Synthesis of nitrogen- and oxygen-containing macrocycles - Derivatives of lithocholic acid

Article abstract of DOI:10.1002/chem.200500784

Palladium-catalyzed amination of 3,24-bis(3-bromophenoxy)cholane (4) with various polyamines and polyoxadiamines 5 taken in 1:1 ratio was used for the synthesis of the macrocycles 6, which contain steroidal and polyamine moieties and were obtained in 38-6

Full text of DOI:10.1002/chem.200500784

DOI: 10.1002/chem.200500784
Synthesis of Nitrogen- and Oxygen-Containing Macrocycles—Derivatives of
Lithocholic Acid
Alexei D. Averin, Elena R. Ranyuk, Nikolai V. Lukashev, and Irina P. Beletskaya*[a]
Abstract: Palladium-catalyzed amina-
tion of 3,24-bis(3-bromophenoxy)cho-
lane (4) with various polyamines and
polyoxadiamines 5 taken in 1:1 ratio
was used for the synthesis of the mac-
rocycles 6, which contain steroidal and
polyamine moieties and were obtained
in 38–65% yields. The same reaction
with excess polyamine (2.2–3 equiv)
provided bis(polyamino) derivatives of
3,24-diphenoxycholane 7 in excellent
yields, whereas the diarylation of poly-
amines with two equivalents of 3,24-
bis(3-bromophenoxy)cholane afforded
their bis(steroidal) derivatives 8. Com-
pounds 7 and 8 were employed in the
syntheses of cyclodimers 9, which pos-
sess two steroidal and two polyamine
fragments; the efficiency of two meth-
ods was compared.
Keywords: amination · catalysis ·
macrocycles · polyamines · steroids
Introduction
The steroidal scaffold is one of the biggest rigid chiral frag-
ments occurring in nature. Since the time when steroidal
dimers were found to be the byproducts in the synthesis of
functionalized steroids, a great number of such compounds,
synthetic or isolated from living species, have been investi-
gated. The growing interest in the dimers of steroids is ex-
plained by the potential of these compounds to be used for
modeling biological systems and for the molecular recogni-
tion in enzymatic processes.[1]
Macrocycles based on steroidal fragments can be divided
into three main groups: cyclocholeates, cholaphanes, and
other macrocyclic molecules containing a steroidal moiety
(or moieties) and other aromatic or aliphatic linkers. Cyclo-
choleates are macrocyclic lactones obtained by the cycliza-
tion of 2–6 molecules of cholic acid in a head-to-tail
manner.
were shown to be macrocyclic molecules with adjustable
cavity size for trapping polar molecules of different geome-
try and dimensions.[7] Brady and Sanders elaborated another
approach to the synthesis of cyclodimers based on transes-
terification reactions, called “living” macrolactonization.[11,12]
Cholaphanes which constitute another class of steroidal
macrocycles contain 2–4 cholic acid fragments arranged in a
head-to-head or head-to-tail manner linked by means of var-
ious functional groups.[13]
The general approach to such compounds is based on the
Yamaguchi macrolactonization of cholic acid monomers or
dimers.[2] A number of such macrocycles were obtained by
using 2,6-dichlorobenzoyl chloride or dicyclohexylcarbodi-
imide and 4-N,N-dimethylaminopyridine.[3–10] Cyclocholeates
[a] Dr. A. D. Averin, E. R. Ranyuk, Prof. N. V. Lukashev,
Prof. I. P. Beletskaya
Department of Chemistry
Lomonosov Moscow State University
Leninskie Gory, Moscow, 119992 (Russia)
Fax : (+7)095-939-3618
E-mail: beletska@org.chem.msu.ru
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FULL PAPER
Such cyclodimers possess conformational rigidity that
makes them useful receptors. Some of them exhibit an ex-
traordinary ability in the strereoselective recognition of car-
bohydrate derivatives in organic solvents.[14,15] Introduction
of various functional groups makes them ideal compounds
for molecular recognition.[16] The first synthetic cholaphanes
were constructed by using the formation of cyclic amides as
a key step.[15,17,18] To improve the flexibility of the macrocy-
cle, ester groups were used for the cyclization.[19–23] Chola-
phanes containing amide and ester groups are susceptible to
acidic and basic conditions, and to the reduction by metal or
hydrogen. Ra, Cho, and Choi developed the synthesis of the
cholaphane in which steroidal fragments are linked through
ethyleneglycol moieties.[24]
Results and Discussion
The scaffold of lithocholic acid 1 was chosen as a steroidal
fragment to be incorporated into nitrogen- and oxygen-con-
taining macrocycles prepared by the catalytic amination.
The A and B rings of this steroid are cis-conjugated; this
feauture was thought to favor the cyclization. To use this ap-
proach we had to functionalize the starting lithocholic acid
with halogenoaryl substituents. In the first stage lithocholic
acid was reduced with in situ obtained diborane into chola-
nediol 2. This compound was transformed into 3,24-bis(3-
bromophenoxy)cholane (4) by using the Mitsunobu reac-
tion[34] in overall 40% yield (Scheme 1).
3-Bromophenol was used in this reaction because an elec-
tron-donor alkoxy group in ortho- and para-positions would
hinder the amination reaction. We have established that the
use of two equivalents of 3-bromophenol, triphenyl phos-
phine, and diethyl azodicarboxylate (DEAD) at room tem-
perature leads to the arylation of only the primary hydroxyl
in 2 giving 24-(3-bromophenoxy)-cholan-3-ol (3). Diarylated
compound 4 is formed only upon the action of additional
two equivalents of the reagents, after stirring at 45–508C for
8 h. When applying four equivalents of the reagents at once
followed by heating, the yield of 4 is somewhat poorer.
The reaction of compound 4 with a number of polyamines
5a–h (Scheme 2) was achieved with the known [Pd(dba)2]/
BINAP (dba=dibenzylideneacetone, BINAP=2,2’-bis(di-
phenylphosphino)-1,1’-binaphthyl) catalytic system proposed
by Buchwald in 1996 and thoroughly studied by his group to
show its great synthetic potential.[35,36] Reagents were taken
in equimolar ratio, the reactions were performed in dilute
dioxane (c=0.02m) to suppress the undesirable formation of
oligomers. The amount of the catalytic system was 8 mol%
[Pd(dba)2]/9 mol% BINAP, and sodium tert-butylate was
used as a base. The reactions were run to completion in 7–
Some other macrocycles contain one steroidal and one
polyoxaalkyl chain so that these molecules possess crown
ether cavities (examples of which are shown here).[25–28]
The size of the cycle and its geometry can be finely tuned
depending on the positions in the steroidal fragment to
which polyoxaalkyl chain is attached.
All macrocycles cited above, though they proved to be se-
lective sensors and receptors, have one serious drawback:
their syntheses are multistep
and laborious, and the yields
are often humble. To overcome
these difficulties and to synthe-
size a new series of steroidal
macrocycles, we decided to
apply the method elaborated
recently in our laboratory of
the construction of macrocycles
by the catalytic intramolecular
diamination of dihaloarenes
with polyamines and polyoxa-
polyamines. A series of such
polyazamacrocycles has been
synthesized that incorporate
benzene, pyridine, anthracene,
and
anthraquinone
moiet-
ies.[29–32] This method uses palla-
dium-catalyzed amination of
aryl halides developed by Buch-
wald and Hartwig over the last
decade.[33]
Scheme 1.
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I. P. Beletskaya et al.
lation with our previous obser-
vations. It could be explained
that the more ethylenediamine
fragments are present in a mol-
ecule of polyamine (like in
polyethylenepolyamines), the
more important is the forma-
tion of chelate palladium–dia-
mine complexes, which with-
draw palladium from the cata-
lytic cycle thus hindering the
amination reaction.
The compounds 6 were char-
acterized by 1H and 13C NM R
spectra and by MALDI-TOF
Scheme 2.
spectroscopy.
Protons
and
Table 1. The synthesis of the macrocycles 6a–h.
carbon atoms of two phenyl
rings differ slightly due to their
unequal surrounding, whereas
protons and quite often carbon
atoms of the polyamine chains
do not “feel” the unsymmetri-
cal character of the whole mol-
ecule and have chemical shifts
similar to those found for sym-
metrically disubstituted poly-
amines, though their proton sig-
Polyamine
t [h]
Product
Yield[a] [%]
1
2
3
4
5
6
7
8
NH2(CH2)3NH(CH2)3NH2 (5a)
8
9
8.5
9
6a
6b
6c
6d
6e
6 f
6g
6h
44
44
42
65
60
38
40
60
NH2(CH2)2NH(CH2)2NH(CH2)2NH2 (5b)
NH2(CH2)2NH(CH2)3NH(CH2)2NH2 (5c)
NH2(CH2)3NH(CH2)2NH(CH2)3NH2 (5d)
NH2(CH2)3NH(CH2)3NH(CH2)3NH2 (5e)
NH2(CH2)2NH(CH2)2NH(CH2)2NH(CH2)2NH2 (5 f)
NH2(CH2)2O(CH2)2O(CH2)2NH2 (5g)
NH2(CH2)3O(CH2)2O(CH2)2O(CH2)3NH2 (5h)
7
10
8.5
7
[a] Yield after chromatography.
10 h, and the resulting macrocycles 6a–h were isolated by
means of column chromatography on silica. The data are
collected in the Table 1. The reaction mixture composition
was investigated by 1H and 13C NMR spectroscopy, which
revealed that macrocycles 6 were formed in very high yields
(about 90%) which is unusual for such types of reactions.
