OCT analogues part 2. Acetylene in the synthesis of useful building blocks for analogues of OCT modified at C-20, C-21, and the D-ring

Article abstract of DOI:10.1055/s-2005-869895

Diols 11 and 12, potential building blocks for the synthesis of 20-epi-OCT, and analogues modified at C-21 and the D-ring, were efficiently synthesized using Pd(II)-catalyzed oxidative rear-rangement of propargylic acetate 7. Georg Thieme Verlag Stuttgart

Full text of DOI:10.1055/s-2005-869895

SPECIAL TOPIC
1701
OCT Analogues Part 2. Acetylene in the Synthesis of Useful Building Blocks
for Analogues of OCT Modified at C-20, C-21, and the D-Ring
A
C
nalogues of
O
C
a
T Modified
r
at C-20
l
,
C-21,
o
and the D-R
s
ing Fernández, Ousmane Diouf, Edelmiro Momán, Generosa Gómez, Yagamare Fall*a
a
b
a,1
a
a
Departamento de Química Orgánica, Facultad de Química, Universidad de Vigo, 36200 Vigo, Pontevedra, Spain
Fax +34(986)812262; E-mail: yagamare@uvigo.es
b
Laboratoire de Chimie Inorganique, Departement de Chimie, Faculté des Sciences et Techniques, Université Cheikh Anta Diop,
Dakar, Sénégal
Received 15 March 2005
with high cell differentiating ability and weak calcemic
effects.
Abstract: Diols 11 and 12, potential building blocks for the synthe-
sis of 20-epi-OCT, and analogues modified at C-21 and the D-ring,
were efficiently synthesized using Pd(II)-catalyzed oxidative rear- Known examples of such analogues include 1a,25-dihy-
rangement of propargylic acetate 7.
3
droxy-22-oxavitamin D (2, OCT). This analogue inhib-
3
4
Key words: synthesis, vitamin D, palladium, alkyne, analogues
its the proliferation of certain cancers, is a potent
immunomodulator in vivo, and does not cause hypercal-
5
caemia. Although many synthetic approaches to OCT
3
,6
have been developed, only a few OCT analogues have
1
a,25-Dihydroxyvitamin D (calcitriol, 1) (Figure 1) is
3
been reported,6
a,c,d
meaning that new synthetic strategies
the hormonally active form of vitamin D . Beside regulat-
ing calcium homeostasis, it is also involved in other cellu-
lar processes, including cell differentiation, immune
3
for accessing potentially interesting analogues of OCT are
still required. In Scheme 1 we describe the synthesis of
compounds 11 and 12, which are useful synthons towards
2
system regulation, and gene transcription. The latter
function, mediated by the nuclear vitamin D receptor
(
found in more than thirty different tissues and cancer cell
O
OH
lines), raises the possibility of developing 1a,25-(OH) -
D analogues with a specific therapeutic applications. The
2
3
i
ii
2%
clinical utility of 1 in the treatment of cancers and skin dis-
orders is limited by its hypercalcemic effects. According-
ly, chemists have pursued the synthesis of analogues of 1
9
H
8
0%
H
6
TBSO
TBSO
5
O
AcO
AcO
CHO
+
O
H
OAc
OH
OH
iii
H
H
H
10%
6
3%
TBSO
H
Calcitriol
7
TBSO
0%
TBSO
9
OCT
8
iv
9
O
H
HO
OH
HO
OH
OAc
vi
97%
1
2
v
O
R
O
R
OH
OH
64%
TBSO
10
H
vii 89%
HO
H
OH
HO
R = OH, H, Alkyl
OH
HO
OH
HO
OH
H
3
4
TBSO
12
Figure 1 Structure of calcitriol and some of its analogues with side–
chain modification.
H
11
TBSO
SYNTHESIS 2005, No. 10, pp 1701–1705
x
x.
x
x
.
2
0
0
5
Scheme 1 Reagents and conditions: (i) LiCCH·EDA, THF, r.t.; (ii)
Advanced online publication: 18.05.2005
DOI: 10.1055/s-2005-869895; Art ID: C03205SS
Georg Thieme Verlag Stuttgart · New York
Ac O, pyridine, DMAP, r.t.; (iii) PdCl (CH CN) , THF, H O, r.t.; (iv)
2
2
3
2
2
DBU, EtOAc, 50 °C; (v) H , Pd/C, EtOAc; (vi) NaBH , MeOH, 0 °C
2
4
©
to r.t.; (vii) NaBH , CeCl ·7H O, MeOH, 0 °C.
