A concise synthesis of the steroidal core of clathsterol

Article abstract of DOI:10.1016/j.tetlet.2010.05.072

The protected steroidal core of clathsterol, a marine natural product with remarkable inhibitory activity against HIV-1 reverse transcriptase, was synthesized starting from readily available tigogenin. The synthetic strategy involved three key reactions: abnormal Baeyer-Villiger rearrangement of the spiroketal of tigogenin, xanthation of steroidal 16-hydroxyl-22-carboxylate dianion, and regioselective epoxide-opening lactonization.

Full text of DOI:10.1016/j.tetlet.2010.05.072

Tetrahedron Letters 51 (2010) 3890–3892
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Tetrahedron Letters
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A concise synthesis of the steroidal core of clathsterol
b,
Rigang Cong a, Yihua Zhang a, , Weisheng Tian
*
*
a Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The protected steroidal core of clathsterol, a marine natural product with remarkable inhibitory activity
against HIV-1 reverse transcriptase, was synthesized starting from readily available tigogenin. The syn-
thetic strategy involved three key reactions: abnormal Baeyer–Villiger rearrangement of the spiroketal
of tigogenin, xanthation of steroidal 16-hydroxyl-22-carboxylate dianion and regioselective epoxide-
opening lactonization.
Received 31 March 2010
Revised 14 May 2010
Accepted 18 May 2010
Available online 24 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
In 2001, Kashman and his co-workers isolated a novel sterol
sulfate, clathsterol (1, Scheme 1), from the Red Sea sponge Clathria
sp.1 It can inhibit human immunodeficiency virus type 1 (HIV-1)
only is cheap and readily available but also possesses the basic
skeleton and requisite functional groups for the synthesis of
clathsterol. Mesylation of 6 with MsCl afforded mesylate 7 in quan-
titative yield, which realized the protection of the C-3 hydroxy
group and the preparation of the precursor for constructing the
D2 double bond at the same time. Mesylate 7 was degradated
reverse transcriptase (RT) at a concentration of 10 lM. The basic
structure of clathsterol was established by spectral data and a
chemical transformation. However, the stereochemistry of C-22,
C-23 and C-24 in its side chain has not been assigned due to con-
formational lability.
Intrigued by its potent biological activity, low abundance and
unique structure, along with our perennial interest in the synthesis
of steroidal natural products,2 we first investigated the synthesis of
its steroidal core (2, Scheme 1) as a part of our project toward the
synthesis, structural determination and biological evaluation of
clathsterol. Target molecule 2 bears all functional groups of the ste-
roidal core of clathsterol with right configuration, and its 16,22-
lactone moiety could serve as the precursor for the construction
of the side chain.3
regioselectively to the corresponding 16,22-c-lactone 8 in 78%
yield by utilizing abnormal Baeyer–Villiger reaction of steroidal
sapogenins found by our group.5 Elimination of the C-3 mesyl
group of lactone 8 with lithium bromide in DMF at 120 °C provided
the desired
D-2 alkene 5 and its regioisomer D-3 alkene in 98%
combined yield in a ratio of 11.5:1 according to 1H NMR analysis.
A similar reaction result has been reported by Takatsuto and Ikek-
awa in 1986.6 The mixture of isomers was employed in the follow-
ing steps because they were inseparable. Treatment of alkene 5
with NaOH in aqueous MeOH gave the corresponding sodium salt
9 quantitatively.
Our retrosynthetic analysis of compound 2 is illustrated in
With compound 9 in hand, we set out to explore the prepara-
tion of 16-xanthate-22-acid 10. Compared with other alcohols,7
xanthation of the C-16 hydroxyl group of 9 proved to be much
harder due to the effect of its C-22 carboxy group. After repeated
try, however, we finally synthesized the desired 16-xanthate-22-
acid 10 in 51% yield (brsm 61%) and its 22-acid ester 10a as the
major by-product in 14% yield (brsm 16%) by increasing the reac-
tion temperature to 80 °C and adding excess reagents. Chugaev
syn-elimination of 10 at 160 °C in free solvent system provided
diene 4 in 95% yield. Compound 4 could also be prepared from
10a via pyrolysis followed by hydrolysis in 89% yield over two
steps. Epoxidation of diene 4 with m-CPBA in CH2Cl2 resulted in
the formation of diepoxide 11, which is unstable and can trans-
formed into lactone 3 and 3a partially when purified on silica gel
column chromatography. The attempts to convert diepoxide 11
into 3 by adding various acids such as PTSA, CSA and BF3ÁEt2O or
bases such as NaH, LiOH and LiOH/H2O2 were all unsuccessful.8
Scheme 1. The 2b,3a-dihydroxy group can be constructed by
acid-catalyzed ring opening of the corresponding epoxide
3
according to the Fürst–Plattner rule.4 Compound 3 in turn can be
synthesized from acid 4 via epoxidation and regioselective intra-
molecular epoxide-opening reaction. The D15 double bond of 4
would be formed regioselectively by Chugaev elimination of the
C-16 xanthate of 5. Compound 5 would be prepared from tigogenin
via regioselective degradation5 of the E/F rings followed by elimi-
nation of the C-3 hydroxyl group.
The synthesis of the target molecule 2 is described in Scheme 2.
Tigogenin is a best choice as the starting material because it not
* Corresponding authors. Tel.: +86 25 83271015; fax: +86 25 86635503 (Y.Z.);
tel./fax: +86 21 54925176 (W.T.).
E-mail addresses: zyhtgd@sohu.com (Y. Zhang), wstian@mail.sioc.ac.cn (W.
Tian).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.072

