Synthesis of a novel enantiopure spiro-b-norestradiol analogue by multiple Pd-catalyzed transformations

Article abstract of DOI:10.1002/ejoc.200400263

The novel tetracyclic spiro compound 13 was synthesized by the use of two subsequent Pd-catalyzed reactions. Firstly, the ortho-bromobenzyl chloride 1 was coupled with the enantiopure boronic ester 8, obtained from the Hajos-Wiechert ketone in a chemoselective Suzuki-type reaction to give 12 in 77% yield. Unexpectedly, the intramolecular Heck reaction then did not provide the annulated compound 6, but the spirocyclic compound 13, containing a quaternary carbon center, in 73% yield. The Heck reaction was also performed under microwave irradiation conditions, allowing a considerably shorter reaction time. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400263

FULL PAPER
Synthesis of a Novel Enantiopure Spiro-B-norestradiol Analogue by Multiple
Pd-Catalyzed Transformations
Lutz F. Tietze,*[a] J. Matthias Wiegand,[a] and Carsten A. Vock[a]
Keywords: Heck reaction / Palladium / Spiro compounds / Steroids / Suzuki reaction
The novel tetracyclic spiro compound 13 was synthesized by
the use of two subsequent Pd-catalyzed reactions. Firstly, the
ortho-bromobenzyl chloride 1 was coupled with the enanti-
opure boronic ester 8, obtained from the Hajos−Wiechert ke-
tone in a chemoselective Suzuki-type reaction to give 12 in
77% yield. Unexpectedly, the intramolecular Heck reaction
cyclic compound 13, containing a quaternary carbon center,
in 73% yield. The Heck reaction was also performed under
microwave irradiation conditions, allowing a considerably
shorter reaction time.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
then did not provide the annulated compound 6, but the spiro- Germany, 2004)
Introduction
Pd-catalyzed reactions such as the Heck reaction or
cross-coupling reactions such as the Suzuki and the Stille
reactions have become very popular for the formation of
CϪC-bonds, thanks to their high tolerance of functional
groups and their general applicability.[1] The efficiency can
often be further improved by use of multiple Pd-catalyzed
transformations, either in a domino process[2,3] or in a
sequential fashion.[4] Nowadays, it is also possible to couple
compounds of lower reactivity, such as organic chlorides,
by employment of highly active catalysts[5] such as the
HerrmannϪBeller palladacene 14, or by application of new
laboratory techniques such as microwave irradiation.[6]
We recently used a multiple Pd-catalyzed process for the
synthesis of the B-norestradiol derivative 4 as a possible
ligand for the maxi-Kϩ-channel (Scheme 1).[4a] Compounds
of this type might show a protective effect on the cardiovas-
cular system and could therefore be usable in the treatment
of cardiovascular diseases. It has been shown that estradiol
5 binds extracellulary to the regulatory β-unit of the maxi-
Kϩ-channel, a key modulator of vascular muscle tone lo-
cated on the endothelium.[7] Unfortunately, 5 cannot be ap-
plied directly as a drug because of its hormonal activity, so
derivatives that still activate the maxi-Kϩ-channel but lack
the hormonal properties are required. One possibility is the
synthesis of B-norsteroids with a 6,5,6,5 ring system, which
have been shown to have reduced hormonal activity in re-
lation to compounds with the natural steroidal 6,6,6,5 scaf-
Scheme 1. (a) 5 mol % [Pd(PPh3)4], NaOH, THF, reflux, 22 h, 72%;
(b) 5 mol % 14, nBu4NOAc, DMF/MeCN/H2O, 140 °C (micro-
wave), 5 min, 70%
fold.[8] In this synthesis the benzylic chloride 1 and the bo-
ronic ester 2 were coupled in a Suzuki reaction to give the
secosteroid 3. The reaction showed high chemoselectivity,
and the coupling took place exclusively at the benzylic chlo-
ride moiety of 1, whereas the aryl bromide moiety seemed
to be inert. In a subsequent intramolecular Heck reaction
the steroidal compound 4 was formed through the use of
14 as catalyst under microwave irradiation conditions.
Our interest now focussed on the synthesis of other estra-
diol analogues, especially in the B-norestradiol series, in
which the positions of the olefinic double bonds differ from
those in 4 as in 6 to allow further functionalizations such
as epoxidation, bis(hydroxylation), and cyclopropanation.
We anticipated that 6 should be available from 1 and 8 via
7 through two Pd-catalyzed transformations as described
for 4 (Scheme 2).
[a]
Institut für Organische Chemie, Georg-August-Universität
Göttingen,
Tammannstr. 2, 37077 Göttingen, Germany
Fax: (internat.) ϩ 49-551-399476
E-mail: ltietze@gwdg.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2004, 4107Ϫ4112
DOI: 10.1002/ejoc.200400263
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4107

L. F. Tietze, J. M. Wiegand, C. A. Vock
FULL PAPER
was directly transesterified to give the more stable cyclic
boronic ester 8.
Analogously to the synthesis of 3, the benzylic chloride
1 and the boronic ester 8 were coupled in a Suzuki reaction
with 5 mol % of [Pd(PPh3)4] as catalyst and NaOH as base
to give the seco-B-norsteroid 12 in 77% yield (Scheme 4).
Again, solely the benzylic chloride moiety of 1 reacted and
no cross-coupling involving the aryl bromide moiety was
observed.
Scheme 2. Retrosynthesis of 6
Surprisingly, when 7 was subjected to the final intramol-
ecular Heck reaction, the ring closure did not take place as
expected to form a steroidal compound of type 6, but a
spirocyclic compound with a quaternary carbon center
was created.