4
3
2

1
702
C. Fernández et al.
SPECIAL TOPIC
the synthesis of OCT analogues 3 and 4 modified at C-20, we could access stereoselectively compounds 11, 12, and
C-21, and the D-ring.
14. The transformation of these useful building blocks
into OCT analogues using an original methodology devel-
We decided to use acetylene chemistry in our preliminary
approach to OCT analogues. Acetylene chemistry has
oped in our laboratories6
c,12b
is currently under way.
been extensively used over the years for the synthesis of a
7
diverse range of organic structures. In the vitamin D field Melting points were determined in open capillaries and are uncor-
1
13
the generation of the vitamin D triene system using a pal- rected. H and C NMR spectra were recorded on a Bruker AMX
spectrometer at 400 and 75.47 MHz, respectively, using TMS as in-
ladium-catalyzed coupling reaction of a dienyne fragment
8
a–8c
8d,e
ternal standard (chemical shifts in d values, J in Hz). Mass spec-
trometry was carried out in a Hewlett Packard 5988A spectrometer.
Flash chromatography was performed on silica gel (Merck 60, 230–
with a vinyl triflate
or bromide
has now become a
classical means for the synthesis of vitamin D analogues.
Use of a Pd(II)-catalyzed oxidative rearrangement fol-
lowed by a base-catalyzed acetate rearrangement is not
4
00 mesh); analytical TLC was performed on plates pre-coated with
silica gel (Merck 60 F254, 0.25 mm).
9
unprecedented in the steroid field, so we anticipated that
using this type of rearrangement would lead to interesting Des-A,B-8b-tert-butyldimethylsiloxypregna-17-ynol (6)
To a suspension of LiCCH·EDA (1.2 g, 12.9 mmol) in anhyd THF
CD ring fragments en route to vitamin D analogues 3 and
1
0
(20 mL) at 0 °C was added dropwise a solution of ketone 5 (3 g, 10.6
mmol) in THF (10 mL). The mixture was stirred overnight at r.t.,
4
. Reaction of ketone 7 with lithium acetylide, ethylene-
diamine (LiCCH·EDA), afforded propargylic alcohol 6 in
0% yield. The latter was acetylated using acetic anhy-
quenched with an aq sat. solution of NH Cl (20 mL), and extracted
4
8
with Et O (2 × 10 mL). The combined organic phases were dried
2
dride to give propargylic acetate 7. The stage was set for over Na SO . Filtration and solvent evaporation afforded a residue,
2
4
1
1
the Pd(II)-catalyzed oxidative rearrangement, which led which was chromatographed on silica gel (EtOAc–hexane, 5:95), to
afford 2.6 g of alcohol 6 (80%).
to aldehyde 8 (63%) and ketone 9 (10%). Base-catalyzed
9
rearrangement of 8 cleanly afforded a,b-unsaturated ke- White solid; mp 52 °C; R 0.67 (EtOAc–hexane, 1:4).
f
tone 10 in 90% yield. Ketone 10, on hydrogenation with
Pd/C gave ketone 9 in 64% yield, the latter was stereose-
1
H NMR (CDCl ): d = 4.01 (1 H, d, J = 2.3 Hz, H-8), 2.55 (1 H, s,
3
≡
CH), 2.27 (1 H, m), 1.94 (1 H, m), 1.40–1.77 (10 H, m), 1.08 (3 H,
lectively reduced to diol 12 using sodium borohydride in s, CH ), 0.90 [9 H, s, SiC(CH ) ], 0.03 (3 H, s, CH Si), 0.01 (3 H, s,
3
3
3
3
methanol. Reduction of ketone 10 using Luche conditions CH
Si).
3
1
3
afforded stereoselectively diol 11. The stereochemistry at
C-20 in compounds 11 and 12 was established by chemi- 17), 69.24 (CH-8), 47.40 (CH-14), 46.12 (C-13), 38.21 (CH ),
C NMR (CDCl ): d = 87.88 (C≡CH), 80.03 (C≡CH), 73.69 (C-
3
2
3
4.06 (CH ), 33.35 (CH ), 25.74 [SiC(CH ) ], 21.50 (CH ), 17.94
cal correlation (Scheme 2).
2 2 3 3 2
[
(
SiC(CH ) ], 17.21 (CH ), 14.25 (CH ), –4.87 (CH Si), –5.24
3 3 2 3 3
CH Si).
3
OH
HO
OH
0
HO
+
+
2
0
LRMS: m/z (%) = 309 [M + 1, (5)], 308 [M – CH , (20)], 251
3
[
1
2
i
+
M – t-Bu, (64)], 233 (33), 225 (37), 215 (15), 159 (17), 133 (26),
31 (28), 117 (24), 115 (17), 105 (24), 93 (19), 91 (27), 81 (25), 79
80%
(21), 77 (95), 75 (95), 73 (63), 67 (18), 59 (15), 58 (100), 57 (19),
55 (19).
