Synthesis of functionalised enantiopure steroids from estrone and cholestanone through organolithium intermediates

Article abstract of DOI:10.1016/S0957-4166(01)00121-5

The reaction of epoxides 1 and 8 derived from estrone and cholestanone, respectively, with an excess of lithium and a catalytic amount of DTBB (7 mol%) in THF at -78°C led to formation of the corresponding β-oxido-functionalised organolithium intermediate

Full text of DOI:10.1016/S0957-4166(01)00121-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 801–810
Synthesis of functionalised enantiopure steroids from estrone and
cholestanone through organolithium intermediates
Miguel Yus,* Tatiana Soler and Francisco Foubelo
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Received 5 March 2001; accepted 7 March 2001
Abstract—The reaction of epoxides 1 and 8 derived from estrone and cholestanone, respectively, with an excess of lithium and a
catalytic amount of DTBB (7 mol%) in THF at −78°C led to formation of the corresponding b-oxido-functionalised organo-
lithium intermediates 2 and 9, respectively, in a regio- and stereoselective manner. Treatment of these intermediates with different
electrophiles [H2O, D2O, PhCHO, Me2CO, Et2CO, (CH2)5CO, CO2] at −78 to 20°C afforded, after hydrolysis with water,
enantiomerically pure derivatives 3 and 10, respectively. When protected ketones 5 and 6 derived from
D-glucose and D-fructose
were used as the electrophile, the reaction with 2 gave the expected mixed products 3g and 3h, respectively, which consist of a
steroid and a carbohydrate fragment. The reaction of O-protected estrone 4 as the electrophilic component and intermediate 2
afforded the C2-symmetric steroid dimer 3f. The stereochemistry of the products was unambiguously determined by correlation
with X-ray data for compound 3d and by comparison with the known compound 6a. Finally, the addition of the dianions 13,
resulting from the DTBB-catalysed lithiation of phthalan 12a and isochroman 12b, to the O-protected estrone 4 and to
cholestanone 9 led to the formation of the diols 14, 15 and 16. Diols 14 were cyclised under Mitsunobu reaction conditions to
the corresponding heterocycles 17. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
tion with electrophilic reagents undergo functionality
transfer to the electrophile, giving polyfunctionalised
molecules in a single step. Of precursors to this class of
organolithium reagent, heterocyclic compounds8 such
as epoxides are of interest as ring opening can be
carried out in a stoichiometric9 or a catalytic10 arene-
promoted lithiation reaction.
It is well-known that steroids are very important bio-
logically active molecules and are widely represented in
both the plant and animal kingdoms, their biosynthesis
being almost the same in both cases.1a In spite of the
fact that steroids have many common structural fea-
tures, small changes in the functionalities attached to
the steroid skeleton can cause marked changes in their
biological activity.1b For this reason, it is interesting to
selectively transform naturally occurring steroids to
new functionalised structures which may as a conse-
quence have new bioactivity and possible therapeutic
applications. This strategy would be a typical example
of EPC (enantiomerically pure compounds) synthesis,2
which takes advantage of the chiral pool of natural
products for elaboration to more sophisticated chiral
molecules.
Herein, we report arene-catalysed lithiation of epoxides
derived from estrone or cholestanone for the generation
of functionalised organolithium intermediates, which
are used in turn to introduce different electrophilic
fragments to the steroid skeleton. In this way, function-
alised steroid and steroid-like molecules are readily
prepared.11
2. Results and discussion
Over the last decade we have used an arene-catalysed
lithiation3–6 for the preparation of very reactive organo-
lithium compounds under very mild conditions. Among
these intermediates we find especially interesting func-
tionalised organolithium compounds,7 which on reac-
The reaction of the epoxy steroid 1 derived from
estrone 7 with an excess of lithium (1:16 molar ratio)
and a catalytic amount of 4,4%-di-tert-butylbiphenyl
(DTBB, 1:0.14 molar ratio, 7 mol%) in THF at −78°C
for 2 h gave a solution of the corresponding b-oxido
organolithium intermediate 2, which by treatment with
different electrophiles [H2O, D2O, PhCHO, Me2CO,
(CH2)5CO, 4, 5, 6 (Fig. 1), CO2] at the same tempera-
ture for 10 min led, after hydrolysis with water (or
* Corresponding author. URL: http://www.ua.es/dept.quimorg;
e-mail: yus@ua.es
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00121-5

802
M. Yus et al. / Tetrahedron: Asymmetry 12 (2001) 801–810
O
OH
E
OLi
Li
i
ii, iii
O
O
O
O
1
2
3
Scheme 1. Reagents and conditions: (i) Li, DTBB (7 mol%), THF, −78°C, 2 h; (ii) E+=H2O, D2O, PhCHO, Me2CO, Et2CO,
(CH2)5CO, 4, 5, 6, CO2, −78°C, 10 min; (iii) H2O, −78 to 20°C or 0.1 M HCl, −78 to 20°C.
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
4
6
5
Figure 1.
aqueous hydrochloric acid when CO2 was used as elec-
trophile), to the expected functionalised steroids 3
(Scheme 1 and Table 1). The common stereochemistry
for compounds 1 and 3 was assigned not only by NMR
experiments, but also by X-ray analysis of compound
3d11 (Table 1, entry 4), in which the stereochemistry of
C-(17) contains oxygen in a b-situation. Concerning the
possible asymmetric induction with a prochiral elec-
trophile, a ca. 1:1 diastereomeric mixture was isolated
when benzaldehyde was used as the electrophile (Table
1, entry 3 and footnote d), whilst in contrast dimer 3f
with C2 symmetry was obtained when ketone 4 was
used as the electrophile because attack of the organo-
lithium intermediate takes place exclusively from the
less hindered face of the ketone (Table 1, entry 6 and
Fig. 2). When ketones 5 and 6, which derive from
D
-glucose and D-fructose, respectively, were used as
electrophiles, sugar–steroid hybrids 3g and 3h were
obtained, respectively (Table 1, entries 7 and 8 and Fig.
2). The stereochemistry of these compounds again cor-
responds to attack of the organolithium intermediate 2
on the less hindered upper faces of the ketones 5 and 6.
Compound 1 was prepared from estrone 7 by first
ethoxymethyl ether formation to give ketone 4, fol-
lowed by epoxidation with trimethylsulfonium iodide
and sodium hydride in DMSO at room temperature
(Scheme 2). These reaction conditions led exclusively to
Table 1. Preparation of compounds 3 and 10
Entry
Starting epoxide
Intermediate
Electrophile
Producta
No.
E
Yield (%)b
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
1
8
8
8
8
8
2
2
2
2
2
2
2
2
2
9
9
9
9
9
H2O
D2O
3a
3b
3c
3d
H
D
\99
\99c
55d
60
27
26
16
10
31
\99
\99g
25d
20
PhCHO
Me2CO
(CH2)5CO
4e
PhCHOH
Me2COH
(CH2)5COH
–
–
–
CO2H
H
D
PhCHOH
Et2COH
(CH2)5CO
3e
3ff
3gf
3hf
3i
5e
6e
9
CO2
H2O
D2O
PhCHO
Et2CO
(CH2)5CO
10
11
12
13
14
10a
10b
10c
10d
10e
30
a All compounds 3 or 10 were >95% pure (300 MHz 1H NMR) and were fully characterised by spectroscopic means (IR, 1H and 13C NMR, and
MS).
b Isolated yield after column chromatography (silica gel, hexane/ethyl acetate) based on the starting epoxide 1 or 8.
c A ca. 90% deuterium incorporation was obtained (MS).
d As a ca. 1:1 diastereomeric mixture.
e See Fig. 1.
f See Fig. 2.
g A ca. 60% deuterium incorporation was obtained (13C NMR).

M. Yus et al. / Tetrahedron: Asymmetry 12 (2001) 801–810
803
OH HO
O
O
O
O
3f
O
O
OH
OH
O
O
O
O
O
HO
O
O
O
O
O OH
O
O
3h
3g
Figure 2.
