Synthetic approaches towards 4-functionalized estrone derivatives

Article abstract of DOI:10.1055/s-0032-1316816

Directed ortho-lithiation of estrone carbamate followed by reaction with electrophiles afforded 2-substituted estrone derivatives. Reductive cleavage of the carbamate group followed by O-allylation and Claisen rearrangement led to new 4-functionalized est

Full text of DOI:10.1055/s-0032-1316816

3822▌
PAPER
paper
Synthetic Approaches towards 4-Functionalized Estrone Derivatives
4-Functionalized Estrone Derivatives
Uwe Schön,a Josef Messinger,a Wladimir Solodenko,b Andreas Kirschning*b
a
Abbott Products GmbH, Abbott Laboratories GmbH, Freundallee 9A, 30173 Hannover, Germany
b
Institut für Organische Chemie and Biomolekulares Wirkstoffzentrum (BMWZ), Leibniz Universität Hannover, Schneiderberg 1b, 30167
Hannover, Germany
E-mail: andreas.kirschning@oci.uni-hannover.de
Received: 05.08.2012; Accepted after revision: 28.09.2012
In this report we disclose our investigations on the selec-
Abstract: Directed ortho-lithiation of estrone carbamate followed
tive synthesis of 4-substituted estrone derivatives by ex-
by reaction with electrophiles afforded 2-substituted estrone deriv-
ploiting the ortho-directed lithiation of estrone carbamate
atives. Reductive cleavage of the carbamate group followed by O-
allylation and Claisen rearrangement led to new 4-functionalized
5.10
estrone derivatives.
For realizing this approach a robust protection of the 17-
keto group was required, which we found to be the acetal
functionality. Estrone (1) was protected under standard
Key words: carbanions, Claisen rearrangement, estrone, ortho-
lithiation, steroids
conditions and the resulting acetal was treated with dieth-
ylcarbamoyl chloride in pyridine in the presence of trieth-
ylamine. The desired carbamate 5 was obtained in 84%
overall yield (Scheme 2). It is noteworthy that carbamo-
ylation proceeded slowly without completion in the ab-
sence of triethylamine.
Steroids are a biologically important class of natural com-
pounds with a large range of pharmaceutical applica-
tions.1,2 Specific functionalization of the tetracyclic core
is still a key synthetic issue and current methods have
been reviewed.3–5
1.
HO
OH
, p-TsOH
benzene, Δ
2. Et2NC(O)Cl
Et3N⋅Py, 80 °C
Steroidal derivatives exert a wide range of biological ac-
tions. These include receptor agonists or antagonists of
estrogens, androgens, corticoids, and inhibitors of ste-
roidogenic enzymes.6,7 Besides manual chemistry, combi-
natorial methods have also been pursued to generate
compound libraries.8
O
O
O
H
H
H
H
H
H
HO
O
5 (84%)
1
O
NEt2
As part of an ongoing research program we were interest-
ed in synthesizing new estrone derivatives functionalized
at C-4. However, synthesis of these estrones is still not
well explored. A common approach utilizes the Claisen
rearrangement of estrone allyl ether (2).9 The published
results show that this method creates mixtures of 2-allyl-
(3) and 4-allylestrone (4) (Scheme 1).
Scheme 2 Preparation of esterone 3-(N,N-diethyl)carbamate 5
Treatment of carbamate 5 with sec-butyllithium in the
presence of TMEDA (THF, –78 °C, 1 h) followed by trap-
ping of the carbanion with electrophiles such as methyl io-
dide or trimethylsilyl chloride afforded the corresponding
estrone derivatives 6 and its 4-isomer 7 (ratio = 10:1) as
well as 10 in synthetically useful yields (Scheme 3).
Clearly, substitution at C-2 is favored over functionaliza-
tion at C-4, reflecting the preferred site of lithiation. It can
be assumed that this preference is based on sterical
grounds. The regioselectivity of ortho-lithiation observed
for carbamate 5 correlates well with the results reported
for ortho-metalation of estrone derivatives with the
3-methoxymethyl substituent as directing group.11
O
C-2
H
Claisen rearrangement of 2
2-allyl (3) 4-allyl (4)
1 R = H (estrone)
2 R = allyl
H
H
RO
Troisi (ref. 9a)
Holton (ref. 9b)
Patton (ref. 9c)
40%
25%
28%
60%
75%
58%
C-4
2, Δ
O
O
The methyl-substituted carbamates 6 and 7 could smooth-
ly be deprotected for liberating the keto group at C-17
yielding estrone derivatives 8 and 9.
H
H
+
H
H
H
H
HO
HO
In a similar manner, the 2-position can exclusively be
functionalized as amide, when the lithiated intermediate
was reacted with diethylcarbamoyl chloride. Hydrolysis
of the acetal group yielded estrone derivative 11 in good
yield. Remarkably, when lithiation of 5 was initiated and
the solution was allowed to warm to room temperature in
the absence of an electrophile, estrone derivative 12 was
3
4
Scheme 1 Claisen rearrangement of estrone allyl ether (2)
SYNTHESIS 2012, 44, 3822–3828
Advanced online publication: 05.11.2012
DOI: 10.1055/s-0032-1316816; Art ID: SS-2012-Z0646-OP
© Georg Thieme Verlag Stuttgart · New York
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0
3
9
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7
8
8
1
1
4
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4-Functionalized Estrone Derivatives
3823
1. s-BuLi (1.1 equiv)
TMEDA (1.1 equiv)
THF, –78 °C, N2, 1 h
ly, this approach did not provide 4-alkylation products un-
der the common conditions. Instead, the 1,3-migration of
the carbamido group was the prevailing process. There-
fore, we pursued an alternative approach that is based on
the Claisen rearrangement.
O
O
O
O
H
H
2. MeI (2 equiv), N2,
–78 °C ---> r.t.
H
H
H
H
5
+
O
O
6 (76%)
7 (7%)
Et2N
O
Our first attempt of O-allylation of estrone derivative 12
under standard conditions (allyl bromide, acetone,
K2CO3, heat) failed. We assumed that H-bonding of the
phenolic proton with the neighboring carboxamide group
is responsible for this lack of reactivity. However, after
metalation with sodium hydride in THF under refluxing
conditions in the presence of an excess of allyl bromide,
the targeted allyl ether 13 was isolated in 62% yield. It is
noteworthy that no allylation in the α-position of the keto
group took place. Upon heating, allyl ether 13 smoothly
underwent Claisen rearrangement with migration of the
allyl group to the only vacant ortho-position affording 2-
(N,N-diethylcarboxamide)-4-allylestrone (14) in 77%
yield (Scheme 5).
Et2N
O
aq 2 M HCl, THF, r.t.
O
O
H
H
H
O
H
H
H
O
+
Et2N
O
Et2N
O
8
9
97%
1. s-BuLi (1.1 equiv)
TMEDA (1.1 equiv)
THF, –78 °C, N2, 1 h
O
O
H
2 Me3SiCl (1.2 equiv), N2,
–78 °C ---> r.t.
