Novel macrocyclic bile acid derivatives; Selective and easy binding of two cholic acid moieties at the 3-and 3'-positions

Article abstract of DOI:10.1055/s-0029-1217057

The synthesis of macrocyclic derivatives of bile acids (cholaphanes) is elaborated using the formation of ester or amide linkages at the 3a,3'a-and 24,24'-positions of lithocholic, deoxycholic or cholic acids. The conditions were found under which the sel

Full text of DOI:10.1055/s-0029-1217057

PAPER
4175
Novel Macrocyclic Bile Acid Derivatives; Selective and Easy Binding of Two
Cholic Acid Moieties at the 3- and 3¢-Positions
N
ovel Macrocyclic
i
Bile
A
k
c
id Derivati
o
ves lay V. Lukashev,*a Alexey V. Kazantsev,a Alexey D. Averin,a Pavel A. Donez,a Mikhail S. Baranov,a
Elina Sievänen,b Erkki Kolehmainenb
a
Chemistry Department, Moscow State Lomonosov University, Vorobievy Gory 1, Str. 3, 119991 Moscow, Russian Federation
Fax +7(495)4223297; E-mail: nvluk@org.chem.msu.ru
Department of Chemistry, University of Jyväskylä, P.O. Box 35, 40014 Jyväskylä, Finland
b
Received 22 June 2009; revised 3 August 2009
for condensation.15 Similar cyclic amides of bile acids –
Abstract: The synthesis of macrocyclic derivatives of bile acids
cyclocholamides7,8,16,17 – are also known which, in some
(cholaphanes) is elaborated using the formation of ester or amide
cases, contain amino acids fragments.18–20 The Ugi reac-
linkages at the 3a,3¢a- and 24,24¢-positions of lithocholic, deoxy-
tion has been used for the synthesis of N-substituted cy-
cholic or cholic acids. The conditions were found under which the
selective diacylation at the 3a,3¢a- and 24,24¢-positions of two mol- clocholamides.21,22
ecules of cholic acid by dichloroanhydrides of arene(hetarene)di-
carboxylic acid proceeds in good yields without prior protection of
Cholaphanes are another type of steroidal macrocycles;
these contain 2–4 bile acid moieties which are linked by
different spacers at the 3- and 24-positions of the steroidal
backbone. Such molecules can exist as ‘head-to-tail’ (I)
and ‘head-to-head’ (II) isomers (Figure 1). Diamide23,24
or ester25 linkages are the most common with spacer A,
while ester groups are most frequently used with spacer
B.23,25,26 More rare cases include ether groups as spacers A
and B.27 Syntheses of cholaphanes (II) often starts with
spacer A formation. The second step is the cyclization of
the dimeric intermediate through formation of the spacer
B. The Yamaguchi method employing ester formation
gives such macrocycles in poor 9–11% yield.23,25 The re-
action of steroidal 3-(bromoacetates) with dicesium
terephthalate or with dicesium 3,5-pyridinedicarboxylate
affords cholaphanes in high yields 70–95%.11,24,26
the 7a- and 12a-hydroxy groups.
Key words: macrocycles, bile acids, cyclophanes, cholaphanes,
cyclizations
Bile acids are naturally occurring chiral compounds with
a rigid steroidal skeleton that possess one to three endo-
hydroxy groups and an iso-pentanoic acid side chain. The
chemistry of the macrocyclic derivatives of bile acids has
been flourishing since the 1990s due to the possible use of
such compounds as selective receptors for cations and
anions1–5 and because they are such versatile organic mol-
ecules.6–11 Another interesting use of macrocycles derived
from bile acids is ion channels modeling.12
Up to now, various macrocycles of this type, which con-
tain from a single to several bile acid units, have been syn-
thesized and investigated. The simplest molecules from
the synthetic point of view are the cyclocholates, which
are often obtained by the Yamaguchi macrolactonization
method1,6,13,14 or by the use of dicyclohexylcarbodiimide
The use of ester or ether bonds in A spacers between the
24- and 24¢-positions is not frequent. Ester spacers are
synthesized by the reaction of lithocholic acid chloroan-
hydride with corresponding diols.25 The yields of the in-
termediate acylic 24,24¢-diester do not exceed 40%. Ether
bridges are synthesized by the preliminary reduction of
O
O
R
R
A
R
A
R
A/B
B
R
O
R
R
R
O
I
II
Figure 1
SYNTHESIS 2009, No. 24, pp 4175–4182
x
x.
x
x
.
2
0
0
9
Advanced online publication: 19.10.2009
DOI: 10.1055/s-0029-1217057; Art ID: Z13409SS
© Georg Thieme Verlag Stuttgart · New York

4176
N. V. Lukashev et al.
PAPER
the bile acid’s carboxyl group to the hydroxy group. It is tant new approaches to the generation of macrocyclic
to be noted that the approach using ether spacers is labo- structures with steroidal fragments.
