Ortho-Formylation of estrogens. Synthesis of the anti-cancer agent 2-methoxyestradiol

Article abstract of DOI:10.1016/j.tet.2011.08.005

Several estrogens were mono-formylated using a mixture of paraformaldehyde, MgCl₂, and Et₃N in refluxing THF. In all cases, the 2-isomer was formed as the major product with high regioselectivity compared to the 4-isomer. Excellent to high yields were obtained in all examples except one. The method was applied for an efficient synthesis of the anti-cancer agent 2-methoxyestradiol.

Full text of DOI:10.1016/j.tet.2011.08.005

Tetrahedron 67 (2011) 7738e7742
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Tetrahedron
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ortho-Formylation of estrogens. Synthesis of the anti-cancer agent
2-methoxyestradiol
*
Øyvind W. Akselsen, Trond Vidar Hansen
School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068, Blindern, N-0316 Oslo, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 April 2011
Received in revised form 18 July 2011
Accepted 2 August 2011
Available online 6 August 2011
Several estrogens were mono-formylated using a mixture of paraformaldehyde, MgCl2, and Et3N in re-
fluxing THF. In all cases, the 2-isomer was formed as the major product with high regioselectivity
compared to the 4-isomer. Excellent to high yields were obtained in all examples except one. The method
was applied for an efficient synthesis of the anti-cancer agent 2-methoxyestradiol.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
ortho-Formylation
Estrogens
2-Methoxyestradiol
1. Introduction
several classical formylation reactions.5 Unfortunately, the yields
are often only moderate and the lack of regioselectivity is apparant.6
Estrogens exhibit many interesting biological activities and
several are used as pharmaceuticals (Fig. 1). The synthesis of es-
trogens and their derivatives continues to attract interest as it is
evident from the numerous studies that have been reported over
the last five decades.1,2
Moreover, the reaction conditions are quite harsh and often envi-
ronmentally disagreeable reagents must be employed. The recently
reported regioselective ortho-formylation of substituted phenols
using the MgCl2eEt3N base system and paraformaldehyde yields
salicylaldehydes in excellent yields.7 This method has been
employed for the preparation of useful intermediates and natural
products.8 We wanted to investigate if this methodology could be
applied in regioselective formylation of estrogens. Taylor and co-
workers have used this method for the synthesis of 4-substituted
salicylaldehydes of estrone derivatives that were protected in the
2-position; however, the regioselectivity was not an issue for these
examples.9 Herein a practical, regioselective, and operationally
simple procedure for the formylation of estrogens 2, 6e12 is
reported. Furthermore, this procedure was applied in a practical and
scalable synthesis of 2-methoxyestradiol (1).
Fig. 1. Examples of bioactive estrogens.
One example of a bioactive estrogen is 2-methoxyestradiol (1)
that exhibits promising anti-cancer activity and has entered clinical
trials.3 Several syntheses of 1 have been reported;4 however, most of
them are hampered by problems, such as low yields and formation
of both 2- and 4-regioisomers by protocols that are not easily
adaptable for large scale preparations. Hence, improved synthetic
routes are still desired. One attractive approach for a preparative
scale synthesis of 2-methoxyestradiol (1) is by regioselective ortho-
formylation of estradiol (2) to its 2-substituted salicylaldehyde.
Salicylaldehydes are accessible from the corresponding phenols by
2. Results and discussion
When estradiol (2) was reacted with
4 equiv of para-
formaldehyde in the presence of 3 equiv of both MgCl2 and Et3N,
the regioisomeric aldehydes 13a and 13b were obtained in an ex-
cellent 92% yield (Table 1). According to LC/MS and 1H NMR anal-
yses the regioisomeric ratio was determined to be 13:1 in favor of
the 2-substituted aldehyde 13a. The aldehydes 14a and 14b were
obtained in 86% yield when 17a ethinyl estradiol (6) was reacted
under the same conditions; in this case the regioisomeric ratio was
6:1 in favor of 14a.
* Corresponding author. Tel.: þ47 22857450; fax: þ47 22855947; e-mail address:
t.v.hansen@farmasi.uio.no (T.V. Hansen).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.005

Ø.W. Akselsen, T.V. Hansen / Tetrahedron 67 (2011) 7738e7742
7739
Table 1
ortho-Formylation of estrogens
Estrogen
R1
R2
R3
Product
Regioisomeric ratioa
Yieldc
%
2
6
7
8
OH
OH
OH
H
OAc
OH
]O
H
H
H
H
H
H
OH
H
13a:13b
14a:14b
15a:15b
16a:16b
17a:17b
18a:18b
19a:19b
20a:20b
13:1
6:1
92
86
90
85
90
15
90
74d
CCH
CH2CH3
OH
H
H
12:1
13:1
8:1
9
10
11
12
n.d.b
9:1
OCH2CH2O
H
12:1
a
The regioisomeric ratios of the salicylaldehydes were determined by LC/MS analysis.
Not determined.
The yields and regioisomeric ratios are based on three experiments. The regioisomeric ratios were constant in all experiments.
b
c
d
A 12:1 regioisomeric mixture of 19a and 19b was also obtained in 14% isolated yield.
