Stereoselective synthesis of novel 19-nor-steroids by a double Heck reaction

Article abstract of DOI:10.1002/1099-0690(200105)2001:9<1619::AID-EJOC1619>3.0.CO;2-T

The estrane 4 was synthesized by two successive Heck reactions starting from enantiopure 2 and the cyclohexenone 5, which contains a (Z)-bromovinyl group. The first intermolecular Pd-catalyzed reaction leads to 10 in a highly regio and diastereoselective

Full text of DOI:10.1002/1099-0690(200105)2001:9<1619::AID-EJOC1619>3.0.CO;2-T

FULL PAPER
Stereoselective Synthesis of Novel 19-Nor-Steroids by a Double Heck Reaction
Lutz F. Tietze*[a] and Sönke Petersen[a]
Dedicated to Professor Frank-Gerrit Klärner on the occasion of his 60th birthday
Keywords: Cycloadditions / Ketones / Palladium / Steroids / Catalysis
The estrane 4 was synthesized by two successive Heck reac- 10 to give the corresponding enol triflate 14 followed by an
tions starting from enantiopure 2 and the cyclohexenone 5,
which contains a (Z)-bromovinyl group. The first intermo-
lecular Pd-catalyzed reaction leads to 10 in a highly regio-
and diastereoselective manner. Transformation of the enone
intramolecular Heck reaction affords the cyclized product 4
with an unusual cis-junction of the rings B and C in high
yield.
Introduction
ring B of the steroidal skeleton is obtained by two success-
ive Heck reactions. The retrosynthetic analysis of 4 leads to
Due to their biological activity and broad application in the (Z)-(2-bromoethenyl)cyclohexenone (5) and the chiral
pharmacology, steroids are an attractive synthetic goal in hydrindane 2 (Scheme 2). The latter compound can easily
academia as well as in industry. Since the first total syn- be obtained from the HajosϪWiechert ketone 7[18] in a five-
thesis of equilenin in 1939 by Bachmann et al.,[1] numerous step sequence including a stereoselective intramolecular Pd-
synthetic approaches to obtain the tetracyclic structure of catalyzed rearrangement of an allyl formate developed by
steroids have been developed,[2] many of them relying on Tsuji et al.,[19,20] which leads to the desired trans-annulation
biomimetic cyclizations of polyolefins,[3] cycloadditions,[4Ϫ8] of the two rings.[21] The A-ring precursor 5, bearing an oxy-
or transition metal-catalyzed cyclizations of alkenes and al- gen at C-1 and a bromovinyl moiety at C-2, is accessible in
kynes.[9,10] But the number of total syntheses of steroids is five steps from the commercially available cyclohexenone 6.
rather small compared to the countless partial syntheses
and derivatizations of naturally occurring steroids.[11] How-
ever, a total synthetic approach is indispensable in order to
gain access to analogs that cannot be derived from natural
steroids. Recently, we have shown that the double Heck re-
action[12,13] of 1 and 2 gives access to the estradiol derivative
3 in a very efficient way (Scheme 1).[14,15] A similar ap-
proach has also been successfully employed in the synthesis
of -homoestradiols[16] and novel aza-heterocycles.[17]
Scheme 1. Convergent synthesis of the estradiol derivative 3
Scheme 2. Retrosynthetic analysis of the estrane 4
Here we describe the stereoselective synthesis of the novel
19-nor-steroid 4 with a nonaromatic ring A in which the
[a]
Results and Discussion
Georg-August-Universität Göttingen,
Institut für Organische Chemie
Tammannstraße 2, 37077 Göttingen, Germany
For the synthesis of 5, the known dimethyl cyclohex-
Fax: (internat.) ϩ 49-(0)551/39-9476
E-mail: ltietze@gwdg.de
enone 6[22,23] was transformed into the aldehyde 8 by hydro-
Eur. J. Org. Chem. 2001, 1619Ϫ1624
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0509Ϫ1619 $ 17.50ϩ.50/0
1619

L. F. Tietze, S. Petersen
FULL PAPER
genation of the double bond, Claisen ester condensation
with formic acid ethyl ester,[24,25] and subsequent oxidation
with DDQ[26] (Scheme 3). A CoreyϪFuchs reaction of 8
with tetrabromomethane,[27] followed by the reductive Pd-
catalyzed replacement of the (E)-bromo atom with a hy-
dride using nBu3SnH[28] afforded the bromoalkene 5 in
good overall yield. For the two vinylic hydrogens in 5 a
coupling constant of J ϭ 8.0 Hz is observed in the 1H
NMR spectrum, which confirms the (Z)-configuration of
the double bond.
Scheme 3. Synthesis of 5: a) H2, Pd/C, pentane, 24 h, 99%; b) NaH,
HCO2Et, CyH, reflux, 4 h; CH3CO2H, 94%; c) DDQ, dioxane,
room temp., 5 min., 76%; d) CBr4, PPh3, CH2Cl2, 0 °C Ǟ room
temp., 2.5 h, 79%; e) nBu3SnH, Pd(PPh3)4, toluene, room temp.,
2 h, 71%
Scheme 4. Intermolecular Heck reaction of 5 and 2: a) 1.0 mol-%
13, nBu4NOAc, DMF/CH3CN/H2O, 115 °C, 7 h, 56% (Z)-10, 10%
dimer 12, traces (E)-11
For the intermolecular Heck reaction of 5 and 2 several
catalysts were investigated (Scheme 4). The usual Pd cata-
lyst derived from Pd(OAc)2 and triphenylphosphane as li-
gand gave the desired product 10 in 47% yield. In contrast, ever, a high selectivity would also be obtained if one as-
Pd(PPh3)4 as catalyst and additional silver salt afforded 10 sumes that the first step to give the two possible regioisom-
in only 29%. The best result (with 56% yield) was obtained eric Pd intermediates is reversible under the reaction condi-
employing the palladacycle 13, introduced by Herrmann, tions, and that the subsequent elimination of a PdH species
Beller et al.,[29,30] at 115 °C with tetrabutylammonium acet- to provide the undesired regioisomer is slow compared to
ate as base; it is noteworthy that a small amount of water the formation of 10.
