Phytosterols as precursors for the synthesis of aromatase inhibitors: Hemisynthesis of testololactone and testolactone

Article abstract of DOI:10.1016/j.steroids.2015.02.011

Using β-sitosterol and stigmasterol as precursor materials, a concise and efficient hemisynthesis of aromatase inhibitors: testololactone and testolactone was accomplished in a well-established reaction scheme. It involves highly effective Oppaneur oxidation of both β-sitosterol as well as stigmasterol to generate the required enone moiety in ring 'A' of the desired steroid system. The Oppaneur oxidation products of both β-sitosterol and stigmasterol were then subjected to oxidative cleavage of the side chain to produce 4-androstene-3,17-dione. Baeyer-Villiger oxidation of 4-androstene-3,17-dione using m-CPBA yielded testololactone. Dehydrogenation of 4-androstene-3,17-dione using phenylselenyl chloride in ethyl acetate followed by selenoxide elimination with H₂O₂ in dichloromethane furnished androstenedienone. Baeyer-Villiger oxidation of the resulting androstenedienone yielded the desired testolactone (overall yield 33%). This expeditious reaction scheme may be exploited for the bulk production of aromatase inhibitors (especially testolactone marketed under the brand name Teslac) from the most abundant and naturally occurring phytosterols like β-sitosterol.

Full text of DOI:10.1016/j.steroids.2015.02.011

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Contents lists available at ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
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Phytosterols as precursors for the synthesis of aromatase inhibitors:
Hemisynthesis of testololactone and testolactone
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⇑
Shabir H. Lone, Khursheed A. Bhat
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Bioorganic Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Srinagar, 190005 Jammu and Kashmir, India
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a r t i c l e i n f o
a b s t r a c t
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Article history:
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Using b-sitosterol and stigmasterol as precursor materials, a concise and efficient hemisynthesis of aro-
matase inhibitors: testololactone and testolactone was accomplished in a well-established reaction
scheme. It involves highly effective Oppaneur oxidation of both b-sitosterol as well as stigmasterol to
generate the required enone moiety in ring ‘A’ of the desired steroid system. The Oppaneur oxidation
products of both b-sitosterol and stigmasterol were then subjected to oxidative cleavage of the side chain
to produce 4-androstene-3,17-dione. Baeyer–Villiger oxidation of 4-androstene-3,17-dione using
m-CPBA yielded testololactone. Dehydrogenation of 4-androstene-3,17-dione using phenylselenyl chlo-
ride in ethyl acetate followed by selenoxide elimination with H2O2 in dichloromethane furnished
androstenedienone. Baeyer–Villiger oxidation of the resulting androstenedienone yielded the desired
testolactone (overall yield 33%). This expeditious reaction scheme may be exploited for the bulk produc-
tion of aromatase inhibitors (especially testolactone marketed under the brand name Teslac) from the
most abundant and naturally occurring phytosterols like b-sitosterol.
Received 4 October 2014
Received in revised form 13 January 2015
Accepted 9 February 2015
Available online xxxx
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Keywords:
Sitosterol
Stigmasterol
Testololactone
Testolactone
Teslac
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Ó 2015 Published by Elsevier Inc.
