) and
triphenylphosphane (7 mg, 0.025 mmol) in degassed dioxane
(2.5 mL). After 10 min, a solution of compound 26 (250 mg,
0.83 mmol) in dioxane (2 mL) was added. The reaction mixture was
stirred at room temperature for 3 d, then passed through a short
pad of silica gel and the solvent was removed. The crude product
was purified by flash chromatography on silica gel (EtOAc/heptane
= 1:1) to give compound 33 (130 mg, 52%) as white crystals. 1H
NMR (300 MHz, CDCl3): δ = 0.95 (s, 3 H, 18-Me), 1.13 (s, 3 H,
19-Me), 1.20–2.57 (m, 14 H), 2.34–2.52 (m, 2 H), 2.68 (dt, 3J = 2.2/
15 Hz, 1 H), 4.11 (m, 1 H, 7-H), 5.81 (s, 1 H, 4-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 13.5 (C-18), 17.0 (C-19), 20.1 (CH2), 21.3
(CH2), 30.9 (CH), 31.0 (CH2), 33.9 (CH2), 35.4 (CH2), 35.7 (CH2),
38.5 (C), 39.4 (CH), 41.0 (CH2), 45.6 (CH), 47.3 (C), 67.0 (C-7),
127.1 (C-4), 167.1 (C-5), 198.8 (CO), 207.0 (CO) ppm. IR (film):
1
der vacuum (30 mg, 98%). H NMR (300 MHz, CDCl3): δ = 0.69
(s, 3 H, 18-Me), 0.96 (d, 3J = 6.4 Hz, 3 H, 21-Me), 0.97 (s, 3 H,
19-Me), 1.26 (bs, 9 H, Boc), 0.85–2.50 (m, 24 H), 3.39 (m, 1 H,
OH), 4.03 (s, 1 H, 12-H), 4.30 (s, 1 H, 2Ј-H), 4.61 (m, 1 H, 3-H),
4.87 (m, 1 H, 3Ј-H), 5.19 (s, 1 H, 7-H), 5.26 (m, 1 H, NH), 7.17–
8.10 (m, 10 H, Har) ppm. 13C NMR (75 MHz, CDCl3): δ = 12.4
(C-18), 17.2 (C-21), 22.4 (C-19), 22.9 (CH2), 25.5 (CH2), 26.5
(CH2), 27.1 (CH2), 28.1 (3 CH3 of Boc), 28.3 (CH), 30.7 (CH2),
30.5 (CH2), 30.8 (C), 31.4 (CH2), 33.6 (CH), 34.2 (CH2), 34.6
(CH2), 38.3 (CH), 40.8 (CH), 42.0 (CH), 46.5 (C), 47.0 (CH), 56.5
(C-3Ј), 71.3 (C-7), 72.6 (C-12), 73.9 (C-2Ј), 76.3 (C-3), 77.4 (C),
126.6, 127.4, 129.5, 129.6, 130.6, 132.7 (12 Car), 154.9 (CO), 165.7
(CO), 171.0 (CO), 178.6 (CO) ppm. IR (film): ν
= 3405,
˜
max
1713 cm–1. [α]2D0 = +13 (c = 1.0, CH2Cl2). MS (ESI, MeOH): m/z
(%) = 798.4 (100) [M + Na]+. C45H61NO10 (775.97): calcd. C 69.65,
H 7.92, N 1.81; found C 69.42, H 7.88, N 1.52.