H
11
H
TBSO
12
TBSO
ii
HRMS: m/z calcd for C H O Si, 308.2172; found, 308.2172.
1
8
32
2
55%
Des-A,B-8b-tert-butyldimethylsiloxy-17-acetoxypregn-17-yne
7)
(
A mixture of alcohol 6 (1.7 g, 5.5 mmol), Ac O (5.6 mL, 55.2
2
mmol), pyridine (4.5 mL, 55.2 mmol), and DMAP (cat.) was stirred
at r.t. for 9 d. MeOH (10 mL) was added and the mixture was stirred
at r.t. for 30 min. After removal of MeOH, the residue was extracted
OH
0
OH
0
TsO
2
2
iii
with Et O (2 × 10 mL). The combined organic phases were washed
2
with 10% HCl (2 × 15 mL) and dried over Na SO . Filtration and
8
0%
2
4
H
H
solvent evaporation afforded a residue, which was chromato-
graphed on silica gel (EtOAc–hexane, 5:95) to afford 1.8 g of ace-
tate 7 (92%).
TBSO
13
TBSO
14
Scheme 2 Reagents and conditions: (i) H , Pd/C, EtOAc, r.t.; (ii) p-
2
TsCl, pyridine, 0 °C; (iii) LiALH , Et O, 0 °C to r.t.
4
2
White solid; mp 44 °C; R 0.86 (EtOAc–hexane, 1:5).
f
1
H NMR (CDCl ): d = 4.02 (1 H, d, J = 2.3 Hz, H-8), 2.67 (1 H, m),
3
Catalytic hydrogenation of 11 yielded a compound whose 2.56 (1 H, s, C≡CH), 2.01 (3 H, s, CH CO), 1.08 (3 H, s, CH ), 0.87
3
3
[
1
9 H, s, SiC(CH ) ], 0.00 (3 H, s, CH Si), –0.02 (3 H, s, CH Si).
3 3 3 3
spectral data were identical to those of compound 12, thus
establishing that the stereochemistry at C-20 is the same
3
C NMR (CDCl ): d = 169.60 (CCO), 84.47 (C≡CH), 83.76
3
for 11 and 12. Selective tosylation of the primary alcohol (C≡CH), 74.60 (C-17), 69.02 (CH-8), 47.02 (CH-13), 45.83 (C-14),
3
6.59 (CH ), 34.03 (CH ), 33.82 (CH ), 25.75 [SiC(CH ) ], 21.90
of 12 followed by reduction with LiAlH afforded known
2
2
2
3 3
4
1
2
(CH ), 21.36 (CH CO), 17.97 [SiC(CH ) ], 17.17 (CH ), 15.03
(
2 3 3 3 2
alcohol 14, confirming unambiguously the stereochem-
istry at C-20 for compounds 11 and 12.
CH -18), –4.81 (CH Si), –5.22 (CH Si).
3 3 3
+
LRMS: m/z (%) = 447 (6), 446 (19), 350 [M , (8)], 349 (12), 293
[
1
In conclusion we have demonstrated that using Pd(II)-cat-
alyzed oxidative rearrangement of propargylic acetate 7
+
+
M – t-Bu, (8)], 292 (25), 291 [M – AcO, (100)], 289 (5), 171 (8),
60 (8), 159 (60), 157 (7), 154 (11).
Synthesis 2005, No. 10, 1701–1705 © Thieme Stuttgart · New York

SPECIAL TOPIC
Analogues of OCT Modified at C-20, C-21, and the D-Ring
1703
HRMS: m/z calcd for C H O Si, 351.2355; found, 351.2339.
which was chromatographed on silica gel (EtOAc–hexane, 25:75)
2
0
35
3
to afford 496 mg of 10 (90%).
Des-A,B-8b-tert-butyldimethylsiloxy-20-acetoxypregn-17(20)-
ene-21-al (8) and Des-A,B-8b-tert-butyldimethylsiloxy-21-acet-
oxypregnan-20-one (9)
Yellow oil; R 0.40 (EtOAc–hexane,15:85).
f
1
H NMR (CDCl ): d = 6.69 (1 H, s, H-16), 4.92 (1 H, d, J = 16.1 Hz,
3
H-22), 4.84 (1 H, J = 16.1 Hz, H-22), 4.09 (1 H, d, J = 1.3 Hz, H-8),
To a solution of acetate 7 (0.738 g, 2.1 mmol) in THF (24 mL) was
2
.42 (1 H, m, H-15), 2.28 (1 H, d, J = 12.5 Hz, H-15), 2.12 (3 H, s,
added PdCl (CH CN) (546 mg, 2.1 mmol) and H O (38 mL, 2.1
2
3
2
2
CH CO 1.84 (1 H, m, H-14), 1.12 (3 H, s, CH ), 0.84 [9 H, s,
mmol). The mixture was protected from light by means of an alumi-
num foil and stirred at r.t. for 3 h. An aq sat. solution of NaHCO3
3
3
SiC(CH ) ], –0.01 (3 H, s, CH Si), –0.02 (3 H, s, CH Si).
