Stereoselective syntheses of 20-epi cholanic acid derivatives from 16-dehydropregnenolone acetate

Article abstract of DOI:10.1016/j.tet.2007.04.014

A stereoselective total synthesis of naturally occurring 20-epi cholanic acid derivatives has been realized, starting from readily available 16-dehydropregnenolone acetate. The key step of these syntheses involves an ionic hydrogenation of a C-20,22-ketene dithioacetal and deoxygenation of steroidal C-20 tert-alcohols, to set up the unnatural C(20R) configuration with 100% stereoselectivity. The unnatural C-22 aldehydes with C(20R) stereocenters thus obtained were elaborated to 20-epi cholanic acid derivatives. Two derivatives of 20-epi cholanic acid were synthesized and their structures have been confirmed by single crystal X-ray analysis. Catalytic hydrogenation of 16-dehydropregnenolone acetate and 16-dehydropregnenolone in ethanol affords C-5,C-16 tetrahydro products. Crystal structure analysis of one of these products revealed C-5α and C-17α configurations of the hydrogen atoms.

Full text of DOI:10.1016/j.tet.2007.04.014

Tetrahedron 63 (2007) 5622–5635
Stereoselective syntheses of 20-epi cholanic acid derivatives from
16-dehydropregnenolone acetate
a,
Bapurao B. Shingate,a Braja G. Hazra,a, Vandana S. Pore, Rajesh G. Gonnadeb,y and
*
*
Mohan M. Bhadbhadeb,y
aOrganic Chemistry Synthesis Division, National Chemical Laboratory, Pune 411 008, India
bCentre for Materials Characterization, National Chemical Laboratory, Pune 411 008, India
Received 5 December 2006; revised 14 March 2007; accepted 5 April 2007
Available online 14 April 2007
Abstract—A stereoselective total synthesis of naturally occurring 20-epi cholanic acid derivatives has been realized, starting from readily
available 16-dehydropregnenolone acetate. The key step of these syntheses involves an ionic hydrogenation of a C-20,22-ketene dithioacetal
and deoxygenation of steroidal C-20 tert-alcohols, to set up the unnatural C(20R) configuration with 100% stereoselectivity. The unnatural C-
22 aldehydes with C(20R) stereocenters thus obtained were elaborated to 20-epi cholanic acid derivatives. Two derivatives of 20-epi cholanic
acid were synthesized and their structures have been confirmed by single crystal X-ray analysis. Catalytic hydrogenation of 16-dehydropreg-
nenolone acetate and 16-dehydropregnenolone in ethanol affords C-5,C-16 tetrahydro products. Crystal structure analysis of one of these
products revealed C-5a and C-17a configurations of the hydrogen atoms.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
to introduce such modified side chains into readily available
steroids. Compounds with unnatural configuration at C-20
have attracted attention because of the interesting biological
activities of these epimers9 and hence methods for their
stereoselective synthesis are highly desirable. Koreeda has
pointed10 that 20-isocholesterol 1 (Chart 1) with C(20S) ste-
reochemistry showed significant in vitro inhibitory activity
The isolation and synthesis of many biologically important
steroids with modified side chains,1 such as ecdysones,2 me-
tabolite of vitamin D3,3 brassinosteroids,4 squalamine,5
OSW-1,6 contignasterol,7 and marine sterols,8 have stimu-
lated much interest for the development of efficient methods
R'
20
H
H
25
R
23
OH
OH
H
H
H
H
F
H
H
HO
1
1
OH
HO
HO
H
2a, R = CH3, R' = H
3
, R = H, R' = CH
2b
3
O
O
O
O
H
H
H
H
OMe
OMe
OMe
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
AcO
AcO
AcO
AcO
H
5
4
6
7
Chart 1. Isocholesterol 1, vitamin D3 2, deltanoid (Ro 26-9228) 3, and 20(S) cholanic acid derivatives 4–7.
Keywords: Ionic hydrogenation; Catalytic hydrogenation; Steroidal aldehydes; 20-epi Cholanic acid derivatives; Wittig reaction.
* Corresponding authors. Tel.: +91 20 25902055; fax: +91 20 25902624; e-mail addresses: bg.hazra@ncl.res.in; vs.pore@ncl.res.in
Tel.: +91 20 25902252; fax: +91 20 25902642.
y
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.014

B. B. Shingate et al. / Tetrahedron 63 (2007) 5622–5635
5623
H
H
H
H
CHO
H
CHO
H
CHO
H
CHO
H
OPG
H
H
H
H
H
H
H
H
H
H
H
PGO
AcO
AcO
H
OMe
10
8
9
11
Chart 2. Steroidal C(20R) aldehydes 8–11.
for the conversion of cholesterol to pregnenolone. Recently,
it has been reported9f,11 that in the 20-epi analog of the
metabolite of vitamin D3, 2a is more potent in regulating
cell growth and cell differentiation than the corresponding
compound with natural C-20 stereoisomer 2b. It is also
interesting to mention that the 20-epi analog 2a exhibits im-
munosuppressive properties12 and that of 1a-fluoro-16,23-
diene-20-epi hybrid deltanoid (Ro 26-9228) 3 is in human
clinical trials for the treatment of osteoporosis13 (Chart 1).
Djerassi et al.9a,b have isolated four 20-epi cholanic acid
derivatives 4–7 (Chart 1) with unnatural configuration at
C-20 from a sea pen, Ptilosarcus guerneyi and also devised
methods for their synthesis. The key intermediate for the syn-
thesis of these sterols 4–7 is the unnatural C(20R) aldehyde 9,
which was obtained by epimerization of the corresponding
(20S)aldehydein pooryield (Chart 2). Again, synthesis ofthe
20-epi cholanic acid derivatives 4, 5, and 7 has been carried
out by Takano et al.14a and by Dauben and Brookhart.14b The
aldehyde 8 has been prepared by base catalyzed epimeriza-
tion15 of natural C(20S) aldehyde and Lewis acid catalyzed
rearrangement of a C-20,22-oxido steroid16 in poor yield.
The unnatural C(20R) aldehyde 11 was prepared by epimeri-
zation of the corresponding 20(S) aldehyde, is the key inter-
mediate for the synthesis of the 20-epi vitamin D3 analogs.17
Construction of the steroidal side chain with unnatural con-
figuration at C-20 by using various organometallic re-
agents,18 specific reactions,19 and rearrangements20 has
been documented. However, much attention has not been
given for the synthesis of unnatural configuration at C-20
starting from readily available21 16-dehydropregnenolone
acetate (16-DPA) 12. We have reported22 the synthesis of
S
O
H
OH
O
S
H
H
H
a
d
H
+
H
H
H
H
H
H
AcO
RO
TBDMSO
OH
13
, R = Ac
12
16
b
c
H
14, R = H
15, R = TBDMS
H
H
H
(4%)
RO
17, R = TBDMS
18, R = H
19, R = Ac
e
f
S
S
H
S
j
S
H
H
H
H
g
16
H
H
H
H
RO
RO
23, R = Ac
24, R = H
25, R = Ts
20, R = TBDMS
21, R = H
22, R = Ac
h
i
k
l
S
H
H
H
H
CHO
H
CHO
H
S
H
H
H
n
o
m
25
23
H
H
H
H
H
H
AcO
8
OMe
9
OMe
26
Scheme 1. Reagents and conditions: (a) 10% Pd–C, H2, EtOAc, 45 psi, 30 ꢀC, 12 h, 98%; (b) KOH, MeOH, H2O, 30 ꢀC, 2 h, 97%; (c) TBDMSCl, imidazole,
DMF, 30 ꢀC, 10 h, 92%; (d) 1,3-dithiane, n-BuLi, THF, ꢁ30 ꢀC for 2 h and 0 ꢀC for 12 h, 82%; (e) n-Bu4NF, THF, 30 ꢀC, 18 h, 93%; (f) Ac2O, pyridine, DMAP,
25 ꢀC, 2 h, 96%; (g) SOCl2, pyridine, CH2Cl2, ꢁ5 ꢀC, 5 min, 84%; (h) n-Bu4NF, THF, 25 ꢀC, 12 h, 93%; (i) Ac2O, pyridine, DMAP, 30 ꢀC, 3 h 98%; (j) Et3SiH,
CF3COOH, CH2Cl2, 25 ꢀC, 18 h, 89%; (k) KOH, MeOH, THF, 30 ꢀC, 4 h, 92%; (l) p-toluenesulfonyl chloride, pyridine, 30 ꢀC, 12 h, 94%; (m) HgO, HgCl2,
CH3CN, H2O, reflux, 3 h, 96%; (n) MeOH, CH3COONa, reflux, 4 h, 83%; (o) Dess–Martin periodinane, CH3CN, CH2Cl2–H2O, 30 ꢀC, 5 h, 55%.