significantly increased the reaction rate. Traces of the (E)-
The enone 10 was converted into the enol triflate 14 in
isomer 11 and variable amounts of 5 to 10% of the butadi- 94% yield by treatment with potassium hexamethyldisilaz-
ene 12 were obtained as by-products. The formation of 12, ide (KHMDS) and N-phenyltriflimide (Tf2NPh) at Ϫ78 °C
which results from a Pd-catalyzed homocoupling of the vi- (Scheme 5);[34,35] compound 14 was initially exposed to
nyl bromide 5, could be avoided by employing a twofold standard Heck conditions [Pd(OAc)2, PPh3 and NEt3 in
excess of 2. The alkene 2 is stable under these reaction con- MeCN at 70 °C], which provided the desired tetracyclic
ditions and the unchanged excess can be reisolated quantit- product 4 in 51% yield. However, when the reaction was
atively. The use of the catalyst system consisting of performed with Pd(dppb) as catalyst and excess KOAc as
[Pd(CH3CN)2Cl2]·6Ph4PCl and dimethylglycine as additive base in N,N-dimethylacetamide at 75 °C, the estrane 4 could
recently reported by Reetz et al.,[31,32] led to a complete de- be obtained in 85% yield.[36] Compound 4 represents a new
composition of the bromoalkene 5.
type of steroid skeleton with an unnatural cis-B/C ring fu-
The facial selectivity in the formation of 10 is obviously sion and unsaturations in the positions 1(10), 4, 6, and 11,
caused by the angular methyl group in 2 directing the attack which allow further derivatizations.
of 5 to the sterically less-hindered α-side of 2; on the con-
Homogeneous hydrogenation employing Wilkinson’s
trary, the regioselective CϪC coupling at C-4 of 2 cannot catalyst allowed the selective reduction of the sterically less-
easily be explained. Since C-5 is clearly sterically less hindered ∆6,7 double bond in 4 (Scheme 6). Thus, 4 was
hindered than C-4 one would expect the CϪC-coupling to transformed into the triene 15 in the presence of 10 mol-%
take place at this carbon atom according to the empirical (PPh3)3RhCl in methanol/ethyl acetate at a hydrogen pres-
theorem of Heck reactions. We therefore assume that the sure of 3 bar and ambient temperature in 84% yield. The
11,12
transformation is governed by a stereoelectronic effect;
∆
double bond is much less reactive under these condi-
thus, as the first step an attack of palladium occurs at C-5 tions, since attack at the β-face of 4 is hindered by the angu-
from the α-face to allow a chair-like transition state with a lar methyl group, while attack at the α-face is hindered by
subsequent syn addition of the vinyl group at C-4 (structure the annulated cyclohexane ring.
T1); an attack of palladium at C-4 in 2 would lead to an
The 1,3-butadiene moiety in ring A of 4 can undergo
energetically less-favored boat-like transition state.[33] How- cycloaddition reactions; while N-phenylmaleimide proved
1620
Eur. J. Org. Chem. 2001, 1619Ϫ1624

Stereoselective Synthesis of Novel 19-Nor-Steroids by a Double Heck Reaction
FULL PAPER
the one at C-9, could be detected. The configuration of 16
was also confirmed by NOESY experiments, which show
an interaction between one of the methyl groups at C-3 and
the proton at C-14.
Conclusion
The novel 19-nor-steroid derivative 4 was synthesized in
an efficient approach by forming the ring B of the steroid
skeleton using two subsequent stereoselective Heck reac-
tions. Rings B and C of 4 have the unnatural cis-configura-
Scheme 5. Conversion of enone 10 to enol triflate 14 and sub-
sequent Pd-catalyzed cyclization to estrane 4: a) KHMDS, Tf2NPh, tion and the double bonds in 4 can be used for further inter-
THF, Ϫ78 °C, 30 min., 94%; b) Pd(dba)2, dppb, KOAc, DMAC,
75 °C, 18 h, 85%
esting functionalizations, as shown by the DielsϪAlder
cycloaddition of 4 with tetracyanoethylene.
Experimental Section
General: All reactions were performed in ovenϪdried glassware un-
der an argon atmosphere. Solvents were degassed by the freeze-
pump-thaw methodology. TLC chromatography was performed on
precoated silica gel SIL G/UV254 plates (Macherey, Nagel & Co.),
and silica gel 32Ϫ63 (0.032Ϫ0.064 mm) (Merck) was used for col-
umn chromatography. Melting points: Mettler FP61. Optical rota-
tions: PerkinϪElmer 241. IR: Bruker IFS 25. UV/Vis:
PerkinϪElmer Lambda 9. NMR: Varian VXR-200 (200 MHz, 1H),
Bruker AM-300 (300 MHz, 75 MHz, 1H and 13C, respectively),
Varian VXR-500 (500 MHz, 125 MHz, for 1H and 13C, respect-
ively). For H and 13C NMR, CDCl3 as solvent, TMS as internal
standard. Chemical shifts are reported on the δ scale. Signals are
quoted as s (singlet), d (doublet), t (triplet), q (quadruplet), m (mul-
tiplet) and br (broad). MS: Varian MAT 311A (70 eV, EI). HRMS:
Varian MAT 731. Elemental analysis: Mikroanalytisches Labor des
Instituts für Organische Chemie der Universität Göttingen.
1
Scheme 6. Derivatization of steroid 4 by hydrogenation and
DielsϪAlder reaction: a) (PPh3)3RhCl, 3 bar H2, EtOAc, MeOH,
12 h, 84%; b) TCNE, toluene, reflux, 2 days, 74%
not to be reactive enough as dienophile, the reaction of 4
and tetracyanoethylene (TCNE) led to the cycloadduct 16
in 74% yield as a single diastereomer. Thus, the attack of
the dienophile takes place exclusively from the β-face; this
is caused by the hinge-shaped conformation of 4 which pre-
vents an attack from the α-face hence overruling the shield-
ing effect of the angular methyl group. However, as ex-
pected, due to the steric hindrance the DielsϪAlder reac-
tion is rather slow; thus, to obtain a nearly complete conver-
sion a reaction time of 2 days at 110 °C was necessary.
The structures of the new compounds were confirmed by
2-(2,2-Dibromovinyl)-4,4-dimethylcyclohex-2-enone (9): A solution
of PPh3 (60.1 g, 229 mmol) in CH2Cl2 (160 mL) was added slowly
to a stirred solution of CBr4 (38.0 g, 115 mmol) in CH2Cl2
(170 mL) at 0 °C under an argon atmosphere. The reaction mixture
was stirred for 30 min., and then a solution of the aldehyde 8
(8.72 g, 57.3 mmol) in CH2Cl2 (170 mL) was added within 1 h.
