Stereoselective syntheses of unnatural steroidal C(20R) aldehydes by ionic hydrogenation of C-20 tertiary alcohols

Article abstract of DOI:10.1016/j.tetlet.2006.10.116

Syntheses of three unnatural steroidal C(20R) aldehydes have been realised from 16-dehydropregnenolone acetate. The salient feature of the synthesis is the ionic hydrogenation of C-20 tertiary alcohols leading to the formation of the C(20R) unnatural isomer with complete stereoselectivity. Oxidative hydrolysis of the dithiane moiety furnished the C(20R) aldehydes.

Full text of DOI:10.1016/j.tetlet.2006.10.116

Tetrahedron Letters 47 (2006) 9343–9347
Stereoselective syntheses of unnatural steroidal C(20R)
aldehydes by ionic hydrogenation of C-20 tertiary alcohols
a
a,
a
*
Bapurao B. Shingate, Braja G. Hazra, Vandana S. Pore,
b,ꢀ
b,ꢀ
Rajesh G. Gonnade and Mohan M. Bhadbhade
a
Organic Chemistry Synthesis Division, National Chemical Laboratory, Pune 411 008, India
Centre for Materials Characterization, National Chemical Laboratory, Pune 411 008, India
b
Received 8 August 2006; revised 13 October 2006; accepted 19 October 2006
Available online 9 November 2006
Abstract—Syntheses of three unnatural steroidal C(20R) aldehydes have been realised from 16-dehydropregnenolone acetate. The
salient feature of the synthesis is the ionic hydrogenation of C-20 tertiary alcohols leading to the formation of the C(20R) unnatural
isomer with complete stereoselectivity. Oxidative hydrolysis of the dithiane moiety furnished the C(20R) aldehydes.
ꢀ
2006 Elsevier Ltd. All rights reserved.
1
0
Steroidal C-20 aldehydes are useful intermediates for the
synthesis of a variety of biologically active steroids such
available.
pared
These 20-epi isomers have been pre-
from unnatural steroidal C(20R) aldehydes
5
,11,12
1
a
1b
1c,d
as brassinosteroids,
OSW-1 ecdysones and sterols. Compounds with
unnatural configuration at C-20 such as isocholesterol
squalamine,
vitamin D3,
5–8 (Fig. 2), which in turn were obtained by epimerisa-
1
e
1f
2
5,11,12
tion
of the corresponding C(20S) aldehydes and
1
3
acid catalysed rearrangement of C-20,22-oxido ste-
roids. However, the yields of these aldehydes following
these methods are typically poor. Therefore, it was desir-
able to explore and establish an efficient route for the
stereoselective synthesis of steroidal C(20R) aldehydes.
1
, with C(20S) stereochemistry showed a significant
in vitro inhibitory activity for the conversion of choles-
3
terol to pregnenolone. In addition, 20-epi vitamin D
3
4
5
2
a, 20-epi cholanic acid derivatives 4a–d and other
0-epi steroids have attracted attention because of the
6
2
interesting biological activities of these epimers and
hence the methods for their stereoselective synthesis
Recently, we reported14 the synthesis of C(20R) alde-
hydes 5 (in five steps with an overall yield of 65%) and
6 (in eight steps with an overall yield of 27%) from a
common intermediate 10 by the ionic hydrogenation
of the C-20,22-ketene dithioacetal with a 100% stereo-
4
,7
are highly desirable (Fig. 1). Recently, it was reported
that the 20-epi analogue of the metabolite of vitamin D3,
a is more potent in regulating cell growth and differen-
2
1
4
tiation than the corresponding natural C-20 stereoiso-
selectivity. In continuation of this work, we report
here the stereoselective synthesis of aldehydes 5 and 6
by deoxygenation of steroidal C-20 tertiary alcohols
10–12 with 100% C(20R) stereoselectivity (Scheme 1).
This method involves fewer steps from the same inter-
mediate 10 and leads to excellent overall yields (alde-
hyde 5 in four steps with an overall yield of 81% and
aldehyde 6 in four steps with an overall yield of 38%).