Reacting 17
a
ethyl estradiol (7) under the aforementioned
also observed in the reaction mixture. These esters were identified
by LC/MS and 1H NMR analyses and were easily hydrolyzed with
aqueous LiOH in methanol before work-up and chromatography
yielded the target salicylaldehydes. Several other groups have also
observed the formation of these esters in much higher yields when
a combination of EtMgBr, HMPA, and paraformaldehyde in benzene
at reflux was employed,10 rendering support for the advantages for
our protocol. Structural assignments of all products were based on
spectral data and by comparison with literature values.4j,6b,10a,11
The ortho-formylation procedure with the MgCl2/Et3N-base sys-
tem was employed in an efficient synthesis of the anti-cancer agent
2-methoxyestradiol (1). Again, formylation of estradiol (2) afforded
a 13:1 mixture of 13a and 13b. This mixture of aldehydes was con-
verted to the MOM-protected aldehydes 21a and 21b under standard
conditions.12 Separation by column chromatography yielded 21a in
60% isolated yield over the three steps. Applying the Dakin oxida-
tion13 conditions to 21a gave the corresponding phenol 22 in 86%
yield with physical and spectral data in accord with those previously
reported.4j Methylation of the phenol 22 under known conditions
yielded compound 23 that was deprotected14 to 2-methoxyestradiol
(1) in 70% yield over the two last steps (Scheme 1). Thus, starting
from 2, a synthesis of 1 was achieved in 36% overall yield.
conditions afforded the two regioisomers 15a and 15b in 90% yield
in a 12:1 ratio, respectively.
The 17
a
epimer 8 yielded comparable results using this ortho-
-acetate 9
formylationprotocol, affording 16a and 16b. When the 17
b
was formylated with the MgCl2/Et3N-base system, aldehydes 17a
and 17b were formed as 8:1 mixture in a combined 90% yield. Again
the 2-substituted aldehyde was the major product. Disappointingly,
estriol (10) yielded only 15% yield of the two aldehydes 18a and 18b.
On the other hand, when estrone (11) was subjected to the afore-
mentioned formylation conditions, a mixture of the isomers 19a and
19b was formed in a combined 90% yield. Formylation of the acetal
protected estrone 12 afforded a regioisomeric ratio of 12:1 in favor of
the 2-substituted regioisomer 20a. Deprotection of the acetal group
in 12 occurred under the slightly acidic work-up conditions; the
aldehydes 19a and 19b were also isolated in a combined 14% yield
after chromatography (Table 1). Increasing the amount of MgCl2,
Et3N or paraformaldehyde did not alter the regioisomeric outcome
in any of the reactions. Changing the solvent resulted in complex
reaction mixtures and significantly lower yields of the ortho-for-
mylated products. In the ortho-formylation of estradiol (2) and its
epimer 8 less than 10% of the corresponding 17-formate esters were
Scheme 1. Synthesis of 2-methoxyestradiol (1).

7740
Ø.W. Akselsen, T.V. Hansen / Tetrahedron 67 (2011) 7738e7742
3. Conclusion
2-carbaldehyde (15a). Purification by chromatography (hexane/
EtOAc, 9:1e8:2) afforded a colorless solid (131 mg, 80%) with mp
In conclusion, the experimentally simple and regioselective or-
tho-formylation protocol of phenols was extended to several es-
trogens. All but one of the formylations occurred with high to
excellent yields. In all cases, formation of the 2-isomer was highly
preferred. The practical use of this method was proven with an
efficient synthesis of the anti-cancer agent 2-methoxyestradiol (1).
Our synthesis compares favorably with respect to simplicity, yield
and especially regioselectivity with those reported.4
157e158 ꢁC (CHCl3) (lit.4b mp 156e157 ꢁC); Rf 0.26 (hexane/EtOAc,
8:2); IR (KBr, cmꢂ1
CDCl3)
) n
: 3487, 3413, 3318, 1653; 1H NMR (300 MHz,
d
¼10.74 (s, 1H), 9.77 (s, 1H), 7.38 (s, 1H), 6.65 (s, 1H),
2.91e2.78 (m, 2H), 2.31 (m, 1H), 2.11 (m, 1H), 2.03e1.92 (m, 1H),
1.92e1.81 (m, 1H), 1.69e1.18 (m, 12H), 0.98 (t, J¼7.3 Hz, 3H), 0.89 (s,
3H); 13C NMR (75 MHz, CDCl3)
d
¼196.1, 159.2, 148.1, 132.8, 130.4,
118.9, 116.9, 83.4, 49.5, 46.5, 43.2, 39.2, 33.6, 31.3, 30.2, 28.8, 27.0,
26.2, 23.3, 14.4, 7.8; LC/MS [Mꢃþꢂ1] 327; ½a D20
þ51.8 (c 0.50, THF).
ꢄ
4. Experimental section
4.1. General
4.2.4. (8R,9S,13S,14S,17S)-17-Ethyl-3,17-dihydroxy-13-methyl-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-
4-carbaldehyde (15b). 1H NMR (200 MHz, CDCl3)
d
¼11.96 (s, 1H),
10.34 (s, 1H), 7.45 (d, J¼9.0 Hz, 1H), 6.75 (d, J¼8.9 Hz, 1H).
All reagents and solvents were used as purchased without fur-
ther purification unless stated otherwise. Melting points are un-
corrected. Analytical TLC was performed using silica gel 60 F254
glass plates (Merck). Flash column chromatography was performed
on silica gel 60 Geduran (35e75 mm, EM Science). IR spectra were
obtained on a PerkineElmer Spectrum BX series FT-IR spectro-
photometer only selected peaks are reported. NMR spectra were
recorded on a Bruker Avance DPX-300 MHz or DPX200 spectrom-
eter for 1H NMR and 75 or 50 MHz for 13C NMR, respectively.
Coupling constants (J) are reported in hertz, and chemical shifts are
reported in parts per million relative to CDCl3 (7.24 ppm for 1H and
77.0 ppm for 13C) and DMSO-d6 (2.50 ppm for 1H, 39.52 ppm for
13C). Mass spectra were recorded at 70 eV with Fission’s VG Pro
spectrometer. High resolution mass spectra were performed with
a VG Prospec mass spectrometer and with a Micromass Q-TOF-2Ô.