3
3
3
3
(
12 mL) and Et O (24 mL) were added. The organic phase was
13
2
C NMR (CDCl ,): d = 190.23 (C-20), 170.32 (COCH ), 151.93
3 3
washed with an aq sat. solution of NaHCO (3 × 10 mL) and the
3
(C-17), 143.57 (CH-16), 68.43 (CH-8), 65.56 (CH -22), 53.50 (CH-
2
combined aqueous phases were extracted with Et O (3 × 10
2
14), 46.54 (C-13), 35.14 (CH ), 34.21 (CH ), 32.25 (CH ), 25.69
2
2
2
mL).The combined organic phases were dried over Na SO . Filtra-
2
4
[SiC(CH ) ], 20.48 (CH -25), 19.01 (CH -18), 17.93 [SiC(CH ) ],
3 3 3 3 3 3
tion and solvent evaporation afforded a residue, which was chro-
matographed on silica gel (EtOAc–hexane, 2:98–5:95) to afford
1
7.67 (CH ), –4.86 (CH -MeSi), –5.24 (CH Si).
2 3 3
+
LRMS: m/z (%) = 323 [M – COCH ] (5), 311 (6), 310 (22), 309
3
4
86 mg of 8 (63%) and 78 mg of 9 (10%).
+
[
M – t-Bu] (96), 269 (6), 268 (21), 267 (100), 250 (5), 249 (25),
1
7
61 (9), 147 (7), 147 (5), 133 (9), 117 (10), 105 (7), 91 (9), 75 (35),
3 (25).
Compound 8
Yellow solid; mp 59 °C; R 0.36 (EtOAc–hexane, 15:85).
f
1
HRMS: m/z calcd for C20H O Si, 366.2226; found, 366.2234.
34 4
H NMR (CDCl ): d = 9.55 (1 H, s, CHO), 4.12 (1 H, d, J = 2.4 Hz,
3
H-8), 2.92 (1 H, m, H-16), 2.82 (1 H, t, J = 9.2 Hz, H-16), 2.19 (3
H, s, CH CO), 1.15 (3 H, s, CH -18), 0.86 [9 H, s, SiC(CH ) ], 0.01
(
1
Synthesis of 9 by Hydrogenation of 10
To a solution of 10 (0.089 g, 0.242 mmol) in anhyd EtOAc (6 mL)
was added Pd/C (6 mg) and the mixture was stirred at r.t. for 4 d un-
3
3
3 3
3 H, s, CH Si), 0.00 (3 H, s, CH Si).
3
3
3
C NMR (CDCl ): d = 184.17 (CHO), 169.00 (CO), 162.83 and
3
der a H atmosphere. After rapid filtration through silica gel and
2
1
1
2
37.84 (C-17 and C-20), 69.08 (CH-8), 50.71 (CH-14), 46.71 (C-
washing with EtOAc, the solvent was concentrated and the residue
chromatographed on silica gel using (EtOAc–hexane, 10:90) to af-
ford 0.057 g of 9 (64%).
3), 35.64 (CH ), 33.82 (CH ), 26.09 (CH ), 25.70 [SiC(CH ) ],
2
2
2
3 3
3.66 (CH ), 20.31 and 18.83 (CH CO and C-18), 17.92
2
3
[
SiC(CH ) ], 17.42 (CH ), –4.87 (CH Si), –5.20 (CH Si).
3 3 2 3 3
+
+
(20S)-Des-A,B-8b-tert-butyldimethylsiloxypregn-16(17)-ene-
20,21-diol (11)
To a solution of 10 (0.101 g, 0.275 mmol) in MeOH (4 mL) at r.t.