rious because it demands multiple protecting and depro-
Analysis of the literature data shows that the synthesis of
tecting steps.27 Cyclic dimers in which the hydroxy
macrocycles based on deoxycholic and cholic acids using
groups at the 7a- and 12a-positions of the cholic acid are
chloroanhydrides of organic acids is often hindered by
their non-selectivity towards hydroxy groups at the 3a-,
linked have also been described.28
Also widespread are macrocycles consisting of one bile 7a- and 12a-positions. Due to this fact, lithocholic acid is
acid moiety3 connected to cholacrown ethers.4,29 Palladi- widely used for the synthesis of macrocycles because it
um-catalyzed amination,30,31 metathesis,32 and copper- possesses only one hydroxy group at position 3a. Howev-
catalyzed 1,3-dipolar cycloaddition33 have become impor- er, this acid has a hydrophobic backbone and possesses
R2
O
OR3
O
R2
O
R1
OBn
C6F5OH, DCC, CH2Cl2
Cl
B
Cl
B
DMAP, Et3N, CH2Cl2
R1
R1
HO
O
OR3
O
R2
1a–d R3 = Bn
H2, Pd/C, THF
2a–d R3 = H
R2
O
R2
OC6F5
R1
O
O
O
O
R1
R1
H
A
H
B
B
A
DMAP, Et3N, CH2Cl2
O
O
R1
OC6F5
O
R2
R2
4a–e
3a–d
H
N
O
O
O
1–3a: R1 = R2 = H, B = terephthaloyl
4a: R1 = R2 = H, B =
, A =
, A =
, 50%
N
H
1–3b: R1 = H, R2 = OH, B = pyridine 2,6-dicarbonyl
1–3c: R1 = R2 = OH, B = isophthaloyl
O
1–3d: R1 = R2 = OH, B = terephthaloyl
H
N
H
N
4b: R1 = R2 = H, B =
, 37%
O
2
H
H
N
N
4c: R1 = H, R2 = OH, B =
, A =
, 37%
O
N
O
O
H
H
N
N
4d: R1 = R2 = OH, B =
, 34%
, A =
O
2
O
O
O
O
H
H
4e: R1 = R2 = OH, B =
N
N
, A =
, 28%
O
2
Scheme 1
Synthesis 2009, No. 24, 4175–4182 © Thieme Stuttgart · New York

PAPER
Novel Macrocyclic Bile Acid Derivatives
4177
less valuable coordination properties. We have also found groups. In some cases this gives rise to the possibility of
that deoxycholic and cholic acids cannot be used in palla- selective acylation of the 3a-hydroxy of cholates, for ex-
dium-catalyzed amination reactions because of the low ample by bromoacetyl bromide11,24 or by chloroacetic an-
solubility of intermediate products.30,31 All these facts tak- hydride.5 Trimesoyl chloride was also proposed for
en together forced us to try more classical methods for the selective acylation of three molecules of cholic acid in tol-
synthesis of new types of cholaphanes and to search for uene and DMAP under reflux at the 3-position.35 Howev-
convenient procedures for acylation of cholic acid deriva- er, we were unable to carry out selective bis(acylation) of
tives.
two molecules of methyl cholate with dichloroanhydrides
of arenedicarboxylic acids under conditions described in
the papers mentioned above. In this paper we demonstrate
that, by modifying this approach, one can obtain
cholaphanes from cholic acid without initial protection of
the hydroxy groups at positions 7a and 12a. The approach
uses a selective acylation of cholic acid esters at the 3a-
and 3¢a-positions (Scheme 1).
Recently, we have proposed a method for the synthesis of
lithocholaphanes by the initial formation of the spacer B.
In these molecules either both spacers A and B were
equipped with ester groups, or spacer B contained ester
groups and spacer A contained a (poly)oxadiamide
bridge.34 It is known that the reactivity of the equatorial
3a-hydroxy group in cholic acid in the acylation reaction
is higher than that of the axial 7a- and 12a-hydroxy
R
OTr
R
Cl
Cl
R
OTr
O
R
O
O
HBr (concd)
OTr
O
MeOH–CH2Cl2
R = H: DMAP, Et3N, PhMe, 100 °C
R = OH: DMAP, Py, CH2Cl2, r.t.
HO
R
O
O
R
5a: R = H; 5b: R = OH
R
O
X
R
OH
R
O
O
O
Cl-X-Cl
R
O
R
R = H: DMAP, Et3N, PhMe, 100 °C
R = OH: DMAP, Et3N, CH2Cl2, r.t.
OH
O
R
R
O
O
O
R
O
6a: R = H; 6b: R = OH
7a–g
O
O
O
, 45%
7g: R = OH, X =
, 18%
7a: R = H, X =
7b: R = H, X =
7d: R = H, X =
7e: R = H, X =
, 14%
, 27%
O
O
O
O
O
O
O
, 11%
, 21%
S
N
N
O
O
O
7c: R = H, X =
7f: R = OH, X =
, 17%
O
O
Scheme 2
Synthesis 2009, No. 24, 4175–4182 © Thieme Stuttgart · New York

4178
N. V. Lukashev et al.
PAPER
The benzyl ester of lithocholic acid36 and the benzyl esters of de-
oxycholic and cholic acids37 were prepared according to the litera-
ture. 5b-Cholane-3a,24-diol, 24-triphenylmethoxy-5b-cholan-3a-
ol, dibenzyl 3a,3¢a-(terephthaloyloxy)bis(5b-cholan-24-oate) (1a),
3a,3¢a-(terephthaloyloxy)bis(5b-cholan-24-oic acid) (2a), bis(pen-
tafluorophenyl) 3a,3¢a-(terephthaloyloxy)bis(5b-cholan-24-oate)
(3a), bis(24-triphenylmethoxy)-3a,3¢a-(isophthaloyloxy)bis(5b-
cholane) (5a), 3a,3¢a-(isophthaloyloxy)bis(5b-cholan-24-ol) (6a)
were obtained according to Valkonen et al.34 5b-Cholane-
Previously, we presented the synthesis of a diester linker
binding positions 3a and 3¢a of the lithocholic acid benzyl
esters. This was achieved by the action of aromatic dicar-
boxylic acid dichloroanhydrides in toluene at 100 °C for
12 hours.34 However, since this method proved to be use-
less for the synthesis of deoxycholic and cholic acid
dimers similar to 1b,c due to competitive acylation of the
7a- and 12a-hydroxy groups, we have found milder con-
ditions for selective 3a,3¢a-diacylation: in our new proto-
col, dichloromethane or tetrahydrofuran was used instead
of toluene, and the reaction was run at ambient tempera-
ture. These reaction conditions allowed us to obtain com-
pounds 1b–d in yields up to 65% without formation of
3a,7a,12a,24-tetraol
and
24-triphenylmethoxy-5b-cholane-
3a,7a,12a-triol were synthesized as previously described.38 1H (400
MHz) and 13C (100 MHz) NMR spectra were recorded on a Bruker
Avance 400 spectrometer; 1H (500 MHz) and 13C (126 MHz) NMR
spectra were recorded on a Bruker Avance DRX 500 FT spectrom-
eter. Methylene and methyne protons of steroid cores which are
significant admixtures of products in which the hydroxy present in 1H NMR spectra as complex unresolved multiplets in the
1.0–2.8 ppm region are not indicated. Only significant peaks are
shown. MALDI-TOF spectra were recorded on Bruker Daltonics
Ultraflex mass spectrometer using dithranol as matrix. Electrospray
mass spectroscopic measurements were performed by using an LCT
time of flight (TOF) mass spectrometer with electrospray ionization
(ESI; Micromass LCT).
groups at the 7- and 12-positions were affected. To form
the diamide spacer A, we proposed the reaction of di-
amines with pentafluorophenyl esters at positions 24 and
24¢. Yields at the macrocyclization step varied from 34%
to 50%, which is 1.5–2 times higher than described in the
literature for analogous compounds. The yields of
cholaphanes did not change significantly when changing
lithocholic acid for deoxycholic or cholic acids.