After continuation of stirring for 1 h at 0 °C and 1.5 h at room
temp., the mixture was poured onto petroleum ether (1.5 L), fil-
tered, and concentrated in vacuo. Purification of the residue by
column chromatography (petroleum ether/ethyl acetate, 10:1) pro-
vided 13.9 g (45.3 mmol, 79%) of the vinyl dibromide 9. Rf ϭ 0.38
(petroleum ether/ethyl acetate, 10:1). Ϫ UV (CH3CN): λmax (lg ε) ϭ
216 nm (3.64), 266 (3.21). Ϫ IR (neat): ν˜ ϭ 2960, 2928, 2864, 1682,
1
NMR spectroscopy. In the H NMR spectrum of 10 the
signals of 5ЈЈ-H and 6ЈЈ-H were found at δ ϭ 5.35 and δ ϭ
5.64, respectively, with a coupling constant for these pro-
tons of J ϭ 9.8 Hz. The protons at C-2Ј and C-1Ј resonate
at δ ϭ 5.36 and δ ϭ 6.11, respectively, with a coupling con-
stant of J ϭ 11.4 Hz, which is a typical value for a (Z)
1
1602 cmϪ1. Ϫ H NMR (200 MHz, CDCl3): δ ϭ 1.22 (s, 6 H, 2 ϫ
CH3), 1.89 (t, J ϭ 6.8 Hz, 2 H, 5-H2), 2.51 (t, J ϭ 6.8 Hz, 2 H, 6-
H2), 7.12 (br. s, 1 H, 3-H), 7.21 (br. s, 1 H, 1Ј-H). Ϫ 13C NMR
(50.3 MHz, CDCl3): δ ϭ 27.5 (2 ϫ CH3), 33.6 (C-4), 34.3 (C-5),
35.2 (C-6), 91.1 (C-2Ј), 131.2 (C-3), 132.1 (C-2), 159.1 (C-1Ј), 196.5
(C-1). Ϫ EI-MS (70 eV): m/z (%) ϭ 307.9 (4) [Mϩ], 227.0 (100)
[Mϩ Ϫ Br]. Ϫ EI-HRMS (C10H12Br2O): calcd. 305.9255; found
305.9255.
1
double bond. In the H NMR spectrum of 4, doublets of
doublets at δ ϭ 5.53 and δ ϭ 5.64 are found for the protons
at C-7 and C-11, respectively. The doublets at δ ϭ 5.81 and
δ ϭ 5.89 were assigned to the protons at C-12 and C-6. The
coupling constant between 6-H and 7-H is J ϭ 9.8 Hz; the
one between 11-H and 12-H has a comparable value of J ϭ
10.2 Hz. The cis-orientation of the rings B and C in 4 was
confirmed by 1H-1H NOESY experiments in which interac-
tions between the protons of the methyl group at C-13 and
(Z)-2-(2-Bromovinyl)-4,4-dimethylcyclohex-2-enone
(5):
Neat
nBu3SnH (10.6 g, 36.4 mmol) was added with a syringe to a thor-
oughly degassed solution of the 1,1-dibromoalkene 9 (10.2 g,
33.1 mmol) and Pd(PPh3)4 (1.53 g, 4.0 mol-%) in anhydrous tolu-
the proton at C-8, as well as between the proton at C-8 and ene (200 mL). The reaction mixture was stirred for 2.5 h at room
Eur. J. Org. Chem. 2001, 1619Ϫ1624 1621

L. F. Tietze, S. Petersen
FULL PAPER
temp., poured onto petroleum ether (600 mL), washed with water
(200 mL) and brine (200 mL), and dried over MgSO4. Concentra-
tion in vacuo and purification by column chromatography (petro-
H, 7ЈЈa-CH3), 1.12 (s, 9 H, 1ЈЈ-OtBu), 1.15 (s, 6 H, 2 ϫ 4-CH3),
1.17Ϫ1.70 (m, 4 H, 2ЈЈ-Ha, 3ЈЈ-H2, 3ЈЈa-H), 1.76Ϫ1.90 (m, 2 H, 7ЈЈ-
Ha, 2ЈЈ-Hb), 1.81 (t, J ϭ 6.8 Hz, 2 H, 5-H2), 1.99 (ddt, J ϭ 17.3,
leum ether/ethyl acetate, 100:1) afforded 5.42 g (23.7 mmol, 71%) 5.2, 1.5 Hz, 1 H, 7ЈЈ-Hb), 2.46 (t, J ϭ 6.8 Hz, 2 H, 6-H2), 2.59 (mc,
of the (Z)-bromoalkene 5. Rf ϭ 0.34 (petroleum ether/ethyl acetate, 1 H, 4ЈЈ-H), 3.46 (t, J ϭ 8.3 Hz, 1 H, 1ЈЈ-H), 5.45 (dddd, J ϭ 9.8,
10:1). Ϫ UV (CH3CN): λmax (lg ε) ϭ 211 nm (3.79), 262 (3.24). Ϫ 2.2, 1.1, 1.1 Hz, 1 H, 5ЈЈ-H), 5.64 (dddd, J ϭ 9.8, 4.9. 2.5, 2.5 Hz,
IR (neat): ν˜ ϭ 2958, 2928, 2864, 1682, 1608 cmϪ1. Ϫ 1H NMR 1 H, 6ЈЈ-H), 5.95 (dd, J ϭ 15.8, 8.3 Hz, 1 H, 2Ј-H), 6.19 (d, J ϭ
(200 MHz, CDCl3): δ ϭ 1.24 (s, 6 H, 2 ϫ CH3), 1.90 (t, J ϭ 6.8 Hz,
15.8 Hz, 1 H, 1Ј-H), 6.55 (s, 1 H, 3-H). Ϫ 13C NMR (50.3 MHz,
2 H, 5-H2), 2.53 (t, J ϭ 6.8 Hz, 2 H, 6-H2), 6.41 (d, J ϭ 8.0 Hz, 1 CDCl3): δ ϭ 11.3 (7ЈЈa-CH3), 24.8 (C-2ЈЈ), 28.0 (2 ϫ 4-CH3), 28.7
H, 2Ј-H), 6.87 (dd, J ϭ 8.0, 1.0 Hz, 1 H, 1Ј-H), 7.28 (d, J ϭ 1.0 Hz, [OC(CH3)3], 30.5 (C-3ЈЈ), 33.1 (C-4), 35.0 (C-6), 35.8 (C-5), 38.7
1 H, 3-H). Ϫ 13C NMR (50.3 MHz, CDCl3): δ ϭ 27.7 (2 ϫ CH3), (C-7ЈЈ), 41.5 (C-7ЈЈa), 43.6 (C-4ЈЈ), 46.1 (C-3ЈЈa), 72.2 [OC(CH3)3],
33.4 (C-4), 34.3 (C-6), 35.3 (C-5), 108.7 (C-2Ј), 126.4 (C-1Ј), 130.8
80.6 (C-1ЈЈ), 123.7 (C-1Ј), 126.7 (C-6ЈЈ), 129.1 (C-5ЈЈ), 133.9 (C-2),
(C-2), 158.7 (C-3), 197.3 (C-1). Ϫ EI-MS (70 eV): m/z (%) ϭ 228.0 134.8 (C-2Ј), 153.1 (C-3), 198.1 (C-1). Ϫ EI-MS (70 eV): m/z (%) ϭ
(2) [Mϩ], 149.1 (100) [Mϩ Ϫ Br]. EI-HRMS (C10H13BrO): calcd. 356.3 (19) [Mϩ], 299.2 (26) [Mϩ Ϫ C4H9], 57.0 (100) [C4H9ϩ], 40.9
228.0149; found 228.0149. Ϫ C10H13BrO (229.1): calcd. C 52.42, H
(57) [C3H5ϩ]. Ϫ EI-HRMS (C24H36O2): calcd. 356.2715, found
5.72, Br 34.87; found C 52.51, H 5.71, Br 34.71.