For example, in our previous syntheses of macrocycles from
1,8-dichloroanthracene and 1,8-dichloroanthraquinone the
yields did not exceed 70%, whereas for the macrocycles de-
rived from 2,6- and 3,5-dibromopyridine they did not exceed
30–40%.[32] Another feature of this reaction is the following:
when employing triethylenetetraamine 5b or tetraethylene-
pentaamine 5 f, the yields of corresponding macrocycles 6b
and 6 f were almost as high as with other polyamines (en-
tries 2, 6), both in the reaction mixtures and after chroma-
tography. This is opposite to our previous observations in
the reactions with 1-bromo-2,6-dichlorobenzene and dihalo-
pyridines.[31,32] We could explain it by the fact that in the
present case the amination of bromophenyl groups and not
the diamination of dihalobenzene takes place (introduction
of the second amino group in the same benzene ring is hin-
dered by the electron-donor character of the amino substitu-
ent). Also much better yields of the macrocycles 6 might be
due to a possible perfect fitting of polyamines to two ste-
roid-born bromophenoxy moieties. Higher yields (60–65%)
of the macrocyles 6d,e,h (entries 4, 5, 8) can result from the
use of starting polyamines 5d,e,h with a more appropriate
length (12, 13, and 15 atoms, respectively) and also from
better ratios of C to N atoms in the polyamines, especially
in the case of trioxadiamine 5h. This fact is in a good corre-
nals are often broad and singlets are often observed in place
of multiplets (e.g., for 6e,f). In some cases (6d,e) the carbon
atoms of two ends of the polyamine chains differ slightly
due to nonsymmetry of the molecule.
According to our evaluations, triamine 5a is probably the
shortest polyamine that can form the cycle upon the reac-
tion with 3,24-bis(3-bromophenoxy)chlolane (4) due to the
geometry of the latter. Although we did not introduce short-
er triamines and diamines in this reaction, propanediamine
was used in the synthesis of the cycles containing steroidal
moieties; however, this required the presence of two steroi-
dal and two polyamine fragments in such macrocycles,
which we call cyclodimers (vide infra).
The change of the reaction conditions can dramatically
alter the result of the amination of 3,24-bis(3-bromophenox-
y)cholane (4). The reaction of 4 with 2.5–3 equivalents of
corresponding polyamines 5 in the presence of the same
amount of the catalyst, as in the reactions described above,
but in more concentrated solutions (c=0.1m) led to bis-
(polyamino) substituted steroids 7 (Scheme 3).
Compounds 7a,d,e,g,h were formed in excellent yields
(over 90%) according to 1H and 13C NMR spectra. As a
result of the use of more concentrated solutions, no macro-
cycles 6 were registered in the reaction mixtures. In the case
of propanediamine 5i, the main product 7i was formed in
60% yield together with cyclodimer 9i (40% yield).
MALDI-TOF spectra supported the formation of diaminat-
ed products 7; also linear oligomers that contained several
steroidal and polyamine fragments were not detected. Com-
pounds 7g and 7h were isolated by column chromatography
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Steroids
FULL PAPER
1H NMR spectra at d=4.5–
4.6 ppm, depending on the sub-
stituent (bromophenoxy or ami-
nophenoxy) attached to this
atom, but the difference does
not
exceed
0.02 ppm.
In
13C NMR spectra two signals
are observed for some carbon
atoms of the steroidal scaffold,
but these data are not sufficient
to discern between shown re-
gioisomers.
Macrocycles
with
larger
cavity size are of particular in-
terest due to their potential to
Scheme 3.
selectively bind big ions and
in 45 and 82% yields, respectively. The chromatography of
other bis(polyamino) substituted steroids 7a,d,e,g poses a
serious problem due to the presence of several amino
groups, which results in a strong affinity to silica of such
compounds.
The application of two equivalents of compound 4 in the
reactions with corresponding polyamines 5 afforded the syn-
thesis of another series of linear derivatives of cholanediol,
that is, the bis(steroidal) deriva-
polar molecules. To synthesize such macrocycles that contain
two steroidal and two polyamine moieties we used two alter-
native approaches. The first one (route a) is based on the
synthesis of bis(polyamino)-substituted steroids 7 followed
by their reaction with the second molecule of 4; the second
approach includes the synthesis of Na,Nw-bis(steroidal) de-
rivatives of polyamines followed by their reaction with the
second molecule of polyamine.
tives of polyamines 8g–i
(Scheme 4). These reactions
were run under the same condi-
tions as those mentioned above
and the yields of target com-
pounds in the reaction mixtures
were about 90% (estimated by
NMR spectroscopy). Com-
pounds 8g and 8h were isolated
by column chromatography to
give 43 and 39% yields, respec-
tively, while the compound 8i
was used in situ for further cyc-
lization. This reaction is also
notable for the fact that it ran
smoothly and was not compli-
cated by the formation of by-
products like linear oligomers
or macrocycles 6, although they
are easily produced as men-
tioned above. The product 8
may be a mixture of three pos-
sible regioisomers: head-to-
head, head-to-tail, and tail-to-
1
tail. In H and 13C NMR spectra
of compounds 8, the signals of
bromophenyl and aminophenyl
rings differ substantially, while
the patterns of steroidal moiet-
ies are complicated. Two differ-
ent singlets for the protons at
C3 atoms are observed in Scheme 4.
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I. P. Beletskaya et al.
with bisphenoxycholane 4, only
noncyclic compound 10 was iso-
lated in 17% yield; this com-
pound is an intermediate on the
way to cyclodimer 9h. Never-
theless further prolonged heat-
ing of this intermediate with an
additional amount of the cata-
lyst did not afford desirable
macrocycle. This compound
might be a mixture of four pos-
sible regioisomers (only one is
shown at the Scheme 5), but as
in the case of compounds 8
they cannot be distinguished by
NMR spectroscopy (if all of
them are formed). In contrast,
route a was found to be effi-
cient for the synthesis of cyclo-
dimer 9i, which was formed in
approximately 90% yield in the
reaction mixture (40% after
chromatography, entry 3). This
fact can be explained by a com-
parative rigidity of the starting
molecule 7i in comparison with
7g,h, which possess longer and
much more flexible polyamine
chains. It was mentioned above
that even in the synthesis of 7i
the formation of cyclodimer 9i
in 40% yield was observed,
though the reaction conditions
in that case were not favorable
(high concentration, excess of
diamine). Thus one may assume
that compounds 7i and 4 fit
Scheme 5.
each other as regards their ge-
ometry.
The synthesis of cyclodimers 9 by route a was carried out
The synthesis of cyclodimers 9 according to route b is
based on the reaction of equimolar amounts of bis(steroi-
dal)-substituted polyamines 8g–i with corresponding poly-
amines 5g–i (Scheme 6). The same reaction conditions as
those described for route a were applied. Route b was found
to be efficient for the synthesis of all cyclodimers 9g–i; the
better yields after chromatography were registered for 9g,h
(Table 3, entries 1, 2). The synthesis of cyclodimer 9i was
found to be more efficient through route a, as route b pro-
vided only 20% yield of this compound (entry 3). It is to be
noted that NMR spectra of the reaction mixtures revealed
near to quantitative yields of all target cyclodimers in this
reaction. Compounds 9 can be the mixtures of two re-
gioisomers (head-to-head and head-to-tail), but they are to-
tally indistinguishable by their NMR spectra. The head-to-
head isomer of 9 is produced from the head-to-head and
tail-to-tail isomers of 8, whereas the head-to-tail isomer of 9
is a result of the reaction of the head-to-tail isomer of 8.
by using diluted solutions of the reagents in dioxane (c=
0.02m) and the same amount of the catalyst, but longer
reflux (18–28 h) was applied to favour the cyclization. Start-
ing compounds 7g–i and 4 were taken in equimolar amounts
(Scheme 5). Data about the yields of corresponding cyclo-
dimers 9 are presented in the Table 2.
This method proved to be inefficient for the synthesis of
cyclodimers 9g,h (Table 2, entries 1, 2), in the reaction of 7h
Table 2. Synthesis of cyclodimers 9 by route a.
Polyamine
Aryl halide
t [h]
Product
Yield[a] [%]
1
2
3
7g
7h
7i
4
4
4
24
24
28
–
–
9i
0
0[b]
40
[a] Yield after chromatography. [b] Non-cyclic intermediate 10 was isolat-
ed in 17% yield.
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Steroids
FULL PAPER
Experimental Section
All reactions were conducted under
dry argon using absolute solvents. Di-
oxane and THF were purified by the
distillation over NaOH and sodium;
dichloromethane was distilled over
CaH2. Triphenyl phosphine was recrys-
tallized from ethanol; other commer-
cially available compounds except tet-
raethylenepentaamine were employed
without special purification. Tetraethy-
lenepentaamine (technical quality)
was purified by several recrystalliza-
tions of its monohydrate from toluene
at À188C followed by the decomposi-
tion of the hydrate in vacuum at
1008C. Free triethylenetetraamine was
synthesized from its dihydrochloride
by the action of KOH in methanol.
[Pd(dba)2] was prepared according to
the described procedure.[37] Column
chromatography was carried out on
silica gel (Merck, 40–60 mm). 1H and
13C NMR spectra were recorded with
the Bruker Avance-400 spectrometer
(400 and 100.6 MHz, respectively);
MALDI-TOF spectra were registered
using Bruker Daltonics Proflex III
mass spectrometer.
