Stereoselective synthesis of new halogen-containing D-homoestrone derivatives

Article abstract of DOI:10.1055/s-2002-20455

The Lewis acid-induced cyclization of the 3-methyl and 3-benzyl ethers of an unsaturated secoestrone aldehyde furnished D-homosteroids containing 16β-oriented halogens on the sterane skeleton.

Full text of DOI:10.1055/s-2002-20455

LETTER
419
Stereoselective Synthesis of New Halogen-containing D-Homoestrone
Derivatives
Stereoselective
.
S
ynthesis of
F
Ne
w
D
-Homo
r
estrone
D
a
erivativesnk, E. Mernyák, J. Wölfling, Gy. Schneider*
Department of Organic Chemistry, University of Szeged, Dóm tér 8., 6720 Szeged, Hungary
Fax +36(62)544200; E-mail: schneider@chem.u-szeged.hu
Received 12 November 2001
of Lewis acids presumably results in a predominantly
stepwise ionic pathway via a -hydroxy-carbocation af-
fording homoallylic alcohols or/and -halohydrins de-
pending on the reaction conditions,4 though mainly
reactions catalyzed by BF3 OEt2 and chlorine-containing
acids leading to unsaturated compounds have been stud-
ied. However the cationic process leading to 1,3-halohy-
drins often competes with the ‘ene’ reaction, and can even
become the exclusive pathway. We recently reported that
halogenated D-homoestrone derivatives can readily be ob-
tained by Lewis acid-catalyzed cyclization of arylimines
Abstract: The Lewis acid-induced cyclization of the 3-methyl and
3-benzyl ethers of an unsaturated secoestrone aldehyde furnished D-
homosteroids containing 16 -oriented halogens on the sterane skel-
eton.
Key words: Lewis acids, intramolecular Prins reaction, fluorina-
tion, stereoselective synthesis, D-homosteroids
The cyclization of olefinic aldehydes by an internal Prins
mechanism is a well-known procedure for the formation
of five-1, six-2 and seven-membered3 rings. The presence
+
-
-
O
C
O
MXn
O
O
MXn
H
C
H
MXn
H
H
H
H
+
H
H
H
H
H
H
R1O
R1O
4
3
1 R1= Me
2 R1= Bn
X-/ R22O
MXn
R2
X
.
5, 10
BF3 OEt2
F
F
Cl
Br
I*
Et
H
H
H
H
OR2
.
6, 11
7, 12
8, 13
9, 14
BF3 OEt2
main stereoisomer
side-product
SnCl4
ZnBr2
H
OH
H
.
β
BF3 OEt2
X
+
X
X
H
H
R1O
α
HO
β
β
H
R1O
OR2
5-14
X
H
H
5-9 R1= Me
10-14 R1= Bn
a
b
c
β
β
α
β
α
β
6a-9a
6b-9b
11a-14a
11b-14b
Jones oxidation
O
O
H
H
X
X
15-22
X
H
H
H
H
a
b
β
α
15, 19
16, 20
17, 21
18, 22
F
Cl
Br
I
R1O
R1O
23 R1= Me
24 R1= Bn
15-18 R1= Me
19-22 R1= Bn
* The iodine is from the NaI applied
Scheme
Synlett 2002, No. 3, 04 03 2002. Article Identifier:
1437-2096,E;2002,0,03,0419,0422,ftx,en;G32801ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

420
É. Frank et al.
LETTER
derived from the normal secoestrone aldehyde (1) and ble isomers was detected (entries 1 and 5). The addition of
substituted anilines.5 All of these reactions exhibited high fluorine in either the 16 or the 16 position can be ex-
chemo- and stereoselectivity, and homoallylic alcohols plained by its small atomic size, comparable to that of hy-
were not produced.
drogen, though particularly 16 -fluorination occurred.
The 17a-ethyl ethers (5a,b, 10a,b), produced by
transetherification of the 17a-hydroxy group with the ap-
plied BF3 OEt2, were also obtained and isolated, but in
overall amounts of less than 5% (entries 1 and 5).