The LC/MS analyses were performed on an Agilent Technologies
4.2.5. (8R,9S,13S,14S,17S)-2-Formyl-3-hydroxy-13-methyl-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta-[a]phenanthren-
17-yl acetate (17a). An analytical sample was made according to
Peters et al.:10e mp 181e182 ꢁC (hexane/EtOAc) ꢂ1(lit.11 mp
184e185 ꢁC); Rf 0.50 (hexane/EtOAc, 2:1); IR (KBr, cm
) n: 3427,
1728, 1652; 1H NMR (300 MHz, CDCl3)
7.38 (s, 1H), 6.66 (s, 1H), 4.67 (t, J¼8.4 Hz, 1H), 2.93e2.75 (m, 2H),
2.37e2.08 (m, 3H), 2.04 (s, 3H), 1.95e1.81 (m, 2H), 1.79e1.63 (m,
1H), 1.61e1.16 (m, 8H), 0.81 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
¼10.74 (s, 1H), 9.78 (s, 1H),
d
¼196.0, 171.1, 159.2, 147.9, 132.5, 130.5, 118.9, 116.9, 82.5, 49.7, 43.2,
42.8, 38.1, 36.6, 30.0, 27.5, 26.7, 26.0, 23.2, 21.1, 12.0; LC/MS [Mꢃþꢂ1]
341; ½a 2D0
þ52.6 (c 0.50, THF).
ꢄ
4.2.6. (8R,9S,13S,14S,17S)-4-Formyl-3-hydroxy-13-methyl-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta-[a]phenanthren-
1200 Series (Eclipse XDB-C18 5
Agilent 6310 ion Trap.
m
m 4.6ꢀ150 mm), coupled with an
17-yl acetate (17b). 1H NMR (200 MHz, CDCl3)
(s, 1H), 7.38 (d, J¼9.0 Hz, 1H), 6.68 (d, J¼8.8 Hz, 1H).
d
¼11.90 (s, 1H), 10.27
4.2. General procedure for the ortho-formylation of estrogens
4. 2. 7 . ( 8R, 9S ,13S ,14S )-3 -Hyd ro xy- 13- methyl-17 -o xo-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta-[a]phenanthrene-
2-carbaldehyde (19a). Purification by chromatography (hexane/
EtOAc, 9:1e8:2) afforded a colorless solid (459 mg, 77%) with mp
164e165 ꢁC (hexane/EtOAc) (lit.6b,10a mp 158e160 ꢁC (CHCl3)); Rf
To a solution of the estrogen (1 mmol) in dry THF (10 mL), an-
hydrous MgCl2 (285 mg, 3 mmol), Et3N (0.42 mL, 3 mmol), and
paraformaldehyde (120 mg, 4 mmol) were added under an argon
atmosphere. The reaction mixture was heated to reflux for 1e2 h,
and monitored by TLC (hexane/EtOAc, 7:3). After complete con-
sumption of the estrogen, the reaction mixture was cooled and
quenched (1 M HCl, 10 mL). The aqueous phase was extracted with
EtOAc (3ꢀ10 mL) and the combined organic phases were washed
with brine and then dried (MgSO4). Analytical pure samples were
obtained by column chromatography or recrystallization.
0.26 (hexane/EtOAc 7:3); IR (KBr, cmꢂ1
NMR (300 MHz, CDCl3):
) n
: 3449, 1736, 1651; 1H
d
¼10.76 (s, 1H), 9.79 (s, 1H), 7.40 (s, 1H),
6.69 (s, 1H), 3.01e2.79 (m, 2H), 2.50 (dd, J¼18.4, 8.3 Hz, 1H), 2.39 (s,
1H), 2.29e1.92 (m, 5H), 1.69e1.34 (m, 6H), 0.90 (s, 3H); 13C NMR
(75 MHz, CDCl3):
d
¼196.5, 159.7, 148.1, 132.5, 130.9, 119.4, 117.5,
50.8, 48.3, 43.8, 38.4, 36.2, 31.8, 30.4, 26.5, 26.2, 22.0, 14.2. LC/MS
[Mꢃþꢂ1] 297; ½a 2D0
ꢄ
þ130 (c 0.50, THF), ½a D20
þ85.0 (c 0.50, CHCl3)
ꢄ
(lit.11a
½ ꢄ þ151 (CHCl3)).
a D
4.2.1. (8R,9S,13S,14S,17R)-17-Ethynyl-3,17-dihydroxy-13-methyl-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta-[a]phenanthrene-
2-carbaldehyde (14a). Purification by recrystallization from Et2O
afforded a colorless solid (209 mg, 65%) with mp 201e202 ꢁC (Et2O)
(lit.10a mp 210e215 ꢁC); Rf 0.51 (hexane/acetone, 6:4); IR (KBr,
4. 2. 8 . ( 8R, 9S ,13S ,14S )-3 -Hyd ro xy- 13- methyl-17 -o xo-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta-[a]phenanthrene-
4-carbaldehyde (19b). Purification by chromatography (hexane/
EtOAc, 9:1e8:2) yellow solid (36 mg, 6%) with mp 244e247 ꢁC
(decomp., EtOAc) (lit.6b mp 244e246 ꢁC (EtOAc)); Rf 0.26 (hexane/
cmꢂ1 : 3488, 3255, 2102, 1659; 1H NMR (300 MHz, CDCl3)
) n
d
¼10.75 (s, 1H), 9.79 (s, 1H), 7.40 (s, 1H), 6.67 (s, 1H), 2.86 (s, 2H),
2.59 (s, 1H), 2.45e2.10 (m, 3H), 2.10e1.24 (m, 11H), 0.88 (s, 3H); 13C
NMR (75 MHz, CDCl3)
¼196.1, 159.2, 148.0, 132.6, 130.5, 118.9,
EtOAc 7:3); IR (KBr, cmꢂ1
CDCl3)
) n
: 3440, 1734, 1644; 1H NMR (300 MHz,
¼11.99 (s, 1H), 10.40 (s, 1H), 7.48 (d, J¼8.9 Hz, 1H), 6.81 (d,
d
d
J¼8.9 Hz, 1H), 3.38 (dd, J¼16.9, 5.7 Hz, 1H), 3.27e3.07 (m, 1H), 2.52
(dd, J¼18.3, 8.5 Hz, 1H), 2.42e1.86 (m, 6H), 1.76e1.35 (m, 7H), 0.92
116.9, 87.4, 79.7, 74.1, 49.4, 47.0, 42.9, 39.0, 38.9, 32.5, 30.1, 26.7,
26.2, 22.7, 12.6; LC/MS [Mꢃþꢂ1] 323; ½a D20
ꢄ
ꢂ27.0 (c 0.50, THF).