Stereoselective synthesis of the unknown C-5(6)-satu-
rated C(20R) aldehyde 22 by deoxygenation of the
C-20 tertiary alcohol group of compound 20 is also
reported here (Scheme 2). Aldehyde 22 is an excellent
starting material for the synthesis of a variety of C-5
mer 2b. It is also interesting that the 20-epi analogue
8
2
a exhibits immunosuppressive properties and that
the 1a-fluoro-16,23-diene-20-epi hybrid deltanoid (Ro
6-9228) 3 is in human clinical trials for the treatment
2
9
of osteoporosis.
Several reports on the construction of the steroidal side
chain with unnatural configuration at C-20 using diffi-
cult to access reagents and specialised conditions are
Keywords: Stereoselective synthesis; Ionic hydrogenation; 1,3-Dithi-
ane; Unnatural C-20 aldehydes; Oxidative hydrolysis.
5
*
Corresponding author. Tel.: +91 20 25902055; fax: +91 20
5902624; e-mail: bg.hazra@ncl.res.in
saturated C-20-epi steroid side chain compounds.
2
Taking full advantage of the ionic hydrogenation of
tertiary alcohols, generation of the C(20R) stereocentre
ꢀ
Tel.: +91 20 25902252; fax: +91 20 25902636.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.116

9344
B. B. Shingate et al. / Tetrahedron Letters 47 (2006) 9343–9347
H
R'
R
H
2
5
2
0
23
OH
OH
H
H
H
H
H
H
F
HO
1
1
HO
OH
HO
2
a, R = CH ,R' = H
3
3
2b, R = H, R' = CH3
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
H
4a
4b
4c
4d
Figure 1. Isocholesterol 1, vitamin D
3
2, deltanoid (Ro 26-9228) 3 and 20(S) cholanic acid derivatives 4a–d.
H
H
H
H
CHO
H
CHO
H
CHO
H
CHO
H
OPG
H
H
H
H
H
H
H
H
H
H
H
AcO
THPO
PGO
H
OMe
5
6
7
8
Figure 2. Steroidal C(20R) aldehydes 5–8.
leading to the formation of steroidal C(20R) aldehydes
, 6 and 22 has been carried out successfully and is doc-
ionic hydrogenation with triethylsilane for the stereose-
lective reduction of hydroxylated estradiol derivatives
1
8
5
umented here.
have been well documented. On the basis of these find-
ings, we envisaged that C-20 tertiary alcohol 10 on ionic
hydrogenation would lead to the C-20 deoxygenated
Commercially available 16-dehydropregnenolone ace-
tate 9 was converted15a into its C(20R) tert-alcohol 10
in four steps with a 71% overall yield (Scheme 1). The
14
product in a single step instead of two steps (dehydra-
tion followed by ionic hydrogenation). It would also be
of interest to determine the extent of stereospecificity on
deoxygenation of the C-20 tertiary alcohol.
3
-tert-butyldimethylsilyl group of compound 10 was
deprotected with n-Bu NF in tetrahydrofuran followed
4
by the selective acetylation of the secondary alcohol of
diol 11 to afford acetate 12 in an 89% yield in two steps.
