A synthesis of 17-epi-calcidiol

Article abstract of DOI:10.1016/j.tetlet.2004.08.050

The first synthetic approach to 17-epi-calcidiol 4 and congeners is presented. Key steps of the synthesis involve Pd-catalyzed reaction of the androst-16-ene derivative 6 with alkyl diazoacetates producing the respective cyclopropane derivatives 5, and li

Full text of DOI:10.1016/j.tetlet.2004.08.050

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7479–7482
A synthesis of 17-epi-calcidiol
Alicja Kurek-Tyrlik, Karol Michalak, Zofia Urbanczyk-Lipkowska and Jerzy Wicha*
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44, 01-224 Warsaw, Poland
Received 18 June 2004; revised 27 July 2004; accepted 6 August 2004
Available online 26 August 2004
Abstract—The first synthetic approach to 17-epi-calcidiol 4 and congeners is presented. Key steps of the synthesis involve Pd-cat-
alyzed reaction of the androst-16-ene derivative 6 with alkyl diazoacetates producing the respective cyclopropane derivatives 5, and
lithium in liquid ammonia reduction of 5 leading to 17a-pregnane-20-carboxylic acid derivatives 9. The side chain was attached to
ester 19 in a known manner.
Ó 2004 Elsevier Ltd. All rights reserved.
Calcitriol 1 (Fig. 1), the hormonally active metabolite of
calciol (vitamin D3), shows a broad spectrum of biolog-
ical activities.1 Its prime function consists in providing
adequate calcium and phosphorus concentration in
circulating fluids to support skeletal mineralization. Non-
calcemic activities of 1 proved useful in controlling vari-
ous human diseases, including skin and immune system
metabolic disorders. Calcidiol 2 is the biosynthetic pre-
cursor of calcitriol showing similar but weaker biologi-
cal activities. Several synthetic analogues of calcitriol
are presently available as drugs or have been accepted
for advanced clinical trials2 and have stimulated the
search for new structures having improved therapeutic
properties.3 In continuing our work on synthesis and
biological evaluation of calcitriol stereoisomers4 we were
interested in epimers of the natural products, 17-epi-cal-
citriol 3 and 17-epi-calcidiol 4. It was reasoned that 4
will be accessible from alkyl 16a,20-cyclo-17a-preg-
nane-21-carboxylates 5 by reductive fission of the
C16–C20 bond, followed by side chain elaboration.
Intermediates 5, in turn, would be obtained by diastere-
oselective cyclopropanation of the easily available
androstane derivative 6. In the present communication
we report the first synthesis of 17-epi-calciol derivatives
and, en route, the synthesis of some 17-epi-cholesterol
derivatives.
The starting material for the synthesis, 6, was prepared
by reduction of 17-iodo-3a,5-cyclo-5a-androst-16-ene5
with sodium in ethanol. To a solution of 6 in
20
25
17
H
OH
16
H
CO2R
H
H
X
H
H
H
H
H
H
3
1
OMe
OMe
HO
1, 17α-H, X = OH, Calcitriol
2, 17α-H, X= H, Calcidiol
3, 17β-H, X = OH, 17-epi-Calcitriol
4, 17β-H, X = H, 17-epi-Calcidiol
5
6
Figure 1. Structures of calcitriol (1a,25-dihydroxy vitamin D3) 1, calcidiol 2, their 17-epi-analogues 3 and 4, and the respective synthetic precursors.
Keywords: Vitamin D synthesis; Cyclopropanation; Alkyl diazoacetates; Lithium in liquid ammonia.
*
Corresponding author. Tel.: +48 22 6328117; fax: +48 22 632 6681; e-mail: jwicha@icho.edu.pl
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.050