LRMS: m/z (%) = 325 [M – COCH , (9)], 312 (13), 311 [M –
3
+
t-Bu] (57), 295 [M – CH O] (5), 252 (15), 251 (75), 177 (33), 169
2
(
1
(
7
10), 160 (6), 159 (46), 149 (6), 147 (5), 143 (19), 136 (6), 135 (53),
34 (9), 133 (33), 131 (7), 121 (8), 119 (20), 118 (6), 117 (66), 107
18), 105 (9), 95 (7), 93 (21) 91 (15), 83 (6), 81 (16), 79 (14), 76 (7),
5 (100), 73 (51), 67 (10).
was added CeCl ·7H O (0.112 g, 0.30 mmol); the temperature was
3
2
reduced to 0 °C and NaBH (0.095 g, 2.51 mmol) was added. The
4
mixture was stirred at 0 °C for 30 min then allowed to warm to r.t.
Stirring was continued for 3 h. The MeOH was removed on a rotary
HRMS: m/z calcd for C H O Si, 366.2226; found, 366.2222.
2
0
34
4
evaporator, H O (10 mL) was added and the product extracted with
2
Et O (2 × 10 mL). The combined organic phases were dried over
2
Compound 9
Colorless oil; R 0.37 (EtOAc–hexane, 15:85).
Na SO . Filtration and solvent evaporation afforded a residue,
2
4
f
which was recrystallized from EtOAc–hexane to afford 73 mg of
diol 11 (89%).
1
H NMR (CDCl ): d = 4.65 (1 H, d, J = 16.8 Hz, H-22), 4.52 (1 H,
3
d, J = 16.8 Hz, H-22), 4.04 (1 H, d, J = 2.5 Hz, H-8), 2.45 (1 H, t,
Yellow solid; mp 276 °C; R 0.19 (EtOAc–hexane, 40:60).
f
J = 9.0 Hz, H-17), 2.20 (1 H, m, H-14), 2.15 (3 H, s, CH CO), 0.88
3
1
H NMR (CDCl ): d = 5.67 (1 H, t, J = 1.5 Hz, H-16), 4.22 (1 H, br
(
(
1
3 H, s, CH ), 0.86 [9 H, s, SiC(CH ) ], 0.00 (3 H, s, CH Si), –0.01
3
3
3 3
3
s, H-20), 4.08 (1 H, s, H-8), 3.64 (2 H, m, CH -22), 2.26 (1 H, m, H-
3 H, s, CH Si).
2
3
1
4), 1.06 (3 H, s, CH ), 0.86 [9 H, s, SiC(CH ) ], 0.0068 (3 H, s,
3
3
3
3
C NMR (CDCl ): d = 203.59 (C-20), 170.21 (COCH ), 69.20
3
3
CH Si), 0.0000 (3 H, s, CH Si).
3
3
(
CH -22), 68.80 (CH-8), 60.08 and 53.29 (CH-17 and C-14), 44.32
2
1
3
C NMR (CDCl ): d = 154.15 (C-17), 125.62 (CH-16), 69.06 (CH-
(
C-13), 39.51 (CH ), 34.12 (CH ), 25.71 [SiC(CH ) ], 23.19 (CH ),
3
2
2
3 3
2
8
3
), 68.81 (CH-20), 66.10 (CH -22), 55.07 (CH-14), 46.03 (C-13),
5.61 (CH ), 34.45 (CH ), 30.93 (CH ), 25.75 [SiC(CH ) ], 19.52
2
1
1.72 (CH ), 20.46 (CH CO), 17.95 [SiC(CH ) ], 17.58 (CH ),
2
2
3
3 3
2
5.42 (CH ), –4.86 (CH Si), –5.23 (CH Si).
2
2
2
3 3
3
3
3
(
(
CH ), 17.99 [SiC(CH ) ], 17.88 (CH ), –4.86 (CH Si), –5.19
+
+
3 3 3 2 3
LRMS: m/z (%) = 325 [M – COCH ] (9), 312 (13), 311 [M – t-Bu]
3
CH Si).
+
3
(
57), 295 [M – CH O] (5), 252 (15), 251 (75), 177 (33), 169 (10),
2
1
(
1
(
60 (6), 159 (46), 149 (6), 147 (5), 143 (19), 136 (6), 135 (53), 134
9), 133 (33), 131 (7), 121 (8), 119 (20), 118 (6), 117 (66), 107 (18),
05 (9), 95 (7), 93 (21), 91 (15), 83 (6), 81 (16), 79 (14), 76 (7), 75
100), 73 (51), 67 (10).