Results and Discussion
Scheme 4. (a) 5 mol % [Pd(PPh3)4], NaOH, THF, reflux, 16 h, 77%;
(b) 5 mol % 14, nBu4NOAc, DMF/MeCN/H2O, 180 °C (micro-
wave), 30 min, 73%
The boronic ester 8 was prepared in four steps starting
from the enantiopure HajosϪWiechert ketone derivative 9
(Scheme 3).[9] Bromination of 9 in a mixture of diethyl ether
and acetic acid in the presence of the base 2,4,6-collidine
provided the corresponding α-bromo enone 20, which was
then reduced under Luche[10] conditions to give the α-
bromo allylic alcohol 10. Treatment of 10 with mesyl chlo-
ride and NEt3 as base yielded the mesylate, which was di-
rectly heated in DBU to give the vinyl bromide 11. The
attack of the base did not take place at the methylene moi-
ety adjacent to the OH group, presumably because of the
high steric demand of DBU, but at the vinylogous position.
Bromine/lithium exchange and quenching with B(OiPr)3
yielded the corresponding diisopropyl boronic ester, which
When 12 was heated in a mixture of DMF, MeCN, and
H2O with 5 mol % 14 as catalyst and nBu4NOAc as base,
either under microwave irradiation conditions at 180 °C for
30 min or at 120 °C for 18 h, the novel spirocyclic system
13 was obtained as a single diastereomer in 73% yield under
both sets of conditions. The structure of 13 was determined
by NMR experiments: the HMBC spectrum, for example,
showed correlations between C-11b and 1-H, 2-H, 3-H, 4-
H2, 6-H, 7-H2, 11-H and 3a-CH3 (Scheme 5).[11] The con-
figuration of the new stereogenic center C-11b was deter-
mined by NOE experiments, with selective irradiation at
frequencies assigned to the angular methyl group at C-3a
and to the aromatic proton 11-H revealing a strong corre-
lation and thus a cis orientation of the angular methyl
group and the aromatic ring. On the other hand, there was
no correlation of the methyl group and 1-H, clearly indicat-
ing that C-11b had to have the proposed (R) configuration.
Thus, in the Heck reaction of 12 the olefinic double bond
in the five-membered ring was, surprisingly, attacked by the
PdϪaryl species from the β-face despite the high steric de-
Scheme 3. (a) Br2, 2,4,6-collidine, Et2O, HOAc, room temp., dark,
24 h, 80%; (b) NaBH4, CeCl3·7H2O, MeOH, room temp., 4 h, 80%;
(c) MsCl, NEt3, CH2Cl2, room temp., 6 h; (d) DBU, 100 °C, 69%
(over two steps); (e) tBuLi, TMEDA, B(OiPr)3, THF, Ϫ78 °C to
room temp., 1 h; (f) 2,2-dimethylpropane-1,3-diol, toluene, room
temp., 16 h, 68% (over two steps)
Scheme 5. Structure determination of 13 by HMBC and NOE
experiments
4108
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 4107Ϫ4112

Synthesis of a Novel Enantiopure Spiro-B-norestradiol Analogue
FULL PAPER
mand of the angular methyl group. The selective formation Experimental Section
of the spiro compound could be explained by the fact that
exo-trig additions are favored over endo-trig additions. On
the other hand, it could also be possible that the carbopal-
ladation is reversible and that only in the intermediate lead-
ing to the spiro compound can a conformation appropriate
to allow a fast β-hydride elimination be adopted.[4f,12]
It should be noted that 13 is not very stable and decom-
poses in chloroform solution at 20 °C within 48 h. It was
therefore subjected to further transformations (Scheme 6).
Hydrogenation of the two olefinic double bonds with
20 mol % PtO2·H2O as catalyst afforded the stable com-
pound 15, which bears another stereogenic center, in a
highly stereoselective manner. Its configuration was again
determined by NOE experiments. As would be expected,
the attack of hydrogen took place from the less crowded α-
face of the molecule to give 15 with an (R) configuration at
C-6a.11 The tBu protection group was then removed in 97%
yield with TMSI as weak Lewis acid. Interestingly, it was
not possible to acylate the resulting alcohol 16, probably
because of the strong shielding of the hydroxy group by the
angular methyl group and the aromatic ring. Oxidation of
16 with DessϪMartin periodinane was possible, however,
providing the ketone 18 in 76% yield, and this was then
transformed into the corresponding 2,4-dinitrophenyl hy-
drazone 19.