Me3Si
O
1. NaH, THF, r.t.
H
H
5
O
O
2. CH2=CHCH2Br
H
THF. 70 °C
205 °C, 2.5 h
Et2N
Et2N
O
10 (82%)
12
H
H
O
Scheme 3 Selective ortho-lithiation of esterone 3-(N,N-diethyl)carba-
mate 5 followed by electrophilic trapping
O
13 (62%)
O
H
formed and isolated in good yield after acidic removal of
the ketal group. This 1,3-migration of the carbamido
group12 resembles an anionic ortho-Fries rearrangement
and exclusively furnishes the 2-substituted product 12
(Scheme 4).
Et2N
H
H
HO
14 (77%)
Scheme 5 Claisen rearrangement of allyl ether 13
O
1. s-BuLi (1.1 equiv)
TMEDA (1.1 equiv)
THF, –78 °C, N2, 1 h
O
O
H
However, as the carbamido group at C-2 is not removable,
we pursued to introduce a group at C2 that can be easily
cleaved after functionalization of the 4-position. Thus, the
silyl derivative 10 served as starting point (Scheme 6).
First, the carbamate was removed under reductive condi-
tions and this was followed by O-allylation to yield allyl
ether 16. With this precursor in hand, the Claisen rear-
rangement was performed at 209 °C raising the tempera-
ture to 220 °C after three hours.
Et2N
Et2N
2. Et2NCOCl (1.2 equiv), N2
–78 °C ---> r.t. (78%)
H
H
3. aq 2 M HCl, THF, r.t. (86%)
11
O
5
O
1. sec-BuLi (1.2 equiv)
TMEDA (1.2 equiv), THF
O
H
N2, –78 °C ---> r.t. (61%)
2. aq 2 M HCl, THF (93%)
Et2N
H
H
Thin layer chromatography revealed only one new spot
very close to that of the starting material. However, NMR
analysis of the crude product showed a mixture of prod-
ucts. After treatment under acidic conditions, three com-
pounds, namely 4-allylestrone (4) (dominating product),
17, and 2,4-diallylestrone (18) were isolated by flash
chromatography on silica gel (Scheme 6).
HO
12
Scheme 4 1,3-Migration of carbamido group of esterone 3-(N,N-di-
ethyl)carbamate 5
In essence, the ortho-lithiation strategy allows to modify
C-2 in estrone. It can also serve to specifically introduce a
substituent like the allyl group in the 4-position. For
achieving this goal, the 2-position needs to be blocked
first before C-4 can specifically be addressed. Indeed, it
looked tempting to carry out a second directed ortho-lithi-
ation/alkylation protocol starting from carbamate 10 for
targeting the 4-alkylated estrone derivatives. Unfortunate-
For better understanding of these results, several addition-
al experiments were carried out (data on reaction scheme
not shown). Claisen rearrangement of silylated allyl ether
17 that still contains the keto group was performed at
204 °C and afforded the crude product revealing a few di-
agnostic signals (for 1-Harom and 2-Harom and the trimeth-
ylsilyl group) in the complex 1H NMR spectrum.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3822–3828

3824
U. Schön et al.
PAPER
in an intermolecular process to furnish the corresponding
2,4-diallyl derivative. During acidic removal of the acetal
group also the aryl silyl ether group is cleaved which lib-
erated the phenol functionality and gave the products 4,
17, and 18.
O
O
1. NaH, THF, r.t.
H
Me3Si
HO
LiAlH4
2. CH2=CHCH2Br
65 °C
H
H
10
THF, Δ
O
15 (96%)
In summary, directed ortho-lithiation of estrone carba-
mates followed by reaction with different electrophiles af-
ford 2-substituted estrone derivatives in synthetically
useful yields. 4-Substituted derivatives were obtained
from these products after reductive cleavage of the carba-
mate group, O-allylation and Claisen rearrangement.
These principal studies allow to specifically address func-
tionalization of the 2- or 4-position in estrone (1).
H
Me3Si
O
H
H
O
O
1. 209–220 °C, 6 h
2. HCl, THF
H
17 (2.5%)
Me3Si
O
H
H
+
O
H
R2
16 (93%)
H
H
NMR spectra were recorded on a Bruker Avance I 400 spectrometer
at 400 MHz (1H NMR) or 100 MHz (13C NMR) in CDCl3 using
TMS as the internal standard. IR spectra were recorded on a Bruker
Vektor 22 FT-IR spectrophotometer (GoldenGate ATR unit). Mass
spectra were obtained at 70 eV with a type VG Autospec apparatus
(Micromass). Optical rotations were measured on a PerkinElmer
Polarimeter 241. Melting points were determined in open glass cap-
illaries on an Electrothermal IA 9200 apparatus and are uncorrect-
ed. Analytical TLC was performed using precoated silica gel 60 F254
plates (Merck, Darmstadt), and the spots were visualized with UV
light at 254 nm or with vanillin reagent. Flash column chromatog-
raphy was performed on Merck silica gel 60 (230–400 mesh). Com-
mercially available starting materials and reagents were purchased
from Fluka, Acros, and Aldrich and used as received. All solvents
were dried by conventional methods.
HO
R1
O
O
4 R1 = allyl, R2 = H (51%)
18 R1 = R2 = allyl (8%)
H
Me3Si
HO
H
H
19
Scheme 6 Claisen rearrangement of allyl ether 16.
However, the phenolic hydroxyl group was not present.
After acidic treatment of this crude product, pure 4-al-
lylestrone (4) was isolated in 49% yield. When 2-silylated
estrone ketal 15 was heated under the conditions of
Claisen rearrangement (204 °C, 5.5 h), full conversion
was achieved, and O-silylated estrone ketal 20 was isolat-
ed in 77% yield as a single product (Scheme 7).
Estrone Ethylene Ketal 3-(N,N-Diethyl)carbamate 5
Estrone Ethylene Ketal: A mixture of estrone (1; 595 mg, 2.2
mmol), p-TsOH·H2O (38 mg, 0.2 mmol), and ethylene glycol (2.78
g, 44.8 mmol) in anhyd benzene (15 mL) was stirred under reflux-
ing conditions in a Dean–Stark device for 12 h. After cooling to r.t.,
the mixture was poured into H2O (30 mL) and extracted with
CH2Cl2 (2 × 30 mL). The combined organic extracts were washed
with H2O (30 mL) and dried (Na2SO4). Concentration and flash
chromatography of the residue on silica gel (hexane–EtOAc, 2:1)
afforded estrone ethylene ketal as a colorless solid; yield: 623 mg (2
mmol, 90%); mp 182–183 °C (Lit.15 mp 180–181 °C); [α]D25 +27.1
(c = 1.0, CH2Cl2) {Lit.16 [α]D25 +26.2 (c = 1.0, CHCl3)}.
O
O
O
O
204 °C
5.5 h
H
H
Me3Si
HO
H
H
H
H
Me3SiO
IR (ATR): 3297 cm–1 (OH).