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1. Introduction
production, and thus stopping/reducing the tumor. The circulating
oestrogens have been recognized as major contributors to the
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Natural products generally represent unique scaffolds which
contribute to the design, discovery and thus the synthesis of new
chemical compounds. Steroids act as a repertoire of such lipophilic
structures, characteristic of the living world that perform impor-
tant physiological functions within the living systems such as, hor-
mones, regulators and provitamins. These compounds exhibit a
wide array of bioactivities vital for human life [1–4]. Apart from
the cancers of skin, breast cancer is generally considered the most
prevalent cancer in women and ranks second as a cause of tumor-
related death only after lung cancer [5]. Presently, it is envisaged
that one in about eight women of America will develop breast can-
cer some time during her life. About two-thirds of breast related
tumors require estrogens to grow and hence are called hormone-
dependent [6]. One approach in treating such cancers involves
obstruction of hormone production. Aromatase which is also
known as estrogen synthase, has always been found to be the most
promising target for the treatment of breast cancer [7] because
inhibition of the aromatase enzyme leads to decreased estrogen
growth of some mammary tumors. Therefore suppressing the
oestrogen action by affecting their biosynthesis at the androstene-
dione–oestrone aromatization step, by means of inhibitors of
enzyme estrogen-synthetase, has become an effective option for
the treatment of such hormone-dependent breast cancer. Among
the naturally occurring steroids, which possess a moderate aro-
matase inhibitory activity include pollinastanol (1), cycloeucalenol
(2), cycloeucalenol linolenate (3), 24-methylenecholesterol (4) and
their fatty acid conjugates-24-methylenecholesterol linolenate (5)
and 24-methylenecholesterol palmitate (6) (Fig. 1) extracted from
Brassica rapa L. These natural molecules are known to inhibit the
human placental aromatase with IC50 values ranging from 0.03 to
0.45 mM [8]. b-sitosterol (7) and stigmasterol (8) obtained from
Atractylodes macrocephala are reported to inhibit more than 50%
of aromatase activity at about 10 mM concentration [9]. 6b-hy-
droxystigmast-4-en-3-one (9) has been found to be a weak aro-
matase inhibitor in cell-based assays [10]. Since the naturally
occurring aromatase inhibitors are weak in their action, both ster-
oidal as well as non-steroidal aromatase inhibitors have been
developed, which exhibit this enzyme inhibition at nano-molar
concentrations. Among the synthesized steroidal inhibitors that
cause aromatase inhibition include testolactone, testololactone
and exemestane. Testolactone, marketed under the trade name
⇑
Corresponding author at: Indian Institute of Integrative Medicine, P/O Sanat
Nagar, Srinagar, 190005 Jammu and Kashmir, India. Tel.: +91 1942431253x123;
fax: +91 1942441331.
E-mail address: kabhat@iiim.ac.in (K.A. Bhat).
http://dx.doi.org/10.1016/j.steroids.2015.02.011
0039-128X/Ó 2015 Published by Elsevier Inc.
Please cite this article in press as: Lone SH, Bhat KA. Phytosterols as precursors for the synthesis of aromatase inhibitors: Hemisynthesis of testololactone
and testolactone. Steroids (2015), http://dx.doi.org/10.1016/j.steroids.2015.02.011

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TESLAC is regarded as a pioneer drug to treat breast cancer [11]. So
far there are a few literature reports which highlight the synthetic
routes for the preparation of these aromatase inhibitors. Testolo-
lactone has been previously synthesized from a variety of sub-
trometer manufactured by Shimadzu Corporation, Kyoto, Japan.
All the compounds were analysed in full scan mode with nitrogen
serving as interface gas. Detection was done in ESI mode having
probe voltage of 180.0 V, with probe temperature of 400 °C. Ele-
mental analysis was carried on vario EL III analyser.
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stances using biotransformation approach [12–15].
A recent
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study highlights the multifunctional conversion of steroids using
pencillium sps [16]. Testolactone has been synthesized in a multi-
step functional biotransformation from dehydroepiandrosterone
(DHEA) and pregnanolone using Fusarium oxysporum [17]. But till
now there has not been a single approach to synthesize these
potent inhibitors using the naturally known abundant phytosterols
like b-sitosterol and stigmasterol. Based on the aforementioned
facts as well as our ongoing research program to search for natural
product based medicinal leads [18–20], we turned our attention
towards the hemisynthesis of steroidal based aromatase inhibitors
using well known abundant sterols like b-sitosterol and stigmas-
terol as starting material.
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2.2. Synthesis
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2.2.1. Synthesis of 4-stigmasten-3-one (10)
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To a solution of b-sitosterol (7) (200 mg, 0.483 mmol) in 9 ml of
toluene and 2.5 ml (0.031 mol) of cyclohexanone, was added alu-
minum isopropoxide (400 mg, 1.95 mmol) in 4 ml of warm toluene.
The reaction mixture was refluxed for 5 h and shaken for one minute
with 5 ml of water and 2 ml of 3.6 N sulfuric acid. The organic layer
was washed with 20 ml of brine, dried over sodium sulfate, filtered
throughcelite, and concentrated undervaccum. The oily residuewas
purified by flash chromatography (15% ethyl acetate–hexane on
silica gel) and recrystallization from aqueous acetone yielde color-
less needles of 4-stigmasten-3-one (10) (140 mg, 0.3398 mmol,
70%). 4-Stigmasten-3-one (10): mp = 191–193 °C, (C29H48O; calcd
C, 84.40; H, 11.72; found C, 84.43; H, 11.68%). 1H NMR (400 MHz,
CDCl3) d 6.01 (s, 1H), 2.55 (m, 4H), 2.04 (m, 4H), 1.84 (m, 3H), 1.56
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2. Materials and methods
2.1. General
(m, 8H), 1.25 (m, 9H), 1.16 (m, 9H), 0.92 (m, 5H), 0.75 (m, 8H). 13
C
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NMR (100 MHz, CDCl3) 199.64, 171.41, 125.63, 57.24, 55.67, 54.07,