5624
B. B. Shingate et al. / Tetrahedron 63 (2007) 5622–5635
steroidal C-20 tert-alcohols, (ii) study of the effects of sol-
S
S
H
OH
H
vents on catalytic hydrogenation of 16-DPA 12 and 16-dehy-
dropregnenolone 29 and confirmation of the stereochemistry
of tetrahydro product by crystal structure analysis, (iii) the
elaboration of the unnatural C(20R) aldehyde 8 to naturally
occurring 20-epi cholanic acid derivatives 4 and 5, also (iv)
conversion of C-5(6)-saturated unnatural C(20R) aldehyde
10 to cholanic acid derivatives 6 and 7 (Scheme 4). The
structures of naturally occurring 20-epi cholanic acid deriv-
atives 4 and 6 were confirmed unambiguously by single
crystal X-ray analysis.
S
S
H
H
H
c
8
H
H
H
H
d
RO
AcO
23
16, R = TBDMS
27, R = H
a
b
S
H
28, R = Ac
S
H
H
c
16 or 27
9
H
H
2. Results and discussion
HO
24
2.1. Synthesis of steroidal unnatural C(20R) aldehydes 8
and 9 by ionic hydrogenation of the C-20,22-ketene
dithioacetal
Scheme 2. Reagents and conditions: (a) n-Bu4NF, THF, 30 ꢀC, 18 h, 93%;
(b) Ac2O, pyridine, DMAP, 25 ꢀC, 2 h, 96%; (c) Et3SiH, BF3$OEt2, DCM,
0 ꢀC, 10 min, 90–94%; (d) see Scheme 1, reagents and conditions: (l), (n),
and (o).
Commercially available 16-dehydropregnenolone acetate 12
on chemoselective catalytic hydrogenation with 10% palla-
dium on charcoal in ethyl acetate, hydrolysis of the acetate
13 with potassium hydroxide in aqueous methanol, followed
by protection of 3b-hydroxy group in N,N-dimethylform-
amide (DMF) afforded compound 1524 with an overall yield
of 87% in three steps (Scheme 1). Compound 15 on reaction
with 2-lithio-1,3-dithiane in THF at ꢁ30 ꢀC furnished ste-
reoselectively the C-20-hydroxydithiane 16 in 82% yield.
Addition of 2-lithio-1,3-dithiane to 20-keto pregna deriva-
tives is known25 to generate stereoselectively the C(20R)
configuration at this center. When the addition of compound
steroidal unnatural C(20R) aldehydes 8 and 9 by the ionic
hydrogenation of the C-20,22-ketene dithioacetal 22 with
excellent unnatural C(20R) stereoselectivity (Scheme 1).
Very recently, we have reported23 the synthesis of the
same aldehydes 8 and 9 by the deoxygenation of tertiary al-
cohols 16, 27, and 28 (Scheme 2). Synthesis of the C-5(6)-
saturated unnatural C(20R) aldehyde 10 by deoxygenation
of alcohol 35 has also been reported23 (Scheme 3). Now
we wish to report here: (i) details of the ionic hydrogenation
of the C-20,22-ketene dithioacetal and deoxygenation of
S
OH
O
O
S
H
H
H
H
H
b
d
a
12
+
H
H
H
H
H
H
OH
RO
TBDMSO
HO
H
H
H
29
30, R = H
31, R = TBDMS
32
c
H
H
H
TBDMSO
H
33 (5%)
S
S
H
OH
H
CHO
H
S
S
H
H
H
H
H
g
e
h
32
H
H
H
H
H
H
RO
AcO
AcO
H
H
H
10
34, R = H
36
f
35, R = Ac
O
H
H
b
12
H
H
AcO
H
37
Scheme 3. Reagents and conditions: (a) KOH, t-BuOH, H2O, 30 ꢀC, 10 h, 96%; (b) 10% Pd–C, H2, EtOH, 55 psi, 30 ꢀC, 12 h, 99%; (c) TBDMSCl, imidazole,
DMF, 30 ꢀC, 10 h, 97%; (d) 1,3-dithiane, n-BuLi, THF, ꢁ30 ꢀC for 2 h and 0 ꢀC for 12 h, 82%; (e) n-Bu4NF, THF, 30 ꢀC, 18 h, 93%; (f) Ac2O, pyridine, DMAP,
25 ꢀC, 2 h, 97%; (g) Et3SiH, BF3$OEt2, DCM, 0 ꢀC, 10 min, 94%; (h) HgO, HgCl2, CH3CN, H2O, reflux, 3 h, 96%.

B. B. Shingate et al. / Tetrahedron 63 (2007) 5622–5635
5625
O
O
H
H
H
CHO
H
OMe
OMe
H
H
H
H
H
a
b
H
H
H
H
H
H
AcO
AcO
AcO
AcO
O
4
5
8
O
H
H
H
CHO
OMe
OMe
H
H
H
H
H
H
a
b
H
H
H
H
H
H
AcO
AcO
H
H
H
7
6
10
Scheme 4. Reagents and conditions: (a) Ph3P]CHCO2Me, THF, reflux, 48 h, 4 (95%), 6 (93%); (b) H2, 10% Pd–C, EtOAc, 45 psi, 10 h, 5 (99%), 6 (97%).
15 to 2-lithio-1,3-dithiane was done at ꢁ45 ꢀC, C-20-hydr-
oxydithiane 16 was isolated in 77% yield, along with the
side product 17 (4%). This compound 17 was then prepared
in 91% yield by the reaction of 15 with n-BuLi. The C(20S)
configuration of compound 17 was confirmed by X-ray anal-
ysis of the 3b-acetate 19 (obtained by deprotection of
TBDMS group in compound 17 and acetylation of the
hydroxy product 18) (Fig. 1).
In the present ionic hydrogenation, there is formation of car-
bocation at C-22 to give the sulfur-stabilized intermediate29b
22A (Chart 3). Concomitant protonation (from F3CCOOH)
at C-20 in compound 22 from the less hindered a-face of
the steroid backbone led to the formation of carbocation at
C-22, followed by simultaneous transfer of hydride (from
Et3SiH) at C-22 resulted in the exclusive formation of the
C(20R)-methyl product 23. Ionic hydrogenation of com-
pound 22 is chemoselective as the 5,6-double bond is
unaffected.
Dehydration of the C(20R)-tert-alcohol 16 following a
literature procedure27 afforded ketene dithioacetal 20 in
69% yield (Scheme 1). Use of SOCl2–pyridine in CH2Cl2
at ꢁ5 ꢀC for 5 min gave C-20,22-ketene dithioacetal 20 in
84% yield. The attempted reduction of the C-20,22-double
bond of compounds 20–22 by catalytic hydrogenation with
Pd–C, with Mg in methanol, and with Zn in acetic acid28 re-
sulted in recovery of the starting materials. Ionic hydrogena-
tion29 of compound 20 with triethylsilane and trifluoroacetic
acid in dichloromethane at varying temperatures (0–30 ꢀC)
led to a mixture of products, in which deprotection of the
TBDMS group takes place and 3b-hydroxy compound 21
was isolated in 58% yield. Compound 21 was then obtained
by deprotection of the TBDMS group of 20 with n-tetra-
butylammonium fluoride (n-Bu4NF). Acetylation of the
3b-OH group of compound 21 with acetic anhydride and
catalytic N,N-dimethylaminopyridine (DMAP) in pyridine
furnished the 3b-acetate 22 in 86% yield over two steps.
Ionic hydrogenation of the C-20,22-ketene dithioacetal 22
using triethylsilane and trifluoroacetic acid afforded the
C(20R) saturated compound 23 in 89% yield.
Exclusive formation of the unnatural C(20R)-methyl com-
pound 23 by ionic hydrogenation of the C-20,22-ketene
dithioacetal 22 is confirmed by a single C-21 methyl at
1
d 1.05 ppm (d, J¼6 Hz) in the H NMR spectrum and by
a single methyl signal at d 15.8 ppm in the 13C NMR spec-
trum. This was further confirmed unequivocally by crystal
structure analysis (Fig. 2).
S
H
S
S
H
H
+
21
H
22
H
S
S
S
20
H_
H+
H
H
H
H
H
AcO
22
22A
23
Chart 3. Mechanism of ionic hydrogenation of the C-20,22-ketene dithio-
acetal 22.
Figure 1. ORTEP26 view of 3b-acetoxy-20(S)-hydroxy-20-butyl-pregna-5-ene 19.

5626
B. B. Shingate et al. / Tetrahedron 63 (2007) 5622–5635
Figure 2. ORTEP view of 3b-acetoxy-pregna-5-en-(20R)-20-dithiane 23.
The crystal structure shows that the C-20 dithiane moiety is
to the left side of 17(20)-bond. It is known30 from crystal
structure data of sterols with the C-20 natural configuration
that the conformation about 17(20)-bond in the usual view of
the molecule C-22 is to the right. The preference of this
‘right handed’ rotational isomer probably derives from its
having the smallest of the groups on C-20 (the H-atom) in
front and, therefore, adjacent to C-18 in a pseudo 1,3-diaxial
fashion. On the other hand, in the C-20 unnatural configura-
tion, it should be the left-handed conformer, which is skew,
and which possesses the least steric compression, i.e., an
opposite conformational preference compared to the natural
one.
unnatural C(20R) configuration with 100% stereoselectivity
(Scheme 2). Compound 24 has been converted to its
iso-methyl ether 26. Intermediates 23 and 24 have been
elaborated to unnatural C(20R) aldehydes 8 and 9,
respectively.22,23
2.2.2. Synthesis of C-5(6)-saturated unnatural C(20R) al-
dehyde 10 by deoxygenation of C-20 tert-alcohol 35. After
the successful synthesis of steroidal C(20R) aldehydes 8 and
9, our next goal was to synthesize C-5(6)-saturated aldehyde
10. Starting from 16-dehydropregnenolone acetate 12, prep-
aration of the C-5(6)-saturated C(20R) aldehyde 10 was car-
ried out, following the procedure adopted for the synthesis of
aldehydes 8 and 9, which involved ionic hydrogenation of
the C-20 tertiary alcohol as a key step. 16-Dehydropregne-
nolone acetate 12 was converted to 3b-hydroxy compound
29 in 96% yield (Scheme 3). There are very recent reports
on the catalytic hydrogenation of pregnenolone 14 with
10% Pd–C in tetrahydrofuran–glacial acetic acid35a and in
ethanol35b to get compound 30 in 90% and 100% yield, re-
spectively. Marker has reported21 the hydrogenation of com-
pound 29 in the presence of 3% palladium–barium sulfate in
neutral solvents, such as ethanol and ether, to give 16,17-di-
hydro product 14, in which 5,6-olefinic bond remains
unchanged.
Removal of the C-20 dithiane moiety of compound 23 by ox-
idative hydrolysis afforded the known aldehyde9c,15 8 in
96% yield (Scheme 1). Hydrolysis of the 3b-acetate 23, to-
sylation of the 3b-hydroxy compound 24, and treatment of
the tosylate 25 with CH3COONa in dry CH3OH gave the
iso-methyl ether 26 in three steps with an overall 72% yield.
Oxidative hydrolysis of the C-20 dithiane moiety of com-
pound 26 results in the opening of the iso-methyl ether, de-
protection of the dithiane moiety, and formation of other
products, which were not characterized. Therefore, the
cleavage of the C-20 dithiane moiety of the acid-sensitive
iso-methyl ether 26 was carried out31 using Dess–Martin
periodinane reagent under mild conditions to afford the
known9b aldehyde 9 in 55% yield.
3b-Hydroxy compound 29 on catalytic hydrogenation in
ethanol with 10% Pd–C afforded 5a-pregnane-3b-ol-20-
one 30 in 99% yield (Scheme 3). Similarly, hydrogenation
of 16-dehydropregnenolone acetate 12 in ethanol has no
chemoselectivity, the tetrahydro compound 37 was isolated
in 98% yield. It is worth mentioning here that catalytic hy-
drogenation of 12 and 29 with 10% Pd–C in ethyl acetate
is chemoselective and reduces only the 16(17)-double
bond to afford36a compounds 13 and 14, respectively, in al-
most quantitative yields. Similar chemoselective reduction
of 16(17)-double bond is also reported by Marino and
Abe.36b A general trend, which could be termed ‘solvent ef-
fect’, is emerging from these hydrogenation experiments.
However, detail study of selective hydrogenation of 5(6)
and 16(17)-double bonds in compounds 12 and 29 in ethyl
acetate and ethanol has not been explored earlier and re-
ported here for the first time. The 3b-hydroxy group of 30
was transformed to its TBDMS derivative 31 in excellent
yield (97%). Compound 31 is an useful intermediate37 for
2.2. Stereoselective deoxygenation of steroidal C-20
tert-alcohols by ionic hydrogenation
2.2.1. Synthesis of steroidal unnatural C(20R) aldehydes
8 and 9 by deoxygenation of C-20 tert-alcohols 16, 27, and
28. Ionic hydrogenation is an effective method to reduce
tertiary alcohols.32 Very recently, stereoselective deoxy-
genation of the steroidal tertiary alcohols with triethylsilane
and BF3$OEt2 has been reported.33 Deoxygenative reduc-
tion of anomeric tertiary hydroxy group of lactols, bearing
1,3-dithianyl moiety at the same position, to cyclic ethers
has been documented.34 On the basis of these findings, we
have carried out23 deoxygenation of the C-20 tertiary alco-
hols possessing a-hydroxy-1,3-dithianyl moiety in com-
pounds 16, 27, and 28 with triethylsilane–borontrifluoride
diethyl etherate to get the products 23 and 24 having

