Convergent stereoselective and efficient synthesis of furanic-steroid derivatives

Article abstract of DOI:10.1016/j.tet.2011.01.083

The stereoselective synthesis of furanic-steroid derivatives involving ring-closing metathesis and catalytic hydrogenation as key steps is described. The synthetic strategy was first illustrated by the synthesis of the furanic-estrane derivative 1 in seven steps starting from estrone and 2-methylene-propane-1,3-diol. This compound initially targeted as a potential inhibitor of 17β-hydroxysteroid dehydrogenase type 1 by a docking experiment was found to inhibit the enzyme. The scope of this new strategy was also extended to furanic-androstane derivatives by synthesizing compound 20.

Full text of DOI:10.1016/j.tet.2011.01.083

Tetrahedron 67 (2011) 2434e2440
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Convergent stereoselective and efficient synthesis of furanic-steroid derivatives
*
ꢀ
Siham Farhane, Michelle-Audrey Fournier, Rene Maltais, Donald Poirier
ꢀ
ꢀ
Laboratory of Medicinal Chemistry, CHUQ (CHUL)dResearch Center and Laval University, 2705 Laurier Boulevard, Quebec, Quebec G1V 4G2, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective synthesis of furanic-steroid derivatives involving ring-closing metathesis and cata-
lytic hydrogenation as key steps is described. The synthetic strategy was first illustrated by the synthesis
of the furanic-estrane derivative 1 in seven steps starting from estrone and 2-methylene-propane-1,3-
Received 17 November 2010
Received in revised form 24 January 2011
Accepted 26 January 2011
diol. This compound initially targeted as a potential inhibitor of 17b-hydroxysteroid dehydrogenase type
Available online 2 February 2011
1 by a docking experiment was found to inhibit the enzyme. The scope of this new strategy was also
extended to furanic-androstane derivatives by synthesizing compound 20.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Steroid
Chemical synthesis
Furanic derivative
Ring-closing metathesis
1. Introduction
adenosine hybrid inhibitor,20 complexed with 17
b-HSD1. The re-
sults of these experiments have suggested that the furanic de-
rivative 1 (Scheme 1) might generate favorable interactions with
the active site of the enzyme. Furthermore, such a steroid derivative
is not expected to be metabolized at positions 16 and 17 because
the furanic moiety blocks these two positions, thus avoiding the
hydroxylation and glucuronidation reactions,21 both crucial phase I
and phase II steroid metabolism reactions. In fact, with a C17-ether
function, which is more stable, rigid, and less estrogenic than the
C17-hydroxyl group of E2, the furanic compound 1 circumvents
Estrogenic hormones are well known to be involved in the de-
velopment and progression of estrogen-dependent diseases, such
as breast cancer.1,2 Among the different types of breast tumors, the
majority are initially stimulated by estrogens, and estradiol (E2)
plays a crucial role in their growth. Hormonal control is conse-
quently a logical choice in the treatment of hormone-dependent
breast cancer (HDBC) and endocrine therapies were developed
because they are less toxic than chemotherapy. Antiestrogens
(AE) that block off the estrogen receptor (ER), have been designed
and their efficiency has been proven by several clinical trials.3e7
A complementary approach to the treatment of HDBC using an
AE consists in lowering the level of E2 by inhibiting one of the
steroidogenic enzymes involved in the biosynthesis of E2.8e11
a drawback of several 17b-HSD1 inhibitors that have been de-
veloped until now. Herein, we report a short and efficient strategy
to synthesize the furanic-estrane (C18-steroid) derivative 1 using
Grubbs metathesis reaction as a key step. The methodology was
also extended to androstane (C19-steroid) nucleus by generating
compound 20.