50.63, 47.16, 45.67, 42.76, 40.31, 39.63, 36.35, 34.66, 33.97, 29.32,
28.34, 26.14, 24.28, 23.68, 21.18, 19.92, 19.30, 18.93, 18.03, 12.68,
12.36. ESI-MS at m/z = 413 for [M+1]+.
b-sitosterol and stigmasterol were both isolated from the
underground parts of Senecio graciliflorus DC. However bulk of the-
se natural products was also purchased commercially. All the che-
mical reagents were of analytical grade and purchased from
commercial suppliers (Sigma–Aldrich) and used without further
purification unless otherwise stated. All the solvents used were
of LR grade. The reactions were monitored on TLC plates precoated
with silica-gel G F254. The spots were visualized both under 254 nm
UV-light as well as by staining with ceric ammonium sulfate. Col-
umn chromatography was carried out using normal phase silica-
gel (60–120). All the reaction products were characterized using
1H and 13C NMR spectra along with mass analysis. 1H and 13C
NMR were recorded on 400 MHz bruker spectrometer with TMS
as an internal standard. Chemical shift values were reported in
ppm units and coupling constants were measured as Hz. Mass
spectra were carried out on LC–MS 8030 tandem mass spec-
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2.2.2. Synthesis of 4,22-stigmastdien-3-one (11)
To a solutionof stigmasterol (8) (200 mg, 0.483 mmol) in 10 ml of
toluene and 2.5 ml (0.03 mol) of cyclohexanone was added alu-
minum isopropoxide (400 mg, 1.95 mmol) in 4 ml of warm toluene.
The reaction mixture was refluxed for 5 h and shaken for 1 min with
5 ml of water and 2 ml of 3.6 N sulfuric acid. The organic layer was
washed with 20 ml of brine, dried over sodium sulfate, filtered
through celite, and concentrated under reduced pressure. The oily
residue was purified by flash chromatography (15% ethyl acetate–
hexane on silica gel) and recrystallization from aqueous acetone to
give colorless needles of 4,22-stigmastdien-3-one (11) (134 mg,
R1O
RO
R2
24-Methylenecholestrol/
4) R= H
Pollinastanol/ 1, R1 =H, R2 = H
Cycloeucalenol/
5) R= linolenate
6) R =palmitate
2) R1 = H, R2 = CH3
3) R1= linolenate, R2 =CH3
HO
HO
O
OH
Sitosterol/7
Stigmasterol/8
Fig. 1. Naturally occurring aromatase inhibitors.
6-Hydroxystigmast-4-en-3-one/9
Please cite this article in press as: Lone SH, Bhat KA. Phytosterols as precursors for the synthesis of aromatase inhibitors: Hemisynthesis of testololactone
and testolactone. Steroids (2015), http://dx.doi.org/10.1016/j.steroids.2015.02.011

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0.326 mmol, 67%). 4,22-Stigmastdien-3-one (11): mp = 184–185 °C,
(C29H46O; calcd C, 84.81; H, 11.29; found C, 84.87; H, 11.34%); 1H
NMR (400 MHz, CDCl3) d 6.15 (s, 1H), 5.05–4.97 (m, 1H), 5.18–5.10
(m, 1H), 2.67–2.64 (m, 1H), 2.48–2.44 (m, 3H), 2.05–1.85 (m, 4H),
1.6–1.5 (m, 7H), 1.25 (m, 7H), 1.16 (s, 6H), 0.92 (m, 4H), 0.75 (m,
8H). 13C NMR (400 MHz, CDCl3) d 199.85, 171.91,138.00, 130.02,
125.63, 56.78, 56.10, 51.27, 47.03, 46.04, 42.76, 40.03, 39.37,
36.26, 35.77, 34.44, 34.19, 34.07, 29.39, 28.23, 26.30, 24.19, 23.30,
21.10, 19.24, 17.73, 12.19, 12.11. ESI-MS at m/z = 411 for [M+1]+.