ν
= 3435, 1735, 1659 cm–1. [α]2D3 = +202 (c = 1.0, CH2Cl2). MS
˜
max
∆
4,6-Androstene-3,17-dione (25): PTSA (0.26 g, 1.4 mmol) and 4-
(ESI, MeOH): m/z = 325.2 [MNa]+. HRMS (APCI): calcd. for
chloranil (3.43 g, 13.96 mmol) were added to a solution of 4-andro-
stene-3,17-dione (6; 2.0 g, 6.98 mmol) in a 7:3 mixture of tert-butyl
alcohol and toluene (300 mL). The reaction mixture was stirred at
105 °C for 16 h, cooled and filtered. The solvent was evaporated
under reduced pressure and the residue was diluted with CH2Cl2
(100 mL). The organic layer was washed with water, a solution of
5% NaOH (4×50 mL) and brine (3×50 mL), dried with MgSO4,
filtered and concentrated. The crude mixture was purified by col-
umn chromatography on silica gel (EtOAc/heptane = 3:7) to afford
the desired compound as a pale-yellow amorphous solid (1.45 g,
73%). 1H NMR (300 MHz, CDCl3): δ = 0.91 (s, 3 H, 18-Me), 1.08
(s, 3 H, 19-Me), 1.10–2.60 (m, 15 H), 5.63 (s, 1 H, 7-H), 6.12 (s, 2
H, 4-H + 6-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1 (C-18),
16.3 (C-19), 19.9 (CH2), 21.3 (CH2), 29.2 (CH2), 30.9 (CH2), 33.8
(CH2), 35.7 (CH2), 36.0 (C), 36.9 (CH), 48.6 (CH), 50.6 (CH), 53.7
(C), 124.0 (C-7), 128.6 (C-4), 138.4 (C-6), 163.0 (C-5), 199.2 (C-
C19H26NaO3 325.1780; found 325.1766.
7α-Benzoyloxy-5β-androstane-3,17-dione (28): A solution of ben-
zoic acid (594 mg, 4.9 mmol) and dicyclohexylcarbodiimide
(1003 mg, 4.9 mmol) in toluene (10 mL) was stirred at room tem-
perature for 5 min. 4-(Dimethylamino)pyridine (237 mg,
1.93 mmol) and compound 27 (370 mg, 1.21 mmol) were then
added. The resulting solution was stirred at 45 °C for 24 h. The
reaction mixture was cooled and filtered. The solvent was removed
under reduced pressure. The crude mixture was diluted with
CH2Cl2 (100 mL), and the organic phase was washed with aqueous
HCl (1 , 50 mL), a saturated solution of NaHCO3 (50 mL) and
brine. The organic layer was dried with MgSO4, filtered and evapo-
rated under reduced pressure. The crude mixture was purified by
column chromatography on silica gel (EtOAc/heptane = 3:7 then
1:1) to afford compound 28 (407 mg, 83%) as a white amorphous
1
solid. H NMR (300 MHz, CDCl3): δ = 0.94 (s, 3 H, 18-Me), 1.13
17), 210.7 (C-3) ppm. IR (film): ν
= 1739, 1663, 1618 cm–1.
˜
max
(s, 3 H, 19-Me), 1.36–2.21 (m, 17 H), 2.27–2.50 (m, 2 H), 3.01 (t,
3J = 14.6 Hz, 1 H, 4-H), 5.38 (d, 3J = 2.6 Hz, 1 H, 7-H), 7.47–7.95
(m, 5 H, Har) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.5 (C-18),
20.4 (CH2), 21.4 (CH2), 21.8 (C-19), 30.9 (CH2), 31.4 (CH2), 35.2
(C), 35.6 (CH2), 35.9 (CH), 36.5 (CH2), 36.8 (CH2), 38.1 (CH),
42.3 (CH), 44.6 (CH2), 46.1 (CH), 47.7 (C), 70.4 (C-7), 128.7, 129.3,
[α]2D3 = +128 (c = 1.0, CH2Cl2). MS (ESI, MeOH): m/z = 307.2
[MNa]+. C19H24O2 (284.39): calcd. C 80.44, H 8.52; found C 80.24,
H 8.51.
6α,7α-Dihydro-6,7-epoxyandrost-4-ene-3,17-dione (26): This com-
pound, prepared as reported previously,[24] gave the expected spec-
tral and analytical data.
130.0, 133.3 (6 C ), 165.5 (CO), 211.7 (2 CO) ppm. IR (film): ν
˜
ar
max
= 1737, 1711 cm–1. [α]2D3 = +57 (c = 1.0, CH2Cl2). MS (ESI,
7α-Hydroxy-5β-androstane-3,17-dione (27): Formic acid (596 µL,
5.30 mmol) and distilled triethylamine (878 µL, 2.10 mmol) were
MeOH): m/z
=
431.2 [MNa]+. HRMS (APCI): calcd. for
C26H32NaO4 431.2198; found 431.2215.