Dibenzyl 3a,3a¢-[Arene(hetarene)dicarbonyl-
oxy]bis[7H(OH),12a-hydroxy-5b-cholan-24-oate]s (1b–d);
General Procedure
Another approach was elaborated for the synthesis of
cholaphanes with two diester bridges (Scheme 2). In this
To the corresponding dichloroanhydride of arene(hetarene)dicar-
boxylic acid (0.225 mmol) in anhyd THF (1.5 mL), DMAP (18 mg,
case, mild acylation conditions (CH2Cl2, 20 °C, DMAP, 0.14 mmol), Et3N (0.26 mL) and the benzyl ester of deoxycholic
acid (241 mg, 0.5 mmol) or the benzyl ester of cholic acid (249 mg,
0.5 mmol) were added consecutively. The mixture was stirred for
pyridine) afforded the cholic acid dimer 5b in 56% yield.
Deprotection according to a standard procedure gave the
18 h at r.t., diluted with CH2Cl2 (50 mL) and washed with 5%
corresponding 24,24¢-diols, which were introduced into
NaHCO3 (2 × 10 mL). The organic layer was dried over Na2SO4
the reaction with dicarboxylic acid dichloroanhydrides. In
and the solvent evaporated under reduced pressure. The product
the case of the transformation of 6b into 7f and 7g, mild
acylation conditions were used again to prevent undesir-
able acylation at positions 7 and 12.
was purified by column chromatography [(CH2Cl2–MeOH, 99:1;
Rf = 0.70) for 1b or (CH2Cl2–MeOH, 20:1; Rf = 0.50) for 1c,d] to
give 1b–d as white crystalline solids.
1
Cholaphanes thus obtained were characterized using H
Dibenzyl 3a,3a¢-(2,6-Pyridinedicarbonyloxy)bis(12a-hydroxy-
5b-cholan-24-oate) (1b)
Yield: 173 mg (70%).
and 13C NMR as well as MALDI-TOF and ESI-TOF MS
1
techniques. The most important feature of the H NMR
spectra of the target compounds, which supports the pro-
posed structure of cholaphanes, is substantial deshielding
of the 3b-protons (from 3.4 ppm to 4.8 ppm). A similar
deshielding was observed for the lithocholic acid benzyl
ester after its cyclization into the dimeric product 1a. In
the case of the cyclization using diamide spacers, a nota-
ble shielding of the protons at C23 occurred (from 2.7
ppm to 2.1 ppm) whereas in the case of the diester bridge
formation in 7a–g we observed deshielding of the protons
at C24 (from 3.6 to 4.4–4.5 ppm).
3
1H NMR (400 MHz, CDCl3): d = 8.24 (d, J = 7.8 Hz, 2 H, ArH-
3,5), 8.15 (t, 3J = 7.8 Hz, 1 H, ArH-4), 7.34 (m, 10 H, Ph), 5.10 (m,
4 H, CH2-Ph), 5.06 (m, 2 H, 3b-H, 3b¢-H), 3.95 (br s, 2 H, 12b-H,
12b¢-H), 2.45–2.22 (m, 4 H, 23-CH2, 23¢-CH2), 0.94 (m, 12 H, 21-
CH3, 21¢-CH3, 19-CH3, 19¢-CH3), 0.64 (s, 6 H, 18-CH3, 18¢-CH3).
13C NMR (100 MHz, CDCl3): d = 174.0 [C(24)=O], 164.0 (ArC=O)
148.9 (ArC-2,6), 138.0 (ArC-4), 136.1 (PhC-1), 128.5 (PhC-2,6),
128.1 (PhC-3,4,5), 127.6 (ArC-3,5), 76.4 (3-CH), 73.0 (12-CH),
66.0 (Ph-CH2), 48.2, 47.2, 46.4, 41.8, 35.9, 35.0, 34.9, 34.1, 33.5,
31.9, 31.2, 30.8, 28.6, 27.4, 26.9, 26.3, 26.0, 23.6 (19-CH3), 23.0,
17.2 (21-CH3), 12.7 (18-CH3).
In conclusion, we report here a straightforward and syn-
thetic route to bile acid derived macrocycles which can be
utilized as an aid in designing suitable receptors and hosts
to be used in various supramolecular systems and in
nanochemical applications.
Dibenzyl 3a,3a¢-(Isophthaloyloxy)bis(7a,12a-dihydroxy-5b-
cholan-24-oate) (1c)
Yield: 109 mg (43%).
1H NMR (400 MHz, CDCl3): d = 8.63 (t, 4J = 1.7 Hz, 1 H, ArH-2),
8.18 (dd, 3J1 = 7.8 Hz, 4J2 = 1.7 Hz, 2 H, ArH-4,6), 7.47 (t, 3J = 7.8
Hz, 1 H, ArH-5), 7.34 (m, 10 H, Ph), 5.10 (m, 4 H, CH2-Ph), 4.84
(m, 2 H, 3b-H, 3b¢-H), 3.97 (br s, 2 H, 12b-H, 12b¢-H), 3.85 (br s,
2 H, 7b-H, 7b¢-H), 2.53–2.38 (m, 4 H, 23-CH2, 23¢-CH2), 0.97 (d,
3J = 5.8 Hz, 6 H, 21-CH3, 21¢-CH3), 0.93 (s, 6 H, 19-CH3, 19¢-CH3),
0.67 (s, 6 H, 18-CH3, 18¢-CH3).