356.2715.
(Z,Z)-1,4-Bis(5,5-dimethyl-2-oxocyclohexenyl)-1,3-butadiene (12):
Rf ϭ 0.11 (petroleum ether/ethyl acetate, 10:1). Ϫ UV (CH3CN):
λmax (lg ε) ϭ 225 nm (3.55), 267 (3.74), 276 (3.71), 289 (3.64), 319
Intermolecular Heck reaction of 5 and 2: trans-Di(µ-acetato)-bis[o-
(di-o-tolylphosphanyl)benzyl]dipalladium(II) (13; 9.0 mg, 1.0 mol-
%) was added to a thoroughly degassed solution of the hexahy-
droindene 2 (416 mg, 2.00 mmol), the bromoalkene 5 (229 mg,
1.00 mmol) and nBu4NOAc (754 mg, 2.50 mmol) in DMF/CH3CN/
H2O (1:1:0.2, 15 mL) under an argon atmosphere. The reaction
mixture was stirred for 6 h at 115 °C and cooled to room temp.
Diethyl ether (25 mL) and water (25 mL) were added, and the
aqueous phase was extracted with diethyl ether (2 ϫ 50 mL). The
combined organic layers were washed with brine, dried with
MgSO4 and concentrated in vacuo. Purification of the residue by
column chromatography (petroleum ether/ethyl acetate, 20:1) gave
200 mg (0.56 mmol, 56%) of the desired product 10 and 15.0 mg
(50.0 µmol, 10%) of the dimer 12. Furthermore 276 mg
(1.32 mmol) of the remaining hydrindane 2 and traces of 11 were
isolated.
1
(3.70). Ϫ IR (neat): ν˜ ϭ 3040, 2958, 2864, 1672, 1360 cmϪ1. Ϫ H
NMR (300 MHz, CDCl3): δ ϭ 1.19 (s, 12 H, 4 ϫ CH3), 1.85 (t,
J ϭ 7.0 Hz, 4 H, 2 ϫ 4Ј-H2), 2.51 (t, J ϭ 7.0 Hz, 4 H, 2 ϫ 3Ј-H2),
6.40 (mc, 2 H, 2-H, 3-H), 6.68 (s, 2 H, 2 ϫ 6Ј-H), 6.79 (mc, 2 H,
1-H, 4-H). Ϫ 13C NMR (50.3 MHz, CDCl3): δ ϭ 28.0 (4 ϫ CH3),
33.4 (2 ϫ C-5Ј), 35.1 (2 ϫ C-4Ј), 35.7 (2 ϫ C-3Ј), 126.9 (C-2, C-3),
131.3 (C-1, C-4), 133.0 (2 ϫ C-1Ј), 153.9 (2 ϫ C-6Ј), 198.1 (2 ϫ C-
2Ј). Ϫ EI-MS (70 eV): m/z (%) ϭ 298.2 (8) [Mϩ], 200.1 (100) [Mϩ
Ϫ C6H10O], 91.0 (75) [C7H7ϩ]. Ϫ C20H26O2 (298.4): calcd. C 80.50,
H 8.78; found C 80.30, H 8.88.
(Z)-Trifluoromethanesulfonic Acid 6-{2-[(1R,3aS,4S,7aS)-1-tert-
Butoxy-2,3,3a,4,7,7a-hexyhydro-7a-methyl-1H-inden-4-yl]vinyl}-
4,4-dimethylcyclohexa-1,5-dienyl Ester (14): KHMDS (3.9 mL of a
0.5  solution in toluene, 1.95 mmol) was added to a solution of
enone 10 (458 mg, 1.28 mmol) and N-phenyltriflamide (597 mg,
1.67 mmol) in THF (5 mL) at Ϫ78 °C. After 30 min., the reaction
mixture was allowed to warm to room temp., diluted with ethyl
acetate (50 mL) and washed successively with saturated aqueous
solutions of NH4Cl (20 mL), NaHCO3 (20 mL) and brine (20 mL).
The organic phase was dried with MgSO4 and concentrated in va-
cuo. The residual oil was subjected to flash chromatography (petro-
leum ether/ethyl acetate, 100:1) to afford 590 mg (1.21 mmol, 94%)
of the triflate 14. Rf ϭ 0.47 (petroleum ether/ethyl acetate, 30:1).