We now describe the ring closure of aldehydes 1 and 2
(Scheme), derived from the 3-methyl and 3-benzyl ethers
of estrone,6 which furnished halo-D-homoestrone deriva-
tives in good yields. Treatment of the aldehyde (1 or 2)
.
with 1.1 equivalents of BF3 OEt2, SnCl4 or ZnBr2 or a 5- The structures of the products were determined by NMR
fold excess of anhydrous NaI in the presence of a catalytic spectroscopy; the stereochemistry at C-16 and C-17a in
.
amount of BF3 OEt2 in CH2Cl2 led chemoselectively to the ring D of the D-homosteroids (6a–9a, 11a–14a) follows
corresponding halohydrins.7–9 Furthermore, all these from the 17a -H doublet-like multiplet at around = 3.2
transformations proceeded in a highly stereoselective (there is a broad singlet at around = 3.5 for 17a -H in
manner, with the 16 -halo-17a -hydroxy-D-homoster- 6b–9b and 11b–14b), and from the 16-H multiplet at
oids (6a–9a, 11a–14a) as main products, and the 16 - around = 3.9-5.0, which corresponds to two diaxial and
halo-17a -hydroxy isomers (6b–9b, 11b–14b) as minor two axial-equatorial couplings.
products (Table, entries 1–8). The favored formation of
The stereoisomerism of the 17a-hydroxy group was also
the 16 ,17a diastereomers can be explained by addition
proved by oxidation. The enantiopure main products and
of the alkene moiety to the intermediate oxonium ion anti
the mixtures of the 17a isomers with Jones reagent (8 N)
to the angular methyl group in 3, which allows the hy-
in acetone10 resulted in 16 -halo-17a-ketones (15a–22a)
droxy group to take up the position. However, the stere-
as main products. By the elimination of hydrogen halides,
oselective addition of the nucleophile to the cation 4 takes
16,17-unsaturated oxo compounds11 (23, 24) were also
place syn to the angular methyl group. This is not surpris-
obtained (Scheme). The halo-ketone and the enone were
found to be produced in a ratio of nearly 2:1 in each reac-
ing since the halo atom probably prefers an equatorial ori-
entation. When BF3 OEt2 in CH2Cl2 was used to prepare
tion (entries 9–16). Oxidation of the 16-fluoro-17a-hy-
fluoro derivatives, one more (6c or 11c) of the four possi-
droxy isomers after separation of the 17a-ethers by
Table Ring Closure of Aldehydes
Entry
1
Substrate(s)
Reagent (equiv)
BF3 OEt2 (1.1)
Overall yield [%]
90
Products
Ratioa
1
5a+5b
5b
6a+6b+6c
65:12:8
2
3
4
5
1
1
1
2
SnCl4 (1.1)
83
84
80
90
7a+7b
8a+8b
9a+9b
73:10
69:15
72:8
ZnBr2 (1.1)
BF3 OEt2 (0.17), NaI (5)
BF3 OEt2 (1.1)
10a+10b
3b
11a+11b+11c
71:9:7
6
7
2
SnCl4 (1.1)
80
85
71
91
97
94
90
95
95
93
91
12a+12b
13a+13b
14a+14b
15a+15b+23
16a+23
75:5
2
ZnBr2 (1.1)
78:7
8
2
BF3 OEt2 (0.17), NaI (5)
65:6
9
6a+6b+6c
7a+7b
8a+8b
9a+9b
11a+11b+11c
12a+12b
13a+13b
14a+14b
Jones
Jones
Jones
Jones
Jones
Jones
Jones
Jones
59:7:25
62:35
63:31
62:28
61:9:25
65:30
60:33
59:32
10
11
12
13
14
15
16
17a+23
18a+23
19a+19b+24
20a+24
21a+24
22a+24
a Determined after purification by column chromatography.
b 5a, 5b and 10a, 10b were not separated in pure form.
Synlett 2002, No. 3, 419–422 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of New D-Homoestrone Derivatives
421
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).
column chromatography also gave the corresponding
16 -fluoro-17a-ketone in small quantities (entries 9 and
13). The 1H NMR spectra of 15–22 reveal that the C-17a-
H signal has disappeared as compared to the spectra of the
corresponding 17a-hydroxy compounds, while the 17-H
double doublet (J = 10.0 Hz, J = 2.0 Hz) at around = 5.9
and the C-16 multiplet at around = 6.9 can be identified
in the spectra of the conjugated derivatives 23 and 24.