O
O
O
i,ii
iii
HO
O
O
O
O
7
4
1
Scheme 2. Reagents and conditions: (i) BunLi (1.2 equiv.), THF, −78°C; (ii) EtOCH2Cl, THF, −78°C; (iii) NaH (5 equiv.), Me3SI
(2 equiv.), DMSO, 25°C.
the epoxy steroid 1, while the use of trimethylsulfoxo-
nium iodide and potassium tert-butoxide in tert-
butanol gave a 4:1 diastereomeric mixture of 1 and its
C17 epimeric epoxide, respectively. Ketone 5 was pre-
pared from commercially available 1,2;5,6-di-O-iso-
was isolated after hydrolysis, proof that asymmetric
induction was not occurring in the process (Table 1,
entry 12 and footnote d).
Starting epoxy steroid 8 was prepared in a single step
by a known methodology from commercially available
cholestanone 11 by treatment with trimethylsulfoxo-
nium iodide and potassium tert-butoxide in tert-
butanol (Scheme 4).
propylidene-a-
with pyridinium chlorochromate in dichloromethane,
and finally, ketone 6 was prepared starting from
D-glucofuranose, which was oxidised
D
-
fructose by successive formation of the corres-
ponding 1,2;5,6-di-O-iso-propylidene derivative and
oxidation.10d
In the last part of this study we used a different
approach to prepare structurally modified steroids,
which consisted of adding functionalised organolithium
compounds to estrone derivative 4 (Fig. 1) and
cholestanone 11 (Scheme 4). Dianions 13a and 13b,
easily available by reductive opening of phthalan 12a13
and isochroman 12b14 with lithium and a catalytic
amount of DTBB, were used as organolithium compo-
nents. The reaction of these anions with estrone deriva-
tive 4 afforded, after hydrolysis, the expected com-
pounds 14, from exclusive nucleophilic attack of the
organolithium intermediate 13 on the less hindered face
The above described procedure was applied to epoxide
8 derived from cholestanone. Thus, intermediate 9 was
formed and reacted with several electrophiles [H2O,
D2O, PhCHO, Et2CO, (CH2)5CO] to yield, after final
hydrolysis, the expected products 10 (Scheme 3 and
Table 1). In this case, the new stereochemistry at C-(3)
in compounds 8 and 10 was assigned by comparison of
physical data for compound 10a with those described in
the literature.12 When benzaldehyde was used as elec-
trophile a ca. 1:1 diastereomeric mixture of diols 10c
i
ii, iii
Li
OLi
E
O
OH
8
9
10
Scheme 3. Reagents and conditions: (i) Li, DTBB (7 mol%), THF, −78°C, 2 h; (ii) E+=H2O, D2O, PhCHO, Et2CO, (CH2)5CO,
−78°C, 10 min; (iii) H2O, −78 to 20°C.

804
M. Yus et al. / Tetrahedron: Asymmetry 12 (2001) 801–810
i
O
O
11
8
Scheme 4. Reagents and conditions: (i) KOBut (1 equiv.), MeSOI (1 equiv.), ButOH, 50°C, 2.5 h.
of the carbonyl group. However, in the case of
cholestanone, the same reaction yielded an almost 1:1
mixture of epimeric diols 15 and 16, with nucleophilic
attack occurring indiscriminately to both faces of the
carbonyl group. Assignment of the stereochemistry of
diols 15 and 16 was made on the basis of the study of
their NMR spectra and by correlation with other simi-
lar compounds (e.g. 10a) of known stereochemistry.
Finally, diols 14 were cyclised under Mitsunobu reac-
tion conditions to yield heterocycles 17 (Scheme 5).
movar apparatus. FT-IR spectra were obtained on a
Nicolet Impact 400D spectrophotometer, NMR spectra
1
were recorded on a Bruker AC-300 (300 MHz for H
and 75 MHz for 13C) using CDCl as solvent and TMS
as internal standard; chemical shifts are given in (ppm)
and coupling constants (J) are given in hertz. 13C NMR
assignments were made on the basis of DEPT experi-
ments. Mass spectra (EI) were obtained at 70 eV on a
Shimadzu QP-5000 spectrometer, fragment ions in m/z
with relative intensities (%) in parentheses. Elemental
analyses were performed by the Microanalyses Service
at the University of Alicante. High resolution mass
spectra were performed by the corresponding service at
the University of Alicante using a Finnigan MAT 95 S
apparatus. The purity of volatile products and the
chromatographic analyses (GLC) were determined with
a Hewlett-Packard HP-5890 instrument equipped with
a flame ionisation detector and a 12 m capillary column
(0.2 mm diam., 0.33 mm film thickness), using nitrogen
In conclusion, we have reported here a novel means of
preparing structurally modified steroids involving reac-
tions between functionalised organolithium compounds
derived from steroids with ketones. Yields are in some
cases modest due to partial decomposition of the reac-
tion products during purification by column chro-
matography. In all cases, structurally modified
molecules with potential biological activity are
prepared.
(2 mL/min) as carrier gas, Tinjector=275°C, Tcolumn
=
60°C (3 min) and 60–270°C (15°C/min). Thin-layer
chromatography (TLC) was carried out on Schleicher
& Schuell F1500/LS 254 plates coated with a 0.2 mm
layer of silica gel; Rf values are given under these
conditions. Column chromatography was performed
using silica gel 60 of 35–70 mesh. All starting materials
3. Experimental
3.1. General
Melting points were obtained with a Reichert Ther-
OH
( )n
OH
( )n
O
v
O
( )n
O
O
O
O
14a: n=1
14b: n=2
17a: n=1
17b: n=2
12a: n=1
12b: n=2
ii,iii
i
Li
OLi
iv,iii
+
HO
( )n
HO
( )n
OH
( )n
OH
16a: n=1
16b: n=2
13a: n=1
13b: n=2
15a: n=1
15b: n=2
Scheme 5. Reagents and conditions: (i) Li, DTBB (2.5 mol%), THF, −78 to 20°C, 30 min; (ii) 4, −78°C, 10 min; (iii) H2O, −78 to
20°C; (iv) 11, −78°C, 10 min; (v) PPh3, DIAD, PhH reflux, 3 h.

M. Yus et al. / Tetrahedron: Asymmetry 12 (2001) 801–810
805
were commercially available (Acros, Aldrich, Fluka) of
3.4. Preparation of epoxide 8
the best grade and were used without further purifica-
tion. THF was dried over benzophenone ketyl under a
nitrogen atmosphere and distilled before use.
To a solution of trimethylsulfoxonium iodide (0.693 g,
3.0 mmol) in tert-butanol (10 mL) was added a solution
of potassium tert-butoxide (0.37 g, 3.0 mmol) in tert-
butanol (10 mL) at 50°C under nitrogen. The mixture
was stirred for 30 min at this temperature, a solution of
cholestanone 11 (0.773 g, 2.0 mmol) in tert-butanol (10
mL) was added and the mixture stirred for a further 3
h. The resulting mixture was evaporated (15 mmHg),
the residue hydrolysed with water (30 mL) and
extracted with ethyl acetate (3×40 mL). The organic
layer was dried over anhydrous sodium sulfate, filtered
and evaporated (15 mmHg). The crude product was
purified by column chromatography (silica gel, hex-
ane:ethyl acetate) to give 3,3%-anhydro-3b-hydroxy-
methyl-5a-cholestan-3a-ol 8: (85% yield) Rf 0.49
3.2. Preparation of compound 4
To a THF solution (40 mL) of estrone 7 (0.54 g, 2.0
mmol) at −78°C under nitrogen was added dropwise
n-butyllithium in hexane solution (1.6 M, 1.62 mL, 2.4
mmol). After
5 min at the same temperature,
chloromethyl ethyl ether (0.83 mL, 4.88 mmol) was
added and the reaction mixture was allowed to rise to
25°C overnight and then hydrolysed with water (20
mL) and extracted with ethyl acetate (3×20 mL). The
organic layer was dried over anhydrous sodium sulfate,
filtered and evaporated (15 mmHg). The resulting
residue was purified by column chromatography (silica
(hexane:ethyl
acetate,
10:1);
mp
124–125°C
gel,
hexane:ethyl
acetate)
to
give
3-O-
(dichloromethane/pentane); w (KBr) 1030 cm−1 (CO);
lH 0.63–2.03 (46H, m), 2.59 (2H, m, CH2O); lC 11.25,
12.1, 18.6 (CH3), 21.0 (CH2), 22.5, 22.8 (CH3), 23.8,
24.2 (CH2), 27.9 (CH), 28.2, 28.6, 29.2, 31.8 (CH2), 35.4
(CCH3), 35.5, 35.8 (CH), 35.85, 36.0 (CH2), 36.2, 39.5,
40.0 (CH2), 42.5 (CCH3), 43.7 (CH), 53.4 (CH2), 54.0
(CH), 56.2, 56.5 (CH), 58.6 (OCCH2); m/z 400 (M+,
13%), 246 (33), 245 (35), 177 (37), 149 (13), 123 (11),
122 (11), 121 (19), 108 (35), 107 (33), 105 (24), 95 (32),
93 (35), 91 (21), 83 (22), 81 (40), 79 (29), 71 (20), 69
(26), 68 (17), 67 (43), 57 (60), 55 (85), 43 (100), 41 (70),
40 (35). Anal. calcd for C28H48O: C, 83.93; H, 12.07.