Among these enzymes, 17
b-hydroxysteroid dehydrogenase type 1
(17 -HSD1) is responsible for the reduction of the keto group at
b
position 17 of estrone (E1) to give the most potent of the human
2. Results and discussion
estrogens, E2.12,13
Inhibitors of 17
b
-HSD1 have been reported by several groups,
One strategy to obtain the furanic derivative 1 would be to start
by an alkylation at position 16 of 17-ketosteroid E1 with an ap-
propriate secondary bromide properly protected and ending by
a cyclization. However, taking into account the considerable time
needed to prepare the suitable nucleophile and the well known low
reactivity of 17-ketosteroids for the alkylation at C16 using an
unactivated bromide,20,22,23 we instead designed a new strategy for
the synthesis of 1, which is outlined in Scheme 1. Briefly, the chiral
furanic compound 1 will be generated by a stereoselective hydro-
genation of 2, which will be obtained by a metathesis of olefin 3
previously generated from alcohol 4 and allylic bromide 5. Our
and this field has been reviewed by ourselves14e16 as well as by
others.17,18 An ongoing program in our laboratory is aimed at the
design and synthesis of novel potent inhibitors of 17
treatment of HDBC. Our interest in furanic compounds as inhibitors
b-HSD1 for the
of 17b-HSD1 arose from the result of preliminary docking studies,
using the three-dimensional structure of EM-1745,19 an E2/
* Corresponding author. Tel.: þ1 418 654 2296; fax: þ1 418 654 2761; e-mail
address: donald.poirier@crchul.ulaval.ca (D. Poirier).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.083

S. Farhane et al. / Tetrahedron 67 (2011) 2434e2440
2435
of the furanic moiety. It is thus possible to introduce molecular
diversity at both C3 and C30-positions of 1.
The intermediate 4 was easily synthesized in four steps from E1
(Scheme 3). After a classical benzylation of E1 into Bn-E1 (8), the
next step involved introducing a methylene group at C16, following
known methodology that was previously reported for another E1
derivative.24 Bn-E1 (8) is thus transformed to the Mannich base 9,
which in boiling acetic anhydride leads to 16-methylene derivative
10 in 70% yield for two steps. This conjugated ketone was treated
with NaBH4 to give 16-methylene-E2 (4) and a small quantity
(4e12%) of 16b-methyl-E2, a side product resulting from both the
carbonyl and double bond reductions. However, this amount of side
product could be decreased or eliminated by using the Luche re-
duction conditions (NaBH4, CeCl3).25 Furthermore, the reduction of
the carbonyl at position 17 is well known to proceed stereo-
selectively due to the presence of the 18-CH3 group on the
b
-face of
the steroid nucleus.20,22,23 Consequently, only the 17
was observed.
b-OH isomer 4
The synthesis of 1 was performed in three steps starting from 4
(Scheme 3). The steroid 11 was first obtained in excellent yield by
O-alkylation of the hydroxy group of 4 in presence of bromide 5a
and NaH. The unsaturated five-membered ring compound 12 was
next generated from olefin 11 by a ring-closing metathesis
(RCM).26e28 In fact, producing a tetrasubstituted carbonecarbon
double bond by RCM represents a challenge, but new ruthenium
catalysts were recently reported to form tetrasubstituted olefins
with increased efficacy.29,30 We isolated the dihydrofuran 12 in 66%
yield by using the commercially available second generation
Grubbs catalyst. However, we found that it was more convenient to
proceed with the double bond saturation rapidly. During this last
step in the synthesis of 1, the tetrasubstituted double bond of 12
was stereoselectively reduced and the two benzyl ether groups
were cleaved using the same catalytic hydrogenation conditions
(H2, 3 atm). Thanks to the axial 18-CH3 group on the steroid
b-face,
the two hydrogen atoms add to the double bond by the less hin-
dered steroid a-face, thus providing the compound 1 with 16R and
20R-configuration.
The 16R and 20R-stereochemistry of furanic compound 1 was
confirmed by NMR spectroscopy (NOESY) after establishing the
assignment of key protons and carbons by COSY, HSQC, and HMBC
experiments,31 and comparison of data reported in literature for
Scheme 1. Retrosynthetic analysis for the synthesis of furanic-estrane derivative 1.
steroid compounds.32,33 The S-configuration of H17 (
a
-H in steroid
nomenclature) and S-configuration of C13 (
b-orientation of CH3-
convergent strategy will begin by the preparation of steroid 4 and
bromide 5 from E1 and 2-methylene-propane-1,3-diol (6), re-
spectively, both commercially available.
18) being well known, both NMR signals were used as starting
point for structure elucidation using a NOESY experiment (Fig. 1).
The NOESY spectrum showed an interaction between H17 and
The bromoolefin 5a was prepared from 6 as shown in Scheme 2.