(
20S)-Des-A,B-8b-tert-butyldimethylsiloxypregna-20,21-diol
(
12)
To a solution of 9 (0.04 g, 0.109 mmol) in MeOH (2 mL) at 0 °C
was added NaBH (0.041 g, 1.085 mmol). The mixture was stirred
4
HRMS: m/z calcd for C H O Si, 368.2383; found, 366.2379.
at 0 °C for 30 min then allowed to warm to r.t. Stirring was contin-
ued for 3 h at r.t. The MeOH was removed on a rotory evaporator,
H O (5 mL) was added and the product was extracted with Et O
2
0
36
4
Des-A,B-8b-tert-butyldimethylsiloxy-21-acetoxypregn-16(17)-
ene-20-one (10)
To a solution of aldehyde 8 (0.551 g, 1.5 mmol) in anhyd EtOAc (42
2
2
(3 × 5 mL).The combined organic phases were dried over Na SO .
2
4
Filtration and solvent evaporation afforded a residue which was
chromatographed on silica gel (EtOAc–hexane, 15:85) to afford 35
mg of 12 (97%).
°
C) was added DBU (0.115 mL, 0.752 mmol) and the mixture was
stirred at 50 °C for 23 h. The reaction was quenched by adding an
aq solution of HCl (10%; 33 mL) and the product was extracted with
EtOAc (3 × 22 mL). The combined organic phases were dried over
Na SO . Filtration and solvent evaporation afforded a residue,
Yellow oil; R 0.41 (EtOAc–hexane, 60:40).
f
2
4
Synthesis 2005, No. 10, 1701–1705 © Thieme Stuttgart · New York

1
704
C. Fernández et al.
SPECIAL TOPIC
1
+
H NMR (CDCl ): d = 4.02 (1 H, d, J = 2.5 Hz, H-8), 3.65 (2 H, m,
2
LRMS: m/z (%) = 409 (9), 408 (29), 311 [M – H] (15), 296 (11),
3
+
+
CH -22), 3.37 (1 H, m, H-20), 2.01 (1 H, d, J = 12.3 Hz, H-14), 1.02
295 [M – OH] (43), 255 [M – t-Bu] (5), 237 (15), 179 (5), 171
(
(
1
3 H, s, CH ), 0.89 [9 H, s, SiC(CH ) ], 0.01 (3 H, s, CH Si), –0.01
(11), 164 (13), 163 (100), 161 (17), 154 (9).
3
3 3
3
3 H, s, CH Si).
3
HRMS: m/z calcd for C H OSi, 312.2485; found, 312.2451.
1
8
35
3
C NMR (CDCl ): d = 74.29 (CH-20), 69.01 (CH-8), 66.34 (CH -
3
2
2
3
2), 53.03, 52.38 (CH-17 and C-14), 42.04 (C-13), 40.70 (CH ),
2
Acknowledgment
4.42 (CH ), 25.79 [SiC(CH ) ], 23.68 (CH ), 23.29 (CH ), 18.01
2
3 3
2
2
[
(
SiC(CH ) ], 17.49 (CH ), 14.32 (CH ), –4.81 (CH Si), –5.19
3 3 2 3 3
This work was supported by a grant from the Xunta de Galicia
PGIDIT04BTF301031PR). O. D. thanks the Ministerio de Asuntos
CH Si).
3
(
Exteriores for a MAE fellowship.
Synthesis of 12 by Hydrogenation of 11
To a solution of 11 (0.015 g, 0.046 mmol) in anhyd EtOAc (1.2 mL)
was added Pd/C (cat.) and the mixture stirred at r.t. for 25 h under a
References
H atmosphere. After rapid filtration through silica gel and washing
2
with EtOAc, the solvent was concentrated and the residue chro-
matographed on silica gel (EtOAc–hexane, 10:90) to afford 0.065 g
of 12 (80%).
(1) New address: E. Momán, Department of Pharmaceutical and
Medicinal Chemistry, Royal College of Surgeons in Ireland,
123 St. Stephen’s Green, Dublin 2, Ireland.
(
2) For general reviews of vitamin D chemistry and biology,
see: (a) Vitamin D: Chemistry Biology and Clinical
Applications of the Steroid Hormone; Norman, A. W.;
Bouillon, R.; Thomasset, M., Eds.; Vitamin D Workshop
Inc.: Riverside CA, 1997. (b) Feldman, D.; Glorieux, F. H.;
Pike, J. W. Vitamin D; Academic Press: San Diego, 1997.
(c) Pardo, R.; Santelli, M. Bull. Soc. Chim. Fr. 1985, 98.
(d) Dai, H.; Posner, G. H. Synthesis 1994, 1383. (e) Zhu,
G.-D.; Okamura, W. H. Chem. Rev. 1995, 95, 1877.
(f) Posner, G. H.; Kahraman, M. Eur. J. Org. Chem. 2003,
3889.