(3a,5b)-Cholane-3,24-diol (2): An
argon-flushed
equipped with a condenser, dropping
funnel, and magnetic stirrer, was
three-necked
flask,
Scheme 6.
a
charged with sodium borohydride
(113 mmol, 3.92 g), lithocholic acid 1 (15 mmol, 5.61 g), absolute THF
(150 mL). BF3·Et2O (150 mmol, 18.5 mL) was added dropwise with stir-
ring; after which the stirring was continued for 2 h. The reaction mass
was slowly treated with water (100 mL) to dissolve resulting boric acid
and extracted with dichloromethane (300 mL). The emulsion that was
formed during extraction was destroyed by the addition of a concentrated
aqueous solution of sodium chloride. The water layer was washed with
dichloromethane (2”50 mL), combined organic layers were dried over
sodium sulfate, and the crude product was obtained after the evaporation
Table 3. Synthesis of cyclodimers 9g–i by route b.
Polyamine
Aryl halide
t [h]
Product
Yield[a] [%]
1
2
3
5g
5h
5i
8g
8h
8i
18
24
28
9g
9h
9i
35
34
20
[a] Yield after chromatography.
of the solvent in vacuum. Diol
2 was recrystallized from acetone
(400 mL). Yield: 4.34 g (80%); M.p. 172–1738C.[24] 1H NMR (400 MHz,
CDCl3): d=0.63 (s, 3H), 0.91 (s, 3H), 0.92 (d, J=5.6 Hz, 3H), 0.95–1.89
(m, 27H), 1.93–1.97 (m, 1H), 3.55–3.65 ppm (m, 3H); 13C NM R
(100.6 MHz, CDCl3): d=12.03, 18.63, 20.82, 23.36, 24.21, 26.42, 27.19,
28.30, 29.43, 30.55, 31.82, 34.56, 35.34, 35.57, 35.85, 36.46, 40.19, 40.45,
42.10, 42.70, 56.18, 56.51, 63.59, 71.86 ppm.
Conclusion
To sum up, we have elaborated a convenient method for the
synthesis of nitrogen- and oxygen-containing macrocycles in-
corporating steroidal moieties; the method is based on intra-
molecular catalytic diamination of 3,24-bis(3-bromophenox-
y)cholane. This approach provided unusually high yields of
macrocycles containing various numbers of nitrogen and
oxygen atoms. Two routes have been elaborated for the syn-
thesis of cyclodimers: either the use of bis(polyamino) deriv-
atives of diphenoxycholane or by utilizing bis(steroidal) de-
rivatives of polyamines; their efficiency has been compared
for different polyamines. The research is to be continued;
the proposed method will be applied to the synthesis of vari-
ous macrocycles containing other steroidal and aromatic
spacers and polyamine chains of different length.
(3a,5b)-24-(3-Bromophenoxy)cholan-3-ol (3): A two-necked flask flushed
with argon, equipped with a condenser and magnetic stirrer, was charged
with absolute THF (25 mL), cholanediol 2 (1 mmol, 362 mg), 3-bromo-
phenol (2 mmol, 346 mg), triphenyl phosphine (2 mmol, 524 mg), and so-
lution of DEAD in toluene (40%, 2 mmol, 0.92 mL). The reaction mix-
ture was stirred at room temperature for 2 days and concentrated in
vacuum up to the volume of 5 mL, diethyl ether (5 mL) was added, and
the precipitation of triphenyl phosphine oxide was observed. The solution
was filtered off, the precipitate was washed with diethyl ether, the solvent
was evaporated in vacuum, and the crude product was obtained as a
pale-yellow oil. The oil was subjected to chromatography on silica with
CH2Cl2 as an eluent. Yield (colourless oil): 204 mg (39%); 1H NM R
(400 MHz, CDCl3): d=0.64 (s, 3H), 0.90 (s, 3H), 0.93 (d, J=6.6 Hz, 3H),
0.97–1.87 (m, 26H), 1.95 (dd, J=11.9, 3.2 Hz, 1H), 2.19 (brs, 1H), 3.61
(ddd, J=15.4, 10.8, 4.6 Hz, 1H), 3.87 (m, 2H), 6.80 (ddd, J=8.4, 2.6,
1.3 Hz, 1H), 7.01–7.05 (m, 2H), 7.10 ppm (t, J=8.4 Hz, 1H); 13C NM R
(100.6 MHz, CDCl3): d=11.98, 18.53, 20.74, 23.30, 24.13, 25.69, 26.35,
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I. P. Beletskaya et al.
27.12, 28.19, 30.37, 31.94, 34.46, 35.29, 35.41, 35.74, 36.27, 40.10, 40.37,
42.02, 42.60, 56.02, 56.39, 68.66, 71.73, 113.45, 117.68, 122.67, 123.42,
130.35, 159.84 ppm.
(1C), 25.92 (1C), 26.23 (1C), 26.58 (1C), 28.23 (1C), 29.61 (1C), 30.44
(1C), 32.08 (1C), 34.80 (1C), 35.49 (1C), 35.63 (1C), 36.93 (1C), 39.99
(1C), 40.24 (1C), 42.70 (1C), 43.45 (2C), 48.42 (2C), 48.97 (2C), 56.17
(1C), 56.62 (1C), 68.23 (1C), 72.29 (1C), 99.43 (1C), 101.12 (1C), 103.17
(1C), 104.71 (1C), 105.69 (1C), 105.92 (1C), 129.75 (1C), 129.79 (1C),
149.81 (2C), 158.93 (1C), 160.34 ppm (1C); MALDI-TOF (dithranol):
m/z: 1313.70 [2M+H]+, 1969.90 [3M]+.
(3b,5b)-3,24-Bis(3-bromophenoxy)cholane (4): A two-necked flask flush-
ed with argon, equipped with a condenser and magnetic stirrer, was
charged with absolute THF (250 mL), cholanediol 2 (10 mmol, 3.62 g), 3-
bromophenol (20 mmol, 3.46 g), triphenylphosphine (20 mmol, 5.24 g),
and a solution of DEAD in toluene (40%, 20 mmol, 9.2 mL). The reac-
tion mixture was stirred at room temperature for 2 days. Then the addi-
tional amount of 3-bromophenol (3.46 g, 20 mmol), triphenylphosphine
(20 mmol, 5.24 g), and a solution of DEAD in toluene (40%, 20 mmol,
9.2 mL) was added, and the reaction mixture was stirred at 45–508C for
24 h. Then the reaction mixture was concentrated in vacuum up to the
volume of 25 mL, diethyl ether (25 mL) was added, and the precipitation
of triphenylphosphine oxide was observed. The solution was filtered off,
the precipitate was washed with diethyl ether, the solvent was evaporated
in vacuum, and the crude product was obtained as a pale-yellow oil. The
oil was subjected to chromatography on silica with CH2Cl2 as an eluent.
Yield (colourless oil): 2.89 g (43%); 1H NMR (400 MHz, CDCl3): d=
0.67 (s, 3H), 0.96 (d, J=6.3 Hz, 3H), 0.98 (s, 3H), 1.00–2.01 (m, 28H),
3.85–3.93 (m, 2H), 4.56 (brs, 1H), 6.80–6.84 (m, 2H), 7.01–7.07 (m, 4H),
7.11 (t, J=8.0 Hz, 1H), 7.12 ppm (t, J=8.4 Hz, 1H); 13C NM R
(100.6 MHz, CDCl3): d=12.06 (1C), 18.60 (1C), 21.09 (1C), 23.80 (1C),
24.18 (1C), 24.49 (1C), 25.74 (1C), 26.21 (1C), 26.54 (1C), 28.26 (1C),
30.25 (1C), 30.32 (1C), 32.02 (1C), 34.82 (1C), 35.47 (1C), 35.64 (1C),
36.92 (1C), 40.01 (1C), 40.23 (1C), 42.72 (1C), 56.15 (1C), 56.61 (1C),
68.71 (1C), 73.08 (1C), 113.51 (1C), 114.74 (1C), 117.71 (1C), 119.28
(1C), 122.74 (1C), 123.31 (1C), 123.49 (1C), 130.43 (br, 3C), 158.60
(1C), 159.92 ppm (1C).
Compound 6c: From
4 (0.25 mmol, 168 mg) and tetraamine 5c
(0.25 mmol, 40 mg), in the presence of [Pd(dba)2] (12 mg), BINAP
(14 mg), and tBuONa (100 mg) in dioxane (12 mL) and after 8.5 h of
reflux, macrocycle 6c was obtained as a viscous pale-yellow oil. Yield:
70 mg (42%); eluent CH2Cl2/MeOH/NH3 100:20:3; 1H NMR (400 MHz,
CDCl3): d=0.64 (s, 3H), 0.93 (d, J=6.5 Hz, 3H), 0.95 (s, 3H), 0.99–2.05
(m, 30H), 2.89 (brs, 8H), 3.28 (brs, 4H), 3.84 (brs, 2H), 4.51 (s, 1H),
6.10–6.29 (m, 6H), 6.96–7.05 ppm (m, 2H); 13C NMR (100.6 MHz,
CDCl3): d=12.06 (1C), 18.60 (1C), 21.07 (1C), 23.82 (1C), 24.18 (1C),
24.61 (1C), 25.95 (1C), 26.23 (1C), 26.59 (1C), 28.26 (1C), 30.45 (br,
3C), 32.09 (1C), 34.82 (1C), 35.54 (1C), 36.63 (1C), 36.95 (1C), 39.97
(1C), 40.23 (1C), 42.06 (2C), 42.70 (1C), 47.66 (2C), 48.89 (2C), 56.17
(1C), 56.60 (1C), 68.31 (1C), 72.31 (1C), 99.26 (1C), 100.84 (1C), 103.34
(1C), 104.62 (1C), 105.59 (1C), 105.81 (1C), 129.93 (1C), 130.01 (1C),
149.29 (2C), 158.99 (1C), 160.40 ppm (1C) ppm; MALDI-TOF (dithra-
nol): m/z: 671.16 [M+H]+.
