Synthesis of novel halogen-containing D-homoestrone and 13α-D-homoestrone derivatives by Lewis acid-induced intramolecular Prins reaction

Article abstract of DOI:10.1016/S0040-4020(02)00742-1

A simple synthetic route has been developed for the synthesis of 16-halo-D-homosteroids in both the normal and 13-epiestrone series by the Lewis acid-catalyzed cyclization of an unsaturated secoestrone aldehyde and its 13α isomer.

Full text of DOI:10.1016/S0040-4020(02)00742-1

Tetrahedron 58 (2002) 6851–6861
Synthesis of novel halogen-containing D-homoestrone
and 13a-D-homoestrone derivatives by Lewis acid-induced
intramolecular Prins reaction
a
Janos Wolfling, Eva Frank, Erzsebet Mernyak, Gabor Bunkoczi, Jose A. Cvesta Seijo
a
a
b
b
´
´
´
´
´
´
¨
and Gyula Schneidera
,
*
a
´
´
Department of Organic Chemistry, University of Szeged, Dom ter 8, H-6720 Szeged, Hungary
¨ ¨
Institute of Inorganic Chemistry, University of Gottingen, Tammannstr. 4, D-37077 Gottingen, Germany
b
Dedicated to Professor Lutz F. Tietze on the occasion of his 60th birthday
Received 18 April 2002; revised 6 June 2002; accepted 28 June 2002
Abstract—A simple synthetic route has been developed for the synthesis of 16-halo-D-homosteroids in both the normal and 13-epiestrone
series by the Lewis acid-catalyzed cyclization of an unsaturated secoestrone aldehyde and its 13a isomer. q 2002 Elsevier Science Ltd. All
rights reserved.
1. Introduction
carbocation is formed by addition of the alkene moiety to
the formyl carbon; this is followed by the entry of a
nucleophile to give a substituted cycloadduct or result in
homoallyl alcohols by elimination. The ratio of the two
products is determined mainly by the reaction conditions.6
Halogen-containing estrogens are of great importance in the
diagnosis1 and chemotherapy2 of estrogen receptor-positive
human breast tumors. Introduction of halogens into steroidal
hormones usually does not affect, but it may enhance the
receptor affinity, while at the same time it reduces the
tumorigenicity.3 Additionally, these drugs are often asso-
ciated with increased potency in consequence of the
suppression of undesired metabolic reactions and the
reduced binding to serum proteins.4 Consequently, efforts
have been directed toward the synthesis of such analogs of
estrogens that are hormonally inactive or at least have a
favorable ratio of tumor inhibitory to hormonal activity.
Besides the substitution of the strongly electronegative
halogens onto the sterane skeleton, other structural modifi-
cations, such as D-ring expansion5 or/and 13-epimerization
might alter the receptor site affinity appropriately and result
in a reduction of the estrogenic activity of the sex hormone
analogs.
During preliminary experiments, we have synthesized the
3-methyl and 3-benzyl ethers of the secoestrone aldehyde
1a8a and 1b8b via a multistep pathway from estrone
3-methyl and benzyl ether in the normal series. After
epimerization of estrone 3-methyl ether, the similar fragmen-
tation was carried out in the 13a series to produce 6.†
We recently reported the Lewis acid-catalyzed aza-Prins
cycloaddition of olefinic arylimines 3, derived from 1a and
substituted anilines 2, to give 16b-halo-D-homoestrone
derivatives 4 (Scheme 1).7 All of these reactions exhibited
high chemo- and stereoselectivity, and homoallylic amines
were not produced by elimination. Our aim was next to
investigate whether the cyclization of the secoaldehyde 1
and its 13-epimer 6 follows the above stereo- and chemo-
selectivity.9 The unsaturated aldehydes 1 and 6 were
expected to undergo Prins reactions on treatment with a
Lewis acid, via the corresponding oxonium ions 5 and 7.
Herein we report a stereoselective synthesis of some
halogenated D-homoestrone and 13a-D-homoestrone
derivatives by means of internal Lewis acid-induced Prins
reactions of an unsaturated secoestrone aldehyde and its
13-epimer. The acid-catalyzed cycloaddition of olefinic
aldehydes via an intramolecular Prins mechanism generally
proceeds by a stepwise ionic pathway. First a b-hydroxy-
2. Results and discussion
The 3-methyl or 3-benzyl ether of aldehyde 1a or 1b was
Keywords: cycloadditions; D-homosteroids; halogenation; ring expansion;
stereoselectivity.
†
The synthesis and structural characterization of 6 will be published
´ ´
elsewhere: Wolfling, J.; Mernyak, E.; Forgo, P.; Schneider, Gy. Steroids,
*
¨
in preparation.
Corresponding author. Tel.: þ36-62-544276; fax: þ36-62-544200;
e-mail: schneider@chem.u-szeged.hu
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00742-1

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J. Wolfling et al. / Tetrahedron 58 (2002) 6851–6861
6852
Scheme 2. Synthesis of 16-halogenated D-homosteroid analogs 9–18 from
the estrone derivatives 1a and 1b.
explained by addition of the alkene moiety to the oxonium
ion anti to the angular methyl group in 5, while the
subsequent addition of the nucleophile to the cation 8 takes
place syn to the angular methyl group.
Accordingly, the 17a-hydroxy group and the 16-halogen,
both take up the b position, to result in a cis product. The
entry of the halogen from this direction is not surprising
since it probably prefers an equatorial orientation. One
additional isomer (10c or 15c) was isolated by using
BF3·OEt2 in CH2Cl2 to obtain fluoro derivatives. The
smaller size of the fluorine atom, comparable to that of
hydrogen, could explain the entry from the 16a or 16b
position, although in this case the 16b-fluorinated product
predominates. During the fluorination, the 17a-ethyl ethers
9a,b and 14a,b were also produced by transetherification of
the 17a-hydroxy group with the applied BF3·OEt2, but in
overall amounts of less than 5%. Interestingly, this
transetherification proved to be predominant when the
same BF3·OEt2-initiated cyclization was carried out with
the 13a-secoaldehyde 6 (Scheme 3).
Scheme 1. Synthesis of 17ab-arylamino-16b-halo-D-homosteroids by
internal aza-Prins cyclization via the olefinic arylimines 3, and the
proposed formation of oxonium salts 5 and 7 from the normal and
13-epiestrone derivatives 1 and 6; MXn¼Lewis acid.
treated with 1.1 equiv. of BF3·OEt2, SnCl4 or ZnBr2 or a
5-fold excess of anhydrous NaI in the presence of a catalytic
amount of BF3·OEt2 in CH2Cl2 to give the corresponding
halohydrins chemoselectively; the formation of homoallylic
alcohols was not observed. Furthermore, all transformations
proceeded in a highly stereoselective manner; only two of
the four possible isomers were isolated: the 16b-halo-17ab-
hydroxy-D-homosteroids (10a–13a and 15a–18a) as
main products and the 16b-halo-17aa-hydroxy isomers
(10b–13b and 15b–18b) as minor products (Scheme 2).
The reason for the application of the 3-benzyl ether
fragment 1b is that the benzyloxy group can easily be
removed by catalytic hydrogenation to give the potentially
more active 3-hydroxy derivative. We believe that the
compounds are obtained in a two-step mechanism from the
initially formed oxonium ion 5 via the secondary carbo-
cation 8 as an intermediate. The cation 8 could be further
transformed by the addition of a halide as a nucleophile. The
favored formation of the 16b,17ab diastereomers can be
The reaction of 6 with 1.1 equiv. of BF3·OEt2 in ice-cold
CH2Cl2 afforded a single 16-fluorinated-17-ethoxy isomer
20, while only 23 was obtained when a 5-fold excess of
anhydrous NaI in dichloromethane containing 1.1 equiv. of
BF3·OEt2 was reacted under reflux. In the latter case, in
contrast with the ring closure of the normal secoaldehyde 1,
the stoichiometric amount was needed to accomplish the
transformation, instead of a catalytic amount of BF3·OEt2.
In spite of the fact that both the propenyl side chain and the
formyl group have b orientation in 6, the rates of reaction in
the 13a series and the reactivity of 6 during all cyclizations

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J. Wolfling et al. / Tetrahedron 58 (2002) 6851–6861
6853
Scheme 4. Oxidation of 16-halo-D-homoestrone derivatives.
Scheme 3. Synthesis of 16-halogenated D-homosteroid analogs 20–24 in
the 13a series.
All the experimental results demonstrated that the
Prins reaction exhibited high stereoselectivity, which was
definitely more expressed in the 13-epi series (Table 1). The
structural identification of all products was carried out by
NMR spectroscopy; the stereochemistry at C-16 and C-17a
in ring D of the normal D-homosteroids (10a–13a,
15a–18a) follows from the 17aa-H doublet-like multiplet
at around d¼3.2 (there is a broad singlet at around d¼3.5 for
17ab-H in 10b–13b and 15b–18b), and from the 16-H
multiplet at around d¼3.9–5.0, which corresponds to two
diaxial and two axial–equatorial couplings.
were reduced in comparison with those for the normal
aldehyde 1. On treatment of 6 with ZnBr2, two different
types of product were produced: the corresponding
16-bromo-17-hydroxy derivative 22 and a homoallylic
alcohol 24, in a nearly 1:1 ratio. In spite of the similar
reaction conditions, this was the only case when the
formation of the homoallylic alcohol was detected. While
the SnCl4-induced cyclization of the normal aldehyde
furnished two types of compound (11a and 11b or 16a
and 16b), the same reaction in the 13-epi series resulted
stereospecifically in only one product (21).
The spatial orientation of the 17a-hydroxy function was also
Table 1. Products of the cyclizations of 1 and 6 in the presence of different Lewis acids
Entry
1
Substrate
Lewis acid (equiv.)
