Stereoselective synthesis of Certonardolsterol D3

Article abstract of DOI:10.1016/j.tet.2008.07.091

The first stereoselective synthesis of Certonardolsterol D₃ was described. Ene reaction and improved allylic oxidation were employed as key steps for efficient construction of the desired 3β,6α,15β-triol steroidal framework. The chiral side cha

Full text of DOI:10.1016/j.tet.2008.07.091

Tetrahedron 64 (2008) 9738–9744
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of Certonardolsterol D3
*
Biao Jiang , He-ping Shi, Min Xu, Wan-jun Wang, Wei-shan Zhou
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fengling Road, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 May 2008
Received in revised form 21 July 2008
Accepted 22 July 2008
Available online 26 July 2008
The first stereoselective synthesis of Certonardolsterol D3 was described. Ene reaction and improved
allylic oxidation were employed as key steps for efficient construction of the desired 3b,6a,15b-triol
steroidal framework. The chiral side chain in Certonardolsterol D3 was finally introduced by Julia
olefination.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Polyhydroxysterol
Certonardolsterol
Ene reaction
Julia olefination
1. Introduction
Certonardolsterol D3 2, a member of the novel certonardol-
sterols, was isolated as colorless needles and was defined as (24R)
In recent years, the discovery of interesting polyhydroxy ste-
roids, mainly isolated from marine sources, has gained considerable
attention.1 These compounds have shown promising pharmaceu-
tical activities as leading agents for the development of novel
therapeutics.2 Starfish appears to be the richest source of poly-
hydroxy steroids. Almost 44 polyhydroxysterols were isolated from
starfish Certonardoa semiregularis collected from Korean waters,
which showed remarkably stronger cytotoxicity than those sapo-
nins in it.3 The vast majority of them bears hydroxyl group mainly
24-ethyl-5R-cholestane-3b,6a,15b
,242-tetrol.3 Its toxicity was
briefly studied for its minute amounts in appearance (1.3 mg/9 kg).
A small panel of human solid tumor cell lines were selected for the
test of the toxicity and the performance of certonadosterol D3
(ED50¼0.68–2.48
mg/mL) was noticeable. In our continuing in-
terest in biological activity studies of marine natural products, we
endeavoured to develop efficient methodology for synthesizing
this class of sterols. Herein, we reported an efficient method for
stereocontrolled synthesis of C22 steroidal aldehyde
6 from
in positions 3
b
, 4
a
(or 4
b
), 6
a
(or 6
b
), 15
a
(or 15
b
), and 16
a
, and
common source of C17 steroid dehydroepiandrosterone (5), which
was subsequently converted into Certonardolsterol D3 stereo-
selectively in high yield.
hydroxyl methyl or hydroxyl ethyl group in the position of C-24 or
C-25 of side chain, for example, Certonardolsterol D2 (1) and Cer-
tonardolsterol D3 (2). These highly oxygenated steroids often occur
as complex mixtures that are very difficult to separate into in-
dividual components with limited amounts. The purpose of bi-
ological activity investigation has stimulated the request for
a universal methodology for the stereoselective synthesis of the
class of polyhydroxy steroids practically. In our previous report, we
accomplished the first synthesis of Certonardolsterol D2 (1) from
the natural diosgenin (3)4 via the C22-steroid, 23,24-bisnorcholanic
lactone 4, which was derived from sapogenins with peroxyacetic
acid in the presence of catalytic concentration of H2SO4 and iodine.5
The side chain was facilely stereoselective installed via Julia olefi-
nation with a chiral alkyl sulfone (Fig. 1).
2. Results and discussion
Taking into account the report of an efficient stereocontrolled
access to 15- and 16-hydroxy steroids by Riccardis et al.,6 we
designed a novel synthesis pathway of 3b,6a,15b-triol steroidal
aldehyde 6 as outlined in Scheme 1. Commercially available
dehydroepiandrosterone 5 was first protected with ethylene glycol
in 94% yield.
(BH3$THF, 0 ꢀC) and oxidation (30% H2O2, 0 ꢀC) of B-ring double
bond to afford 3 ,6 -diol 7 in 75% yield. After releasing the pro-
6a-Hydroxyl was formed by hydroboration
b
a
tecting group of the C-17 ketone with concentrated hydrochloride
in methanol, the resulted crude 3,6-diol was masked as silyl ether
with (t-Bu)Me2SiOTf/2,6-lutidine in dichloromethane to give the
C-17 ketone 9 in 79% yield for two steps. The C-17 ketone 9
was then converted to Z olefin with trace of its E isomer
* Corresponding author.
E-mail address: jiangb@mail.sioc.ac.cn (B. Jiang).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.091

B. Jiang et al. / Tetrahedron 64 (2008) 9738–9744
9739
OH
OH
24
17
15
OH
OH
6
3
HO
HO
OH
Certonardolsterol D3 (2)
OH
Certonardolsterol D2 (1)
O
O
O
Oxidation
O
HO
HO
OH
Diosgenin (3)
23,24-bisnorcholanic lactone 4
C22-Steroid
O
O
OR
RO
HO
OR
(+)-dehydroepiandrosterone (5)
C22-triol steroidal aldehyde 6
C17-Steroid
Figure 1. Certonardolsterol D2, Certonardolsterol D3 and conversion of steroids.
(<5%) by Wittig reaction. C-17 ketone
9
was heated with
conversion of the free hydroxyl in 23 into its benzyl ether (BnBr/
NaH) and removal of the silyl protection group with hydrogen
chloride in methanol gave the (R)-alcohol 24 with 85% yield.
(R)-Alcohol 24 was subjected to a Mitsunobu reaction using
2-mercaptobenzothiazole as nucleophile affording high yield of
(2R)-butyl sulphide 25. Oxidation under hydrogen peroxide and
ammonium molybdate tetrahydrate at 0 ꢀC provided (R)-butyl
sulphone 26 in 84% yield.
(ethyl)triphenylphosphonium bromide and t-BuOK in dry THF to
afford compound 10 in 92% yield. An ene reaction of 10 with
paraformaldehyde in the presence of a catalytic amount of bor-
ontrifluoride etherate was performed to afford the alcohol 11
stereospecifically in 76% yield, which was subsequently protected
as its acetate 12. By using an improved allylic oxidation,7 C-15
ketone group in steroidal frame was introduced by oxidation of 12
with N-hydroxy phthalimide and Na2Cr2O7$2H2O in acetone at
With the C22 3b,6a,15b-triol steroidal aldehyde 6 steroid frame
40 ꢀC to afford
nation of 13 over 20% Pd/C and subsequent reduction by NaBH4
afforded the desired 15
-hydroxyl steroid 15 in 94% yield. 1H NMR
a,
b-unsaturated ketone 13 in 74% yield. Hydroge-
and C7 (R)-butyl sulphone 26 in hand, their assembling to obtain
Certonardolsterol D3 was accomplished by Julia olefination. A Julia
olefination between aldehyde 6 and (R)-butyl sulphone 26 was
performed with the LiHMDS at ꢁ78 ꢀC, which provided 22E-olefin
27 exclusively in 93% yield (Scheme 4). 22E-Olefin 27 contained all
structure features of Certonardolsterol D3. Simultaneous satura-
tion of C-22-E double bond and cleavage of the benzyl ether gave
sterol 28 in excellent yield when hydrogenation of 27 over
Pd(OH)2 in ethanol. Finally, deprotection of the three hydroxyls in
the sterol nucleus with 6 M HCl completed the synthesis of
Certonardolsterol D3 in 99% for two steps. The spectroscopic data
was in agreement with the published values for natural Certo-
nardolsterol D3.3
b
spectra shows a triplet (J¼6.0 Hz) at 4.22 ppm for the 15-hydroxyl
C–H in 15, which implies 15-hydroxyl group has the expected
b
-configuration.4,6 After masking 15
b
hydroxyl with methoxy-
methyl chloride and hydrolysis of the C-22 acetyl, C17
,6 ,15 -triol steroidal aldehyde 6 was obtained in 99% yield by
3
b
a
b
Dess–Martin oxidation.