(8) Typical Procedure for the Synthesis of 16 -Chloro-D-
homoestra-1,3,5(10)-triene-3,17a-diol-3-methyl Ether
Isomers (7a and 7b): 298 mg (1.00 mmol) of 1 was
dissolved in 5 mL of ice-cold CH2Cl2 and 0.13 mL (278 mg,
1.1 mmol) of anhydrous SnCl4 in 2 mL of CH2Cl2 was added
dropwise during stirring of the mixture under an argon
atmosphere for 2 h. The solution was then diluted with water
(10 mL) and extracted with CH2Cl2 (3 10 mL), and the
combined organic phases were dried over Na2SO4.
In conclusion, this is a simple and efficient synthesis of
halogenated D-homoestrone derivatives involving the use
of different Lewis acids and intramolecular cationic cy-
clization. In addition to its simplicity and the mild reaction
conditions, the method provides products with high selec-
tivity, which makes it a very useful process for the substi-
tution of various halogens onto the sterane skeleton.
Evaporation in vacuo and purification by column
chromatography (silica gel, CH2Cl2) afforded 244 mg (73%)
of 7a and 34 mg (10%) of 7b as white solids. 7a: mp 90–92
°C; Rf 0.27 (EtOAc–CH2Cl2 = 2: 98); 1H NMR (400 MHz,
CDCl3): = 0.88 (s, 3 H, 18-H3), 2.85 (m, 2 H, 6-H2), 3.28
(m, 1 H, 17a -H), 3.78 (s, 3 H, 3-OMe), 3.90 (m, 1 H, 16 -
H), 6.63 (d, 1 H, J4-2 = 2.7 Hz, 4-H), 6.72 (dd, 1 H, J2-1 = 8.6
Hz, J2-4 = 2.7 Hz, 2-H) and 7.21 (d, 1 H, J1-2 = 8.6 Hz, 1-H).
13C NMR (100 MHz, CDCl3): = 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 m/z (relative intensity): 336(37), 334
(M+, 100), 173(13) and 147(7). 7b: mp 92–94 ºC; Rf 0.31
Acknowledgement
We thank the Hungarian Scientific Research Fund (OTKA
T032265) and the Hungarian Ministry of Education (FKFP 0110/
2000) for financial support of this work.
(EtOAc–CH2Cl2 = 2: 98); 1H NMR (500 MHz, CDCl3):
0.91 (s, 3 H, 18-H3), 2.84 (m, 2 H, 6-H2), 3.54 (bs, 1 H, 17a -
H), 3.78 (s, 3 H, 3-OMe), 4.29 (m, 1 H, 16 -H), 6.63 (d, 1 H,
=
References
(1) (a) Andersen, N. H.; Hadley, S. W.; Kelly, J. D.; Bacon, E.
R. J. Org. Chem. 1985, 50, 4144. (b) Ladouceur, G.;
Paquette, L. A. Synthesis 1992, 185. (c) Masse, C. E.;
Dakin, L. A.; Knight, B. S.; Panek, J. S. J. Org. Chem. 1997,
62, 9335. (d) Barbero, A.; Garcia, C.; Pulido, F. J.
Tetrahedron 2000, 56, 2739.
(2) (a) Cheney, D. L.; Paquette, L. A. J. Org. Chem. 1989, 54,
3334. (b) Deguin, B.; Florent, J.-C.; Monneret, C. J. Org.
Chem. 1991, 56, 405. (c) McIntosh, M. C.; Weinreb, S. M.
J. Org. Chem. 1991, 56, 5010. (d) Peron, G. L. N.;
Kitteringham, J.; Kilburn, J. D. Tetrahedron Lett. 1999, 40,
3045.
(3) (a) Schäfer, H.-J.; Baringhaus, K.-H. Liebigs Ann. Chem.
1990, 355. (b) Molander, G. A.; Cameron, K. O. J. Am.
Chem. Soc. 1993, 115, 830. (c) Harmata, M.; Barnes, C. L.
J. Am. Chem. Soc. 1990, 112, 5655.
(4) (a) Balog, A.; Geib, S. J.; Curran, D. P. J. Org. Chem. 1995,
60, 345. (b) Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S.
Synthesis 1990, 646. (c) Snider, B. B. In: Comprehensive
Organic Synthesis, Vol. 2; Trost, B. M.; Fleming, I., Eds.;
Heathcock C. H., Pergamon Press: Oxford, 1991, Part 2,
527.