(s, 3H); 13C NMR (75 MHz, CDCl3)
d
¼195.5, 161.6, 139.3, 135.4, 131.1,
117.5, 115.9, 50.1, 47.8, 43.9, 37.5, 35.8, 31.5, 26.1, 26.0, 25.4, 21.5,
4.2.2. (8R,9S,13S,14S,17R)-17-Ethynyl-3,17-dihydroxy-13-methyl-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta-[a]phenanthrene-
13.8; LC/MS [Mꢃþꢂ1] 297; ½a D20
þ123 (c 0.50, THF).
ꢄ
4-carbaldehyde (14b). 1H NMR (200 MHz, CDCl3)
10.36 (s, 1H), 7.47 (d, J¼8.9 Hz, 1H), 6.77 (d, J¼9.2 Hz, 1H).
d
¼11.97 (s, 1H),
4.2.9. (8R,9S,13S,14S)-3-Hydroxy-13-methyl-6,7,8,9,11,12,13,14,15,16-
decahydrospiro[cyclopenta[a]-phenanthrene-17,20-[1,3]dioxolane]-2-
carbaldehyde (20a). Purification by chromatography (hexane/
EtOAc, 9:1e8:2) afforded a colorless solid (67 mg, 64%) with mp
128e129 ꢁC; (lit.10a mp 129e131 ꢁC) Rf 0.43 (hexane/acetone, 1:3);
4.2.3. (8R,9S,13S,14S,17S)-17-Ethyl-3,17-dihydroxy-13-methyl-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]-phenanthrene-

Ø.W. Akselsen, T.V. Hansen / Tetrahedron 67 (2011) 7738e7742
7741
IR (KBr, cmꢂ1
)
n
: 3420, 1653; 1H NMR (200 MHz, CDCl3)
d¼10.74 (s,
þ27.0 (c 1.00, THF); HRMS calcd for C19H23O3 [Mꢃþ]: 300.1725.
1H), 9.78 (s,1H), 7.38 (s,1H), 6.66 (s,1H), 4.01e3.78 (m, 4H), 3.11 (m,
1H), 2.93e2.73 (m, 2H), 2.24 (m, 2H), 2.09e1.15 (m, 11H), 0.86 (s,
Found 300.1729.
3H); 13C NMR (75 MHz, CDCl3)
d
¼196.0, 159.2, 148.1, 132.8, 130.5,
4. 3. 4. (8R, 9S,13S,14S,17R)-3,17-Dihydroxy-13-methyl-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta-[a]phenanthrene-
119.2, 118.9, 116.9, 65.2, 64.5, 49.3, 46.0, 43.0, 38.6, 34.1, 30.4, 30.1,
26.5, 26.0, 22.3, 14.3; LC/MS [Mꢃþꢂ1] 341; ½a D20
ꢄ
þ60.2 (c 0.50, THF).
4-carbaldehyde (16b). 1H NMR (200 MHz, CDCl3)
10.31 (s, 1H), 7.41 (d, J¼9.0 Hz, 1H), 6.72 (d, J¼8.7 Hz, 1H).
d
¼11.92 (s, 1H),
4 . 2 . 1 0 . ( 8 R , 9 S , 1 3 S , 1 4 S ) - 3 - H y d r o x y - 1 3 - m e t h y l -
6,7,8,9,11,12,13,14,15,16-decahydrospiro[cyclopenta[a]-phenanthrene-
17,20-[1,3]dioxolane]-4-carbaldehyde (20b). 1H NMR (200 MHz,
4.3.5. (8R,9S,13S,14S,17S)-3,17-Bis(methoxymethoxy)-13-methyl-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta-[a]phenanthrene-
2-carbaldehyde (21a). The mixture of aldehydes 13a and 13b
obtained from the ortho-formylation reaction of estradiol (2,
1 mmol) was dissolved in dry THF (3 mL) in a flame dried round
bottle flask. Diisopropylethylamine (1 mL, 6.4 mmol) and chlor-
CDCl3)
J¼8.8 Hz, 1H).
d
¼11.95 (s, 1H), 10.34 (s, 1H), 7.45 (d, J¼8.9 Hz, 1H), 6.75 (d,
4.3. Hydrolysis of 17-formate esters
omethyl methyl ether (400 mL, 5.3 mmol) was added. The reaction
mixture was heated to reflux for 4 h before being cooled to room
temperature where upon H2O (10 mL) was added and the reaction
mixture was extracted with Et2O (3ꢀ10 mL). The combined organic
phases were washed with aqueous AcOH (10%, 5 mL) and aqueous
NaHCO3 solution (10 mL), dried (MgSO4) and concentrated. Purifi-
cation by chromatography (heptane/EtOAc, 9:1 to 6:4) yielded 21a
as a yellow semi solid (232 mg, 60% over two steps). Rf 0.43 (hex-
The crude reaction mixture was suspended in methanol (33 mg/
mL) and LiOH (2 M, 1 mL) was added and an exothermic reaction
occurred. The reaction mixture became instantly yellow. The re-
action mixture was stirred for 15 min before HCl (1 M) was added
until the reaction mixture became acidic, where after the reaction
mixture was extracted with EtOAc (2ꢀ10 mL). The combined or-
ganic phases were washed with brine and dried (MgSO4). LC/MS-
and 1H NMR-analyses showed complete hydrolysis of the 17-
formate. The hydrolysis did not change the 2- and 4-
regioisomeric ratio.