General Remarks: Melting points were measured with a Mettler
FP61 melting point apparatus and are uncorrected. Optical ro-
1
tations were taken with a PerkinϪElmer 241 spectrometer. H and
13C NMR spectra were recorded with Mercury-200, VXR-200, Un-
ity 300, Inova-500, Unity Inova-600 (Varian) or AMX 300 (Bruker)
spectrometers. Chemical shifts are reported in δ ppm referenced to
TMS (1H NMR) or to CDCl3 (13C NMR) as internal standard. IR
spectra were taken with a Bruker IFS 25 and UV spectra with a
PerkinϪElmer Lambda 2 spectrometer. Mass spectra were meas-
ured with a Varian MAT 311A (low resolution) and with a
MAT 731 (high resolution). Microwave heating was performed in
a Personal Chemistry SmithCreator microwave reactor. Precoated
silica gel SIL G/UV254 (MachereyϪNagel & Co) was used for TLC,
and Kieselgel 60 (0.032Ϫ0.063 nm, Merck) for flash chromatogra-
phy. All reactions were performed under argon in oven-dried glass-
ware. Solvents were dried and distilled prior to use by the usual
laboratory methods, commercially available chemicals were used
without further purification, 2-bromo-5-methoxybenzyl chloride
(1) and (Ϫ)-(1S,7aS)-1-tert-butoxy-7a-methyl-1,2,3,6,7,7a-hexa-
hydroinden-5-one (9) are known substances and can be prepared
by literature methods.[9,13]
(؊)-(1S,7aS)-4-Bromo-1-tert-butoxy-7a-methyl-1,2,3,6,7,7a-hexa-
hydroinden-5-one (20): A solution of Br2 (5.00 equiv., 250 mmol,
12.8 mL) in HOAc (325 mL) was added at 0 °C to a solution of
enone 9 (1.00 equiv., 50.0 mmol, 11.1 g) in Et2O (500 mL) and
2,4,6-collidine (100 mL), and the mixture was then stirred in the
absence of light at room temperature for 24 h. Excess bromine was
destroyed by addition of a saturated solution of Na2S2O3, and the
aqueous layer was then separated and extracted three times with
Et2O. The combined organic phases were washed with a saturated
solution of NaHCO3 and dried with Na2SO4, and the solvent was
removed in vacuo. Recrystallisation (pentane) of the residue yielded
20 (12.0 g, 39.8 mmol, 80%) as a white solid. Rf ϭ 0.45 (pentane/
1
tBuOMe, 9:1). M.p. 103 °C. [α]2D0 ϭ Ϫ47.0 (c ϭ 0.5 in CHCl3). H
NMR (600 MHz, CDCl3): δ ϭ 1.13 (s, 3 H, 7a-CH3), 1.16 [s, 9 H,
C(CH3)3], 1.79 (dt, J ϭ 13.7, 5.2 Hz, 1 H, 7-Hb), 1.83 (ddt, J ϭ
22.9, 20.8, 10.2 Hz, 1 H, 2-Hb), 1.98Ϫ2.04 (m, 2 H, 2-Ha, 7-Ha),
2.45 (dt, J ϭ 20.8, 9.3 Hz, 1 H, 3-Hb), 2.58Ϫ2.66 (m, 2 H, 3-Ha, 6-
Hb), 2.71 (ddd, J ϭ 17.9, 14.4, 5.2 Hz, 1 H, 6-Ha), 3.63 (dd, J ϭ
10.2, 7.3 Hz, 1 H, 1-H) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ
15.67 (7a-CH3), 28.57 [C(CH3)3], 29.60, 30.17 (C-3, C-7), 33.68,
34.13 (C-2, C-6), 48.64 (C-7a), 73.28 [C(CH3)3], 79.75 (C-1), 118.4
(C-4), 173.5 (C-3a), 190.7 (C-5) ppm. IR (KBr): ν˜ ϭ 2972 cmϪ1
(CH), 1686 (CϭO), 1097 (CϪOϪC). UV (MeCN): λmax. (lg ε) ϭ
258 nm (3.924). MS (DCI, 200 eV): m/z (%) ϭ 622, 620, 618 (26)
[2 M ϩ NH4ϩ], 320, 318 (100) [M ϩ NH4ϩ]. C14H21BrO2 (301.22):
calcd. C 55.82, H 7.03; found C 55.76, H 6.82.
Scheme 6. (a) 20 mol % PtO2·H2O, H2, MeOH, room temp. 18 h,
96%; (b) TMSI, CH2Cl2, room temp., dark, 16 h, 97%; (c) DMP,
CH2Cl2, room temp., 6 h, 76%; (d) 2,4-dinitrophenylhydrazine,
H2SO4, EtOH, room temp., 1 h, 77%
Conclusion
(؊)-(1S,5S,7aS)-4-Bromo-1-tert-butoxy-7a-methyl-2,3,5,6,7,7a-
The novel unusual spirocyclic compound 13 was synthe- hexahydro-1H-inden-5-ol (10): NaBH4 (1.20 equiv., 27.9 mmol,
1.06 g) was added portionwise at 0 °C to a solution of α-bromo-
enone 20 (1.00 equiv., 23.2 mmol, 7.00 g) and CeCl3·7H2O (1.20
equiv., 27.9 mmol, 10.4 g) in MeOH (75 mL), and the mixture was
then stirred at room temperature for 4 h. The solvent was removed
in vacuo, and the resulting residue was taken up in Et2O and a
saturated solution of NH4Cl. The aqueous layer was separated and
extracted three times with Et2O, the combined organic phases were
dried with Na2SO4, and the solvent was removed in vacuo. After
purification of the crude product by flash chromatography (200 g
SiO2; pentane/tBuOMe, 9:1), 10 was obtained (5.63 g, 18.6 mmol,
80%) as a colorless oil that slowly crystallized. Rf ϭ 0.37 (pentane/
sized by a sequence of two Pd-catalyzed reactions as the
key steps, starting from the benzylic chloride 1 and the bo-
ronic ester 8. In the first Suzuki reaction the benzylic chlo-
ride moiety showed a much higher reactivity than the aryl
bromide moiety, allowing a chemoselective transformation.
In the subsequent intramolecular Heck reaction of 12 only
the spiro compound 13 was formed, and none of the ex-
pected annulated compounds such as 6. Here the attack of
the PdϪaryl species takes places syn to the angular methyl
group.