B. B. Shingate et al. / Tetrahedron 63 (2007) 5622–5635
5627
the synthesis of azasterols, which are the inhibitors of sterol
24-methyltransferase in Leishmania species and Trypano-
soma cruzi. Crystal structure analysis of compound 31 un-
ambiguously reveals a-orientation of two hydrogens at C-5
and C-17 (Fig. 3).
synthesis of the 20-epi cholanic acid derivatives 4 and 5
from aldehyde 9 in three and four steps, respectively, in mod-
erate yield. Again, these authors have synthesized 20-epi
cholanic acid derivatives 6 with poor overall yield (z2%)
and compound 7 from 5 by catalytic hydrogenation in excel-
lent yield.
The compound 31 on reaction with 2-lithio-1,3-dithiane
gave 32 as a major product in 82% yield along with minor
amount of 33 (5%). Compound 32 on deprotection of the
TBDMS group with n-Bu4NF yielded 3,20-diol 34 in 93%
yield. The stereochemistry at C-20 of the 3b-hydroxy com-
pound 34 was assigned by spectroscopic data and unambig-
uously confirmed by single crystal X-ray structure analysis
(Fig. 4).
Elaboration of steroidal aldehyde 8 to methyl (20S,22E)-
3b-acetoxychola-5,22-dienoate 4 and methyl (20S)-3b-
acetoxychol-5-enoate 5 and also synthesis of methyl
(20S,22E)-3b-acetoxy-5a-chol-22-enate 6 and methyl (20S)-
3b-acetoxy-5a-cholanate 7 from the saturated aldehyde 10
is reported here. Wittig reaction on aldehydes 8 and 10
with carbomethoxymethylenetriphenylphosphorane38 (Ph3P]
CHCO2Me) in refluxing tetrahydrofuran for 48 h afforded
methyl (20S,22E)-3b-acetoxychola-5,22-dienoate 4 and
methyl (20S,22E)-3b-acetoxy-5a-chol-22-enate 6 in 95 and
93% yields, respectively (Scheme 4). Catalytic hydrogena-
tion of compounds 4 and 6 on 10% Pd–C in ethyl acetate
yielded methyl (20S)-3b-acetoxychol-5-enoate 5 and methyl
(20S)-3b-acetoxy-5a-cholanate 7 in 99 and 97% yields,
respectively.
Selective acetylation of the 3b-hydroxy group of compound
34 furnished the 3b-acetate 35, which on deoxygenation of
the C-20 tertiary alcohol by ionic hydrogenation afforded
compound 36 exclusively with unnatural C(20R) configura-
tion over two steps in 95% yield (Scheme 3). The synthesis
of the C(20R) aldehyde 10 in 96% yield by oxidative hydro-
lysis of C-20 dithiane moiety of compound 36 with HgO–
HgCl2 has been reported by us.23
Thus, the 20-epi cholanic acid derivatives 4–7 have been
synthesized from readily available 16-dehydropregnenolone
acetate 12 in 9 and 10 steps with an excellent overall yield of
55%. The physical and spectral properties of compounds
4–7 are identical in all respects with the compounds 4–7 re-
ported earlier.9b (20S)-Stereochemistry and C(22E)-configu-
ration in compounds 4 and 6 have been unequivocally
2.3. Elaboration of steroidal unnatural C(20R)
aldehydes to 20-epi cholanic acid derivatives 4–7
Djerassi and Vanderah obtained9b the crucial unnatural
C(20R) aldehyde 9 from stigmasterol in very poor yield
(z6%) over six steps. These authors have reported the
Figure 3. ORTEP view of 3b-tert-butyldimethylsilyloxy-5a-pregna-20-one 31.
Figure 4. ORTEP view of 3b,20(R)-dihydroxy-5a-pregna-20-dithiane 34 with methanol solvate.

5628
B. B. Shingate et al. / Tetrahedron 63 (2007) 5622–5635
Figure 5. ORTEP view of methyl (20S,22E)-3b-acetoxychola-5,22-dienoate 4.
Figure 6. ORTEP view of methyl (20S,22E)-3b-acetoxy-5a-chol-22-enate 6.
confirmed by single crystal X-ray structure analysis (Figs. 5
and 6).
The methodology used for the synthesis of 20-epi cholanic
acid derivatives may be useful for the synthesis of a variety
of other 20-epi steroids such as 20-epi vitamin D3 (which is
more active than the natural one), epi-cholesterol (which
shows totally different activity than natural cholesterol),
and other 20-epi steroids, whose biological activity has not
been explored yet.
3. Conclusions
A highly stereoselective total syntheses of naturally occur-
ring 20-epi cholanic acid derivatives have been achieved
via unnatural C(20R) aldehydes, starting from readily avail-
able 16-dehydropregnenolone acetate. Ionic hydrogenation
of the C-20,22-ketene dithioacetal or deoxygenation of ste-
roidal C-20 tert-alcohols is the key step to set the unnatural
C(20R) configuration with 100% stereoselectivity. The sol-
vent effect on the catalytic hydrogenation of 16-dehydro-
pregnenolone acetate and 16-dehydropregnenolone has
been thoroughly studied. The stereochemistries of the two
cholanic acid derivatives 4 and 6 at C-5,C-17,C-20, and
also C-22(E) configuration have been explicitly confirmed
by single crystal X-rays.
4. Experimental section
4.1. General methods
All melting points were determined on Yanco Micro melting
point apparatus and are uncorrected. Optical rotations were
obtained on Bellingham and Stanly ADP-220 Polarimeter.
Yields refer to chromatographically and spectroscopically
(1H and 13C NMR) homogeneous materials, unless other-
wise stated. Reactions were monitored by thin-layer