13C NMR (100 MHz, CDCl3): d = 174.0 [C(24)=O], 165.3
(ArC=O), 136.1 (PhC-1), 133.4 (ArC-4,6), 131.2 (ArC-1,3), 130.7
(ArC-2), 128.5 (PhC-2,6), 128.2 (PhC-3,4,5 and ArC-5), 75.2 (3-
Lithocholic acid was purchased from Sigma, deoxycholic and chol-
ic acids were purchased from Acros Organic and used without fur-
ther purification. Isophthalic and terephthalic acids and other
reagents were analytical grade reagents and used as purchased. All
solvents used in chromatography were also analytical grade re-
agents and used without further purification. Column chromatogra-
phy was performed on silica gel 60 (0.040–0.063 mm) from Merck.
Synthesis 2009, No. 24, 4175–4182 © Thieme Stuttgart · New York

PAPER
Novel Macrocyclic Bile Acid Derivatives
4179
CH), 72.9 (12-CH), 68.2 (7-CH), 66.1 (Ph-CH2), 47.2, 46.5, 42.0,
41.2, 39.4, 35.2, 35.1, 34.8, 34.7, 34.4, 31.3, 30.8, 28.4, 27.4, 26.7,
26.6, 23.1 (19-CH3), 22.4, 17.3 (21-CH3), 12.5 (18-CH3).
13C NMR (100 MHz, CD3OD): d = 180.6 [C(24)=O], 170.5
(ArC=O), 135.9 (ArC-1,4), 130.4 (ArC-2,3,5,6), 77.3 (3-CH), 74.0
(12-CH), 69.0 (7-CH), 48.1, 47.5, 43.0, 42.9, 41.0, 36.9, 36.4, 36.1,
36.0, 35.6, 32.7, 32.5, 29.5, 28.7, 27.9, 27.6, 24.2 (19-CH3), 23.0,
17.7 (21-CH3), 13.0 (18-CH3).
Dibenzyl 3a,3a¢-(Terephthaloyloxy)bis(7a,12a-dihydroxy-5b-
cholan-24-oate) (1d)
Yield: 165 mg (65%).
Bis(pentafluorophenyl) 3a,3a¢-[Arene(hetarene)dicarbonyl-
oxy]bis[7H(OH),12a-hydroxy-5b-cholan-24-oate]s (3b–d);
General Procedure
1H NMR (400 MHz, CDCl3): d = 8.07 (s, 4 H, ArH-2,3,5,6), 7.34
(m, 10 H, Ph), 5.10 (m, 4 H, CH2-Ph), 4.83 (m, 2 H, 3b-H, 3b¢-H),
3.99 (br s, 2 H, 12b-H, 12b¢-H), 3.86 (br s, 2 H, 7b-H, 7b¢-H), 2.54–
2.38 (m, 4 H, 23-CH2, 23¢-CH2), 0.97 (d, 3J = 5.9 Hz, 6 H, 21-CH3,
21¢-CH3), 0.93 (s, 6 H, 19-CH3, 19¢-CH3), 0.68 (s, 6 H, 18-CH3, 18¢-
CH3).
13C NMR (100 MHz, CDCl3): d = 174.0 [C(24)=O], 165.4
(ArC=O), 136.0 (PhC-1), 134.4 (ArC-1,4), 129.3 (ArC-2,3,5,6),
128.5 (PhC-2,6), 128.2 (PhC-3,4,5), 75.4 (3-CH), 72.9 (12-CH),
68.2 (7-CH), 66.1 (Ph-CH2), 47.3, 46.5, 42.0, 41.2, 39.5, 35.2, 35.1,
34.8, 34.7, 34.4, 31.3, 30.8, 28.4, 27.4, 26.7, 26.6, 23.1 (19-CH3),
22.5, 17.3 (21-CH3), 12.5 (18-CH3).
To a stirred solution of the corresponding 2b–d (0.61 mmol) in an-
hyd CH2Cl2 (17 mL), pentafluorophenol (282 mg, 1.53 mmol) and
dicyclohexylcarbodiimide (380 mg, 1.84 mmol) were added at the
same time. After being stirred for 18 h at r.t., the mixture was dilut-
ed with CH2Cl2 (20 mL) and filtered. The filtrate was washed with
5% NaHCO3 (10 mL), and H2O (10 mL), then dried over Na2SO4
and evaporated to dryness. The crude product was purified by col-
umn chromatography (CH2Cl2–MeOH, 98:2; Rf = 0.60).
Bis(pentafluorophenyl) 3a,3a¢-(2,6-Pyridinedicarbonyl-
oxy)bis(12a-hydroxy-5b-cholan-24-oate) (3b)
Yield: 457 mg (60%).
3a,3a¢-[Arene(hetarene)dicarbonyloxy]bis[7H(OH),12a-hy-
droxy-5b-cholan-24-oic Acid]s (2b–d); General Procedure
To a mixture of the corresponding dibenzyl ester 1b–d (0.64 mmol)
and 10% Pd/C (20 mg), anhyd THF (10 mL) was added. The flask
was purged with H2 for 1–2 s, connected to a balloon of H2 and
stirred for 24 h at r.t. The mixture was filtered through a short plug
of silica gel to remove the catalyst. The filtrate was evaporated to
dryness to give 2b–d as a white crystalline solid.
3
1H NMR (400 MHz, CDCl3): d = 8.25 (d, J = 7.8 Hz, 2 H, ArH-
3,5), 8.01 (t, 3J = 7.8 Hz, 1 H, ArH-4), 5.03 (m, 2 H, 3b-H, 3b¢-H),
4.00 (br s, 2 H, 12b-H, 12b¢-H), 2.78–2.55 (m, 4 H, 23-CH2, 23¢-
CH2), 1.03 (d, 3J = 5.7 Hz, 6 H, 21-CH3, 21¢-CH3), 0.94 (s, 6 H, 19-
CH3, 19¢-CH3), 0.70 (s, 6 H, 18-CH3, 18¢-CH3).
13C NMR (100 MHz, CDCl3): d = 170.0 [C(24)=O], 164.0
(ArC=O), 148.8 (ArC-2,6), 140.0–130.0 (m, C6F5), 138.2 (ArC-4),
127.7 (ArC-3,5), 76.4 (3-CH), 73.1 (12-CH), 48.3, 47.1, 46.5, 41.8,
35.9, 35.0, 34.9, 34.1, 33.6, 31.9, 30.7, 30.4, 28.7, 27.4, 26.9, 26.3,
26.0, 23.6 (19-CH3), 23.0, 17.2 (21-CH3), 12.7 (18-CH3).