The attempted ionic hydrogenation of C-20 tert-alcohol
1
2 using triethylsilane and trifluoroacetic acid in di-
1
9
Ionic hydrogenation is an effective method for the re-
chloromethane at 34 ꢁC for 2 h furnished deoxygen-
ated product 13 having the C(20R) stereochemistry in
a low yield (41%). When the same reaction was carried
1
6
moval of tertiary alcohols and there are several reports
on the deoxygenation of steroidal alcohols. Palladium-
catalysed hydrogenolysis of steroidal C-20 tertiary
out using Et SiH and borontrifluoride–diethyl etherate
3
1
7a
17b
allylic carbonates, radical deoxygenation of steroi-
dal tertiary alcohols via trifluoroacetates using diphen-
ylsilane/di-tert-butylperoxide, radical deoxygenation
(BF ÆOEt ) at 0 ꢁC for 10 min, the C-20 deoxygenated
3
2
product 13 was obtained in an excellent yield (94%)
(Scheme 1). Compound 10, on exposure to similar reac-
tion conditions (Et SiH, BF ÆOEt ), led to deoxygen-
1
7c
of steroidal C-11 tertiary oxalates, deoxygenation of
20R)-20-hydroxy-20-isoxazolinyl steroids to isosteroi-
dal side chains by trifluoroacetic acid in refluxing nitro-
3
3
2
(
ation of the C-20 tert-alcohol along with deprotection
of the TBDMS group to give compound 14 in a 90%
yield. Under identical reaction conditions, the 3,20-diol
1
7d
methane in the presence of lithium perchlorate
and

B. B. Shingate et al. / Tetrahedron Letters 47 (2006) 9343–9347
9345
S
S
H
OH
H
O
S
H
S
H
H
H
Ref. 15
RO
c
H
H
H
H
H
H
AcO
AcO
9
10, R = TBDMS
13
a
11, R = H
d
b
12, R = Ac
S
5
H
S
H
H
c
Ref. 14
10 or 11
H
H
6
HO
14
Scheme 1. Reagents and conditions: (a) n-Bu
4
NF (2 equiv), THF, 30 ꢁC, 18 h, 93%; (b) Ac O (2 equiv), pyridine, DMAP (0.2 equiv), 25 ꢁC, 2 h, 96%;
2
(
c) Et
3
SiH (6 equiv), BF
3
ÆOEt
2
(10 equiv), DCM, 0 ꢁC, 10 min, 90–94%; (d) HgO (1.25 equiv), HgCl
2
3 2
(2 equiv), CH CN, H O, reflux, 3 h, 96%.
O
O
H
H
H
a
b
d
9
H
H
H
H
HO
RO
H
15
16, R = H
7, R = TBDMS
c
1
S
H
S
OH
H
H
CHO
H
S
S
H
H
H
H
g
h
H
H
H
H
H
H
RO
AcO
AcO
H
H
H
1
8, R = TBDMS
9, R = H
0, R = Ac
Scheme 2. Reagents and conditions: (a) KOH (5 equiv), t-BuOH, H
TBDMSCl (1.25 equiv), imidazole (1.5 equiv), DMF, 30 ꢁC, 10 h, 97%; (d) 1,3-dithiane (1.5 equiv), n-BuLi (1.8 equiv), THF, ꢀ30 ꢁC for 2 h and 0 ꢁC
for 12 h, 82%; (e) n-Bu NF (2 equiv), THF, 30 ꢁC, 18 h, 93%; (f) Ac O (2 equiv), pyridine, DMAP (0.2 equiv), 25 ꢁC, 2 h, 97%; (g) Et SiH (6 equiv),
BF ÆOEt (10 equiv), DCM, 0 ꢁC, 10 min, 94%; (h) HgO (1.25 equiv), HgCl (2 equiv), CH CN, H O, reflux, 3 h, 96%.
21
22
e
1
f
2
2
O, 30 ꢁC, 10 h, 96%; (b) 10% Pd/C, H , EtOH, 55 psi, 30 ꢁC, 12 h, 99%; (c)
2
4
2
3
3
2
2
3
2
1
1 furnished the same product 14 in an excellent yield
and spectroscopic data of compounds 13 and 14 were
(
92%). It is worth mentioning that varying the tempera-
found to be identical in all respect with the compounds
1
4
ture (ꢀ35 to 30 ꢁC) for the ionic hydrogenation of 12
gave the same product and yield with small differences
in the reaction time (30 min to 5 min). The physical
synthesised earlier by the ionic hydrogenation of the
C-20,22-ketene dithioacetal. We have carried out the
X-ray crystallographic analysis of compound 13 and

9346
B. B. Shingate et al. / Tetrahedron Letters 47 (2006) 9343–9347
18
OH 21
H
20
BF .Et O
+
17
3
2
H
2
2
+
S
S
S S
S
S
A
B
Et SiH
3
S S
H
H
S
S
C
C(20R)
Figure 4. Proposed mechanism for the deoxygenation of tert-alcohols.
hydrogenation14 of a C-20,22-ketene dithioacetal to a
C-20,22-dihydro product is governed by protonation
with trifluoroacetic acid at C-20 leading to the observed
stereochemical outcome. Thus, ionic hydrogenation of a
C-20,22-ketene dithioacetal and also ionic hydrogena-
tion of C-20 tert-alcohols, both lead to the generation
of the C(20R) unnatural configuration with 100%
selectivity.