B. B. Shingate et al. / Tetrahedron 63 (2007) 5622–5635
5629
chromatography (TLC) using TLC aluminum sheets, silica
gel 60-F254 precoated, Merck, Germany and locating the
spots using UV light as the visualizing agent or spraying
with ethanolic phosphomolybdic acid (PMA) solution
followed by heating. Flash column chromatography was
carried out with silica gel (300–400 mesh). Preparative
thin-layer chromatography separations were carried out on
0.25 mm E. Merck silica gel plates (60-F254). 1H and
13C NMR spectra were recorded on Bruker AC-200
(200 MHz) at 200.13 and 50.32, or on a Bruker MSL-300
(300 MHz) at 300.13 and 75.47 or on a Bruker DRX-500
(500 MHz) spectrophotometer at 500.13 and 125.78, respec-
tively. Chemical shifts are given in d values relative to TMS
(tetramethylsilane) as internal standard. IR spectra were re-
corded on Shimadzu 8400 series FTIR instrument and values
are reported in cmꢁ1 units. Specific rotations ([a]D) are
reported in deg/dm and the concentration (c) is given in
g/100 ml in the specific solvent. Mass spectra were recorded
by either LC–MS or MS-TOF API QSTAR PULSAR spec-
trophotometer, samples introduced by infusion method us-
ing Electrospray Ionization Technique. Elemental analyses
were performed by CHNS-O EA 1108-Elemental analyzer,
Carloerba Instrument (Italy) or Elementor Vario EL (Ger-
many) and were within ꢂ0.4% of calculated values.
Elution with the same solvent system afforded 3b-tert-butyl-
dimethylsilyloxy-(20R)-20-hydroxy-pregna-5-en-20-dithiane
16 (3.415 g, 82%) as a colorless solid, from which, 75 mg
was crystallized from 5 mL of solvent (dichloromethane–
hexane 2:8). Mp: 229–230 ꢀC. [a]D30 ꢁ56.6 (c 2.4, CHCl3).
IR (Nujol, cmꢁ1): 3450 (–OH). 1H NMR (CDCl3,
300 MHz): d 5.32 (d, 1H, J¼6 Hz, 6-H), 4.15 (s, 1H, 22-
H), 3.49 (m, 1H, 3-H), 2.88 (m, 4H, dithiane-CH2), 1.44
(s, 3H, 21-H3), 1.00 (s, 3H, 19-H3), 0.89 (s, 9H, SiCMe3),
0.88 (s, 3H, 18-H3), 0.06 (s, 6H, SiMe2). 13C NMR
(CDCl3, 75 MHz): d 141.6 (C), 121.0 (CH), 76.8 (C), 72.6
(CH), 61.2 (CH), 56.9 (CH), 55.2 (CH), 50.1 (CH), 43.0
(C), 42.8 (CH2), 40.2 (CH2), 37.4 (CH2), 36.6 (C), 32.1
(CH2), 31.8 (CH2), 31.5 (CH2), 31.3 (CH), 30.8 (CH2),
26.0 (CH2), 25.9 (3ꢃCH3), 24.2 (CH3), 23.7 (CH2), 21.7
(CH2), 21.0 (CH2), 19.4 (CH3), 13.4 (CH3), ꢁ4.6
(2ꢃCH3). Anal. Calcd for C31H54O2SiS2: C, 67.63; H,
9.68. Found: C, 67.91; H, 9.35.
4.1.2. 3b,20(R)-Dihydroxy-pregna-5-en-20-dithiane (27).
To the solution of 3b-tert-butyldimethylsilyloxy-(20R)-20-
hydroxy-5-en-20-dithiane 16 (0.55 g, 1 mmol) in dry tetra-
hydrofuran (7 mL), 1 M of n-tetrabutylammonium fluoride
in tetrahydrofuran (2 mL, 2 mmol) was added. The reaction
mixture was stirred at 30 ꢀC for 12 h and then quenched with
aqueous ammonium chloride. Tetrahydrofuran was removed
under vacuo and the reaction mixture was extracted with eth-
yl acetate (2ꢃ100 mL). The combined organic extracts were
washed with brine (2ꢃ25 mL) and dried over Na2SO4. Sol-
vent was removed under reduced pressure to afford the crude
compound (0.523 g). Column chromatographic purification
over silica gel using ethyl acetate–petroleum ether (20:80,
Rf 0.4, 25% EA–PE) as eluant gave 27 (0.405 g, 93%) as
a colorless solid, out of which 58 mg was crystallized from
4 mL of solvent (ethyl acetate–hexane 6:4). Mp: 204 ꢀC.
[a]D26.8 ꢁ50.70 (c 0.35, CHCl3). IR (Nujol, cmꢁ1): 3506
(–OH). 1H NMR (CDCl3, 300 MHz): d 5.35 (d, 1H,
J¼6 Hz, 6-H), 4.15 (s, 1H, 22-H), 3.52 (m, 1H, 3-H), 2.88
(m, 4H, dithiane-CH2), 2.27 (d, 2H, J¼6 Hz, 4-H), 1.44 (s,
3H, 21-H3), 1.01 (s, 3H, 19-H3), 0.88 (s, 3H, 18-H3). 13C
NMR (CDCl3, 125 MHz): d 140.9 (C), 121.6 (CH), 76.8
(C), 71.8 (CH), 61.3 (CH), 56.9 (CH), 55.2 (CH), 50.1
(CH), 43.0 (C), 42.3 (CH2), 40.2 (CH2), 37.3 (CH2), 36.5
(C), 31.8 (CH2), 31.7 (CH2), 31.5 (CH2), 31.4 (CH2), 30.8
(CH2), 26.0 (CH2), 24.2 (CH3), 23.8 (CH2), 21.7 (CH2),
21.0 (CH2), 19.4 (CH3), 13.4 (CH3). MS (LC–MS) m/z:
454.99 (M+H2O), 435.99, 419.99, 339.99. Anal. Calcd for
C25H40O2S2: C, 68.75; H, 9.23; S, 14.68. Found: C, 68.69;
H, 9.40; S, 14.55.
4.1.1. 3b-tert-Butyldimethylsilyloxy-(20R)-20-hydroxy-
pregna-5-en-20-dithiane (16) and 3b-tert-butyl-dime-
thylsilyloxy-(20S)-20-hydroxy-20-butyl-pregna-5-ene
(17). In a two-necked round bottom flask equipped with
a magnetic stirring bar and a septum, 1,3-dithiane
(1.362 g, 11.34 mmol) was placed in dry tetrahydrofuran
(15 mL). The solution was cooled to ꢁ30 ꢀC and n-BuLi
in hexane (1.7 M, 8 mL, 13.6 mmol) was added to it drop-
wise under nitrogen atmosphere. The reaction mixture be-
came pale yellow and it was stirred at that temperature
for a period of 2 h. To it 3b-tert-butyldimethylsilyloxy-
pregna-5-en-20-one 1539 (3.256 g, 7.56 mmol) in anhydrous
tetrahydrofuran (20 mL) was added dropwise at ꢁ30 ꢀC
under nitrogen atmosphere. The reaction mixture slowly
brought to 0 ꢀC and was stirred at that temperature for an ad-
ditional 12 h. After the completion of the reaction, it was
quenched with cold saturated ammonium chloride solution
and THF was removed under reduced pressure. The residue
was extracted with ethyl acetate (4ꢃ100 mL). The organic
layer was washed with water (2ꢃ50 mL), brine (2ꢃ
50 mL), and dried over Na2SO4. Solvent was removed under
reduced pressure to afford crude compound (3.923 g). Flash
column chromatographic purification over silica gel using
ethyl acetate–petroleum ether (1:99, Rf 0.4 10% EA–PE)
as eluant afforded pure 3b-tert-butyldimethylsilyloxy-
(20S)-20-hydroxy-20-butyl-pregna-5-ene 17 (0.148 g, 4%)
as a white solid. Mp: 128–130 ꢀC (ethyl acetate–petroleum
4.1.3. 3b-Acetoxy-20(R)-hydroxy-pregna-5-en-20-
dithiane (28). To the solution of 3b,20(R)-dihydr-
oxy-pregna-5-en-20-dithiane 27 (0.436 g, 1 mmol) in dry
pyridine (2 mL) were added acetic anhydride (0.19 mL,
2 mmol) and catalytic amount of N,N-dimethylaminopyr-
idine (0.024 g, 0.2 mmol). The reaction mixture was stirred
at 25 ꢀC for 2 h, quenched with crushed ice, and extracted
with ethyl acetate (2ꢃ100 mL). The combined organic ex-
tracts were washed with brine (2ꢃ25 mL) and dried over
Na2SO4. The solvent was removed under reduced pressure
to give crude compound 28 (0.465 g). Column chromato-
graphic purification over silica gel using ethyl acetate–petro-
leum ether (6:94, Rf 0.5, 10% EA–PE) as an eluant afforded
1
ether). IR (Nujol, cmꢁ1): 3315 (–OH). H NMR (CDCl3,
300 MHz): d 5.32 (d, 1H, J¼6 Hz, 6-H), 3.49 (m, 1H, 3-
H), 1.28 (s, 3H, 21-H3), 1.01 (s, 3H, 19-H3), 0.89 (s, 9H,
SiCMe3), 0.87 (s, 3H, 18-H3), 0.06 (s, 6H, SiMe2). 13C
NMR (CDCl3, 75 MHz): d 141.6 (C), 121.0 (CH), 75.1
(C), 72.6 (CH), 57.8 (CH), 57.0 (CH), 50.2 (CH), 43.7
(CH2), 42.8 (CH2), 42.7 (C), 40.2 (CH2), 37.4 (CH2), 36.6
(C), 32.1 (CH2), 31.8 (CH2), 31.4 (CH2), 26.4 (CH3), 25.9
(3ꢃCH3), 23.7 (CH2), 23.3 (CH2), 22.4 (CH2), 20.9 (CH2),
19.4 (CH3), 18.2 (C), 14.0 (CH3), 13.6 (CH3), ꢁ4.6
(2ꢃCH3).