20 (77%)
15
1H NMR (CDCl3): δ = 0.88 (s, 3 H, CH3), 1.22–1.64 (m, 6 H), 1.70–
1.90 (m, 4 H), 1.97–2.07 (m, 1 H), 2.15–2.27 (m, 1 H), 2.28–2.34
(m, 1 H), 2.72–2.85 (m, 2 H), 3.87–3.99 (m, 4 H, OCH2CH2O), 4.91
(s, 1 H, OH), 6.56 (d, J = 2.7 Hz, 1 Harom), 6.62 (dd, J = 8.5, 2.7 Hz,
Scheme 7 Thermal C → O migration of trimethylsilyl group
This thermal 1,3-migration of the trimethylsilyl group13 1 Harom), 7.15 (d, J = 8.5 Hz, 1 Harom).
can be considered as a protodesilylation14 promoted by the
acidic phenolic proton and trapping of the cleaved silyl
species by the phenolate anion. O-Silylated estrone ketal
20 was prepared also directly through the silylation of es-
trone ketal with trimethylchlorosilane. Acidic treatment
of estrone ketal 20 under the conditions used for the re-
moval of the acetal protection (2 M HCl, THF, r.t., 2 h)
gave estrone 1 in 95% isolated yield.
13C NMR (CDCl3): δ = 14.48, 22.48, 26.27, 27.05, 29.75, 30.86,
34.36, 39.15, 43.72, 46.30, 49.47, 64.72, 65.38, 112.76, 115.38,
119.65, 126.67, 132.88, 138.45, 153.45.
LRMS: m/z = 314 (M+, 35%).
HRMS: m/z calcd for C20H26O3 (M+): 314.1882; found: 314.1888.
Carbamate 5: To a solution of the above estrone ethylene ketal
(1.568 g, 4.99 mmol) in anhyd pyridine (20 mL) was added diethyl-
carbamoyl chloride (1.356 g, 10 mmol) and Et3N (1.012 g, 10
mmol) in one portion. The mixture was stirred at 80 °C overnight
and then cooled to r.t. H2O (100 mL) was added, the mixture was
stirred for 30 min, and extracted with EtOAc (100 mL). The aque-
ous phase was extracted with EtOAc (3 × 30 mL). The combined
organic phases were washed with H2O (40 mL), aq 1 M HCl (5 × 40
mL), brine (3 × 40 mL), and dried (Na2SO4). Concentration under
vacuum and flash chromatography of the residue on silica gel (hex-
ane–EtOAc, 3:1) gave carbamate 5 as a colorless solid; yield: 1.923
These findings allow us to rationalize the results described
in Scheme 6. Indeed, the Claisen rearrangement of allyl
ether 16 proceeded smoothly with the formation of the 4-
allyl derivative 19. Then, thermal C → O migration of the
trimethylsilyl group occurs to yield the corresponding aryl
silyl ether, which may react with a second O-allyl group
Synthesis 2012, 44, 3822–3828
© Georg Thieme Verlag Stuttgart · New York

PAPER
4-Functionalized Estrone Derivatives
2-Methylestrone Carbamate 8
The title compound was obtained after deprotection of compound 6
according to general procedure B as a colorless solid; yield: 47 mg
(97%); mp 169–172 °C.
3825
g (4.65 mmol, 93%); yield over two steps: 84%; mp 139–142 °C;
[α]D25 +20.8 (c = 1.0, CH2Cl2).
IR (ATR): 1713 cm–1 (C=O).
1H NMR (CDCl3): δ = 0.88 (s, 3 H, CH3), 1.19 (t, J = 7.8 Hz, 3 H,
CH3), 1.23 (t, J = 7.8 Hz, 3 H, CH3), 1.27–1.69 (m, 6 H), 1.70–1.91
(m, 4 H), 1.98–2.08 (m, 1 H), 2.20–2.38 (m, 2 H), 2.80–2.90 (m, 2
H), 3.32–3.46 (m, 4 H, CH2NCH2), 3.85–4.00 (m, 4 H,
OCH2CH2O), 6.82 (d, J = 2.4 Hz, 1 Harom), 6.87 (dd, J = 8.4, 2.4 Hz,
1 Harom), 7.25 (d, J = 8.4 Hz, 1 Harom).
13C NMR (CDCl3): δ = 13.52, 14.33, 14.42, 22.47, 26.12, 26.95,
29.64, 30.81, 34.33, 38.87, 41.93, 42.27, 43.92, 46.21, 49.49, 64.68,
65.35, 118.88, 119.51, 121.79, 126.25, 137.32, 138.06, 149.32,
154.64.
IR (ATR): 1732, 1704 cm–1 (C=O).
1H NMR (CDCl3): δ = 0.90 (s, 3 H, CH3), 1.20 (t, J = 7.0 Hz, 3 H,
CH2CH3), 1.26 (t, J = 7.0 Hz, 3 H, CH2CH3), 1.38–1.68 (m, 6 H),
1.89–2.18 (m, 4 H), 2.16 (s, 3 H, 2-CH3), 2.19–2.29 (m, 1 H), 2.35–
2.42 (m, 1 H), 2.43–2.53 (m, 1 H), 2.86 (dd, J = 8.5, 3.8 Hz, 2 H,
CH2C=O), 3.39 (q, J = 7.0 Hz, 2 H, NCH2CH3), 3.44 (q, J = 7.0 Hz,
2 H, NCH2CH3), 6.79 (s, 1 Harom, H-4), 7.11 (s, 1 Harom, H-1).
13C NMR (CDCl3): δ = 13.58, 13.98, 14.40, 16.26, 21.74, 25.97,
26.63, 29.10, 31.73, 36.02, 38.28, 41.97, 42.33, 44.26, 48.12, 50.61,
122.27, 127.46, 128.02, 135.22, 136.78, 148.04, 154.34, 221.14.
LRMS: m/z = 383 (M+, 59%).
HRMS: m/z calcd for C24H33NO3 (M+): 383.2460; found: 383.2464.
According to the 1H NMR spectrum, compound 8 contained about
8% of the 4-methyl isomer 9, which was not chromatographically
separable from the major isomer 8.
LRMS: m/z = 413 (M+, 56%).
HRMS: m/z calcd for C25H35NO4 (M+): 413.2566; found: 413.2566.
Lithiation of Carbamate 5 Followed by Reaction with Electro-
philes; General Procedure A
A solution of carbamate 5 (62 mg, 0.15 mmol) in THF (0.5 mL) was
added via a syringe to a stirred solution of s-BuLi (127 μL of 1.3 M
solution in cyclohexane, 0.165 mmol, 1.1 equiv) and TMEDA (25
μL, 0.165 mmol, 1.1 equiv) in THF (1 mL) at –78 °C under N2 at-
mosphere. The resulting greenish solution was stirred at –78 °C for
1 h, treated dropwise via a syringe with a solution of an electrophile
(0.18 mmol, 1.2 equiv) in THF (0.5 mL), stirred at this temperature
for 1 h, and then the reaction mixture was allowed to warm to r.t.
The mixture was hydrolyzed with sat. aq NH4Cl (2 mL) and extract-
ed with EtOAc (2 × 5 mL). The combined organic extracts were
washed with brine (5 mL) and dried (Na2SO4). Concentration under
reduced pressure und flash chromatography of the residue on the
silica gel using hexane–EtOAc as an eluent afforded the products.
2-Trimethylsilylestrone Ketal Carbamate 10
The title compound was obtained as a colorless foam from 5 accord-
ing to general procedure A using Me3SiCl as an electrophile; yield:
120 mg (82%); mp 137–138 °C; [α]D25 +23.5 (c = 1.0, CH2Cl2).
IR (ATR): 1714 cm–1 (C=O).