Compound 6d: From
4 (0.28 mmol, 195 mg) and tetraamine 5d
(0.28 mmol, 48 mg), in the presence of [Pd(dba)2] (13 mg), BINAP
(16 mg), and tBuONa (108 mg) in dioxane (14 mL) and after 9 h of
reflux, macrocycle 6d was obtained as a viscous pale-yellow oil. Yield:
130 mg (65%); eluent CH2Cl2/MeOH/NH3 100:20:3–10:3:1; 1H NM R
(400 MHz, CDCl3): d=0.65 (s, 3H), 0.94 (d, J=5.6 Hz, 3H), 0.96 (s, 3H),
0.99–2.08 (m, 28H), 1.77 (q, J=6.2 Hz, 4H), 2.71 (s, 4H), 2.72 (t, J=
6.3 Hz, 4H), 3.15 (t, J=5.2 Hz, 4H), 3.87 (brs, 2H), 4.54 (brs, 1H), 6.09–
6.28 (m, 6H), 6.97–7.06 ppm (m, 2H); 13C NMR (100.6 MHz, CDCl3):
d=12.04 (1C), 18.59 (1C), 21.07 (1C), 23.80 (1C), 24.18 (1C), 24.66
(1C), 25.95 (1C), 26.23 (1C), 26.58 (1C), 28.24 (1C), 29.54 (2C), 29.62
(2C), 32.08 (1C), 34.81 (1C), 35.49 (1C), 35.64 (1C), 36.93 (1C), 39.99
(1C), 40.24 (1C), 42.59 (1C), 42.66 (1C), 42.70 (1C), 48.08 (2C), 49.42
(2C), 56.18 (1C), 56.62 (1C), 68.23 (1C), 72.27 (1C), 99.22 (1C), 100.90
(1C), 102.84 (1C), 104.37 (1C), 105.56 (1C), 105.76 (1C), 129.72 (1C),
129.77 (1C), 149.89 (1C), 149.93 (1C), 158.96 (1C), 160.36 ppm (1C);
MALDI-TOF (dithranol): m/z: 685.46 [M+H]+, 1369.9 [2M+H]+.
General method for the synthesis of macrocycles 6a–h: A two-necked
flask equipped with a condenser and flushed with argon was charged
with compound 4 (0.25–0.5 mmol, 168–336 mg), [Pd(dba)2] (8 mol%, 12–
24 mg), BINAP (9 mol%, 14–28 mg), absolute dioxane (12–25 mL), ap-
propriate polyamine (0.25–0.5 mmol), and sodium tert-butylate (1–
2 mmol, 100–200 mg). The reaction mixture was refluxed for 7–10 h and
then cooled to ambient temperature. The NaBr precipitate was filtered
off, dioxane was evaporated in vacuum, and a solid or oily residue was
obtained. The residue was subjected to chromatography on silica with a
sequence of eluents: CH2Cl2, CH2Cl2/MeOH 100:1–3:1, CH2Cl2/MeOH/
NH3 100:20:1–10:3:1. Amount of silica used: 40 mL/0.5 mmol.
Compound 6a: From 4 (0.25 mmol, 168 mg) and triamine 5a (0.25 mmol,
33 mg), in the presence of [Pd(dba)2] (12 mg), BINAP (14 mg), and
tBuONa (100 mg) in dioxane (12 mL), and after 8 h of reflux, macrocycle
6a was obtained as a viscous pale-yellow oil. Yield: 71 mg (44%); eluent
CH2Cl2/MeOH/NH3 100:20:3–10:3:1; 1H NMR (400 MHz, CDCl3): d=
0.65 (s, 3H), 0.93 (d, J=6.6 Hz, 3H), 0.96 (s, 3H), 0.98–2.07 (m, 28H),
1.84 (q, J=7.6 Hz, 4H), 2.78 (t, J=6.3 Hz, 4H), 3.17 (t, J=6.9 Hz, 4H),
3.81–3.90 (m, 2H), 4.53 (s, 1H), 6.11–6.26 (m, 6H), 6.98–7.06 ppm (m,
2H) (here and in the following 1H NMR spectra signals for NH protons
are omitted for the reason of their inconstancy); 13C NMR (100.6 MHz,
CDCl3): d=12.04 (1C), 18.59 (1C), 21.06 (1C), 23.80 (1C), 24.18 (1C),
24.64 (1C), 25.94 (1C), 26.23 (1C), 26.58 (1C), 28.24 (1C), 29.36 (1C),
29.49 (1C), 29.63 (2C), 32.08 (1C), 34.81 (1C), 35.50 (1C), 35.64 (1C),
36.93 (1C), 39.98 (1C), 40.24 (1C), 42.70 (2C), 42.83 (1C), 48.22 (2C),
56.17 (1C), 56.63 (1C), 68.23 (1C), 72.25 (1C), 99.18 (1C), 100.83 (1C),
102.79 (1C), 102.90 (1C), 105.57 (1C), 105.78 (1C), 129.77 (1C), 129.81
(1C), 149.81 (1C), 149.89 (1C), 158.97 (1C), 160.37 ppm (1C); MALDI-
TOF (dithranol): m/z: 642.12 [M+H]+.
Compound 6e: From 4 (0.25 mmol, 168 mg) and tetraamine 5e
(0.25 mmol, 47 mg), in the presence of [Pd(dba)2] (12 mg), BINAP
(14 mg), and tBuONa (100 mg) in dioxane (12 mL) and after 7 h of
reflux, macrocycle 6e was obtained as a viscous pale-yellow oil. Yield:
104 mg (60%); eluent CH2Cl2/MeOH/NH3 10:3:1; 1H NMR (400 MHz,
CDCl3): d=0.64 (s, 3H), 0.93 (d, J=6.5 Hz, 3H), 0.96 (s, 3H), 0.98–2.02
(m, 28H), 1.79 (brs, 6H), 2.70–2.83 (m, 8H), 3.12 (brs, 4H), 3.85 (brs,
2H), 4.53 (s, 1H), 6.10–6.26 (m, 6H), 7.00 (t, J=8.0 Hz, 1H), 7.03 ppm
(t, J=8.1 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): d=11.90 (1C), 18.45
(1C), 20.92 (1C), 23.67 (1C), 24.03 (1C), 24.51 (1C), 25.81 (1C), 26.09
(1C), 26.44 (1C), 28.10 (1C), 29.22 (2C), 29.48 (1C), 30.17 (1C), 30.32
(1C), 31.95 (1C), 33.62 (1C), 34.67 (1C), 35.36 (1C), 35.49 (1C), 36.80
(1C), 39.84 (1C), 40.11 (1C), 40.14 (1C), 42.56 (1C), 42.62 (1C), 47.69
(1C), 48.16 (1C), 48.24 (1C), 56.04 (1C), 56.47 (1C), 68.05 (1C), 72.07
(1C), 99.02 (1C), 100.69 (1C), 102.59 (1C), 104.15 (1C), 105.41 (1C),
105.62 (1C), 129.59 (2C), 149.78 (1C), 149.82 (1C), 158.80 (1C),
160.21 ppm (1C).
Compound 6 f: From
4 (0.25 mmol, 168 mg) and pentaamine 5 f
Compound 6b: From
4
(0.28 mmol, 195 mg) and tetraamine 5b
(0.25 mmol, 47 mg), in the presence of [Pd(dba)2] (12 mg), BINAP
(14 mg), and tBuONa (100 mg) in dioxane (12 mL) and after 10 h of
reflux, macrocycle 6 f was obtained as a viscous pale-yellow oil. Yield:
66 mg (38%); eluent CH2Cl2/MeOH/NH3 100:20:3–10:3:1; 1H NM R
(400 MHz, CDCl3): d=0.66 (s, 3H), 0.97 (brs, 6H), 0.86–2.05 (m, 28H),
2.70 (s, 8H), 2.84 (brs, 4H), 3.16 (brs, 4H), 3.87 (brs, 2H), 4.54 (s, 1H),
6.08–6.30 (m, 6H), 6.97–7.03 ppm (m, 2H); 13C NMR (100.6 MHz,
CDCl3): d=12.06 (1C), 18.60 (1C), 21.08 (1C), 23.83 (1C), 24.19 (1C),
24.65 (1C), 25.95 (1C), 26.24 (1C), 26.58 (1C), 28.26 (1C), 30.45 (2C),
32.08 (1C), 34.83 (1C), 35.52 (1C), 35.64 (1C), 36.94 (1C), 39.99 (1C),
(0.28 mmol, 41 mg), in the presence of [Pd(dba)2] (13 mg), BINAP
(16 mg), and tBuONa (108 mg) in dioxane (14 mL) and after 9 h of
reflux, macrocycle 6b was obtained as beige crystals. M.p. 108–1108C;
yield 81 mg (44%); eluent CH2Cl2/MeOH/NH3 10:3:1; 1H NM R
(400 MHz, CDCl3): d=0.65 (s, 3H), 0.94 (d, J=6.6 Hz, 3H), 0.96 (s, 3H),
0.99–2.01 (m, 28H), 2.73 (s, 4H), 2.85 (t, J=5.4 Hz, 4H), 3.18 (t, J=
5.4 Hz, 4H), 3.86 (s, 2H), 4.53 (s, 1H), 6.11–6.29 (m, 6H), 7.02 (t, J=
7.9 Hz, 1H), 7.03 ppm (t, J=8.0 Hz, 1H); 13C NMR (100.6 MHz, CDCl3):
d=12.04 (1C), 18.58 (1C), 21.06 (1C), 23.79 (1C), 24.16 (1C), 24.65
7036
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 7030 – 7039

Steroids
FULL PAPER
40.24 (1C), 42.72 (1C), 43.42 (2C), 48.42 (2C), 48.99 (2C), 49.22 (2C),
56.17 (1C), 56.63 (1C), 68.25 (1C), 72.28 (1C), 99.42 (1C), 101.12 (1C),
103.10 (1C), 104.68 (1C), 105.72 (1C), 105.94 (1C), 129.78 (1C), 129.85
(1C), 149.79 (1C), 149.83 (1C), 158.93 (1C), 160.34 ppm (1C); MALDI-
TOF (dithranol): m/z: 700.13 [M+H]+.