Figure 3. ORTEP view of 3b-acetoxy-5a-pregna-20(R)-20-dithiane 21.
1
4
found it to be identical with that reported. Following a
1
4
known procedure, intermediates 13 and 14 have been
elaborated to C(20R) aldehydes 5 and 6.
After the successful synthesis of steroidal C(20R)
aldehydes 5 and 6, our next goal was to synthesise
C-5(6)-saturated aldehyde 22. Hydrolysis of the acetate
functionality of 16-dehydropregnenolone acetate 9 with
KOH in t-butanol followed by the catalytic hydrogena-
tion of 15 in ethanol with 10% Pd/C afforded 5a-preg-
nane-3b-ol-20-one 16 in a 95% yield in two steps
Removal of the C-20-dithiane moiety by the oxidative
hydrolysis of compound 21 with HgO–HgCl yielded
2
C(20R) aldehyde 22 in a 96% yield. This is the first
report of the stereoselective synthesis of C(20R)
aldehyde 22 with a 100% selectivity from 16-dehydro-
pregnenolone acetate 9.
(
Scheme 2). It is interesting to note that the catalytic
hydrogenation of compound 15 with 10% Pd/C in ethyl
In summary, steroidal C-20 tert-alcohols were obtained
from 16-dehydropregnenolone acetate in an excellent
overall yield. Ionic hydrogenation of the tert-alcohols
with Et SiH–BF ÆOEt led to the C(20R) unnatural con-
figuration with a 100% selectivity, which was confirmed
unambiguously by X-ray crystallographic analysis. Util-
isation of these unnatural C(20R) aldehydes to elaborate
the side chain of a large variety of highly potent natu-
rally occurring 20-epi steroids is in progress.
1
5
acetate only reduced the 16(17)-double bond, while in
ethanol both the 5(6) and 16(17)-double bonds were
reduced. A general trend that could be termed ‘solvent
effect’ is emerging from these hydrogenation experiments.
3
3
2
The 3b-OH group of 16 was transformed to its TBDMS
2
0
derivative 17 in an excellent yield (97%). The exposure
of compound 17 to 2-lithio-1,3-dithiane and deprotec-
2
1
tion of the TBDMS group of 18 with n-Bu NF yielded
4
3
,20-diol 19 in a 76% yield over two steps. Selective
acetylation of the 3-hydroxy group of compound 19
furnished acetate 20 in a 97% yield. Compound 20 on
ionic hydrogenation with triethylsilane and borontri-
fluoride–diethyl etherate in dichloromethane at 0 ꢁC
afforded compound 21 in an excellent yield (94%).
Acknowledgements
B.B.S. thanks the University Grants Commission, New
Delhi, for Research Fellowships (Junior and Senior).
The Emeritus Scientist Scheme awarded to B.G.H. by
the Council of Scientific and Industrial Research, New
Delhi, is gratefully acknowledged.
The unnatural C(20R) configuration in compound 21
2
2
was assigned by physical and spectroscopic data and
confirmed unambiguously by single crystal X-ray analy-
23
sis (Fig. 3).
References and notes
Regarding the stereochemical outcome of deoxygen-
ation of C-20 tert-alcohols 10–12 and 20 by ionic
hydrogenation, it can be anticipated that there may be
a 1,2-hydride shift from C-22 of dithiane moiety of inter-
mediate A leading to sulfur stabilised carbocation B.
Hydride transfer from triethylsilane to C-22 leads to
the formation of compound C (Fig. 4). During deoxy-
genation of the C-20 tertiary alcohol, a 1,2-hydride shift
from the less hindered a-face determines the stereochem-
ical outcome of the product. On the other hand, ionic
1
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24
8
21. Compound 18: crystalline solid; ½aꢁ ꢀ17.39 (c 0.57,
D
ꢀ
1
1
CHCl
CDCl
3
). IR (Nujol, cm ) 3388 (OH). H NMR (200 MHz,
4
2, 1569–1575.
