An efficient one-pot synthesis generating 4-ene-3,6-dione functionalised steroids from steroidal 5-en-3β-ols using a modified Jones oxidation methodology

Article abstract of DOI:10.1016/j.steroids.2005.07.007

Steroids with 4-ene-3,6-dione functionality have application in natural product chemistry, as synthetic intermediates and as aromatase inhibitors. Here, we report a two-phase oxidation of a range of steroidal 5-en-3β-ols into corresponding 4-ene-3,6-diones using a modified Jones oxidation. The new reaction affords high yields (77-89%) of product in relatively short reaction times (1-2 h). The simplicity of this reaction gives significant advantages over previously reported methodologies.

Full text of DOI:10.1016/j.steroids.2005.07.007

steroids 7 1 ( 2 0 0 6 ) 30–33
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An efficient one-pot synthesis generating 4-ene-3,6-dione
functionalised steroids from steroidal 5-en-3␤-ols using a
modified Jones oxidation methodology
A. Christy Hunter∗, Shelley-Marie Priest
Molecular Targeting and Polymer Toxicology Group, School of Pharmacy and Biomolecular Sciences,
University of Brighton, East Sussex BN2 4GJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Steroids with 4-ene-3,6-dione functionality have application in natural product chemistry,
as synthetic intermediates and as aromatase inhibitors. Here, we report a two-phase oxida-
tion of a range of steroidal 5-en-3␤-ols into corresponding 4-ene-3,6-diones using a modified
Jones oxidation. The new reaction affords high yields (77–89%) of product in relatively short
reaction times (1–2 h). The simplicity of this reaction gives significant advantages over pre-
viously reported methodologies.
Received 13 June 2005
Accepted 29 July 2005
Available online 23 September 2005
Keywords:
© 2005 Elsevier Inc. All rights reserved.
4-Ene-3,6-dione
Jones oxidation
One-pot synthesis
Aromatase inhibitor
1.
Introduction
is performed in comparatively high solvent volume at low
temperature.
ꢀ4-3,6-Dione functionalised steroids are natural products
[1–4], important intermediates in further transformation of
the steroid nucleus [5] and have proved useful molecular
probes in the study of aromatase inhibition [6–9]. Synthet-
ically ꢀ5-3␤-ols, which are widely commercially available,
have been used as the initial substrate or their acetate [10]
in both multi step [6,10] and single step reaction schemes
[11–15] in formation of 4-ene-3,6-diones. The reagents and
chemical techniques employed are diverse with many earlier
methodologies resulting in low yields [11]. Here, we present
a chemically simple, rapid, economical and diverse ‘one-pot’
synthesis with significant advantages over the currently avail-
able reaction methodologies for generation of ꢀ4-3,6-dione
functionalised steroids. The reaction is based on the classi-
cal Jones oxidation [16] using chromium(VI) as oxidant, but
2.
Experimental
2.1.
Chemicals and reagents
3␤-Hydroxy-androst-5-ene 1 was prepared as described previ-
ously [17]. Dehydroisoandrosterone 2, Pregnenolone 4, Choles-
terol 6 and Chromium trioxide were supplied by the Aldrich
Chemical Company (UK). 3␤-Hydroxy-13␣-androst-5-en-17-
one 3 was synthesized using the method of Boar et al. [18].
16-Dehydropregnenolone 5 was purchased from Steraloids
(UK). Solvents used were of analytical grade, silica for col-
umn chromatography was Merck 9385 and TLC was per-
formed with Macherey-Nagel Alugram® SIL G/UV254. The Jones
∗
Corresponding author. Tel.: +44 1273 642088; fax: +44 1273 679333.
E-mail address: c.hunter@bton.ac.uk (A.C. Hunter).
0039-128X/$ – see front matter © 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2005.07.007