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A. Kurek-Tyrlik et al. / Tetrahedron Letters 45 (2004) 7479–7482
dichloromethane (DCM) containing palladium(II) ace-
tate,6 a solution of tert-butyl diazoacetate in DCM
was slowly added7 by means of a syringe pump. A prod-
uct was obtained to which structure 5a (Scheme 1) was
lematic, the whole reduction product was oxidized12
with DMSO in the presence of PyÆSO3 and the resulting
mixture of aldehydes was further oxidized with potas-
sium permanganate in tert-butanol in the presence of
NaH2PO4 to give a mixture of carboxylic acids 9 and
12. At this stage, acid 9 was easily purified by chroma-
tography on silica gel. Crystalline 9 was obtained in
76% overall yield from 5d.
1
assigned on the basis of its H and 13C NMR spectra.
Product 5a was contaminated with side products derived
from the diazoester (ca. 5%) and could not be purified
by column chromatography. Treatment of 5a with
sodium methoxide in methanol at reflux followed by
chromatography afforded pure methyl ester 5d in a
93% yield from 6.
Alkylation of methyl ester 13 (obtained by esterification
of 9 with diazomethane) was carried out via an earlier
developed method.13 It was rewarding to learn that the
reaction affords the diastereomerically pure product
(as an oil) in nearly quantitative yield. Several deriva-
tives of this product were examined in the search for a
crystalline material suitable for single crystal X-ray analy-
sis. The structure was eventually solved14 for acid 17
prepared as showed in Scheme 2. It revealed that the
product 14 with the (20S) configuration was formed.
X-ray analysis also confirmed the assumed stereoselec-
tivity in the cyclopropanation reaction and the regio-
selectivity of the reductive cleavage of the cyclopropane
ring (Fig. 2).
Palladium-catalyzed reaction of 6 with ethyl diazoace-
tate (commercial reagent) provided a mixture of cyclo-
propane derivatives 5b and 5c differing in
configuration at C20, in a ratio of ca. 7:1 (by 1H
NMR). This mixture was subjected to methanolysis to
give a single isomer 5d in 89% yield from 6. Similarly,
6 and methyl diazoacetate gave 5d and 5e in a ratio of
7:1. Treatment of tert-butyl ester 5a (ca. 90% pure) with
lithium in liquid ammonia8–10 afforded a mixture of
products. A neutral fraction, isolated in ca. 50% yield,
was reduced with LiAlH4 to give a mixture of alcohols
that were identified as 7 (36% yield) and 10 (11% yield).
The acid fraction contained mainly compound 12. No
product of alternative fission of the C17–C20 bond
was detected. It was subsequently found that reduction
of methyl (5d) or ethyl esters (mixture 5b and 5c) also
proceeded virtually regioselectively; moreover with these
esters only small amounts of acid 12 were formed.11 In
the most efficient procedure developed (Scheme 1),
methyl ester 5d was treated with Li in liquid ammonia
containing tert-butyl alcohol and THF at reflux temper-
ature to give a mixture of alcohol 7, aldehyde 8 and
alcohol 10 with the cyclopropane ring retained, in nearly
quantitative yield. Since chromatographic separation of
the undesired component of the mixture (10) was prob-
The side chain was attached to 14 in a known manner,15
as illustrated in Scheme 2. Ester 14 was reduced to alco-
hol 15. The respective tosylate 16 was allowed to react
with the lithium derivative of 3-methyl-1-butyn-3-yl
2-tetrahydropyranyl ether, and the product 20 was
subjected to catalytic reduction followed by removal of
the protective groups. 25-Hydroxy-17-epi-cholesterol
18 was obtained in over 70% yield from 14.
Acetate 19 was subjected to a bromination–dehydrobro-
mination procedure16 to give 17-epi-7-dehydrocholeste-
ryl acetate 22 in ca. 40% yield. This product was
hydrolyzed and the crude diol 23 was dissolved in a mix-
R1
H
R
R
H
H
R2
H
H
H
H
H
H
H
H
H
H
H
H
OMe
OMe
OMe
5a, R1 = COOtBu, R2 = H
5b, R1 = COOEt, R2 = H
5c, R1 = H, R2 = COOEt
5d, R1 = COOMe, R2 = H
5e, R1= H, R2 = COOMe
7, R = CH2OH
8, R = CHO
9, R = CO2H
10, R = CH2OH
11, R = CHO
12, R = CO2H
Practical synthetic approach to intermediate 9:
1. N2CHCOOEt-
Li/
DMSO-Py SO3/
DCM
1. KMnO4-NaH2PO4/
tert-BuOH
2. chromatography
3 mol% Pd(OAc)2 NH3-tert-BuOH-
2. MeONa/MeOH THF
[7+8+10]
[8 + 11]
6
5d
9
89%
76%
yield from 5d
Scheme 1. 16a,17a-Cyclopregnan-20-oic acid derivatives obtained by palladium-catalyzed reaction of ene 6 with alkyl diazoacetates, and their
reduction products.