collected. The organic layers were then combined and concentrat-
ed under vaccum to yield crude residue which was purified using
column chromatography to produce pure androstenedienone (15)
in 90% yields (40 mg, 0.140 mmol). 1,4-androstadien-3,17-dione
(15): mp = 139–140 °C; (C19H24O2; calcd C, 80.24; H, 8.51; found
C, 80.20; H, 8.54%). 1H NMR (400 MHz, CDCl3)
d 7.00 (d,
J = 9.8 Hz, 1H), 6.23 (s, 1H), 6.17 (d, J = 9.6 Hz, 1H), 2.54–2.39 (m,
2H), 2.37–2.27 (m, 2H), 2.15 (s, 2H), 1.97–1.81 (m, 2H), 1.48 (s,
5H), 1.30–0.88 (m, 8H). 13C NMR (101 MHz, CDCl3) d 221.23,
186.08, 161.29, 155.98, 127.98, 127.13, 50.99, 50.31, 48.31, 47.85,
43.65, 40.04, 35.80, 31.37, 30.53, 30.33, 22.71, 22.09, 21.79,
14.09. ESI-MS at m/z = 285 for [M+1]+ and 326 for [M+1+ACN]+.
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2.2.3. Synthesis of 4-androstene-3,17-dione (12)
A solution of compound 10/11 in DMF was distributed in various
Erlenmeyer flasks and incubated with a culture containing Mycobac-
terium sps (NRRL B-3805). At the end of the inoculation the culture
broth was acidified with acetic acid to a pH of 3.0 and extracted with
CHCl3. The combined extract layers were washed with distilled H2O
and dried over sodium sulfate and evaporated to dryness to yield a
solid residue. Chromatographic separation over silica gel column
and elution with hexane:ethylacetate (70:30) afforded the desired
compound 12 in 80% yields. 4-Androstene-3,17-dione (12):
mp = 171–172 °C; (C19H26O2; calcd C, 79.68; H, 9.15; found C,
79.63; H, 9.09%). 1H NMR (400 MHz, CDCl3) d 5.69 (s, 1H) 2.36 (m,
4H), 2.00 (m, 4H), 1.81 (d, J = 15.8 Hz, 1H), 1.68 (m, 3H), 1.58–1.34
(m, 2H), 1.24 (m, 2H), 1.16 (s, 3H), 1.01 (m, 2H), 0.87 (s, 3H). 13C
NMR (101 MHz, CDCl3) d 222.12, 199.35, 170.41, 124.28, 105.7,
53.97, 51.00, 47.63, 38.79, 35.88, 35.85, 35.30, 34.05, 32.70, 31.44,
30.90, 21.88, 20.46, 17.53, 13.85, 18.51. ESI-MS at m/z = 287 for
[M+1]+.
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2.2.7. Synthesis of testolactone (16)
A solution of compound 15 (40 mg, 0.140 mmol), NaHCO3
(1.2 eq) and m-CPBA (36 mg, 0.21 mmol) in CH2Cl2 (6 ml) was stir-
red at room temperature overnight. The reaction mixture was
washed with Na2SO3 and saturated brine solution, dried over anhy-
drous Na2SO4 and concentrated under pressure to give a crude resi-
due which was crystallised from acetone to yield 16 (85%).
Testolactone (16) (overall yield 33%); mp = 216–218 °C, (C19H24O3;
calcd C, 75.97; H, 8.05; 11.72; found C, 76.00; H, 8.10%). 1H NMR
(400 MHz, CDCl3) d 7.00 (d, J = 10.2 Hz, 1H), 6.24 (d, J = 10.9 Hz,
1H), 6.07 (s, 1H), 2.6–2.74 (m, 2H), 2.47–2.37 (m, 2H), 2.15–1.78
(m, 5H), 1.71–1.40 (m, 6H), 1.36 (s, 3H), 1.19 (s, 3H). 13C NMR
(101 MHz, CDCl3) d 186.45, 170.80, 167.63, 154.83, 128.10, 124.72,
82.91, 51.61, 45.66, 43.39, 39.02, 37.76, 32.45, 32.10, 29.02, 23.37,
20.50, 20.21, 18.89. ESI-MS at m/z = 301 for [M+1]+ and 342 for
[M+1+ACN]+.