Compound 7d: From
4
(0.22 mmol, 150 mg) and tetraamine 5d
(0.66 mmol, 115 mg), in the presence of [Pd(dba)2] (10 mg), BINAP
(12 mg), and tBuONa (85 mg) in absolute dioxane (2 mL) and after re-
fluxing for 5 h, bis(polyamino) derivative 7d was obtained as a pale-
yellow oil. Yield in the reaction mixture >90%. 1H NMR (400 MHz,
CDCl3): d=0.66 (s, 3H), 0.94 (d, J=6.3 Hz, 3H), 0.97 (s, 3H), 1.00–2.02
(m, 28H), 1.62 (q, J=7.0 Hz, 4H), 1.78 (q, J=6.5 Hz, 4H), 2.65 (t, J=
7.0 Hz, 4H), 2.69–2.72 (m, 12H), 2.74 (t, J=6.5 Hz, 4H), 3.15 (t, J=
6.6 Hz, 4H), 3.87 (brs, 2H), 4.54 (brs, 1H), 6.12–6.25 (m, 6H), 7.02 (t,
J=7.8 Hz, 1H), 7.04 ppm (t, J=8.1 Hz, 1H); 13C NMR (100.6 MHz,
CDCl3): d=11.92 (1C), 18.47 (1C), 20.94 (1C), 23.69 (1C), 24.05 (1C),
24.51 (1C), 25.80 (1C), 26.10 (1C), 26.45 (1C), 28.12 (1C), 29.32 (1C),
29.36 (1C), 30.32 (2C), 31.95 (1C), 33.64 (2C), 34.69 (1C), 35.38 (1C),
35.50 (1C), 36.81 (1C), 39.84 (1C), 40.10 (3C), 42.48 (2C), 42.57 (1C),
47.53 (2C), 47.93 (2C), 49.28 (4C), 56.03 (1C), 56.49 (1C), 68.09 (1C),
72.10 (1C), 99.04 (1C), 100.72 (1C), 102.63 (1C), 104.19 (1C), 105.42
(1C), 105.64 (1C), 129.59 (1C), 129.64 (1C), 149.75 (1C), 149.80 (1C),
158.82 (1C), 160.23 ppm (1C); MALDI-TOF (dithranol): m/z: 859.76
[M+H]+.
Compound 6g: From
4 (0.28 mmol, 195 mg) and dioxadiamine 5g
(0.28 mmol, 42 mg), in the presence of [Pd(dba)2] (13 mg), BINAP
(16 mg), and tBuONa (110 mg) in dioxane (14 mL) and after 9 h of
reflux, macrocycle 6g was obtained as a viscous pale-yellow oil. Yield:
74 mg (40%); eluent CH2Cl2/MeOH 10:1–5:1; 1H NMR (400 MHz,
CDCl3): d=0.65 (s, 3H), 0.94 (d, J=6.6 Hz, 3H), 0.96 (s, 3H), 0.99–2.04
(m, 28H), 3.27 (t, J=4.7 Hz, 4H), 3.63 (s, 4H), 3.69 (t, J=4.7 Hz, 4H),
3.86 (brs, 2H), 4.53 (s, 1H), 6.15–6.28 (m, 6H), 7.03 (t, J=8.0 Hz, 1H),
7.04 ppm (t, J=8.3 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): d=12.06
(1C), 18.61 (1C), 21.09 (1C), 23.82 (1C), 24.19 (1C), 24.66 (1C), 25.95
(1C), 26.25 (1C), 26.60 (1C), 28.26 (1C), 29.64 (1C), 30.46 (1C), 32.10
(1C), 34.83 (1C), 35.52 (1C), 35.66 (1C), 36.96 (1C), 40.01 (1C), 40.27
(1C), 42.73 (1C), 43.42 (2C), 56.20 (1C), 56.64 (1C), 68.26 (1C), 69.60
(2C), 70.19 (2C), 72.34 (1C), 99.65 (1C), 101.36 (1C), 103.40 (1C),
104.93 (1C), 105.89 (1C), 106.10 (1C), 129.79 (1C), 129.83 (1C), 149.49
(1C), 149.55 (1C), 158.95 (1C), 160.35 ppm (1C).
Compound 7e: From
4 (0.22 mmol, 150 mg) and tetraamine 5e
(0.66 mmol, 124 mg), in the presence of [Pd(dba)2] (10 mg), BINAP
(12 mg), and tBuONa (85 mg) in absolute dioxane (2 mL) and after re-
fluxing for 5 h, bis(polyamino) derivative 7e was obtained as a pale-
yellow oil. Yield in the reaction mixture >90%. 1H NMR (400 MHz,
CDCl3): d=0.65 (s, 3H), 0.94 (d, J=6.5 Hz, 3H), 0.96 (s, 3H), 0.99–1.98
(m, 28H), 1.61 (q, J=6.9 Hz, 4H), 1.65 (q, J=6.9 Hz, 4H), 1.76 (q, J=
6.1 Hz, 4H), 2.59–2.73 (m, 20H), 3.14 (brs, 4H), 3.86 (brs, 2H), 4.53
(brs, 1H), 6.10–6.24 (m, 6H), 7.01 (t, J=7.6 Hz, 1H), 7.02 ppm (t, J=
7.8 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): d=11.84 (1C), 18.39 (1C),
20.85 (1C), 23.61 (1C), 23.97 (1C), 24.43 (1C), 25.72 (1C), 26.02 (1C),
26.37 (1C), 28.04 (1C), 29.14 (1C), 29.19 (1C), 30.08 (2C), 30.24 (2C),
31.87 (1C), 33.56 (2C), 34.60 (1C), 35.29 (1C), 35.42 (1C), 36.72 (1C),
39.76 (1C), 40.01 (1C), 40.09 (2C), 42.48 (1C), 42.55 (2C), 47.60 (2C),
48.10 (2C), 48.24 (2C), 48.32 (2C), 55.95 (1C), 56.40 (1C), 67.99 (1C),
71.99 (1C), 98.92 (1C), 100.59 (1C), 102.50 (1C), 104.07 (1C), 105.33
(1C), 105.55 (1C), 129.48 (1C), 129.53 (1C), 149.70 (1C), 149.74 (1C),
158.72 (1C), 160.13 ppm (1C); MALDI-TOF (dithranol): m/z: 887.82
[M+H]+.
Compound 6h: From
4 (0.5 mmol, 336 mg) and trioxadiamine 5h
(0.5 mmol, 110 mg), in the presence of [Pd(dba)2] (23 mg), BINAP
(28 mg), and tBuONa (200 mg) in dioxane (25 mL) and after 7 h of
reflux, macrocycle 6h was obtained as yellow crystals. M.p. 90–928C;
yield 220 mg (60%); eluent CH2Cl2/MeOH 10:1–3:1; 1H NM R
(400 MHz, CDCl3): d=0.65 (s, 3H), 0.94 (d, J=6.3 Hz, 3H), 0.97 (s, 3H),
1.00–2.02 (m, 28H), 1.86 (q, J=6.4 Hz, 4H), 3.19 (t, J=6.5 Hz, 2H), 3.20
(t, J=6.5 Hz, 2H), 3.58–3.69 (m, 12H), 3.84–3.88 (m, 2H), 4.53 (brs,
1H), 6.12–6.25 (m, 6H), 7.01 (t, J=7.9 Hz, 1H), 7.02 ppm (t, J=8.1 Hz,
1H); 13C NMR (100.6 MHz, CDCl3): d=12.06 (1C), 18.62 (1C), 21.10
(1C), 23.83 (1C), 24.21 (1C), 24.70 (1C), 26.00 (1C), 26.26 (1C), 26.61
(1C), 28.26 (1C), 29.13 (1C), 29.19 (1C), 30.49 (2C), 32.13 (1C), 34.85
(1C), 35.54 (1C), 35.68 (1C), 36.98 (1C), 40.03 (1C), 40.28 (1C), 41.68
(2C), 42.74 (1C), 56.23 (1C), 56.66 (1C), 68.27 (1C), 69.70 (2C), 70.24
(2C), 70.62 (2C), 72.30 (1C), 99.25 (1C), 100.95 (1C), 102.78 (1C),
104.30 (1C), 105.62 (1C), 105.83 (1C), 129.71 (1C), 129.77 (1C), 149.90
(1C), 149.96 (1C), 158.99 (1C), 160.40 ppm (1C); MALDI-TOF (dithra-
nol): m/z: 731.35 [M+H]+.