Found: C, 83.59; H, 11.93%. [h]2D0=+40.5 [c=1.0
(CH2Cl2)].
ethoxymethylestrone 4: (95% yield) Rf 0.42 (hex-
ane:ethyl acetate, 4:1); w (film) 3039, 3008 (ArH), 1736
(CꢀO), 1613, 1502 (ArC), 1008 cm−1 (CO); lH 0.90 (3H,
s, CH3), 1.23 (3H, t, J=7.0, CH3CH2), 1.28–1.66 (6H,
m), 1.93–2.54 (7H, m), 2.87–2.90 (2H, m), 3.72 (2H, q,
J=7.3, CH3CH2), 5.19 (2H, s, OCH2O), 6.79 (1H, s,
ArH), 6.83 (1H, d, J=8.5, ArH), 7.19 (1H, d, J=8.5,
ArH); lC 13.8, 15.0 (CH3), 21.5, 25.8, 26.5, 29.5, 31.5,
35.8 (CH2), 38.2, 44.0 (CH), 47.9 (CCH3), 50.3 (CH),
64.0 (CH3CH2O), 93.1 (OCH2O), 113.8, 116.2, 126.2,
(ArCH), 133.1, 137.7, 155.4 (ArC), 220.8 (CꢀO); m/z
328 (M+, 13%), 59 (100), 41 (15) [found: M+, 328.2029;
C21H28O3 requires: M, 328.2038]; [h]2D0=+124.7 [c=0.9
(CH2Cl2)].
3.5. DTBB-catalysed lithiation of epoxides 1 and 8, and
reaction with electrophiles. Isolation of compounds 3 and
10. General procedure
3.3. Preparation of epoxide 1
To a suspension of sodium hydride (95%, 0.63 g, 25.0
mmol) and trimethylsulfonium iodide (2.1 g, 10.0
mmol) in DMSO (30 mL) was added dropwise a solu-
tion of ketone 4 (1.64 g, 5.0 mmol) in a mixture of
THF/DMSO (5/10 mL) at 25°C. The reaction mixture
was stirred at the same temperature for 12 h,
hydrolysed with water (40 mL) and extracted with ethyl
acetate (4×30 mL). The organic layer was washed with
water (5×20 mL), dried over anhydrous sodium sulfate
filtered and evaporated (15 mmHg). The resulting
residue was purified by column chromatography (silica
gel, hexane:ethyl acetate) to give 17,17%-anhydro-3-O-
ethoxymethyl-17a-hydroxymethyl-17b-estradiol 1: (86%
yield) Rf 0.35 (hexane:ethyl acetate, 10:1); w (film) 3036
(ArH), 1619, 1502 (ArC), 1013 cm−1 (CO); lH 0.91 (3H,
s, CH3), 1.22 (3H, t, J=7.0, CH3CH2), 1.34–1.54 (6H,
m), 1.83–2.07 (5H, m), 2.22–2.34 (2H, m), 2.62 (1H, d,
J=5.2, CCHHO), 2.84–2.89 (2H, m), 2.94 (1H, d,
J=5.2, CCHHO), 3.71 (2H, q, J=7.3, CH3CH2), 5.18
(2H, s, OCH2O), 6.77 (1H, s, ArH), 6.28 (1H, d, J=8.5,
ArH), 7.18 (1H, d, J=8.5, ArH); lC 14.2, 15.0 (CH3),
23.2, 25.9, 27.1, 29.0, 29.6, 33.9 (CH2), 38.8 (CH), 40.3
(CCH3), 43.8, 51.8 (CH), 53.5 (OCH2O), 64.0
(CH2CH3), 70.4 (CCH2O), 93.1 (OCH2O), 113.6, 116.1,
126.2 (ArCH), 133.4, 137.8, 155.3 (ArC); m/z 342 (M+,
9.5%), 59 (100), 41 (17) [found: M+, 342.2187; C22H30O3
requires: M, 342.2195]; [h]2D0=+51.4 [c=1.1 (CH2Cl2)].
To a cooled (−78°C) blue suspension of powdered
lithium (0.10 g, 14.0 mmol) and a catalytic amount of
4,4%-di-tert-butylbiphenyl (0.04 g, 0.15 mmol) in THF
(5 mL) was added the corresponding epoxide (1.0
mmol) under nitrogen and the mixture was stirred at
the same temperature for 2 h. The corresponding elec-
trophile (1.2 mmol; 0.5 mL in the case of water and
deuterium oxide; CO2 was bubbled for 30 min) was
added at −78°C and after 10 min the mixture was
hydrolysed with water (20 mL) and the temperature
allowed to rise to 20°C overnight. The reaction mixture
was extracted with ethyl acetate (3×20 mL). The
organic layer was dried over anhydrous sodium sulfate,
filtered and evaporated (15 mmHg). The resulting
residue was purified by column chromatography (silica
gel, hexane:ethyl acetate) and/or recrystallised to yield
pure products 3 and 10. Yields are included in Table 1.
Physical, spectroscopic and analytical data follow.
3.5.1. 3-O-Ethoxymethyl-17a-methyl-17b-estradiol 3a.
Rf 0.42 (hexane:ethyl acetate, 2:1); w (film) 3661–3133
(OH), 3036 (ArH), 1605, 1501 (ArC), 1153, 1099, 1012
cm−1 (CO); lH 0.89 (3H, s, CH3), 1.23 (3H, t, J=7.0,
CH3CH2), 1.27 (3H, s, COHCH3), 1.30–1.90 (12H, m),
2.16 (1H, br s, OH), 2.29–2.33 (1H, m), 2.83–2.86
(2H, m), 3.72 (2H, q, J=7.0, CH3CH2), 5.19 (2H, s,

806
M. Yus et al. / Tetrahedron: Asymmetry 12 (2001) 801–810
OCH2O), 6.78 (1H, s, ArH), 6.83 (1H, dd, J=8.5, 2.7,
ArH), 7.20 (1H, d, J=8.5, ArH); lC 13.8, 15.1 (CH3),
22.9 (CH2), 25.8 (COHCH3), 26.2, 27.4, 29.75, 31.7
(CH2), 39.0 (CH2), 39.5, 43.9 (CH), 45.7 (CCH3), 49.7
(CH), 60.0 (CH2CH3), 81.6 (COH), 93.2 (OCH2O),
113.65, 116.2, 126.2 (ArCH), 133.8, 138.0, 155.2 (ArC);
m/z 344 (M+, 21.5%), 241 (11), 159 (10), 59 (100); 44
(15), 43 (32), 41 (22), 40 (16) [found: M+, 344.2360;
C22H32O3 requires: M, 344.2351]; [h]2D0=+38.2 [c=1.5
(CH2Cl2)].