In parallel, a nine-step route was launched to construct the
chiral piece of steroidal side chain (Scheme 3). Initially, we tried
to introduce the hydroxyl ethyl group by reaction of oxirane with
titanium enolate derived from (R)-oxazolidinone 18 with TiCl4 in
the presence of Hunig’s base.8 The reaction gave fruitless results
without the isolation of 19 (Scheme 2). Switching into alkylation
of the lithium enolate (LDA, ꢁ78 ꢀC) with tert-butylbromoacetate
afforded (2R0,R)-20 in 93% yield. Removal of oxazolidinone aux-
iliary with LiOH in the presence of 30% H2O2 gave (2R)-acid ester
21 in 87% yield. The acid moiety of 21 was selectively reduced
with BH3$Me2S in THF at room temperature for 24 h to afford
alcohol 22 quantitatively. After protection of the hydroxyl group
with (t-Bu)Me2SiOTf/2,6-lutidine, the ester part was converted
into alcohol by reduction with DIBAL-H at ꢁ78 ꢀC for 1 h to give
(R)-alcohol 23 in 91% yield for two steps. Subsequently,
3. Conclusion
In summary, an efficient and highly stereoselective convergent
synthesis of Certonardolsterol D3 has been achieved from com-
mercially available (þ)-dehydroepiandrosterone 5. The combina-
tion of an ene reaction and improved allylic oxidation was proved to
be efficient to construct the C15 functional group in sterol skeleton.
The highly selective Julia olefination was used to couple the chiral
side chain for steroid.

9740
B. Jiang et al. / Tetrahedron 64 (2008) 9738–9744
O
O
O
O
O
O
(c)
(b)
(d)
(a)
TBSO
HO
HO
OTBS
HO
OH
8
(+)-Dehydroepiandrosterone 5
7
9
OR
(g)
OAc
(h)
OAc
(i)
(e)
O
O
TBSO
TBSO
TBSO
TBSO
OTBS
OTBS
OTBS
OTBS
14
11: R=H;
(f)
13
10
12: R=Ac
O
OH
OAc
(k)
OAc
(j)
(l)
TBSO
OMOM
OMOM
OMOM
TBSO
OH
TBSO
TBSO
OTBS
OTBS
17
OTBS
OTBS
15
16
6
Scheme 1. Synthesis of 3b,6a,15b
-triol C-22 steroidal aldehyde 6; (a) ethylene glycol, p-TsOH, benzene, reflux, 94%; (b) (i) BH3$THF, THF, 0 ꢀC to rt; (ii) 10 M NaOH, 30% H2O2, 0 ꢀC to
rt, 74%; (c) (i) HCl/MeOH, reflux; (ii) TBSOTf, 2,6-lutidine, CH2Cl2, rt, 94% for two steps; (d) Ph3PEtBr, t-BuOK, THF, reflux, 92%; (e) BF3$Et2O, (HCHO)n, CH2Cl2, 0 ꢀC, 77%; (f) Ac2O, cat.
DMAP, CH2Cl2, rt, 97%; (g) N-hydroxy phthalimide, NaCr2O7$2H2O, acetone, 40 ꢀC, 49% (74% based on recovery of 12); (h) 10% Pd/C, H2, EtOAc, rt, 99%; (i) NaBH4, THF/MeOH, 0 ꢀC,
94%; (j) MOMCl, DIPEA, CH2Cl2, rt to reflux, 94%; (k) 10% KOH, MeOH, 0 ꢀC to rt, 99%; (l) Dess–Martin periodinane, Py, CH2Cl2, 0 ꢀC to rt, 99%.
4. Experimental section
4.1. General remarks
CDCl3):
d 140.7, 121.4, 119.5, 71.6, 65.1, 64.5, 50.5, 49.9, 45.7, 42.2,
37.2, 36.5, 34.1, 32.1, 31.5, 31.2, 30.5, 22.7, 20.4, 19.4, 14.2.
4.1.2. 17,17-Ethylenedioxy-5a-androstan-3b,6a-diol (8)
1H NMR and 13C NMR spectra were recorded at 300 and
500 MHz using a Varian EM-360A spectrometer with TMS as the
internal standard. Chemical shift (d) values were given in parts per
million. MS were recorded with HP-5989A spectrometer using the
ESI method. The melting points were determined on an SGW X-4
melting point apparatus and were uncorrected. Optical rotations
were obtained with Perkin–Elmer Polarimeter 341 apparatus.
To a solution of compound 7 (2.3 g, 6.9 mmol) in dry THF
(30 mL) under an argon atmosphere at 0 ꢀC, was added BH3
(21.0 mL, 21.0 mmol, 1 M in THF) slowly. The mixture was allowed
to stir for 6 h at room temperature. NaOH (10 N, 5.0 mL, 50.0 mmol)
was added over 30 min at 0 ꢀC. Subsequently, 30% hydrogen per-
oxide (5.0 mL, 44.0 mmol) was added and vigorous stirring con-
tinued at room temperature for 2 h. The reaction mixture was
poured into ice water and filtered to give the crude product. Puri-
fication by column chromatography (CH2Cl2/MeOH, 10:1) gave
compound 8 (1.8 g, 74%) as a white solid. IR (KBr): 3333, 2934, 1049,
4.1.1. 17,17-Ethylenedioxy-androst-5-en-3
To
solution of (þ)-dehydroepiandrosterone
b
-ol (7)9
a
5
(5.0 g,
17.3 mmol) and p-TsOH$H2O (132 mg, 0.69 mmol) in benzene
(50 mL), ethylene glycol (5.0 mL, 90 mmol) was added dropwise.
The mixture was refluxed under a Dean–Stark trap for 5 h. The
reaction mixture was then cooled to room temperature, diluted
with EtOAc (50 mL), washed with saturated NaHCO3 solution
(30 mLꢂ3) and brine (25 mLꢂ3). The organic phase was dried over
anhydrous Na2SO4, filtered and concentrated. Flash chromatogra-
phy (hexane/EtOAc, 3:1) provided 7 (5.4 g, 94%) as a white solid. 1H
1037 cmꢁ1; 1H NMR (300 MHz, CD3OD):
d 3.83–3.74 (m, 4H), 3.44–
3.34 (m, 1H), 3.28–3.26 (m, 1H), 2.11–2.07 (m, 1H), 1.91–1.83 (m,
2H), 0.75 (s, 3H), 0.74 (s, 3H), 0.60–0.58 (m, 1H); 13C NMR (75 MHz,
CD3OD):
d 120.5, 72.0, 70.0, 66.2, 65.6, 553, 52.9, 51.5, 47.2, 42.0,
38.7, 37.5, 36.0, 35.1, 33.0, 31.9, 31.8, 23.7, 21.7, 14.9, 13.9; ESI-MS:
351.2 (MþHþ); HRMS calcd for C21H35Oþ4 :351.2530; found:
351.2530.