BF3·OEt2 (1.1)
Overall yield (%)
90
Products
9aþ9b
Ratioa
5b
65:12:8
73:10
69:15
72:8
3b
71:9:7
75:5
78:7
65:6
75
93
45:45
78
1a
10aþ10bþ10c
11aþ11b
12aþ12b
13aþ13b
14aþ14b
15aþ15bþ15c
16aþ16b
17aþ17b
18aþ18b
20
2
3
4
5
1a
1a
1a
1b
SnCl4 (1.1)
ZnBr2 (1.1)
BF3·OEt2 (0.17), NaI (5)
BF3·OEt2 (1.1)
83
84
80
90
6
7
8
9
10
11
12
1b
1b
1b
6
6
6
SnCl4 (1.1)
ZnBr2 (1.1)
BF3·OEt2 (0.17), NaI (5)
BF3·OEt2 (1.1)
SnCl4 (1.1)
80
85
71
75
93
90
78
21
22þ24
ZnBr2 (1.1)
BF3·OEt2 (1.1), NaI (5)
6
23
a
Determined after purification by column chromatography.
9a,b and 14a,b were not separated in pure form.
b

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J. Wolfling et al. / Tetrahedron 58 (2002) 6851–6861
6854
Figure 1. X-ray crystal structure of 26a with partial atom numbering.
Table 2. Products of oxidation with the Jones reagent
Substrate(s)
Overall yield (%)
Products
Ratioa
10aþ10bþ10c
10a
91
87
97
96
94
92
90
88
95
94
95
94
93
94
91
90
25aþ25bþ33
25aþ33
26aþ33
26aþ33
27aþ33
27aþ33
28aþ33
28aþ33
29aþ29bþ34
29aþ34
30aþ34
30aþ34
31aþ34
31aþ34
32aþ34
32aþ34
59:7:25
55:32
62:35
60:36
63:31
60:32
62:28
58:30
61:9:25
62:32
65:30
64:30
60:33
59:35
59:32
57:33
Figure 2. X-ray crystal structure of 20 with partial atom numbering.
11aþ11b
11a
12aþ12b
12a
16-halo function are on the same face of the molecule.
Additionally, the characteristic signals of 17a-H and 16-H
displayed very similar shapes to those for the normal
derivatives 9–18: the doublet-like multiplet appears at
around d¼3.5 for the 17a-ethoxy compounds 20 and 23, and
at around d¼3.9 for the 17a-hydroxy derivatives 21 and 22,
with the 16-H multiplet at around d¼4.0–4.6. The X-ray
crystal structure analysis of 20 confirmed the cis anellation
of rings C and D, with both in the chair conformation,
and the b,b-orientation of the protons on C-16 and C-17a
(Fig. 2).‡
13aþ13b
13a
15aþ15bþ15c
15a
16aþ16b
16a
17aþ17b
17a
18aþ18b
18a
a
Determined after purification by column chromatography.
indicated by oxidation of the enantiopure main products
(10a–13a and 15a–18a) and the mixtures of the
17a-hydroxy isomers (10aþb–13aþb and 15aþb–
18aþb) with the Jones reagent (8N) in acetone (Scheme
4). The oxidations resulted in the 16b-halo-17a-ketones
25–28 (Fig. 1)‡ and 29–32 as main products, and 16,17-
unsaturated oxo compounds 3310 and 34 as minor products,
in a ratio of nearly 2:1 in each reaction (Table 2). After
removal of the 17a-ethyl ethers 9a,b and 14a,b (see Scheme
2) by column chromatography, the oxidation of the
16-fluoro-17a-hydroxy isomers 10a–c and 15a–c afforded
one more product, the 16a-fluoro-17a-ketone (25b or 29b),
but only in small quantities.
3. Conclusions
In summary, we have developed an efficient synthetic
route for 16-halogenated D-homoestrone derivatives via the
Lewis acid-catalyzed cationic Prins reaction in both the
normal and 13a series. The formation of different halogen
containing, and particularly fluorinated steroid derivatives
usually needs complex, multistep methods,12 or the
substitution takes place on the original sterane skeleton.13
Here we have described the preparation of well-defined
16-halogenated compounds by the formation of a six-
membered ring D and concurrent halogenation. Besides its
simplicity and mild reaction conditions, the cyclizations
display high chemo- and stereoselectivity.
The 1H NMR spectra of 25–32 demonstrate the disappear-
ance of the C-17a-H signal as compared to the spectra of
the corresponding 17a-hydroxy starting materials, while the
17-H double doublet (J¼10.0, 2.0 Hz) at around d¼6.9 can
be identified in the spectra of 33 and 34.
4. Experimental
Melting points were determined on a Kofler block and are
uncorrected. Specific rotation was measured in CHCl3
(c¼1) at 208C with Polamat-A and Perkin–Elmer 241
polarimeters. Mass spectra were obtained on a Varian MAT
311A spectrometer. 1H NMR spectra were obtained in
CDCl3 solution at 200 MHz (Varian VXR 200), at 300 MHz
(Bruker AMX 300) or at 500 MHz (Varian VXR 500), and
the 13C NMR spectra at 50, 75 or 125 MHz on the same
instruments. Chemical shifts are reported relative to TMS;
J values are given in Hz. 13C NMR spectra are
1H-decoupled. For determination of the multiplicities, the
APT pulse sequence was used. Elemental analysis was
carried out in the analytical laboratory of the University of
Szeged. All solvents were distilled prior to use. The
Determination of the exact structures of the 13a-D-
homosteroids 20–23 was more difficult. While the natural
steroids exhibit a relatively rigid molecular framework, the
conformation of rings C and D in 13a-estrones may be
1
flexible.11 The H NMR, 13C NMR and NOESY spectra
permitted the conclusion that the 17a substituents and the
‡
Crystallographic data (excluding structure factors) for the structures in
this paper have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC 182901 (for 26a)
and CCDC 182902 (for 10d). Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK (fax: þ44-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).

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J. Wolfling et al. / Tetrahedron 58 (2002) 6851–6861
6855
reactions were monitored by TLC on Kieselgel-G (Merck Si
254 F) layers (0.25 mm thick). The spots were detected by
spraying with 5% phosphomolybdic acid in 50% aqueous
phosphoric acid. The Rf values were determined for the
spots observed by illumination at 254 and 365 nm.
113.3 (C-4), 126.2 (C-1), 132.5 (C-10), 137.9 (C-5) and
157.5 (C-3); Anal. calcd for C20H27FO2 (318.44): C, 75.44;
H, 8.55; found: C, 75.53; H, 8.45.
4.2.3. D-Homosteroid 10c. Purification of the crude product
by column chromatography (silica gel, CH2Cl2) afforded
25 mg (8%) of 10c as a colorless oil. Rf 0.34 (EtOAc/CHCl3
4.1. General procedure for the synthesis of 16-halo-D-
homosteroids
1
2:98); H NMR (400 MHz, CDCl3) d 0.86 (s, 3H, 18-H3),
1.21–2.40 (overlapping multiplets, 13H), 2.84 (m, 2H,
6-H2), 3.24 (m, 1H, 17aa-H), 3.76 (s, 3H, 3-OMe), 4.99
(dm, 1H, J¼48.5 Hz, 16b-H), 6.63 (d, 1H, J¼2.7 Hz, 4-H),
6.72 (dd, 1H, J¼8.6, 2.7 Hz, 2-H) and 7.21 (d, 1H, J¼
8.6 Hz, 1-H); 13C NMR (100 MHz, CDCl3) d 9.6 (C-18),
25.9 (C-11), 26.6 (C-7), 30.0 (C-6), 30.2 (J¼18.0 Hz, C-15),
35.3 (J¼21.0 Hz, C-17), 36.7 (C-12), 38.3 (C-8), 38. 8
(C-13), 41.7 (C-9), 43.8 (J¼10.6 Hz, C-14), 55.2 (3-OMe),
74.6 (J¼11.0 Hz, C-17a), 89.3 (J¼172.3 Hz, C-16), 111.7
(C-2), 113.4 (C-4), 126.2 (C-1), 132.4 (C-10), 137.6 (C-5)
and 157.5 (C-3); Anal. calcd for C20H27FO2 (318.44): C,
75.44; H, 8.55; found: C, 75.38; H, 8.58.
298 mg (1.00 mmol) of 13b- or 13a-secoestrone 3-methyl
ether (1a or 6) or 375 mg (1.00 mmol) of 13b-secoestrone
3-benzyl ether (1b) was dissolved in 5 mL of CH2Cl2 and,
under defined circumstances, 48% BF3·OEt2 (1.1 mmol) or
some other Lewis acid (SnCl4 or ZnBr2; 1.1 mmol) was
added dropwise during stirring of the mixture under an
argon atmosphere. The reaction was carried out until
complete conversion (TLC) was achieved. The solution
was then diluted with water (10 mL) and neutralized with
NaHCO3, the aqueous phase was extracted with CH2Cl2
(3£10 mL) and the combined organic phases were washed
with brine and dried over Na2SO4. After evaporation in
vacuo, the crude product was purified by column
chromatography.
4.2.4. D-Homosteroid 20. The crude product derived from
the cyclization of 6 was purified by column chromatography
(silica gel, tert-butyl methyl ether/light petroleum 15:85) to
give 260 mg (75%) of 20 as colorless crystals. Mp 88–
908C; Rf 0.60 (CH2Cl2); [a ]2D5¼þ16.2 (c¼1); 1H NMR
(500 MHz, CDCl3) d 1.03 (s, 3H, 18-H3), 1.15 (t, 3H, J¼
7.0 Hz, CH3CH2), 1.24–2.45 (overlapping multiplets, 13H),
2.83 (m, 2H, 6-H2), 3.32 (q, 1H, J¼7.0 Hz, one of CH3CH2),
3.60 (q, 1H, J¼7.0 Hz, one of CH3CH2), 3.51 (m, 1H,
17ab-H), 3.76 (s, 3H, 3-OMe), 4.60 (dm, 1H, J¼49.0 Hz,
16b-H), 6.62 (d, 1H, J¼2.7 Hz, 4-H), 6.71 (dd, 1H, J¼8.6,
2.7 Hz, 2-H) and 7.19 (d, 1H, J¼8.6 Hz, 1-H); 13C NMR
(125 MHz, CDCl3) d 15.6 (CH3CH2), 22.8 (C-18), 26.4,
26.9, 28.5 (d, J¼17.0 Hz, C-15), 30.1, 34.1 (d, J¼16.8 Hz,
C-17), 34.7, 37.3 (C-13), 38.1, 43.3, 47.1 (d, J¼12.1 Hz,
C-14), 55.2 (3-OMe), 65.2 (O-CH2), 73.9 (d, J¼13.5 Hz,
C-17a), 88.1 (d, J¼170.4 Hz, C-16), 111.7 (C-2), 113.3
(C-4), 126.3 (C-1), 132.5 (C-10), 137.7 (C-5) and 157.6
(C-3); EI-MS (70 eV) m/z (%): 346 (100) [Mþ], 326 (10),
227 (26), 173 (12) and 147 (19); Anal. calcd for C22H31FO2
(346.49): C, 76.26; H, 9.02; found: C, 76.08; H, 9.14.