Eur. J. Org. Chem. 2004, 4107Ϫ4112
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L. F. Tietze, J. M. Wiegand, C. A. Vock
FULL PAPER
1
tBuOMe, 9:1). M.p. 60 °C. [α]2D0 ϭ Ϫ17.2 (c ϭ 0.5 in CHCl3). H organic phases were dried with Na2SO4, and the solvent was re-
NMR (500 MHz, CDCl3): δ ϭ 1.00 (s, 3 H, 7a-CH3), 1.12 [s, 9 H, moved in vacuo. Purification of the crude product by flash chroma-
C(CH3)3], 1.35 (td, J ϭ 13.9, 3.2 Hz, 1 H, 7-Hα), 1.65Ϫ1.75 (m, tography (100 g SiO2; pentane/tBuOMe, 19:1) gave 8 as a slightly
2 H, 2-Hβ, 7-Hβ), 1.82Ϫ1.91 (m, 2 H, 2-Hα, 6-Hβ), 2.13Ϫ2.27 (m, yellow solid (1.08 g, 3.39 mmol, 68%). Rf ϭ 0.27Ϫ0.66 (pentane/
1
3 H, 3-Hα, 6-Hα, OH), 2.29Ϫ2.37 (m, 1 H, 3-Hβ), 3.42 (dd, J ϭ
tBuOMe, 9:1). M.p. 100 °C. [α]2D0 ϭ Ϫ58.8 (c ϭ 1.0 in CHCl3). H
10.0, 7.6 Hz, 1 H, 1-H), 4.23 (mc, 1 H, 5-H) ppm. 13C NMR NMR (500 MHz, CDCl3): δ ϭ 0.86 (s, 3 H, 7a-CH3), 0.96 [s, 6 H,
(50.3 MHz, CDCl3): δ ϭ 17.18 (7a-CH3), 28.01 (C-3), 28.66 C(CH3)2], 1.14 [s, 9 H, C(CH3)3], 1.26 (td, J ϭ 12.1, 5.9 Hz, 1 H,
[C(CH3)3], 29.54, 29.63 (C-2, C-6), 33.34 (C-7), 47.52 (C-7a), 71.72 7-Hb), 1.78 (dd, J ϭ 12.4, 5.5 Hz, 1 H, 7-Ha), 2.13Ϫ2.21 (m, 1 H,
(C-5), 72.85 [C(CH3)3], 80.10 (C-1), 121.5 (C-4), 148.2 (C-3a) ppm. 6-Hb), 2.23Ϫ2.36 (m, 3 H, 2-H2, 6-Ha), 3.64 (s, 4 H, 2 ϫ OCH2),
IR (film): ν˜ ϭ 3385 cmϪ1 (OH), 2973 (CH), 1099 (CϪOϪC). UV 3.71 (t, J ϭ 8.2 Hz, 1 H, 1-H), 5.82 (mc, 1 H, 3-H), 6.43Ϫ6.49 (m,
(MeCN): λmax. (lg ε) ϭ 204 nm (3.933). MS (EI, 70 eV): m/z (%) ϭ 1 H, 5-H) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 15.52 (7a-
230, 228 (24) [Mϩ Ϫ C4H8 Ϫ H2O], 167 (37) [Mϩ Ϫ Br Ϫ C4H8], CH3), 21.88 [C(CH3)2], 24.60 (C-6), 28.75 [C(CH3)3], 31.62
149 (39) [Mϩ Ϫ Br Ϫ C4H8 Ϫ H2O], 57 (100) [C4H9ϩ]. C14H23BrO2 [C(CH3)2], 33.59 (C-7), 38.22 (C-2), 44.64 (C-7a), 72.06 (2 ϫ
(303.24): calcd. C 55.45, H 7.65; found C 55.43, H 7.37.
OCH2), 72.40 [C(CH3)3], 81.29 (C-1), 106.9 (C-4), 120.9 (C-3),
141.5 (C-5), 145.9 (C-3a) ppm. IR (KBr): ν˜ ϭ 2969 cmϪ1 (CH),
1579 (CϭC), 1095 (CϪOϪC). UV (MeCN): λmax. (lg ε) ϭ 195 nm
(3.867), 251 (3.876). MS (EI, 70 eV): m/z (%) ϭ 318 (32) [Mϩ], 262
(34) [Mϩ Ϫ C4H8], 233 (64) [Mϩ Ϫ C4H9 Ϫ C2H4], 131 (64) [Mϩ Ϫ
C5H10BO2 Ϫ C4H8 Ϫ H2O], 57 (100) [C4H9ϩ]. C19H31BO3 (318.26):
calcd. 318.2366; found 318.2366.
(؊)-(1S,7aS)-4-Bromo-1-tert-butoxy-7a-methyl-2,6,7,7a-tetrahydro-
1H-indene (11): Mesyl chloride (1.20 equiv., 36.4 mmol, 2.82 mL)
and NEt3 (1.50 equiv., 45.5 mmol, 6.40 mL) were added to a solu-
tion of alcohol 10 (1.00 equiv., 30.3 mmol, 9.20 g) in CH2Cl2
(150 mL), and the reaction mixture was stirred at room tempera-
ture for 6 h. Et2O and brine were then added, the aqueous layer
was separated and extracted three times with Et2O, the combined
organic phases were dried with Na2SO4, and the solvent was re-
moved in vacuo. Without further purification, the obtained mesyl-
(؊)-(1S,7aS)-4-(2-Bromo-5-methoxybenzyl)-1-tert-butoxy-7a-
methyl-2,6,7,7a-tetrahydro-1H-indene (12): A solution of boronic
ester 8 (1.20 equiv., 3.00 mmol, 955 mg), benzylic chloride 1 (1.00
ate was dissolved in DBU (1.20 equiv., 36.4 mmol, 5.50 mL), and equiv., 2.50 mmol, 589 mg), Pd(PPh3)4 (5.00 mol %, 0.13 mmol,
the solution was stirred at 100 °C for 90 min. The reaction mixture
was diluted with Et2O and a saturated solution of NH4Cl, the
aqueous layer was separated and extracted three times with Et2O,
the combined organic phases were washed with brine and dried
with Na2SO4, and the solvent was removed in vacuo. Purification
144 mg), and NaOH (1.50 equiv., 3.75 mmol, 150 mg) in THF
(12.5 mL) was heated at reflux for 16 h. H2O and Et2O were added
to the reaction mixture, the aqueous layer was separated and ex-
tracted three times with Et2O, the combined organic phases were
washed with H2O and dried with Na2SO4, and the solvent was
by flash chromatography (300 g SiO2; pentane/tBuOMe, 24:1) gave removed in vacuo. After flash chromatography (100 g SiO2; pen-
11 as a colorless solid (5.96 g, 20.9 mmol, 69% over two steps).