J
4-2 = 2.7 Hz, 4-H), 6.72 (dd, 1 H, J2-1 = 8.6 Hz, J2-4 = 2.7 Hz,
2-H) and 7.21 (d, 1 H, J1-2 = 8.6 Hz, 1-H). 13C NMR (75
MHz, CDCl3): = 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 m/z (relative intensity): 336(27), 334 (M+, 100),
173(10) and 147(5). C20H27ClO2. The compounds give
correct elemental analyses.
(9) Typical Procedure for the Synthesis of 16 -Bromo-D-
homoestra-1,3,5(10)-triene-3,17a-diol-3-benzyl Ether
Isomers (13a and 13b): A mixture of 375 mg (1 mmol) of
secoestrone-3-benzyl ether 2 and 478 mg (1.00 mmol) of
anhydrous ZnBr2 in 5 mL of CH2Cl2 was heated for 2 h and
then stirred overnight at r.t. The suspension was diluted with
water (10 mL) and neutralized with NaHCO3, the aqueous
phase was extracted with CH2CH2 (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 (silica gel, CH2Cl2)
to give 355 mg (78%) of 13a as a white solid and 31 mg (7%)
of 13b as a yellow oil. 13a: mp 103–105 °C; Rf 0.24
(CH2Cl2); 1H NMR (500 MHz, CDCl3): = 0.90 (s, 3 H, 18-
H3), 2.84 (m, 2 H, 6-H2), 3.27 (m, 1 H, 17a -H), 4.00 (m, 1
(5) (a) Noltemeyer, M.; Tietze, L. F.; Wölfling, J.; Frank, ;
Schneider, G. Acta Cryst. Sect. C 1996, 2258. (b) Wölfling,
J.; Frank, ; Schneider, G.; Tietze, L. F. Synlett 1998, 1205.
(c) Wölfling, J.; Frank, ; Schneider, G.; Tietze, L. F. Eur. J.
Org. Chem. 1999, 3013.
H, 16 -H), 5.02 (s, 2 H, 3-benzyl-CH2), 6.71 (d, 1 H, J4-2
=
2.6 Hz, 4-H), 6.79 (dd, 1 H, J2-1 = 8.6 Hz, J2-4 = 2.6 Hz, 2-H),
7.19 (d, 1 H, J1-2 = 8.6 Hz, 1-H), 7.32 (m, 1 H, 4’-H), 7.38
(m, 2 H, 3’-H and 5’-H) and 7.43 (m, 2 H, 2’-H and 6’-H).
13C NMR (125 MHz, CDCl3): = 10.9 (C-18), 25.9, 26.5,
29.9, 35.4, 36.8, 38.2 (C-16), 38.3 (C-13), 41.5, 43.5 and
47.4 (C-8 and C-9), 48.1 (C-14), 69.9 (3-benzyl-CH2), 78.4
(C-17a), 112.5 (C-2), 114.5 (C-4), 126.2 (C-1), 127.4 (2C,
C-2’ and C-6’), 127.8 (C-4’), 128.5 (2C, C-3’ and C-5’),
132.6 (C-10), 137.2 (C-1’), 137.6 (C-5) and 156.8 (C-3).
(6) Schneider, G.; Bottka, S.; Hackler, L.; Wölfling, J.; Sohár, P.
Liebigs Ann. Chem. 1989, 263.
(7) Spectroscopic Data of 16 -Fluoro-D-homoestra-
1,3,5(10)-triene-3,17a -diol-3-methyl ether(6a): 1H NMR
(400 MHz, CDCl3): = 0.88 (s, 3 H, 18-H3), 2.84 (m, 2 H,
6-H2), 3.27 (m, 1 H, 17a -H), 3.78 (s, 3 H, 3-OMe), 4.54
(dm, 1 H, J = 48.5 Hz, 16 -H), 6.63 (d, 1 H, J4-2 = 2.7 Hz, 4-
H), 6.72 (dd, 1 H, J2-1 = 8.6 Hz, J2-4 = 2.7 Hz, 2-H) and 7.21
(d, 1 H, J1-2 = 8.6 Hz, 1-H). 13C NMR (100 MHz, CDCl3):
= 10.9 (C-18), 25.9 (C-11), 26.6 (C-7), 30.0 (C-6), 30.1 (J =
17.9 Hz, C-15), 34.9 (J = 21.0 Hz, C-17), 36.7 (C-12), 38.8
(C-13), 41.7 (C-8), 43.8 (C-9), 43.9 (J = 10.6 Hz, C-14), 55.2
(3-OMe), 74.6 (J = 11.0 Hz, C-17a), 90.0 (J = 164.1 Hz, C-
13b: Rf 0.37 (CH2Cl2); 1H NMR (500 MHz, CDCl3):
=
0.88 (s, 3 H, 18-H3), 2.83 (m, 2 H, 6-H2), 3.47 (bs, 1 H, 17a -
H), 4.42 (m, 1 H, 16 -H), 5.02 (s, 2 H, 3-benzyl-CH2), 6.71
(d, 1 H, J4-2 = 2.7 Hz, 4-H), 6.78 (dd, 1 H, J2-1 = 8.7 Hz, J2-4
= 2.7 Hz, 2-H), 7.19 (d, 1 H, J1-2 = 8.7 Hz, 1-H), 7.31 (m, 1
Synlett 2002, No. 3, 419–422 ISSN 0936-5214 © Thieme Stuttgart · New York

422
É. Frank et al.