added, under argon, to
a suspension of Pd2(dba)3 (77 mg,
0.025 mmol) and triphenylphosphane (20 mg, 0.025 mmol) in de-
gassed, dry dioxane (22 mL). After 10 min, a solution of compound
26 (892 mg, 2.97 mmol) in dry dioxane (2 mL) was added. The re-
action mixture was stirred at 80 °C for 5 h, then passed through a
short pad of silica gel and the solvent was removed. The crude
product was purified by flash chromatography on silica gel
(CH2Cl2/2% MeOH) to give compound 27 (440 mg, 49%) as white
crystals. 1H NMR (300 MHz, CDCl3): δ = 0.90 (s, 3 H, 18-Me),
7α-Benzoyloxy-3α-hydroxy-5β-androstane-3,17-dione (29): A sus-
pension of lithium tri-tert-butoxyaluminium hydride (249 mg,
0.98 mmol) in anhydrous THF (12 mL) was cooled to 0 °C under
argon. A solution of compound 28 (364 mg, 0.89 mmol) in anhy-
drous THF (3 mL) was then added slowly. The reaction mixture
was stirred at 0 °C for 2 h, then quenched with aqueous HCl (1 ,
5 mL). The resulting milky suspension was stirred at room tem-
perature for 5 min and diluted with CH2Cl2. The organic phase was
washed with a saturated solution of NaHCO3 (10 mL) and brine.
1.04 (s, 3 H, 19-Me), 1.22–1.88 (m, 10 H), 1.97–2.24 (m, 8 H), 2.34-
3
2.52 (m, 2 H), 3.41 (t, J = 14.5 Hz, 1 H, 4-H), 4.09 (s, 1 H, 7-H) The organic layer was dried with MgSO4, filtered and concentrated
ppm. 13C NMR (75 MHz, CDCl3): δ = 13.5 (C-18), 20.3 (CH2), under reduced pressure. The crude mixture was purified by column
21.4 (CH2), 21.8 (C-19), 31.3 (CH2), 33.7 (CH), 34.3 (CH2), 35.5
(C), 35.8 (CH2), 36.8 (CH2), 36.9 (CH2), 38.9 (CH), 43.1 (CH),
45.6 (CH2), 45.7 (CH), 47.6 (C), 67.2 (C-7), 212.0 (2 CO) ppm. IR
chromatography on silica gel (EtOAc/heptane = 3:7) to afford com-
pound 29 (190 mg, 52%) as a white amorphous solid. 1H NMR
(300 MHz, CDCl3): δ = 0.88 (s, 3 H, 18-Me), 1.02 (s, 3 H, 19-Me),
Eur. J. Org. Chem. 2005, 3952–3961
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3959

F. Roussi, Q. A. Ngo, S. Thoret, F. Guéritte, D. Guénard
FULL PAPER
3
1.16–2.19 (m, 19 H), 2.40 (dd, J = 8.7, 19.3 Hz, 1 H, 4- H), 3.50
(m, 1 H, 3- H), 3.71 (s, 1 H, OH), 5.31 (s, 1 H, 7-H), 7.48–8.03 (m,
5 H, Har) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.4 (C-18), 20.4
(CH2), 21.4 (CH2), 22.7 (C-19), 30.41 (CH2), 31.43 (CH2), 31.4
(CH2), 35.0 (CH + C), 35.2 (CH2), 35.6 (CH2), 38.1 (CH), 39.2
(CH2), 41.0 (CH), 46.2 (CH), 47.7 (C), 70.8 (C-3), 71.4 (C-7), 128.6,
129.4, 130.4, 133.1 (6 Car), 165.8 (CO), 209.1 (CO) ppm. IR (film):
Acknowledgments
The authors acknowledge the Vietnamese Government and Prof.
Tran Van Sung, director of the Institute of Chemistry of the NAST,
Hanoi, for the fellowship awarded to Q. A. N.; C. Gaspard and G.
Aubert are acknowledged for cytotoxicity evaluations.
ν
= 3448, 1736, 1709 cm–1. [α]2D3 = +61 (c = 1.0, CH2Cl2). MS
˜
max
(ESI, MeOH): m/z = 433.2 [MNa]+. HRMS (APCI): calcd. for
[1] M. C. Wani, H. L. Taylor, M. E. Wall, P. Coggon, T. A.
McPhail, J. Am. Chem. Soc. 1971, 93, 2325–2327.
C26H34NaO4 433.2355; found 433.2379.