(OCH2O), 113.7, 116.2, 126.3 (ArCH), 133.7, 138.0,
155.3 (ArC); m/z 402 (M+, 0.5%), 387 (11), 354 (16),
255 (31), 99 (16), 81 (29), 59 (100), 55 (17). Anal. calcd
for C25H38O4: C, 74.59; H, 9.51. Found: C, 75.59; H,
9.51%. [h]2D0=+31.2 [c=1.65 (CH2Cl2)].
3.5.5. 3-O-Ethoxymethyl-17a-[(1-hydroxycyclohexyl)-
methyl]-17b-estradiol 3e. Rf 0.46 (hexane:ethyl acetate,
2:1); w (film) 3665–3112 (OH), 3010 (ArH), 1605, 1503
(ArC), 1015 cm−1 (CO); lH 0.89 (3H, s, CH3), 1.10–2.33
(30H, m), 2.84 (2H, m), 3.72 (2H, q, J=7.0, CH3CH2),
5.19 (2H, s, OCH2O), 6.77 (1H, s, ArH), 6.83 (1H, d,
J=8.5, ArH), 7.20 (1H, d, J=8.5, ArH); lC 13.8, 15.1
(CH3), 21.7, 22.9, 25.8, 26.2, 27.4, 29.8, 30.7, 31.3, 31.7,
39.00 (CH2), 39.55, 43.9 (CH), 45.7 (CCH3), 49.7 (CH),
64.0 (CH2CH3), 73.0, 81.6 (COH), 93.2 (OCH2O),
113.65, 116.2, 126.2 (ArCH), 133.8, 138.0, 155.2 (ArC);
m/z 442 (M+, 1%), 99 (12), 81 (25), 59 (100), 55 (17), 43
(12), 41 (17) [found: M+, 442.3081; C28H42O4 requires:
M, 442.3083]; [h]2D0=+77.3 [c=1.3 (CH2Cl2)].
3.5.2. 17a-Deuteriomethyl-3-O-ethoxymethyl-17b-estra-
diol 3b. Mp 70–71°C (dichloromethane/pentane); Rf
0.42 (hexane:ethyl acetate, 2:1); w (KBr) 3678–3099
(OH), 3030 (ArH), 1609, 1500 (ArC), 1151, 1105, 1025
cm−1 (CO); lH 0.89 (3H, s, CH3), 1.23 (3H, t, J=7.0,
CH3CH2), 1.26 (2H, s, CH2D), 1.28–1.91 (12H, m), 2.17
(1H, br s, OH), 2.29–2.33 (1H, m), 2.83–2.88 (2H, m),
3.72 (2H, q, J=7.0, CH3CH2), 5.19 (2H, s, OCH2O),
6.77 (1H, d, J=2.4, ArH), 6.83 (1H, dd, J=8.5, 2.4,
ArH), 7.20 (1H, d, J=8.5, ArH); lC 13.8, 15.1 (CH3),
22.9 (CH2), 25.5 (t, JCD=20.75, CH2D), 26.2, 27.4,
29.8, 31.7, 39.0 (CH2), 39.6, 43.9 (CH), 45.7 (CCH2D),
49.7 (CH), 64.1 (CH2CH3), 81.6 (COH), 93.2 (OCH2O),
113.7, 116.2, 126.3 (ArCH), 133.8, 138.0, 155.2 (ArC);
m/z 345 (M+, 9.5%), 59 (100), 44 (53), 43 (13), 41 (20).
Anal. calcd for C22H31DO3: C, 76.48; H, 9.63. Found:
C, 76.52; H, 9.23%. [h]2D0=+40.7 [c=0.9 (CH2Cl2)].
3.5.6. Compound 3f. Rf 0.25 (hexane:ethyl acetate, 1:1);
w (film) 3644–3110 (OH), 3020 (ArH), 1661, 1499
(ArC), 1014 cm−1 (CO); lH 0.93 (6H, s, 2×CH3), 1.22
(6H, t, J=7.1, 2×CH2CH3), 1.29–2.32 (28H, m), 2.83–
2.85 (4H, m), 3.47 (1H, d, J=11.0, COHCHHCOH),
3.72 (4H, q, J=7.1, 2×OCH2CH3), 3.81 (1H, d, J=
11.0, COHCHHCOH), 5.19 (4H, s, 2×OCH2O), 6.77
(2H, s, ArH), 8.43 (2H, d, J=8.5 ArH), 7.18 (2H, d,
J=8.5, ArH); lC 14.1, 15.1 (CH3), 23.2, 26.2, 27.4,
29.7, 32.4, 33.9 (CH2), 39.35, 43.8 (CH), 45.6 (CCH3),
50.25 (CH), 64.1, 67.0 (CH2), 83.4 (COH), 93.2
(OCH2O), 113.7, 116.2, 126.25 (ArCH), 133.6, 138.0,
155.3 (ArC); m/z 655 (M+−OH, 6%), 604 (10), 580 (14),
563 (18), 554 (19), 500 (14), 454 (18), 393 (23), 381 (19),
374 (23), 360 (42), 352 (26), 344 (30), 339 (42), 327 855),
311 (100), 293 (89), 284 (64), 271 (46), 252 842), 241
(40), 231 (52), 220 (30), 213 (68), 187 (38), 161 (87), 147
(52), 119 (75) [found: M+−(2EtOH+H2O), 562.3453;
C39H46O3 requires: M, 562.3447]; [h]2D0=+34.7 [c=0.9
(CH2Cl2)].
3.5.3. 3-O-Ethoxymethyl-17a-(2-hydroxy-2-phenylethyl)-
17b-estradiol 3c (diastereomeric mixture). Rf 0.31 (hex-
ane:ethyl acetate, 2:1); w (film) 3667–3202 (OH), 3152
(ArH), 1591, 1441 (ArC), 1109, 1042 cm−1 (CO); lH
0.93, 0.94 (3H, 2s, CCH3), 1.21, 1.22 (3H, 2t, J=7.3,
CH2CH3), 1.25–2.34 (17H, m, OH), 2.81–2.84 (2H, m,
PhCH2), 3.71, 3.72 (2H, 2q, J=6.9, CH2CH3), 5.13–
5.19 (3H, m, CH, OCH2O), 6.76–6.84 (2H, m, ArH),
7.13–7.43 (6H, m, ArH); lC 13.7, 14.1, 15.0 (CH3), 22.9,
23.4, 26.1, 26.3, 27.3, 27.4, 29.7, 31.3, 32.9, 34.9 (CH2),
39.5, 39.6, 43.6, 43.7 (CH), 47.0 (CCH3), 49.1, 49.5
(CH), 64.0 (CH2CH3), 72.0, 72.3 (CH), 84.0, 84.6
(COH), 93.1 (OCH2O), 113.7, 116.2, 125.7, 125.8,
126.3, 127.4, 128.4, 128.5 (ArCH), 133.6, 137.9, 138.0,
145.1, 145.4, 155.3 (ArC); m/z 450 (M+, 4%), 107 (22),
104 (15), 79 (37), 77 (25), 59 (100), 41 (11) [found: M+,
450.2775; C29H38O4 requires: M, 450.2770]; [h]2D0=+6.7
[c=1.0 (CH2Cl2)].