NMR (300 MHz, CDCl3):
d
5.36–5.34 (m, 1H), 3.95–3.84 (m, 4H),
4.1.3. 3
17-one (9)
b,6a-Bis[(tert-butyldimethylsilyl)oxy]-5a-andostan-
3.49–3.54 (m, 1H), 1.01 (s, 3H), 0.86 (s, 3H); 13C NMR (75 MHz,
HCl (20 mL, 36%) was added dropwise to a solution of com-
pound 8 (500 mg, 1.43 mmol) in MeOH (50 mL). The mixture was
refluxed for 4 h and cooled to room temperature. The solution was
concentrated to give the crude product, which was used for the
next step without further purification. To a solution of crude
product in CH2Cl2 (10 mL), 2,6-lutidine (1.7 mL, 14.7 mmol) and
TBSOTf (2.1 mL, 9.2 mmol) were added sequentially. The solution
was stirred for 30 min at room temperature and was then
quenched by water. The aqueous layer was extracted with CH2Cl2
TiCl4, DIPEA,
CH2Cl2, 0°C
O
O
O
O
O
N
O
N
O
Bn
19
Bn
18
OH
Scheme 2. Synthetic attempt for compound 19.

B. Jiang et al. / Tetrahedron 64 (2008) 9738–9744
9741
O
O
O
O
O
(c)
(d)
(b)
(a)
(e)
HO
O
N
O
N
HO
O
O
O
Bn
20
Bn
18
t
t
t
O Bu
O Bu
O Bu
21
22
O
S
O
S
N
S
(g)
(f)
TBSO
HO
S
N
OH
OBn
OBn
OBn
23
24
25
26
Scheme 3. Synthesis of (R)-butyl sulfone 26; (a) LDA, BrCH2CO2t-Bu, THF, ꢁ78 ꢀC to rt, 93%; (b) LiOH, H2O2, THF/H2O, 0 ꢀC, 87%; (c) BH3.Me2S, THF, 0 ꢀC to rt, 99%; (d) (i) TBSOTf, 2,6-
lutidine, CH2Cl2, 0 ꢀC to rt; (ii) DIBAL-H, CH2Cl2, ꢁ78 ꢀC, 91% for two steps; (e) (i) NaH, BnBr, cat. TBAI, THF, rt to reflux; (ii) 3.3 M HCl, THF/H2O, rt, 84% for two steps; (f) 2-
mercaptobenzothiazole, PPh3, DIAD, THF, 0 ꢀC, 92%; (h) (NH4)6Mo7O24$4H2O, H2O2, EtOH, 0 ꢀC, 83%.
(10 mLꢂ2).The combined organic extracts were dried over anhy-
drous Na2SO4, filtered and concentrated. Flash chromatography
(hexane/EtOAc, 20:1) afforded ketone 9 (718 mg, 94%) as a white
a solution of BF3$Et2O (23 mL, 0.027 mmol) in CH2Cl2 (10 mL) slowly
by syringe under argon at 0 ꢀC. The reaction mixture was allowed to
stir at the same temperature for 25 min. The reaction was then
quenched by ice water, diluted by CH2Cl2 (10 mL) and filtered. The
filtrate was washed with brine (10 mLꢂ2), dried over anhydrous
Na2SO4, filtered and concentrated. Flash chromatography (hexane/
EtOAc, 15:1) afforded alcohol 11 (80 mg, 77%) as a white solid. Mp
solid. Mp 115–116 ꢀC. [
1084, 836 cmꢁ1 1H NMR (300 MHz, CDCl3):
3.39–3.37 (m,1H), 2.43 (dd,1H, J¼18.6, 9.0 Hz), 0.87 (s,18H), 0.84 (s,
3H), 0.82 (s, 3H), 0.03 (s, 12H); 13C NMR (75 MHz, CDCl3):
221.0,
a]
D
20 74.7 (c 1.00, CHCl3); IR (KBr): 2956, 1742,
;
d 3.51–3.48 (m, 1H),
d
72.1, 69.9, 53.9, 51.7, 51.1, 47.8, 40.6, 37.5, 36.3, 35.7, 33.8, 33.1, 31.6,
31.4, 25.88, 25.86, 21.7, 20.3, 18.3, 18.0, 13.8, 13.5, ꢁ4.1, ꢁ4.7, ꢁ4.8;
EIMS: 519 (MþꢁMe), 477 (Mþꢁt-Bu); HRMS (MALD) calcd for
60–61 ꢀC; [ 20 18.7 (c 0.50, CHCl3); IR (KBr): 2931, 1253, 1089, 836,
a]
773, 668 cmꢁD1; 1H NMR (300 MHz, CDCl3):
d 5.42 (s, 1H), 3.58–3.50
(m, 3H), 3.40 (dt, 1H, J¼10.2, 4.2 Hz), 2.37 (q, 1H, J¼7.2 Hz), 1.02 (d,
C
31H58O3Si2Naþ: 557.3840; found: 557.3817.
3H, J¼6.9 Hz), 0.88 (s, 9H), 0.87 (s, 9H), 0.83 (s, 3H), 0.77 (s, 3H),
0.04 (s, 12H); 13C NMR (75 MHz, CDCl3):
d 157.5, 122.8, 72.2, 70.2,
4.1.4. (17Z)-Ethylidene-3
-andostane (10)
mixture of ketone
triphenylphosphonium bromide (1.5 g, 4.0 mmol) and t-BuOK
(0.42 g, 3.75 mmol) in dry THF (11 mL) was allowed to reflux under
argon for 4 h. After being cooled, the mixture was diluted with
petroleum ether (20 mL) and filtered. The filtrate was concentrated
and purified by flash chromatography (hexane/EtOAc, 100:1) to
b
,6
a
-bis[(tert-butyldimethylsilyl)oxy]-
66.5, 56.9, 54.4, 52.0, 47.1, 41.7, 37.4, 36.4, 35.3, 34.7, 33.2, 32.9, 31.7,
31.1, 25.9, 21.0, 18.3, 18.1, 16.3, 13.5, ꢁ4.0, ꢁ4.6, ꢁ4.7; EIMS: 561
(MþꢁMe), 519 (Mþꢁt-Bu), 489 (Mþꢁt-Buꢁ2Me); HRMS calcd for
5
a
A
9
(0.71 g, 1.33 mmol), (ethyl)-
C
33H61O3Siþ2 : 561.4159; found: 561.4166.
4.1.6. 3
b,6a-Bis[(tert-butyldimethylsilyl)oxy]-5a-23,24-bisnorchol-
16-en-22-acetate (12)
To a solution of alcohol 11 (1.94 g, 3.36 mmol) and DMAP
(40 mg, 0.33 mmol) in dry CH2Cl2 (110 mL) were added freshly
distilled triethylamine (0.97 mL, 6.96 mmol) and Ac2O (0.65 mL,
7.58 mmol) sequentially by syringe. The solution was stirred for
1.5 h at room temperature and quenched by saturated ammonium
chloride (20 mL). The aqueous layer was extracted with CH2Cl2
(20 mLꢂ2). The combined organic extracts were washed with sat-
urated NaHCO3 (30 mLꢂ2), brine (30 mLꢂ2), dried over anhydrous
Na2SO4, filtered and concentrated. Flash chromatography (hexane/
afford 10 (0.67 g, 92%) as a colorless oil. [
a]
20 37.7 (c 0.95, CHCl3); IR
D
(KBr): 2962,1261,1088,1062, 801 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
5.11 (q, 1H, J¼7.5 Hz), 3.56–3.46 (m, 1H), 3.38 (dt, 1H, J¼10.2,
4.5 Hz), 2.37 (dd, 1H, J¼16.8, 7.2 Hz), 1.89 (td, 1H, J¼12.6, 3.9 Hz),
1.64 (d, 3H, J¼6.9 Hz), 0.88 (s, 18H), 0.86 (s, 3H), 0.81 (s, 3H), 0.05 (s,
6H), 0.03 (s, 6H); 13C NMR (75 MHz, CDCl3):
d 150.2, 113.4, 72.3,
70.3, 55.9, 53.8, 51.7, 44.3, 41.8, 37.6, 37.0, 36.3, 33.8, 33.2, 31.7, 31.3,
25.9, 24.3, 21.3, 18.3, 18.1, 16.9, 13.5, 13.1, ꢁ4.1, ꢁ4.6, ꢁ4.7, ꢁ4.8;
EIMS: 531 (MþꢁMe), 489 (Mþꢁt-Bu); HRMS calcd for C33H62O2Siþ2 :
546.4288; found: 546.4286.