ane/acetone, 3:1); IR (KBr, cmꢂ1
(300 MHz, CDCl3)
) n
: 3417, 1675, 1607; 1H NMR
d¼10.40 (s, 1H), 7.74 (s, 1H), 6.88 (s, 1H), 5.24 (s,
2H), 4.69e4.57 (m, 2H), 3.59 (t, J¼8.4 Hz, 1H), 3.49 (s, 3H), 3.35 (s,
3H), 2.92e2.81 (m, 2H), 2.36 (ddd, J¼12.8, 6.9, 3.7 Hz, 1H),
2.22e1.77 (m, 4H), 1.77e1.03 (m, 8H), 0.78 (s, 3H); 13C NMR
4. 3.1. (8R, 9S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]-phenanthrene-
2-carbaldehyde (13a). Purification by chromatography (hexane/
THF, 5:1e3:2) afforded a colorless solid (1.23 g, 82%) with mp
232e234 ꢁC (hexane/THF) (lit.6b,10a mp 231e233 ꢁC (EtOH)); Rf 0.48
(75 MHz, CDCl3)
d
¼189.5, 157.5, 146.3, 134.5, 125.3, 123.3, 115.0,
96.0, 94.6, 86.4, 56.4, 55.2, 50.0, 43.7, 42.9, 38.3, 37.0, 30.4, 28.0,
26.8, 26.1, 23.1, 11.7; ½a D20
þ60.2 (c 0.50, THF); HRMS calcd for
ꢄ
C23H32O5 [Mꢃþ]: 388.2250. Found 388.2265.
(hexane/THF, 3:2); IR (KBr, cmꢂ1
CDCl3)
)
n
: 3358, 1657; 1H NMR (300 MHz,
4.3.6. (8R,9S,13S,14S,17S)-3,17-Bis(methoxymethoxy)-13-methyl-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta-[a]phenanthren-
2-ol (22). A solution of m-chloroperbenzoic acid (77%, 360 mg,
1.6 mmol) in CH2Cl2 (5 mL) was added drop wise to a solution of 21a
(320 mg, 0.8 mmol) in a mixture of CH2Cl2 (7 mL) and sodium
hydrogenphosphate dihydrate (425 mg, 2.4 mmol). The resulting
mixture was stirred at room temperature for 24 h, the reaction mix-
turewas poured into H2O (25 mL) and the product wasextracted with
Et2O (3ꢀ40 mL). The organic layers were washed with saturated
NaHCO3 solution (25 mL), brine (2ꢀ25 mL), and then combined. The
organic phases were dried (MgSO4), and evaporation afforded a yel-
lowoilthatwasdissolvedinMeOH(5mL). Then1 M NaOH(3mL)was
added and the resulting mixture was stirred at room temperature for
2 h. The solution was neutralized to pH 7 with 1:1 NaHCO3/AcOH
solution (15 mL), then methanol was removed under reduced pres-
sure, and the residue was transferred into a mixture of EtOAc and
water (1:1, 50 mL). The aqueous phase was extracted with a second
portion of EtOAc (20 mL). The combined EtOAc fractions were dried
(MgSO4) and evaporated. The product (270 mg, 90%) was pure by 1H
NMR analysis, but was further purified by chromatography on silica
gel (heptane/EtOAc 9:1 to 7:3) affording compound 22 as a colorless
d
¼10.75 (s, 1H), 9.79 (s, 1H), 7.40 (s, 1H), 6.68 (s, 1H),
3.78e3.63 (m, 1H), 2.96e2.76 (m, 2H), 2.33 (ddd, J¼12.9, 6.9, 4.0 Hz,
1H), 2.23e2.03 (m, 2H), 2.03e1.93 (m, 1H), 1.93e1.82 (m, 1H),
1.78e1.61 (m, 1H), 1.46 (s, 9H), 0.77 (s, 3H); 13C NMR (75 MHz,
CDCl3)
d
¼196.1, 159.2, 148.1, 132.7, 130.5, 119.0, 117.0, 81.8, 50.0,
43.4, 43.2, 38.4, 36.5, 30.6, 30.1, 26.7, 26.2, 23.1, 11.0; LC/MS [Mꢃþꢂ1]
299; ½a 2D0
ꢄ
þ89.0 (c 0.50, THF), ½a D20
ꢄ
þ140 (c1.00, dioxane) (lit.11b
½
a 2D0
ꢄ
þ88.0 (c 1.00, dioxane)).