1H NMR (CDCl3): δ = 0.26 [s, 9 H, Si(CH3)3], 0.88 (s, 3 H, CH3),
1.19 (t, J = 7.2 Hz, 3 H, CH2CH3), 1.24 (t, J = 7.0 Hz, CH2CH3),
1.31–1.66 (m, 6 H), 1.71–1.90 (m, 4 H), 1.98–2.08 (m, 1 H), 2.22–
2.40 (m, 2 H), 2.85 (dd, J = 8.3, 3.9 Hz, 2 H), 3.39 (q, J = 7.2 Hz, 2
H, NCH2CH3), 3.46 (q, J = 7.0 Hz, 2 H, NCH2CH3), 3.87–3.99 (m,
4 H, OCH2CH2O), 6.77 (s, 1 Harom, H-4), 7.36 (s, 1 Harom, H-1).
13C NMR (CDCl3): δ = –0.63, 13.46, 14.32, 14.46, 22.51, 26.10,
26.95, 29.68, 30.89, 34.36, 39.00, 41.65, 42.01, 44.05, 46.27, 49.56,
64.73, 65.40, 119.59, 122.28, 128.01, 131.98, 136.88, 139.78,
154.22, 154.77.
Cleavage of Ethylenedioxyketal Protecting Group; General
Procedure B
A solution of estrone ketal derivative (0.5 mmol) in THF (6 mL)
was treated with aq 2 M HCl (2.5 mL). The mixture was shaken at
r.t. for 2.5 h, then sat. aq NaHCO3 (ca. 5 mL) was added dropwise
until pH ca. 8. The mixture was extracted with EtOAc (3 × 10 mL);
the combined organic extracts were washed with H2O (10 mL) and
brine (10 mL), and dried (Na2SO4). Concentration under vacuum
and flash chromatography of the residue on silica gel afforded the
estrone derivative with free 17-keto group.
LRMS: m/z = 485 (M+, 12%).
HRMS: m/z calcd for C28H43NO4Si (M+): 485.2961; found:
485.2963.
2-Carbamoylated Estrone Carbamate 11
The title compound was prepared from 5 according to general pro-
cedure A using diethylcarbamoyl chloride as an electrophile.
2-Methylestrone Ketal Carbamate 6
The title compound was obtained as a colorless solid as the major
product from 5 according to general procedure A using MeI as an
electrophile; yield: 49 mg (76%); mp 145–148 °C.
Intermediate Ethylene Ketal: The intermediate ethylene ketal pro-
tected derivative was obtained as a colorless, glassy solid that soft-
22
IR (ATR): 1716 cm–1 (C=O).
ens at 70–80 °C; yield: 60 mg (78%); [α]D +26.2 (c = 1.0,
CH2Cl2).
IR (ATR): 1634, 1715 cm–1 (C=O).
1H NMR (CDCl3): δ = 0.87 (s, 3 H, CH3), 1.13–1.28 (m, 6 H, 2 ×
CH3), 1.29–1.67 (m, 6 H), 1.70–1.90 (m, 4 H), 2.00–2.10 (m, 1 H),
2.16 (s, 3 H, 2-CH3), 2.20–2.38 (m, 2 H), 2.77–2.87 (m, 2 H), 3.34–
3.47 (m, 4 H, CH2NCH2), 3.86–3.98 (m, 4 H, OCH2CH2O), 6.77 (s,
1 Harom, H-4), 7.10 (s, 1 Harom, H-1).
13C NMR (CDCl3): δ = 13.59, 14.42, 14.46, 16.26, 22.51, 26.18,
27.07, 29.25, 30.86, 34.36, 38.95, 41.96, 42.30, 43.92, 46.24, 49.55,
64.71, 65.38, 119.58, 122.17, 127.19, 128.00, 135.52, 137.48,
147.83, 154.40.
1H NMR (CDCl3): δ = 0.87 (s, 3 H, CH3), 1.04 (t, J = 7.1 Hz, 3 H,
CH3), 1.15 (t, J = 7.1 Hz, 3 H, CH3), 1.19 (t, J = 7.0 Hz, 6 H, 2 ×
CH3), 1.28–1.92 (m, 10 H), 1.97–2.07 (m, 1 H), 2.20–2.32 (m, 2 H),
2.80–2.88 (m, 2 H), 3.08–3.41 (m, 8 H, 4 × NCH2), 3.83–3.97 (m,
4 H, OCH2CH2O), 6.90 (s, 1 Harom, H-4), 7.14 (s, 1 Harom, H-1).
13C NMR (CDCl3): δ = 12.86, 13.51, 14.12, 14.26, 14.44, 22.48,
26.14, 26.85, 29.53, 30.76, 34.34, 38.76, 38.78, 42.10, 42.28, 42.95,
43.83, 46.20, 49.47, 65.40, 67.71, 119.49, 123.11, 123.81, 127.82,
137.62, 138.86, 145.11, 153.97, 168.46.
LRMS: m/z = 427 (M+, 67%).
HRMS: m/z calcd for C26H37NO4 (M+): 427.2723; found: 427.2723.
LRMS: m/z = 512 (M+, 67%).
HRMS: m/z calcd for C30H44N2O5 (M+): 512.3250; found:
Product 6 could not be separated chromatographically from the mi-
nor product, the 4-methylated carbamate 7. The latter was identified
based on diagnostic 1H NMR signals of aromatic protons: δ = 6.86
(d, J = 8.6 Hz, 1 Harom, H-2) and 7.16 (d, J = 8.6 Hz, 1 Harom, H-1).
All other signals overlapped with signals of the major product 6.
The estimated yield of compound 7 was 7%; the total yield of ortho-
methylated carbamates 6 and 7 was 83%.
512.3251.
Carbamate 11: Deprotection of the above protected carbamate ac-
cording to general procedure B gave the carbamate 11 as a colorless
20
solid; yield: 47 mg (86%); mp 147–150 °C; [α]D +78.7 (c = 1.1,
CH2Cl2).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3822–3828

3826
U. Schön et al.
PAPER
IR (ATR): 1732, 1704, 1633 cm–1 (C=O).
forded allyl ether 13 as a colorless solid; yield: 120 mg (0.293
mmol, 62%); mp 176–177 °C; [α]D20 +118.6 (c = 1.03, CH2Cl2).
IR (ATR): 1733, 1626 cm–1 (C=O).