5630
B. B. Shingate et al. / Tetrahedron 63 (2007) 5622–5635
pure product 28 (0.46 g, 96%) as a colorless solid. From this
41 mg was crystallized in 3.5 mL of solvent (ethyl acetate–
hexane 3:7). Mp: 212–213 ꢀC. [a]D26.5 ꢁ57.83 (c 0.4,
CHCl3). IR (Nujol, cmꢁ1): 3506 (–OH), 1728 (–OCOCH3).
1H NMR (CDCl3, 300 MHz): d 5.37 (d, 1H, J¼6 Hz, 6-H),
4.60 (m, 1H, 3-H), 4.14 (s, 1H, 22-H), 2.88 (m, 4H,
dithiane-CH2), 2.33 (d, 2H, J¼6 Hz, 4-H), 2.03 (s,
3H, –OCOCH3), 1.44 (s, 3H, 21-H3), 1.02 (s, 3H, 19-H3),
0.88 (s, 3H, 18-H3). 13C NMR (CDCl3, 125 MHz): d 170.4
(C), 139.8 (C), 122.5 (CH), 76.8 (C), 74.0 (CH), 61.3 (CH),
56.8 (CH), 55.2 (CH), 50.0 (CH), 43.0 (C), 40.1 (CH2), 38.1
(CH2), 37.0 (CH2), 36.5 (C), 31.7 (CH2), 31.5 (CH), 31.4
(CH2), 30.8 (CH2), 27.8 (CH2), 26.0 (CH2), 24.2 (CH3),
23.7 (CH2), 21.7 (CH2), 21.4 (CH3), 20.9 (CH2), 19.3
(CH3), 13.4 (CH3). MS (LC–MS) m/z: 497 (M+H2O), 478
(M+), 461.99. Anal. Calcd for C27H42O3S2: C, 67.73; H,
8.84; S, 13.39. Found: C, 67.70; H, 8.46; S, 13.27.
42.6 (C), 42.3 (CH2), 40.5 (CH), 39.0 (CH2), 37.3 (CH2),
36.5 (C), 31.9 (CH), 31.8 (CH2), 31.7 (CH2), 31.7 (CH2),
30.7 (CH2), 27.3 (CH2), 26.5 (CH2), 20.5 (CH2), 21.2
(CH2), 19.4 (CH3), 16.0 (CH3), 12.1 (CH3). MS (LC–MS)
m/z: 438.02 (M+H2O), 422.02 (M+2). Anal. Calcd for
C25H40OS2: C, 71.37; H, 9.58; S, 15.24. Found: C, 71.17;
H, 9.62; S, 15.15.
4.1.6. 3b-Acetoxy-pregna-5-en-(20R)-22-aldehyde (8). To
a suspension of 3b-acetoxy-pregna-5-en-(20R)-20-dithiane
23 (0.231 g, 0.5 mmol) in CH3CN (5 mL) and H2O
(0.5 mL), HgO (0.16 g, 0.75 mmol) and HgCl2 (0.27 g,
1 mmol) were added. The reaction mixture was refluxed
for 3 h with vigorous stirring. The solid mass was filtered
through a pad of Celite and the residue was thoroughly
washed with ethyl acetate. The filtrate was diluted with
more ethyl acetate (100 mL). The total organic extracts
were washed with brine (2ꢃ25 mL), dried over Na2SO4,
and concentrated under reduced pressure to give a solid
(0.2 g), which was chromatographed over silica gel using
ethyl acetate–petroleum ether (2:98, Rf 0.42, 10% EA–PE)
as an eluant to afford pure compound 8 (0.18 g, 96%) as
a colorless solid. From this 33 mg was crystallized in
2 mL of solvent (ethyl acetate–hexane 3:7). Mp: 118–
120 ꢀC (lit.15 120–121 ꢀC). [a]2D4.6 ꢁ57.14 (c 0.385,
CHCl3). IR (Nujol, cmꢁ1): 2960, 1730 (–OCOCH3), 1710
4.1.4. 3b-Acetoxy-pregna-5-en-(20R)-20-dithiane (23).
The solution of 3b-acetoxy-20(R)-hydroxy-pregna-5-en-
20-dithiane 28 (0.239 g, 0.5 mmol) in dichloromethane
(5 mL) was cooled to 0 ꢀC. To it triethylsilane (0.48 mL,
3 mmol) was added, stirred for 10 min, and then borontri-
fluoride diethyl etherate (0.63 mL, 5 mmol) in dichlorome-
thane (2 mL) was added dropwise. The mixture was stirred
for 10 min and 10% sodium bicarbonate (10 mL) was added.
The reaction mixture was extracted with dichloromethane
(2ꢃ100 mL). The combined organic extracts were washed
with brine (2ꢃ25 mL), dried over Na2SO4, and concentrated
under reduced pressure to afford crude compound 23
(0.235 g). Flash chromatographic purification over silica
gel using ethyl acetate–petroleum ether (1:99, Rf 0.5, 10%
EA–PE) as an eluant gave pure compound 23 (0.204 g,
94%) as a colorless solid. From this 63 mg was crystallized
in 3 mL of solvent (diethyl ether–hexane 2:8). Mp: 175–
176 ꢀC. [a]D27.5 ꢁ32 (c 0.5, CHCl3). IR (Nujol, cmꢁ1):
1730 (–OCOCH3), 1236, 1045. 1H NMR (CDCl3,
200 MHz): d 5.38 (d, 1H, J¼6 Hz, 6-H), 4.62 (m, 1H, 3-
H), 4.39 (d, 1H, J¼4 Hz, 22-H), 2.85 (m, 4H, dithiane-
CH2), 2.04 (s, 3H, OCOCH3), 1.05 (d, 1H, J¼6 Hz, 21-
H3), 1.03 (s, 3H, 19-H3), 0.71 (s, 3H, 18-H3). 13C NMR
(CDCl3, 75 MHz): d 170.3 (C), 139.6 (C), 122.5 (CH),
73.9 (CH), 56.2 (CH), 55.5 (CH), 52.0 (CH), 50.1 (CH),
42.5 (C), 40.4 (CH), 38.9 (CH2), 38.1 (CH2), 36.6 (C),
36.1 (CH2), 31.9 (CH), 31.8 (CH2), 31.7 (CH2), 30.6
(CH2), 27.7 (CH2), 27.2 (CH2), 26.4 (CH2), 24.0 (CH2),
21.3 (CH3), 21.1 (CH2), 19.3 (CH3), 15.8 (CH3), 12.1
(CH3). MS (EI) m/z: 480.01 (M+H2O), 464.02 (M+1).
Anal. Calcd for C27H42O2S2: C, 70.69; H, 9.42; S, 14.54.
Found: C, 70.27; H, 9.14; S, 14.15.
1
(CHO), 1247. H NMR (CDCl3, 500 MHz): d 9.55 (d, 1H,
J¼5 Hz, CHO), 5.38 (d, 1H, J¼6 Hz, 6-H), 4.60 (m, 1H,
3-H), 2.03 (s, 3H, OCOCH3), 1.03 (d, 1H, J¼6 Hz, 21-
H3), 1.01 (s, 3H, 19-H3), 0.69 (s, 3H, 18-H3). 13C NMR
(CDCl3, 125 MHz): d 205.6 (CH), 170.4 (C), 139.8 (C),
122.3 (CH), 73.9 (CH), 56.2 (CH), 52.0 (CH), 50.1 (CH),
48.8 (CH), 42.2 (CH), 38.5 (C), 38.1 (C), 37.0 (CH2), 31.9
(CH2), 31.8 (CH), 29.7 (CH2), 27.8 (CH2), 26.5 (CH2),
23.9 (CH2), 21.4 (CH3), 20.8 (CH2), 19.3 (CH3), 13.5
(CH3), 12.8 (CH3). MS (LC–MS) m/z: 391.02 (M+H2O),
373.03 (M+1), 313.03. Anal. Calcd for C24H36O3: C,
77.37; H, 9.74. Found: C, 77.13; H, 9.83.
4.1.7. 3a,5-cyclo-6b-Methoxy-pregna-(20R)-22-aldehyde
(9). To a solution of 3a,5-cyclo-6b-methoxy-pregna-(20R)-
20-dithiane 26 (0.043 g, 0.1 mmol) in 1 mL of 8:1:1
MeCN–CH2Cl2–H2O was added Dess–Martin periodinane
reagent (0.085 g, 0.2 mmol) in one portion. The reaction
mixture was stirred at room temperature, exposed to air,
for 5 h. The reaction was quenched with 5 mL of 50%
NaHCO3 and extracted with dichloromethane (2ꢃ50 mL).
The combined organic extracts were washed with brine
(2ꢃ25 mL), dried over Na2SO4, and concentrated under
reduced pressure followed by purification of the product
by preparative thin-layer chromatography affords (0.02 g,
55%) the desired C-22 aldehyde 9 as a gum. [a]2D7 +42.97
4.1.5. 3b-hydroxy-pregna-5-en-(20R)-20-dithiane (24).
The procedure for the synthesis of 23 was followed. From
16 or 27 was obtained 90–92% of the title compound as a
white solid. From this 38 mg was crystallized in 2 mL of sol-
vent (ethyl acetate–hexane 4:6). Mp 184–185 ꢀC. [a]D25 ꢁ32
1
(c 0.605, CHCl3). H NMR (CDCl3, 500 MHz): d 9.55 (d,
1H, J¼6 Hz, CHO), 3.33 (s, 1H, OCH3), 1.03 (d, 3H,
J¼5 Hz, 21-H3), 1.01 (s, 3H, 19-H3), 0.73 (s, 3H, 18-H3).
The 1H NMR data of 9 is similar to the reported39 one.
1
(c 0.75, CHCl3). IR (Nujol, cmꢁ1): 3310 (–OH). H NMR
(CDCl3, 200 MHz): d 5.35 (d, 1H, J¼6 Hz, 6-H), 4.39 (d,
J¼4 Hz, 1H, 22-H), 3.54 (m, 1H, 3-H), 2.84 (m, 4H, di-
thiane-CH2), 2.30 (d, 2H, J¼6 Hz, 4-H), 1.05 (d, 3H,
J¼6 Hz, 21-H3), 1.02 (s, 3H, 19-H3), 0.71 (s, 3H, 18-H3).
13C NMR (CDCl3, 125 MHz): d 140.7 (C), 121.6 (CH),
71.8 (CH), 56.3 (CH), 55.6 (CH), 52.0 (CH), 50.2 (CH),
4.1.8. 16-Dehydropregnenolone (29). To a stirred solution
of 16-dehydropregnenolone acetate 12 (5.340 g, 15 mmol)
in tert-butanol (125 mL) was added solution of KOH
(4.2 g, 75 mmol) in H2O (5 ml). The reaction mixture was
stirred for 10 h at 30 ꢀC and tert-butanol was removed under
reduced pressure, crushed ice was added to it. The solid was