steroids 7 1 ( 2 0 0 6 ) 30–33
31
reagent refers to a preparation of chromium trioxide (26.72 g)
in sulfuric acid (23 mL) added to 100 mL of precooled (4 ◦C)
water.
H), 6.19 (1H, s, 4-H); HRMS ESI: calc. for M + Na+: 323.1622; obsd.
323.1622.
2.3.5. Pregna-4-ene-3,6,20-trione 10
2.2.
Analysis and identification of steroid products
Pregnenolone 4 underwent the modified Jones oxidation (Sec-
tion 2.3.1) affording pregna-4-ene-3,6,20-trione 10 (1.85 g, 89%)
which crystallized from ethyl acetate as needles m.p. 198 ◦C
(198–200 ◦C) [5] IR cm−1: 1698, 1689, 1674, 1653 1H-NMR (CDCl3)
ı: 0.68 (3H, s, 18-H), 1.17 (3H, s, 19-H), 2.15 (3H, s, 21-H), 6.18 (1H,
d, J 0.5 Hz, 4-H); HRMS ESI: calc. for M + Na+: 351.1935; obsd.
351.1930.
Characteristic shift values and signals [19,20] in the 1H and
13C NMR spectra from the starting compounds were used to
confirm product structure in combination with DEPT anal-
ysis to identify the nature of the carbon. Spectra were
recorded on a Bruker WM 360 Spectrometer, all samples
were analysed in deuteriochloroform using tetramethylsi-
lane as the internal standard. Infra red absorption spectra
were recorded directly on a Nicolet Avatar 320 FT-IR fitted
with a Smart Golden Gate®. All melting points were deter-
mined on an electrothermal melting point apparatus and are
uncorrected.
2.3.6. Pregna-4,16-diene-3,6,20-trione 11
5,16-Pregnadien-3ˇ-ol-20-one 5 (1 g) underwent the modified
Jones oxidation (Section 2.3.1) affording pregna-4,16-diene-
3,6,20-trione 11 (800 mg, 77%) which crystallized from ethanol
as needles m.p. 208–209 ◦C (207–209 ◦C) [6] IR cm−1: 1684, 1660
1H-NMR (CDCl3) ı: 0.95 (3H, s, 18-H), 1.20 (3H, s, 19-H), 2.28 (3H,
s, 21-H), 6.19 (1H, s, 4-H), 6.72 (1H, t, J = 2Hz, 16-H); HRMS ESI:
calc. for M + Na+: 349.1779; obsd. 349.1774.
2.3.
Synthesis of steroidal derivatives 7–12 using the
modified Jones oxidation
2.3.1. The modified Jones oxidation for generation of
4-ene-3,6-diones
2.3.7. Cholest-4-ene-3,6-dione 12
Cholesterol 6 underwent the modified Jones oxidation (Section
2.3.1) affording cholest-4-ene-3,6-dione 12 (1.75 g, 86%) which fol-
lowing column chromatography crystallized from acetone as
needles m.p. 131–133 ◦C (132–134 ◦C) [13] IR cm−1: 1685, 1679,
1600 br 1H-NMR (CDCl3) ı: 0.72 (3H, s, 18-H), 0.86 (3H, d, J 1.5 Hz,
26-H), 0.92 (3H, d, J 1.5 Hz, 27-H), 1.11 (3H, s, 21-H), 1.167 (3H,
s, 19-H) 6.17 (1H, s, 4-H); HRMS ESI: calc. for M + Na+: 421.3082;
obsd. 421.3077.
Steroid (2 g) was dissolved in acetone (250 mL) and cooled
to 0 ◦C. Jones reagent was added dropwise until a persistent
orange color was obtained. The reaction mixture was stirred
(1–2 h) at 0 ◦C. Once TLC had confirmed the reaction was com-
plete the system was allowed to warm up to room tempera-
ture. The reaction mixture was then quenched with methanol,
producing a dark green solution, the solvent from which was
then removed in vacuo. The steroid was extracted with ethyl
acetate and washed with water and saturated sodium chloride
and the organic layer dried over sodium sulfate. The organic
solvent was then evaporated in vacuo and the resulting prod-
uct was crystallized directly or chromatographed on a column
of silica.
Table 1 – 13C NMR of products 7–12 in CDCl3
Position
7
8
9
10
11
12
39.45
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
35.48
35.38
36.32
35.47
35.31
33.78
199.87
125.37
161.22
202.45
47.05
34.47
51.13
39.88
20.33
37.96
40.75
54.68
20.89
25.23
21.05
14.17
17.47
35.60
201.10
125.85
159.38
200.35
45.36
33.62
51.37
39.68
20.15
33.86
47.60
50.77
21.56
30.83
218.74
13.65
17.55
34.73
199.94
126.77
160.99
201.97
36.20
46.22
52.32
36.41
22.42
31.74
48.41
51.75
21.04
34.53
220.07
24.68
18.43
33.91
201.61
125.66
160.44
199.27
46.47
33.97
63.09
39.59
20.82
38.09
43.78
56.46
22.76
24.11
50.65
13.24
17.51
208.82
31.43
33.92
201.64
125.76
160.68
199.47
46.49
32.39
51.17
39.83
20.63
34.06
46.13
56.06
31.91
143.76
154.68
15.73
17.46
196.63
27.12
36.05
199.69
125.42
161.18
202.43
35.50
35.66
50.95
39.82
20.86
38.80
42.52
56.53
23.78
33.94
55.94
11.88
18.64
34.20
17.48
39.12
23.95
46.79
28.00
22.54
22.80
2.3.2. Androst-4-ene-3,6-dione 7
3ˇ-Hydroxy-androst-5-ene 1 underwent the modified Jones oxi-
dation (Section 2.3.1) affording androst-4-ene-3,6-dione 7 (1.84 g,
88%) which crystallized from light petroleum ether as needles
m.p. 139 ◦C (138–140 ◦C) [21] IR cm−1: 1669, 1647 and 1617. 1H-
NMR (CDCl3) ı: 0.77 (3H, s, 18-H), 1.17 (3H, s, 19-H) 6.17 (1H, s,
4-H); HRMS ESI: calc. for M + Na+: 309.1830; obsd. 309.1825.
2.3.3. Androst-4-ene-3,6,17-trione 8
Dehydroisoandrosterone 2 underwent the modified Jones oxi-
dation (Section 2.3.1) affording androst-4-ene-3,6,17-trione 8
(1.79 g, 85%) which crystallized as cubes from ethyl acetate
m.p. 229–230 ◦C (227–228 ◦C) [22] IR cm−1: 1731, 1682, 1668 and
1653 1H-NMR (CDCl3) ı: 0.94 (3H, s, 18-H), 1.21 (3H, s, 19-H),
6.20 (1H, s, 4-H); HRMS ESI: calc. for M + Na+: 323.1622; obsd.
323.1617.
2.3.4. 13␣-Androst-4-ene-3,6,17-trione 9
3ˇ-Hydroxy-13˛-androst-5-en-17-one 3 underwent the modified
Jones oxidation (Section 2.3.1) affording 13˛-androst-4-ene-
3,6,20-trione 9 (1.82 g, 87%) which crystallized as needles from
ethyl acetate m.p. 182 ◦C (181–182 ◦C) [10] IR cm−1: 1730, 1715
and 1687 1H-NMR (CDCl3) ı: 1.02 (3H, s, 18-H), 1.05 (3H, s, 19-