tane/tBuOMe, 99:1), 12 was obtained (784 mg, 1.93 mmol, 77%) as
a colorless oil. Rf ϭ 0.60 (pentane/tBuOMe, 24:1). [α]2D0 ϭ Ϫ63.7
(c ϭ 1.0 in CHCl3). 1H NMR (200 MHz, CDCl3): δ ϭ 0.95 (s, 3 H,
Rf ϭ 0.83 (pentane/tBuOMe, 24:1). M.p. 62 °C. [α]2D0 ϭ Ϫ26.0 (c ϭ
1
0.5 in CHCl3). H NMR (300 MHz, CDCl3): δ ϭ 0.95 (s, 3 H, 7a-
CH3), 1.17 [s, 9 H, C(CH3)3], 1.36 (td, J ϭ 12.2, 5.9 Hz, 1 H, 7- 7a-CH3), 1.17 [s, 9 H, C(CH3)3], 1.34 (td, J ϭ 12.1, 6.1 Hz, 1 H, 7-
Hb), 1.78Ϫ1.86 (m, 1 H, 7-Ha), 2.16Ϫ2.28 (m, 1 H, 6-Hb), Hb), 1.77Ϫ1.88 (m, 1 H, 7-Ha), 2.06Ϫ2.47 (m, 4 H, 2-H2, 6-H2),
2.30Ϫ2.50 (m, 3 H, 2-H2, 6-Ha), 3.83 (t, J ϭ 8.0 Hz, 1 H, 1-H), 3.48 (d, J ϭ 16.4 Hz, 1 H, 1Ј-Hb), 3.58 (d, J ϭ 16.4 Hz, 1 H, 1Ј-
5.64 (mc, 1 H, 3-H), 6.05Ϫ6.10 (mc, 1 H, 5-H) ppm. 13C NMR Ha), 3.74 (s, 3 H, OCH3), 3.78 (t, J ϭ 8.4 Hz, 1 H, 1-H), 5.32 (mc,
(50.3 MHz, CDCl3): δ ϭ 15.42 (7a-CH3), 26.07 (C-6), 28.64 1 H, 3-H), 5.36Ϫ5.43 (m, 1 H, 5-H), 6.62 (dd, J ϭ 8.7, 3.1 Hz, 1 H,
[C(CH3)3], 33.11 (C-7), 37.61 (C-2), 47.59 (C-7a), 72.74 [C(CH3)3], 4ЈЈ-H), 6.73 (d, J ϭ 3.1 Hz, 1 H, 6ЈЈ-H), 7.40 (d, J ϭ 8.7 Hz, 1 H,
81.41 (C-1), 117.3 (C-4), 123.8 (C-3), 130.7 (C-5), 144.2 (C-3a) 3ЈЈ-H) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 15.54 (7a-CH3),
ppm. IR (KBr): ν˜
(CϪOϪC). UV (MeCN): λmax. (lg ε) ϭ 244 nm (3.900). MS (EI,
70 eV): m/z (%) ϭ 286, 284 (11) [Mϩ], 230, 228 (14) [Mϩ Ϫ C4H8], (C-4ЈЈ), 115.4 (C-2ЈЈ), 115.7 (C-6ЈЈ), 118.1 (C-3), 127.6 (C-5), 130.9
201, 199 (10) [Mϩ Ϫ C4H9 Ϫ C2H4], 149 (14) [Mϩ Ϫ Br Ϫ C4H8],
(C-4), 132.9 (C-3ЈЈ), 140.7, 145.5 (C-3a, C-1ЈЈ), 158.8 (C-5ЈЈ) ppm.
57 (100) [C4H9ϩ]. C14H21BrO (285.22): calcd. 284.0776; found IR (film): ν˜ ϭ 2972 cmϪ1 (CH), 1593 (CϭC), 1469 (CϭC), 1094
ϭ
2972 cmϪ1 (CH), 1587 (CϭC), 1088 23.72 (C-6), 28.72 [C(CH3)3], 33.88 (C-7), 38.14 (C-2), 38.75 (C-
1Ј), 45.29 (C-7a), 55.32 (OCH3), 72.52 [C(CH3)3], 81.36 (C-1), 113.4
284.0776.
(CϪOϪC). UV (MeCN): λmax. (lg ε) ϭ 200 nm (4.618), 231
(4.245), 281 (3.299). MS (EI, 70 eV): m/z (%) ϭ 406, 404 (1) [Mϩ],
325 (42) [Mϩ Ϫ Br], 296 (38) [Mϩ Ϫ Br Ϫ C4H8], 251 (43) [Mϩ
Ϫ
(؊)-2-((1S,7aS)-1-tert-Butoxy-7a-methyl-2,6,7,7a-tetrahydro-1H-
inden-4-yl)-5,5-dimethyl-[1,3,2]dioxaborinane (8): tBuLi (2.05
equiv., 10.3 mmol, 6.83 mL, 1.5  in pentane) was added at Ϫ78
°C to a solution of vinyl bromide 11 (1.00 equiv., 5.00 mmol,
1.43 g) and TMEDA (1.10 equiv., 5.50 mmol, 830 µL) in THF
(50 mL), and the mixture was stirred at this temperature for 20 min.
B(OiPr)3 (2.00 equiv., 10.0 mmol, 2.32 mL) was then added, and
the reaction mixture was stirred at Ϫ78 °C for 2 h, at 0 °C for 1 h,
Br Ϫ C4H8 Ϫ H2O], 225 (100) [Mϩ Ϫ Br Ϫ C4H8 Ϫ C2H2 Ϫ H2O],
201, 199 (34) [C8H8BrOϩ], 57 (62) [C4H9ϩ]. C22H29BrO2 (405.38):
calcd. C 65.18, H 7.21; found C 65.50, H 6.89.