R. Cong et al. / Tetrahedron Letters 51 (2010) 3890–3892
3891
OR
23
O
O
22
24
OR
16 OH
O
O
2
3
NaO3SO
NaO3SO
TESO
15
O
OAc
R=COCH2CH2CH3
OBn
OH
TESO
clathsterol (1)
2
3
O
O
O
OH
O
O
HO
tigogenin (6)
5
4
Scheme 1. Retrosynthetic analysis of the steroidal core of clathsterol.
O
O
O
MsCl, DMAP,
py, CH 2Cl2, rt
quant
CH3COOOH, H2SO4,
I2, CH3COOH, rt
LiBr, DMF,
120 °C
98%
O
O
O
6
78%
MsO
MsO
7
8
5
NaOH,
MeOH-H2O, rt
1) 160 °C, 95%; 2) NaOH, MeOH-THF-H2O, reflux, 94%
quant
CO2H
CO2Na
CO2Et
OCS2Et
CO2H
OCS2Et
NaH, CS2, EtI,
THF, reflux
OH
160 °C
95%
+
10
10a
4
9
51% (brsm 61%)
14% (brsm 16%)
m-CPBA,
CH2Cl2, rt
O
O
O
O
CO2H
silica gel,
rt
+
O
O
O
O
OH
3
11
3a
(47%, 2 steps)
(34%, 2 steps)
BnBr, NaH, TBAI,
THF, rt
89%
O
O
H2SO4,
O
TESCl, imidazole,
DMF, rt
O
THF-H2O, reflux
2
HO
HO
quant
76%
O
OBn
OBn
13
12
Scheme 2. Synthesis of compound 2.
The reaction system became quite complex when these acids were
used, while no reaction occurred under basic conditions. Finally,
this problem was solved by adsorbing crude 11 on excess silica
gel (w/w = 1/10) at room temperature for two days to furnish the
coupling constant between 15-H and 14-H in 3 is 10.5 Hz, which
shows the 15-H should be in b position. Through further observa-
tion, it was found that the ratio of 3 and 3a was not related to the
reaction time. These facts suggest us that 11 is a mixture of
desired lactone 3 in 47% yield over two steps along with
kene 3a as a serious side product in 34% yield over two steps.
The configuration of the 2,3-epoxide was assigned due to the
D
-14 al-
15a,16a
- and 15b,16b-epoxide.10 Compound 3a is considered to
be generated from 15b,16b-epoxide and could also be used to syn-
thesize the target molecule 2.11 Benzyl protection of the C-15 hy-
droxy group of lactone 3 took place readily in the presence of
tetrabutylammonium iodide (TBAI) to afford ether 12 in 89% yield.
a
presence of the C-19 angular methyl group which blocks the b-face
of the A ring when the D2 double bond of 4 was epoxidized.9 The

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R. Cong et al. / Tetrahedron Letters 51 (2010) 3890–3892
Treatment of 12 with sulfuric acid in aqueous THF at reflux for one
References and notes
hour provided the desired 2b,3a
-diol 13 exclusively12 according to
the Fürst–Plattner rule. The 1H NMR signals of 2-H and 3-H in 13
(broad singlet at 3.88 ppm and broad singlet at 3.84 ppm) also con-
firm that C-2 hydroxy group and C-3 hydroxy group are situated in
the axial positions. Protection of the resulting hydroxy groups as
the triethylsilyl (TES) ethers finished the synthesis of 2.
In summary, the protected steroidal core of clathsterol 2 has
been synthesized in 12% overall yield over 11 steps starting from
tigogenin. This concise synthesis involves the following three key
points: (1) applying abnormal Baeyer–Villiger rearrangement of
steroidal sapogenin to the synthesis of the steroidal core of claths-
terol for the first time; (2) successful preparation of the C-16 xan-
thate of steroidal 16-hydroxyl-22-carboxylate dianion and
successive regioselective construction of its D15 double bond
through Chugaev elimination; and (3) regioselective intramolecu-
lar epoxide-opening lactonization catalyzed by silica gel. It is also
noteworthy to mention here that all the newly-built stereocenters
of 2 were constructed skillfully relying on substrate control with-
out using any chiral catalysts in this synthesis.
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Supplementary data
11. For two examples of using steroidal
D-14 double bond to introduce the
Supplementary data (experimental procedures, analytical data,
and copies of 1H and 13C NMR spectra for all new compounds)
associated with this article can be found, in the online version, at
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a
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