EtOAc, 10:1) afforded 12 (2.02 g, 97%) as a white solid. Mp 103–
20
104 ꢀC; [
a
]
34.7 (c 1.00, CHCl3). IR (KBr): 2931, 1737, 1228, 1091,
D
835, 773 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d 5.38 (s, 1H), 4.13–4.08
4.1.5. 3
16-en-22-ol (11)
To suspension of 10 (100 mg, 0.18 mmol) and para-
b
,6
a
-Bis[(tert-butyldimethylsilyl)oxy]-5
a
-23,24-bisnorchol-
(m, 1H), 3.95–3.89 (m, 1H), 3.53–3.48 (m, 1H), 3.40 (dt, 1H, J¼10.2,
4.2 Hz), 2.43 (q, 1H, J¼6.9 Hz), 2.03 (s, 3H), 1.04 (d, 3H, J¼7.2 Hz),
0.88 (s, 18H), 0.82 (s, 3H), 0.74 (s, 3H), 0.040 (s, 6H), 0.037 (s, 6H);
a
formaldehyde (0.032 g, 0.9 mmol) in dry CH2Cl2 (10 mL) was added
13C NMR (75 MHz, CDCl3):
d 171.2,156.9,122.5, 72.3, 70.2, 68.6, 56.6,
OH
OBn
(b)
(c)
(a)
Certonardolsterol D3
6
OMOM
OMOM
TBSO
TBSO
OTBS
OTBS
28
27
Scheme 4. Synthesis of Certonardolsterol D3; (a) 26, LiHMDS (1.0 M in hexane), THF, ꢁ78 ꢀC to rt, 93%; (b) Pd(OH)2, H2, EtOH/EtOAc, rt; (c) 6 M HCl, THF/H2O, rt, 99% for two steps.

9742
B. Jiang et al. / Tetrahedron 64 (2008) 9738–9744
54.4, 52.0, 47.2, 41.7, 37.4, 36.4, 34.7, 33.2, 32.9, 31.7, 31.4, 31.1, 25.9,
21.0, 20.9, 18.7, 18.3, 18.1, 16.2, 13.5, ꢁ4.1, ꢁ4.6, ꢁ4.7; EIMS: 561
(Mþꢁt-Bu), 501 (Mþꢁ2t-Bu); HRMS calcd for C32H57O4Siþ2 :
561.3795; found: 561.3796.
31.7, 30.2, 25.9, 25.8, 21.0, 18.3, 18.0, 17.2, 14.6, 13.4, ꢁ4.1, ꢁ4.6, ꢁ4.7,
ꢁ4.8; ESI-MS: 659.2 (MþNaþ); HRMS calcd for C36H68O5Si2Naþ:
659.4504; found: 659.4498.
4.1.10. 22-Acetoxy-3b,6a-bis[(tert-butyldimethylsilyl)oxy]-15b-
4.1.7. 22-Acetoxy-3
b,6
a
-bis[(tert-butyldimethylsilyl)oxy]-5
a-
methoxymethyl-5 -23,24-bisnorcholane (16)
a
23,24-bisnorchol-16-ene-15-one (13)
To a solution of 15 (50 mg, 0.08 mmol) and N,N-diisopropyl-
A mixture of 12 (30 mg, 0.048 mmol), N-hydroxy phthalimide
(32 mg, 0.20 mmol) and Na2Cr2O7$2H2O (30 mg, 0.10 mmol) in
freshly distilled acetone (1.5 mL) was stirred at 40 ꢀC for 3 h. Ad-
ditional N-hydroxy phthalimide (32 mg, 0.20 mmol) and
Na2Cr2O7$2H2O (30 mg, 0.10 mmol) were added and the reaction
mixture was allowed to keep overnight at the same temperature.
Saturated sodium sulfite (2 mL) was added to remove the oxidant.
After the reaction mixture was filtered, the filtrate was extracted
with EtOAc (15 mLꢂ2). The combined organic extracts were
washed with brine (20 mLꢂ2), dried over anhydrous Na2SO4, fil-
tered and concentrated. The crude product was purified by flash
ethylamine (0.15 mL, 0.86 mmol) in freshly distilled CH2Cl2 (7 mL),
MOMCl (45 mL) was added slowly by syringe. The solution was
allowed to reflux overnight. After being cooled to room tempera-
ture, the reaction was quenched by water. The aqueous layer was
extracted with CH2Cl2 (10 mLꢂ2). The combined organic extracts
were washed with 0.1 M HCl (5 mLꢂ2), saturated NaHCO3
(8 mLꢂ2) and brine (10 mLꢂ3), dried over anhydrous Na2SO4, fil-
tered and concentrated in vacuo. Flash chromatography (hexane/
EtOAc, 20:1) afforded 16 (50 mg, 94%) as a colorless oil. [
a]
20 16.2 (c
D
4.2, CHCl3); IR (KBr): 2856, 1743, 1249, 1083, 836, 774 cmꢁ1
;
1H
NMR (300 MHz, CDCl3): 4.61, 4.53 (AB, 2H, JAB¼6.3 Hz), 4.04 (dd,
1H, J¼10.8, 3.3 Hz), 3.87 (t, 1H, J¼6.0 Hz), 3.77 (dd, 1H, J¼10.5,
7.5 Hz), 3.51–3.47 (m, 1H), 3.42–3.38 (m, 1H), 3.34 (s, 3H), 2.31–2.27
(m,1H), 2.03 (s, 3H),1.00 (d, 3H, J¼6.6 Hz), 0.89 (s, 3H), 0.86 (s,18H),
0.82 (s, 3H), 0.02 (s, 6H), 0.01 (s, 3H), ꢁ0.004 (s, 3H); 13C NMR
chromatography (hexane/EtOAc, 8:1) afforded 13 (15 mg, 74%,
20
10 mg of 12 was recovered) as a light yellow oil. [
a
]
22.7 (c 1.60,
D
CHCl3); IR (KBr): 2930, 1743, 1712, 1471, 1097, 836, 775 cmꢁ1
;
1H
NMR (300 MHz, CDCl3): 5.66 (s, 1H), 4.15–4.04 (m, 2H), 3.53–3.49
d
(m, 1H), 3.46–3.42 (m, 1H), 2.97–2.93 (m, 1H), 2.79 (q, 1H, J¼7.2 Hz),
(75 MHz, CDCl3): d 171.3, 97.5, 78.0, 72.2, 70.1, 69.3, 60.1, 55.9, 54.1,
0.99 (s, 3H), 0.89 (s, 9H), 0.87 (s, 9H), 0.85 (s, 3H), 0.06 (s, 6H), 0.04
52.9, 51.8, 42.6, 41.0, 40.7, 38.4, 37.6, 36.3, 35.4, 33.1, 31.7, 30.4,
25.89, 25.88, 20.94, 20.92, 18.3, 18.1, 17.2, 14.2, 13.5, ꢁ4.2, ꢁ4.66,
ꢁ4.75, ꢁ4.8; ESI-MS: 703.3 (MþNaþ); HRMS calcd for
(s, 6H); 13C NMR (75 MHz, CDCl3):
d 206.7, 183.3, 170.8, 125.6, 72.0,
69.7, 67.0, 63.3, 54.3, 51.9, 46.9, 39.8, 37.3, 36.3, 33.0, 32.3, 32.2, 31.6,
30.9, 25.92, 25.88, 23.4, 20.8, 18.3, 18.1, 17.8, 13.5, ꢁ4.0, ꢁ4.68.