3.5.7. Compound 3g. Mp 209–210°C (dichloromethane/
pentane); Rf 0.33 (hexane:ethyl acetate, 2:1); w (KBr)
3631–3145 (OH), 3020 (ArH), 1615, 1497 (ArC), 1218,
1082, 1005 cm−1 (CO); lH 0.90 (3H, s, CH3), 1.23 (2H,
t, J=7.0, CH3CH2O), 1.37, 1.38, 1.46, 1.59 (12H, 4s,
4×CH3), 1.30–1.74 (10H, m), 1.87–2.00 (3H, m), 2.17–
2.32 (2H, m), 2.80–2.85 (4H, m), 3.72 (2H, q, J=7.0,
CH3CH2O), 3.82 (1H, d, J=7.7, COHCHCHCH2),
3.91–3.95 (1H, m, CHCHH), 4.10–4.22 (2H, m,
CHCHH), 5.06 (1H, d, J=3.3, CHCHO2), 5.19 (2H, s,
OCH2O), 5.72 (1H, d, J=3.3, OCHO), 6.78 (1H, s,
ArH), 6.83 (1H, d, J=8.5, ArH), 7.20 (1H, d, J=8.5,
ArH); lC 13.8, 15.1 (CH3), 23.5 (CH2), 25.5 (CH3), 26.2
(CH2), 26.5, 26.6, 26.7 (4×CH3), 27.3, 29.8, 31.2, 35.2,
37.4 (CH2), 39.7, 43.7 (CH), 47.65 (C), 48.8 (CH),
64.05, 67.9 (CH2), 73.1 (CH), 79.8 (C), 81.9, 82.9 (CH),
83.1 (COH), 93.2 (OCH2), 103.8 (OCHO), 109.6, 112.4
[O2C(CH3)2], 113.7, 116.2, 126.2 (ArCH), 133.5, 138.0,
155.3 (ArC); m/z 602 (M+, 11%), 569 (16), 544 (48), 529
3.5.4. 3-O-Ethoxymethyl-17a-(2-hydroxy-2-methylpro-
pyl)-17b-estradiol 3d. Mp 119–120°C (dichloromethane/
pentane); Rf 0.30 (hexane:ethyl acetate, 2:1); w (KBr)
3680–3045 (OH), 3011 (ArH), 1605, 1503 (ArC), 1152,
1027, 1004 cm−1 (CO); lH 0.89 (3H, s, CH3), 1.23 (3H,
t, J=7.0, CH3CH2), 1.30 (3H, s, COHCH3), 1.46 (3H,
s, COHCH3), 1.34–1.71 (10H, m), 1.87–1.91 (1H, m),
2.04–2.20 (2H, m), 2.32–2.42 (2H, m), 2.82–2.85 (2H,
m), 3.07 (2H, br s, OH), 3.71 (2H, q, J=7.0, CH3CH2),
5.19 (2H, s, OCH2O), 6.77 (1H, d, J=2.1, ArH), 6.83
(1H, dd, J=8.5, 2.1, ArH), 7.20 (1H, d, J=8.5, ArH);
lC 13.8, 15.1 (CH3), 23.8, 26.4, 27.4, 29.8 (CH2), 30.0
(CH3), 31.8 (CH2), 33.4 (CH3), 37.2 (CH2), 39.8, 43.7
(CH), 44.9 (CH2), 47.9 (CCH3), 49.0 (CH), 64.1
(OCH2CH3), 72.1 (COHCH3), 84.3 (COHCH2), 93.2

M. Yus et al. / Tetrahedron: Asymmetry 12 (2001) 801–810
807
(19), 502 (23), 485 (50), 467 (29), 393 (51), 311 (64), 255
(50), 219 (100), 181 (83), 160 (51), 119 (88), 69 (95)
[found: M+, 602.3459; C34H50O9 requires: M, 602.3455].
Anal. calcd for C34H50O9: C, 67.74; H, 8.37. Found: C,
67.81; H,8.43%. [h]2D0=+31.4 [c=0.9 (CH2Cl2)].
57 (34), 55 (37), 43 (63), 41 (21) [found: M+, 402.3853;
C28H50O requires: M, 402.3862]; [h]2D0=+36.2 [c=0.9
(CH2Cl2)].
3.5.11. 3b-Deuteriomethyl-5a-cholestan-3a-ol 10b. Mp
124–125°C (dichloromethane/pentane); Rf 0.24 (hex-
ane:ethyl acetate, 10:1); w (KBr) 3615–3028 (OH), 1472,
1444 [CH(CH3)2], 1382 cm−1 (CO); lH 0.58–1.97 (37 H),
0.57 (3H, s, CH3), 0.67 (3H, s, CH3), 0.79 (6H, d,
J=6.7, 2×CHCH3), 0.84 (3H, d, J=6.7, CHCH3); lC
11.2, 12.1, 18.7 (CH3), 21.0 (CH2), 22.5, 22.8 (CH3),
23.8, 24.2 (CH2), 28.0 (CH), 28.2, 28.5 (CH2), 31.2
(CH2D, t, JCD=18.9), 32.0, 34.0, 34.9 (CH2), 35.5, 35.8
(CH), 36.2, 39.5 (CH2), 40.1 (CH2), 41.15 (CH), 41.8
(CH2), 42.6 (CCH3), 54.2, 56.3, 56.5 (CH), 69.8
(CCH3), 76.6 (COH); m/z 403 (M+, 16%), 402 (12), 369
(31), 248 (21), 245 (16), 231 (38), 229 (100), 215 (16),
161 (29), 135 (23), 122 (25), 95 (42), 93 (28), 91 (20), 81
(40), 79 (31), 71 (34), 69 (25), 67 (16), 57 (32), 55 (38),
43 (53). Anal. calcd for C28H49DO: C, 83.30; H, 12.73.
Found: C, 83.23; H,12.64%. [h]2D0=+35.8 [c=0.8
(CH2Cl2)].
3.5.8. Compound 3h. Rf 0.37 (hexane:ethyl acetate, 2:1);
w (film) 3625–3120 (OH), 3032 (ArH), 1610, 1501
(ArC), 1198 cm−1 (CO); lH 0.92 (3H, s, CH3), 1.23 (3H,
t, J=7.0, CH3CH2), 1.35 (3H, s, CH3), 1.42 (3H, s,
CH3), 1.48 (3H, s, CH3), 1.56 (3H, s, CH3), 1.51–1.92
(13H, m), 1.99–2.07 (1H, m), 2.32 (2H, s, OH), 2.37–
2.51 (1H, m), 2.87 (2H, m), 3.72 (2H, q, J=7.0,
CH2CH3), 3.99 (1H, d, J=9.8, CCHHO), 4.07–4.18
(3H, m, CHCH2), 4.26 (1H, d, J=4.9, CHCHCH2),
4.33 (1H, d, J=9.8, CCHHO), 5.20 (2H, s, OCH2O),
6.80 (1H, br s, ArH), 6.87 (1H, d, J=8.5, ArH), 7.44
(1H, d, J=8.5, ArH); lC 13.4, 15.1 (CH3), 20.7, 23.1
(CH2), 25.4, 25.7, 25.75, 26.2 (CH3), 29.7, 29.8 (CH2),
31.95 (C), 32.2 (CH), 32.3 (CH2), 40.2 (C), 41.8, 44.7
(CH), 47.7, 53.8, 60.0 (CH2), 64.2 (OCH2), 71.4 (CH),
71.8 (CH2), 72.7 (C), 74.8 (CH), 93.0 (OCH2O), 106.6
(C), 109.3, 112.45 [O2C(CH3)2], 114.4, 116.4, 126.4
(ArCH), 135.35, 138.35, 156.7 (ArC); m/z 602 (M+,
2%), 555 (12), 455 (17), 354 (15), 324 (19), 285 (18), 267
(32), 231 (31), 195 (22), 181 (54), 155 (21), 133 (48), 105
824), 69 (100) [found: M+, 602.3460; C34H50O9 requires:
602.3455]; [h]2D0=−25.3 [c=1.1 (CH2Cl2)].