One hydroxyl group of the diol 6 was selectively protected using
benzyl bromide (BnBr) and NaH as base to provide 7a. The latter
was then submitted to a bromination of the remaining primary
alcohol using triphenylphosphine and carbon tetrabromide to give
5a. The same sequence of reactions was also performed using TBS-
Cl and imidazole as base to provide 7b and then 5b after bromi-
nation. The use of a TBS group instead of a benzyl (Bn) group allows
discrimination between the OH of steroid backbone and the CH2OH
H16, thus setting the a-stereochemistry of H16. The R-configura-
tion of H20 was next confirmed by the presence of a NOE signal
between H16 and H20. These two protons are thus clearly on the
same side of the furanic ring (a-steroid side) as expected by the
mechanism of Pd-catalyzed hydrogenation. We also observed
a NOE signal between the C18 and one methylenic H of 10-CH2O
(10 -H) and a NOE signal between 10 -H and H20. All the results
b a
discussed above confirm without a doubt the 20R-stereochemistry
and the presence of the 30-CH2OH group on the same
-steroid
b
Scheme 2. Synthesis of bromoolefin 5.

2436
S. Farhane et al. / Tetrahedron 67 (2011) 2434e2440
Scheme 3. Synthesis of furanic compound 1.
side than the CH3-18. Interestingly, this isomer is the one, which
was predicted to interact favorably with the enzyme in our pre-
liminary docking study.
Furanic-estrane derivative 1 was evaluated for its ability to in-
hibit the transformation of labeled E1 into E2 catalyzed by 17b-
treatment in refluxing acetic anhydride. This side product was
however easily transformed to 14 after hydrolysis of acetate and
protection as a TBS ether. Reduction of 14 with NaBH4 gave a 90%
yield of the alcohol 16. The next steps involve the 17-O-alkylation of
16 with primary bromide 5a to give 17, the ring-closing metathesis
to obtain the unsaturated dihydrofuran 18, and the catalytic hy-
drogenation to afford exclusively the isomer 19. Finally, after
cleavage of the TBS ether protective group in acidic solution, the
chiral furanic-androstane compound 20 was successfully obtained.
As described above for 1, the NMR analysis of 20 demonstrated the
R-configuration at C16 and C20.
HSD1. According to an established procedure using homogenized
HEK-293 cells overexpressing the enzyme,34 compound 1 was
tested at two concentrations (0.1 and 1
of 55 and 70%, respectively. It was thus a more effective inhibitor
than the natural substrate E1 and the first generation of 17 -HSD1
inhibitor EM-251,35 which gave 40 and 45% of inhibition at 0.1
M,
mM) and showed inhibition
b
m
respectively. A docking experiment showed the presence of two
key interactions between 1 and the enzyme (Fig. 2). Indeed, two
hydrogen bonds are clearly apparent between the 3-OH and His221
3. Conclusion
and the 17
produced by 1.
b
-O and Tyr155, thus supporting the inhibitory activity
We have developed an efficient strategy for the preparation of
furanic-steroid derivatives in three steps from a 16-methylenic
steroid with an overall yield of 29%. Ring-closing metathesis and
catalytic hydrogenation are the key steps in this synthesis. When
using two different protective groups, the synthetic strategy allows
us to introduce a molecular diversity at both C3 and C30-positions,
which are two locations playing a crucial role in maximizing in-
teractions between steroidal derivatives and targeted enzymes,
To expand the scope of the straightforward sequence of re-
actions providing 1, a different steroid scaffold was next tested. We
selected androsterone (ADT), a C19-androstane nucleus previously
reported as a lead compound for 17b
-HSD3 inhibitors.36,37 We
therefore used the same chemical route as for the synthesis of 1 to
afford the furanic-androstane derivative 20 with the desired 20R-
configuration (Scheme 4). The 16-methylene-3-O-TBS-ADT (14)
was prepared from ADT similarly as described for 4 in 54% yield.
This yield is lower than expected but is explained by the formation
of 16-methylene-3-O-Ac-ADT (15) in 25% yield during the
such as 17b
-HSD1.38,39 The strategy could also be used for the
preparation of additional steroidal or non-steroidal furanic de-
rivatives, thus extending our methodology to other families of
therapeutic agents.