Compound 7g: From
4 (0.7 mmol, 470 mg) and dioxadiamine 5g
(1.75 mmol, 259 mg), in the presence of [Pd(dba)2] (23 mg), BINAP
(39 mg), and tBuONa (270 mg) in absolute dioxane (6 mL) and after re-
fluxing for 7 h, bis(polyamino) derivative 7g was obtained as a pale-
yellow oil. Yield: 225 mg (40%); eluent CH2Cl2/MeOH 5:1; 1H NM R
(400 MHz, CDCl3): d=0.64 (s, 3H), 0.93 (d, J=6.6 Hz, 3H), 0.96 (s, 3H),
0.99–2.00 (m, 28H), 2.85 (brs, 4H), 3.25 (t, J=4.8 Hz, 4H), 3.49 (brs,
4H), 3.59 (s, 8H), 3.66 (t, J=5.0 Hz, 4H), 3.81–3.89 (m, 2H), 4.52 (brs,
1H), 6.15–6.28 (m, 6H), 7.00 (t, J=7.8 Hz, 1H), 7.02 ppm (t, J=7.9 Hz,
1H); 13C NMR (100.6 MHz, CDCl3): d=12.01 (1C), 18.59 (1C), 21.03
(1C), 23.78 (1C), 24.15 (1C), 24.60 (1C), 25.88 (1C), 26.19 (1C), 26.55
(1C), 28.21 (1C), 30.41 (1C), 32.04 (1C), 34.78 (1C), 35.47 (1C), 35.60
(1C), 36.91 (1C), 39.95 (1C), 40.20 (1C), 41.10 (1C), 42.67 (1C), 43.42
(2C), 56.12 (1C), 56.58 (1C), 68.22 (1C), 69.56 (2C), 69.60 (2C), 70.09
(4C), 71.92 (2C), 72.26 (1C), 99.51 (1C), 101.19 (1C), 103.16 (1C),
104.82 (1C), 105.79 (1C), 106.04 (1C), 129.74 (1C), 129.79 (1C), 149.54
(1C), 149.59 (1C), 158.88 (1C), 160.29 ppm (1C); MALDI-TOF (dithra-
nol): m/z: 807.48 [M+H]+.
General method for the synthesis of bis(polyamino)-substituted steroids
7a,d,e,g–i: A two-necked flask, equipped with a condenser and flushed
with argon, was charged with 4 (0.22–1.35 mmol, 148–907 mg), [Pd(dba)2]
(8 mol%, 10–62 mg), BINAP (9 mol%, 12–76 mg), absolute dioxane (2–
13 mL), the appropriiate polyamine (0.55–5.4 mmol), and tBuONa (0.9–
5.4 mmol, 90–520 mg). The reaction mixture was refluxed for 5–8 h and
then cooled down. NaBr was filtered off, dioxane was evaporated in
vacuum, and the residue was subjected to chromatography on silica using
a sequence of eluents: CH2Cl2, CH2Cl2/MeOH 100:1–3:1 (in the case of
7g,h).
Compound 7a: From 4 (0.22 mmol, 150 mg) and triamine 5a (0.66 mmol,
86 mg), in the presence of [Pd(dba)2] (10 mg), BINAP (12 mg), and
tBuONa (85 mg) in absolute dioxane (2 mL) and after refluxing for 5 h,
bis(polyamino) derivative 7a was obtained as a pale-yellow oil. Yield in
the reaction mixture >90%. 1H NMR (400 MHz, CDCl3): d=0.64 (s,
3H), 0.94 (d, J=6.5 Hz, 3H), 0.97 (s, 3H), 0.98–1.94 (m, 28H), 1.61 (q,
J=6.9 Hz, 4H), 1.77 (q, J=6.6 Hz, 4H), 2.64 (t, J=7.1 Hz, 4H), 2.71 (t,
J=5.8 Hz, 4H), 2.75 (t, J=5.8 Hz, 4H), 3.14 (t, J=5.7 Hz, 4H), 3.76–3.85
(m, 2H), 4.54 (brs, 1H), 6.06–6.20 (m, 6H), 7.02 (t, J=7.8 Hz, 1H),
7.03 ppm (t, J=8.0 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): d=11.90
(1C), 18.44 (1C), 20.91 (1C), 23.66 (1C), 24.02 (1C), 24.49 (1C), 25.78
(1C), 26.07 (1C), 26.42 (1C), 28.10 (1C), 29.20 (1C), 29.25 (1C), 30.29
(2C), 31.92 (1C), 33.59 (2C), 34.66 (1C), 35.35 (1C), 35.48 (1C), 36.79
(1C), 39.82 (1C), 40.11 (1C), 40.16 (2C), 42.54 (1C), 42.66 (2C), 47.64
(2C), 48.23 (2C), 56.00 (1C), 56.46 (1C), 68.06 (1C), 72.07 (1C), 98.97
(1C), 100.64 (1C), 102.59 (1C), 104.16 (1C), 105.41 (1C), 105.62 (1C),
129.56 (1C), 129.61 (1C), 149.75 (1C), 149.79 (1C), 158.79 (1C),
160.20 ppm (1C); MALDI-TOF (dithranol): m/z: 773.64 [M+H]+.
Compound 7h: From
4 (1.35 mmol, 908 mg) and trioxadiamine 5h
(5.4 mmol, 1.19 g), in the presence of [Pd(dba)2] (62 mg), BINAP
(76 mg), and tBuONa (520 mg) in absolute dioxane (13 mL) and after re-
fluxing for 8 h, bis(polyamino) derivative 7h was obtained as a pale-
yellow oil. Yield: 1.05 g (82%); eluent CH2Cl2/MeOH 5:1; 1H NM R
(400 MHz, CDCl3): d=0.63 (s, 3H), 0.92 (d, J=6.6 Hz, 3H), 0.95 (s, 3H),
0.98–2.02 (m, 28H), 1.84 (brs, 4H), 1.89 (q, J=6.3 Hz, 4H), 2.99 (t, J=
5.5 Hz, 4H), 3.18 (t, J=5.7 Hz, 4H), 3.55–3.66 (m, 24H), 3.82–3.88 (m,
2H), 4.52 (brs, 1H), 6.10–6.26 (m, 6H), 6.99 (t, J=7.8 Hz, 1H), 7.00 ppm
(t, J=8.0 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): d=12.01 (1C), 18.57
(1C), 21.04 (1C), 23.78 (1C), 24.14 (1C), 24.63 (1C), 25.89 (1C), 26.19
(1C), 26.55 (1C), 28.11 (1C), 28.21 (2C), 28.81 (1C), 28.98 (2C), 30.43
Chem. Eur. J. 2005, 11, 7030 – 7039
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7037

I. P. Beletskaya et al.
(1C), 32.06 (1C), 34.79 (1C), 35.47 (1C), 35.61 (1C), 36.93 (1C), 39.74
(2C), 39.96 (1C), 40.21 (1C), 41.61 (2C), 42.67 (1C), 56.11 (1C), 56.59
(1C), 68.24 (1C), 69.56 (2C), 69.78 (2C), 69.87 (2C), 69.97 (4C), 70.38
(2C), 72.24 (1C), 99.45 (1C), 101.06 (1C), 103.00 (1C), 104.72 (1C),
105.84 (1C), 106.08 (1C), 129.71 (1C), 129.74 (1C),149.83 (1C), 149.86
(1C), 158.90 (1C), 160.31 ppm (1C); MALDI-TOF (dithranol), m/z:
951.60 [M+H]+.
7.12 ppm (t, J=8.3 Hz, 1H); 13C NMR (100.6 MHz, CDCl3, a mixture of
3 possible isomers): d=12.06 (2C-ster), 18.60 (2C-ster), 21.08 (2C-ster),
23.81 (2C-ster), 24.18 (2C-ster), 24.47 and 24.67 (2C-ster), 25.73 and
25.95 (2C-ster), 26.21 and 26.24 (2C-ster), 26.54 and 26.58 (2C-ster),
28.26 (2C-ster), 29.08 and 29.14 (NCH2CH2CH2O, 2C-diamine), 30.22
and 30.30 (2C-ster), 30.47 (2C-ster), 32.01 and 32.09 (2C-ster), 34.82
(2C-ster), 35.47 and 35.52 (2C-ster), 35.64 (2C-ster), 36.92 (2C-ster),
40.00 (2C-ster), 40.24 (2C-ster), 41.68 (NCH2, 2C-diamine), 42.72 (2C-
ster), 56.15 (2C-ster), 56.63 (2C-ster), 68.22 and 68.71 (2C-ster), 69.70
(OCH2, 2C-diamine), 70.23 (OCH2, 2C-diamine), 70.62 (OCH2, 2C-dia-
mine), 72.22 and 73.07 (2C-ster), 99.16 (1C-Ar), 100.84 (1C-Ar), 102.68
(1C-Ar), 104.24 (1C-Ar), 105.57 (1C-Ar), 105.81 (1C-Ar), 113.52 (1C-
Ar), 114.74 (1C-Ar), 117.68 (1C-Ar), 119.25 (1C-Ar), 122.72 (1C-Ar),
123.29 (1C-Ar), 123.47 (1C-Ar), 129.34 (1C-Ar), 129.71 (1C-Ar), 129.77
(1C-Ar), 130.43 (2C-Ar), 149.89 (1C-Ar), 149.94 (1C-Ar), 158.59 (1C-
Ar), 158.95 (1C-Ar), 159.90 (1C-Ar), 160.36 ppm (1C-Ar).