[2] For a review, see: D. Guénard, F. Guéritte-Voegelein, P. Potier,
Acc. Chem. Res. 1993, 26, 160–167.
7α-Benzoyloxy-3α-[N-Boc-N,O-(2,4-dimethoxybenzylidene)-β-phen-
ylisoserinoyl]-5β-androstan-17-one (30): 1,3-Dicyclohexylcarbodii-
mide (139 mg, 0.68 mmol), 4-(dimethylamino)pyridine (61 mg,
0.50 mmol) and protected side-chain 11 (270 mg, 0.68 mmol) were
added to a solution of compound 29 (184 mg, 0.45 mmol) in tolu-
ene (8 mL). The reaction mixture was stirred at 80 °C for 4 h, co-
oled and filtered. The toluene was evaporated under reduced pres-
sure and the residue was diluted with CH2Cl2. The organic layer
was washed with aqueous HCl (1 ), a saturated solution of
NaHCO3 and brine, dried with MgSO4, filtered and concentrated.
The crude mixture was purified by column chromatography on sil-
ica gel (EtOAc/heptane = 3:7) to afford the desired compound 30
[3] P. B. Schiff, J. Fant, S. B. Horwitz, Nature 1979, 277, 665–667.
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gales, Proc. Natl. Acad. Sci. USA 2001, 98, 5312–5316.
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Cherian, H. Sham, S. H. Rosenberg, S.-C. Ng, Eur. J. Cancer
2000, 36, 1565–1571.
1
(315 mg, 88%) as a white amorphous solid. H NMR (300 MHz,
CDCl3): δ = 0.80 (s, 3 H, 18-Me), 0.92 (s, 3 H, 19-Me), 1.00 (s, 9
3
H, Boc), 1.19–2.26 (m, 20 H), 3.73 (s, 3 H, OCH3), 4.31 (d, J =
[11] a) J.-N. Denis, A. E. Greene, A. A. Serra, M.-J. Luche, J. Org.
Chem. 1986, 51, 46–50; b) S. Py, C. W. Harwig, S. Banerjee,
D. L. Brown, A. G. Fallis, Tetrahedron Lett. 1998, 39, 6139–
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Y. Hamajima, M. Kohno, Chem. Pharm. Bull. 1999, 47, 1334–
1337; d) G. Gentile, D. Fattori, M. Botta, F. Corelli, D. Fusar-
Bassini, D. Lamba, Can. J. Chem. 2000, 78, 925–934; e) D.
Arad, A. P. Bollon, B. W. Poland, D. C. Young, WO 01/05779
A2, 25.01.2001; f) R. Barycki, M. Gumulka, M. Masnyk,
W. M. Daniewski, M. Kobus, M. Luczak, Collect. Czech.
Chem. Commun. 2002, 67, 75–82; g) J. Howarth, P. Kenny, S.
McDonnell, A. O’Connor, Bioorg. Med. Chem. Lett. 2003, 13,
2693–2697; h) U. Klar, H. Graf, O. Shenk, B. Röhr, H. Schulz,
Bioorg. Med. Chem. Lett. 1998, 8, 1397–1402; i) X. Geng, R.
Geney, P. Pera, R. J. Bernacki, I. Ojima, Bioorg. Med. Chem.
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Thornqvist, U. Berg, M. Wallin, T. Frejd, Org. Biomol. Chem.
2004, 2, 3085–3090.
O. Querolle, J. Dubois, S. Thoret, F. Roussi, F. Guéritte, D.
Guénard, J. Med. Chem. 2004, 47, 5937–5944.
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erry, Cancer Res. 2003, 63, 3211–3220.
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Nampoothiri, E. Hamel, M. Cushman, J. Med. Chem. 2000,
43, 2419–2429.
[15] P. Verdier-Pinard, Z. Wang, A. K. Mohanakrishnan, M. Cush-
man, E. Hamel, Mol. Pharmacol. 2000, 57, 568–575.
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Perkin Trans. 1 1990, 2245–2250.