(
20S)-Des-A,B-8b-tert-butyldimethylsiloxy-21-tosyloxypreg-
nan-20-ol (13)
To a solution of diol 12 (0.036 g, 0.174 mmol) in anhyd pyridine
(1.2 mL) at 0 °C was added p-TsCl (0.123 g, 0.626 mmol). The mix-
ture was stirred for 17 h then poured into crushed ice. NaHCO (8
3
mL) was added and the product was extracted with Et O (3 × 15
2
mL). The combined organic phases were washed with aq HCl (10%;
2
× 20 mL) and dried over Na SO . Filtration and solvent evapora-
2
4
tion afforded a residue, which was chromatographed on silica gel
EtOAc–hexane, 4:96–50:50) to afford 29 mg of 13 (55%).
(
(
3) (a) Murayama, E.; Miyamoto, K.; Kubodera, N.; Mori, T.;
Matsunaga, I. Chem. Pharm. Bull. 1986, 34, 4410.
(b) Tanimori, S.; Mingqi, H. Synth. Commun. 199, 23, 2861.
(c) Calverley, M. J.; Hansen, K.; Binderup, L. Patent
Application No. WO 90/0991, 1990. (d) Hansen, K.;
Calverly, M. J.; Binderup, L. Proceedings of the Vitamin D
Workshop Paris 1991, 161.
Colorless oil; R 0.60 (EtOAc–hexane, 30:70).
f
1
H NMR (CDCl ): d = 7.79 (2 H, d, J = 8.3 Hz, Ar), 7.35 (2 H, d,
3
J = 8.2 Hz, Ar), 4.06 (1 H, dd, J = 10, 2.1 Hz, H-22), 4.00 (1 H, d,
J = 2.4 Hz, H-8), 3.85 (1 H, dd, J = 10, 6.2 Hz, H-22), 3.74 (1 H, br
s, H-20), 2.45 (3 H, s, CH Ts), 2.02 (1 H, d, J = 12.5 Hz, H-14), 0.97
3
(
(
1
3 H, s, CH ), 0.87 [9 H, s, SiC(CH ) ], 0.00 (3 H, s, CH Si), –0.02
3
3 3
3
3 H, s, CH Si).
(4) (a) Oikawa, T.; Yoshida, Y.; Shimamura, M.; Ashino-Fuse,
3
3
H.; Iwaguchi, T.; Tominaga, T. Anticancer Drugs 1991, 2,
C NMR (CDCl ): d = 144.97 (ArC), 132.71 (ArC), 129.90
3
4
75. (b) Abe, J.; Nakano, T.; Nishii, Y.; Matsumoto, T.;
Ogata, E.; Ikeda, K. Endocrinology 1991, 129, 832.
c) Abe-Hashimoto, J.; Kikuchi, T.; Matsumoto, T.; Nishii,
(
ArCH), 127.96 (ArCH), 74.25 (CH -22), 71.87 (CH-20), 68.96
2
(
CH-8), 52.29 and 52.17 (CH-17 and CH-14), 42.18 (C-13), 40.36
(
(
CH ), 34.37 (CH ), 25.77 [SiC(CH ) ], 23.76 (CH ), 23.24 (CH ),
2
2
3
3
2
2
Y.; Ogata, E.; Ikeka, K. Cancer Res. 1993, 53, 2534.
5) Abe, J.; Takita, Y.; Nakano, T.; Miyaura, C.; Suda, T.;
Nishii, Y. Endocrinology 1989, 124, 2645.
6) (a) White, M. C.; Burke, M. D.; Peleg, S.; Brem, H.; Posner,
G. H. Bioorg. Med. Chem. 2001, 9, 1691. (b) Fall, Y.
Tetrahedron Lett. 1997, 38, 4909. (c) Fall, Y.; González,
V.; Vidal, B.; Mouriño, A. Tetrahedron Lett. 2002, 43, 427.
2
–
1.63 (PhCH ), 18.00 [SiC(CH ) ], 17.43 (CH ), 14.02 (CH ),
3
3 3
2
3
(
(
4.81 (CH Si), –5.21 (CH Si).
3
3
(
20R)-Des-A,B-8b-tert-butyldimethylsiloxypregnan-20-ol (14)
To a solution of tosylate 13 (0.023 g, 0.048 mmol) in anhyd Et O (5
2
mL) at 0 °C was added LiAlH (0.028 g, 0.715 mmol) and the mix-
4
ture was stirred for 4 h and the temperature was raised to r.t. over
(d) Leesson, P. A.; Martel, A. M.; Castaner, R. Drugs Future
this time. Excess LiAlH was carefully destroyed by addition of
4
1
996, 21, 1229. (e) Kubodera, N.; Watanabe, H. Bioorg.