1H NMR (CDCl3): δ = 0.90 (s, 3 H, CH3), 1.03 (t, J = 7.1 Hz, 3 H,
NCH2CH3), 1.23 (t, J = 7.1 Hz, 3 H, NCH2CH3), 1.35–1.70 (m, 6
H), 1.90–2.60 (m, 7 H), 2.88 (dd, J = 7.8, 3.4 Hz, 2 H, CH2C=O),
3.18 (q, J = 7.1 Hz, 2 H, NCH2CH3), 3.30–3.80 (2 br s, 2 H,
NCH2CH3), 4.50 (ddd, J = 4.1, 1.6, 1.6 Hz, 2 H, OCH2CH=CH2),
5.22 (ddt, J = 10.4, 1.6, 1.6 Hz, 1 Holef), 5.36 (ddt, J = 17.3, 1.6, 1.6
Hz, 1 Holef), 5.99 (ddt, J = 17.3, 10.4, 5.1 Hz, 1 Holef), 6.59 (s, 1
1H NMR (CDCl3): δ = 0.90 (s, 3 H, CH3), 1.05 (t, J = 7.0 Hz, 3 H,
CH2CH3), 1.16 (t, J = 7.0 Hz, 3 H, CH2CH3), 1.19 (t, J = 7.2 Hz, 6
H, 2 × CH2CH3), 1.38–1.65 (m, 6 H), 1.93–2.16 (m, 4 H), 2.20–2.40
(m, 2 H), 2.43–2.57 (m, 1 H), 2.91 (dd, J = 8.5, 3.8 Hz, CH2C=O),
3.10–3.50 (m, 4 H, 2 × NCH2), 3.35 (q, J = 7.0 Hz, 2 H, NCH2CH3),
3.37 (q, J = 7.0 Hz, 2 H, NCH2CH3), 6.93 (s, 1 Harom, H-4), 7.14 (s,
1 Harom, H-1).
13C NMR (CDCl3): δ = 12.88, 13.51, 13.96, 14.17, 14.26, 21.71,
25.91, 26.41, 29.38, 31.63, 35.98, 38.09, 38.84, 42.12, 42.31, 42.98,
44.15, 48.05, 50.55, 123.25, 123.83, 128.09, 136.93, 138.55,
145.35, 153.93, 168.26, 220.85.
Harom, H-4), 7.11 (s, 1 Harom, H-1).
13C NMR (CDCl3): δ = 13.03, 13.99, 14.23, 21.72, 26.62, 29.86,
31.67, 35,99, 38.37, 38.89, 42.93, 44.03, 48.12, 50.54, 69.34,
112.92, 117.08, 125.29, 132.65, 133.35, 138.33, 152.28, 169.16,
220.87.
LRMS: m/z = 409 (M+, 70%).
HRMS: m/z calcd for C26H35NO3 (M+): 409.2617; found: 409.2614.
LRMS: m/z = 468 (M+, 20%).
HRMS: m/z calcd for C28H40N2O4 (M+): 468.2988; found:
468.2978.
2-Carbamoylestrone (12)
Intermediate Ethylene Ketal Protected Derivative: Standard meta-
lation of carbamate 5 (62 mg, 0.15 mmol) was conducted, followed
by slow (2 h) warming of the reaction mixture to r.t. in the absence
of any electrophile. After standard workup of the reaction mixture,
the intermediate ethylene ketal protected derivative was isolated as
a colorless foam; yield: 38 mg (61%); mp 110–113 °C; [α]D20 +28.3
(c = 1.0, CH2Cl2).
2-(N,N-Diethylcarboxamide)-4-allylestrone (14)
Allyl ether 13 (98 mg, 0.239 mmol) was heated at 205 °C under N2
atmosphere for 2.5 h. Purification by flash chromatography on silica
gel (hexane–EtOAc, 2:1) afforded the title compound 14 as a color-
less foam; yield: 75 mg (0.183 mmol, 77%); mp 46–52 °C (‘cara-
melization’ in the form of transparent glassy drops, no meniscus);
[α]D20 +108.0 (c = 1.0, CH2Cl2).
IR (ATR): ~3120 (O–H, br), 1582 cm–1 (C=O).
1H NMR (CDCl3): δ = 0.89 (s, 3 H, CH3), 1.28 (t, J = 7.1 Hz, 6 H,
2 × CH2CH3), 1.23–1.68 (m, 6 H), 1.72–1.90 (m, 4 H), 1.98–2.05
(m, 1 H), 2.15–2.28 (m, 2 H), 2.75–2.86 (m, 2 H), 3.48 (q, J = 7.1
Hz, 2 H, NCH2CH3), 3.55 (q, J = 7.1 Hz, 2 H, NCH2CH3), 3.83–
IR (ATR): 3074 (O–H, br), 1737, 1624 (C=O), 1581 cm–1 (C=C).
1H NMR (CDCl3): δ = 0.91 (s, 3 H, CH3), 1.29 (t, J = 7.1 Hz, 6 H,
2 × NCH2CH3), 1.32–1.58 (m, 5 H), 1.90–2.34 (m, 7 H), 2.41–2.51
(m, 1 H), 2.66–2.78 (m, 1 H), 2.89–2.98 (m, 1 H), 3.38–3.48 (m 2
H, ArCH2CH=), 3.52 (q, J = 7.1 Hz, 4 H, 2 × NCH2CH3), 4.97 (ddt,
J = 17.3, 1.7, 1.7 Hz, 1 Holef), 5.00 (ddt, J = 10.2, 1.5, 1.4 Hz, 1
Holef), 5.94 (ddt, J = 17.3, 10.2, 6.1 Hz, 1 Holef), 7.12 (s, 1 Harom, H-
1), 9.87 (s, 1 H, OH).
13C NMR (CDCl3): δ = 13.65, 13.94, 21.69, 26.32, 26.67, 26.74,
30.12, 31.70, 36.02, 37.71, 42.37, 44.19, 47.97, 50.57, 114.82,
115.28, 122.36, 126.11, 129.97, 135.85, 139.93, 154.79, 172.45,
220.93.
3.99 (m, 4 H, OCH2CH2O), 6.70 (s, 1 Harom, H-4), 7.18 (s, 1 Harom
H-1), 9.66 (s, 1 H, OH).
,
13C NMR (CDCl3): δ = 13.62, 14.47, 22.48, 26.34, 26.93, 29.71,
30.77, 34.33, 39.05, 42.36, 43.51, 46.19, 49.44, 64.71, 65.40,
115.52, 117.52, 119.49, 124.38, 130.78, 142.11, 156.66, 172.06.
LRMS: m/z = 413 (M+, 100%).
HRMS: m/z calcd for C25H35NO4 (M+): 413.2566; found: 413.2567.
2-Carbamoylestrone (12): Deprotection of the above intermediate
ketal derivative (37 mg, 0.089 mmol) according to general proce-
dure B gave 2-carbamoylestrone (12) as a colorless solid; yield: 30
mg (93%); mp 160–162 °C; [α]D20 +129.5 (c = 1.5, CH2Cl2).
LRMS: m/z = 409 (M+, 100%).
HRMS: m/z calcd for C26H35NO3 (M+): 409.2617; found: 409.2614.
2-Trimethylsilylestrone Ketal 15
IR (ATR): ~3120 (O–H, br), 1733 (C=O), 1574 cm–1.