B. B. Shingate et al. / Tetrahedron 63 (2007) 5622–5635
5631
filtered and washed with cold water (5ꢃ25 mL). It was then
dried to yield 16-dehydropregnenolone 29 (4.52 g, 96%) as
a colorless solid. From this 100 mg was crystallized in 5 mL
of solvent (methanol–dichloromethane 9:1). Mp: 214–
215 ꢀC (lit.40 216 ꢀC). [a]D22.5 ꢁ27.27 (c 0.66, CH3OH). IR
(Nujol, cmꢁ1): 1654 (C]O), 3390 (–OH). 1H NMR
(300 MHz, CDCl3): d 6.72 (t, 1H, J¼3 Hz, 16-H), 5.37 (d,
1H, J¼5 Hz, 6-H), 3.53 (m, 1H, 3-H), 2.26 (s, 3H,
COCH3), 1.05 (s, 3H, 19-H3), 0.92 (s, 3H, 18-H3). 13C
NMR (75 MHz, CDCl3): d 196.7 (C), 155.4 (C), 144.2
(CH), 141.4 (C), 120.9 (CH), 71.6 (CH), 56.4 (CH), 50.5
(CH), 46.1 (C), 42.2 (CH2), 37.1 (CH2), 36.7 (CH), 34.7
(CH2), 32.2 (CH2), 31.6 (CH2), 31.5 (CH2), 30.2 (CH),
27.0 (CH3), 20.6 (CH2), 19.2 (CH3), 15.7 (CH3). MS (LC–
MS) m/z: 315 (M+1), 337 (M+Na), 353 (M+K). Anal. Calcd
for C21H30O2$0.5CH4O: C, 78.13; H, 9.76. Found: C, 78.12;
H, 9.78.
NMR (50 MHz, CDCl3): d 209.6 (C), 72.0 (CH), 63.8
(CH), 56.7 (CH), 54.3 (CH), 45.0 (CH), 44.2 (C), 39.1
(CH2), 38.6 (CH2), 37.1 (CH2), 35.5 (C), 35.4 (CH), 32.0
(CH2), 31.9 (CH2), 31.5 (CH3), 28.6 (CH2), 25.9 (3ꢃCH3),
24.4 (CH2), 22.7 (CH2), 21.2 (CH2), 18.2 (C), 13.4 (CH3),
12.3 (CH3), ꢁ4.6 (2ꢃCH3). Anal. Calcd for C27H48O2Si:
C, 74.93; H, 11.17. Found: C, 75.00; H, 11.37.
4.1.11. 3b-tert-Butyldimethylsilyloxy-(20R)-20-hydroxy-
5a-pregna-20-dithiane (32) and 3b-tert-butyl-dimethyl-
silyloxy-(20S)-20-hydroxy-20-butyl-5a-pregnane (33).
Compounds 32 (2.2673 g, 82%) and 33 (0.123 g, 5%)
were obtained from compound 31 (2.163 g, 5 mmol) follow-
ing identical experimental procedure adopted for the prepa-
ration of compounds 16 and 17 from compound 15.
4.1.11.1. Compound 32. Mp: 217–219 ꢀC (acetone).
[a]D23.7 ꢁ17.39 (c 0.57, CHCl3). IR (Nujol, cmꢁ1): 3388
1
4.1.9. 3b-Hydroxy-5a,17a-pregna-20-one (30). To a solu-
tion of 16-dehydropregnenolone 29 (1.572 g, 5 mmol) in
ethanol (100 mL) was added Pd–C catalyst (0.157 g, 10%)
and hydrogenation was carried out using Parr apparatus
at 55 psi pressure at 30 ꢀC for 12 h. The reaction mixture
was filtered and the filtrate was evaporated under reduced
pressure to obtain 3b-hydroxy-5a,17a-pregna-20-one 30
(1.576 g, 99%) as a colorless solid. From this 150 mg was
crystallized in 10 mL of solvent (methanol–dichlorome-
thane 9:1). Mp: 193–195 ꢀC (lit.41a 193–195 ꢀC, lit.41b
192–195 ꢀC, and lit.42 194 ꢀC). [a]2D3 +90.78 (c 0.70,
CH3OH) (lit.42 +93 and +91). IR (Nujol, cmꢁ1): 1691
(–OH). H NMR (200 MHz, CDCl3): d 4.14 (s, 1H, 22-H),
3.52 (m, 1H, 3-H), 2.90 (m, 4H, dithiane-CH2), 1.42 (s,
3H, 21-H3), 0.88 (s, 9H, SiCMe3), 0.85 (s, 3H, 19-H3),
0.79 (s, 3H, 18-H3), 0.05 (s, 6H, SiMe2). 13C NMR
(50 MHz, CDCl3): d 78.0 (C), 72.4 (CH), 61.5 (CH), 56.8
(CH), 55.5 (CH), 54.6 (CH), 45.2 (CH), 43.5 (C), 40.7
(CH2), 38.9 (CH2), 37.4 (CH2), 35.7 (C), 35.1 (CH), 32.2
(2ꢃCH2), 31.8 (CH2), 31.1 (CH2), 29.0 (CH2), 26.3 (CH2),
26.2 (3ꢃCH3), 24.4 (CH3), 23.9 (CH2), 21.9 (CH2), 21.4
(CH2), 18.5 (C), 13.9 (CH3), 12.6 (CH3), ꢁ4.3 (2ꢃCH3).
Anal. Calcd for C31H56O2SiS2: C, 67.33; H, 10.20; S,
11.59. Found: C, 67.22; H, 9.96; S, 11.33.
1
(C]O), 3388 (–OH). H NMR (200 MHz, CDCl3): d 3.60
(m, 1H, 3-H), 2.11 (s, 3H, COCH3), 0.81 (s, 3H, 19-H3),
0.60 (s, 3H, 18-H3). 13C NMR (50 MHz, CDCl3): d 209.7
(C), 70.9 (CH), 63.7 (CH), 56.5 (CH), 54.1 (CH), 44.7
(CH), 44.1 (C), 38.9 (CH2), 37.9 (CH2), 36.9 (CH2), 35.3
(C), 35.3 (CH), 31.9 (CH2), 31.4 (CH3), 31.2 (CH2), 28.5
(CH2), 24.3 (CH2), 22.6 (CH2), 21.1 (CH2), 13.3 (CH3),
12.2 (CH3). MS (LC–MS) m/z: 319 (M+1), 341 (M+Na),
357 (M+K). Anal. Calcd for C21H34O2: C, 79.19; H,
10.75. Found: C, 78.89; H, 11.03.
4.1.11.2. Compound 33. Mp: 124–126 ꢀC (ethyl acetate–
hexane). [a]3D1 +3.36 (c 0.59, CHCl3). IR (Nujol, cmꢁ1):
3392 (–OH). H NMR (CDCl3, 200 MHz): d 3.52 (m, 1H,
1
3-H), 1.24 (s, 3H, 21-H3), 0.86 (s, 9H, SiCMe3), 0.81 (s,
3H, 19-H3), 0.78 (s, 3H, 18-H3), 0.03 (s, 6H, SiMe2). 13C
NMR (CDCl3, 50 MHz): d 75.2 (C), 72.1 (CH), 57.7 (CH),
56.7 (CH), 54.4 (CH), 45.0 (CH), 43.7 (CH2), 42.9 (C),
40.4 (CH), 48.6 (CH2), 37.2 (CH2), 35.5 (C), 34.8 (CH),
32.0 (CH2), 31.9 (CH2), 28.8 (CH2), 26.5 (CH2), 26.4
(CH3), 25.9 (3ꢃCH3), 23.7 (CH2), 23.3 (CH2), 22.3 (CH2),
21.1 (CH2), 18.2 (C), 14.1 (CH3), 13.8 (CH3), 12.4 (CH3),
ꢁ4.6 (2ꢃCH3). Anal. Calcd for C31H58O2Si: C, 75.85; H,
11.91. Found: C, 75.70; H, 11.56.
4.1.10. 3b-tert-Butyldimethylsilyloxy-5a,17a-pregna-20-
one (31). To a solution of 3b-hydroxy-5a,17a-pregna-20-
one 30 (3.185 g, 10 mmol) in dry DMF (90 mL) under nitro-
gen atmosphere were added imidazole (1.020 g, 15 mmol)
and tert-butyldimethylsilyl chloride (1.875 g, 12.5 mmol).
The mixture was stirred at 30 ꢀC for 10 h. The resulting sus-
pension was quenched with cold water and extracted with di-
ethyl ether (2ꢃ200 mL) and washed with saturated sodium
bicarbonate (2ꢃ75 mL), 1 M HCl (2ꢃ25 mL), and water
(2ꢃ50 mL). The organic extracts were washed with brine
(2ꢃ50 mL) and dried over Na2SO4. Removal of solvent un-
der reduced pressure afforded crude compound (4.340 g).
Column chromatographic purification over silica gel using
ethyl acetate–petroleum ether (3:97; Rf 0.4, 10% EA–PE)
as an eluant afforded 3b-tert-butyldimethylsilyloxy-5a,17a-
pregna-20-one 31 (4.197 g, 97%) as a colorless solid. From
this 200 mg was crystallized in 10 mL of solvent (metha-
nol–dichloromethane 9:1). Mp: 140–141 ꢀC (lit.37 139–
140 ꢀC). [a]D23.4 +70.17 (c 0.57, CHCl3). IR (Nujol, cmꢁ1):
1708 (C]O). 1H NMR (200 MHz, CDCl3): d 3.55 (m, 1H,
3-H), 2.11 (s, 3H, COCH3), 0.89 (s, 9H, SiCMe3), 0.80 (s,
3H, 19-H3), 0.60 (s, 3H, 18-H3), 0.05 (s, 6H, SiMe2). 13C
4.1.12. 3b,20(R)-Dihydroxy-5a-pregna-20-dithiane (34).
The procedure for the synthesis of 27 was followed. From
32 was obtained 93% of the title compound as a white solid.
From this 50 mg was crystallized in 4 mL of solvent (meth-
anol–dichloromethane 9:1). Mp: 198–200 ꢀC. [a]D24 ꢁ13.63
1
(c 0.44, CHCl3). IR (Nujol, cmꢁ1): 3328 (–OH). H NMR
(200 MHz, CDCl3): d 4.14 (s, 1H, 22-H), 3.59 (m, 1H, 3-
H), 2.88 (m, 4H, dithiane-CH2), 1.42 (s, 3H, 21-H3), 0.85
(s, 3H, 19-H3), 0.80 (s, 3H, 18-H3). 13C NMR (CDCl3,
50 MHz): d 76.7 (C), 71.1 (CH), 61.1 (CH), 56.4 (CH),
55.1 (CH), 54.1 (CH), 44.7 (CH), 43.1 (C), 40.2 (CH2),
38.0 (CH2), 36.9 (CH2), 35.3 (C), 34.7 (CH), 31.8 (CH2),
31.4 (CH2), 31.3 (CH2), 30.7 (CH2), 28.6 (CH2), 25.9
(CH2), 24.0 (CH3), 23.5 (CH2), 21.5 (CH2), 21.0 (CH2),
13.5 (CH3), 12.2 (CH3).
4.1.13. 3b-Acetoxy-20(R)-hydroxy-5a-pregna-20-di-
thiane (35). The procedure for the synthesis of 28 was