3a,3a¢-(2,6-Pyridinedicarbonyloxy)bis(12a-hydroxy-5b-cholan-
24-oic Acid) (2b)
Yield: 563 mg (96%).
Bis(pentafluorophenyl) 3a,3a¢-(Isophthaloyloxy)bis(7a,12a-di-
hydroxy-5b-cholan-24-oate) (3c)
3
1H NMR (400 MHz, CDCl3): d = 8.21 (d, J = 7.8 Hz, 2 H, ArH-
3,5), 7.99 (t, 3J = 7.8 Hz, 1 H, ArH-4), 5.01 (m, 2 H, 3b-H, 3b¢-H),
3.95 (br s, 2 H, 12b-H, 12b¢-H), 0.94 (m, 12 H, 21-CH3, 21¢-CH3,
19-CH3, 19¢-CH3), 0.67 (s, 6 H, 18-CH3, 18¢-CH3).
13C NMR (100 MHz, CDCl3): d = 178.9 [C(24)=O], 164.1
(ArC=O), 148.7 (ArC-2,6), 138.3 (ArC-4), 127.9 (ArC-3,5), 76.9
(3-CH), 73.1 (12-CH), 48.0, 47.0, 46.5, 42.0, 35.9, 35.2, 35.0, 34.2,
33.5, 31.9, 31.2, 30.7, 28.5, 27.5, 27.0, 26.3, 26.1, 23.7 (19-CH3),
23.0, 17.3 (21-CH3), 12.7 (18-CH3).
Yield: 678 mg (87%).
1H NMR (400 MHz, CDCl3): d = 8.63 (t, 4J = 1.7 Hz, 1 H, ArH-2),
8.19 (dd, 3J1 = 7.8 Hz, 4J2 = 1.7 Hz, 2 H, ArH-4,6), 7.48 (t, 3J = 7.8
Hz, 1 H, ArH-5), 4.85 (m, 2 H, 3b-H, 3b¢-H), 4.02 (br s, 2 H, 12b-
H, 12b¢-H), 3.88 (br s, 2 H, 7b-H, 7b¢-H), 2.76–2.55 (m, 4 H, 23-
CH2, 23¢-CH2), 1.05 (d, 3J = 5.8 Hz, 6 H, 21-CH3, 21¢-CH3), 0.94 (s,
6 H, 19-CH3, 19¢-CH3), 0.73 (s, 6 H, 18-CH3, 18¢-CH3).
13C NMR (100 MHz, CDCl3): d = 174.0 [C(24)=O], 165.4
(ArC=O), 140.0–130.0 (m, C6F5), 133.5 (ArC-4,6), 131.2 (ArC-
1,3), 130.7 (ArC-2), 128.3 (ArC-5), 75.3 (3-CH), 72.9 (12-CH),
68.3 (7-CH), 47.1, 46.5, 42.0, 41.2, 39.5, 35.2, 35.1, 34.8, 34.7,
34.5, 31.3, 30.7, 28.5, 27.4, 26.8, 26.7, 23.1 (19-CH3), 22.4, 17.2
(21-CH3), 12.5 (18-CH3).
3a,3a¢-(Isophthaloyloxy)bis(7a,12a-dihydroxy-5b-cholan-24-
oic Acid) (2c)
Yield: 600 mg (99%).
1H NMR (400 MHz, DMSO-d6): d = 8.58 (t, 4J = 1.7 Hz, 1 H, ArH-
3
4
2), 8.20 (dd, J1 = 7.8 Hz, J2 = 1.7 Hz, 2 H, ArH-4,6), 7.51 (t,
3J = 7.8 Hz, 1 H, ArH-5), 4.83 (m, 2 H, 3b-H, 3b¢-H), 3.98 (br s,
2 H, 12b-H, 12b¢-H), 3.87 (br s, 2 H, 7b-H, 7b¢-H), 2.50–2.35 (m,
4 H, 23-CH2, 23¢-CH2), 0.96 (d, 3J = 5.8 Hz, 6 H, 21-CH3, 21¢-CH3),
0.94 (s, 6 H, 19-CH3, 19¢-CH3), 0.70 (s, 6 H, 18-CH3, 18¢-CH3).
Bis(pentafluorophenyl) 3a,3a¢-(Terephthaloyloxy)bis(7a,12a-
dihydroxy-5b-cholan-24-oate) (3d)
Yield: 663 mg (85%).
1H NMR (400 MHz, CDCl3): d = 8.06 (s, 4 H, ArH-2,3,5,6), 4.84
(m, 2 H, 3b-H, 3b¢-H), 4.03 (br s, 2 H, 12b-H, 12b¢-H), 3.88 (br s,
2 H, 7b-H, 7b¢-H), 2.78–2.57 (m, 4 H, 23-CH2, 23¢-CH2), 1.06 (d,
3J = 5.8 Hz, 6 H, 21-CH3, 21¢-CH3), 0.94 (s, 6 H, 19-CH3, 19¢-CH3),
0.73 (s, 6 H, 18-CH3, 18¢-CH3).
13C NMR (100 MHz, CDCl3): d = 170.0 [C(24)=O], 165.4
(ArC=O), 140.0–130.0 (m, C6F5), 134.4 (ArC-1,4), 129.3 (ArC-
2,3,5,6), 75.5 (3-CH), 73.0 (12-CH), 68.3 (7-CH), 47.2, 46.6, 42.0,
41.2, 39.4, 35.2, 35.0, 34.8, 34.7, 34.5, 30.7, 30.4, 28.4, 27.4, 26.8,
26.7, 23.1 (19-CH3), 22.5, 17.2 (21-CH3), 12.5 (18-CH3).
13C NMR (100 MHz, CD3OD): d = 178.9 [C(24)=O], 166.6
(ArC=O), 134.6 (ArC-4,6), 132.6 (ArC-1,3), 131.1 (ArC-2), 129.9
(ArC-5), 77.2 (3-CH), 74.0 (12-CH), 69.0 (7-CH), 48.1, 47.5, 43.0,
42.9, 41.0, 36.8, 36.4, 36.0, 35.9, 35.6, 32.6, 32.5, 29.5, 28.7, 27.9,
27.7, 24.2 (19-CH3), 23.0, 17.7 (21-CH3), 13.0 (18-CH3).