S. Farhane et al. / Tetrahedron 67 (2011) 2434e2440
2437
Fig. 1. Partial NOESY spectrum (0e4.3 ppm) obtained for 1 dissolved in CDCl3.
4. Experimental
230e400 mesh silica gel. 1H and 13C NMR spectra were recorded
with a Bruker AVANCE 400 spectrometer at 400 MHz. The chemical
4.1. General remarks
shifts (d) are expressed in parts per million and referenced to
chloroform (centered at 7.26 and 77.00 ppm), acetone (centered at
2.07 and 206.26 ppm) or dimethyl sulfoxide (centered at 2.49 and
39.50 ppm) for 1H and 13C, respectively. Low-resolution mass
spectra (LRMS) were recorded with an LCQ Finnigan apparatus (San
Jose, CA, USA) equipped with an atmospheric pressure chemical
ionization (APCI) source on positive or negative mode. High-reso-
lution mass spectra (HRMS) were provided by Pierre Audet from the
Reagents were obtained from SigmaeAldrich Canada Co. (Oak-
ville, ON, Canada). Usual solvents were obtained from Fisher Sci-
ꢀ
entific and VWR (Montreal, Qc, Canada) and were used as received.
Anhydrous solvents were purchased from Aldrich and VWR in
SureSeal bottles, which were conserved under positive argon
pressure. All anhydrous reactions were performed in oven-dried
glassware under positive argon pressure. Thin-layer chromatogra-
phy (TLC) was performed on 0.25-mm silica gel 60 F254 plates
(Whatman, Maidstone, England), and compounds were visualized
by exposure to UV light (254 nM) and/or with a solution of am-
monium heptamolybdate tetrahydrate (with heating). Flash chro-
ꢀ
Deptartment of Chemistry at Laval University (Quebec, Qc, Canada).
4.2. Selective benzylation of diol 6 to give 7a
To
a cooled solution of 2-methylene-propane-1,3-diol (6)
ꢀ
matography was performed on Silicycle 60 (Quebec, Qc, Canada)
(0.12 mmol) in dry THF (60 mL) was added NaH (60% in oil,

2438
S. Farhane et al. / Tetrahedron 67 (2011) 2434e2440
NMR (CDCl3): 64.4, 71.7, 72.2, 113.5, 127.7 (4C), 128.4, 137.9, 144.9.
LRMS for C11H15O2 (MþH)þ: 178.9 m/z.
4.3. Bromination of 7a to give 5a
A solution of the alcohol 7a (0.56 mmol), PPh3 (1.11 mmol), and
CBr4 (1.11 mmol) in dry CH2Cl2 (15 mL) was stirred at 0 ꢀC under
argon. The reaction was monitored by TLC and was completed after
3 h. The crude mixture was purified by flash chromatography
(hexanes/EtOAc) to give the bromide 5a.
4.3.1. ((2-(Bromomethyl)allyloxy)methyl)benzene (5a). Yield¼82%.
1H NMR (acetone-d6): 4.18 (s, CH2Br, and CH2OBn), 4.55 (s,
OCH2Ph), 5.32 and 5.43 (2s, C]CH2), 7.30e7.50 (m, OCH2Ph). 13C
NMR (CDCl3): 33.0, 70.3, 72.4, 117.2, 127.7 (4C), 128.4, 137.9, 142.3.
LRMS for C11H12O79Br (MꢁH)ꢁ: 239.0 m/z. HRMS calcd for
C11H1279Br (Mꢁ[OH])þ: 375.2319, found 375.2332.
Fig. 2. Docking result obtained for furanic-estrane compound 1.
4.4. General procedure for the synthesis of 16-methylene
derivative of estrone and androsterone (compounds 10 and 14)
0.12 mmol). After 2 h at 0 ꢀC, benzyl bromide (0.15 mmol) was
added and the mixture was stirred for 4 h at 0 ꢀC. The reaction was
then quenched at 0 ꢀC with a saturated NH4Cl aqueous solution and
the mixture was extracted with EtOAc. The organic layers were
combined and washed with water, dried over Na2SO4, filtered, and
evaporated under reduced pressure. The crude material was puri-
fied by flash chromatography (hexanes/EtOAc) to afford 7a.