A solution of 2-trimethylsilyl carbamate 10 (595 mg, 1.225 mmol)
in anhyd THF (5 mL) was added at 0 °C to a stirred suspension of
LiAlH4 (232 mg, 6.125 mmol) in anhyd THF (7 mL) under N2. Af-
ter stirring under refluxing conditions for 22 h, the mixture was
cooled to r.t. and treated with H2O (232 μL), 15% aq NaOH (232
μL), and H2O (696 μL). After stirring for 10 min, the precipitate
formed was filtered off and washed on the filter with THF (5 mL)
and EtOAc (4 × 5 mL). The combined organic phases were dried
(Na2SO4). Concentration under vacuum and flash chromatography
of the residue on silica gel (hexane–EtOAc, 3.5:1) afforded 2-tri-
methylsilyl estrone ketal 15 as a colorless solid; yield: 457 mg
1H NMR (CDCl3): δ = 0.92 (s, 3 H, CH3), 1.29 (t, J = 7.0 Hz, 6 H,
2 × CH2CH3), 1.35–1.65 (m, 5 H), 1.93–2.34 (m, 7 H), 2.45–2.57
(m, 1 H), 2.88 (dd, J = 8.5, 4.2 Hz, 2 H, CH2C=O), 3.50 (q, J = 7.0
Hz, 2 H, NCH2CH3), 3.53 (q, J = 7.0 Hz, 2 H, NCH2CH3), 6.73 (s,
1 Harom, H-4), 7.18 (s, 1 Harom, H-1), 9.65 (s, 1 H, OH).
13C NMR (CDCl3): δ = 13.67, 13.98, 21.72, 26.10, 26.49, 29.57,
31.67, 35.99, 38.37, 42.36, 42.41, 43.86, 48.05, 50.53, 115.78,
117.65, 124.38, 130.11, 141.76, 156.86, 171.94, 220.83.
LRMS: m/z = 369 (M+, 90%).
HRMS: m/z calcd for C23H31NO3 (M+): 369.2304; found: 369.2301.
20
(1.182 mmol, 96%); mp 101–103 °C; [α]D +33.3 (c = 1.0,
CH2Cl2).
IR (ATR): 3416 cm–1 (O–H).
Allyl Ether 13
To a solution of 12 (174 mg, 0.471 mmol) in anhyd THF (3 mL) was
added NaH (24 mg, 1 mmol, 80% suspension in mineral oil). After
stirring for 1 h at r.t., allyl bromide (121 mg, 1 mmol) was added,
and the mixture was stirred at 70 °C overnight. The mixture was hy-
drolyzed with H2O (3 mL), then aq 1 M HCl was added dropwise
until pH ~4, and the mixture was extracted with EtOAc (10 mL).
The aqueous layer was extracted with EtOAc (2 × 5 mL), the com-
bined organic phases were washed with H2O (5 mL), brine (5 mL),
and dried (Na2SO4). Concentration under vacuum and flash chro-
matography of the residue on silica gel (hexane–EtOAc, 1:1) af-
1H NMR (CDCl3): δ = 0.30 [s, 9 H, Si(CH3)3], 0.88 (s, 3 H, CH3),
1.23–1.67 (m, 6 H), 1.70–1.90 (m, 4 H), 1.97–2.07 (m, 1 H), 2.15–
2.27 (m, 1 H), 2.30–2.40 (m, 1 H), 2.72–2.87 (m, 2 H), 3.87–3.99
(m, 4 H, OCH2CH2O), 4.67(s, 1 H, OH), 6.42 (s, 1 Harom, H-4), 7.29
(s, 1 Harom, H-1).
13C NMR (CDCl3): δ = –0.68, 14.48, 22.52, 26.28, 27.03, 29.74,
30.91, 34.38, 39.33, 43.84, 46.33, 49.50, 64.74, 65.40, 114.70,
119.62, 122.33, 132.38, 132.41, 139.95, 158.37.
LRMS: m/z = 386 (M+, 35%).
Synthesis 2012, 44, 3822–3828
© Georg Thieme Verlag Stuttgart · New York

PAPER
4-Functionalized Estrone Derivatives
3827
HRMS: m/z calcd for C23H34O3Si (M+): 386.2277; found 386.2280.
1H NMR (CDCl3): δ = 0.90 (s, 3 H, CH3), 1.20–1.70 (m, 6 H), 1.90–
2.54 (m, 7 H), 2.68–2.94 (m, 2 H), 3.35–3.47 (m, 4 H, 2 × ArCH2),
4.95–5.07 (m, 3 H, 2 × Holef and OH), 5.13–5.23 (m, 2 H, 2 × Holef),
5.90–6.07 (m, 2 H, 2 × Holef), 6.98 (s, 1 Harom, H-1).
13C NMR (CDCl3): δ = 13.98, 21.71, 26.37, 26.79, 26.90, 30.50,
31.77, 36.01, 36.06, 37.82, 44.48, 48.08, 50.60, 115.42, 116.69,
122.68,124.01, 125.54, 132.42, 134.51, 135.88, 136.92, 150.91,
221,24.
Allyl Ether 16
To a solution of 2-trimehylsilylestrone ketal 15 (435 mg, 1.125
mmol) in anhyd THF (5 mL) was added NaH (54 mg, 2.25 mmol,
80% suspension in mineral oil). After stirring for 1 h at r.t., allyl
bromide (272 mg, 2.25 mmol) was added, and the mixture was
stirred at 60 °C overnight. The mixture was hydrolyzed with sat. aq
NH4Cl (10 mL) and extracted with EtOAc (3 × 10 mL). The com-
bined organic phases were washed with brine (25 mL) and dried
(Na2SO4). Concentration under vacuum and flash chromatography
of the residue on silica gel (hexane–EtOAc, 3.5:1) afforded allyl
ether 16 as a colorless adhesive foam that softens at 100–105 °C;
yield: 448 mg (1.05 mmol, 93%); [α]D25 +25.9 (c = 1.0, CH2Cl2).
LRMS: m/z 350 (M+, 100%).
HRMS: m/z calcd for C24H30O2 (M+): 350.2246; found: 350.2247.
2-Trimethylsilylestrone Allyl Ether 17
2-Trimethylsilylestrone: To a solution of 2-trimethylsilylestrone ke-
tal 15 (250 mg, 0.65 mmol) in THF (7 mL) was added aq 2 M HCl
(2 mL), and the mixture was shaken at r.t. for 2 h. After workup ac-
cording to general procedure B and flash chromatography of the
crude product on silica gel (hexane–EtOAc, 3:1), 2-trimethylsi-
lylestrone was obtained as a colorless solid (186 mg, 0.543 mmol,
84%); mp 207–209 °C; [α]D20 +147.8 (c = 1.0, CH2Cl2).
IR (ATR): 1596 cm–1 (C=C).
1H NMR (CDCl3): δ = 0.27 [s, 9 H, Si(CH3)3], 0.88 (s, 3 H, CH3),
1.25–1.70 (m, 6 H), 1.70–1.90 (m, 4 H), 1.95–2.08 (m, 1 H), 2.20–
2.28 (m, 1 H), 2.30–2.40 (m, 1 H), 2.77–2.90 (m, 2 H), 3.86–3.98
(m, 4 H, OCH2CH2O), 4.50 (ddd, J = 5.0, 1.4, 1.4 Hz, 2 H,
OCH2CH=CH2), 5.25 (ddt, J = 10.3, 1.4, 1.4 Hz, 1 Holef), 5.40 (ddt,
J = 17.2, 1.4, 1.4 Hz, 1 Holef), 6.06 (ddt, J = 17.2, 10.3, 5.0 Hz, 1
IR (ATR): 3275 (O–H), 1717 cm–1 (C=O).
1H NMR (CDCl3): δ = 0.30 [s, 9 H, Si(CH3)3], 0.91 (s, 3 H, CH3),
1.35–1.65 (m, 6 H), 1.94–2.20 (m, 4 H), 2.20–2.30 (m, 1 H), 2.40–
2.55 (m, 2 H), 2.82–2.92 (m, 2 H), 4.84 (s, 1 H, OH), 6.45 (s, 1
H
olef), 6.54 (s, 1 Harom, H-4), 7.32 (s, 1 Harom, H-1).