3a,3a¢-(Terephthaloyloxy)bis(7a,12a-dihydroxy-5b-cholan-24-
oic Acid) (2d)
Yield: 598 mg (99%).
1H NMR (400 MHz, DMSO-d6): d = 8.05 (s, 4 H, ArH-2,3,5,6),
4.83 (m, 2 H, 3b-H, 3b¢-H), 4.01 (br s, 2 H, 12b-H, 12b¢-H), 3.88 (br
s, 2 H, 7b-H, 7b¢-H), 2.55–2.38 (m, 4 H, 23-CH2, 23¢-CH2), 0.99 (d,
3J = 5.8 Hz, 6 H, 21-CH3, 21¢-CH3), 0.94 (s, 6 H, 19-CH3, 19¢-CH3),
0.71 (s, 6 H, 18-CH3, 18¢-CH3).
Preparation of Macrocycles 4a–e; Typical Procedure
To a stirred solution of the corresponding 3a–d (0.06 mmol) in
CH2Cl2 (6 mL), DMAP (22 mg, 0.18 mmol), Et3N (25 mL, 0.18
Synthesis 2009, No. 24, 4175–4182 © Thieme Stuttgart · New York

4180
N. V. Lukashev et al.
PAPER
mmol) and the corresponding diamine (0.06 mmol) was added in
one portion. After stirring for 12–15 h, the mixture was diluted with
CH2Cl2 (50 mL) and washed with H2O (20 mL). The organic layer
was dried over MgSO4 and concentrated. The crude product was pu-
rified by column chromatography (CH2Cl2–MeOH, 20:1; Rf =
0.1~0.3).
13C NMR (100 MHz, CDCl3): d = 175.4 (NHC=O), 165.4 (ArC=O),
134.9 (ArC-4,6), 130.8 (ArC-1,3), 128.8 (ArC-2), 127.9 (ArC-5),
75.2 (3-CH), 72.5 (12-CH), 71.0 (O-CH2), 70.6 (O-CH2), 68.2 (7-
CH), 46.3, 44.5, 43.8, 41.2, 39.2, 39.1, 35.5, 35.4, 35.0, 34.6, 34.1,
31.2, 30.5, 28.7, 28.1, 27.5, 25.5, 22.9 (19-CH3), 22.6, 17.6 (21-
CH3), 11.8 (18-CH3).
MALDI-TOF: m/z [M + H]+ calcd for C62H95N2O12: 1059.69;
found: 1059.45.
Cyclic N,N¢-(Ethanediyl) 3a,3¢a-(Terephthaloyloxy)bis(5b-
cholan-24-amide) (4a)
Yield: 27 mg (50%).
Anal. Calcd for C62H94N2O12: C, 70.29; H, 8.94; N, 2.64. Found: C,
69.99; H, 8.77; N, 2.55.
1H NMR (500 MHz, CDCl3): d = 8.10 (s, 4 H, ArH-2,3,5,6), 6.19
(br s, 2 H, NH), 5.05 (m, 2 H, 3b-H, 3b¢-H), 3.45–3.33 (m, 4 H, NH-
CH2), 2.18–2.08 (m, 4 H, 23-CH2, 23¢-CH2), 1.06–0.95 (m, 12 H,
19-CH3, 19¢-CH3, 21-CH3, 21¢-CH3), 0.66 (s, 6 H, 18-CH3, 18¢-
CH3).
13C NMR (126 MHz, CDCl3): d = 175.0 (NHC=O), 165.0 (ArC=O),
134.7 (ArC-1,4), 129.5 (ArC-2,3,5,6), 74.2 (3-CH), 57.1, 54.6,
42.7, 41.4, 40.7 (CH2-NH), 40.6, 40.4, 35.5, 34.8, 34.7, 34.3, 31.9,
31.6, 31.5 (23-CH2), 28.0, 26.7, 26.4, 26.1, 24.0, 23.1 (19-CH3),
20.9, 18.5 (21-CH3), 12.1 (18-CH3).
Cyclic N,N¢-(3,6-Dioxa-1,8-octanediyl) 3a,3a¢-(Terephthaloyl-
oxy)bis(7a,12a-dihydroxy-5b-cholan-24-amide) (4e)
Yield: 18 mg (28%).
1H NMR (400 MHz, CDCl3): d = 8.06 (s, 4 H, ArH-2,3,5,6), 5.86
(m, 2 H, NH), 4.90 (m, 2 H, 3b-H, 3b¢-H), 3.99 (br s, 2 H, 12b-H,
12b¢-H), 3.87 (br s, 2 H, 7b-H, 7b¢-H), 3.64–3.42 (m, 12 H, CH2-O,
CH2-NH), 1.01 (d, 3J = 6.4 Hz, 6 H, 21-CH3, 21¢-CH3), 0.92 (s, 6 H,
19-CH3, 19¢-CH3), 0.70 (s, 6 H, 18-CH3, 18¢-CH3).
13C NMR (100 MHz, CDCl3): d = 173.7 (NHC=O), 165.3 (ArC=O),
134.4 (ArC-1,4), 129.4 (ArC-2,3,5,6), 74.7 (3-CH), 72.8 (12-CH),
70.0 (O-CH2), 69.8 (O-CH2), 68.2 (7-CH), 46.4, 45.6, 42.6, 41.1,
39.4, 39.1, 35.1, 34.8, 34.5, 34.4, 34.3, 31.5, 31.3, 28.6, 27.3, 27.1,
26.6, 23.0 (19-CH3), 22.5, 17.5 (21-CH3), 12.5 (18-CH3).
MS (ESI-TOF): m/z [M + Na]+ calcd for C58H86N2O6Na: 929.64;
found: 929.67.
Cyclic N,N¢-(3,6-Dioxa-1,8-octanediyl) 3a,3¢a-(Terephthaloyl-
oxy)bis(5b-cholan-24-amide) (4b)
Yield: 21 mg (37%).
MALDI-TOF: m/z [M + H]+ calcd for C62H95N2O12: 1059.69;
found: 1059.92.