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2.2.4. Synthesis of testololactone (13)
A solution of compound 12 (55 mg, 0.192 mmol), NaHCO3
(1.5 eq) and m-CPBA (40 mg, 0.23 mmol) in CH2Cl2 (7 ml) was stir-
red at room temperature overnight. The reaction mixture was
washed with Na2SO3, and saturated brine solution, dried over anhy-
drous Na2SO4 and concentrated under pressure to give a crude resi-
due which was crystallized from acetone to yield 13 (47 mg,
0.155 mmol) in 85% yield. Testololactone (13): (overall yield 46%);
mp = 207–208 °C; (C19H26O3; calcd C, 75.46; H, 8.67; found C,
75.50; H, 9.12%). 1H NMR (400 MHz, CDCl3) d (s, 1H), 2.7–2.49 (m,
4H), 2.25–2.10 (m, 2H), 2.06–1.78 (m, 7H), 1.89–1.34 (m, 5H), 1.31
(s, 3H), 1.20 (m, 1H), 1.04 (s, 3H). 13C NMR (101 MHz, CDCl3) d
199.32, 172.69, 171.41, 128.09, 82.63, 50.92, 46.56, 45.96, 41.51,
39.34, 38.42, 32.78, 31.79, 30.61, 29.32, 29.01, 23.06, 20.81, 20.20.
ESI-MS at m/z = 303 [M+1]+ and 342 for [M+1+K]+.
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3. Results and discussion
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Testololactone (13) and testolactone (14) were prepared from
easily available phytosterols like b-sitosterol (7)/stigmasterol (8)
via a simple reaction scheme (Scheme 1). b-sitosterol (7) as well as
stigmasterol (8) were subjected to Oppaneur oxidation using cyclo-
hexanone and aluminium isopropoxide under reflux conditions in
boiling toluene to yield 4-stigmasten-3-one (10) and 4,22-stig-
mastedien-3-one (11) respectively. The formation of both the prod-
ucts 10 and 11 was easily confirmed by the appearance of a
downfield singlet at d 5.85 ppm in the proton NMR spectrum corre-
sponding to the a-proton (C-4 proton) in the enone system of both
compounds 10 and 11.
This was further confirmed by the appearance of signals at d
199 ppm in 13C NMR spectra corresponding to the 3-oxo carbon
of 10 and 11 along with the disappearance of signals at d 71 ppm
corresponding to C-3 hydroxylated carbons in both sitosterol (7)
and stigmasterol (8). Next step was to carry out the cleavage of
side chain to furnish the C-17 keto functionality as is required in
both the end products. Initially a number of chemical methods
were tried but none succeeded to furnish the desired 4-an-
drostene-3,17-dienone (12). Consequently biotransformation
approach was used to synthesize the required compound 12. Treat-
ment of the either compound (10 or 11) with Mycobacterium spe-
cies (NRRL B-3805) yielded 4-androstene-3,17-dienone (12) in
excellent yields. Formation of 4-androstene-3,17-dienone (12)
could easily be confirmed by the appearance of a very downfield
carbon resonance at d 221 ppm in 13C NMR spectrum which corre-
sponds to the C-17 keto-carbon-moiety along with the disappear-
ance of some ten carbon signals corresponding to the loss of side
chains in both 10 and 11. Baeyer–Villiger oxidation of 4-an-
drostene-3,17-dienone (12) using m-CPBA in presence of NaHCO3
yielded the desired product testololactone (13) in excellent yield,
the structure of which was confirmed easily by the disappearance
of carbon signal at d 221 ppm and appearance of additional peak at
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2.2.5. Synthesis of 2-phenylseleno-4-androstene-3,17-dione (14)
A solution of 4-androstene-3, 17-dione (12) (55 mg, 0.192 mmol)
and phenylselenyl chloride (110 mg, 3 equivalents) in ethyl acetate
(10 ml) was stirred for 2 h at room temperature. After the comple-
tion of reaction the solvent was evaporated and the residue was
subjected to flash chromatography in Hex:EtOAc (75:25) to furnish
2-phenylseleno-4-androstenedione (14) in 75% yields; mp = 233–
235 °C; (C25H30O3Se; calcd C, 65.64; H, 6.61; found C, 65.61; H,
6.67%). 1H NMR (400 MHz, CDCl3) d 7.30–7.24 (m, 3H), 7.11–6.87
(m, 1H), 6.20 (s, 1H), 6.13 (s, 1H), 4.88 (s, 1H), 2.48 (m, 2H), 2.29
(m, 2H), 2.09 (m, 3H), 2.00–1.74 (m, 3H), 1.69 (s, 3H), 1.40–1.19
(m, 34H), 0.96 (s, 3H). 13C NMR (101 MHz, CDCl3) d 219.11, 185.82,
161.32, 156.32, 132.52, 129.34, 128.07, 126.85, 50.92, 49.98, 48.72,
48.41, 47.13, 43.35, 40.58, 35.83, 31.47, 30.21, 22.65, 21.73, 21.47,