Crystal data, M¼346.47; orthorhombic; P212121; a¼
4.2. Cyclization of 1a, 1b or 6 in the presence of BF3·OEt2
According to the general procedure, compound 1a or 6
(298 mg, 1.00 mmol) or 1b (375 mg, 1.00 mmol) and
BF3·OEt2 (48% solution in Et2O, 0.32 mL, 1.1 mmol)
were allowed to react in ice-cold CH2Cl2 for 4 h.
4.2.1. D-Homosteroid 10a. The crude product derived from
the cyclization of 1a was purified by column chroma-
tography (silica gel, CH2Cl2) to give 207 mg (65%) of 10a
1
as a colorless oil. Rf 0.25 (EtOAc/CHCl3 2:98); H NMR
(400 MHz, CDCl3) d 0.88 (s, 3H, 18-H3), 1.14–2.50
(overlapping multiplets, 13H), 2.84 (m, 2H, 6-H2), 3.27
(m, 1H, 17aa-H), 3.78 (s, 3H, 3-OMe), 4.54 (dm, 1H,
J¼48.5 Hz, 16a-H), 6.63 (d, 1H, J¼2.7 Hz, 4-H), 6.72 (dd,
1H, J¼8.6, 2.7 Hz, 2-H) and 7.21 (d, 1H, J¼8.6 Hz, 1-H);
13C NMR (100 MHz, CDCl3) d 10.9 (C-18), 25.9 (C-11),
26.6 (C-7), 30.0 (C-6), 30.1 (J¼17.9 Hz, C-15), 34.9 (J¼
21.0 Hz, C-17), 36.7 (C-12), 38.8 (C-13), 41.7 (C-8), 43.8
(C-9), 43.9 (J¼10.6 Hz, C-14), 55.2 (3-OMe), 74.6 (J¼
11.0 Hz, C-17a), 90.0 (J¼164.1 Hz, C-16), 111.6 (C-2),
113.4 (C-4), 126.2 (C-1), 132.4 (C-10), 137.7 (C-5) and
157.5 (C-3); Anal. calcd for C20H27FO2 (318.44): C, 75.44;
H, 8.55; found: C, 75.58; H, 8.37.
˚
˚
˚
8.0450(16) A, b¼11.514(2) A, c¼20.595(4) A, V¼
3
1907.7(7) A ; Z¼4; m(Mo Ka)¼0.082 mm21; F000¼752;
˚
DC¼1.206 g/cm3;
crystal
dimensions:
0.30£0.30£
0.20 mm3. A total of 30,670 reflections were collected
using w and 4 scans to a maximum 2u value of 58.408, and
2863 reflections with no intensity cutoff were used in the
structure determination. Final R and wR values were 0.043
and 0.116, respectively. The maximum and minimum peaks
4.2.2. D-Homosteroid 10b. The crude product derived from
the cyclization of 1a was purified by column chroma-
tography (silica gel, CH2Cl2) to give 38 mg (12%) of 10b as
a colorless oil. Rf 0.32 (EtOAc/CHCl3 2:98); 1H NMR
(400 MHz, CDCl3) d 0.90 (s, 3H, 18-H3), 1.16–2.48
(overlapping multiplets, 13H), 2.84 (m, 2H, 6-H2), 3.65
(m, 1H, 17ab-H), 3.78 (s, 3H, 3-OMe), 4.89 (dm, 1H, J¼
48.5 Hz, 16a-H), 6.63 (d, 1H, J¼2.7 Hz, 4-H), 6.72 (dd, 1H,
J¼8.6, 2.7 Hz, 2-H) and 7.21 (d, 1H, J¼8.6 Hz, 1-H); 13C
NMR (100 MHz, CDCl3) d 17.3 (C-18), 25.9 (C-11), 26.6
(C-7), 30.0 (C-6), 30.6 (J¼17.2 Hz, C-15), 35.3 (J¼
18.3 Hz, C-17), 36.7 (C-12), 38.8 (C-13), 39.0 (C-8), 39.5
(J¼9.9 Hz, C-14), 43.1 (C-9), 55.2 (3-OMe), 76.5 (J¼
13.3 Hz, C-17a), 90.0 (J¼168.1 Hz, C-16), 111.7 (C-2),
2
3
˚
in the difference map were 0.264 and 20.214 e /A ,
respectively.
4.2.5. D-Homosteroid 15a. The crude product derived from
the cyclization of 1b was purified by column chroma-
tography (silica gel, CH2Cl2) to give 280 mg (71%) of 15a
1
as a colorless oil. Rf 0.22 (CHCl3); H NMR (400 MHz,
CDCl3) d 0.87 (s, 3H, 18-H3), 1.22–2.41 (overlapping
multiplets, 13H), 2.84 (m, 2H, 6-H2), 3.27 (m, 1H, 17aa-H),
4.55 (dm, 1H, J¼48.5 Hz, 16a-H), 5.02 (s, 2H, 3-benzyl-
CH2), 6.70 (d, 1H, J¼2.6 Hz, 4-H), 6.77 (dd, 1H, J¼8.7,
2.6 Hz, 2-H), 7.21 (d, 1H, J¼8.7 Hz, 1-H), 7.30 (t-like m,

¨
J. Wolfling et al. / Tetrahedron 58 (2002) 6851–6861
6856
1H, 400-H), 7.37 (m, 2H, 30-H and 50-H) and 7.42 (m, 2H, 20-H
and 6 -H); 13C NMR (100 MHz, CDCl3) d 10.9 (C-18), 25.9
(C-11), 26.6 (C-7), 30.0 (C-6), 30.1 (J¼17.6 Hz, C-15), 34.9
(J¼20.9 Hz, C-17), 36.7 (C-12), 38.7 (C-13), 41.6 (C-8),
43.8 (C-9), 43.8 (J¼10.6 Hz, C-14), 69.9 (3-benzyl-CH2),
74.5 (J¼10.8 Hz, C-17a), 90.0 (J¼164.0 Hz, C0-16), 1120.4
(C-2), 114.5 (C-4), 126.3 (C-1), 127.04 (2C, C-2 and C-6 ),
127.8 (C-40), 128.5 (2C, C-30 and C-5 ), 132.7 (C-10), 137.3
(C-10), 137.7 (C-5) and 156.9 (C-3); Anal. calcd for
C26H31FO2 (394.53): C, 79.15; H, 7.92; found: C, 79.32;
H 8.04.
2:98); H NMR (400 MHz, CDCl3) d 0.88 (s, 3H, 18-H3),
1.20–2.38 (overlapping multiplets, 13H), 2.85 (m, 2H,
6-H2), 3.28 (m, 1H, 17aa-H), 3.78 (s, 3H, 3-OMe), 3.90 (m,
1H, 16a-H), 6.63 (d, 1H, J¼2.7 Hz, 4-H), 6.72 (dd, 1H,
J¼8.6, 2.7 Hz, 2-H) and 7.21 (d, 1H, J¼8.6 Hz, 1-H); 13C
NMR (100 MHz, CDCl3) d 10.9 (C-18), 25.9, 26.6, 30.0,
34.5, 36.8, 37.5 (C-13), 38.3 (C-8), 40.5, 43.5 (C-9), 47.0
(C-14), 55.2 (3-OMe), 56.3 (C-16), 77.9 (C-17a), 111.7
(C-2), 113.4 (C-4), 126.3 (C-1), 132.4 (C-10), 137.7 (C-5)
and 157.6 (C-3); EI-MS (70 eV) m/z (%): 336 (37), 334
(100) [Mþ], 173 (13) and 147 (7); Anal. calcd for
C20H27ClO2 (334.89): C, 71.73; H, 8.13; found: C, 71.65;
H, 8.18.
1
4.2.6. D-Homosteroid 15b. Purification of the crude product
by column chromatography (silica gel, CH2Cl2) afforded
1
36 mg (9%) of 15b as a colorless oil. Rf 0.32 (CHCl3); H
4.3.2. D-Homosteroid 11b. Purification of the crude product
by column chromatography (silica gel, CH2Cl2) afforded
34 mg (10%) of 11b as a white solid. Mp 92–948C; Rf 0.31
(EtOAc/CH2Cl2 2:98); 1H NMR (500 MHz, CDCl3) d 0.91
(s, 3H, 18-H3), 1.25–2.63 (overlapping multiplets, 13H),
2.84 (m, 2H, 6-H2), 3.54 (bs, 1H, 17ab-H), 3.78 (s, 3H,
3-OMe), 4.29 (m, 1H, 16a-H), 6.63 (d, 1H, J¼2.7 Hz, 4-H),
6.72 (dd, 1H, J¼8.6, 2.7 Hz, 2-H) and 7.21 (d, 1H,
J¼8.6 Hz, 1-H); 13C NMR (75 MHz, CDCl3) d 17.2
(C-18), 26.1, 26.2, 30.0, 34.1, 35.1, 37.4 (C-13), 39.0
(C-8), 39.5, 41.7 and 43.1 (C-9 and C-14), 55.2 (3-OMe),
56.6 (C-16), 76.5 (C-17a), 111.7 (C-2), 113.4 (C-4), 126.2
(C-1), 132.5 (C-10), 137.8 (C-5) and 157.5 (C-3); EI-MS
(70 eV) m/z (%): 336 (27), 334 (100) [Mþ], 173 (10) and
147 (5); Anal. calcd for C20H27ClO2 (334.89): C, 71.73; H,
8.13; found: C, 71.60; H, 8.27.