(؊)-(3S,3aS,11bR)-3-tert-Butoxy-9-methoxy-3a-methyl-3,3a,4,5,
7,11b-hexahydro-cyclopenta[d]fluorene (13): A solution of seco com-
pound 12 (1.00 equiv., 250 µmol, 101 mg), catalyst 14 (5.00 mol %,
and at room temperature for 1 h. Brine and Et2O were added, the 12.5 µmol, 11.7 mg), and nBu4NOAc (2.00 equiv., 500 µmol,
aqueous layer was separated and extracted three times with Et2O,
the combined organic phases were dried with Na2SO4, and the sol-
vent was removed in vacuo. The resulting residue was taken up in
151 mg) in a mixture of DMF/MeCN/H2O (5 mL, 5:5:1) was
heated at 180 °C for 30 min with application of microwave ir-
radiation. (Alternatively, the reaction mixture can be heated under
toluene (50 mL), 2,2-dimethylpropane-1,3-diol (1.20 equiv., standard conditions at 120 °C for 18 h.) H2O and Et2O were then
6.00 mmol, 620 mg) was added, and the mixture was stirred at added, the aqueous layer was separated and extracted three times
room temperature for 16 h. H2O was added, the aqueous layer was
with Et2O, the combined organic phases were dried with Na2SO4,
separated and extracted three times with CH2Cl2, the combined and the solvent was removed in vacuo. The crude product was puri-
4110
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4107Ϫ4112

Synthesis of a Novel Enantiopure Spiro-B-norestradiol Analogue
FULL PAPER
fied by flash chromatography (50 g SiO2; pentane/tBuOMe, 200:1)
to give 13 as a colorless oil (59.3 mg, 183 µmol, 73%). Rf ϭ 0.68
(pentane/tBuOMe, 24:1). [α]2D0 ϭ Ϫ117.3 (c ϭ 1.0 in CHCl3). 1H
(dd, J ϭ 15.5, 8.5 Hz, 1 H, 7-Hb), 2.72 (dd, J ϭ 15.5, 8.0 Hz, 1 H,
7-Ha), 3.78 (s, 3 H, OCH3), 3.96 (dd, J ϭ 7.4, 3.5 Hz, 1 H, 3-H),
6.67Ϫ6.74 (m, 2 H, 8-H, 10-H), 7.40 (d, J ϭ 8.3 Hz, 1 H, 11-H)
NMR (600 MHz, CDCl3): δ ϭ 0.88 (s, 3 H, 3a-CH3), 1.27 [s, 9 H, ppm. 13C NMR (150 MHz, CDCl3): δ ϭ 17.82 (C-5, 3a-CH3),
C(CH3)3], 1.45 (dd, J ϭ 12.6, 5.3 Hz, 1 H, 4-Hβ), 1.74 (td, J ϭ 25.98 (C-6), 31.65 (C-2), 33.97 (C-4), 35.44 (C-1), 36.56 (C-7), 44.85
12.6, 5.9 Hz, 1 H, 4-Hα), 1.98Ϫ2.04 (m, 1 H, 5-Hα), 2.12Ϫ2.20 (m,
(C-6a), 47.63 (C-3a), 55.19 (OCH3), 56.93 (C-11b), 82.43 (C-3),
1 H, 5-Hβ), 3.32 (d, J ϭ 17.6 Hz, 1 H, 7-Hb), 3.64Ϫ3.69 (m, 1 H, 109.7 (C-8), 111.4 (C-10), 125.6 (C-11), 143.4 (C-11a), 144.7 (C-
7-Ha), 3.75 (s, 3 H, OCH3), 3.96 (d, J ϭ 2.5 Hz, 1 H, 3-H), 5.55 7a), 158.1 (C-9) ppm. IR (film): ν˜ ϭ 3441 cmϪ1 (OH), 2925 (CH),
(dd, J ϭ 5.6, 2.5 Hz, 1 H, 2-H), 5.62 (mc, 1 H, 6-H), 5.85 (d, J ϭ
1489, 1246 (CϪOH). UV (MeCN): λmax. (lg ε) ϭ 200 nm (4.606),
5.6 Hz, 1 H, 1-H), 6.68Ϫ6.71 (m, 2 H, 8-H, 10-H), 7.70Ϫ7.72 (m, 221 (3.886), 228 (3.895), 281 (3.380), 288 (3.328). MS (EI, 70 eV):
1 H, 11-H) ppm. 13C NMR (75.5 MHz, CDCl3): δ ϭ 14.83 (3a-
CH3), 22.86 (C-5), 28.58 [C(CH3)3], 34.81 (C-4), 38.35 (C-7), 42.85
(C-3a), 55.24 (OCH3), 64.41 (C-11b), 73.24 [C(CH3)3], 83.29 (C-3),
108.8 (C-8), 112.2 (C-10), 120.0 (C-6), 128.0 (C-11), 128.1 (C-2),
138.6 (C-11a), 140.9 (C-6a), 141.3 (C-1), 142.5 (C-7a), 158.4 (C-9)
m/z (%) ϭ 272 (100) [Mϩ], 213 (36) [Mϩ Ϫ C3H7O], 173 (50), 160
(51). C18H24O2 (272.39): calcd. 272.1776; found 272.1776.
(؊)-(3aS,6aR,11bR)-9-Methoxy-3a-methyl-1,2,4,5,6,6a,7,11b-
octahydro-3aH-cyclopenta[d]fluoren-3-one (18): DMP (1.50 equiv.,
248 µmol, 105 mg) was added at 0 °C to a solution of alcohol 16
(1.00 equiv., 165 µmol, 45.0 mg) in CH2Cl2 (2.5 mL), and the reac-
tion mixture was stirred at room temperature for 6 h. A saturated
solution of NaHCO3 (1.5 mL) and a solution of Na2S2O3 (1 ,
1.5 mL) were added simultaneously, and the reaction mixture was
stirred until it became clear again. H2O and CH2Cl2 were added,
ppm. IR (KBr): ν˜
ϭ
2971 cmϪ1 (CH), 1607 (CϭC), 1079
(CϪOϪC). UV (MeCN): λmax. (lg ε) ϭ 200 nm (4.540), 236
(4.287), 281 (3.501), 288 (3.453), 325 (2.554), 339 (2.557). MS (EI,
70 eV): m/z (%) ϭ 324 (74) [Mϩ], 286 (100) [Mϩ Ϫ C4H8], 250 (36)
[Mϩ Ϫ C4H8 Ϫ H2O], 57 (42) [C4H9ϩ]. C22H28O2 (324.46).