4. 3. 2. (8R, 9S,13S,14S,17S)-3,17-Dihydroxy-13-methyl-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]-phenanthrene-
4-carbaldehyde (13b). Purification by chromatography (hexane/
THF, 5:1e3:2) afforded pale yellow crystals (71 mg, 5%) with mp
150e151 ꢁC (CHCl3) (lit.6b mp 144e145 ꢁC (MeOH)); Rf 0.48 (hex-
) n
ane/THF, 3:2); IR (KBr, cmꢂ1 : 3451, 1640; 1H NMR (300 MHz,
CDCl3)
d
¼11.99 (s, 1H), 10.37 (s, 1H), 7.48 (d, J¼8.8 Hz, 1H), 6.79 (d,
J¼8.8 Hz, 1H), 3.74 (t, J¼8.1 Hz, 1H), 3.32 (dd, J¼16.9, 5.1 Hz, 1H),
3.24e2.99 (m, 1H), 2.40e1.08 (m, 15H), 0.79 (s, 3H); 13C NMR
(75 MHz, CDCl3)
d
¼195.7, 161.4, 139.5, 135.5, 131.6, 117.5, 115.6, 81.7,
49.7, 43.8, 43.1, 37.9, 36.6, 30.6, 26.7, 26.5, 25.5, 23.0, 11.0; LC/MS
[Mꢃþꢂ1] 299; ½a 2D0
ꢄ
þ94.8 (c 0.25, THF).
oil (258mg, 86%). Rf 0.35 (heptane/EtOAc, 3:2); IR (KBr, cmꢂ1
1H NMR (300 MHz, CDCl3)
) n: 3545;
d¼6.87 (s,1H), 6.77 (s,1H), 5.95 (s,1H), 5.13
4.3.3. (8R,9S,13S,14S,17R)-3,17-Dihydroxy-13-methyl-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-
2-carbaldehyde (16a). Purification by chromatography (hexane/
THF, 9:1e8:2) afforded a colorless solid (50 mg, 69%) with mp
181e182 ꢁC (hexane/THF); Rf 0.30 (hexane/acetone, 3:1); IR (KBr,
(s, 2H), 4.65(s, 2H), 3.59 (t, J¼8.4 Hz,1H), 3.49 (s, 3H), 3.36(s, 3H), 2.75
(dd, J¼10.6, 4.5 Hz, 2H), 2.23e1.95 (m, 3H), 1.90e1.76 (m, 1H),
1.75e1.06 (m, 8H), 0.79 (s, 3H); 13C NMR (75 MHz, CDCl3)
d¼144.0,
142.3, 135.0, 128.2, 115.8, 112.3, 95.9, 86.5, 56.2, 55.0, 49.9, 44.0, 42.8,
38.4, 37.2, 29.0, 28.0, 27.3, 26.2, 23.0, 11.6; ½a D20
þ48.8 (c 0.50, THF);
ꢄ
cmꢂ1
)
n
: 3339, 1655; 1H NMR (300 MHz, CDCl3)
d
¼10.75 (s, 1H),
HRMS calcd for C22H32O5 [Mꢃþ]: 376.2250. Found 376.2253.
9.79 (s, 1H), 7.42 (s, 1H), 6.68 (s, 1H), 3.80 (d, J¼5.8 Hz, 1H),
2.96e2.75 (m, 2H), 2.45e2.32 (m, 1H), 2.29e2.12 (m, 2H), 1.99e1.71
(m, 3H), 1.71e1.13 (m, 9H), 0.69 (s, 3H); 13C NMR (75 MHz, CDCl3)
4.3.7. (8R,9S,13S,14S,17S)-2-Methoxy-3,17-bis(methoxymethoxy)-13-
methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phen-
anthrene (23). A solution of 22 (380 mg,1 mmol) in anhydrous DMF
(15 mL) containing anhydrous K2CO3 (1.38 g,10 mmol) was stirred at
d
¼196.1, 159.2, 148.2, 132.8, 130.5, 118.9, 116.9, 79.9, 47.7, 45.5, 43.1,
38.7, 32.5, 31.3, 30.3, 27.6, 26.1, 24.2, 17.0; LC/MS [Mꢃþꢂ1] 299; ½a D20
ꢄ

7742
Ø.W. Akselsen, T.V. Hansen / Tetrahedron 67 (2011) 7738e7742
€
(d) Corey, E. J.; Kurti, L. Enantioselective Chemical Synthesis; Direct Book Publishing:
Dallas, Texas, 2010, pp 258e260, and references cited therein.
room temperature for 10 min. Iodomethane (781 mg, 5.5 mmol) was
introduced into the reaction mixture, followed by the addition of
tetra-butylammoniumiodide (8.5 mg, 0.03 mmol). The resulting
mixture was stirred at room temperature for 5 h and then another
portion of iodomethane (781 mg, 5.5 mmol) was introduced. After
20 h, the reaction mixture was poured into brine (20 mL) and the
products were extracted with EtOAc (3ꢀ10 mL). The EtOAc layers
were washed with brine (20 mL) and several portions of H2O,
combined, dried (MgSO4), and evaporated todryness. Purificationby
flash chromatography (heptane/EtOAc, 9:1 to 7:3) gave 23 (331 mg,
85%) as a colorless oil. Rf 0.50 (heptane/EtOAc,1:1). Recrystallization
fromMeOH yielded a colorlesssolidꢂw1ith mp 68e70ꢁC (MeOH) (lit.4j
2. Selected examples: (a) Ananchenko, S. N.; Torgov, I. V. Tetrahedron Lett. 1963, 19,
1553e1558; (b) Hu, Q.-Y.; Rege, P. D.; Corey, E. J. J. Am. Chem. Soc. 2004, 126,
5984e5986; (c) Herrmann, P.; Budesinsky, M.; Kotora, M. J. Org. Chem. 2008, 73,
6202e6206; (d) Soorukram, D.; Knochel, P. Org. Lett. 2007, 9, 1021e1023; (e)
ꢀ
ꢀ
Eignerova, B.; Sedlak, D.; Dracínsky, M.; Bartunek, P.; Kotora, M. J. Med. Chem.
ꢀ
ꢀ
2010, 53, 6947e6953; (f) Sedlak, D.; Novak, P.; Kotora, M.; Bartunek, P. J. Med.