Ϫ [α]2D0 ϭ Ϫ18.8 (c ϭ 1, CHCl3). Ϫ UV (CH3CN): λmax (lg ε) ϭ
222 nm (3.45), 270 (2.74), 313 (2.10), 330 (2.06). Ϫ IR (neat): ν˜ ϭ
(Z)-2-{2-[(1R,3aS,4S,7aS)-1-tert-Butoxy-2,3,3a,4,7,7a-hexahydro-
7a-methyl-1H-indene-4-yl]vinyl}-4,4-dimethylcyclohex-2-enone (10):
Rf ϭ 0.12 (petroleum ether/ethyl acetate, 40:1). Ϫ [α]2D0 ϭ Ϫ39.3
(c ϭ 0.4, CHCl3). Ϫ UV (CH3CN): λmax (lg ε) ϭ 208 nm (3.68),
260 (3.01). Ϫ IR (neat): ν˜ ϭ 3014, 2964, 2930, 2870, 1680, 1464,
1
1388, 1360, 692 cmϪ1. Ϫ H NMR (500 MHz, CDCl3): δ ϭ 0.69
(s, 3 H, 7ЈЈa-CH3), 1.10 (s, 9 H, 1ЈЈ-OtBu), 1.16 (s, 6 H, 2 ϫ 4-
CH3), 1.18Ϫ1.63 (m, 4 H, 2ЈЈ-Ha, 3ЈЈ-H2, 3ЈЈa-H), 1.73Ϫ1.83 (m, 2
H, 7ЈЈ-Ha, 2ЈЈ-Hb), 1.84 (t, J ϭ 6.4 Hz, 2 H, 5-H2), 1.99 (ddt, J ϭ
17.2, 5.0, 1.8 Hz, 1 H, 7ЈЈ-Hb), 2.46 (t, J ϭ 6.4 Hz, 2 H, 6-H2), 2.94
(mc, 1 H, 4ЈЈ-H), 3.47 (t, J ϭ 8.5 Hz, 1 H, 1ЈЈ-H), 5.35 (dddd, J ϭ
9.8, 2.8, 1.4, 1.4 Hz, 1 H, 5ЈЈ-H), 5.36 (dd, J ϭ 11.4, 10.5 Hz, 1 H,
2Ј-H), 5.64 (dddd, J ϭ 9.8, 5.0, 2.5, 2.5 Hz, 1 H, 6ЈЈ-H), 6.11 (d,
J ϭ 11.4 Hz, 1 H, 1Ј-H), 6.49 (s, 1 H, 3-H). Ϫ 13C NMR
(50.3 MHz, CDCl3): δ ϭ 11.3 (7ЈЈa-CH3), 24.9 (C-2ЈЈ), 27.7 (4-
CH3), 28.1 (4-CH3), 28.7 [OC(CH3)3], 30.5 (C-3ЈЈ), 33.2 (C-4), 34.6
(C-6), 35.8 (C-5), 38.4 (C-4ЈЈ), 38.8 (C-7ЈЈ), 41.3 (C-7ЈЈa), 46.2 (C-
3ЈЈa), 72.2 [OC(CH3)3], 80.6 (C-1ЈЈ), 124.3 (C-1Ј), 127.3 (C-6ЈЈ),
129.1 (C-5ЈЈ), 132.9 (C-2), 136.6 (C-2Ј), 156.6 (C-3), 198.8 (C-1). Ϫ
EI-MS (70 eV): m/z (%) ϭ 356.2 (9) [Mϩ], 299.2 (18) [Mϩ Ϫ C4H9],
168.1 (56) [C10H16Oϩ], 124.1 (100) [C8H12Oϩ], 57.0 (56) [C4H9ϩ],
41.0 (19) [C3H5ϩ]. Ϫ EI-HRMS (C24H36O2): calcd. 356.2715;
found 356.2715. Ϫ C24H36O2 (356.5): calcd. C 80.85, H 10.18;
found C 80.62, H 10.27.
1
3017, 2969, 2932, 2874, 1389, 1362, 1210, 1144 cmϪ1. Ϫ H NMR
(500 MHz, CDCl3): δ ϭ 0.80 (s, 3 H, 7ЈЈa-CH3), 0.84 (s, 3H, 4-
CH3), 1.01 (s, 3 H, 4-CH3), 1.08 (s, 9 H, 1ЈЈ-OtBu), 1.12Ϫ1.84 (m,
7 H, 2ЈЈ-H2, 3ЈЈ-H2, 3ЈЈa-H, 7ЈЈ-Ha, 3-Ha), 1.74 (dd, J ϭ 9.2, 4.7 Hz,
1 H, 3-Hb), 2.04 (mc, 1 H, 7ЈЈ-Hb), 3.22 (mc, 1 H, 4ЈЈ-H), 3.28 (t,
J ϭ 8.1 Hz, 1 H, 1ЈЈ-H), 5.33 (t, J ϭ 4.7 Hz, 1 H, 2-H), 5.48 (dd,
J ϭ 10.9, 10.9 Hz, 1 H, 2Ј-H), 5.54 (br. s, 1 H, 5-H), 5.60 (dddd,
J ϭ 9.8, 2.6, 1.5, 1.5 Hz, 1 H, 5ЈЈ-H), 5.69 (dddd, J ϭ 9.8, 4.9, 2.3,
2.3 Hz, 1 H, 6ЈЈ-H), 6.12 (d, J ϭ 10.9 Hz, 1 H, 1Ј-H). Ϫ 13C NMR
(50.3 MHz, CDCl3): δ ϭ 11.2 (7ЈЈa-CH3), 24.9 (C-3ЈЈ), 26.5 (4-
CH3), 27.1 (4-CH3), 28.4 [OC(CH3)3], 30.5 (C-2ЈЈ), 31.1 (C-4), 36.0
(C-7ЈЈ), 38.7 (C-3), 38.9 (C-4ЈЈ), 41.3 (C-7ЈЈa), 45.9 (C-3ЈЈa), 71.7
[OC(CH3)3], 80.4 (C-1ЈЈ), 114.5 (C-2), 118.7 (q, J ϭ 320 Hz, CF3),
122.9 (C-1Ј), 126.7 (C-6), 127.2 (C-6ЈЈ), 128.8 (C-5ЈЈ), 138.5 (C-2Ј),
139.9 (C-5), 145.8 (C-1). Ϫ EI-MS (70 eV): m/z (%) ϭ 488.3 (12)
[Mϩ], 357.0 (58) [Mϩ Ϫ F3CSO2], 119.1 (35) [C9H11ϩ], 105.0 (44)
(E)-2-{1-[(1R,3aS,4S,7aS)-1-tert-Butoxy-2,3,3a,7,7,7a-hexahydro-
7a-methyl-1H-indene-4-yl]vinyl}-4,4-dimethylcyclohex-2-enone (11):
Rf ϭ 0.15 (petroleum ether/ethyl acetate, 40:1). Ϫ [α]2D0 ϭ Ϫ77.0
(c ϭ 0.5, CHCl3). Ϫ UV (CH3CN): λmax (lg ε) ϭ 211 nm (3.44), [C8H9ϩ], 91.0 (100) [C7H7ϩ], 69.0 (40) [CF3ϩ], 57.0 (58) [C4H9ϩ],
273 (2.97). Ϫ IR (neat): ν˜ ϭ 3016, 2967, 2930, 2871, 1681, 1461,
40.9 (52) [C3H5ϩ]. Ϫ EI-HRMS (C25H35F3O4S): calcd. 488.2208;
1
1389, 1362 cmϪ1. Ϫ H NMR (500 MHz, CDCl3): δ ϭ 0.74 (s, 3
found 488.2208.