ꢁ4.75, ꢁ4.8; ESI-MS: 575 (Mþꢁt-Bu), 515 (Mþꢁ4Me); HRMS calcd
for C32H55O5Siþ2 : 575.3588; found: 575.3583.
C
38H72O6Si2Naþ: 703.4752; found: 703.4760.
4.1.11. 3
b,6a-Bis[(tert-butyldimethylsilyl)oxy]-15b-methoxy-
methyl-5
a
-23,24-bisnorcholan-22-ol (17)
4.1.8. 22-Acetoxy-3
23,24-bisnorcholan-15-one (14)
b
,6
a
-bis[(tert-butyldimethylsilyl)oxy]-5
a
-
Compound 16 (84 mg, 0.12 mmol) in MeOH (13 mL) was treated
with KOH solution (4.8 mL, 10 wt % in MeOH) under ice-salt bath.
The reaction mixture was warmed to room temperature and stirred
for 1 h. The solution was diluted with EtOAc, acidified with 0.3 M
HCl (3 mLꢂ2), washed with saturated NaHCO3 (5 mLꢂ2) and brine
(10 mLꢂ3), dried over anhydrous Na2SO4, filtered and concentrated
in vacuo. Flash chromatography (hexane/EtOAc, 10:1 to 4:1) affor-
Ketone 13 (64 mg, 0.1 mmol) in EtOAc (2.5 mL) was hydroge-
nated over 10 wt % Pd/C (8 mg) for 2 days. After the reaction mix-
ture was diluted by EtOAc (10 mL), the catalyst was removed by
filtration through Celite. The filtrate was concentrated. Flash
chromatography (hexane/EtOAc, 8:1) afforded 14 (64 mg, 99%) as
a white solid. Mp 72–73 ꢀC; [
a
]
20 27.9 (c 1.00, CHCl3); IR (KBr): 2955,
ded 17 (78 mg, 99%) as a white solid. Mp 123–124 ꢀC; [
a]
20 12.5 (c
D
D
1743, 1251, 1082, 836, 774 cmꢁ1
;
1H NMR (300 MHz, CDCl3): 4.01
2.85, CHCl3); IR (KBr): 2932, 1251, 1093, 836, 776 cmꢁ1
;
1H NMR
(dd, 1H, J¼10.8, 3.3 Hz), 3.81 (dd, 1H, J¼10.8, 6.6 Hz), 3.53–3.46 (m,
1H), 3.39 (dt, 1H, J¼9.6, 4.2 Hz), 2.92–2.88 (m, 1H), 2.42 (dd, 1H,
J¼18.3, 8.4 Hz), 2.10–2.08 (m, 2H), 2.05 (s, 3H), 1.08 (d, 3H,
J¼6.6 Hz), 0.873 (s, 9H), 0.866 (s, 9H), 0.79 (s, 3H), 0.74 (s, 3H), 0.07
(300 MHz, CDCl3): 4.62, 4.54 (AB, 2H, JAB¼6.3 Hz), 3.87 (t, 1H,
J¼6.0 Hz), 3.64–3.61 (m, 1H), 3.53–3.46 (m, 1H), 3.43–3.39 (m, 2H),
3.35 (s, 3H), 2.36–2.26 (m, 1H), 1.03 (d, 3H, J¼5.7 Hz), 0.90 (s, 3H),
0.87 (s, 18H), 0.82 (s, 3H), 0.03 (s, 6H), 0.01 (s, 3H), ꢁ0.001 (s, 3H);
(s, 3H), 0.04 (s, 3H), 0.03 (s, 6H); 13C NMR (75 MHz, CDCl3):
d
214.44,
13C NMR (75 MHz, CDCl3):
d 97.6, 78.3, 72.3, 70.1, 67.7, 60.2, 55.9,
171.2, 72.1, 69.7, 68.9, 65.0, 53.3, 51.7, 48.1, 42.2, 41.1, 40.1, 39.5, 37.5,
36.2, 35.3, 33.0, 31.6, 30.5, 25.9, 20.9, 20.6, 18.3, 18.1, 17.5, 13.4, 12.9,
ꢁ4.1, ꢁ4.67, ꢁ4.72, ꢁ4.9; ESI-MS: 635.5 (MþHþ); HRMS calcd for
54.2, 52.6, 51.9, 42.5, 41.0, 40.7, 38.5, 38.4, 37.6, 36.3, 35.4, 33.1, 31.7,
30.4, 25.9, 20.9, 18.3, 18.1, 16.7, 14.2, 13.5, ꢁ4.2, ꢁ4.65, ꢁ4.75, ꢁ4.8;
ESI-MS: 661.2 (MþNaþ); HRMS calcd for C36H70O5Si2Naþ:
661.4663; found: 661.4654.
C
36H66O5Si2Naþ: 657.4359; found: 657.4341.
4.1.9. 22-Acetoxy-3
b,6
a
-bis[(tert-butyldimethylsilyl)oxy]-5
a-
4.1.12. 3
b a-Bis[(tert-butyldimethylsilyl)oxy]-15b-methoxy-
,6
23,24-bisnorcholan-15
b
-ol (15)
methyl-5a-23,24-bisnorcholan-22-al (6)
To a solution of 14 (19 mg, 0.03 mmol) in THF (3 mL) and MeOH
(1 mL) was added NaBH4 (6 mg, 0.15 mmol) at 0 ꢀC. The mixture
was allowed to stir at the same temperature for 30 min and
quenched by water. The aqueous layer was extracted with CH2Cl2
(5 mLꢂ3). The combined organic extracts were washed with brine
(10 mLꢂ2), dried over anhydrous Na2SO4, filtered and concen-
Preparation of pyridine-buffered Dess–Martin periodinane stock
solution: to a suspension of Dess–Martin periodinane (52 mg,
0.12 mmol) in freshly distilled CH2Cl2 (2 mL) under argon, pyridine
(60 m
L, 0.5 mmol) was added at 0 ꢀC. The clear solution was used
within 20 min.
To a solution of alcohol 17 (20 mg, 0.03 mmol) in freshly distilled
CH2Cl2 (1.5 mL) under argon, the freshly prepared pyridine-buff-
ered Dess–Martin periodinane (2 mL, 0.12 mmol) was added by
syringe under ice bath. The solution was warmed to room tem-
perature and stirred for 1 h. The reaction was quenched by 1:1
saturated NaHCO3/sodium bisulfite (5 mL) and stirred for 15 min.