(؊)-(3S,3aS,6aR,11bR)-3-tert-Butoxy-9-methoxy-3a-methyl-1,2,3, the aqueous layer was separated and extracted three times with
3a,4,5,6,6a,7,11b-decahydrocyclopenta[d]fluorene (15): PtO2·H2O CH2Cl2, the combined organic phases were dried with Na2SO4, and
(20.0 mol %, 45.6 µmol, 11.2 mg) was added to a solution of diene the solvent was removed in vacuo. Purification by flash chromatog-
13 (1.00 equiv., 228 µmol, 74.0 mg) in MeOH (5 mL), and the reac-
tion mixture was stirred at room temperature under hydrogen for
18 h. After filtration and removal of the solvent, the residue was Ϫ21.5 (c ϭ 0.2 in CHCl3). H NMR (600 MHz, CDCl3): δ ϭ 0.74
raphy (5 g SiO2; pentane/tBuOMe, 9:1) gave 18 (34.0 mg, 126 µmol,
76%) as a colorless oil. Rf ϭ 0.34 (pentane/tBuOMe, 9:1). [α]2D0
ϭ
1
purified by flash chromatography (25 g SiO2; pentane/tBuOMe,
200:1) to give 15 as a colorless oil (72.0 mg, 219 µmol, 96%). Rf ϭ
0.70 (pentane/tBuOMe, 24:1). [α]2D0 ϭ Ϫ9.4 (c ϭ 1.0 in CHCl3). 1H
(s, 3 H, 3a-CH3), 1.22Ϫ1.30 (m, 1 H, 4-Hb), 1.40Ϫ1.56 (m, 3 H, 4-
Ha, 5-H2), 1.60Ϫ1.65 (m, 1 H, 6-Hb), 1.66Ϫ1.73 (m, 1 H, 6-Ha),
2.03 (ddd, J ϭ 13.6, 9.2, 5.2 Hz, 1 H, 1-Hb), 2.22Ϫ2.28 (m, 2 H, 1-
NMR (600 MHz, CDCl3): δ ϭ 0.88 (s, 3 H, 3a-CH3), 1.14 [s, 9 H, Ha, 6a-H), 2.51Ϫ2.62 (m, 2 H, 2-H2), 2.69 (dd, J ϭ 15.6, 9.4 Hz,
C(CH3)3], 1.20Ϫ1.26 (m, 1 H, 4-Hb), 1.36Ϫ1.43 (m, 2 H, 4-Ha, 6- 1 H, 7-Hb), 2.80 (dd, J ϭ 15.6, 7.9 Hz, 1 H, 7-Ha), 3.75 (s, 3 H,
Hb), 1.48Ϫ1.53 (m, 2 H, 5-H2), 1.58Ϫ1.63 (m, 1 H, 6-Ha), OCH3), 6.66 (dd, J ϭ 8.4, 2.5 Hz, 1 H, 10-H), 6.75 (d, J ϭ 2.5 Hz,
1.68Ϫ1.74 (m, 1 H, 2-Hb), 1.89 (t, J ϭ 8.3 Hz, 2 H, 1-H2), 1 H, 8-H), 6.95 (d, J ϭ 8.4 Hz, 1 H, 11-H) ppm. 13C NMR
2.12Ϫ2.20 (m, 2 H, 2-Ha, 6a-H), 2.54 (dd, J ϭ 15.4, 6.7 Hz, 1 H, (50.3 MHz, CDCl3): δ ϭ 17.46 (C-5), 18.75 (3a-CH3), 25.46 (C-6),
7-Hβ), 2.79 (dd, J ϭ 15.4, 7.2 Hz, 1 H, 7-Hα), 3.76Ϫ3.80 (m, 4 H, 29.78 (C-1), 31.43 (C-4), 35.28 (C-2), 36.61 (C-7), 43.77 (C-6a),
3-H, OCH3), 6.66 (dd, J ϭ 8.5, 2.5 Hz, 1 H, 10-H), 6.70 (d, J ϭ
2.5 Hz, 1 H, 8-H), 7.47 (d, J ϭ 8.5 Hz, 1 H, 11-H) ppm. 13C NMR 10), 123.4 (C-11), 141.5 (C-11a), 144.5 (C-7a), 158.7 (C-9), 223.0
(50.3 MHz, CDCl3): δ ϭ 18.80 (C-5), 19.25 (3a-CH3), 27.37 (C-6),
(C-3) ppm. IR (film): ν˜ ϭ 2934 cmϪ1 (CH), 1733 (CϭO), 1489,
52.74 (C-3a), 55.17 (C-11b), 55.25 (OCH3), 110.4 (C-8), 112.3 (C-
28.71 [C(CH3)3], 32.30 (C-2), 33.66 (C-4), 35.79 (C-1), 37.07 (C- 1248. UV (MeCN): λmax. (lg ε) ϭ 199 nm (4.589), 220 (3.897), 282
7), 44.41 (C-6a), 47.18 (C-3a), 55.17 (OCH3), 57.18 (C-11b), 72.61 (3.397). MS (EI, 70 eV): m/z (%) ϭ 270 (100) [Mϩ], 213 (35) [Mϩ
[C(CH3)3], 79.08 (C-3), 109.6 (C-8), 111.3 (C-10), 126.8 (C-11), Ϫ C3H5O], 185 (28) [Mϩ Ϫ C3H5O Ϫ C2H4]. C18H22O2 (270.37):
142.9 (C-11a), 144.8 (C-7a), 157.9 (C-9) ppm. IR (KBr): ν˜ ϭ
2928 cmϪ1 (CH), 1489, 1086 (CϪOϪC). UV (MeCN): λmax.