13C NMR (CDCl3): δ = –0.64, 14.49, 22.51, 26.25, 27.12, 30.28,
30.94, 34.39, 39.35, 43.90, 46.35, 49.51, 64.74, 65.40, 68.77,
111.01, 116.98, 119.61, 125.09, 132.26, 132.27, 133.84, 139.64,
161.41.
LRMS: m/z = 426 (M+, 47%).
HRMS: m/z calcd for C26H38O3Si (M+): 426.2590; found: 426.2589.
Harom, H-4), 7.29 (s, 1 Harom, H-1).
13C NMR (CDCl3): δ = –0.70, 14.00, 21.74, 26.06, 26.60, 29.59,
31.74, 36.04, 38.64, 44.20, 48.19, 50.54, 114.73, 122.67, 131.67,
132.37, 139.60, 158.60, 221.36.
LRMS: m/z = 342 (M+, 100%).
Claisen Rearrangement of Allyl Ether 16
HRMS: m/z calcd for C21H30O2Si (M+): 342.2015; found: 342.2013.
Allyl ether 16 (416 mg, 0.975 mmol) was heated at 209 °C for 3 h
and then at 220 °C for 3 h under N2. TLC analyses of the crude prod-
uct revealed only one spot, and the corresponding fraction was iso-
lated after flash chromatography on silica gel (hexane–
EtOAc, 95:5) as an adhesive colorless solid (297 mg). According to
1H NMR analysis, this fraction contained a mixture of compounds.
A portion of this fraction (280 mg) was dissolved in THF (7 mL),
aq 2 M HCl (2.6 mL) was added, and the mixture was shaken at r.t.
for 3 h. After workup according to general procedure B, flash chro-
matography on silica gel (hexane–EtOAc, 3:1) afforded compounds
17 (9 mg, 0.023 mmol, 2.5%), 4-allylestrone (4; 153 mg, 0.493
mmol, 51%), and 2,4-diallylestrone (18; 27 mg, 0.077 mmol, 8%).
2-Trimethylsilylestrone Allyl Ether 17: NaH (24 mg, 1 mmol, 80%
suspension in mineral oil) was added to a solution of 2-trimethylsi-
lylestrone (173 mg, 0.505 mmol) in anhyd THF (3 mL). After stir-
ring for 1 h at r.t., allyl bromide (122 mg, 1 mmol) was added, and
the mixture was stirred at 65 °C overnight. After cooling to r.t., the
mixture was hydrolyzed with sat. aq NH4Cl (5 mL) and extracted
with EtOAc (3 × 10 mL). The combined organic phases were
washed with brine (15 mL) and dried (Na2SO4). Concentration un-
der vacuum and flash chromatography of the residue on silica gel
(hexane–EtOAc, 3:1) afforded 17 as a colorless solid (142 mg,
0.371 mmol, 73%); mp 145–147 °C; [α]D +125.4 (c = 1.0,
CH2Cl2).
IR (ATR): 1736 (C=O), 1595 cm–1 (C=C).
1H NMR (CDCl3): δ = 0.27 [s, 9 H, Si(CH3)3], 0.91 (s, 3 H, CH3),
1.20–1.70 (m, 6 H), 1.92–2.34 (m, 5 H), 2.40–2.60 (m, 2 H), 2.84–
2.97 (m, 2 H),), 4.51 (ddd, J = 5.1, 1.4, 1.4 Hz, 2 H,
OCH2CH=CH2), 5.25 (ddt, J = 10.4, 1.4, 1.4 Hz, 1 Holef), 5.40 (ddt,
J = 17.1, 1.4, 1.4 Hz, 1 Holef), 6.06 (ddt, J = 17.1, 10.4, 5.1 Hz, 1
20
4-Allylestrone (4)
25
Colorless solid; mp 129–131 °C (Lit.9c mp 131–132 °C); [α]D
25
+118.1 (c = 1.0, CH2Cl2) {Lit.9b [α]D +115.3 (c = 1.0, 1,4-diox-
ane)}.
IR (ATR): 3351 (O–H), 1720 (C=O), 1636 cm–1 (C=C).
1H NMR (CDCl3): δ = 0.90 (s, 3 H, CH3), 1.20–1.70 (m, 6 H), 1.90–
2.50 (m, 7 H), 2.70–2.95 (m, 2 H), 3.42 (ddd, J = 5.8, 1.5, 1.5 Hz, 2
H, ArCH2), 4.86 (s, 1 H, OH), 5.03 (ddt, J = 17.1, 1.7, 1.7 Hz, 1
Holef), 6.55 (s, 1 Harom, H-4), 7.32 (s, 1 Harom, H-1).
13C NMR (CDCl3): δ = –0.66, 14.02, 21.74, 26.04, 26.69, 30.14,
31.78, 36.04, 38.67, 44.26, 48.20, 50.55, 68.79, 111.01, 117.07,
125.42, 131.60, 132.26, 133.75, 139.34, 161.56, 221.20.
LRMS: m/z = 382 (M+, 100%).
HRMS: m/z calcd for C24H34O2Si (M+): 382.2328; found: 382.2326.
H
olef), 5.06 (ddt, J = 10.6, 1.6, 1.6 Hz, 1 Holef), 5.96 (ddt, J = 17.1,
10.6, 5.8 Hz, 1 Holef), 6.67 (d, J = 8.4 Hz, 1 Harom, H-4), 7.10 (d,
J = 8.4 Hz, 1 Harom, H-1).
13C NMR (CDCl3): δ = 13.27, 21.71, 26.32, 26.84, 26.86, 30.28,
31.75, 36.06, 37.73, 44.51, 48.09, 50.58, 113.24, 115.49, 123.45,
124.55, 132.73, 135.69, 136.33, 152.14, 221.30.
LRMS: m/z = 310 (M+, 100%).
HRMS: m/z calcd for C21H26O2 (M+): 310.1933; found: 310.1935.
Thermal Transformation of 2-Trimethylsilylestrone Allyl
Ether 17
2-Trimethylsilylestrone allyl ether 17 (111 mg, 0.290 mmol) was
heated at 204 °C for 6 h under N2. The crude mixture was taken up
in CCl4 (1 mL), trifluoroacetic acid (1 mL) was added, and the mix-
ture was shaken at r.t. overnight. Dilution with EtOAc (10 mL),
washing with sat. aq NaHCO3 (5 mL) and brine (5 mL), drying
(Na2SO4), concentration under vacuum and flash chromatography
of the residue on silica gel (hexane–EtOAc, 3:1) afforded 4-al-
2,4-Diallylestrone (18)
20
White solid; mp 117–119 °C (Lit.9c mp 121.5–122 °C); [α]D
+107.0 (c = 0.5, CH2Cl2).
IR (ATR): 3407 (OH), 1721 (C=O), 1636 cm–1 (C=C).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3822–3828

3828
U. Schön et al.
PAPER
lylestrone (4; 44 mg, 0.142 mmol, 49%). For characterization, see
above.
13C NMR (CDCl3): δ = 13.99, 21.73, 26.06, 26.63, 29.61, 31.70,
36.03, 38.48, 44.09, 48.18, 50.54, 112.96, 115.42, 126.67, 132.21,
138.19, 153.65, 221.34.