To
a
solution of N,N,N0,N0-tetramethyldiaminomethane
(11.6 mmol) in diethylether (14.6 mL) was added, dropwise, a so-
lution of acetyl chloride (11.6 mmol) in diethylether (11 mL). After
30 min of stirring, the precipitate was rapidly filtered off and sus-
pended in acetonitrile (15 mL). Addition of 3-O-benzylestrone (8)40
or 3-O-tert-butyldimethylsilyl androsterone (13)41 (2.0 g) was fol-
lowed by stirring at 80 ꢀC for 12 h. After cooling, the solvent was
evaporated under reduced pressure, the residue taken up in 1 N HCl
(100 mL), and the mixture was extracted with diethylether. A
4.2.1. 2-(Benzyloxymethyl)prop-2-en-1-ol (7a). Yield¼40%. 1H NMR
(CDCl3): 2.20 (s, OH), 4.10 (s, CH2OBn), 4.19 (s, CH2OH), 4.52 (s,
OCH2Ph), 5.16 and 5.21 (2s, C]CH2), 7.28e7.38 (m, OCH2Ph). 13C
Scheme 4. Synthesis of furanic-androstane derivative 20.

S. Farhane et al. / Tetrahedron 67 (2011) 2434e2440
2439
solution of 2 N NaOH was added dropwise (pH¼11) and the mix-
ture was extracted with diethylether. The solvent was evaporated
under reduced pressure and the crude Mannich base was dissolved
in acetic anhydride (6 mL) and refluxed at 140 ꢀC for 12 h. After
cooling, the reaction mixture was carefully dropped into a satu-
rated NaHCO3 solution (100 mL), stirred for another 15 min at
25 ꢀC, and extracted with CH2Cl2. The organic layers were com-
bined and washed with water, dried over MgSO4, filtered, and
evaporated under reduced pressure. The crude material was puri-
fied by flash chromatography (hexanes/EtOAc) to give 10 or 14.
(MþH)þ: 419.2 m/z. HRMS calcd for C26H47O2Si (MþH)þ: 419.3340,
found 419.3331.
4.6. General procedure for O-alkylation of methylenic
steroids (synthesis of 11 and 17)
To a cooled solution of alcohol 4 or 16 (0.267 mmol) in dry DMF
(1 mL) was added NaH (60% in oil, 0.4 mmol). After 1 h at 0 ꢀC, the
solution of 5a (0.267 mmol) in dry DMF (1.2 mL) was added and the
mixture was stirred for 3 h at 0 ꢀC. The reaction was then quenched
at 0 ꢀC with a saturated NH4Cl aqueous solution and extracted with
EtOAc. The organic layers were combined and washed with water,
dried over Na2SO4, filtered, and evaporated under reduced pres-
sure. The crude material was purified by flash chromatography
(hexanes/EtOAc) to yield 11 or 17.
4.4.1. 3-(Benzyloxy)-16-methylideneestra-1(10),2,4-trien-17-one
(10). Yield¼70%. 1H NMR (CDCl3): 0.94 (s, 18-CH3), 1.30e2.50 (un-
assigned CH and CH2), 2.70 (dd, J1¼6.2 Hz, J2¼15.5 Hz,15
a-CH), 2.91
(m, 6-CH2), 5.05 (s, OCH2Ph), 5.42 and 6.11 (2s, C]CH2), 6.75 (d,
J¼2.3 Hz, 4-CH), 6.81 (dd, J1¼2.4 Hz, J2¼8.6 Hz, 2-CH), 7.22 (d,
J¼8.6 Hz, 1-CH), 7.30e7.45 (m, OCH2Ph). 13C NMR (CDCl3): 14.2,
25.9, 26.7, 29.0, 29.6, 31.6, 37.8, 43.9, 47.7, 48.1, 69.9, 112.4, 114.9,
118.8, 126.3 (2C), 127.5, 127.9 (2C), 128.5, 132.3, 137.2, 137.7, 144.4,
156.9, 208.6. LRMS for C26H29O2 (MþH)þ: 373.1 m/z. HRMS calcd for
C26H29O2 (MþH)þ: 373.2162, found 373.2161.