1622
Eur. J. Org. Chem. 2001, 1619Ϫ1624

Stereoselective Synthesis of Novel 19-Nor-Steroids by a Double Heck Reaction
FULL PAPER
Intramolecular Heck reaction of Enol Triflate 14. (؊)-17β-tert-Bu-
toxy-3,3-dimethyl-9β-estra-1(10),4,6,11-tetraene (4): A 0.07  solu-
tion of Pd(dppb) in N,N-dimethylacetamide (DMAC) was prepared
by stirring Pd(dba)2 (52.8 mg, 92.0 µmol, 13 mol-%) and 1,4-bis(di-
(؊)-17β-tert-Butoxy-3,3-dimethyl-1,4-(ethanotetracarbonitrile)-9β-
estra-5(10),6,11-triene (16): solution of tetracyanoethylene
(18.0 mg, 140 µmol) in toluene (4 mL) was added to a solution of
the steroid 4 (30.0 mg, 87.0 µmol) in anhydrous toluene (3 mL) at
A
phenylphosphanyl)butane (dppb) (43.2 mg, 101 µmol, 14 mol-%) room temp. The reaction mixture was refluxed for 2 d, cooled to
in DMAC (1.5 mL) under argon at room temp. until the initial
dark red suspension became a green-orange solution (about
15 min.). To this solution was added a solution of the enol triflate
room temp., diluted with diethyl ether (20 mL) and washed with
saturated NaHSO3 solution. The separated organic phase was
washed with brine, dried with Na2SO4 and concentrated in vacuo.
14 (208 mg, 426 µmol) in DMAC (3 mL) and solid anhydrous Purification by column chromatography (petroleum ether/ethyl
KOAc (379 mg, 3.86 mmol). The reaction mixture was thoroughly acetate, 10:1) afforded 30.0 mg (64.0 µmol, 74%) of the
degassed, stirred at 75 °C for 18 h, cooled to room temp., and di-
luted with diethyl ether (20 mL). After stirring in air for 5 min. the
mixture was filtered through a pad of silica gel (8.0 g) wetted with
DielsϪAlder product 16 as a white solid. Rf ϭ 0.25 (petroleum
ether/ethyl acetate, 10:1). Ϫ [α]2D0 ϭ Ϫ130.3 (c ϭ 0.4, CHCl3). Ϫ
UV (CH3CN): λmax (lg ε) ϭ 279 nm (2.93). Ϫ IR (KBr): ν˜ ϭ 3019,
diethyl ether, and the filter pad rinsed with diethyl ether (400 mL). 2973, 2941, 2876, 1458, 1363 cmϪ1. Ϫ 1H NMR (500 MHz,
The filtrate was concentrated in vacuo. Purification of the residue
by column chromatography on silica gel (petroleum ether/ethyl
acetate, 30:1) gave 123 mg (362 µmol, 85%) of 4. Rf ϭ 0.14 (petro-
CDCl3): δ ϭ 0.81 (s, 3 H, 13-CH3), 1.00 (s, 3 H, 3-CH3), 1.13 (s, 9
H, 17-OtBu), 1.17Ϫ1.60 (m, 3 H, 15-H2, 16-Ha), 1.36 (dd, J ϭ 14.5,
3.2 Hz, 1 H, 2-Ha), 1.49 (s, 3 H, 3-CH3), 1.67 (ddd, J ϭ 12.3, 12.3,
leum ether/ethyl acetate, 100:1). Ϫ [α]2D0 ϭ Ϫ289.0 (c ϭ 1, CHCl3). 6.7 Hz, 1 H, 14-H), 1.88Ϫ1.97 (m, 1 H, 16-Hb), 2.08 (dd, J ϭ 14.5,
Ϫ UV (CH3CN): λmax (lg ε) ϭ 220 nm (3.63), 226 (3.68), 269
2.4 Hz, 1 H, 2-Hb), 2.73 (dddd, J ϭ 12.3, 10.1, 3.2, 2.3 Hz, 1 H, 8-
(3.16). Ϫ IR (neat): ν˜ ϭ 3022, 2970, 2906, 2869, 1388, 1375, 1360, H), 2.96 (s, 1 H, 4-H), 3.43 (dd, J ϭ 8.8, 7.0 Hz, 1 H, 17-H), 3.57
1
714 cmϪ1. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 0.83 (s, 3 H, 13- (ddd, J ϭ 10.1, 4.4, 2.0 Hz, 1 H, 9-H), 3.64 (dd, J ϭ 3.2, 2.4 Hz,
CH3), 0.93 (s, 3 H, 3-CH3), 1.03 (s, 3 H, 3-CH3), 1.12 (s, 9 H, 17-
OtBu), 1.18Ϫ1.55 (m, 4 H, 14-H, 15-H2, 16-Ha), 1.87 (mc, 1 H, 16- H, 7-H), 6.12 (dd, J ϭ 9.9, 2.0 Hz, 1 H, 12-H). Ϫ 13C NMR
Hb), 1.96 (ddd, J ϭ 16.9, 6.4, 1.6 Hz, 1 H, 2-Ha), 2.01 (ddd, J ϭ (75.5 MHz, CDCl3): δ ϭ 14.3 (13-CH3), 22.8 (C-15), 28.7 [17-
1 H, 1-H), 5.64 (dd, J ϭ 9.9, 4.4 Hz, 1 H, 11-H), 5.84 (m, 2 H, 6-
16.9, 4.1, 2.6 Hz, 1 H, 2-Hb), 2.41 (ddd, J ϭ 10.9, 5.6, 5.6 Hz, 1 H, OC(CH3)3], 29.4 (3-CH3), 31.6 (C-16), 32.7 (C-3), 32.8 (3-CH3),