1H NMR (500 MHz, CDCl3): d = 8.09 (s, 4 H, ArH-2,3,5,6), 5.79 (t,
3J = 5.5 Hz, 2 H, NH), 5.05 (m, 2 H, 3b-H, 3b¢-H), 3.66–3.46 (m,
12 H, NH-CH2, O-CH2), 2.11–2.03 (m, 4 H, 23-CH2, 23¢-CH2),
0.97 (s, 6 H, 19-CH3, 19¢-CH3), 0.95 (d, 3J = 6.5 Hz, 6 H, 21-CH3,
21¢-CH3), 0.67 (s, 6 H, 18-CH3, 18¢-CH3).
13C NMR (126 MHz, CDCl3): d = 173.7 (NHC=O), 165.2 (ArC=O),
134.5 (ArC-1,4), 129.4 (ArC-2,3,5,6), 75.0 (3-CH), 70.1 (O-CH2),
69.9 (O-CH2), 56.8, 55.1, 42.7, 41.8, 40.7, 40.3, 39.1 (CH2-NH),
35.7, 35.0, 34.9, 34.5, 32.2, 32.2, 31.8 (23-CH2), 28.2, 26.9, 26.7,
26.3, 24.1, 23.3 (19-CH3), 20.9, 18.5 (21-CH3), 12.1 (18-CH3).
Anal. Calcd for solvate 4e*CH2Cl2 C63H96Cl2N2O12: C, 66.12; H,
8.46; N, 2.45. Found: C, 66.30; H, 8.41; N, 2.30
Bis(24-triphenylmethoxy)-3a,3¢a-(isophthaloyloxy)bis(5b-
cholane-7a,12a-diol) (5b)
To isophthaloyl dichloride (57 mg, 0.28 mmol) in CH2Cl2 (1.5 mL),
DMAP (18 mg, 0.2 mmol), pyridine (0.33 mL) and 24-triphenyl-
methoxy-5b-cholan-3a,7a,12a-triol (400 mg, 0.63 mmol) were
added consecutively at r.t. The mixture was stirred for 24 h, diluted
with CH2Cl2 (50 mL) and washed with 5% NaHCO3 (2 × 20 mL).
The organic layer was dried over Na2SO4 and the solvent evaporat-
ed under reduced pressure. The product was purified by column
chromatography (CH2Cl2–MeOH, 20:1; Rf = 0.40) to give 5b as a
white crystalline solid.
MS (ESI-TOF): m/z [M + Na]+ calcd for C62H94N2O8Na: 1017.69;
found: 1017.70.
Cyclic N,N¢-(3-Oxa-1,5-pentanediyl) 3a,3a¢-(2,6-Pyridinedicar-
bonyloxy)bis(12a-hydroxy-5b-cholan-24-amide) (4c)
Yield: 22 mg (37%).
Yield: 222 mg (56%).
1H NMR (400 MHz, CDCl3): d = 8.63 (t, 4J = 1.7 Hz, 1 H, ArH-2),
8.18 (dd, 3J1 = 7.8 Hz, 4J2 = 1.7 Hz, 2 H, ArH-4,6), 7.47 (t, 3J = 7.8
Hz, 1 H, ArH-5), 7.44–7.18 (m, 30 H, PhH-2,3,4,5,6), 4.84 (m, 2 H,
3b-H, 3b¢-H), 4.00 (br s, 2 H, 12b-H, 12b¢-H), 3.86 (br s, 2 H, 7b-
3
1H NMR (400 MHz, CDCl3): d = 8.27 (d, J = 7.8 Hz, 2 H, ArH-
3,5), 7.97 (t, 3J = 7.8 Hz, 1 H, ArH-4), 6.10 (m, 2 H, NH), 4.89 (m,
2 H, 3b-H, 3b¢-H), 3.98 (br s, 2 H, 12b-H, 12b¢-H), 3.56–3.38 (m,
3
8 H, NHCH2CH2O), 0.99 (d, J = 6.3 Hz, 6 H, 21-CH3, 21¢-CH3),
3
H, 7b¢-H), 3.02 (m, 4 H, 24-CH2, 24¢-CH2), 0.96 (d, J = 6.4 Hz,
0.95 (s, 6 H, 19-CH3, 19¢-CH3), 0.66 (s, 6 H, 18-CH3, 18¢-CH3).
6 H, 21-CH3, 21¢-CH3), 0.93 (s, 6 H, 19-CH3, 19¢-CH3), 0.68 (s,
13C NMR (100 MHz, CDCl3): d = 173.7 (NHC=O), 164.7 (ArC=O),
148.7 (ArC-2,6), 138.1 (ArC-4), 127.9 (ArC-3,5), 77.0 (3-CH), 73.0
(12-CH), 70.1 (O-CH2), 47.6, 47.6, 46.6, 42.0, 39.2, 36.1, 35.2,
35.0, 34.4, 34.3, 33.6, 32.0, 31.8, 28.7, 27.4, 27.1, 26.2, 26.1, 23.9
(19-CH3), 23.1, 17.8 (21-CH3), 12.8 (18-CH3).
6 H, 18-CH3, 18¢-CH3).
13C NMR (100 MHz, CDCl3): d = 165.3 (ArC=O), 144.5 (PhC-1),
133.4 (ArC-4,6), 131.2 (ArC-1,3), 130.7 (ArC-2), 128.6 (PhC-2,6),
128.5 (ArC-5), 127.6 (PhC-3,5), 126.7 (PhC-4), 86.2 (C-Ph3), 75.2
(3-CH), 72.9 (12-CH), 68.2 (7-CH), 64.0 (24-CH2), 47.5, 46.5,
42.0, 41.2, 39.5, 35.3, 35.2, 34.8, 34.6, 34.4, 32.2, 28.3, 27.5, 26.8,
26.7, 26.6, 23.2 (19-CH3), 22.5, 17.7 (21-CH3), 12.5 (18-CH3).
Cyclic N,N¢-(3,6-Dioxa-1,8-octanediyl) 3a,3a¢-(Isophthaloyl-
oxy)bis(7a,12a-dihydroxy-5b-cholan-24-amide) (4d)
Yield: 22 mg (35%).