NMR (400 MHz, CDCl3) d 0.89 (s, 3H, 18-H3), 1.23–2.41
(overlapping multiplets, 13H), 2.84 (m, 2H, 6-H2), 3.66 (m,
1H, 17ab-H), 4.89 (dm, 1H, J¼48.5 Hz, 16a-H), 5.02 (s,
2H, 3-benzyl-CH2), 6.64 (d, 1H, J¼2.7 Hz, 4-H), 6.74 (dd,
1H, J¼8.6, 2.7 Hz, 2-H), 7.21 (d, 1H, J¼8.6 Hz, 1-H), 7.30
(t-like m,0 1H, 40-H), 7.37 (m, 2H, 30-H and 50-H) and 7.42
(m, 2H, 2 -H and 60-H); 13C NMR (100 MHz, CDCl3) d 17.3
(C-18), 25.9 (C-11), 26.6 (C-7), 30.0 (C-6), 30.6 (J¼
17.2 Hz, C-15), 35.3 (J¼18.2 Hz, C-17), 36.7 (C-12), 38.8
(C-13), 39.0 (C-8), 39.5 (J¼9.8 Hz, C-14), 43.1 (C-9), 69.9
(3-benzyl-CH2), 76.5 (J¼13.3 Hz, C-17a), 90.0 (J¼
168.1 Hz, C-16), 111.7 (C-2), 113.3 (C-4), 126.2 (C-1),
127.4 (2C, C-20 and C-60), 127.8 (C-40), 128.5 (2C, C-30 and
C-50), 132.5 (C-10), 137.2 (C-10), 137.9 (C-5) and 157.5
(C-3); Anal. calcd for C26H31FO2 (394.53): C, 79.15; H,
7.92; found: C, 79.30; H, 7.85.
4.3.3. D-Homosteroid 21. The crude product derived from
the cyclization of 6 was purified by column chromatography
(silica gel, tert-butyl methyl ether/light petroleum 20:80) to
give 312 mg (93%) of 21 as white crystals. Mp 144–1468C;
Rf 0.14 (CH2Cl2); [a]D25¼þ63.0 (c¼1); 1H NMR (500 MHz,
CDCl3) d 1.03 (s, 3H, 18-H3), 1.17–2.46 (overlapping
multiplets, 13H), 2.81 (m, 2H, 6-H2), 3.76 (s, 3H, 3-OMe),
3.95 (overlapping multiplets, 2H, 16b-H and 17ab-H), 6.61
(d, 1H, J¼2.6 Hz, 4-H), 6.70 (dd, 1H, J¼8.6, 2.6 Hz, 2-H)
and 7.17 (d, 1H, J¼8.6 Hz, 1-H); 13C NMR (125 MHz,
CDCl3) d 21.8 (C-18), 25.9, 26.9, 30.0, 33.0, 34.9, 37.2
(C-13), 37.5, 41.6, 43.1, 48.8, 53.9, 55.2 (3-OMe), 67.6
(C-17a), 111.8 (C-2), 113.4 (C-4), 126.3 (C-1), 132.4
(C-10), 137.7 (C-5) and 157.7 (C-3); EI-MS (70 eV) m/z
(%): 336 (32), 334 (100) [Mþ], 173 (14), 147 (10) and 59
(8); Anal. calcd for C20H27ClO2 (334.89): C, 71.73; H, 8.13;
found: C, 71.83; H, 8.05.
4.2.7. D-Homosteroid 15c. The crude product derived from
the cyclization of 1b was purified by column chroma-
tography (silica gel, CH2Cl2) to give 27 mg (7%) of 15c as a
colorless oil. Rf 0.42 (CHCl3); 1H NMR (400 MHz, CDCl3)
d 0.86 (s, 3H, 18-H3), 1.18–2.43 (overlapping multiplets,
13H), 2.84 (m, 2H, 6-H2), 3.24 (m, 1H, 17aa-H), 4.99 (dm,
1H, J¼48.5 Hz, 16b-H), 5.02 (s, 2H, 3-benzyl-CH2), 6.63
(d, 1H, J¼2.7 Hz, 4-H), 6.72 (dd, 1H, J¼8.6, 2.7 0Hz, 2-H),
7.21 (d, 10H, J¼8.6 Hz, 1-H), 7.30 (t-like m, 1H, 4 -H), 7.37
NMR (100 MHz, CDCl3) d 9.6 (C-18), 25.9 (C-11), 26.6
(C-7), 30.0 (C-6), 30.2 (J¼18.0 Hz, C-15), 35.3 (J¼
21.0 Hz, C-17), 36.7 (C-12), 38.3 (C-8), 38. 8 (C-13), 41.7
(C-9), 43.7 (J¼10.6 Hz, C-14), 69.9 (3-benzyl-CH2), 74.6
(J¼11.0 Hz, C-17a), 89.3 (J¼172.3 Hz, C-16), 111.5 (C-2),
113.4 (C-4), 126.2 (C-1), 127.4 (2C, C-20 and C-60), 1270.8
(C-40), 128.5 (2C, C-30 and C-50), 132.4 (C-10), 137.2 (C-1 ),
137.6 (C-5) and 157.5 (C-3); Anal. calcd for C26H31FO2
(394.53): C, 79.15; H, 7.92; found: C, 79.07; H, 7.85.
(m, 2H, 3 -H and 50-H) and 7.42 (m, 2H, 20-H and 60-H); 13
C
4.3.4. D-Homosteroid 16a. The crude product derived from
the cyclization of 1b was purified by column chroma-
tography (silica gel, CH2Cl2) to give 308 mg (75%) of 16a
as white crystals. Mp 99–1018C; Rf 0.34 (EtOAc/CHCl3
4.3. Cyclization of 1a, 1b or 6 in the presence of SnCl4
1
2:98); [a ]2D5¼þ50.2 (c¼1); H NMR (400 MHz, CDCl3) d
According to the general procedure, compound 1a or 6
(298 mg, 1.00 mmol) or 1b (375 mg, 1.00 mmol) and SnCl4
(278 mg, 0.13 mL, 1.1 mmol) were reacted in ice-cold
CH2Cl2 for 2 h.
0.87 (s, 3H, 18-H3), 1.18–2.45 (overlapping multiplets,
13H), 2.83 (m, 2H, 6-H2), 3.27 (m, 1H, 17aa-H), 3.87 (m,
1H, 16a-H), 5.03 (s, 2H, 3-benzyl-CH2), 6.71 (d, 1H, J¼
2.6 Hz, 4-H), 6.78 (dd, 1H, J¼8.7, 2.6 Hz, 2-H), 7.20 (d, 1H,
J¼8.70 Hz, 1-H), 7.30 (t-like m, 10H, 40-H), 7.37 (m, 2H, 30-H
and 5 -H) and 7.42 (m, 2H, 2 -H and 60-H); 13C NMR
(100 MHz, CDCl3) d 10.9 (C-18), 25.9, 26.6, 29.0, 34.5,
36.8, 37.5 (C-13), 38.3 (C-8), 40.5, 43.5 (C-9), 46.9 (C-14),
56.3 (C-16), 69.9 (3-benzyl-CH2), 77.9 (C-17a), 112.5
4.3.1. D-Homosteroid 11a. The crude product derived from
the cyclization of 1a was purified by column chroma-
tography (silica gel, CH2Cl2) to give 244 mg (73%) of 11a
as a white solid. Mp 90–928C; Rf 0.27 (EtOAc/CH2Cl2

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6857
(C-2), 114.5 (C-4), 126.3 (C-1), 127.04 (2C, C-20 and C-60),
127.9 (C-40), 128.5 (2C, C-30 and C-5 ), 132.7 (C-10), 137.3
(C-10), 137.7 (C-5) and 156.9 (C-3); EI-MS (70 eV) m/z
(%): 410 (74) [Mþ] and 91 (100); Anal. calcd for
C26H31ClO2 (410.99): C, 75.99; H, 7.60; found: C, 75.80;
H, 7.53.
calcd for C20H27BrO2 (379.34): C, 63.33; H, 7.17; found: C,
63.41; H, 7.25.
4.4.3. D-Homosteroid 22. The crude product derived from
the cyclization of 6 was purified by column chromatography
(silica gel, CH2Cl2) to give 171 mg (45%) of 22 as white
crystals. Mp 145–1478C; Rf 0.16 (CH2Cl2); [a ]2D5¼þ104.2
1
4.3.5. D-Homosteroid 16b. Purification of the crude product
by column chromatography (silica gel, CH2Cl2) afforded
20 mg (5%) of 16b as a colorless oil. Rf 0.46 (EtOAc/CHCl3
(c¼1); H NMR (500 MHz, CDCl3) d 1.03 (s, 3H, 18-H3),
1.17–2.41 (overlapping multiplets, 13H), 2.81 (m, 2H,
6-H2), 3.76 (s, 3H, 3-OMe), 3.90 (m, 1H, 17ab-H), 4.07 (m,
1H, 16b-H), 6.61 (d, 1H, J¼2.6 Hz, 4-H), 6.70 (dd, 1H,
J¼8.6, 2.6 Hz, 2-H) and 7.17 (d, 1H, J¼8.6 Hz, 1-H); 13C
NMR (125 MHz, CDCl3) d 21.7 (C-18), 25.8, 26.8, 29.9,
33.8, 34.9, 37.2 (C-13), 37.3, 42.5, 42.9, 45.2, 49.7, 55.2
(3-OMe), 68.0 (C-17a), 111.7 (C-2), 113.3 (C-4), 126.2
(C-1), 132.3 (C-10), 137.6 (C-5), and 157.6 (C-3); EI-MS
(70 eV) m/z (%): 380 (100), 378 (98) [Mþ], 298 (4), 213 (7),
199 (6), 173 (17) and 147 (16); Anal. calcd for C20H27BrO2
(379.34): C, 63.33; H, 7.17; found: C, 63.21; H, 6.95.