32
3.
steroids 7 1 ( 2 0 0 6 ) 30–33
bond resonance signal underwent a downfield shift of 0.1 ppm
Results and discussion
consistent with the 4-H in the increased electronegative envi-
ronment of the 4-ene-3,6-dione system. The 13C NMR spectra
for the products (Table 1) contained two new quaternary (C3
and C6) resonance signals (199–202 ppm) replacing a methy-
lene (C6) and methyne (C3) signal in the starting material
supporting the formation of two new six ring ketones. The
nature of the double bond resonance signal values changed
significantly with the C4 value shifting 19 ppm cf. the C6 res-
onance value of the starting materials and the quaternary C5
Utilization of the modified Jones oxidation methodology
afforded the steroids 7–12 (Fig. 1) in high yield (77–89%). The
products were readily identified with clearly defined changes
in both 1H and 13C NMR spectra compared to the starting mate-
rials. All product spectra were devoid of the 3␣-H signal (tt)
at 3.6 ppm present in the starting materials, which supports
oxidation at C3 following reaction. In each case the double
Fig. 1 – Synthesis and yields of 4-ene-3,6-dione functionalised steroids (7–12) following modified Jones oxidation with
ꢀ5-3␤-ols (1–6).

steroids 7 1 ( 2 0 0 6 ) 30–33
33
value increased by 6 ppm, both of which are consistent with
the formation of a 4-ene-3,6-dione [20] as were melting points,
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