3.5.12. 3b-[(2-Hydroxy-2-phenyl)ethyl]-5a-cholestan-3a-
ol 10c (diastereomeric mixture). Mp 195–196°C
(dichloromethane/pentane); Rf 0.42 (hexane:ethyl ace-
tate, 3:1); w (KBr) 3703–3120 (OH), 3058, 3024 (ArH),
1062 cm−1 (CO); lH 0.65, 0.75 (6H, 2s, 2×CH3), 0.86
(6H, d, J=6.4, 2×CHCH3), 0.91 (3H, d, J=6.2,
CHCH3), 1.00–2.03 (33H, m), 3.05 (1H, br s, OH), 3.91
(1H; br s, OH), 5.10 (1H, d, J=10.5, CHOH), 7.24–
7.32 (5H, m, ArCH); lC 11.2, 11.3, 12.1, 18.7 (CH3),
21.0 (CH2), 22.5, 22.8 (CH3), 23.8, 24.2 (CH2), 28.0
(CH), 28.2, 28.4, 28.7, 32.0, 32.05, 33.8 (CH2), 35.5,
35.8 (CH), 35.9 (CCH3), 36.2, 38.4, 39.5, 40.0 (CH2),
40.5 (CH), 42.5 (CH2), 42.6 (CCH3), 51.5 (CH2), 54.2,
56.2, 56.5 (CH), 71.3 (CHOH), 72.6, 72.65 (COH),
125.6, 127.4, 128.4 (ArCH), 144.9 (ArC); m/z 508 (M+,
2%), 490 (10), 417 (21), 369 (33), 245 (63), 229 (21), 169
(31), 95 (42), 93 (28), 91 (100), 81 (42), 71 (36), 69 (26),
57 (35), 55 (31). Anal. calcd for C35H56O2: C, 82.61; H,
11.10. Found: C, 82.75; H,11.07%. [h]2D0=+46.9 [c=0.8
(CH2Cl2)].
3.5.9. 17a-Carboxymethyl-3-O-ethoxymethyl-17b-estra-
diol 3i. Rf 0.20 (hexane:ethyl acetate, 2:1); w (film)
3695–2611 (COOH), 3062 (ArH), 1734 (CꢀO), 1610,
1516 (ArC), 1233, 1014 cm−1 (CO); lH 0.75 (3H, s,
CH3), 1.25 (3H, t, J=7.3, CH3CH2), 1.30–2.33 (13H,
m), 2.57 (1H, d, J=16.2, CHHCO2H), 2.74 (1H, d,
J=16.2, CHHCO2H), 2.81–2.83 (3H, m, PhCH2, OH),
3.72 (2H, q, J=7.1, CH3CH2), 5.19 (2H, s, OCH2O),
6.77 (1H, s, ArH), 6.82 (1H, d, J=8.5, ArH), 7.17 (1H,
d, J=8.5, ArH), 8.06 (1H, br s, CO2H); lC 13.8, 15.1
(CH3), 21.6, 25.8, 26.5 (CH2), 29.6 (CH), 31.6, 35.9
(CH2), 38.3 (CH2CO2H), 43.6 (CCH3), 44.0 (CH2),
48.0, 50.4 (CH), 64.1 (CH2CH3), 82.1 (COH), 93.2
(OCH2O), 113.8, 116.2, 126.3 (ArCH), 133.1, 137.8,
155.4 (ArC), 176.9 (CO2H); m/z 388 (M+, 0.1%), 59
(100), 41 (15) [found: M+, 388.2230; C23H32O5 requires:
M, 388.2249]; [h]D20=+114.0 [c=1.2 (CH2Cl2)].
3.5.13. 3b-(2-Hydroxy-2-ethylbutyl)-5a-cholestan-3a-ol
10d. Rf 0.16 (hexane:ethyl acetate, 2:1); w (film) 3578–
3032 (OH), 1236, 1052 cm−1 (CO); lH 0.65 (3H, s,
CH3), 0.75 (3H, s, CH3), 0.84–2.06 (52H, m), 2.24 (2H,
br s, 2×OH); lC 7.8, 11.2, 12.1, 18.6 (CH3), 21.0 (CH2),
22.5, 22.8 (CH3), 23.8, 24.2 (CH2), 28.0 (CH), 28.2,
28.5, 29.8, 30.9, 31.4, 32.0, 33.3 (CH2), 35.5, 35.8 (CH),
36.1 (CCH3), 36.2, 36.7, 39.5, 40.0 (CH2), 40.5 (CH),
42.6 (CCH3), 54.2, 56.2, 56.5 (CH), 71.9 (2×COH); m/z
471 [M+−(OH), 0.05%], 387 (37), 107 (11), 91 (25), 81
(16), 79 (15), 71 (24), 70 (11), 69 (26), 67 (14), 57 (54),
56 (18), 55 (43), 45 (10), 43 (100), 42 (11), 41 (47)
[found: M+−(OH), 471.4556; C33H58O requires:
471.4566]; [h]D20=+25.4 [c=0.85 (CH2Cl2)].
3.5.10. 3b-Methyl-5a-cholestan-3a-ol 10a.12 Mp 123–
124°C (dichloromethane/pentane); Rf 0.24 (hexane:ethyl
acetate, 10:1); w (KBr) 3545–3102 (OH), 1102 cm−1
(CO); lH 0.65 (3H, s, CH3), 0.74 (3H, s, CH3), 0.85
(6H, d, J=6.7, 2×CHCH3), 0.90 (3H, d, J=6.7,
CHCH3), 1.19 (3H, s, COHCH3), 0.64–1.98 (32H, m);
lC 11.2, 12.1, 18.7 (CH3), 21.0 (CH2), 22.5, 22.8 (CH3),
23.8, 24.2 (CH2), 28.0 (CH), 28.2, 28.5 (CH2), 31.6
(CH3), 32.0, 34.1, 34.9 (CH2), 35.5, 35.8 (CH), 36.2,
39.5, 40.1 (CH2), 41.15 (CH), 41.8 (CH2), 42.6, 46.7 (C),
54.2, 56.3, 56.5 (CH), 69.8 (COH); m/z 402 (M+, 24%),
369 (33), 262 (10), 248 (24), 244 (14), 232 (15), 231 (42),
230 (28), 229 (100), 215 (15), 179 (16), 163 (14), 162
(14), 161 (27), 159 (13), 149 (21), 147 (14), 135 (26), 122
(25), 109 (21), 107 (24), 105 (25), 97 (23), 95 (40), 93
(31), 91 (21), 81 (39), 79 (29), 71 (34), 69 (25), 67 (21),
3.5.14. 3b-[(1-Hydroxycyclohexyl)methyl]-5a-cholestan-
3a-ol 10e. Mp 183–184°C (dichloromethane/pentane);
Rf 0.15 (hexane:ethyl acetate, 10/1); w (KBr) 3637–3051
(OH), 1113, 1014 cm−1 (CO); lH 0.64–1.82 (57H), 1.94–

808
M. Yus et al. / Tetrahedron: Asymmetry 12 (2001) 801–810
1.97 (2H, m, CH2C), 3.17 (1H, br s, OH); lC 11.2, 12.1,
18.7 (CH3), 21.0, 22.3 (CH2), 22.6, 22.8 (CH3), 23.8,
24.2, 25.6 (CH2), 28.0 (CH), 28.2, 28.5, 28.6, 32.1, 33.8
(CH2), 34.0 (CCH3), 34.9 (CH2), 35.4 (CCH3), 35.5
(CH), 35.6 (CH2), 35.8 (CH), 36.2, 39.5, 40.0, 40.1
(CH2), 40.7 (CH), 41.15 (COH), 41.9, 42.6 (CH2), 54.2,
56.3, 56.5 (CH), 73.3 (COH); m/z 500 (M+, 0.12%), 99
(58), 81 (47), 79 (14), 71 (17), 70 (11), 69 (21), 67 (15),
57 (30), 56 (18), 55 (58), 54 (11), 43 (100), 42 (18), 41
(35). Anal. calcd for C34H60O2: C, 81.54; H, 12.07.
Found: C, 81.63; H, 11.89%. [h]2D0=+21.5 [c=0.85
(CH2Cl2)].