Chem. 2010, 53, 4290e4294; (g) Farhane, S.; Fournier, M.-F.; Maltais, R.; Poirier,
D. Tetrahedron 2011, 67, 2434e2440.
3. (a) Sutherland, T. E.; Anderson, R. L.; Hughes, R. A.; Altmann, E.; Schuliga, M.;
Ziogas, J.; Stewart, A. G. Drug Discov. Today 2007, 13, 577e584; (b) Lakhani, N. J.;
Sarkar, M. A.; Venitz, J.; Figg, W. D. Pharmacotherapy 2003, 23, 165e172; (c)
Seegers, J. C.; Aveling, M.-L.; van Aswegen, C. H.; Cross, M.; Koch, F.; Joubert, W.
S. J. Steroid Biochem. 1989, 32, 797e809; (d) Fotsis, T.; Zhang, Y.; Pepper, M. S.;
Adlercreutz, H.; Montesano, R.; Nawroth, P. P.; Schweigerer, L. Nature 1994, 368,
237e239; (e) D’Amato, R. J.; Lin, C. M.; Flynn, E.; Folkman, J.; Hamel, E. Proc.
Natl. Acad. Sci. U.S.A. 1994, 91, 3964e3968; (f) Hamel, E.; Lin, C. M.; Flynn, E.;
D’Amato, R. J. Biochemistry 1996, 35, 1304e1310; (g) Mueck, A. O.; Seeger, H.
Steroids 2010, 75, 625e631.
4. (a) Fishman, J. J. Am. Chem. Soc. 1958, 80, 1213e1216; (b) de Ruggieri, P.;
Gandolfi, C.; Guzzi, U.; Ormonoterapia, Richter. U.S. Patent, 3,562,260, 1971; (c)
Rao, P. N.; Burdett, J. E., Jr. Synthesis 1977, 168e169; (d) Numazawa, M.; Ogura,
Y. J. Chem. Soc., Chem. Commun. 1983, 533e534; (e) Chen, S.-H.; Luo, G.-R.; Wu,
X.-S.; Chen, M.; Zhao, H.-M. Steroids 1986, 47, 63e81; (f) He, H.-M.; Cushman,
M. Bioorg. Med. Chem. Lett. 1994, 4, 1725e1728; (g) Lovely, C. J.; Brueggemeier,
R. W. Tetrahedron Lett. 1994, 35, 8735e8738; (h) Lovely, C. J.; Gilbert, N. E.;
Liberto, M. M.; Sharp, D. W.; Lin, Y. C.; Brueggemeier, R. W. J. Med. Chem. 1996,
39, 1917e1923; (i) Le Bras, J.; Rager, M. N.; Besace, Y.; Amouri, H.; Vaissermann,
J. Organometallics 1997, 16, 1765e1771; (j) Wang, Z.; Cushman, M. Synth.
Commun. 1998, 28, 4431e4437; (k) Kiuru, P. S.; Wahala, K. Steroids 2003, 68,
373e375; (l) Rao, P. N.; Cessac, J. W. Steroids 2002, 67, 1065e1070; (m) Paaren,
H. E.; Duff, S. R. U.S. Patent, 6,448,419, 2002; (n) Leese, M. P.; Hejaz, H. A. M.;
Mahon, M. F.; Newman, S. P.; Purohit, A.; Reed, M. J.; Potter, B. V. L. J. Med.
Chem. 2005, 48, 5243e5256; (o) Hou, Y.; Meyers, C. Y.; Akomeah, M. J. Org.
Chem. 2009, 74, 6362e6364; (p) Xin, M.; You, Q.; Xiang, H. Steroids 2010, 75,
53e56.
5. Olah, G. A.; Ohannasian, L.; Arvanaghi, M. Chem. Rev. 1987, 87, 671e686.
6. (a) For a review, see Laird, T. In Comprehensive Organic Chemistry; Stoddart, J. F.,
Ed.; Pergamon: Oxford, 1979; Vol. 1, pp 1105e1160; (b) Pert, D. J.; Ridley, D. D.
Aust. J. Chem. 1989, 42, 405e419.
mp 69e70 ꢁC (MeOH)); IR (KBr, cm
CDCl3)
) n
: 3435; 1H NMR (300 MHz,
d
¼6.87 (s, 1H), 6.84 (s, 1H), 5.19 (s, 2H), 4.70e4.62 (m, 2H),
3.85 (s, 3H), 3.62 (t, J¼8.4 Hz,1H), 3.51 (s, 3H), 3.38 (s, 3H), 2.89e2.72
(m, 2H), 2.33e1.95 (m, 4H),1.95e1.79 (m,1H),1.77e1.11 (m, 8H), 0.81
(s, 3H); 13C NMR (75 MHz, CDCl3)
d¼147.5, 144.2, 134.0, 128.8, 116.7,
109.3, 95.8, 95.4, 86.4, 55.9, 55.9, 54.9, 49.8, 44.2, 42.8, 38.4, 37.1,
28.9, 28.0, 27.1, 26.3, 22.9,11.6; ½a D20
þ64.0 (c 0.50, THF); HRMS calcd
ꢄ
for C23H34O5 [Mꢃþ]: 390.2406. Found 390.2400.
4 . 3 . 8 . ( 8 R , 9 S , 13 S , 14 S ,17 S ) - 2 - M e t h o x y - 13 - m e t h y l -
7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta-[a]phenanthrene-
3,17-diol (1). To a solution of 23 (206 mg, 0.53 mmol) in THF (3 mL)
was added HCl (6 M, 3 mL) at room temperature and the resulting
solutionwas stirred at room temperature for 5 h. The reaction mixture
was poured into brine (20 mL) and the products were extracted with
EtOAc (3ꢀ20 mL). The EtOAc layers were washed with saturated
NaHCO3 solution (10 mL) and brine (20 mL), then combined, dried
(MgSO4), and evaporated. Purification by chromatography (CH2Cl2/
EtOAc 9:1) gave 1 (131 mg, 82%) and recrystallization from CHCl3
yielded a colorless solid with mp 185e186 ꢁC (CHCl3) (lit.4a mp
€
€ €
7. (a) Hofsløkken, N. U.; Skattebøl, L. Acta Chem. Scand. 1999, 53, 258e262; (b)
Hansen, T. V.; Skattebøl, L. Org. Synth. 2005, 82, 64e68.