3.75 Hz, 1 H, 2Ј-H), 4.38 (m, 1 H, 3-H), 5.22 (m, 2 H, 3Ј-H + 7-
H), 6.28 (s, 1 H, 4Ј-H), 6.78–7.93 (m, 14 H, Har) ppm. 13C NMR
(75 MHz, CDCl3): δ = 13.5 (C-18), 20.0 (CH2), 21.4 (CH2), 22.6
(C-19), 25.0 (CH2), 27.9 (3 CH3 of Boc), 31. 3 (2 CH2), 34.1 (CH2),
34.8 (CH + C), 35.0 (CH2), 35.2 (CH2), 38.1 (CH), 41.8 (CH), 45.8
(C), 46.2 (CH), 55.3 (OCH3), 63.0 (C-3Ј), 70.6 (C-7), 75.6 (C-3),
80.6 (C), 83.0 (C-2Ј), 91.8 (C-4Ј), 113.6, 127.8, 128.6, 129.4, 130.4,
133.2 (18 Car), 160.1 (CO), 163.0 (CO), 165.2 (CO), 209.2 (CO)
ppm. IR (film): ν
= 1737, 1709 cm–1. [α]2D3 = +58 (c = 1.0,
˜
max
CH2Cl2). MS (ESI, MeOH): m/z = 814.5 [MNa]+. HRMS (APCI):
calcd. for C48H57NNaO9 814.3931; found 814.3929.
7α-Benzoyloxy-3α-(N-Boc-β-phenylisoserinoyl)-5β-androstan-17-one
(31): Compound 30 (315 mg, 0.40 mmol) and PTSA (227 mg,
1.23 mmol) were dissolved in MeOH (10 mL). The resulting solu-
tion was stirred at room temperature for 3 h and then quenched
with an excess of CH2Cl2 (25 mL). The organic layer was washed
with a saturated solution of NaHCO3 and brine, dried with
MgSO4, filtered and concentrated. The crude mixture was purified
by column chromatography on silica gel (CH2Cl2/2% MeOH) to
afford the desired compound 31 (205 mg, 76%) as a white amorph-
[12]
1
ous solid. H NMR (300 MHz, CDCl3): δ = 0.81 (s, 3 H, 18-Me),
0.95 (s, 3 H, 19-Me), 1.00 (s, 9 H, Boc), 1.06–2.37 (m, 20 H), 3.00
(s, 1 H, OH), 4.25 (s, 1 H, 2Ј-H), 4.57 (m, 1 H, 3-H), 4.83 (m, 1 H,
3Ј-H), 5.12 (d, 3J = 9.4 Hz, 1 H, NH), 5.26 (s, 1 H, 7-H), 7.09–7.98
(m, 10 H, Har) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.3 (C-18),
19.8 (CH2), 21.2 (CH2), 22.4 (C-19), 26.4 (CH2), 28.0 (3 CH3 of
Boc), 31.3 (CH2), 31.6 (C), 33.7 (CH2), 34.2 (CH2), 34.6 (CH2),
35.8 (CH), 35.4 (CH2), 37.8 (CH), 40.6 (CH), 45.9 (CH), 47.5 (C),
56.3 (C-3Ј), 70.2 (C-7), 73.8 (C-2Ј), 76.2 (C-3), 79.5 (C), 126.7,
127.6, 128.4, 128.6, 129.4, 130.1, 130.4, 133.1, 139.0 (12 Car), 154.9
[17] M. E. Jung, T. W. Johnson, Tetrahedron 2001, 57, 1449–1481.
[18] E. Didier, E. Fouque, I. Taillepied, A. Commerçon, Tetrahe-
dron Lett. 1994, 35, 2349–2352.
[19] A. M. M. Hossain, D. N. Kirk, G. Mitra, Steroids 1976, 27,
603–608.
(CO), 165.6 (CO), 171.1 (CO), 209.9 (CO) ppm. IR (film): ν
=
˜
max
[20] P. M. Wovkulich, A. D. Batcho, M. R. Uskokovic, Helv. Chim.
´
3442, 1714 cm–1. [α]2D3 = +54 (c = 1.0, CH2Cl2). MS (ESI, MeOH):
m/z = 696.3 [MNa]+. HRMS (APCI): calcd. for C40H51NNaO8
696.3512; found 696.3524.
Acta 1984, 67, 612–615.
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Supporting Information: Characterisation data for compounds 18,
21, 23, 28, 30 and 31.
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New Steroidal Compounds as Potential Mimics of Taxoids
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Received: March 18, 2005
Published Online: August 4, 2005
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