A. Kurek-Tyrlik et al. / Tetrahedron Letters 45 (2004) 7479–7482
7481
H
H
COOR
H
CH2OR
CO2Me
H
H
LiAlH4
LDA-MeI
H
H
H
H
H
H
H
H
H
OMe
15, R = H
16, R = Ts
OMe
9, R = H
13, R = Me
OMe
BuLi
14
TsCl/
Et3N
CH2N2
1. TsOH
2. NaOH/
aq. MeOH
OTHP
H
H
COOH
R
H
H
H
H
H
H
OH
TsOH
H
H
H
H
H
H
HO
RO
OMe
CMe2OTHP
CH2CH2CMe2OTHP
17
H2/
18, R = H
19, R = Ac
20, R =
21, R =
Pd-C,
NaHCO3
Scheme 2. Synthesis of the 17-epi-cholesterol derivatives 18 and 19.
Spectroscopic and analytical data of selected new com-
pounds: Methyl 3a,5:16a:20(S)-bicyclo-5a,17a-preg-
nane-21-oate (5d) 1H NMR (200MHz, CDCl3): 0.41
(dd, J = 8.1, 5.1Hz, 1H, C4–Ha), 0.62 (t, J = 5.1Hz,
1H, C4–Hb), overlapping 0.5–0.7 (m, 1H), 0.90 (s, 3H,
C18–H), 1.00 (s, 3H, C19–H) overlapping 0.7–1.9 (m,
18H) 2.73 (t, J = 2.6Hz, 1H, C6–H), 3.29 (s, 3H,
OMe), 3.6 (s, 3H, COOMe); 13C NMR (50MHz):
13.02, 19.20, 19.66, 20.13, 21.32, 22.37, 24.82, 25.07,
27.04, 28.98, 33.16, 35.08, 35.20, 35.31, 38.32, 41.07,
43.51, 47.16, 48.61, 51.41, 56.53, 82.09, 174.58; HRMS:
calcd for C23H34O3: 358.25080; found: 358.25175.
Figure 2. ORTEP plot of the X-ray structure of 17.
ture of diethyl ether and toluene, and irradiated with a
medium-pressure mercury lamp until ca. 50% of the sub-
strate was consumed (HPLC). Then, the solvent was re-
moved under reduced pressure and the crude product
was dissolved in ethanol and heated under reflux for
6h. The resulting product was chromatographed on a
preparative HPLC column to give 17-epi-calcidiol 4
(Scheme 3).
Methyl
6b-methoxy-3a,5-cyclo-23,24-bisnor-5a,17a-
cholane (14) 1H NMR (200MHz, CDCl3): 0.42 (dd,
J = 8.1, 5.1Hz, 1H), 0.63 (t, J = 4.9Hz, 1H,), 0.84 (s,
3H, C–19H), 1.00 (s, 3H, C–18H), 1.09 (d, J = 6.8Hz,
3H, C–21H) overlapping, 0.7–2.1 (m, 19H), 2.28 (dq,
J = 10.5, 6.8Hz, 1H, C–20H), 2.76 (t, J = 2.8Hz, 1H,
C–6H), 3.31 (s, 3H, OMe), 3.65 (s, 3H, COOMe); 13C
NMR: 13.77, 17.88, 19.90, 22.12, 23.45, 25.59, 26.44,
26.49, 31.26, 34.00, 34.75, 35.86, 42.09, 36.29, 44.04,
44.32, 48.37, 51.07, 52.01, 52.62, 57.15, 82.94, 178.6;
HRMS: calcd for C24H38O3: 374.28210; found:
374.28173.
The transformation of 4 into 3 and the biological
activity of these compounds will be reported in due
course.
H
OH
1. N-Bromohydantoin
2. collidine, xylene, reflux
3. chromatography
1. photolysis
H
2. EtOH, reflux
H
3. HPLC
OH
19
H
H
HO
RO
22, R = Ac
23, R = H
KOH/
MeOH
4
Scheme 3. Synthesis of 17-epi-calcidiol 4.