4.6.1. (17b)-3-(Benzyloxy)-17-({2-[(benzyloxy)methyl]prop-2-en-1-
yl}oxy)-16-methylideneestra-1(10),2,4-triene (11). Yield¼80%. 1H
NMR (CDCl3): 0.81 (s, 18-CH3), 1.25e2.40 (unassigned CH and CH2),
2.45 (dd, J1¼7.4 Hz, J2¼16.4 Hz, 15
a-CH), 2.88 (m, 6-CH2), 3.84 (s,
-CH), 4.14 (s, CH2OBn), 4.22 and 4.33 (2d, J¼12.5 Hz, OCH2C]
17a
CH2), 4.57 (s, OCH2Ph of side chain), 5.06 (s, OCH2Ph at position 3),
5.06 and 5.21 (2s, C]CH2 at C16), 5.28 and 5.32 (2s, C]CH2 of side
chain), 6.75 (d, J¼2.4 Hz, 4-CH), 6.82 (dd, J1¼2.6 Hz, J2¼8.6 Hz, 2-
CH), 7.23 (d, J¼8.6 Hz, 1-CH), 7.30e7.50 (m, 2ꢂCH2Ph). 13C NMR
(CDCl3): 11.7, 26.5, 27.2, 29.7, 30.4, 38.0, 38.1, 43.6, 43.7, 47.1, 69.9,
70.9, 71.8, 72.2, 90.5, 108.5, 112.3, 114.3, 114.8, 126.2 (2C), 127.4 (2C),
127.6, 127.7 (2C), 127.8, 128.3 (2C), 128.5, 132.7, 137.3, 137.9, 138.3,
143.1, 150.3, 156.7. LRMS for C37H41O3 (MꢁH)ꢁ: 533.6 m/z.
4.4.2. (3a,5a)-3-{[tert-Butyl(dimethyl)silyl]oxy}-16-methylidenean-
drostan-17-one (14). Yield¼54%. 1H NMR (CDCl3): 0.01 (s, Si(CH3)2),
0.76 (s, 19-CH3), 0.85 (s, 18-CH3, and SiC(CH3)3), 0.80e2.20 (un-
assigned CH and CH2), 2.52 (dd, J1¼6.4 Hz, J2¼15.5 Hz,15
a-CH), 3.93
(t, J¼2.5 Hz, 3
b
-CH), 5.31 and 6.01 (2s, C]CH2). 13C NMR (CDCl3):
ꢁ4.9 (2C), 11.3, 14.1, 18.0, 20.0, 25.8 (3C), 28.3, 29.1, 29.6, 31.0, 31.5,
32.2, 34.5, 36.1, 36.6, 39.0, 47.9, 48.6, 54.3, 66.6, 118.2, 144.6, 208.8.
LRMS for C26H45O2Si (MþH)þ: 417.0 m/z. HRMS: calcd for C20H29
O
(Mꢁ[TBSO])þ: 285.2218, found 285.2220.
4.6.2. (3a,5a,17b)-17-({2-[(Benzyloxy)methyl]prop-2-en-1-yl}oxy)-
3-{[tert-butyl(dimethyl)silyl] oxy}-16-methylideneandrostane (17).
Yield¼78%. 1H NMR (CDCl3): 0.06 (s, Si(CH3)2), 0.76 (s, 19-CH3), 0.80
(s, 18-CH3), 0.93 (s, SiC(CH3)3), 0.90e2.00 (unassigned CH and CH2),
4.5. General procedure for the reduction of 17-ketone into
17
b
-hydroxy group (synthesis of 4 and 16)
2.33 (dd, J1¼7.4 Hz, J2¼16.6 Hz, 15
a
-CH), 3.74 (s, 17
a-CH), 4.00 (s,
3b
-CH), 4.12 (s, CH2OBn), 4.18 and 4.30 (2d, J¼12.5 Hz, OCH2C]
NaBH4 (0.85 mmol) was added to a cooled (0 ꢀC) solution of 10 or
CH2), 4.54 (s, OCH2Ph of side chain), 5.01 and 5.16 (2s, C]CH2), 5.25
and 5.29 (2s, C]CH2 of side chain), 7.25e7.40 (m, CH2Ph). 13C NMR
(CDCl3): ꢁ4.8 (2C), 11.3, 11.7, 18.0, 20.5, 25.8 (3C), 28.4, 29.6, 30.6,
31.6, 32.3, 34.8, 36.0, 36.7, 38.0, 39.0, 43.4, 48.0, 54.2, 66.7, 70.8, 71.7,
72.1, 90.5, 108.1, 114.1, 127.5, 127.6 (2C), 128.3 (2C), 138.2, 143.1,
150.6. LRMS for C37H59O3Si (MþH)þ: 579.2 m/z.
14 (0.5 mmol) in MeOH (12.7 mL) and CH2Cl2 (2.5 mL). After the
mixture was stirred for 3e4 h at 0 ꢀC, the reaction was quenched by
addition of water and extraction was performed with CH2Cl2. The
organic phase was dried over Na2SO4 and evaporated to dryness.