Compound 7i: From 4 (0.22 mmol, 150 mg) and diaminopropane 5i
(0.66 mmol, 124 mg), in the presence of [Pd(dba)2] (10 mg), BINAP
(12 mg), and tBuONa (85 mg) in absolute dioxane (2 mL) and after re-
fluxing for 5 h, bis(polyamino) derivative 7i was obtained as a pale-
yellow oil. Yield in the reaction mixture ca 60%. 1H NMR (400 MHz,
CDCl3): d=0.68 (s, 3H), 0.99 (brs, 6H), 1.03–2.05 (m, 28H), 1.73 (brs,
4H), 2.80 (brs, 4H), 3.16 (brs, 4H), 3.89 (brs, 2H), 4.55 (brs, 1H), 6.14–
6.30 (m, 6H), 7.01–7.09 ppm (m, 2H); 13C NMR (100.6 MHz, CDCl3):
d=11.98 (1C), 18.55 (1C), 21.02 (1C), 23.74 (1C), 24.12 (1C), 24.61
(1C), 25.89 (1C), 26.18 (1C), 26.53 (1C), 28.17 (1C), 30.41 (2C), 32.05
(1C), 32.77 (2C), 34.75 (1C), 35.42 (1C), 35.60 (1C), 36.89 (1C), 39.96
(2C), 40.19 (1C), 41.79 (2C), 41.95 (1C), 42.65 (1C), 56.14 (1C), 56.57
(1C), 68.18 (1C), 72.24 (1C), 99.19 (1C), 100.87 (1C), 102.89 (1C),
104.43 (1C), 105.49 (1C), 105.69 (1C), 129.66 (1C), 129.71 (1C), 149.53
(1C), 149.80 (1C), 158.93 (1C), 160.34 ppm (1C); MALDI-TOF (dithra-
nol): m/z: 658.83 [M]+.
Compound 8i: From
4 (0.78 mmol, 520 mg), diaminopropane 5i
(0.39 mmol, 29 mg), in the presence of [Pd(dba)2] (18 mg), BINAP
(22 mg), and tBuONa (150 mg) in absolute dioxane (4 mL) and after
4.5 h reflux, bis(steroidal) derivative 8i was obtained as a yellowish oil.
1
Yield in the reaction mixture ca 90%. H NMR (400 MHz, CDCl3, a mix-
ture of 3 possible isomers): d=0.68 (s, 6H), 0.99 (brs, 12H), 1.03–2.05
(m, 58H), 3.21 (brs, 4H), 3.89 (brs, 4H), 4.55 (brs, 2H), 6.11–6.30 (m,
6H), 6.78–6.85 (m, 2H), 7.00–7.18 ppm (m, 8H); 13C NMR (100.6 MHz,
CDCl3, a mixture of 3 possible isomers): d=11.99 (2C-ster), 18.54 (2C-
ster), 21.03 (2C-ster), 23.72 (2C-ster), 24.11 (2C-ster), 24.42 and 24.61
(2C-ster), 25.68 and 25.91 (2C-ster), 26.15 (2C-ster), 26.47 and 26.53
(2C-ster), 28.18 (2C-ster), 29.10 and 29.57 (2C-ster), 30.20 and 30.25
(2C-ster), 30.42 (NCH2CH2CH2N, 1C-diamine), 31.97 and 32.05 (2C-
ster), 34.75 (2C-ster), 35.39 (2C-ster), 35.58 (2C-ster), 36.85 (2C-ster),
39.96 (2C-ster), 40.17 (2C-ster), 41.79 (NCH2, 2C-diamine), 42.65 (2C-
ster), 56.10 (2C-ster), 56.55 (2C-ster), 68.17 and 68.63 (2C-ster), 72.24
and 73.04 (2C-ster), 99.32 (1C-Ar), 100.95 (1C-Ar), 103.16 (1C-Ar),
104.68 (1C-Ar), 105.59 (1C-Ar), 105.78 (1C-Ar), 113.44 (1C-Ar), 114.66
(1C-Ar), 117.68 (1C-Ar), 119.23 (1C-Ar),122.65 (1C-Ar), 123.24 (1C-
Ar), 123.41 (1C-Ar), 127.91 (1C-Ar), 129.77 (2C-Ar), 130.34 (2C-Ar),
149.47 (1C-Ar), 149.53 (1C-Ar), 158.56 (1C-Ar), 158.95 (1C-Ar), 159.87
(1C-Ar), 160.35 ppm (1C-Ar).
General method for the synthesis of bis(steroidal) derivatives of poly-
amines 8g–i: A two-necked flask equipped with a condenser and flushed
with argon was charged with compound 4 (0.78–1.97 mmol, 0.52–1.32 g),
[Pd(dba)2] (8 mol%, 14–41 mg), BINAP (9 mol%, 17–50 mg), the corre-
sponding polyamine (0.31–0.9 mmol), absolute dioxane (3–9 mL), and
tBuONa (1.2–3.6 mmol, 120–350 mg). The reaction mixture was refluxed
for 4.5–5 h and then cooled down. The precipitate of NaBr was filtered
off, and dioxane was evaporated in vacuum. The residue was subjected to
chromatography on silica with a sequence of eluents: CH2Cl2, CH2Cl2/
MeOH 500:1–3:1 (in the case of 8g,h).
Compound 8g: From
4 (1.97 mmol, 1.32 g) and dioxadiamine 5g
(0.9 mmol, 133 mg), in the presence of [Pd(dba)2] (41 mg), BINAP
(50 mg), and tBuONa (350 mg) in absolute dioxane (9 mL) and after
4.5 h reflux, bis(steroidal) derivative 8g was obtained as a yellowish oil.
Yield: 500 mg (43%); eluent CH2Cl2/MeOH 250:1, 10:1–3:1. 1H NM R
(400 MHz, CDCl3, a mixture of 3 possible isomers): d=0.68 (s, 6H), 0.96
(d, J=6.4 Hz, 6H), 0.99 (s, 6H), 1.01–2.03 (m, 56H), 3.29 (t, J=4.8 Hz,
4H), 3.64 (s, 8H), 3.69 (t, J=4.8 Hz, 4H), 3.85–3.94 (m, 4H), 4.54 (brs,
1H), 4.56 (brs, 1H), 6.15–6.30 (m, 6H), 6.82 (d, J=8.0 Hz, 2H), 7.00–
7.07 (m, 6H), 7.11 (t, J=8.0 Hz, 1H), 7.12 ppm (t, J=8.1 Hz, 1H);
13C NMR (100.6 MHz, CDCl3, a mixture of 3 possible isomers): d=12.06
(2C-ster), 18.61 (2C-ster), 21.10 (2C-ster), 23.81 (2C-ster), 24.18 (2C-
ster), 24.51 and 24.69 (2C-ster), 25.76 and 25.97 (2C-ster), 26.15 (2C-
ster), 26.56 and 26.61 (2C-ster), 28.24 (2C-ster), 30.29 and 30.32 (2C-
ster), 30.48 (2C-ster), 32.04 and 32.12 (2C-ster), 34.83 (2C-ster), 35.47
and 35.50 (2C-ster), 35.68 (2C-ster), 36.95 (2C-ster), 40.05 (2C-ster),
40.27 (2C-ster), 42.74 (2C-ster), 43.52 (NCH2, 2C-diamine), 56.20 (2C-
ster), 56.64 (2C-ster), 68.26 and 68.74 (2C-ster), 69.64 and 69.68 (OCH2,
2C-diamine), 70.20 (OCH2, 2C-diamine), 72.36 and 73.16 (2C-ster),
99.67 (1C-Ar), 101.36 (1C-Ar), 103.41 (1C-Ar), 105.02 (1C-Ar), 105.87
(1C-Ar), 106.09 (1C-Ar), 113.53 (1C-Ar), 114.77 (1C-Ar), 117.76 (1C-
Ar), 119.32 (1C-Ar), 122.72 (1C-Ar), 123.32 (1C-Ar), 123.49 (1C-Ar),
129.31 (1C-Ar), 129.78 (1C-Ar), 129.82 (1C-Ar), 130.41 (2C-Ar), 149.54
(1C-Ar), 149.59 (1C-Ar), 158.63 (1C-Ar), 158.97 (1C-Ar), 159.94 (1C-
Ar), 160.37 ppm (1C-Ar).
Cyclodimer 9g: A two-necked flask, equipped with a condenser and
flushed with argon, was charged with 8g (0.21 mmol, 280 mg), dioxadi-
amine 5g (0.21 mmol, 31 mg), [Pd(dba)2] (10 mg), BINAP (12 mg),
tBuONa (0.84 mmol, 80 mg), and absolute dioxane (10.5 mL), and the re-
action mixture was refluxed for 18 h. After cooling down to ambient tem-
perature, and filtration and evaporation of the solvent, the crude product
was subjected to chromatography on silica to obtain cyclodimer 9g as a
yellowish oil. Yield: 97 mg (35%); eluent CH2Cl2/MeOH 200:1, 10:1–
2.5:1; 1H NMR (400 MHz, CDCl3, a mixture of 2 possible isomers): d=
0.66 (s, 6H), 0.94 (d, J=5.6 Hz, 6H), 0.97 (s, 6H), 1.00–2.03 (m, 56H),
3.28 (t, J=5.0 Hz, 8H), 3.63 (s, 8H), 3.69 (t, J=4.9 Hz, 8H), 3.83–3.90
(m, 4H), 4.53 (brs, 2H), 6.15–6.29 (m, 12H), 7.02 (t, J=8.1 Hz, 2H),
7.03 ppm (t, J=8.0 Hz, 2H); 13C NMR (100.6 MHz, CDCl3, a mixture of
2 possible isomers): d=12.09 (2C), 18.64 (2C), 21.13 (2C), 23.84 (2C),
24.21 (2C), 24.71 (2C), 26.02 (2C), 26.29 (2C), 26.63 (2C), 28.27 (2C),
29.66 (2C), 30.50 (2C), 32.15 (2C), 34.87 (2C), 35.55 (2C), 35.71 (2C),
37.01 (2C), 40.08 (2C), 40.31 (2C), 42.78 (2C), 43.55 (4C), 56.26 (2C),
56.69 (2C), 68.32 (2C), 69.68 (2C), 69.72 (2C), 70.24 (4C), 72.42 (2C),
99.72 (2C), 101.43 (2C), 103.46 (2C), 105.04 (2C), 105.94 (2C), 106.15
(2C), 129.81 (2C), 129.86 (2C), 149.57 (2C), 149.62 (2C), 159.01 (2C),
160.42 ppm (2C).