1
2:98); H NMR (500 MHz, CDCl3) d 0.91 (s, 3H, 18-H3),
1.19–2.45 (overlapping multiplets, 13H), 2.84 (m, 2H,
6-H2), 3.54 (bs, 1H, 17ab-H), 4.27 (m, 1H, 16a-H), 5.03 (s,
2H, 3-benzyl-CH2), 6.65 (d, 1H, J¼2.7 Hz, 4-H), 6.75 (dd,
1H, J¼8.6, 2.7 Hz, 2-H), 7.21 (d, 1H, J¼8.6 Hz, 1-H), 7.30
(t-like m,0 1H, 40-H), 7.37 (m, 2H, 30-H and 50-H) and 7.42
(m, 2H, 2 -H and 60-H); 13C NMR (75 MHz, CDCl3) d 17.2
(C-18), 26.1, 26.2, 30.0, 34.1, 35.1, 37.4 (C-13), 39.0 (C-8),
40.5, 41.7 and 43.1 (C-9 and C-14), 56.6 (C-16), 69.8
(3-benzyl-CH2), 76.5 (C-17a), 112.4 (C-2), 114.5 (C-4),
126.3 (C0-1), 127.4 (2C, C-20 and C-60), 127.9 (C-40), 128.5
(2C, C-3 and C-50), 132.5 (C-10), 137.3 (C-10), 137.8 (C-5)
and 157.5 (C-3); Anal. calcd for C26H31ClO2 (410.99): C,
75.99; H, 7.60; found: C, 75.83; H, 7.54.
4.4.4. D-Homosteroid 24. The crude product derived from
the cyclization of 6 was purified by column chromatography
(silica gel, CH2Cl2) to give 134 mg (45%) of 24 as white
crystals. Mp 137–1398C; Rf 0.12 (CH2Cl2); [a ]2D5¼290.5
1
(c¼1); H NMR (500 MHz, CDCl3) d 0.92 (s, 3H, 18-H3),
4.4. Cyclization of 1a, 1b or 6 in the presence of ZnBr2
1.25–2.29 (overlapping multiplets, 11H), 2.81 (m, 2H,
6-H2), 3.77 (s, 3H, 3-OMe), 4.13 (m, 1H, 17ab-H), 5.56 (m,
1H, 16-H), 5.88 (m, 1H, 15-H), 6.59 (d, 1H, J¼2.6 Hz, 4-H),
6.70 (dd, 1H, J¼8.6, 2.6 Hz, 2-H) and 7.18 (d, 1H,
J¼8.6 Hz, 1-H); 13C NMR (125 MHz, CDCl3) d 20.9
(C-18), 25.9, 27.2, 30.1, 32.9, 34.4, 36.6 (C-13), 43.1, 44.1,
50.2, 55.2 (3-OMe), 66.2 (C-17a), 111.6 (C-2), 113.5 (C-4),
124.5 and 129.6 (C-15 and C-16), 126.4 (C-1), 132.5 (C-10),
137.9 (C-5) and 157.5 (C-3); Anal. calcd for C20H26O2
(298.43): C, 80.50; H, 8.78; found: C, 80.42; H, 8.85.
According to the general procedure, compound 1a or 6
(298 mg, 1.00 mmol) or 1b (375 mg, 1.00 mmol) and
anhydrous ZnBr2 (250 mg, 1.1 mmol) were reacted in
CH2Cl2 under reflux for 144 h.
4.4.1. D-Homosteroid 12a. The crude product derived from
the cyclization of 1a was purified by column chroma-
tography (silica gel, CH2Cl2) to give 262 mg (69%) of 12a
as white crystals. Mp 97–1008C; Rf 0.27 (EtOAc/CHCl3
1
2:98); [a ]2D5¼þ55.3 (c¼1); H NMR (400 MHz, CDCl3) d
4.4.5. D-Homosteroid 17a. Purification of the crude product
by column chromatography (silica gel, CH2Cl2) afforded
355 mg (78%) of 17a as white crystals. Mp 103–1058C; Rf
0.89 (s, 3H, 18-H3), 1.25–2.36 (overlapping multiplets,
13H), 2.85 (m, 2H, 6-H2), 3.27 (m, 1H, 17aa-H), 3.77 (s,
3H, 3-OMe), 4.00 (m, 1H, 16a-H), 6.62 (d, 1H, J¼2.4 Hz,
4-H), 6.70 (dd, 1H, J¼8.6, 2.4 Hz, 2-H) and 7.20 (d, 1H,
J¼8.6 Hz, 1-H); 13C NMR (100 MHz, CDCl3) d 10.9
(C-18), 25.9, 26.6, 30.0, 35.4, 36.8, 38.2, 38.3 (C-8), 41.5,
43.5 (C-9), 47.3 and 48.2 (C-14 and C-16), 55.2 (3-OMe),
78.4 (C-17a), 111.7 (C-2), 113.4 (C-4), 126.2 (C-1), 132.3
(C-10), 137.6 (C-5) and 157.6 (C-3); EI-MS (70 eV) m/z
(%): 380 (98), 378 (100) [Mþ], 298 (22), 173 (36), 147 (24)
and 83 (24); Anal. calcd for C20H27BrO2 (379.34): C, 63.33;
H, 7.17; found: C, 63.43; H, 7.25.
1
0.24 (CHCl3); H NMR (500 MHz, CDCl3) d 0.80 (s, 3H,
18-H3), 1.20–2.40 (overlapping multiplets, 13H), 2.82 (m,
2H, 6-H2), 3.23 (m, 1H, 17aa-H), 3.99 (m, 1H, 16a-H), 5.02
(s, 2H, 3-benzyl-CH2), 6.71 (d, 1H, J¼2.5 Hz, 4-H), 6.78
(dd, 1H, J¼8.5, 2.5 Hz, 2-H), 7.20 (d, 1H, J¼8.5 Hz, 1-H),
7.31 (t-like m, 1H, 40-H), 7.38 (m, 2H, 30-H and 50-H) and
7.42 (m, 2H, 20-H and 60-H); 13C NMR (125 MHz, CDCl3) d
10.8 (C-18), 25.9, 26.5, 29.9, 35.4, 36.8, 38.2 (C-16), 38.3
(C-13), 41.5, 43.5 (C-9), 47.4 and 48.1 (C-8 and C-14), 69.9
(3-benzyl-CH2), 78.4 (C-17a), 112.5 (C-2), 114.4 (C-4),
126.2 (C0-1), 127.4 (2C, C-20 and C-60), 127.8 (C-40), 128.5
(2C, C-3 and C-50), 132.6 (C-10), 137.2 (C-10), 137.6 (C-5)
and 156.8 (C-3); Anal. calcd for C26H31BrO2 (455.44): C,
68.57; H, 6.86; found: C, 68.63; H, 6.95.
4.4.2. D-Homosteroid 12b. Purification of the crude product
by column chromatography (silica gel, CH2Cl2) afforded
57 mg (15%) of 12b as a colorless oil. Rf 0.63
1
(EtOAc/CHCl3 2:98); H NMR (400 MHz, CDCl3) d 0.91
(s, 3H, 18-H3), 1.20–2.32 (overlapping multiplets, 13H),
2.83 (m, 2H, 6-H2), 3.47 (bs, 1H, 17ab-H), 3.77 (s, 3H,
3-OMe), 4.42 (m, 1H, 16a-H), 6.62 (d, 1H, J¼2.7 Hz, 4-H),
6.71 (dd, 1H, J¼8.6, 2.7 Hz, 2-H) and 7.20 (d, 1H,
J¼8.6 Hz, 1-H); 13C NMR (100 MHz, CDCl3) d 17.2
(C-18), 26.0, 26.2, 30.0, 34.2, 36.1, 37.3 (C-13), 39.0 (C-8),
40.6, 42.8 and 43.1 (C-9 and C-14), 48.7 (C-16), 55.2
(3-OMe), 82.2 (C-17a), 111.6 (C-2), 113.4 (C-4), 126.2
(C-1), 132.5 (C-10), 137.8 (C-5) and 157.5 (C-3); Anal.
4.4.6. D-Homosteroid 17b. The crude product derived from
the cyclization of 1b was purified by column chroma-
tography (silica gel, CH2Cl2) to give 32 mg (7%) of 17b as a
colorless oil. Rf 0.37 (CHCl3); 1H NMR (500 MHz, CDCl3)
d 0.91 (s, 3H, 18-H3), 1.21–2.42 (overlapping multiplets,
13H), 2.83 (m, 2H, 6-H2), 3.49 (bs, 1H, 17ab-H), 4.42 (m,
1H, 16a-H), 5.03 (s, 2H, 3-benzyl-CH2), 6.74 (d, 1H, J¼
2.5 Hz, 4-H), 6.78 (dd, 1H, J¼8.5, 2.5 Hz, 2-H), 7.20 (d, 1H,
J¼8.5 Hz, 1-H), 7.31 (t-like m, 1H, 40-H), 7.37 (m, 2H, 30-H

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6858
and 50-H) and 7.42 (m, 2H, 20-H and 60-H); 13C NMR
(125 MHz, CDCl3) d 17.2 (C-18), 26.0, 26.2, 30.0, 34.2,
36.1, 37.3 (C-13), 38.9 (C-16), 40.5, 42.8 and 43.1 and 48.7
(C-8, C-9 and C-14), 69.9 (3-benzyl-CH2), 76.7 (C-17a),
112.5 (C-2), 114.5 (C-4), 126.2 (C-1), 127.4 (2C, C-20 and
C-60), 127.8 (C-40), 128.5 (2C, C-30 and C-50), 132.8 (C-10),
137.3 (C-10), 137.8 (C-5) and 156.8 (C-3); EI-MS (70 eV)
m/z (%): 456 (10), 454 (12) [Mþ] and 91 (100); Anal. calcd
for C26H31BrO2 (455.44): C, 68.57; H, 6.86; found: C,
68.45; H, 6.92.
41.5, 42.9, 50.9, 55.2 (3-OMe), 65.3 (O-CH2), 76.0 (C-17a),
111.8 (C-2), 113.4 (C-4), 126.3 (C-1), 132.6 (C-10), 137.7
(C-5) and 157.6 (C-3); EI-MS (70 eV) m/z (%): 454 (100)
[Mþ], 327 (19), 281 (54), 227 (15), 173 (34) and 147 (51);
Anal. calcd for C22H31IO2 (454.40): C, 58.15; H, 6.88;
found: C, 58.41; H, 6.95.