(lg ε) ϭ 200 nm (4.619), 228 (3.966), 281 (3.427), 287 (3.376). MS
(EI, 70 eV): m/z (%) ϭ 328 (48) [Mϩ], 271 (23) [Mϩ Ϫ C4H9], 253
(30) [Mϩ Ϫ C4H9 Ϫ H2O], 215 (100), 165 (34). C22H32O2 (328.49):
calcd. 328.2402; found 328.2402.
calcd. 270.1620; found 270.1620.
(؉)-(3aS,6aR,11bR)-9-Methoxy-3a-methyl-1,2,4,5,6,6a,7,11b-
octahydro-3aH-cyclopenta[d]fluoren-3-one (2,4-Dinitro-phenylhydra-
zone) (19): A solution of ketone 18 (1.00 equiv., 92.5 µmol, 25.0 mg)
in EtOH (0.25 mL) was added to a solution of 2,4-dinitrophenylhy-
drazine (5.46 equiv., 505 µmol, 100 mg) in a mixture of EtOH
(2.5 mL), H2O (0.75 mL) and concentrated H2SO4 (0.5 mL), and
the reaction mixture was kept at 0 °C for 15 h. After filtration and
purification by flash chromatography (10 g SiO2; pentane/tBuOMe,
9:1), 19 was obtained (32.0 mg, 71.0 µmol, 77%) as an orange solid.
(؊)-(3S,3aS,6aR,11bR)-9-Methoxy-3a-methyl-1,2,3,3a,4,5,6,6a,
7,11b-decahydro-cyclopenta[d]fluoren-3-ol (16): A solution of 15
(1.00 equiv., 36.5 µmol, 12.0 mg) and iodotrimethylsilane (1.00
equiv., 36.5 µmol, 5.2 µL) in CH2Cl2 (3.5 mL) was stirred in the
absence of light at room temperature for 16 h. MeOH (0.1 mL) was
Rf ϭ 0.42 (pentane/tBuOMe, 9:1). [α]2D0 ϭ ϩ177.0 (c ϭ 0.2 in
1
added, and the solution was stirred for another 15 min. H2O was CHCl3). H NMR (300 MHz, CDCl3): δ ϭ 0.93 (s, 3 H, 3a-CH3),
then added, the aqueous layer was separated and extracted three
times with CH2Cl2, the combined organic fractions were dried with
1.41Ϫ1.77 (m, 6 H, 4-H2, 5-H2, 6-H2), 2.13 (ddd, J ϭ 13.6, 9.1,
4.3 Hz, 1 H, 1-Hb), 2.31Ϫ2.44 (m, 2 H, 1-Ha, 6a-H), 2.72Ϫ2.94 (m,
Na2SO4, and the solvent was removed in vacuo. Purification by 4 H, 2-H2, 7-H2), 3.78 (s, 3 H, OCH3), 6.67 (dd, J ϭ 8.4, 2.5 Hz,
flash chromatography (2 g SiO2; pentane/tBuOMe, 4:1) gave 16
(9.9 mg, 36 µmol, 97%) as a colorless oil. Rf ϭ 0.34 (pentane/tBu-
1 H, 10-H), 6.79 (d, J ϭ 2.5 Hz, 1 H, 8-H), 6.88 (d, J ϭ 8.4 Hz,
1 H, 11-H), 7.93 (d, J ϭ 9.6 Hz, 1 H, 6Ј-H), 8.28 (dd, J ϭ 9.6,
OMe, 4:1). [α]2D0 ϭ Ϫ59.8 (c ϭ 1.0 in CHCl3). 1H NMR (300 MHz, 2.6 Hz, 1 H, 5Ј-H), 9.14 (d, J ϭ 2.6 Hz, 1 H, 3Ј-H), 10.91 (s, 1 H,
CDCl3): δ ϭ 0.80 (s, 3 H, 3a-CH3), 1.25Ϫ1.31 (m, 2 H, 4-H2), NH) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 17.80 (C-5), 20.95
1.45Ϫ1.72 (m, 5 H, 5-H2, 6-H2, OH), 1.79Ϫ1.91 (m, 1 H, 2-Hb),
(3a-CH3), 25.17, 26.13 (C-2, C-6), 32.19, 34.72 (C-1, C-4), 36.73
1.95Ϫ2.09 (m, 2 H, 1-H2), 2.20Ϫ2.41 (m, 2 H, 2-Ha, 6a-H), 2.66 (C-7), 43.19 (C-6a), 49.47 (C-3a), 55.30 (OCH3), 56.92 (C-11b),
Eur. J. Org. Chem. 2004, 4107Ϫ4112
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4111

L. F. Tietze, J. M. Wiegand, C. A. Vock
FULL PAPER
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M. Beller, T. H. Riermeier, Eur.
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C.-P. Reisinger, T. H. Riermeier, K. Öfele, M. Beller, Chem.
110.4 (C-8), 112.3 (C-10), 116.5 (C-6Ј), 123.3, 123.5 (C-11, C-3Ј),
128.9 (C-2Ј), 129.9 (C-5Ј), 137.5 (C-4Ј), 141.3 (C-11a), 144.6 (C-
7a), 145.2 (C-1Ј), 158.8 (C-9), 173.0 (C-3) ppm. IR (KBr): ν˜ ϭ
3314 cmϪ1 (NH), 2932 (CH), 1618 (CϭN), 1335 (CϪNO2). UV
(MeCN): λmax. (lg ε) ϭ 198 nm (4.666), 229 (4.309), 269 (3.997),
368 (4.308). MS (EI, 70 eV): m/z (%) ϭ 450 (100) [Mϩ], 415 (29),
253 (58) [Mϩ Ϫ C6H5N4O4]. C24H26N4O5 (450.49): calcd. 450.1903;
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Fonds der Chemischen Industrie and Organon, Oss (Netherlands)
for generous support.
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Early View Article
Published Online August 5, 2004
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Eur. J. Org. Chem. 2004, 4107Ϫ4112