Compound 8h: From
4 (0.78 mmol, 525 mg) and trioxadiamine 5h
Cyclodimer 9h: A two-necked flask, equipped with a condenser and
flushed with argon, was charged with 8h (0.09 mmol, 120 mg), trioxadi-
amine 5h (0.09 mmol, 20 mg), [Pd(dba)2] (4 mg), BINAP (5 mg),
tBuONa (0.36 mmol, 35 mg), and absolute dioxane (4.5 mL), and the re-
action mixture was refluxed for 24 h. After cooling down to ambient tem-
perature, and filtration and evaporation of the solvent, the crude product
was subjected to chromatography on silica to obtain cyclodimer 9h as a
yellowish oil. Yield: 45 mg (34%); eluent CH2Cl2/MeOH 10:1–5:1;
1H NMR (400 MHz, CDCl3, a mixture of 2 possible isomers): d=0.65 (s,
(0.31 mmol, 69 mg), in the presence of [Pd(dba)2] (14 mg), BINAP
(17 mg), and tBuONa (120 mg) in absolute dioxane (3 mL) and after 5 h
reflux, bis(steroidal) derivative 8h was obtained as a yellowish oil. Yield:
170 mg (39%); eluent CH2Cl2/MeOH 250:1, 10:1. 1H NMR (400 MHz,
CDCl3, a mixture of 3 possible isomers): d=0.67 (s, 6H), 0.95 (d, J=
6.3 Hz, 6H), 0.98 (s, 6H), 1.00–2.03 (m, 56H), 1.87 (q, J=6.1 Hz, 4H),
3.20 (t, J=6.6 Hz, 2H), 3.21 (t, J=6.3 Hz, 2H), 3.55–3.69 (m, 12H),
3.83–3.93 (m, 4H), 4.55 (brs, 1H), 4.56 (brs, 1H), 6.13–6.26 (m, 6H),
6.82 (d, J=7.9 Hz, 2H), 7.00–7.07 (m, 6H), 7.11 (t, J=8.1 Hz, 1H),
7038
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 7030 – 7039

Steroids
FULL PAPER
6H), 0.94 (d, J=6.6 Hz, 6H), 0.96 (s, 6H), 0.99–2.01 (m, 56H), 1.86 (q,
J=6.1 Hz, 8H), 3.19 (t, J=6.6 Hz, 8H), 3.54–3.68 (m, 24H), 3.82–3.90
(m, 4H), 4.53 (brs, 2H), 6.12–6.30 (m, 12H), 7.01 (t, J=7.8 Hz, 2H),
7.02 ppm (t, J=7.9 Hz, 2H); 13C NMR (100.6 MHz, CDCl3, a mixture of
2 possible isomers): d=12.05 (2C), 18.60 (2C), 21.07 (2C), 23.83 (2C),
24.18 (2C), 24.64 (2C), 25.95 (2C), 26.23 (2C), 26.58 (2C), 28.26 (2C),
29.04 (2C), 29.09 (2C), 29.65 (2C), 30.45 (2C), 32.08 (2C), 34.82 (2C),
35.52 (2C), 35.63 (2C), 36.95 (2C), 39.97 (2C), 40.24 (2C), 41.68 (4C),
42.70 (2C), 56.17 (2C), 56.62 (2C), 68.22 (2C), 69.69 (4C), 70.21 (4C),
70.60 (4C), 72.21 (2C), 99.16 (2C), 100.87 (2C), 102.69 (2C), 104.23
(2C), 105.59 (2C), 105.81 (2C), 129.70 (2C), 129.76 (2C), 149.84 (2C),
149.88 (2C), 158.93 (2C), 160.34 ppm (2C).
Acknowledgements
This work was supported by RFBR grants N 03-03-32627 and 03-03-
22001.
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Cyclodimer 9i
Route a: A two-necked flask, equipped with a condenser and flushed
with argon, was charged with in situ obtained 7i (0.65 mmol, 428 mg), 4
(0.65 mmol, 437 mg), [Pd(dba)2] (30 mg), BINAP (36 mg), tBuONa
(2.6 mmol, 250 mg), and absolute dioxane (26 mL), and the reaction mix-
ture was refluxed for 28 h. After cooling down to ambient temperature,
and filtration and evaporation of the solvent, the crude product was sub-
jected to chromatography on silica to obtain cyclodimer 9i as a yellowish
oil. Yield: 307 mg (40%); eluent CH2Cl2/MeOH 250:1, 10:1–5:1.
Route b: A two-necked flask, equipped with a condenser and flushed
with argon, was charged with in situ obtained 8i (0.39 mmol, 490 mg), di-
aminopropane 5i (0.39 mmol, 29 mg), [Pd(dba)2] (18 mg), BINAP
(22 mg), tBuONa (1.56 mmol, 150 mg), and absolute dioxane (16 mL),
and the reaction mixture was refluxed for 28 h. After cooling down to
ambient temperature, and filtration and evaporation of the solvent, the
crude product was subjected to chromatography on silica to obtain cyclo-
dimer 9i as a yellowish oil. Yield: 92 mg (20%); eluent CH2Cl2/MeOH
100:1, 10:1–3:1; 1H NMR (400 MHz, CDCl3, a mixture of 2 possible iso-
mers): d=0.67 (s, 6H), 0.95 (d, J=6.3 Hz, 6H), 0.98 (s, 6H), 1.00–2.03
(m, 56H), 1.91 (q, J=6.4 Hz, 4H), 3.19–3.27 (m, 8H), 3.85–3.91 (m, 4H),
4.54 (brs, 2H), 6.15–6.30 (m, 12H), 7.00–7.08 ppm (m, 4H); 13C NM R
(100.6 MHz, CDCl3, a mixture of 2 possible isomers): d=12.01 (2C),
18.57 (2C), 21.04 (2C), 23.76 (2C), 24.14 (2C), 24.62 (2C), 25.91 (2C),
26.21 (2C), 26.55 (2C), 28.20 (2C), 29.09 (2C), 29.57 (2C), 30.43 (2C),
32.07 (2C), 34.87 (2C), 35.45 (2C), 35.61 (2C), 36.91 (2C), 39.98 (2C),
40.22 (2C), 41.80 (4C), 56.17 (2C), 56.59 (2C), 68.20 (2C), 72.27 (2C),
99.32 (2C), 100.97 (2C), 103.17 (2C), 104.68 (2C), 105.61 (2C), 105.79
(2C), 129.75 (2C), 129.79 (2C), 149.49 (2C), 149.54 (2C), 158.96 (2C),
160.36 ppm (2C).
Compound 10: A two-necked flask, equipped with a condenser and flush-
ed with argon, was charged with 7h (0.21 mmol, 198 mg), 4 (0.21 mmol,
148 mg), [Pd(dba)2] (10 mg), BINAP (12 mg), tBuONa (0.84 mmol,
80 mg), and absolute dioxane (10.5 mL), and the reaction mixture was re-
fluxed for 18 h. After cooling down to ambient temperature, and filtra-
tion and evaporation of the solvent, the crude product was subjected to
chromatography on silica to obtain compound 10 as a yellowish oil.
Yield: 56 mg (17%); eluent CH2Cl2/MeOH 5:1–2.5:1. 1H NM R
(400 MHz, CDCl3, a mixture of 4 possible isomers): d=0.64 (s, 6H), 0.93
(d, J=6.3 Hz, 6H), 0.96 (s, 6H), 0.97–2.05 (m, 64H), 3.06 (brs, 2H),
3.14–3.22 (m, 6H), 3.45–3.70 (m, 24H), 3.86 (brs, 4H), 4.52 (brs, 2H),
6.10–6.32 (m, 9H), 6.80 (d, J=8.6 Hz) and 6.85 (d, J=7.8 Hz) (1H, two
signals correspondent to different isomers), 6.95–7.04 (m, 5H), 7.09 (t,
J=8.0 Hz) and 7.10 ppm (t, J=8.2 Hz) (1H, two signals correspondent to
different isomers); 13C NMR (100.6 MHz, CDCl3, a mixture of 4 possible
isomers): d=12.05 (2C), 18.59 (2C), 21.08 (2C), 23.79 (2C), 24.18 (2C),
24.48 and 24.66 (2C), 25.82 and 25.96 (2C), 26.22 (2C), 26.58 (2C), 28.23
(4C), 28.90, 29.10, 29.14 and 29.61 (2C), 30.27 and 30.37 (2C), 30.46
(2C), 32.09 (2C), 34.81 (2C), 35.49 (2C), 35.64 (2C), 36.94 (2C), 39.99
(2C), 40.23 (2C), 41.66 (4C), 42.70 (2C), 56.15 (2C), 56.62 (2C), 68.23
and 68.30 (2C), 69.59–70.59 (m, 12C), 72.26 (2C), 99.16 (3C), 100.84
(3C), 102.69 (3C), 104.23 (3C), 105.58 (3C), 105.80 (3C), 113.52 (1C),
114.75 (1C), 117.70 (1C), 119.26 (1C), 122.72 (1C), 123.30 (1C), 123.48
(1C), 129.70 (3C), 129.75 (3C), 130.42 (3C), 149.89 (3C), 149.94 (3C),
158.59 (1C), 158.96 (3C), 159.91 (1C), 160.37 ppm (3C).
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Received: July 7, 2005
Published online: September 27, 2005
Chem. Eur. J. 2005, 11, 7030 – 7039
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7039