. Posner, G. H.; Kahraman, M. Eur. J. Org. Chem. 2003,
889–3895, and references cited therein.
3
) d = 4.14 (s, 1H, 22-H), 3.52 (m, 1H, 3-H), 2.90 (m,
9
2 3
4H, dithiane-CH ), 1.42 (s, 3H, 21-H ), 0.88 (s, 9H,
3
SiCMe ), 0.85 (s, 3H, 19-H ), 0.79 (s, 3H, 18-H ), 0.05 (s,
3
3
3
1
3
1
0. For construction of the steroidal side chain with unnatural
configuration at C-20 see: (a) Tanabe, M.; Hayashi, K. J.
Am. Chem. Soc. 1980, 102, 862–863; (b) Midland, M. M.;
Kwon, Y. C. Tetrahedron Lett. 1982, 23, 2077–2080; (c)
Schuff, N. R.; Trost, B. M. J. Org. Chem. 1983, 48, 1404–
6H, SiMe
2
). C NMR (50 MHz, CDCl
3
) d = 78.02 (C),
72.38 (CH), 61.48 (CH), 56.84 (CH), 55.45 (CH), 54.57
(CH), 45.22 (CH), 43.48 (C), 40.66 (CH ), 38.90 (CH ),
2
2
37.41 (CH ), 35.70 (C), 35.12 (CH), 32.20 (2 · CH ), 31.78
2
2
(CH
(3 · CH
2
), 31.09 (CH
2
), 29.01 (CH
2
), 26.30 (CH ), 26.22
2
), 21.90 (CH ), 21.37
2
1
412; (d) Tahashi, T.; Ootake, A.; Tsuji, J.; Tachibana, K.
3
), 24.37 (CH
3
), 23.92 (CH
2
Tetrahedron 1985, 41, 5747–5754; (e) Mikami, K.;
Kawamoto, K.; Nakai, T. Chem. Lett. 1985, 115–118; (f)
Koreeda, M.; George, I. A. J. Am. Chem. Soc. 1986, 108,
(CH ), 18.50 (C), 13.85 (CH ), 12.63 (CH ), ꢀ4.28
2
3
3
(2 · CH
3
). Anal. Calcd for C31
H
56
O
2
SiS
2
: C, 67.33; H,
10.20; S, 11.59. Found: C, 67.22; H, 9.96; S, 11.33.
24
8
098–8100; (g) Ibuka, T.; Taga, T.; Shingu, T.; Saitao, M.;
Nishii, S.; Yamamoto, Y. J. Org. Chem. 1988, 53, 3947–
952, and references cited therein; (h) Harada, S.; Kiyono,
H.; Nishio, R.; Taguchi, T.; Hanzawa, Y. J. Org. Chem.
997, 62, 3994–4001, and references cited therein; (i) Yu,
22. Compound 21: crystalline solid; ½aꢁ +11.82 (c 1.01,
D
ꢀ
1
1
CHCl ). IR (Nujol, cm ) 1730 (OCOCH ). H NMR
3
3
3
(200 MHz, CDCl
3
) d = 4.68 (m, 1H, 3-H), 4.37 (d,
J = 2.0 Hz, 1H, 22-H), 2.84 (m, 4H, dithiane-CH
(s, 3H, OCOCH ), 1.06 (d, 3H, J = 6 Hz, 21-H ), 0.82 (s,
3H, 19-H ), 0.67 (s, 3H, 18-H ). C NMR (CDCl3,
2
), 2.02
1
3
3
1
3
W.; Jin, Z. J. Am. Chem. Soc. 2002, 124, 6576–6583; (j)
He, Z.; Yi, C. S.; Donaldson, W. A. Org. Lett. 2003, 5,
3
3
50 MHz) d = 170.48 (C), 73.58 (CH), 55.85 (CH), 55.39
(CH), 54.11 (CH), 51.91 (CH), 44.51 (CH), 42.66 (C),
40.38 (CH), 38.96 (CH ), 36.64 (CH ), 35.35 (C), 35.35
1
567–1569; (k) Watanabe, B.; Yamamoto, S.; Sasaki, K.;
Nakagawa, Y.; Miyagawa, H. Tetrahedron Lett. 2004, 45,
767–2769, and references cited therein; (l) Shi, B.; Wu,
H.; Yu, B.; Wu, J. Angew. Chem., Int. Ed. 2004, 43, 4324–
327; (m) Shi, B.; Tang, P.; Hu, X.; Liu, J. O.; Yu, B. J.