The crude material was purified by flash chromatography (hexanes/
EtOAc) to afford 4 or 16 containing a small quantity (4 and 12% by
NMR, respectively) of the product of double bond reduction (16-
CH3).
4.7. General procedure for the ring-closing metathesis and
catalytic hydrogenation (synthesis of 1 and 19)
4.5.1. (17
b
)-3-(Benzyloxy)-16-methylideneestra-1(10),2,4-trien-17-
To a solution of diene 11 or 17 (0.80 mmol) in dry CH2Cl2 (12 mL)
was added second generation Grubbs catalyst (tricyclohex-
ylphosphine[1,3-bis(2,4,6-tri-methylphenyl)-4,5-dihydroimidazol-
2-ylidene] [benzylidine] ruthenium(IV)dichloride) (0.12 mmol). This
mixture was refluxed overnight, then filtered through Celite and the
solvent evaporated under reduced pressure to give the crude alkene
12 or 18. A suspension of crude 12 or 18 (0.37 mmol) and 10% PdeC
(0.07 mmol) in EtOAc/EtOH: 1/1 (14 mL) was hydrogenated at
3e4 atm for 16 h. After filtration through Celite, the solvent was re-
moved under reduced pressure and purification by flash chroma-
tography (hexanes/EtOAc) afforded 1 or 19.
ol (4). Yield¼96%. 1H NMR (CDCl3): 0.73 (s, 18-CH3), 1.20e2.40
(unassigned CH and CH2), 2.50 (dd, J1¼7.5 Hz, J2¼16.5 Hz, 15
a-CH),
2.88 (m, 6-CH2), 4.01 (s, 17a-CH), 5.06 (s, OCH2Ph), 5.10 and 5.21
(2s, C]CH2), 6.75 (d, J¼2.4 Hz, 4-CH), 6.82 (dd, J1¼2.6 Hz,
J2¼8.5 Hz, 2-CH), 7.24 (d, J¼8.5 Hz, 1-CH), 7.30e7.50 (m, OCH2Ph).
13C NMR (CDCl3): 10.9, 26.3, 27.3, 29.7, 30.5, 36.4, 38.1, 43.3, 43.9,
46.8, 69.9, 83.9, 107.8, 112.2, 114.8, 126.2 (2C), 127.4, 127.8 (2C),
128.5, 132.7, 137.2, 137.8, 153.1, 156.7. LRMS for C26H31O2 (MþH)þ:
375.2 m/z. HRMS calcd for C26H31O2 (MþH)þ: 375.2319, found
375.2332.