4.5.4. D-Homosteroid 18a. The crude product derived from
the cyclization of 1b was purified by column chroma-
tography (silica gel, EtOAc/CHCl3 5:95) to give 327 mg
(65%) of 18a as white crystals. Mp 134–1368C; Rf 0.30
1
4.5. Treatment of 1a, 1b or 6 with NaI in the presence of
BF3·OEt2
(EtOAc/CHCl3 2:98); H NMR (400 MHz, CDCl3) d 0.88
(s, 3H, 18-H3), 1.12–2.50 (overlapping multiplets, 13H),
2.82 (m, 2H, 6-H2), 3.23 (m, 1H, 17aa-H), 4.08 (m, 1H,
16a-H), 5.02 (s, 2H, 3-benzyl-CH2), 6.70 (d, 1H, J¼2.7 Hz,
4-H), 6.77 (dd, 1H, J¼8.7, 2.7 Hz, 2-H), 7.19 (d, 1H, J¼
8.5 Hz, 1-H), 7.30 (t-like m, 1H, 40-H), 7.37 (m, 2H, 30-H
and 50-H) and 7.42 (m, 2H, 20-H and 60-H); 13C NMR
(100 MHz, CDCl3) d 10.9 (C-18), 23.5 (C-16), 25.9, 26.6,
29.9, 36.9, 37.5, 38.1 (C-8), 43.5 (C-9), 43.7, 49.9 (C-14),
69.9 (3-benzyl-CH2), 78.9 (C-17a), 112.5 (C-2), 114.4
(C-4), 126.3 (C-1), 127.04 (2C, C-20 and C-60), 127.9 (C-40),
128.5 (2C, C-30 and C-5 ), 132.6 (C-10), 137.3 (C-10), 137.7
(C-5) and 156.8 (C-3); EI-MS (70 eV) m/z (%): 502 (100)
[Mþ], 376 (6), 374 (11), 92 (8) and 91 (100); Anal. calcd for
C26H31IO2 (502.44): C, 62.15; H, 6.22; found: C, 62.03; H,
6.34.
According to the general procedure, compound 1a or
6 (298 mg, 1.00 mmol) or 1b (375 mg, 1.00 mmol) and
anhydrous NaI (749 mg, 5 mmol) were reacted together, and
48% BF3·OEt2 (0.05 mL, 0.17 mmol 1a and 1b or 0.15 mL,
1.1 mmol for 6) in ice-cold CH2Cl2 was added, and the
mixture was then stirred at rt for 2 h.
4.5.1. D-Homosteroid 13a. The crude product derived from
the cyclization of 1a was purified by column chroma-
tography (silica gel, CH2Cl2) to give 307 mg (72%) of 13a
as white crystals. Mp 88–908C; Rf 0.32 (EtOAc/CHCl3
1
2:98); H NMR (400 MHz, CDCl3) d 0.90 (s, 3H, 18-H3),
1.25–2.45 (overlapping multiplets, 13H), 2.83 (m, 2H,
6-H2), 3.26 (m, 1H, 17aa-H), 3.77 (s, 3H, 3-OMe), 4.10 (m,
1H, 16a-H), 6.62 (d, 1H, J¼2.9 Hz, 4-H), 6.71 (dd, 1H,
J¼8.7, 2.9 Hz, 2-H) and 7.19 (d, 1H, J¼8.7 Hz, 1-H); 13C
NMR (100 MHz, CDCl3) d 11.0 (C-18), 23.5 (C-16), 25.9,
26.6, 30.0, 36.9, 37.6, 38.2 (C-8), 38.5 (C-13), 43.4 (C-9),
43.7, 49.9 (C-14), 55.2 (3-OMe), 79.0 (C-17a), 111.7 (C-2),
113.4 (C-4), 126.2 (C-1), 132.4 (C-10), 137.6 (C-5) and
157.6 (C-3); EI-MS (70 eV) m/z (%): 426 (100) [Mþ], 299
(19), 298 (37), 281 (36), 173 (38) and 147 (43); Anal. calcd
for C20H27IO2 (426.34): C, 56.35; H, 6.38; found: C, 56.47;
H, 6.22.
4.5.5. D-Homosteroid 18b. The crude product derived from
the cyclization of 1b was purified by column chroma-
tography (silica gel, CH2Cl2) to give 30 mg (6%) of 18b as a
yellowish oil. Rf 0.42 (EtOAc/CHCl3 2:98); 1H NMR
(500 MHz, CDCl3) d 0.89 (s, 3H, 18-H3), 1.23–2.48
(overlapping multipletts, 13H), 2.83 (m, 2H, 6-H2), 3.33
(bs, 1H, 17ab-H), 4.52 (m, 1H, 16a-H), 5.02 (s, 2H,
3-benzyl-CH2), 6.65 (d, 1H, J¼2.7 Hz, 4-H), 6.74 (dd, 1H,
J¼8.6, 2.7 Hz, 2-H), 7.19 (d, 1H, 0 J¼8.6 Hz, 1-H), 7.30
(t-like m,0 1H, 40-H), 7.37 (m, 2H, 3 -H and 50-H) and 7.42
(m, 2H, 2 -H and 60-H); Anal. calcd for C26H31IO2 (502.44):
C, 62.15; H, 6.22; found: C, 62,28; H, 6.31.
4.5.2. D-Homosteroid 13b. The crude product derived from
the cyclization of 1a was purified by column chroma-
tography (silica gel, CH2Cl2) to give 34 mg (8%) of 13b as
4.6. Typical procedure for the oxidation of 16-halo-17a-
hydroxy-D-homosteroids
1
a yellowish oil. Rf 0.43 (EtOAc/CHCl3 2:98); H NMR
(500 MHz, CDCl3) d 0.92 (s, 3H, 18-H3), 1.12–2.52 (over-
lapping multiplets, 13H), 2.83 (m, 2H, 6-H2), 3.33 (bs, 1H,
17ab-H), 3.77 (s, 3H, 3-OMe), 4.55 (m, 1H, 16a-H), 6.62
(d, 1H, J¼2.7 Hz, 4-H), 6.71 (dd, 1H, J¼8.6, 2.7 Hz, 2-H)
and 7.19 (d, 1H, J¼8.6 Hz, 1-H); Anal. calcd for C20H27IO2
(426.34): C, 56.35; H, 6.38; found: C, 56.43; H, 6.52.
A certain amount of Jones reagent (8 N) was added
dropwise to 1.00 mmol of pure 16b-halo-17ab-hydroxy-D-
homosteroid (10a–13a or 15a–18a) or a mixture of the
corresponding 17a isomers (10–13 or 15–18) in 10 mL of
acetone, and the solution was stirred until complete
conversion (TLC) was achieved. The solution was next
poured into ice-water and extracted with CH2Cl2
(3£10 mL). The combined organic layers were washed
with water, dried over Na2SO4 and concentrated in vacuo.
The crude product was purified by column chromatography.
4.5.3. D-Homosteroid 23. Purification of the crude product
by column chromatography (silica gel, CH2Cl2/light
petroleum 50:50) afforded 355 mg (78%) of 23 as colorless
crystals. Mp 82–848C; Rf 0.80 (CH2Cl2); [a]2D5¼þ23.8
1
(c¼1); H NMR (500 MHz, CDCl3) d 1.04 (s, 3H, 18-H3),
1.13 (t, 3H, J¼7.0 Hz, CH3CH2), 1.19–2.47 (overlapping
multiplets, 13H), 2.84 (m, 2H, 6-H2), 3.30 (q, 1H, J¼7.0 Hz,
one of CH3CH2), 3.58 (q, 1H, J¼7.0 Hz, one of CH3CH2),
3.49 (m, 1H, 17ab-H), 3.77 (s, 3H, 3-OMe), 4.19 (m, 1H,
16b-H), 6.63 (d, 1H, J¼2.7 Hz, 4-H), 6.71 (dd, 1H, J¼8.6,
2.7 Hz, 2-H), 7.20 (d, 1H, J¼8.6 Hz, 1-H); 13C NMR
(125 MHz, CDCl3) d 15.6 (Et-CH3), 22.4 and 22.8 (C-18
and C-16), 26.4, 26.9, 30.1, 35.2, 36.2, 37.0, 37.3 (C-13),
4.7. Oxidation of 3-methoxy-16-fluoro-17a-hydroxy-D-
homosteroids
According to the typical procedure, 318 mg (1.00 mmol) of
10a or a mixture of 10a, 10b and 10c and 0.3 mL of Jones
reagent were reacted to give 174 mg (55%) of 25a and 95 mg
(32%) of 33 in the former case, and 187 mg (59%) of 25a,
22 mg (7%) of 25b and 74 mg (25%) of 33 in the latter case.

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J. Wolfling et al. / Tetrahedron 58 (2002) 6851–6861
6859
4.7.1. D-Homosteroid 25a. The crude product was purified
by column chromatography (silica gel, light petroleum/
CH2Cl2 20:80) to give 25a as a colorless oil. Rf 0.42 (light
C20H25ClO2 (332.87): C, 72.17; H, 7.57; found: C, 72.08;
H, 7.62. Crystal data, M¼332.85; orthorhombic; P212121;
˚
˚
˚
a¼5.9432(12) A, b¼8.3380(17) A, c¼34.370(7) A, V¼
1
3
1703.2(6) A ; Z¼4; m(Mo Ka)¼0.232 mm21; F000¼712;
˚
petroleum/CH2Cl2 20:80); H NMR (500 MHz, CDCl3) d
1.14 (s, 3H, 18-H3), 1.24–2.43 (overlapping multiplets,
13H), 2.87 (m, 2H, 6-H2), 3.78 (s, 3H, 3-OMe), 4.68 (dm,
1H, J¼49.2 Hz, 16a-H), 6.71 (d, 1H, J¼2.5 Hz, 4-H), 6.79
(dd, 1H, J¼8.6, 2.5 Hz, 2-H) and 7.20 (d, 1H, J¼8.6 Hz,
1-H); Anal. calcd for C20H25FO2 (316.42): C, 75.92; H,
7.96; found: C, 76.05; H, 7.88.
DC¼1.298 g/cm3; crystal dimensions: 1£1£1 mm3. A total
of 10,782 reflections were collected using v scans to a
maximum 2u value of 508, and 2940 reflections with no
intensity cutoff were used in the structure determination.
Final R and wR values were 0.036 and 0.099, respectively.
The maximum and minimum peaks in the difference map
2
3
˚
were 0.170 and 20.183 e /A , respectively.