2
2
2
(CH), 33.89 (CH ), 31.78 (CH ), 31.61 (CH ), 30.53
2 2 2
(CH
(CH
2
), 28.45 (CH
), 23.89 (CH
2
), 27.36 (CH
), 21.33 (CH
2
), 27.20 (CH
), 21.15 (CH
2
), 26.34
), 15.87
4
2
2
3
2
Org. Chem. 2005, 70, 10354–10367; (n) Tsubuki, M.;
Ohinata, A.; Tanaka, T.; Takahashi, K.; Honda, T.
Tetrahedron 2005, 61, 1095–1100.
(CH ), 12.22 (CH ), 12.12 (CH ). MS (LCMS) m/z: 464
3 3 3
+
(M ). Anal. Calcd for C27
13.79. Found: C, 69.87; H, 9.52; S, 13.74.
23. Crystallographic data for 21 (C27
crystal dimensions 0.61 · 0.43 · 0.03 mm , monoclinic,
space group P2 , a = 6.7783(18), b = 6.7783(18), c =
44 2 2
H O S : C, 69.77; H, 9.54; S,
1
1. (a) Goto, R.; Morisaki, M.; Ikekawa, N. Chem. Pharm.
Bull. 1983, 31, 3528–3533; (b) Yamamoto, K.; Sun, W. Y.;
Ohta, M.; Hamada, K.; Deluca, H. F.; Yamada, S. J.
Med. Chem. 1996, 39, 2727–2737; (c) Masuno, H.;
Yamamoto, K.; Wang, X.; Choi, M.; Ooizumi, H.; Shinki,
T.; Yamada, S. J. Med. Chem. 2002, 45, 1825–1834.
2. Sato, Y.; Sonoda, Y.; Saito, H. Chem. Pharm. Bull. 1980,
44 2 2
H O S ): M = 464.74,
3
1
˚
˚
ꢀ1
3
31.048(9) A, b = 95.395(5)ꢁ, V = 2636.4(12) A , Z = 4;
ꢀ
3
q
calcd
= 1.171 g cm , l (Mo-K ) = 0.223 mm , F(000) =
a
1016, 2hmax = 50.00ꢁ, 19022 reflections collected, 8559
unique, 5706 observed (I > 2r (I)) reflections, 567 refined
1
1
2
8, 1150–1156.
2
parameters, R value 0.0527, wR = 0.1124 (all data
3. (a) Sydykov, Zh. S.; Segal, G. M. Izv. Akad. Nauk SSSR,
Ser. Khim. 1976, 11, 2581–2584; (b) Sucrow, W.; Nooy, M.
V. Liebigs Ann. Chem. 1982, 1897–1906; (c) Liu, X.; Pan,
X.; Li, Y.; Liang, X. Huaxue Xuebao 1988, 46, 561–566.
4. Shingate, B. B.; Hazra, B. G.; Pore, V. S.; Gonnade, R.
G.; Bhadbhade, M. M. Chem. Commun. 2004, 2194–2195.
5. (a) Hazra, B. G.; Basu, S.; Bahule, B. B.; Pore, V. S.; Vyas,
B. N.; Ramraj, V. M. Tetrahedron 1997, 53, 4909–4920;
R = 0.0889, wR = 0.1243), S = 1.015, minimum and
2
maximum transmission 0.8771 and 0.9945, respectively,
maximum and minimum residual electron densities +0.295
˚
ꢀ3
and ꢀ0.197 e A . Crystallographic data (excluding struc-
ture factors) for the structure 21 in this letter has been
deposited with the Cambridge Crystallographic Data
Centre as Supplementary publication number CCDC
606459.
1
1