4.5.2. (3
a
,5
a
,17
b
)-3-{[tert-Butyl(dimethyl)silyl]oxy}-16-methyl-
4.7.1. (4bS,6aS,6bS,9R,9aR,10aS,10bR)-9-(hydroxymethyl)-6a-
methyl-5,6,6a,6b,8,9,9a,10,10a,10b,11,12-dodecahydro-4bH-naphtho
[20,10:4,5]indeno[1,2-b]furan-2-ol (1). Yield¼82%. 1H NMR (CDCl3):
0.79 (s, 18-CH3), 1.20e2.35 (unassigned CH and CH2), 2.46 (m, 20-
ideneandrostan-17-ol (16). Yield¼90%. 1H NMR (CDCl3): 0.01 (s, Si
(CH3)2), 0.65 (s, 18-CH3), 0.76 (s, 19-CH3), 0.88 (s, SiC(CH3)3),
0.80e2.00 (unassigned CH and CH2), 2.33 (dd, J1¼7.5 Hz,
J2¼16.4 Hz, 15
a
-CH), 3.87 (s, 17
a
-CH), 3.95 (t, J¼2.4 Hz, 3
b
-CH),
CH), 2.80 (m, 6-CH2, and 16-CH), 3.58 (t, J¼8.8 Hz, 10
a
-CH), 3.68 and
5.00 and 5.12 (2s, C]CH2). 13C NMR (CDCl3): ꢁ4.8 (2C), 11.0, 11.4,
18.1, 20.4, 25.9 (3C), 28.5, 29.7, 30.8, 31.7, 32.3, 35.0, 36.1, 36.5, 36.7,
39.0, 43.1, 47.9, 54.5, 66.8, 84.1, 107.4, 153.6. LRMS for C26H47O2Si
3.79 (2m, 30-CH2O), 4.02 (dd, J1¼7.4 Hz, J2¼8.7 Hz, 10
b-CH), 4.15 (d,
J¼9.0 Hz, 17 -CH), 4.80 (br, OH), 6.55 (d, J¼2.6 Hz, 4-CH), 6.63 (dd,
a
J1¼2.7 Hz, J2¼8.4 Hz, 2-CH), 7.14 (d, J¼8.4 Hz, 1-CH). 13C NMR

2440
S. Farhane et al. / Tetrahedron 67 (2011) 2434e2440
(CDCl3): 12.4, 25.4, 26.6, 27.8, 29.6, 37.9, 38.3, 43.3, 43.6, 44.3, 44.6,
53.5, 62.0, 72.8, 93.6, 112.7, 115.2, 126.5, 132.7, 138.1, 153.3. LRMS for
C21H29O3 (MþH)þ: 329.2 m/z. HRMS calcd for C21H29O3 (MþH)þ:
329.2111, found 329.2113.
compounds 7a, 5a, 10, 14, 4, 16, 11, 17, and 19. Supplementary data
associated with this article can be found in the online version, at
doi:10.1016/j.tet.2011.01.083.
References and notes
4.7.2. [(2R,4aS,4bS,6aS,6bS,9aR,9R,10aS,10bR,12aS)-2-{[tert-Butyl(di-
methyl)silyl]oxy}-4a,6a-dimethyloctadecahydro-1H-naphtho
[20,10:4,5]indeno[1,2-b]furan-9-yl]methanol (19). Yield¼62%. 1H
NMR (CDCl3): 0.01 (s, Si(CH3)2), 0.73 (s, 19-CH3), 0.75 (s, 18-CH3),
0.88 (s, 9H, SiC(CH3)3), 0.90e2.35 (unassigned CH and CH2), 2.40
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The silylated ether 19 was dissolved in a methanolic solution of
HCl (2%, v/v) and the mixture was stirred at room temperature for
3 h. Water was added, the methanol evaporated under reduced
pressure and the residue extracted with EtOAc. The organic layers
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16-CH), 3.36 (m, 10
CH2O), 3.80 (m, 10
a
-CH and 1H of 30-CH2O), 3.47 (m, 1H of 30-
b
-CH and OH), 3.88 (d, J¼9.0 Hz, 17
a-CH), 4.16 (d,
J¼2.3 Hz, 3
b
-CH), 4.47 (t, J¼4.6 Hz, OH). 13C NMR (DMSO-d6): 11.2,
12.5, 20.3, 25.3, 28.3, 28.7, 32.0, 32.1, 34.3, 35.8 (2C), 38.1, 38.6, 43.0,
43.7, 44.1, 53.9, 54.0, 59.9, 64.1, 72.6, 92.8. LRMS for C22H37O3
(MþH)þ: 349.1 m/z. HRMS calcd for C22H36O3Na (MþNa)þ:
371.2557, found 371.2577.
Acknowledgements
We thank the Canadian Institutes of Health Research (CIHR) and
the Canadian Breast Cancer Research Alliance (CBCRA) for an op-
erating grant. We also thank Diane Fournier for advice regarding
docking experiments, Liviu Ciobanu, Richard Labrecque, and Jean-
Yves Sanceau for helpful discussions, and Micheline Harvey for
careful reading of the manuscript.
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estrone as previously reported Ciobanu, L. C.; Poirier, D. J. Comb. Chem. 2003, 5,
429e440.
Supplementary data
1H NMR, COSY, APT, and HSQC spectra of furanic-estrane 1, NMR
spectra of furanic-androstane 20, and NMR spectra of intermediate
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