The aqueous layer was extracted with CH2Cl2 (10 mLꢂ2). The
combined organic extracts were washed with saturated NaHCO3
(5 mLꢂ2) and brine (10 mLꢂ3), dried over anhydrous Na2SO4, fil-
tered and concentrated in vacuo. Flash chromatography (hexane/
trated. Flash chromatography (hexane/EtOAc, 9:1) afforded 15
20
(18 mg, 94%) as a white solid. Mp 114–115 ꢀC; [
a]
4.9 (c 0.9,
D
CHCl3); IR (KBr): 2930, 1730, 1259, 1089, 836, 773 cmꢁ1 1H NMR
;
(300 MHz, CDCl3): 4.22 (t, 1H, J¼6.0 Hz), 4.05 (dd, 1H, J¼10.5,
3.0 Hz), 3.78 (dd, 1H, J¼10.5, 7.2 Hz), 3.52–3.49 (m, 1H),3.42 (dt, 1H,
J¼10.2, 4.5 Hz), 2.39–2.34 (m, 1H), 2.14–2.08 (m, 2H), 2.05 (s, 3H),
1.00 (d, 3H, J¼6.3 Hz), 0.95 (s, 3H), 0.87 (s, 18H), 0.83 (s, 3H), 0.04 (s,
6H), 0.02 (s, 6H); 13C NMR (75 MHz, CDCl3):
d 171.4, 76.6, 72.2, 70.2,
70.0, 69.3, 60.2, 54.1, 53.0, 51.9, 42.4, 41.0, 40.7, 37.6, 36.3, 35.4, 33.1,

B. Jiang et al. / Tetrahedron 64 (2008) 9738–9744
9743
EtOAc, 10:1) afforded aldehyde 6 (20 mg, 99%) as a white solid. Mp
6.9 Hz); 13C NMR (75 MHz, CDCl3):
d
174.0, 80.6, 64.3, 43.6, 35.5,
20
104–105 ꢀC; [
a
]
6.4 (c 2.75, CHCl3); IR (KBr): 2938, 1732, 1259,
28.5, 28.0, 19.9, 19.2; ESI-MS: 225.2 (MþNaþ); HRMS calcd for
D
1095, 773 cmꢁ1; 1H NMR (300 MHz, CDCl3): 9.56 (d, 1H, J¼3.3 Hz),
4.61, 4.53 (AB, 2H, JAB¼6.6 Hz), 3.92 (t, 1H, J¼6.0 Hz), 3.54–3.47 (m,
1H), 3.44–3.39 (m, 1H), 3.34 (s, 3H), 1.12 (d, 3H, J¼7.2 Hz), 0.93 (s,
3H), 0.87 (s, 18H), 0.83 (s, 3H), 0.04 (s, 6H), 0.02 (s, 3H), 0.002 (s,
3H); 13C NMR (75 MHz, CDCl3): 204.6, 97.5, 78.1, 72.2, 70.0, 59.7,
56.0, 54.2, 51.8, 51.1, 49.3, 43.0, 40.9, 40.6, 37.8, 37.6, 36.4, 33.1, 31.7,
30.4, 25.91, 25.89, 20.9, 18.3, 18.1, 14.5, 13.5, 13.4, ꢁ4.2, ꢁ4.6, ꢁ4.7,
ꢁ4.8; ESI-MS: 659.2 (MþNaþ); HRMS calcd for C36H68O5Si2Naþ:
659.4496; found: 659.4498.
C
11H22O3Naþ: 225.1465; found: 225.1461.
4.1.16. (R)-3-[(tert-Butyldimethylsilyloxy)methyl]-4-methyl-
pentan-1-ol (23)
To a solution of 22 (275 mg,1.36 mmol) in dry CH2Cl2 (10 mL) was
added 2,6-lutidine (0.87 mL, 7.5 mmol) and TBSOTf (0.94 mL,
4.1 mmol) at 0 ꢀC. The solution was then warmed to room temper-
ature and stirred for further 30 min. The reaction was quenched by
water and excess 2,6-lutidine was removed by 1 N HCl (1.0 mL). The
aqueous layer was extracted with Et2O (10 mLꢂ3). The combined
organic extracts were washed with brine (15 mLꢂ2), dried over
anhydrous Na2SO4, filtered and concentrated in vacuo. The crude
product was used for the next step without further purification.
To a solution of crude product in dry CH2Cl2 (8 mL) was added
DIBAL-H (8.2 mL, 8.2 mmol, 1 M in toluene) at ꢁ78 ꢀC under argon.
The reaction was stirred for 1 h at the same temperature. The re-
action was quenched by saturated potassium sodium tartrate
(2 mL). The aqueous layer was extracted with Et2O (15 mLꢂ3). The
combined organic extracts were washed with brine (15 mLꢂ2),
dried over anhydrous MgSO4, filtered and concentrated in vacuo.
4.1.13. (4R)-3-[(2R)-4-(tert-Butoxy)-2-(1-methylethyl)-4-
oxobutanoyl]-4-(phenylmethyl)-1,3-oxazolidine-2-one (20)
To a solution of 18 (3.0 g, 11.5 mmol) in freshly distilled THF
(60 mL) were added LDA (7.5 mL, 15 mmol, 2 M in THF) and tert-
butylbromoacetate (8.3 mL, 53.0 mmol) sequentially by syringe at
ꢁ78 ꢀC under argon. The solution was warmed to room tempera-
ture and stirred for 12 h. The reaction was quenched by saturated
ammonium chloride (50 mL). The aqueous layer was extracted with
EtOAc (30 mLꢂ2). The combined organic extracts were washed
with 1 M HCl (10 mLꢂ2), saturated NaHCO3 (15 mLꢂ2), dried over
anhydrous MgSO4, filtered and concentrated in vacuo. Flash chro-
Flash chromatography (hexane/EtOAc, 15:1 to 10:1) afforded alco-
20
matography (hexane/EtOAc, 40:1 to 20:1) afforded 20 (4.02 g, 93%)
hol 23 (390 mg, 91%) as a colorless liquid. [
a]
ꢁ7.2 (c 1.70, CHCl3);
D
20
as a white solid. Mp 135–136 ꢀC; [
a
]
ꢁ52.7 (c 1.0, CHCl3); 1H NMR
IR (KBr): 2958, 1472, 1257, 1089, 1055, 837, 776 cmꢁ1
;
1H NMR
D
(300 MHz, CDCl3):
d
7.36–7.26 (m, 5H), 4.67–4.65 (m, 1H), 4.18–4.14
(300 MHz, CDCl3):
3.32 (br,1H),1.73–1.66 (m, 2H),1.54–1.51 (m,1H),1.48–1.44 (m,1H),
d
3.69–3.61 (m, 2H), 3.52 (dd, 2H, J¼9.9, 8.1 Hz),
(m, 3H), 3.35 (dd, 1H, J¼13.5, 3.0 Hz), 2.88–2.70 (m, 2H), 2.45 (dd,
1H, J¼16.5, 3.6 Hz), 1.99 (q, 1H, J¼6.6 Hz), 1.42 (s, 9H), 1.01 (d, 3H,
0.90 (s, 9H), 0.87 (d, 3H, J¼6.9 Hz), 0.85 (d, 3H, J¼6.6 Hz), 0.07 (s,
J¼6.6 Hz), 0.91 (d, 3H, J¼6.9 Hz); 13C NMR (75 MHz, CDCl3):
d
175.5,
6H); 13C NMR (75 MHz, CDCl3):
d 65.9, 61.9, 45.2, 33.3, 29.7, 25.8,
171.8,153.1,135.8,129.5,128.8,127.1, 80.6, 65.7, 55.6, 44.3, 37.3, 33.4,
19.9, 19.2, 18.2, 0.99, ꢁ5.51, ꢁ5.55; ESI-MS: 247.3 (MþHþ); HRMS
29.7, 28.0, 20.7, 18.3; ESI-MS: 3981.1 (MþNaþ); HRMS calcd for
calcd for C13H30O2SiNaþ: 269.1905; found: 269.1907.