5632
B. B. Shingate et al. / Tetrahedron 63 (2007) 5622–5635
followed. From 34 was obtained 97% of the title compound
as a white solid. From this 60 mg was crystallized in 6 mL of
solvent (methanol–dichloromethane 4:1). Mp: 243–244 ꢀC.
[a]D24 ꢁ17.02 (c 0.7, CHCl3). IR (Nujol, cmꢁ1): 3436
NMR (200 MHz, CDCl3): d 4.68 (m, 1H, 3-H), 2.11 (s,
3H, COCH3), 2.02 (s, 3H, OCOCH3), 0.82 (s, 3H, 19-H3),
0.60 (s, 3H, 18-H3). 13C NMR (50 MHz, CDCl3): d 209.3
(C), 170.5 (C), 73.4 (CH), 63.6 (CH), 56.5 (CH), 53.9
(CH), 44.5 (CH), 44.0 (C), 38.9 (CH2), 36.6 (CH2), 35.3
(CH2), 35.3 (C), 33.8 (CH2), 31.8 (CH2), 31.4 (CH3), 28.3
(CH2), 27.3 (CH2), 24.2 (CH2), 22.6 (CH2), 21.3 (CH3),
21.0 (CH2), 13.3 (CH3), 12.1 (CH3). MS (LC–MS) m/z:
360 (M+). Anal. Calcd for C23H36O3: C, 76.62; H, 10.06.
Found: C, 76.62; H, 10.36.
1
(–OH), 1730 (–OCOCH3). H NMR (200 MHz, CDCl3):
d 4.68 (m, 1H, 3-H), 4.13 (s, 1H, 22-H), 2.90 (m, 4H, di-
thiane-CH2), 2.02 (s, 3H, OCOCH3), 1.42 (s, 3H, 21-H3),
0.85 (s, 3H, 19-H3), 0.82 (s, 3H, 18-H3). 13C NMR
(CDCl3, 50 MHz): d 170.6 (C), 76.7 (C), 73.6 (CH), 61.1
(CH), 56.4 (CH), 55.1 (CH), 54.0 (CH), 44.5 (CH), 43.1
(C), 40.2 (CH2), 36.6 (CH2), 35.3 (C), 34.8 (CH), 33.9
(CH2), 31.7 (CH2), 31.5 (CH2), 30.8 (CH2), 28.5 (CH2),
27.4 (CH2), 26.0 (CH2), 24.0 (CH3), 23.6 (CH2), 21.5
(CH2), 21.4 (CH3), 21.0 (CH2), 13.5 (CH3), 12.1 (CH3).
MS (LC–MS) m/z: 503 (M+Na). Anal. Calcd for
C27H44O3S2: C, 67.45; H, 9.22; S, 13.33. Found: C, 67.08;
H, 9.13; S, 13.56.
4.1.17. Methyl (20S,22E)-3b-acetoxychola-5,22-dienoate
(4). To a solution of 3b-acetoxy-pregna-5-en-(20R)-22-alde-
hyde 8 (0.370 g, 1 mmol) in dry tetrahydrofuran (10 mL)
was added carbomethoxymethylenetriphenylphosphorane
(Ph3P]CHCO2Me) (1.336 g, 4 mmol) and it was refluxed
for 48 h. The reaction mixture was concentrated in vacuo
and the residue was extracted with ethyl acetate (2ꢃ
100 mL). The organic extracts were washed with brine (2ꢃ
25 mL), dried over Na2SO4, and concentrated under reduced
pressure to give a solid (1.7 g), which was chromatographed
over silica gel using ethyl acetate–petroleum ether (4:96, Rf
0.42, 10% EA–PE) as eluant to afford compound 4 (0.407 g,
95%) as a colorless long needles. From this 125 mg was
crystallized in 5 mL of solvent (methanol–dichloromethane
4:1). Mp: 151–152 ꢀC. [a]D25.7 ꢁ84.4 (c 0.91, CHCl3). IR
4.1.14. 3b-Acetoxy-5a-pregna-(20R)-20-dithiane (36).
Deoxygenation of C-20 tert-alcohol of 35 to compound 36
(0.874 g, 94%) was carried out following the procedure (Et3-
SiH, BF3$OEt2, DCM, 0 ꢀC, 10 min.) used for deoxygen-
ation of compound 28 to compound 23. From this 40 mg
was crystallized in 4 mL of solvent (methanol–dichlorome-
thane 9:1). Mp: 176–178 ꢀC. [a]D24.5 +11.82 (c 1.01, CHCl3).
1
IR (Nujol, cmꢁ1): 1730 (–OCOCH3). H NMR (200 MHz,
1
CDCl3): d 4.68 (m, 1H, 3-H), 4.37 (d, 1H, J¼2 Hz, 22-H),
2.84 (m, 4H, dithiane-CH2), 2.02 (s, 3H, OCOCH3), 1.06
(d, 3H, J¼6 Hz, 21-H3), 0.82 (s, 3H, 19-H3), 0.67 (s, 3H,
18-H3). 13C NMR (CDCl3, 50 MHz): d 170.5 (C), 73.6
(CH), 55.9 (CH), 55.4 (CH), 54.1 (CH), 51.9 (CH), 44.5
(CH), 42.7 (C), 40.4 (CH), 39.0 (CH2), 36.6 (CH2), 35.4
(C), 35.4 (CH), 33.9 (CH2), 31.8 (CH2), 31.6 (CH2), 30.5
(CH2), 28.5 (CH2), 27.4 (CH2), 27.2 (CH2), 26.3 (CH2),
23.9 (CH2), 21.3 (CH3), 21.2 (CH2), 15.9 (CH3), 12.2
(CH3), 12.1 (CH3). MS (LC–MS) m/z: 464 (M+). Anal.
Calcd for C27H44O2S2: C, 69.77; H, 9.54; S, 13.79. Found:
C, 69.87; H, 9.52; S, 13.74.
(Nujol, cmꢁ1): 1733 (–OCOCH3) 1718 (–COOCH3). H
NMR (CDCl3, 200 MHz): d 6.90 (dd, 1H, J¼16 and
10 Hz, 22-H), 5.81 (d, 1H, J¼16 Hz, 23-H), 5.38 (d, 1H,
J¼4 Hz, 6-H), 4.61 (m, 1H, 3-H), 3.73 (s, 3H, COOCH3),
2.03 (s, 3H, OCOCH3), 0.99 (d, 3H, J¼4 Hz, 21-H3), 0.97
(s, 3H, 19-H3), 0.64 (s, 3H, 18-H3). 13C NMR (CDCl3,
50 MHz): d 170.5 (C), 167.2 (C), 155.7 (CH), 139.7 (C),
122.4 (CH), 118.4 (CH), 73.9 (CH), 56.3 (CH), 55.9 (CH),
51.3 (CH), 49.9 (CH), 42.2 (C), 39.9 (CH3), 38.6 (CH2),
38.0 (CH2), 36.9 (CH2), 36.5 (C), 31.8 (CH2), 31.8 (CH),
27.7 (CH2), 27.6 (CH2), 24.0 (CH2), 21.4 (CH3), 20.7
(CH2), 20.1 (CH3), 19.2 (CH3), 12.1 (CH3). Anal. Calcd
for C27H40O4: C, 75.66; H, 9.40. Found: C, 75.38; H, 9.68.
4.1.15. 3b-Acetoxy-pregna-(20R)-22-aldehyde (10). Oxi-
dative hydrolysis of C-20 dithiane 36 (0.464 g, 1 mmol) to
the C-22 aldehyde 10 (0.360 g, 96%) was carried out by fol-
lowing identical procedure adopted for compound 8 from 23.
4.1.18. Methyl (20S)-3b-acetoxychol-5-enoate (5). To a so-
lution of methyl (20S,22E)-3b-acetoxychola-5,22-dienoate
4 (0.086 g, 0.2 mmol) in ethyl acetate (7 mL) was added
0.09 g of 10% Pd–C catalyst and hydrogenation was carried
out using Parr apparatus at 45 psi pressure, at 30 ꢀC for 10 h.
The reaction mixture was filtered and the filtrate was evapo-
rated under reduced pressure to obtain methyl (20S)-3b-ace-
toxychol-5-enoate 5 (0.087 g, 98%) as a colorless solid.
From this 25 mg was crystallized in 2 mL of solvent (meth-
anol–dichloromethane 9:1). Mp: 120–121 ꢀC. [a]D25.7 ꢁ52.28
(c 0.76, CHCl3). IR (Nujol, cmꢁ1): 1733 (–OCOCH3), 1725
Mp: 142–145 ꢀC (ethyl acetate–hexane). IR (Nujol, cmꢁ1):
1731 (–OCOCH3), 1716 (CHO). 1H NMR (CDCl3,
200 MHz): d 9.52 (d, 1H, J¼6 Hz, CHO), 4.68 (m, 1H, 3-
H), 2.02 (s, 3H, OCOCH3), 1.03 (d, 1H, J¼8 Hz, 21-H3),
0.81 (s, 3H, 19-H3), 0.66 (s, 3H, 18-H3). 13C NMR
(CDCl3, 50 MHz): d 205.8 (CH), 170.7 (C), 73.6 (CH),
55.9 (CH), 54.2 (CH), 52.0 (CH), 48.5 (CH), 44.6
(CH), 42.3 (C), 38.6 (CH2), 36.7 (CH2), 35.4 (C), 35.5
(CH), 33.9 (CH2), 31.9 (CH2), 28.5 (CH2), 27.4 (CH2),
26.4 (CH2), 23.8 (CH2), 21.4 (CH3), 20.8 (CH2), 13.5
(CH3), 13.0 (CH3), 12.1 (CH3). MS (LC–MS) m/z: 398
(M+Na), 414 (M+K). Anal. Calcd for C24H36O3: C, 76.96;
H, 10.22. Found: C, 76.90; H, 10.18.
1
(–COOCH3). H NMR (CDCl3, 200 MHz): d 5.38 (d, 1H,
J¼4 Hz, 6-H), 4.63 (m, 1H, 3-H), 3.67 (s, 3H, COOCH3),
2.03 (s, 3H, OCOCH3), 1.02 (s, 3H, 19-H3), 0.85 (d, 3H,
J¼4 Hz, 21-H3), 0.69 (s, 3H, 18-H3). 13C NMR (CDCl3,
50 MHz): d 174.7 (C), 170.5 (C), 139.6 (C), 122.5 (CH),
73.9 (CH), 56.6 (CH), 55.4 (CH), 51.4 (CH), 49.9 (CH),
42.3 (C), 39.5 (CH2), 38.1 (CH2), 36.9 (CH2), 36.5 (C),
34.6 (CH3), 31.8 (CH2), 31.8 (CH), 31.0 (CH2), 30.3
(CH2), 28.0 (CH2), 27.7 (CH2), 24.1 (CH2), 21.4 (CH3),
21.0 (CH3), 19.3 (CH3), 18.3 (CH3), 11.9 (CH3). Anal.
Calcd for C27H42O4: C, 75.31; H, 9.83. Found: C, 75.21;
H, 9.81.
4.1.16. 3b-Acetoxy-5a,17a-pregna-20-one (37). The pro-
cedure for the synthesis of 30 was followed. From 12 was
obtained 98% of the title compound as a colorless solid.
Mp: 144–146 ꢀC (methanol). [a]D31 +67 (c 0.92, CHCl3).
IR (Nujol, cmꢁ1): 1731 (–OCOCH3), 1704 (C]O). 1H