(CO); lH 0.97 (3H, s, CH3), 1.23 (3H, t, J=7.0,
CH3CH2), 1.28–1.97 (13H, m), 2.23–2.40 (2H, m), 2.81
(1H, d, J=14.0, COHCHHPh), 2.86–2.89 (2H, m),
2.93–3.08 (3H, m, COHCHHPh, CH2CH2Ph), 3.73
(2H, q, J=7.3, CH3CH2), 3.88–3.92 (2H, m, CH2OH),
5.2 (2H, s, OCH2O), 6.79–6.87 (2H, m, ArH), 7.20–7.32
(5H, m, ArH); lC 14.4, 15.0 (CH3), 23.2, 26.2, 27.4,
29.7, 31.1, 33.6, 35.4, 38.1 (CH2), 39.6, 43.8 (CH), 47.0
(CCH3), 49.4 (CH), 63.3, 64.0 (CH2O), 83.6 (COH),
93.1 (OCH2O), 113.6, 116.1, 125.9, 126.2, 126.5, 129.5,
132.3 (ArCH), 133.7, 137.1, 137.9, 138.4, 155.2 (ArC);
m/z 464 (M+, 4%), 329 (35), 328 (55), 311 (10), 298 (13),
283 (16), 159 (12), 133 (12), 128 (10), 118 (14), 117 (21),
115 (17), 106 (13), 105 (30), 91 (19), 79 (10), 59 (100), 41
(12). Anal. calcd for C30H40O4: C, 77.55; H, 8.68.
Found: C, 77.12; H, 8.91%. [h]2D0=+50.2 [c=1.35
(CH2Cl2)].
3.6. Reaction of intermediates 13 with ketones 4 and 11.
Isolation of compounds 14, 15 and 16. General procedure
To a cooled (0°C) blue suspension of powdered lithium
(0.10 g, 14.0 mmol) and a catalytic amount of 4,4%-di-
tert-butylbiphenyl (0.04 g, 0.15 mmol) in THF (6 mL)
under nitrogen was added phthalan 12a or isochroman
12b (1.0 mmol) and the mixture allowed to warm to
25°C over 30 min. The mixture was cooled to −78°C
and a THF solution (0.5 mL) of ketones 4 or 11 (1.0
mmol) was added dropwise. Stirring was continued at
the same temperature for 10 min, the mixture was
hydrolysed with water (30 mL) and extracted with ethyl
acetate (3×20 mL). The organic layer was dried over
anhydrous sodium sulfate and evaporated (15 mmHg).
The resulting residue was purified by column chro-
matography (silica gel, hexane:ethyl acetate) and/or
recrystallised to yield pure products 14, 15 and 16.
Yields (based on the starting materials 12), physical,
spectroscopic and analytical data follow.
3.6.3. 3b-[2-(Hydroxymethyl)phenylmethyl]-5a-cholestan-
3a-ol 15a. Mp 189–190°C (dichloromethane/pentane)
(15% yield); Rf 0.46 (hexane:ethyl acetate, 2:1); w (KBr)
3664–3051 (OH), 3029 (ArH), 1612, 1470 (ArC), 1114,
1016 cm−1 (CO); lH 0.58–1.91 (48H, m), 2.78 (2H, s,
CH2COH), 4.52 (2H, s, CH2OH), 7.09–7.29 (4H, m,
ArCH); lC 11.3, 12.1, 18.65 (CH3), 21.0 (CH2), 22.5,
22.8 (CH3), 23.8, 24.2 (CH2), 28.0 (CH), 28.2, 28.5,
32.0, 33.8, 33.9 (CH2), 35.5 (CH), 35.75 (CCH3), 35.8
(CH), 36.2, 39.5, 40.0, 40.6 (CH2), 41.1 (CH), 42.6
(CCH3), 46.1 (CH2COH), 54.2, 56.2, 56.5 (CH), 63.4
(CH2OH), 71.6 (COH), 126.9, 127.5, 130.6, 132.2
(ArCH), 135.7, 140.3 (ArC); m/z 508 (M+, 0.2%), 490
(3), 104 (100), 43 (15). Anal. calcd for C35H56O2: C,
82.62; H, 11.09. Found: C, 82.71; H, 10.91%. [h]2D0=
+28.6 [c=0.65 (CH2Cl2)].
3.6.1. 3-O-Ethoxymethyl-17a-[2-(hydroxymethyl)phen-
ylmethyl]-17b-estradiol 14a. Mp 110–111°C (dichl-
oromethane/pentane) (25% yield); Rf 0.25 (hexane:ethyl
acetate, 2:1); w (KBr) 3675–3102 (OH), 3055, 3014
(ArH), 1604, 1498 (ArC), 1141, 1106, 1077, 1012 cm−1
(CO); lH 0.97 (3H, s, CH3), 1.23 (3H, t, J=7.0,
CH3CH2), 1.28–2.41 (15H, m), 2.72 (1H, d, J=13.7,
COHCHHPh), 2.88–2.89 (2H, m), 3.22 (1H, d, J=13.7,
COHCHHPh), 3.73 (2H, q, J=7.3, CH3CH2), 4.46
(1H, d, J=11.6, PhCHHOH), 4.81 (1H, d, J=11.6,
PhCHHOH), 5.19 (2H, s, OCH2O), 6.80 (1H, s, ArH),
6.85 (1H, d, J=8.5, ArH), 7.21–7.41 (5H, m, ArH); lC
14.1, 15.0 (CH3), 22.9, 26.2, 27.4, 29.7, 31.0, 33.4, 37.9
(CH2), 39.7, 43.9 (CH), 47.2 (CCH3), 49.3 (CH), 63.2,
64.0 (CH2O), 83.1 (COH), 93.1 (OCH2O), 113.7, 116.2,
126.2, 126.7, 127.5, 130.5, 132.5 (ArCH), 133.6, 137.0,
137.9, 140.5, 155.2 (ArC); m/z 450 (M+, 14%), 432
[M+−(H2O), 22%], 386 (12), 329 (15), 328 (26), 311 (22),
298 (11), 284 (11), 283 (10), 271 (23), 213 (15), 160 (12),
159 (42), 157 (10), 145 (10), 133 (15), 105 (23), 104
(100), 77 (23), 59 (96), 41 (14). Anal. calcd for
C29H38O4: C, 77.30; H, 8.50. Found: C, 77.04; H,
8.43%. [h]2D0=+55.2 [c=1.1 (CH2Cl2)].
3.6.4. 3b-[2-(2-Hydroxyethyl)phenylmethyl]-5a-choles-
tan-3a-ol 15b. Mp 125–126°C (dichloromethane/pen-
tane) (10% yield); Rf 0.14 (hexane:ethyl acetate, 2:1); w
(KBr) 3640–3114 (OH), 3055 (ArH), 1274 cm−1 (CO);
lH 0.65–2.04 (47H, m), 2.34 (3H, s, CH2COH), 2.98
(2H, t, J=6.7, CH2CH2OH), 3.84 (2H, t, J=6.7,
CH2CH2OH), 7.12–7.15 (4H, m, ArCH); lC 12.1, 12.3,
18.7 (CH3), 21.3 (CH2), 22.5, 22.8 (CH3), 23.8, 24.2
(CH2), 28.0 (CH), 28.2, 28.7, 31.5, 32.1 (CH2), 35.4
(CCH3), 35.5, 35.8 (CH), 36.2, 36.4, 37.0, 38.2, 39.5,
40.0 (CH2), 42.6 (CCH3), 44.9, 54.4, 56.3, 56.5 (CH),
62.6 (CH2OH), 71.4 (COH), 126.0, 126.6, 129.6, 130.4
(ArCH), 136.4, 136.5 (ArC); m/z 504 [M+−(H2O),
0.6%], 388 (29), 387 (100), 369 (15), 136 (44), 118 (41),
117 (39), 105 (38), 95 (19), 93 (25), 91 (25), 81 (30), 79
(20), 71 (13), 69 (11), 57 (15), 55 (22). Anal. calcd for
C36H58O2: C, 82.70; H, 11.18. Found: C, 82.33; H,
11.58%. [h]2D0=+26.7 [c=0.9 (CH2Cl2)].