4.7.2. D-Homosteroid 25b. The crude product was purified
by column chromatography (silica gel, light petroleum/
CH2Cl2 20:80) to give 25b as a colorless oil. Rf 0.53 (light
4.9. Oxidation of 3-methoxy-16-bromo-17a-hydroxy-D-
homosteroids
1
petroleum/CH2Cl2 20:80); H NMR (500 MHz, CDCl3) d
1.14 (s, 3H, 18-H3), 1.20–2.43 (overlapping multiplets,
13H), 2.87 (m, 2H, 6-H2), 3.78 (s, 3H, 3-OMe), 4.97 (dm,
1H, J¼48.6 Hz, 16b-H), 6.70 (d, 1H, J¼2.6 Hz, 4-H), 6.78
(dd, 1H, J¼8.6, 2.6 Hz, 2-H) and 7.20 (d, 1H, J¼8.6 Hz,
1-H); Anal. calcd for C20H25FO2 (316.42): C, 75.92; H,
7.96; found: C, 75.81; H, 8.05.
According to the typical procedure, 379 mg (1.00 mmol) of
12a or a mixture of 12a and 12b and 0.4 mL of Jones
reagent were reacted to give 226 mg (60%) of 27a and
95 mg (32%) of 33 in the former case, and 238 mg (63%) of
27a and 92 mg (31%) of 33 in the latter case.
4.9.1. D-Homosteroid 27a. The crude product was purified
by column chromatography (silica gel, light petroleum/
CH2Cl2 20:80) to give 27a as colorless crystals. Mp 100–
4.7.3. D-Homosteroid 33. The crude product was purified
by column chromatography (silica gel, light petroleum/
CH2Cl2 20:80) to give 25b as colorless crystals. Mp 159–
1
1028C; Rf 0.49 (light petroleum/CH2Cl2 20:80); H NMR
1
1618C; Rf 0.31 (light petroleum/CH2Cl2 20:80); H NMR
(500 MHz, CDCl3) d 1.16 (s, 3H, 18-H3), 1.26–2.58
(overlapping multiplets, 11H), 2.88 (m, 2H, 6-H2), 2.91
(m, 1H), 3.15 (m, 1H), 3.77 (s, 3H, 3-OMe), 4.10 (m, 1H,
16a-H), 6.63 (d, 1H, J¼2.5 Hz, 4-H), 6.72 (dd, 1H, J¼8.6,
2.5 Hz, 2-H) and 7.19 (d, 1H, J¼8.6 Hz, 1-H); Anal. calcd
for C20H25BrO2 (377.33): C, 63.66; H, 6.68; found: C,
63.78; H, 6.91.
(500 MHz, CDCl3) d 1.05 (s, 3H, 18-H3), 1.26–2.56
(overlapping multiplets, 11H), 2.87 (m, 2H, 6-H2), 3.77
(s, 3H, 3-OMe), 5.95 (m, 1H, 17-H), 6.63 (d, 1H, J¼2.7 Hz,
4-H), 6.72 (dd, 1H, J¼8.6, 2.7 Hz, 2-H), 6.88 (m, 1H, 16-H)
and 7.22 (d, 1H, J¼8.6 Hz, 1-H); 13C NMR (125 MHz,
CDCl3) d 15.6 (C-18), 25.9 (2C), 27.2, 29.9, 32.3, 39.3
(C-8), 42.6 (C-9), 44.6 (C-13), 45.5 (C-14), 55.2 (3-OMe),
111.7 (C-2), 113.6 (C-4), 126.3 and 127.8 (C-1 and C-17),
132.2 (C-10), 137.4 (C-5), 147.3 (C-16), 157.7 (C-3) and
205.3 (C-17a); EI-MS (70 eV) m/z (%): 296 (100) [Mþ];
Anal. calcd for C20H24O2 (296.41): C, 81.04; H, 8.16;
found: C, 81.17; H, 8.32.
4.10. Oxidation of 3-methoxy-16-iodo-17a-hydroxy-D-
homosteroids
According to the typical procedure, 426 mg (1.00 mmol) of
13a or a mixture of 13a and 13b and 0.5 mL of Jones
reagent were reacted to give 246 mg (58%) of 28a and
89 mg (30%) of 33 in the former case, and 263 mg (62%) of
28a and 83 mg (28%) of 33 in the latter case.
4.8. Oxidation of 3-methoxy-16-chloro-17a-hydroxy-D-
homosteroids
According to the typical procedure, 335 mg (1.00 mmol) of
11a or a mixture of 11a and 11b and 0.4 mL of Jones
reagent were reacted to give 200 mg (60%) of 26a and
107 mg (36%) of 33 in the former case, and 206 mg (62%)
of 26a and 104 mg (35%) of 33 in the latter case.
4.10.1. D-Homosteroid 28a. The crude product was purified
by column chromatography (silica gel, light petroleum/
CH2Cl2 20:80) to give 28a as a colorless oil. Rf 0.57 (light
1
petroleum/CH2Cl2 20:80); H NMR (500 MHz, CDCl3) d
1.17 (s, 3H, 18-H3), 1.33–2.65 (overlapping multiplets,
11H), 2.87 (m, 2H, 6-H2), 2.98 (m, 1H), 3.27 (m, 1H), 3.77
(s, 3H, 3-OMe), 4.17 (m, 1H, 16a-H), 6.63 (d, 1H, J¼
2.7 Hz, 4-H), 6.72 (dd, 1H, J¼8.6, 2.7 Hz, 2-H) and 7.19 (d,
1H, J¼8.6 Hz, 1-H); 13C NMR (125 MHz, CDCl3) d 16.8
(C-18), 20.5 (C-16), 25.6, 26.6, 28.7, 31.9, 36.4, 37.8 (C-9),
42.6 (C-14), 46.6, 47.6 (C-17), 50.3 (C-13), 55.2 (3-OMe),
111.6 (C-2), 113.4 (C-4), 126.3 (C-1), 131.9 (C-10), 137.3
(C-5), 157.7 (C-3) and 210.4 (C-17a); Anal. calcd for
C20H25IO2 (424.33): C, 56.61; H, 5.94; found: C, 56.84; H,
6.03.
4.8.1. D-Homosteroid 26a. Purification of the crude product
by column chromatography (silica gel, light petroleum/
CH2Cl2 20:80) afforded 26a as colorless crystals. Mp 130–
1
1328C; Rf 0.53 (light petroleum/CH2Cl2 20:80); H NMR
(500 MHz, CDCl3) d 1.15 (s, 3H, 18-H3), 1.29–2.47
(overlapping multiplets, 11H), 2.81 (m, 1H), 2.86 (m, 2H,
6-H2), 2.98 (m, 1H), 3.76 (s, 3H, 3-OMe), 4.00 (m, 1H,
16a-H), 6.62 (d, 1H, J¼2.7 Hz, 4-H), 6.71 (dd, 1H, J¼8.6,
2.7 Hz, 2-H) and 7.19 (d, 1H, J¼8.6 Hz, 1-H); 13C NMR
(125 MHz, CDCl3) d 16.8 (C-18), 25.6, 26.6, 29.8, 34.3,
32.2, 38.4 (C-8), 43.1 (C-9), 46.6 (C-14), 47.2 (C-13), 47.6
(C-17), 55.2 (C-16), 55.8 (3-OMe), 111.8 (C-2), 113.5
(C-4), 126.3 (C-1), 132.0 (C-10), 137.3 (C-5), 157.7 (C-3)
and 210.7 (C-17a); EI-MS (70 eV) m/z (%): 334 (22), 332
(100) [Mþ], 212 (12) and 173 (14); Anal. calcd for
4.11. Oxidation of 3-benzyloxy-16-fluoro-17a-hydroxy-
D-homosteroids
According to the typical procedure, 395 mg (1.00 mmol) of
15a or a mixture of 15a, 15b and 15c and 0.4 mL of Jones

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J. Wolfling et al. / Tetrahedron 58 (2002) 6851–6861
6860
reagent were reacted to give 243 mg (62%) of 29a and
119 mg (32%) of 34 in the former case, and 239 mg (61%)
of 29a, 35 mg (9%) of 29b and 93 mg (25%) of 34 in the
latter case.
1H NMR (500 MHz, CDCl3) d 1.14 (s, 3H, 18-H3), 1.24–
2.45 (overlapping multiplets, 11H), 2.79 (m, 1H), 2.87 (m,
2H, 6-H2), 2.94 (m, 1H), 3.89 (m, 1H, 16a-H), 5.02 (s, 2H,
3-benzyl-CH2), 6.71 (d, 1H, J¼2.6 Hz, 4-H), 6.77 (dd, 1H,
J¼8.7, 2.6 Hz, 02-H), 7.21 (d, 1H,0 J¼8.7 H0z, 1-H), 7.30
(t-like m, 1H, 04 -H), 7.37 (m, 2H, 3 -H and 5 -H), 7.42 (m,
2H, 20-H and 6 -H); Anal. calcd for C26H29ClO2 (408.97): C,
76.36; H, 7.15; found: C, 76.45; H, 7.08.
4.11.1. D-Homosteroid 29a. Purification of the crude
product by column chromatography (silica gel, light
petroleum/CH2Cl2 20:80) afforded 29a as a colorless oil.
Rf 0.46 (light petroleum/CH2Cl2 20:80); 1H NMR (500
MHz, CDCl3) d 1.14 (s, 3H, 18-H3), 1.21–2.83 (over-
lapping multiplets, 13H), 2.87 (m, 2H, 6-H2), 4.68 (dm, 1H,
J¼49.2 Hz, 16a-H), 5.02 (s, 2H, 3-benzyl-CH2), 6.70 (d,
1H, J¼2.6 Hz, 4-H), 6.77 (dd, 1H, J¼8.7, 2.6 Hz, 2-H), 7.21
(d, 1H, J¼8.7 Hz, 1-H), 7.30 (t-like m, 1H, 40-H), 7.37 (m,
2H, 30-H and 50-H) and 7.42 (m, 2H, 20-H and 60-H); Anal.
calcd for C26H29FO2 (392.52): C, 79.56; H, 7.45; found: C,
79.65; H, 7.53.
4.13. Oxidation of 3-benzyloxy-16-bromo-17a-hydroxy-
D-homosteroids
According to the typical procedure, 455 mg (1.00 mmol) of
17a or a mixture of 17a and 17b and 0.5 mL of Jones
reagent were reacted to give 268 mg (59%) of 31a and
130 mg (35%) of 34 in the former case, and 272 mg (60%)
of 31a and 123 mg (33%) of 34 in the latter case.