H O at 0 °C. The product was extracted with Et O (3 × 10 mL) and
2
2
Med. Chem. Lett. 1994, 4, 753. (f) Kubodera, N.; Watanabe,
H.; Kawanishi, T.; Matsumoto, M. Chem. Pharm. Bull.
the combined organic phases were dried over Na SO . Filtration and
2
4
solvent evaporation afforded a residue, which was chromato-
graphed on silica gel (EtOAc–hexane, 5:95) affording 12 mg of 14
1992, 40, 1494.
(
7) (a) Reppe, W. Liebigs Ann. Chem. 1955, 596. (b) Weiberth,
F. J.; Hall, S. S. J. Org. Chem. 1985, 50, 5308. (c) Zimmer,
R. Synthesis 1993, 165. (d) Hoff, S.; Brandsma, L.; Arens, J.
F. Recl. Trav. Chim. Pays-Bas 1968, 87, 916. (e) Tsuji, J.;
Mandai, T. Angew. Chem., Int. Ed. Engl. 1995, 34, 2589.
(f) Neguishi, E.; Yoshida, T.; Abramovitch, A.; Lew, G.;
Williams, R. M. Tetrahedron 1991, 343. (g) Tsuji, J.
(
80%).
Colorless oil; R 0.38 (EtOAc–hexane, 20:80).
f
1
H NMR (CDCl ): d = 3.98 (1 H, s, H-8), 3.69 (1 H, m, H-20), 1.97
3
(
1 H, d, J = 12.3 Hz, H-14), 0.97 (3 H, s, CH -18), 0.85 [9 H, br s,
3
SiC(CH ) ], –0.03 (3 H, s, CH Si), –0.04 (3 H, s, CH Si).
3
3
3
3
1
3
C-NMR (CDCl ): d = 70.17 (CH-20), 69.15 (CH-8), 59.13 and
3
Palladium Reagents and Catalysts; John Wiley: Chichester,
5
2
1
–
2.60 (CH-17 and CH-14), 41.94 (C-13), 40.91 (CH ), 34.41 (CH ),
5.80 [SiC(CH ) ], 24.74 (CH ), 23.34 (CH -21), 23.23 (CH ),
8.02 [SiC(CH ) ], 17.53 (CH ), 14.34 (CH -18), –4.80 (CH Si),
5.18 (CH Si).
2
2
1
995. (h) Sonogashira, K. Comprehensive Organic
3
3
2
3
2
Synthesis, Vol. 3; Pergamon: Oxford, 1990, 521. (i) Farina,
V. Comprehensive Organometallic Chemistry, Vol .12;
Pergamon: Oxford, 1992, 222.
3
3
2
3
3
3
Synthesis 2005, No. 10, 1701–1705 © Thieme Stuttgart · New York

SPECIAL TOPIC
Analogues of OCT Modified at C-20, C-21, and the D-Ring
1705
(
8) (a) Castedo, L.; Mouriño, A.; Sarandeses, L. A. Tetrahedron
Lett. 1986, 27, 1523. (b) Torneiro, M.; Fall, Y.; Castedo, L.;
Mouriño, A. Tetrahedron 1997, 53, 10851. (c) Fall, Y.;
Torneiro, M.; Castedo, L.; Mouriño, A. Tetrahedron 1997,
(10) Fernández, B.; Martínez Pérez, J. A.; Granja, J. R.; Castedo,
L.; Mouriño, A. J. Org. Chem. 1992, 57, 3173.
(11) Mahrwald, R.; Schick, H. Angew. Chem., Int. Ed. Engl.
1991, 30, 593.
5
3, 4703. (d) Trost, B. M.; Dumas, J. J. Am. Chem. Soc.
(12) (a) Posner, G. H.; White, M. C.; Dolan, P.; Peleg, S.;
Kensler, T. W. Bioorg. Med. Chem. Lett 1994, 4, 2919.
(b) Fall, Y. Tetrahedron Lett. 1997, 38, 4909.
1
992, 114, 1924. (e) Trost, B. M.; Dumas, J.; Villa, M. J.
Am. Chem. Soc. 1992, 114, 9836.
(9) (a) Skoda-Földes, R.; Collar, L. Chem. Rev. 2003, 103,
4
095. (b) Kataoka, H.; Watanabe, K.; Miyazaki, K.; Tahara,
S.; Ogu, K.; Matsuoka, R.; Goto, K. Chem. Lett. 1990, 1705.
c) Vijaykumar, D.; Mao, W.; Kirschbaum, K. S.;
Katzenellenbogen, J. A. J. Org. Chem. 2002, 67, 4904.
(
Synthesis 2005, No. 10, 1701–1705 © Thieme Stuttgart · New York