LETTER
H, 4’-H), 7.37 (m, 2 H, 3’-H and 5’-H) and 7.42 (m, 2 H, 2’-
H and 6’-H). 13C NMR (125 MHz, CDCl3): = 17.2 (C-18),
26.0, 26.2, 30.0, 34.2, 36.0, 37.3 (C-13), 39.0 (C-16), 40.5,
42.8 and 43.0 (C-8 and C-9), 48.7 (C-14), 69.9 (3-benzyl-
CH2), 76.8 (C-17a), 112.5 (C-2), 114.5 (C-4), 126.2 (C-1),
127.4 (2C, C-2’ and C-6’), 127.8 (C-4’), 128.5 (2C, C-3’ and
C-5’), 132.8 (C-10), 137.3 (C-1’), 137.8 (C-5) and 156.8 (C-
3), EI MS m/z (relative intensity): 456(12), 454 (M+, 13) and
91(100). C26H31O2Br. The compounds give correct
elemental analyses.
solids. 16a: mp 130–132 °C; Rf 0.53 (PE–CH2Cl2 = 20:80);
1H NMR (500 MHz, CDCl3): = 1.15 (s, 3 H, 18-H3), 2.86
(m, 2 H, 6-H2), 3.76 (s, 3 H, 3-OMe), 4.00 (m, 1 H, 16 -H),
6.62 (d, 1 H, J4-2 = 2.7 Hz, 4-H), 6.71 (dd, 1 H, J2-1 = 8.6 Hz,
J
2-4 = 2.7 Hz, 2-H) and 7.19 (d, 1 H, J1-2 = 8.6 Hz, 1-H). 13
C
NMR (125 MHz, CDCl3): = 16.8 (C-18), 25.6, 26.6, 29.8,
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). C20H25ClO2. 23: mp: 159–161 °C, Rf 0.31
(PE–CH2Cl2 = 20:80); 1H NMR (500 MHz, CDCl3): = 1.05
(s, 3 H, 18-H3), 2.87 (m, 2 H, 6-H2), 3.77 (s, 3 H, 3-OMe),
5.95 (m, 1 H, 16-H), 6.63 (d, 1 H, J4-2 = 2.7 Hz, 4-H), 6.72
(dd, 1 H, J2-1 = 8.6 Hz, J2-4 = 2.7 Hz, 2-H), 6.88 (m, 1 H, 17-
H) and 7.22 (d, 1 H, J1-2 = 8.6 Hz, 1-H). 13C NMR (125 MHz,
CDCl3): = 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). C20H24O2. The compounds give correct
elemental analyses.
(10) Typical Procedure for the Oxidation of 16 -Chloro-D-
homoestra-1,3,5(10)-triene-3,17a-diol-3-methyl Ether
Isomers. 0.35 mL of Jones reagent (8 N) was added
dropwise to 335 mg (1.00 mmol) of pure 7a or a mixture of
7a and 7b in 4 mL of ice-cold acetone, and the solution was
stirred until complete conversion (TLC) was achieved (1 h).
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, and the crude product was purified by column
chromatography (silica gel, PE–CH2Cl2 = 20:80) to afford
206 mg (62%) of 16a and 104 mg (35%) of 23 as white
(11) Johns, W. F.; Salamon, K. W. J. Org. Chem. 1971, 36, 1952.
Synlett 2002, No. 3, 419–422 ISSN 0936-5214 © Thieme Stuttgart · New York