C
21H29NO5Naþ: 398.1937; found: 398.1938.
4.1.17. (R)-2-[2-(Benzyloxy)ethyl]-3-methylbutan-1-ol (24)
4.1.14. (R)-4-(tert-Butoxy)-2-(1-methylethyl)-4-oxo-
To a mixture of 23 (56 mg, 0.23 mmol) and TBAI (21 mg,
0.06 mmol) in freshly distilled THF (2 mL) was added NaH (60% in
mineral oil, 46 mg, 1.15 mmol) and the suspension was allowed to
butanoic acid (21)8a
To a solution of 20 (200 mg, 0.53 mmol) in THF (8.0 mL) and H2O
(2.7 mL) was added 30% H2O2 (0.26 mL, 2.3 mmol) dropwise under
ice-salt bath. LiOH$H2O (36 mg, 0.86 mmol) was added in three
portions and the hydrolysis was allowed to proceed for 3 h at 0 ꢀC.
The reaction was quenched by saturated sodium sulphite (5 mL).
After stirring for 10 min, the solution was extracted with Et2O. The
aqueous layer was acidified by 1 M HCl to pH¼2–3 and extracted
with CH2Cl2 (15 mLꢂ3). The combined CH2Cl2 solution was dried
over anhydrous Na2SO4, filtered and concentrated in vacuo. Flash
stir for 15 min. BnBr (70 mL, 0.58 mmol) was added dropwise and
the mixture was allowed to reflux overnight. The reaction was
quenched by water. The aqueous layer was extracted with EtOAc
(10 mLꢂ3). The combined organic extracts were washed with brine
(10 mLꢂ2), dried over anhydrous Na2SO4, filtered and concentrated
in vacuo. The crude product was used for the next step without
further purification.
HCl (3.3 M, 1 mL) was added to the solution of crude product in
THF (2 mL) and the mixture was allowed to stir at room tempera-
ture for 1 h. The solution was diluted with water (5 mL) and
extracted with EtOAc (10 mLꢂ3). The combined organic extracts
were washed with saturated NaHCO3 (5 mLꢂ3), brine (10 mLꢂ3),
dried over anhydrous Na2SO4, filtered and concentrated in vacuo.
chromatography (hexane/EtOAc, 1:1) afforded chiral acid 21
20
(100 mg, 87%) as a colorless liquid. [
NMR (300 MHz, CDCl3):
a]
ꢁ7.8 (c 4.5, CH2Cl2); 1H
D
d
11.33 (br, 1H), 2.71–2.65 (m, 1H), 2.63–
2.54 (m, 1H), 2.32 (dd, 1H, J¼15.9, 3.3 Hz), 2.02–1.96 (m, 1H), 1.40 (s,
9H), 0.95 (d, 3H, J¼7.2 Hz), 0.92 (d, 3H, J¼7.5 Hz); 13C NMR (75 MHz,
CDCl3):
d
181.0, 171.5, 80.9, 47.5, 33.9, 29.8, 27.9, 20.1, 19.4.
Flash chromatography (hexane/EtOAc, 20:1 to 10:1) afforded al-
20
cohol 24 (43 mg, 84%) as a colorless liquid. [
IR (KBr): 2960, 1455, 1261, 1094, 698 cmꢁ1
CDCl3):
a
]
ꢁ6.7 (c 0.9, CHCl3);
D
4.1.15. (R)-tert-Butyl-3-hydroxymethyl-4-methyl-pentanoate (22)
A solution of acid 21 (85 mg, 0.39 mmol) in freshly distilled THF,
;
1H NMR (300 MHz,
d
7.35–7.26 (m, 5H), 4.53 (s, 2H), 3.64–3.55 (m, 2H), 3.53–
BH3–Me2S complex (45
m
L, 0.45 mmol) was added by syringe under
3.48 (m, 2H), 3.05 (br, 1H), 1.80–1.68 (m, 2H), 1.67–1.62 (m, 1H),
ice-salt bath. The mixture was allowed to warm to room temper-
ature and stirred for 24 h. The reaction was quenched by water
(0.3 mL) with caution at 0 ꢀC. Solid K2CO3 (55 mg) was added and
the mixture was stirred for 2 min. The aqueous layer was extracted
with Et2O (10 mLꢂ3). The combined organic extracts were washed
with brine (10 mLꢂ2), dried over anhydrous Na2SO4, filtered and
1.45–1.42 (m, 1H), 0.89 (d, 3H, J¼7.2 Hz), 0.87 (d, 3H, J¼6.9 Hz); 13
C
NMR (75 MHz, CDCl3):
d 137.7, 128.5, 127.8, 73.2, 69.7, 64.7, 45.6,
29.7, 29.4, 20.0, 19.4; ESI-MS: 245.2 (MþNaþ); HRMS calcd for
C
14H22O2Naþ: 245.1515; found: 245.1512.
4.1.18. (R)-2-[4-(Benzyloxy)-2-isopropylbutylthio]benzo[d]
thiazole (25)
To a mixture of 24 (60 mg, 0.27 mmol), 2-mercaptobenzothi-
azole (68 mg, 0.40 mmol) and PPh3 (106 mg, 0.40 mmol) in freshly
distilled THF (4 mL) was added DIAD (80 mL, 0.40 mmol) dropwise
at 0 ꢀC under argon. After being stirred for 3 h at the same tem-
perature, the reaction was quenched by water. The aqueous layer
concentrated in vacuo. Flash chromatography (hexane/EtOAc, 10:1)
20
afforded 22 (80 mg, 99%) as a colorless liquid. [
a
]
7.7 (c 0.9,
D
CHCl3); IR (KBr): 2964, 1731, 1396, 1155, 1048 cmꢁ1
(300 MHz, CDCl3):
;
1H NMR
d
3.64 (dd, 1H, J¼11.1, 4.5 Hz), 3.51 (dd, 1H,
J¼10.2, 7.2 Hz), 2.54 (br, 1H), 2.26 (m, 2H), 1.83–1.77 (m, 1H), 1.75–
1.71 (m, 1H), 1.42 (s, 9H), 0.88 (d, 3H, J¼6.6 Hz), 0.86 (d, 3H, J¼10.2,

9744
B. Jiang et al. / Tetrahedron 64 (2008) 9738–9744
was extracted with EtOAc (15 mLꢂ3). The combined organic ex-
ꢁ4.7, ꢁ4.8; ESI-MS: 842.5 (MþNHþ4 ); HRMS calcd for
tracts were dried over anhydrous Na2SO4, filtered and concentrated
C
50H88Si2O3Naþ: 847.6079; found: 847.6063.
in vacuo. Flash chromatography (hexane/EtOAc, 60:1) afforded
20
thioether 25 (92 mg, 92%) as a light yellow oil. [
a
]
ꢁ0.3 (c 2.40,
4.1.21. (24R)-24-Ethyl-5a-cholestane-3
(Certonardolsterol D3)
b,6a,15b
,242-terol (2)
D
CHCl3); IR (KBr): 2959, 1457, 1428, 1101, 996, 755 cmꢁ1
(300 MHz, CDCl3):
;
1H NMR
d
7.85 (d, 1H, J¼7.8 Hz), 7.75 (d, 1H, J¼7.8 Hz),
A solution of 27 (10 mg, 0.012 mmol) in EtOAc (1 mL) and ab-
solute EtOH (2 mL) was hydrogenated over 20 wt % Pd(OH)2 on
carbon (4 mg) for 2 days. The suspension was filtered through
Celite. The resulted clear solution was concentrated in vacuo and
gave the crude saturated steroid. The crude product 28 was used for
the next step without further purification.