3.6.5. 3a-[2-(Hydroxymethyl)phenylmethyl] -5a-choles-
tan-3b-ol 16a. Mp 167–168°C (dichloromethane/pen-
tane) (15% yield); Rf 0.26 (hexane:ethyl acetate, 2:1); w
(KBr) 3603–3109 (OH), 3071, 3022 (ArH), 1035, 1014
cm−1 (CO); lH 0.58–1.91 (48H, m), 2.89 (2H, s,
CH2COH), 4.50 (2H, s, CH2OH), 6.99–7.27 (4H, m,
ArCH); lC 12.1, 12.3, 18.65 (CH3), 21.3 (CH2), 22.5,
22.8 (CH3), 23.8, 24.2 (CH2), 28.0 (CH), 28.2, 28.5,
3.6.2. 3-O-Ethoxymethyl-17a-[2-(2-hydroxyethyl)phen-
ylmethyl]-17b-estradiol 14b. Mp 53–54°C (dichloro-
methane/pentane) (30% yield); Rf 0.21 (hexane:ethyl
acetate, 2:1); w (KBr) 3674–3088 (OH), 3065, 3024
(ArH), 1607, 1503 (ArC), 1241, 1149, 1108, 1015 cm−1

M. Yus et al. / Tetrahedron: Asymmetry 12 (2001) 801–810
809
32.1, 34.6 (CH2), 35.6, 35.8 (CH), 36.1 (C), 36.15, 36.3,
39.0, 39.5, 40.0 (CH2), 41.5 (CH2COH), 42.6 (C), 44.0,
54.6, 56.3, 56.5 (CH), 63.3 (CH2OH), 72.8 (COH),
126.8, 127.6, 130.7, 131.5 (ArCH), 136.3, 140.6 (ArC);
m/z 508 (M+, 0.3%), 490 (1), 104 (100), 43 (12). Anal.
calcd for C35H56O2: C, 82.62, H, 11.09. Found: C,
82.66, H, 11.02%. [h]2D0=+27.6 [c=0.95 (CH2Cl2)].
(64), 131 (38), 104 (62), 59 (88) [found: M+, 432.2667;
C29H36O3 requires: 432.2664]; [h]2D0=+21.1 [c=1.15
(CH2Cl2)].
3.7.2. Compound 17b. (15% yield) Rf 0.48 (hexane:ethyl
acetate, 10:1); w (film) 3063, 3021 (ArH), 1614, 1496
(ArC), 1008 cm−1 (CO); lH 0.94 (3H, s, CH3), 1.23 (3H,
t, J=7.1, CH3CH2), 1.25–1.92 (11H, m), 2.20–2.34 (2H,
m), 2.63–2.65 (1H, m, PhCHHCH2), 2.72 (1H, d, J=
14.3, PhCHHC), 2.84–2.87 (2H, m), 3.20–3.23 (1H, m,
PhCH2CHH), 3.28 (1H, d, J=14.3, PhCHHC), 3.58
(1H, m, PhCHHCH2), 3.74 (2H, q, J=7.1, OCH2CH3),
3.95–4.01 (1H, m, PhCH2CHH), 5.19 (2H, s, OCH2O),
6.78–6.86 (2H, m, ArH), 7.05–7.33 (5H, m, ArH); lC
14.5, 15.1 (2×CH3), 23.2, 26.3, 27.6, 29.3, 29.7, 29.8
(CH2), 38.9 (CH2), 39.4 (CH), 44.0 (CH), 44.5 (CH2),
47.9 (CCH3), 49.3 (CH), 64.1, 64.8 (CH2), 85.9 (CO),
93.2 (OCH2O), 113.7, 116.2, 126.16, 126.2, 126.3, 128.7,
130.7 (ArH), 133.9, 138.0, 139.4, 141.6, 155.2 (ArC);
m/z 446 (M+, 10%), 148 (27), 117 (30), 91 (100), 75 (21)
[found: M+, 446.2831; C30H38O3 requires: 446.2821];
[h]2D0=+14.5 [c=0.7 (CH2Cl2)].
3.6.6. 3a-[2-(2-Hydroxyethyl)phenylmethyl]-5a-choles-
tan-3b-ol 16b. Mp 163–164°C (dichloromethane/pen-
tane) (20% yield); Rf 0.26 (hexane:ethyl acetate, 2:1); w
(KBr) 3570–3100 (OH), 3063, 3026 (ArH), 1047 cm−1
(CO); lH 0.64–1.97 (47H, m), 2.05 (OH), 2.81 (2H, s,
CH2COH), 3.01 (2H, t, J=6.7, CH2CH2OH), 3.84 (2H,
t, J=6.7, CH2CH2OH), 7.13–7.26 (4H, m, ArCH); lC
11.3, 12.0, 18.6 (CH3), 20.9 (CH2), 22.5, 22.7 (CH3),
23.8, 24.1 (CH2), 27.9 (CH), 28.2, 28.5, 32.0, 33.6, 33.7
(CH2), 35.5 (CH), 35.7 (CCH3), 35.75 (CH), 36.1, 39.4,
40.0, 40.5 (CH2), 40.7 (CH), 42.5 (CCH3), 46.1 (CH2),
54.1, 56.2, 56.4 (CH), 60.3, 63.4 (CH2), 72.1 (COH),
125.8, 126.7, 129.7, 132.1 (ArCH), 135.8, 138.2 (ArC);
m/z 504 [M+−(H2O), 0.4%], 489 (2), 388 (27), 387 (100),
369 (16), 136 (40), 135 (13), 121 (10), 119 (15), 118 (43),
117 (46), 109 (11), 107 (21), 106 (20), 105 (46), 104 (15),
95 (21), 93 (25), 91 (25), 81 (30), 79 (24), 71 (17), 69
(21), 67 (15), 57 (35), 55 (42), 43 (86), 41 (43). Anal.
calcd for C36H58O2: C, 82.70; H, 11.18. Found: C,
82.91; H, 11.12%. [h]2D0=+24.8 [c=0.75 (CH2Cl2)].
Acknowledgements
This project was financially supported by the DGES
from the Spanish Ministerio de Educacio´n y Cultura
(MEC; grant no. PB97-133).
3.7. Cyclisation of compounds 14. Isolation of com-
pounds 17. General procedure
To a benzene solution (5 mL) of diols 14 (0.25 mmol)
References
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,
ence of 4 A molecular sieves (0.5 g) under nitrogen was
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added dropwise di-iso-propyl azodicarboxylate (0.12
mL, 0.6 mmol) at 25°C. The reaction mixture was
heated at 80°C for 3 h. Then the resulting mixture was
evaporated (15 mmHg), the residue hydrolysed with
water (10 mL) and extracted with ethyl acetate (3×20
mL). The organic layer was dried over anhydrous
sodium sulfate, filtered and evaporated (15 mmHg).
The crude product was purified by column chromatog-
raphy (silica gel, hexane:ethyl acetate) to give com-
pounds 17. Yields (based on the starting materials 14),
physical, spectroscopic and analytical data follow.
3.7.1. Compound 17a. (47% yield) Rf 0.43 (hexane:ethyl
acetate, 10:1); w (film) 3070, 3021 (ArH), 1609, 1497
(ArC), 1085, 1018 cm−1 (CO); lH 0.98 (3H, s, CH3),
1.22 (3H, t, J=7.0, CH3CH2), 1.38–1.87 (9H, m), 1.91–
2.05 (2H, m), 2.19–2.26 (2H, m), 2.64 (1H, d, J=15.9,
CHHPh), 2.83–2.86 (2H, m), 3.10 (1H, d, J=15.9,
CHHPh), 3.71 (2H, q, J=6.7, 7.3, 6.7, CH3CH2), 4.80
(1H, d, J=15.9, OCHHPh), 4.87 (1H, d, J=15.9,
OCHHPh), 5.17 (2H, s, OCH2O), 6.77–6.84 (2H, m,
ArH), 6.95–6.98 (1H, m, ArH), 7.07–7.22 (4H, m,
ArH); lC 13.7, 15.1 (2×CH3), 23.0, 26.3, 27.4, 29.75,
32.5, 33.0, 35.0 (CH2), 39.3, 43.8 (CH), 46.5 (CCH3),
49.9 (CH), 64.0, 64.85 (2×CH2O), 83.95 (CO), 93.2
(OCH2O), 113.65, 116.2, 123.6, 125.65, 126.1, 126.2,
129.1 (ArCH), 133.5, 133.7, 134.7, 137.9, 155.2 (ArC);
m/z 432 (M+, 100%), 311 (37), 286 (49), 271 (65), 159
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.