13. 39. ESI-MS at m/z = 441 for [M+1]+ and 459 for [M+1+H2O]+
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2.2.6. Synthesis of 1,4-androstadi-en-3,17-dione (15)
To a solution of compound 14 (45 mg, 0.149 mmol) in CH2Cl2
was added 30% H2O2 solution and stirred for 4 h until the reaction
was complete as measured by TLC profiling. After completion the
reaction-mixture was worked up in CH2Cl2 and the organic layers
Please cite this article in press as: Lone SH, Bhat KA. Phytosterols as precursors for the synthesis of aromatase inhibitors: Hemisynthesis of testololactone
and testolactone. Steroids (2015), http://dx.doi.org/10.1016/j.steroids.2015.02.011

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14
R
18
R
12
8
12
11
9
11
9
17
16
15
19
19
13 17
14
1
16
1
2
10
2
Al (i-opr)3,
O
Toluene
15
10
8
3
A
6
7
5
O
4
7
Reflux, 12 hrs
HO
3
5
10, 11
4
6
95, 96
10, R =
Sitosterol(7), R =
11,
R =
Stigmasterol(8), R=
(NRRLB-3805)
M
y
c
o
b
a
c
t
e
r
i
u
m
s
p
s
18
O
12
13
14
O
O
11
19
17
m-CPBA, DCM, NaHCO3
1
2
16
9
12 hrs
8
10
15
3
6
7
O
5
O
4
12
13
PhSeCl/EtOAc
O
O
H
Ph Se
O
H2O2, DCM, 6 hrs
O
14
15
1
2
h
r
s
18
O
O
17
12
11
19
13
1
2
3
16
9
14
10
8
15
6
7
O
5
4
16
Scheme 1. Hemisynthesis of testololactone and testolactone.
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283
284
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289
d 171 ppm corresponding to the lactonic carbonyl moiety in 13. On
the other hand a number of procedures were tested to generate the
1,2-double bond as is required in testolactone (16): use of both
phenylselenyl chloride in presence of lithium diisopropyl amide
(LDA) followed by degradation using H2O2 failed to generate the
required 1,2 double bond. 2,3-Dichloro-5,6-dicyano-1,4-benzo-
quinone (DDQ) in either dioxane or toluene also failed to furnish
the required 1,2 double bond. Finally phenylselenyl chloride in
Please cite this article in press as: Lone SH, Bhat KA. Phytosterols as precursors for the synthesis of aromatase inhibitors: Hemisynthesis of testololactone
and testolactone. Steroids (2015), http://dx.doi.org/10.1016/j.steroids.2015.02.011

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ethyl acetate yielded the desired
a-phenylselenide which was
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References
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1,4-androstadiene-3,17-dione (15). Baeyer–Villiger oxidation of
1,4-androstadiene-3,17-dione using m-CPBA in sodium bicarbon-
ate successfully furnished the desired testolactone (16) in
quantitative yield.
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An efficient and highly facile route for the semi synthesis of aro-
matase inhibitors which include testololactone (13) and testolac-
tone (16) was developed using the well-known and most
abundant phytosterols (b-sitosterol, stigmasterol) as precursor
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oxidation, followed by oxidative cleavage using biotransformation
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by selenoxide elimination with H2O2 in DCM furnished
androstenedienone (15) whose Baeyer–Villiger oxidation yielded
testolactone (16). This reaction protocol can be safely used for
the bulk production of testolactone (marketed under the brand
name Teslac) from the easily available and most abundant precur-
sors like sitosterol and stigmasterol and thus offers a novel com-
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a
multifunctional strain Penicillium
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One of the authors Shabir H. Lone is grateful to CSIR (India) for
providing financial assistance in the form of Senior Research Fel-
lowship (Budget head: P-81101). Further the authors acknowledge
the Director, IIIM for supporting the work.
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Appendix A. Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.steroids.2015.02.
011.
372
Please cite this article in press as: Lone SH, Bhat KA. Phytosterols as precursors for the synthesis of aromatase inhibitors: Hemisynthesis of testololactone
and testolactone. Steroids (2015), http://dx.doi.org/10.1016/j.steroids.2015.02.011