) n
184e186 ꢁC (CHCl3)); IR (KBr, cmꢂ1 : 3426, 3198, 1607; 1H NMR
8. (a) Akselsen, Ø. W.; Skattebøl, L.; Hansen, T. V. Tetrahedron Lett. 2009, 50,
6339e6341; (b) Anwar, H. F.; Hansen, T. V. Tetrahedron Lett. 2008, 49,
4443e4445; (c) Anwar, H. F.; Skattebøl, L.; Hansen, T. V. Tetrahedron 2007, 63,
9997e10002; (d) Hansen, T. V.; Skattebøl, L. Tetrahedron Lett. 2005, 46,
3829e3830; (e) Hansen, T. V.; Skattebøl, L. Tetrahedron Lett. 2005, 46,
3357e3358; (f) Odlo, K.; Klaveness, J.; Rongved, P.; Hansen, T. V. Tetrahedron
Lett. 2006, 47, 1101e1103; (g) Anwar, H. F.; Skattebøl, L.; Skramstad, J.; Hansen,
T. V. Tetrahedron Lett. 2005, 46, 5285e5287; (h) Wright, B. J. D.; Hartung, J.;
Peng, F.; Van de Water, R.; Liu, H.; Tan, Q.-H.; Chou, T.-C.; Danishefsky, S. J. J. Am.
Chem. Soc. 2008, 130, 16786e16790; (i) Byun, J. H.; Kim, H. Y.; Kim, Y. S.; Mook-
Jung, I.; Kim, D. J.; Lee, W. K.; Yoo, K. H. Bioorg. Med. Chem. Lett. 2008, 18,
5591e5593; (j) Nichols, D. E.; Frescas, S. P.; Chemel, B. R.; Rehder, K. S.; Zhong,
D.; Lewin, A. H. Bioorg. Med. Chem. 2008, 16, 6116e6123; (k) Chen, Y.; Steinmetz,
M. G. Org. Lett. 2005, 7, 3729e3732; (l) Ueno, T.; Koshiyama, T.; Ohashi, M.;
Kondo, K.; Kono, M.; Suzuki, A.; Yamane, T.; Watanabe, Y. J. Am. Chem. Soc. 2005,
127, 6556e6562.
9. Liu, Y.; Kim, B.; Taylor, S. D. J. Org. Chem. 2007, 72, 8824e8830.
10. (a) Rugang, X.; Tu, Y.; Liu, H.; Xu, J.; Zhao, H. Acta Chim. Sinica 1988, 46,
14e20; (b) Casiraghi, G.; Casnati, G.; Cornia, M.; Pochini, A.; Puglia, G.; Sar-
tori, G.; Ungaro, R. J. Chem. Soc., Perkin Trans. 1 1978, 318e321; (c) Casiraghi,
G.; Casnati, G.; Cornia, M.; Pochini, A.; Sartori, G.; Ungaro, R. J. Chem. Soc.,
Perkin Trans. 1 1978, 322e325; (d) Spyriounis, D. M.; Rekka, E.; Demopoulos,
V. J.; Kourounakis, P. N. Arch. Pharm. 1991, 324, 533e536; (e) Peters, R. H.;
Chao, W.-R.; Sato, B.; Shigeno, K.; Zaveri, N. T.; Tanabe, M. Steroids 2003, 68,
97e110.
(300 MHz, DMSO)
d
¼8.55 (s, 1H), 6.75 (s, 1H), 6.43 (s, 1H), 4.47 (d,
J¼4.8 Hz, 1H), 3.71 (s, 3H), 3.58e3.44 (m, 1H), 2.74e2.54 (m, 2H),
2.34e2.17 (m,1H), 2.15e2.00 (m,1H),1.97e1.80(m, 2H),1.80e1.70 (m,
1H), 1.64e1.49 (m, 1H), 1.47e0.99 (m, 7H), 0.66 (s, 3H); 13C NMR
(75MHz,DMSO-d6)
d
¼145.5,144.3,130.4,128.3,115.6,109.7, 80.1, 55.8,
49.5, 43.9, 42.8, 38.7, 36.6, 29.9, 28.4, 27.1, 26.2, 22.8,11.3; ½a D20
þ108 (c
ꢄ
0.50, THF); HRMS calcd for C19H26O3 [Mꢃþ]: 302.1991. Found 302.1880.
Acknowledgements
Financial support to Ø.W.A from The School of Pharmacy, Uni-
versity of Oslo is gratefully acknowledged. We also like to thank
Norsk Hydro for a kind gift of anhydrous magnesium chloride.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.08.005.
11. (a) Organon, N. V. NL6506542A, 1966; (b) de Ruggieri, P.; Gandolfi, C.; Guzzi, U.
Tetrahedon Lett. 1966, 7, 205e210.
12. Stork, G.; Takahashi, T. J. Am. Chem. Soc. 1977, 99, 1275e1276.
13. (a) Baeyer, A.; Villiger, V. Ber. Dtsch. Chem. Ges. 1899, 32, 3625e3633; (b) ten
Brink, G. J.; Arends, I. W. C. E.; Sheldon, R. A. Chem. Rev. 2004, 104, 4105e4123.
14. Yardley, J. P.; Fletcher, H., 3rd. Synthesis 1976, 244.
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