8-H), 2.86 (mc, 1 H, 9-H), 3.33 (dd, J ϭ 8.6, 6.0 Hz, 1 H, 17-H), 33.7 (C-8), 35.9 (C-2), 37.4 (C-9), 41.4 (C-2Ј), 42.0 (C-1), 42.1 (2
5.17 (s, 1 H, 4-H), 5.39 (ddd, J ϭ 5.6, 2.8, 2.8 Hz, 1 H, 1-H), 5.53
C, C-14, C-1Ј), 43.9 (C-13), 53.7 (C-4), 72.5 [17-OC(CH3)3], 76.1
(dd, J ϭ 9.8, 6.0 Hz, 1 H, 7-H), 5.64 (dd, J ϭ 10.2, 4.6 Hz, 1 H, (C-17), 111.2, 111.9, 112.1, 112.2 (4 ϫ CN), 120.9 (C-11), 122.2
11-H), 5.81 (d, J ϭ 10.2 Hz, 1 H, 12-H), 5.89 (d, J ϭ 9.8 Hz, 1 H,
(C-6), 130.9 (C-5), 131.8 (C-7), 134.6 (C-10), 139.1 (C-12). Ϫ EI-
6-H). Ϫ 13C NMR (75.5 MHz, CDCl3): δ ϭ 15.3 (13-CH3), 23.1 MS (70 eV): m/z (%) ϭ 446.2 (1) [Mϩ], 392.3 (12) [Mϩ Ϫ C4H8 Ϫ
(C-15), 25.7 (3-CH3), 28.8 [17-OC(CH3)3], 30.1 (3-CH3), 30.6 (C- H2O], 350.2 (14) [Mϩ Ϫ C4H8 Ϫ C4H9], 264.2 (22) [Mϩ Ϫ C4H8
3), 32.0 (C-16), 35.9 (C-8), 38.9 (C-2), 39.2 (C-9), 45.1 (C-14), 46.0
Ϫ H2O Ϫ TCNE], 222.2 (25) [C15H26Oϩ], 57.0 (100) [C4H9ϩ], 41.0
(C-13), 72.3 [17-OC(CH3)3], 76.5 (C-17), 120.9 (C-1), 126.2 (C-11), (10) [C3H5ϩ]. Ϫ EI-HRMS (C30H34N4O): calcd. 466.2733; found
127.2 (C-6), 129.2 (C-7), 130.4 (C-5), 133.4 (C-4), 134.3 (C-10),
135.6 (C-12). Ϫ EI-MS (70 eV): m/z (%) ϭ 338.2 (29) [Mϩ], 281.2
(42) [Mϩ Ϫ C4H9], 263.2 (74) [Mϩ Ϫ C4H9 Ϫ H2O], 57.0 (100)
[C4H9ϩ], 40.9 (37) [C3H5ϩ]. Ϫ EI-HRMS (C24H34O): calcd.
338.2610; found 338.2609.
466.2733.
Acknowledgments
The work was supported by the DFG (SFB 416) and the Fonds
der Chemischen Industrie. We thank Schering AG and Degussa-
Hüls AG for their generous help with chemicals and precious
metals.
(؊)-17β-tert-Butoxy-3,3-dimethyl-9β-estra-1(10),4,11-triene (15): A
solution of 4 (87.0 mg, 257 µmol) and (PPh3)3RhCl (24.0 mg, 10
mol-%) in methanol/ethyl acetate (1:1, 5 mL) was shaken for 12 h
at room temp. under a H2 atmosphere (3 bar). The reaction mixture
was concentrated in vacuo. Purification by column chromatography
(petroleum ether/ethyl acetate, 100:1) gave 74.0 mg (216 µmol, 84%)
15 as colorless oil. Rf ϭ 0.18 (petroleum ether). Ϫ [α]2D0 ϭ Ϫ19.0
(c ϭ 0.2, CHCl3). Ϫ UV (CH3CN): λmax (lg ε) ϭ 243 nm (3.40).
[1]
W. E. Bachmann, W. Cole, A. L. Wilds, J. Am. Chem. Soc.
1939, 61, 974Ϫ975.
[2]
F. J. Zeelen, Nat. Prod. Rep. 1994, 11, 607Ϫ612.
[3]
W. S. Johnson, W. R. Bartlett, B. A. Czeskis, A. Gautier, C. H.
Lee, R. Lemoine, E. J. Leopold, G. R. Luedtke, K. J. Bancroft,
Ϫ IR (neat): ν˜ ϭ 3014, 2972, 2931, 2869, 1659, 1387, 1362 cmϪ1
.
J. Org. Chem. 1999, 64, 9587Ϫ9595.
[4]
1
G. Quinkert, M. del Grosso, A. Döring, W. Döring, R. I.
Ϫ H NMR (300 MHz, C6D6): δ ϭ 0.87 (s, 3 H, 3-CH3), 0.89 (s,
3 H, 3-CH3), 1.02 (s, 9 H, 17-OtBu), 1.05 (s, 3 H, 13-CH3),
1.19Ϫ1.64 (m, 4 H, 14-H, 15-H2, 16-Ha), 1.77Ϫ2.08 (m, 6 H, 2-Ha,
16-Hb, 6-H2, 7-H2), 2.11Ϫ2.37 (m, 2 H, 2-Hb, 8-H), 3.07 (mc, 1 H,
9-H), 3.52 (dd, J ϭ 8.7, 7.0 Hz, 1 H, 17-H), 5.39 (mc, 1 H, 1-H),
5.56 (br. s, 1 H, 4-H), 5.97 (dd, J ϭ 9.9, 4.9 Hz, 1 H, 11-H), 6.09
(d, J ϭ 9.9 Hz, 1 H, 12-H). Ϫ 13C NMR (75.5 MHz, C6D6): δ ϭ
15.5 (13-CH3), 23.4 (C-15), 25.6 (C-7), 28.2 (3-CH3), 28.7 (3-CH3),
28.8 [17-OC(CH3)3], 30.3 (C-3), 31.7 (C-8), 32.5 (C-16), 39.9 (C-9),
41.0 (C-6), 42.3 (C-14), 45.8 (C-2), 46.5 (C-13), 72.2 [17-
OC(CH3)3], 77.6 (C-17), 121.1 (C-1), 123.7 (C-4), 129.0 (C-11),
133.4 (C-5), 134.8 (C-12), 136.0 (C-10). Ϫ EI-MS (70 eV): m/z
(%) ϭ 340.3 (6) [Mϩ], 283.2 (100) [Mϩ Ϫ C4H9], 265.2 (52) [Mϩ
Ϫ C4H9 Ϫ H2O], 105.1 (29) [C8H9ϩ], 57.0 (52) [C4H9ϩ], 41.0 (20)
Schenkel, M. Bauch, G. T. Dambacher, J. W. Bats, G. Zimmer-
mann, G. Dürner, Helv. Chim. Acta 1995, 78, 1345Ϫ1391.