4.11.2. D-Homosteroid 29b. The crude product was purified
by column chromatography (silica gel, light petroleum/
CH2Cl2 20:80) to give 29b as a colorless oil. Rf 0.55 (light
4.13.1. D-Homosteroid 31a. Purification of the crude
product by column chromatography (silica gel, light
petroleum/CH2Cl2 20:80) afforded 31a as a colorless oil.
1H NMR (500 MHz, CDCl3) d 1.12 (s, 3H, 18-H3), 1.26–
2.50 (overlapping multiplets, 11H), 2.86 (m, 2H, 6-H2), 2.90
(m, 1H), 3.20 (m, 1H), 4.05 (m, 1H, 16a-H), 5.02 (s, 2H, 3-
benzyl-CH2), 6.71 (d, 1H, J¼2.6 Hz, 4-H), 6.77 (dd, 1H,
J¼8.7, 2.6 Hz, 2-H), 7.21 (d, 1H, 0 J¼8.7 Hz, 1-H), 7.30
(t-like m, 10H, 40-H), 70.37 (m, 2H, 3 -H and 50-H) and 7.42
(m, 2H, 2 -H and 6 -H); Anal. calcd for C26H29BrO2
(453.42): C, 68.87; H, 6.45; found: C, 68.92; H, 6.53.
1
petroleum/CH2Cl2 20:80); H NMR (500 MHz, CDCl3) d
1.14 (s, 3H, 18-H3), 1.23–2.80 (overlapping multiplets,
13H), 2.87 (m, 2H, 6-H2), 4.97 (dm, 1H, J¼48.6 Hz,
16b-H), 5.02 (s, 2H, 3-benzyl-CH2), 6.70 (d, 1H, J¼2.6 Hz,
4-H), 6.78 (dd, 1H, J¼8.6, 2.6 Hz, 2-H), 7.20 (d, 1H, J¼
8.6 Hz, 1-H), 7.30 (t-like m, 01H, 40-H), 7.37 (m, 2H, 30-H
and 50-H) and 7.42 (m, 2H, 2 -H and 60-H); Anal. calcd for
C26H29FO2 (392.52): C, 79.56; H, 7.45; found: C, 79.74; H,
7.55.
4.14. Oxidation of 3-benzyloxy-16-iodo-17a-hydroxy-D-
homosteroids
4.11.3. D-Homosteroid 34. The crude product was purified
by column chromatography (silica gel, light petroleum/
CH2Cl2 20:80) to give 34 as colorless crystals. Mp 121–
According to the typical procedure, 502 mg (1.00 mmol) of
18a or a mixture of 18a and 18b and 0.5 mL of Jones
reagent were reacted to give 285 mg (57%) of 32a and
123 mg (33%) of 34 in the former case, and 295 mg (59%)
of 32a and 119 mg (32%) of 34 in the latter case.
1
1238C; Rf 0.42 (light petroleum/CH2Cl2 20:80); H NMR
(500 MHz, CDCl3) d 1.04 (s, 3H, 18-H3), 1.28–2.54 (over-
lapping multiplets, 11H), 2.85 (m, 2H, 6-H2), 5.01 (s, 2H,
3-benzyl-CH2), 5.94 (m, 1H, 17-H), 6.70 (d, 1H, J¼2.7 Hz,
4-H), 6.78 (dd, 1H, J¼8.6, 2.7 Hz, 2-H), 6.86 (m, 10H, 16-H),
7.21 (d, 10H, J¼8.6 Hz, 1-H), 7.30 (t-like m, 1H, 4 -H), 7.37
4.14.1. D-Homosteroid 32a. The crude product was purified
by column chromatography (silica gel, light petroleum/
(m, 2H, 3 -H and 50-H) and 7.42 (m, 2H, 20-H and 60-H); 13
C
1
NMR (125 MHz, CDCl3) d 15.6 (C-18), 25.9 (2C), 27.2,
29.9, 32.3, 39.2 (C-8), 42.6 (C-9), 44.6 (C-13), 45.5 (C-14),
69.9 (3-benzyl-CH2), 112.5 (C-2), 114.6 (C-4), 126.4 (C-1),
127.3 (2C, C-20 and C-60), 127.8 (2C, C-17 and C-40), 128.5
(2C, C-30 and C-50), 132.4 (C-10), 137.3 (C-10), 137.5 (C-5),
147.3 (C-16), 156.9 (C-3) and 205.2 (C-17a); EI-MS
(70 eV) m/z (%): 372 (65) [Mþ] and 91 (100); Anal. calcd
for C26H28O2 (372.51): C, 83.83; H, 7.58; found: C, 83.95;
H, 7.41.
CH2Cl2 20:80) to give 32a as a colorless oil. H NMR
(500 MHz, CDCl3) d 1.12 (s, 3H, 18-H3), 1.30–2.60 (over-
lapping multiplets, 11H), 2.87 (m, 2H, 6-H2), 3.20 (m, 2H),
4.09 (m, 1H, 16a-H), 5.02 (s, 2H, 3-benzyl-CH2), 6.71 (d,
1H, J¼2.6 Hz, 4-H), 6.77 (dd, 1H, J¼8.7, 2.6 Hz, 2-H), 7.21
(d, 1H, J¼8.7 Hz, 1-H), 7.30 (t-like m, 1H, 40-H), 7.37 (m,
2H, 30-H and 50-H) and 7.42 (m, 2H, 20-H and 60-H); Anal.
calcd for C26H29IO2 (500.42): C, 62.41; H, 5.84; found: C,
62.55; H, 5.98.
4.12. Oxidation of 3-benzyloxy-16-chloro-17a-hydroxy-
D-homosteroids
Acknowledgments
According to the typical procedure, 411 mg (1.00 mmol) of
16a or a mixture of 16a and 16b and 0.4 mL of Jones
reagent were reacted to give 262 mg (64%) of 30a and
112 mg (30%) of 34 in the former case, and 266 mg (65%)
of 30a and 112 mg (30%) of 34 in the latter case.
The work was supported financially by the Hungarian
Scientific Research Fund (OTKA T032265), the Hungarian
Ministry of Education (FKFP 0110/2000) and the Hungarian-
German Intergovernmental S&T Cooperation Program
´
(Project No. UNG-43/00). The authors thank Peter Forgo
(University of Szeged, Hungary) for the NMR spectra, and
´
4.12.1. D-Homosteroid 30a. Purification of the crude
product by column chromatography (silica gel, light
petroleum/CH2Cl2 20:80) afforded 30a as a colorless oil.
¨
Mrs Gyorgyi Udvarnoki (University of Gottingen,
Germany) for the mass spectra.
¨

¨
J. Wolfling et al. / Tetrahedron 58 (2002) 6851–6861
6861
´
7. (a) Wolfling, J.; Frank, E.; Schneider, Gy.; Tietze, L. F. Synlett
¨
References
´
1998, 1205–1206. (b) Wolfling, J.; Frank, E.; Schneider, Gy.;
¨
Tietze, L. F. Eur. J. Org. Chem. 1999, 3013–3020.
8. (a) Schneider, Gy.; Bottka, S.; Hackler, L.; Wo¨lfling, J.; Sohar,
1. (a) VanBrocklin, H. F.; Carlson, K. E.; Katzenellenbogen,
J. A.; Welch, M. J. J. Med. Chem. 1993, 36, 1619–1629.
(b) Ali, H.; Rousseau, J.; Gantchev, T. G.; Lier, J. E. J. Med.
Chem. 1993, 36, 4255–4263.
´
P. Liebigs Ann. Chem. 1989, 263–267. (b) Tietze, L. F.;
¨ ¨
Schneider, Gy.; Wolfling, J.; Fecher, A.; Nobel, T.; Petersen,
2. Levesque, C.; Merand, Y.; Dufour, J.-M.; Labrie, C.; Labrie,
F. J. Med. Chem. 1991, 34, 1624–1630.
S.; Schuberth, I.; Wulff, C. Chem. Eur. J. 2000, 6, 3755–3760.
9. A short communication has already been published on the
´
3. (a) Diorazio, L. J.; Widdowson, D. A.; Clough, J. M. J. Chem.
Soc., Perkin Trans. 1 1992, 421–426. (b) Pennington, W. T.;
Resnati, G.; DesMarteau, D. D. J. Org. Chem. 1992, 57,
1536–1539.
´
cyclization of the normal secoaldehyde: Frank, E.; Mernyak,
¨
E.; Wolfling, J.; Schneider, Gy. Synlett 2002, 419–422.
10. Johns, W. F.; Salamon, K. W. J. Org. Chem. 1971, 36,
1952–1962.
¨ ¨
¨
11. Schonecker, B.; Lange, C.; Kotteritzsch, M.; Gunther, W.;
4. (a) Kiesewetter, D. O.; Katzenellenbogen, J. A.; Kilbourn,
M. R.; Welsh, M. J. J. Org. Chem. 1984, 49, 4900–4905.
(b) Stalford, A. C.; Maggs, J. L.; Gilchrist, T. L.; Park, B. K.
Steroids 1997, 62, 750–761.
¨
Weston, J.; Anders, E.; Gorls, H. J. Org. Chem. 2000, 65,
5487–5497.
12. Neeman, M.; Mukai, T.; O’Grodnic, J. S.; Rendall, A. L.
J. Chem. Soc., Perkin Trans. 1 1972, 2300–2302.
13. (a) Ali, H.; Rousseau, J.; Lafreniere, J.; Lier, J. E. Steroids
2000, 65, 74–84. (b) Back, T. G.; Brunner, K.; Codding, P. W.;
Roszak, A. W. Heterocycles 1989, 28, 219–238. (c) Diorazio,
L. J.; Widdowson, D. A.; Clough, J. M. J. Chem. Soc., Perkin
Trans. 1 1992, 421–426.
5. (a) Lotz, W. Experientia 1978, 34, 1373–1374. (b) Duax,
W. L.; Smith, G. D.; Swenson, D. C.; Strong, P. D.; Weeks,
C. M.; Ananchenko, S. N.; Egorova, V. V. J. Steroid Biochem.
1981, 14, 1–7.
6. (a) Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S. Synthesis
1990, 646–648. (b) Balog, A.; Geib, S. J.; Curran, D. P. J. Org.
Chem. 1995, 60, 345–352.