B. B. Shingate et al. / Tetrahedron 63 (2007) 5622–5635
5633
˚
4.1.19. Methyl (20S,22E)-3b-acetoxy-5a-chol-22-enoate
(6). Wittig olefination of the aldehyde 10 was carried out
for compound 6 following the procedure for the preparation
of compound 4 from the aldehyde 8.
P212121, a¼6.590(3), b¼12.750(6), c¼30.150(12) A,
V¼2533.5(19) A , Z¼4, rcalcd¼1.129 g cmꢁ3, m(Mo Ka)¼
3
˚
0.074 mmꢁ1, F(000)¼944, 2qmax¼50.00ꢀ, 18,276 reflec-
tions collected, 4436 unique, 2775 observed (I>2s(I))
reflections, 286 refined parameters, R value 0.0812,
wR2¼0.1477 (all data R¼0.1334, wR2¼0.1681), S¼1.075,
minimum and maximum transmission 0.9691 and 0.9967,
respectively, maximum and minimum residual electron
Yield: 93%. Mp: 121–122 ꢀC (MeOH). [a]2D4 +18.18 (c 0.55,
CHCl3). IR (Nujol, cmꢁ1): 1731(–OCOCH3), 1718 (–
COOCH3). H NMR (CDCl3, 200 MHz): d 6.89 (dd, 1H,
1
densities +0.132 and ꢁ0.150 eAꢁ3, CCDC no. 606456.
˚
J¼16 and 10 Hz, 22-H), 5.76 (d, 1H, J¼16 Hz, 23-H),
4.67 (m, 1H, 3-H), 3.73 (s, 3H, COOCH3), 2.02 (s, 3H,
OCOCH3), 0.97 (d, 3H, J¼6 Hz, 21-H3), 0.80 (s, 3H, 19-
H3), 0.61 (s, 3H, 18-H3). 13C NMR (CDCl3, 50 MHz):
d 170.7 (C), 167.3 (C), 155.8 (CH), 118.4 (CH), 73.7
(CH), 56.1 (CH), 54.2 (CH), 51.4 (CH), 44.6 (CH), 42.6
(C), 40.0 (CH), 38.9 (CH2), 36.9 (CH2), 36.7 (CH2), 35.4
(C), 35.4 (CH3), 34.0 (CH2), 31.9 (CH2), 28.5 (CH2), 27.6
(CH2), 27.4 (CH2), 24.0 (CH2), 21.4 (CH3), 20.9 (CH2),
20.1 (CH3), 12.3 (CH3), 12.2 (CH3). Anal. Calcd for
C27H42O4: C, 75.31; H, 9.83. Found: C, 75.23; H, 9.86.
Crystal data for compound 16 (C27H44O3): M¼416.62,
crystal dimensions 0.49ꢃ0.15ꢃ0.11 mm3, orthorhombic,
space group P212121, a¼9.202(4), b¼12.334(6), c¼
21.928(10) A, V¼2489(2) A , Z¼4, rcalcd¼1.112 g cmꢁ3
,
3
˚
˚
m(Mo Ka)¼0.070 mmꢁ1
,
2qmax¼50.0ꢀ, F(000)¼920,
12,394 reflections collected, 4370 unique, 2597 observed
(I>2s(I)) reflections, 277 refined parameters, R value
0.0431, wR2¼0.0841 (all data R¼0.0874, wR2¼0.0934),
S¼0.889, minimum and maximum transmission 0.9665
and 0.9927, maximum and minimum residual electron den-
sities +0.109 and ꢁ0.093 eAꢁ3, CCDC no. 606460.
˚
4.1.20. Methyl (20S)-3b-acetoxy-5a-cholanate (7). Cata-
lytic hydrogenation of compound 6 to compound 7 was
carried out following the procedure adopted for the hydroge-
nation of compound 4 to compound 5.
Crystal data for 31 (C27H48O2Si): M¼432.74, crystal dimen-
sions 0.42ꢃ0.16ꢃ0.09 mm3, orthorhombic, space group
˚
P212121, a¼7.289(3), b¼21.177(9), c¼35.260(15) A, V¼
3
Yield: 97%. Mp: 132–134 ꢀC (CH3OH). [a]D31 +5.71 (c 0.35,
CHCl3). IR (Nujol, cmꢁ1): 1731. 1H NMR (CDCl3,
200 MHz): d 4.69 (m, 1H, 3-H), 3.67 (s, 3H, COOCH3),
2.31 (m, 2H, 23-H2), 2.02 (s, 3H, OCOCH3), 0.83 (d, 3H,
J¼4 Hz, 21-H3), 0.82 (s, 3H, 19-H3), 0.66 (s, 3H, 18-H3).
Anal. Calcd for C27H44O4: C, 74.96; H, 10.25. Found: C,
75.16; H, 10.18.
5443(4) A ,Z¼8, rcalcd¼1.056 gcmꢁ3,m(MoKa)¼0.105 mmꢁ1
,
˚
F(000)¼1920, 2qmax¼50.00ꢀ, 44,081 reflections collected,
9588 unique, 4245 observed (I>2s(I)) reflections, 557 re-
fined parameters, R value 0.0727, wR2¼0.1515 (all data
R¼0.1900, wR2¼0.1911), S¼0.988, minimum and maxi-
mum transmissions 0.9569 and 0.9905, respectively, maxi-
mum and minimum residual electron densities +0.411 and
ꢁ0.274 eAꢁ3, CCDC no. 606457.
˚
4.2. Crystal structure analysis
Crystal data for 34 (C25H42O2S2$2(CH3OH)): M¼502.79,
Crystals of all the compounds were obtained from methanol
by slow evaporation. Crystals of all the compounds were thin
plates and best amongst them were selected using Leica
polarizing microscope. X-ray intensity data of all the
compounds were collected on a Bruker SMARTAPEX CCD
crystal dimensions 0.80ꢃ0.54ꢃ0.02 mm3, orthorhombic,
space group P212121, a¼7.5351(17), b¼10.129(2), c¼
3
37.329(8) A, V¼2849.2(11) A , Z¼4, rcalcd¼1.172 g cmꢁ3
,
˚
˚
m(Mo Ka)¼0.216 mmꢁ1, F(000)¼1104, 2qmax¼50.00ꢀ,
19,132 reflections collected, 4990 unique, 3908 observed
(I>2s(I)) reflections, 307 refined parameters, R value
0.1002, wR2¼0.1629 (all data R¼0.1309, wR2¼0.1715),
S¼1.274, minimum and maximum transmission 0.8469
and 0.9968, respectively, maximum and minimum residual
diffractometer with omega and phi scan mode, lMo Ka
¼
˚
0.71073 A at T¼133(2) K. All the data were corrected for
Lorentzian, polarization, and absorption effects using Bruk-
er’s SAINT and SADABS programs. The crystal structures
were solved by direct method using SHELXS-97 and the
refinement was performed by full matrix least squares of F2
using SHELXL-97.43 Hydrogen atoms were included in the
refinement as per the riding model.
electron densities +0.324 and ꢁ0.202 eAꢁ3, CCDC no.
˚
606458.
Acknowledgements
B.B.S. thanks the University Grants Commission, New Delhi
for Research Fellowship. The Emeritus Scientist Scheme
awarded to B.G.H. by the Council of Scientific and Industrial
Research, New Delhi is gratefully acknowledged.
Crystal data for 4 (C27H40O4): M¼428.59, crystal dimen-
sions 0.23ꢃ0.08ꢃ0.01 mm3, monoclinic, space group
˚
P21, a¼12.017(13), b¼6.259(7), c¼16.890(18) A, b¼
3
104.61(2)ꢀ, V¼1229(2) A , Z¼2, rcalcd¼1.158 g cmꢁ3
,
˚
m(Mo Ka)¼0.076 mmꢁ1
,
F(000)¼468, 2qmax¼50.00ꢀ,
Supplementary data
8729 reflections collected, 4146 unique, 2750 observed
(I>2s(I)) reflections, 285 refined parameters, R value
0.1146, wR2¼0.2481 (all data R¼0.1590, wR2¼0.2707), S¼
1.215, minimum and maximum transmission 0.9826 and
0.9989, respectively, maximum and minimum residual elec-
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.04.014.
tron densities +0.347 and ꢁ0.220 eAꢁ3, CCDC no. 606455.
˚
References and notes
Crystal data for 6 (C27H42O4): M¼430.61, crystal dimen-
sions 0.43ꢃ0.27ꢃ0.05 mm3, orthorhombic, space group
1. (a) Piatak, D. M.; Wicha, J. Chem. Rev. 1978, 78, 199–224;
(b) Redpath, J.; Zeelan, F. J. Chem. Soc. Rev. 1983, 12, 75–98;

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