Thermal Rearrangement of 2-Trimethylsilylestrone Ketal 15
2-Trimethylsilylestrone ketal 15 (72 mg, 0.186 mmol) was heated
at 204 °C for 5.5 h under N2. Flash chromatography of the crude
product on silica gel (hexane–EtOAc, 95:5) afforded O-trimethyl-
silylestrone ketal 20 as a colorless solid (55 mg, 0.142 mmol, 77%);
mp 93–96 °C. For characterization, see below.
HRMS (ESI): m/z calcd for C18H23O2 (M + H)+: 271.1698; found:
271.1697.
Acknowledgment
This work was funded in part by the Fonds der Chemischen Indu-
strie.
O-Trimethylsilylestrone Ketal 20
Esterone Ethylene Ketal: Amberlyst 15 (dry, 100 mg) was added to
a solution of estrone (1; 270 mg, 1 mmol), ethylene glycol (1.241 g,
20 mmol), and trimethyl orthoformate (1.061 g, 10 mmol) in anhyd
toluene (17 mL) and anhyd MeCN (17 mL), and the mixture was
stirred overnight at r.t. Filtration, concentration of the filtrate under
vacuum, and flash chromatography of the residue on silica gel (hex-
ane–EtOAc, 3:1) afforded estrone ethylene ketal as a colorless sol-
id; yield: 311 mg (0.989 mmol, 99%); mp 181–182 °C. For
characterization, see above.
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L.; Saarenketo, P.; Thole, H. Mol. Cell. Endocrinol. 2009,
301, 216.
O-Trimethylsilylestrone Ketal 20: A solution of Me3SiCl (130 mg,
1.2 mmol) in anhyd CH2Cl2 (1 mL) was added to a solution of es-
trone ethylene ketal (317 mg, 1.01 mmol), imidazole (89 mg, 1.3
mmol) and N,N-dimethylaminopyridine (61 mg, 0.5 mmol) in an-
hyd CH2Cl2 (10 mL). The mixture was stirred for 3 h at r.t. and then
concentrated under vacuum to give a white slurry, which was sus-
pended in the eluent (hexane–EtOAc, 9:1) and loaded on the top of
the chromatographic column filled with silica gel. Flash chromatog-
raphy (hexane–EtOAc, 9:1) afforded O-trimethylsilyl estrone ketal
20 as a colorless solid; yield: 360 mg (0.931 mmol, 92%); mp 93–
96 °C; [α]D23 +25.0 (c = 1.0, CH2Cl2).
1H NMR (CDCl3): δ = 0.25 [s, 9 H, Si(CH3)3], 0.88 (s, 3 H, CH3),
1.25–1.67 (m, 6 H), 1.70–1.90 (m, 4 H), 1.97–2.08 (m, 1 H), 2.18–
2.35 (m, 2 H), 2.73–2.89 (m, 2 H), 3.84–4.00 (m, 4 H, OCH2CH2O),
(8) Maltais, R.; Tremblay, M. R.; Ciobanu, L. C.; Poirier, D.
J. Comb. Chem. 2004, 6, 443.
(9) (a) Troisi, L.; Vasapollo, G.; El Ali, B.; Mele, G.; Florio, S.;
Capriati, V. Tetrahedron Lett. 1999, 40, 1771. (b) Holton, P.
G. J. Org. Chem. 1962, 27, 357. (c) Patton, T. L. J. Org.
Chem. 1962, 27, 910. (d) Barner, R.; Boller, A.; Borgulya,
J.; Herzog, E. G.; von Philipsborn, W.; von Planta, C.; Fürst,
A.; Schmid, H. Helv. Chim. Acta 1965, 48, 94.
(10) (a) Snieckus, V. Chem. Rev. 1990, 90, 879. (b) Hartung, C.
G.; Snieckus, V. In Modern Arene Chemistry; Astruc, D.,
Ed.; Wiley-VCH: Weinheim, 2002, 330–367.
6.56 (d, J = 2.4 Hz, 1 Harom, H-4), 6.62 (dd, J = 8.4, 2.4 Hz, 1 Harom
H-2), 7.13 (d, J = 8.4 Hz, 1 Harom, H-1).
,
13C NMR (CDCl3): δ = 0.42, 14.50, 22.51, 26.20, 27.14, 29.78,
30.91, 34.39, 39.12, 43.82, 46.32, 49.55, 64.73, 65.39, 117.29,
119.61, 120.10, 126.33, 133.51, 138.11, 152.96.
LRMS: m/z = 386 (M+, 57%).
HRMS: m/z calcd for C23H34O3Si (M+): 386.2277; found: 386.2279.
(11) (a) Pert, D. J.; Ridley, D. D. Aust. J. Chem. 1987, 40, 303.
(b) Leese, M. P.; Newman, S. P.; Purohit, A.; Reed, M. J.;
Potter, B. V. L. Bioorg. Med. Chem. Lett. 2004, 14, 3135.
(12) Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48, 1935.
(13) Austin, W. F.; Zhang, Y.; Danheiser, R. L. Tetrahedron
2008, 65, 915.
(14) Szele, I. Helv. Chim. Acta 1981, 64, 2733.
(15) Rao, P. N.; Wang, Z. Steroids 1997, 64, 487.
(16) Smith, A. US Patent 3138588, 1964.
(17) Danishefsky, S.; Cain, P. J. Am. Chem. Soc. 1975, 97, 5282.
(18) Quinkert, G.; Del Grosso, M.; Döring, A.; Döring, W.;
Schenkel, R. I.; Bauch, M.; Dambacher, G. T.; Bats, J. W.;
Zimmermann, G.; Dürner, G. Helv. Chim. Acta 1995, 78,
1345.
Acidic Treatment of O-Trimethylsilylestrone Ketal 20
Aq 2 M HCl (0.75 mL) was added to a solution of O-trimethylsi-
lylestrone ketal 20 (91 mg, 0.235 mmol) in THF (2.5 mL). After
shaking for 2 h, the mixture was worked up according to general
procedure B. Flash chromatography of the crude product on silica
gel (hexane–EtOAc, 2:1) afforded estrone (1) as a colorless solid;
yield: 60 mg (0.222 mmol, 95%); mp 254–256 °C (Lit.17 mp 255–
256 °C); [α]D22 +162.8 (c = 1.0, 1,4-dioxane) {Lit.18 [α]D +163.6
20
(c = 0.486, 1,4-dioxane)}.
IR (ATR): 3340 (O–H) 1716 cm–1 (C=O).
1H NMR (CDCl3): δ = 0.91 (s, 3 H, CH3), 1.30–1.65 (m, 6 H), 1.94–
2.19 (m, 4 H), 2.20–2.29 (m, 1 H), 2.37–2.40 (m, 1 H), 2.47–2.54
(m, 1 H), 2.85–2.90 (m, 2 H), 4.86 (s, 1 H, OH), 6.58 (d, J = 2.7 Hz,
1 Harom, H-4), 6.64 (dd, J = 8.4, 2.7 Hz, 1 Harom, H-2), 7.15 (d,
J = 8.4 Hz, 1 Harom, H-1).
Synthesis 2012, 44, 3822–3828
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