7.41 (t, 1H, J¼7.5 Hz), 7.35–7.26 (m, 6H), 4.53 (s, 2H), 3.61 (q, 2H,
J¼5.7 Hz), 3.41 (t, 2H, J¼5.1 Hz), 1.92–1.86 (m, 1H), 1.85–1.77 (m,
2H), 1.77–1.68 (m, 1H), 0.96 (d, 6H, J¼6.6 Hz); 13C NMR (75 MHz,
CDCl3):
d 167.5, 153.2, 138.3, 135.1, 128.3, 127.6, 127.5, 125.9, 124.0,
121.3, 120.9, 72.9, 68.8, 40.9, 35.7, 29.9, 29.7, 19.5, 18.6; ESI-MS:
372.2 (MþHþ); HRMS calcd for C21H26NOSþ2 : 372.1459; found:
372.1450.
To a solution of crude product 28 in THF (2 mL) and H2O (1 mL)
was added 6 M HCl (1 mL). The reaction was monitored by TLC. The
aqueous layer was extracted with EtOAc (10 mLꢂ3). The combined
organic extracts were dried over anhydrous Na2SO4, filtered and
concentrated in vacuo. Flash chromatography (hexane/EtOAc, 10:1
to 3:1) afforded Certonardolsterol D3 2 (6 mg, 99%) as a yellow
4.1.19. (R)-2-(4-(Benzyloxy)-2-isopropylbutylsulfonyl)
benzo[d]thiazole (26)
A solution of 25 (44 mg, 0.12 mmol) in EtOH (1.5 mL) was oxi-
dized with molybdate tetrahydrate (297 mg, 0.24 mmol) and 30%
H2O2 (0.41 mL, 3.6 mmol) at 0 ꢀC for 2 h. The mixture was extracted
with EtOAc (10 mLꢂ3). The combined organic extracts were
washed with brine (10 mLꢂ3), dried over anhydrous Na2SO4, fil-
tered and concentrated in vacuo. Flash chromatography (hexane/
solid. Mp 115–116 ꢀC; [
a]
20 9.8 (c 0.2, CHCl3); IR (KBr): 2964, 1262,
D
1097, 1021, 801 cmꢁ1
;
1H NMR (400 MHz, CD3OD): 4.16 (t, 1H,
J¼5.8 Hz), 3.61–3.50 (m, 2H), 3.49–3.45 (m,1H), 3.38 (td,1H, J¼10.8,
4.7 Hz), 2.38 (dt, 1H, J¼14.5, 8.4 Hz), 2.27 (dt, 1H, J¼12.0, 3.9 Hz),
0.94 (d, 3H, J¼7.2 Hz), 0.93 (s, 3H), 0.87 (d, 3H, J¼6.9 Hz), 0.86 (s,
EtOAc, 15:1–5:1) afforded sulfone 26 (40 mg, 83%) as a colorless oil.
3H), 0.84 (d, 3H, J¼6.9 Hz); 13C NMR (100 MHz, CD3OD):
d 72.0,
20
[
a]
ꢁ1.3 (c 1.55, CHCl3); IR (KBr): 2962, 1473, 1328, 1146, 1098,
70.6, 70.0, 62.2, 62.0, 57.7, 55.7, 53.2, 43.4, 42.7, 42.3, 41.9, 41.8, 38.6,
37.5, 37.2, 34.9, 34.6, 33.1, 32.0, 31.6, 30.5, 28.3, 22.2, 20.0, 19.4, 18.9,
15.2, 13.8; ESI-MS: 487.4 (MþNaþ); HRMS calcd for C29H52O4Naþ:
487.3764; found: 487.3758.
D
763 cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
8.20 (d, 1H, J¼8.4 Hz), 7.98
(d, 1H, J¼8.4 Hz), 7.65–7.55 (m, 2H), 7.31–7.22 (m, 5H), 4.40 (s, 2H),
3.55–3.50 (m, 4H), 2.29–2.24 (m,1H), 2.06–2.00 (m, 1H),1.77 (q, 2H,
J¼6.6 Hz), 0.87 (d, 3H, J¼6.9 Hz), 0.85 (d, 3H, J¼7.2 Hz); 13C NMR
(75 MHz, CDCl3):
d 166.4, 152.6, 138.2, 136.7, 128.2, 127.9, 127.6,
Acknowledgements
127.5, 127.4, 125.3, 122.3, 72.8, 68.3, 56.1, 36.3, 30.0, 29.5, 18.5, 18.2;
ESI-MS: 426.2 (MþNaþ); HRMS calcd for C21H26NO3Sþ2 : 404.1362;
found: 404.1349.
We gratefully acknowledge Science and Technology Commis-
sion of Shanghai Municipality for financial support (064319016).
4.1.20. (E)-(24R)-3
b
,6a
-Bis[(tert-butyldimethylsilyl)oxy]-15
b-
methoxymethyl-24-ethyl-242 benzyloxy-5
a-cholest-22-ene (27)
References and notes
To a mixture of aldehyde 6 (50 mg, 0.078 mmol) and sulfone 26
(14 mg, 0.15 mmol) in freshly distilled THF (3.6 mL) was added
LiHMDS (0.31 mL, 0.31 mmol, 1.0 M in hexane) at ꢁ78 ꢀC under
argon. After being stirred for 1 h at ꢁ78 ꢀC, the solution was
warmed to room temperature and stirred overnight. The reaction
was quenched by water. The aqueous layer was extracted with
EtOAc (15 mLꢂ3). The combined organic extracts were washed
with brine (10 mLꢂ3), dried over anhydrous Na2SO4, filtered and
concentrated in vacuo. Flash chromatography (hexane/EtOAc, 40:1
1. Reviews: (a) Faulkner, D. J. Nat. Prod. Rep. 1998, 15, 113–158 and previous reports
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to 20:1) afforded 27 (60 mg, 93%) as a yellow solid. [
a]
20 16.6 (c 2.0,
D
CHCl3); IR (KBr): 2962, 1261, 1093, 1046, 802 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): 7.28–7.35 (m, 5H), 5.17 (dd, 1H, J¼15.3, 8.1 Hz),
5.06 (dd, 1H, J¼15.3, 8.4 Hz), 4.62, 4.53 (AB, 2H, JAB¼6.3 Hz), 4.45 (d,
2H, J¼12.0 Hz), 3.82 (t, 1H, J¼6.0 Hz), 3.52–3.47 (m, 2H), 3.46–3.38
(m, 2H), 3.35 (s, 3H), 1.00 (d, 3H, J¼6.3 Hz), 0.88 (s, 18H), 0.843 (d,
3H, J¼7.8 Hz), 0.835 (s, 3H), 0.81 (d, 3H, J¼6.9 Hz), 0.05 (s, 6H), 0.03
7. Williams, J. R.; Gong, H.; Hoff, N.; Olubodun, O. I.; Caroll, P. J. Org. Lett. 2004, 6,
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(s, 3H), 0.02 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 138.8, 138.3, 129.0,
128.3, 127.7, 127.4, 97.3, 78.0, 72.9, 72.3, 70.2, 69.2, 60.5, 56.0, 55.8,
54.3, 51.9, 45.6, 42.3, 41.1, 40.8, 40.2, 39.7, 37.6, 36.4, 33.2, 32.6, 32.2,
31.7, 30.4, 29.7, 25.9, 21.0, 20.7, 18.8, 18.3, 18.1, 14.4, 13.5, ꢁ4.1, ꢁ4.6,