7482
A. Kurek-Tyrlik et al. / Tetrahedron Letters 45 (2004) 7479–7482
17a-Cholesteryl acetate (19): 1H NMR (500MHz,
CDCl3) 0.77 (s, 3H, C–18H), 0.82 (d, J = 6.5Hz, 3H,
C–21H), 1.02 (s, 3H, C–19H) and 1.21 (s, 6H, C–26
and C–27H) overlapping 1.10–1.80 (m, ca. 24H), 1.80–
1.90 (m, 2H), 2.03 (s, 3H, COMe), 2.29–2.35 (m, 2H),
4.56–4.64 (m, 1H, C–3H), 5.36–5.39 (m, 1H, C–5H),
13C (125MHz) 16.98, 19.29, 21.07, 21.04, 22.12, 22.27,
26.28, 27.79, 29.26, 29.27, 32.33, 32.45, 33.01, 38.12,
38.37, 43.52, 44.24, 50.13, 52.65, 52.85, 71.03, 73.97,
122.63, 139.61, 170.49. Elemental analysis: calcd for
C29H48O3 (444.69): C, 78.33, H, 10.88%; found: C,
78.37, H, 10.74%.
4. (a) Marczak, S.; Przezdziecka, A.; Wicha, J.; Steinmeyer,
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(5Z,7E)-3S-9,10-seco-17a-Cholesta-5,7,10(19)-trien-3b-ol
(4): k (EtOH) 264nm; 1H NMR (500MHz, CDCl3)
0.63 (s, 3H, C–18H), 0.86 (d, J = 6.6Hz, 3H, C–21H),
1.21 (s, 6H, C–26 and C–27H) and 1.54 (s, H2O) over-
lapping 1.05–1.75 (m, ca. 24H), 1.89–1.96 (m, 1H),
2.11–2.21 (m, 2H), 2.25–2.31 (m, 1H), 2.55–2.59 (m,
1H), 2.81–2.85 (m, 1H), 3.90–3.97 (m, 1H, C–3H),
4.82 (d, J = 2.6Hz, 1H, C–19HE), 5.05 (dt, J = 1.3,
2.6Hz, 1H, C–19HZ), 6.05 (dt, J = ca. 1, 11.3Hz, 1H,
C–7H), 6.23 (d, J = 11.2Hz, 1H, C–6H); EI MS 400
(26) M+, 382 (19) (MÀ18)+, 367 (20) (MÀ18À15), 349
(17), 271 (18) (MÀside chain), 253 (18) (217 À H2O),
211 (15), 176 (22), 161 (18), 158 (60), 136 (100) (C1–
C8 fragment), 118 (98) (136ÀH2O); HR MS calcd for
C27H44O2: 400.3341; found: 400.3338.
7. Doyle, M. P. Chem. Rev. 1986, 86, 919–939.
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53.
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11. With ester 5a cleavage of the C–O bond (path b) is
preferred over cleavage of the C–C bond (path a),
presumably due to the stability of the tert-butyl radical.
R
O
R
Li
Li
O
O
Li
O
O
O
b
a
b
a
R
+
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