[5]
P. A. Wender, T. E. Smith, J. Org. Chem. 1995, 60, 2962Ϫ2963.
[6]
L. Ouellet, P. Langlois, P. Deslongchamps, Synlett 1997,
689Ϫ690.
[7]
H. Nemoto, K. Fukumoto, Tetrahedron 1998, 54, 5425Ϫ5464.
[8]
H. Rigby, N. C. Warshakoon, A. J. Payen, J. Am. Chem. Soc.
1999, 121, 8237Ϫ8245.
[9]
K. P. C. Vollhardt, in Strategies and Tactics in Organic Syn-
thesis,(Ed.: T. Lindberg), Academic Press, New York, 1984,
299Ϫ324.
[10]
K. P. C. Vollhardt, Pure Appl. Chem. 1985, 57, 1819Ϫ1826.
[11]
J. R. Hanson, Nat. Prod. Rep. 1999, 16, 607Ϫ617, and refer-
ences cited therein.
[12]
For an overview of the Heck reaction, see: S. Bräse, A. de Mei-
jere, in Metal-Catalyzed Cross-Coupling Reactions (Eds.: F. Di-
ederich, P. J. Stang), Wiley-VCH, Weinheim, 1998, 99Ϫ166,
and references cited therein.
[C3H5ϩ].
340.2766.
Ϫ EI-HRMS (C24H36O): calcd. 340.2766, found
Eur. J. Org. Chem. 2001, 1619Ϫ1624
1623

L. F. Tietze, S. Petersen
FULL PAPER
[13]
[26]
[27]
[28]
[29]
The application of the Heck reaction in natural product syn-
W. L. Meyer, M. J. Brannon, C. G. Burgos, T. E. Goodwin, R.
W. Howard, J. Org. Chem. 1985, 50, 438Ϫ447.
E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13,
3769Ϫ3772.
thesis has been reviewed in: J. T. Link, L. E. Overman, in
Metal-Catalyzed Cross Coupling Reactions (Eds.: F. Diederich,
P. J. Stang), Wiley-VCH, Weinheim, 1998, 231Ϫ269.
L. F. Tietze, T. Nöbel, M. Spescha, Angew. Chem. 1996, 108,
2385Ϫ2386; Angew. Chem. Int. Ed. Engl. 1996, 35, 2259Ϫ2261.
L. F. Tietze, T. Nöbel, M. Spescha, J. Am. Chem. Soc. 1998,
120, 8971Ϫ8977.
L. F. Tietze, S. Petersen, Eur. J. Org. Chem. 2000, 1827Ϫ1830.
L. F. Tietze, R. Ferraccioli, Synlett 1998, 145Ϫ146.
Z. G. Hajos, D. R. Parrish, Org. Synth. 1985, 63, 26Ϫ36.
L. F. Tietze, P. S. V. Subba Rao, Synlett 1993, 291Ϫ292.
J. Tsuji, T. Mandai, Synthesis 1996, 1Ϫ24.
For an excellent review of the synthesis of trans-hydrindanes
[14]
J. Uenishi, R. Kawahama, O. Yonemitsu, J. Tsuji, J. Org. Chem.
1996, 61, 5716Ϫ5717.
[15]
W. A. Herrmann, C. Broßmer, K. Öfele, C. P. Reisinger, T.
Priermeier, M. Beller, H. Fischer, Angew. Chem. 1995, 107,
1989Ϫ1992; Angew. Chem. Int. Ed. Engl. 1995, 34, 1844Ϫ1847.
W. A. Herrmann, C. Broßmer, C. P. Reisinger, T. H. Riermeier,
K. Öfele, M. Beller, Chem. Eur. J. 1997, 3, 1357Ϫ1364.
M. T. Reetz, G. Lohmer, R. Schwickardi, Angew. Chem. 1998,
110, 492Ϫ495; Angew. Chem. Int. Ed. 1998, 37, 481Ϫ483.
M. T. Reetz, E. Westermann, R. Lohmer, G. Lohmer, Tetrahed-
ron Lett. 1998, 39, 8449Ϫ8452.
[16]
[30]
[31]
[32]
[33]
[34]
[17]
[18]
[19]
[20]
[21]
and their application in steroid and vitamin-D synthesis, see:
P. Jankowski, S. Marczak, J. Wicha, Tetrahedron 1998, 54,
12071Ϫ12150.
Y. Chan, W. W. Epstein, Org. Synth. 1973, 53, 48Ϫ52.
M. E. Flaugh, T. A. Crowell, D. S. Farlow, J. Org. Chem. 1980,
45, 5399Ϫ5400.
H. G. O. Becker et al., Organikum, 19. Aufl., Barth Verlagsge-
sellschaft, Leipzig, 1993, 490Ϫ492.
W. Tochtermann, S. Bruhn, M. Meints, C. Wolff, Tetrahedron
1994, 50, 9657Ϫ9670.
P. C. Amos, D. A. Whiting, J. Chem. Soc., Chem. Commun.
1987, 510Ϫ511.
P. J. Stang, M. Hanack, L. R. Subramanian, Synthesis 1982,
[22]
85Ϫ126.
[23]
[35]
[36]
K. Ritter, Synthesis 1993, 735Ϫ762.
Similar conditions were successfuly employed in the synthesis
of cardenolides: W. Deng, M. S. Jensen, L. E. Overman, P. V.
Rucker, J.-P. Vionnet, J. Org. Chem. 1996, 61, 6760Ϫ6761.
Received September 14, 2000
[24]
[25]
[O00478]
1624
Eur. J. Org. Chem. 2001, 1619Ϫ1624