3a,3¢a-(Isophthaloyloxy)bis(5b-cholane-7a,12a,24-triol) (6b)
Compound 5b (0.16 mmol) was dissolved in a mixture of MeOH (8
mL) and CH2Cl2 (2 mL). To this solution aq 48% HBr (0.3 mL) was
added and the mixture was refluxed for 3 h. The product was ex-
tracted with CH2Cl2 (2× 70 mL) and the organic layer was washed
with H2O (20 mL), dried over MgSO4 and concentrated. The result-
ing oil was purified by chromatography on silica gel (CH2Cl2–
MeOH, 20:1; Rf = 0.05).
3
4
1H NMR (400 MHz, CDCl3): d = 8.33 (dd, J1 = 7.8 Hz, J2 = 1.6
Hz, 2 H, ArH-4,6), 8.21 (br s, 1 H, ArH-2), 7.58 (t, 3J = 7.8 Hz, 1 H,
ArH-5), 7.45 (m, 2 H, NH), 5.02 (m, 2 H, 3b-H, 3b¢-H), 3.96 (br s,
2 H, 12b-H, 12b¢-H), 3.91 (br s, 2 H, 7b-H, 7b¢-H), 4.22–3.47 (m,
3
12 H, CH2-O, CH2-NH), 1.14 (d, J = 6.7 Hz, 6 H, 21-CH3, 21¢-
CH3), 0.96 (s, 6 H, 19-CH3, 19¢-CH3), 0.73 (s, 6 H, 18-CH3, 18¢-
CH3).
Synthesis 2009, No. 24, 4175–4182 © Thieme Stuttgart · New York

PAPER
Novel Macrocyclic Bile Acid Derivatives
4181
Yield: 125 mg (85%).
CH3, 19¢-CH3), 0.95 (d, 3J = 6.5 Hz, 6 H, 21-CH3, 21¢-CH3), 0.66 (s,
6 H, 18-CH3, 18¢-CH3).
1H NMR (400 MHz, CDCl3): d = 8.62 (t, 4J = 1.7 Hz, 1 H, ArH-2),
8.18 (dd, 3J1 = 7.8 Hz, 4J2 = 1.7 Hz, 2 H, ArH-4,6), 7.48 (t, 3J = 7.8
Hz, 1 H, ArH-5), 4.83 (m, 2 H, 3b-H, 3b¢-H), 4.00 (br s, 2 H, 12b-
H, 12b¢-H), 3.86 (br s, 2 H, 7b-H, 7b¢-H), 3.61 (m, 4 H, 24-CH2,
24¢-CH2), 0.98 (d, 3J = 6.4 Hz, 6 H, 21-CH3), 0.93 (s, 6 H, 19-CH3,
19¢-CH3), 0.69 (s, 6 H, 18-CH3, 18¢-CH3).
13C NMR (100 MHz, CDCl3): d = 165.4 (ArC=O), 133.5 (ArC-4,6),
131.3 (ArC-1,3), 130.6 (ArC-2), 128.3 (ArC-5), 75.4 (3-CH), 73.0
(12-CH), 68.3 (7-CH), 63.4 (24-CH2), 47.4, 46.5, 42.0, 41.2, 39.5,
35.4, 35.2, 34.9, 34.7, 34.4, 31.8, 29.5, 28.3, 27.5, 26.8, 26.7, 23.2
(19-CH3), 22.5, 17.7 (21-CH3), 12.6 (18-CH3).
13C NMR (126 MHz, CDCl3): d = 166.0 (ArC=O), 165.8 (Ar¢C=O),
134.3 (Ar¢C-1,4), 133.9 (ArC-4,6), 131.6 (ArC-1,3), 129.5 (Ar¢C-
2,3,5,6), 128.9 (ArC-2), 128.5 (ArC-5), 77.9 (3-CH), 65.5 (24-
CH2), 56.6, 55.9, 42.7, 42.2, 40.6, 40.2, 35.9, 35.6, 35.1, 34.8, 32.4,
32.0, 28.6, 27.2, 26.8, 26.5, 25.5, 24.2, 23.5 (19-CH3), 20.9, 18.8
(21-CH3), 12.0 (18-CH).
MS (ESI-TOF): m/z [M + Na]+ calcd for C64H88O8Na: 1007.64;
found: 1007.73.
Cyclic 3a,3¢a-(Isophthaloyloxy)bis(5b-cholan-24-yloxy)iso-
phthalate (7d)
Preparation of Macrocycles 7a–e; Typical Procedure
Yield: 14 mg (14%).
In a vial with a screw cap, a mixture of 6a (68 mg, 0.08 mmol),
DMAP (3 mg, 0.02 mmol), the corresponding dichloroanhydride (1
equiv) and Et3N (0.5 mL) in toluene (8 mL) was heated on an oil
bath (100 °C) until TLC analysis revealed the reaction was no long-
er proceeding (15–20 h). The solvent was removed under reduced
pressure and the residue was subjected to column chromatography
(CH2Cl2; Rf = 0.20~0.25) to give 7a–e as white crystalline solids.
1H NMR (500 MHz, CDCl3): d = 8.59 (br s, 1 H, Ar¢H-2), 8.46 (br
s, 1 H, ArH-2), 8.25 (m, 4 H, ArH-4,6, Ar¢H-4,6), 7.53 (m, 2 H,
ArH-5, Ar¢H-5), 4.96 (m, 2 H, 3b-H, 3b¢-H), 4.50–4.23 (m, 4 H, 24-
CH2, 24¢-CH2), 0.97 (s, 6 H, 19-CH3, 19¢-CH3), 0.95 (d, 3J = 6.5 Hz,
6 H, 21-CH3, 21¢-CH3), 0.65 (s, 6 H, 18-CH3, 18¢-CH3).
13C NMR (126 MHz, CDCl3): d = 165.9 (Ar¢C=O), 165.7 (ArC=O),
134.3 (ArC-4,6), 134.1 (Ar¢C-4,6), 131.3 (ArC-1,3), 130.9 (Ar¢C-
1,3), 129.8 (Ar¢C-2), 129.0 (ArC-2), 128.7 (Ar¢C-5), 128.6 (ArC-5),
76.1 (3-CH), 65.6 (24-CH2), 56.5, 56.3, 42.8, 42.2, 40.6, 40.3, 35.9,
35.2, 35.1, 34.7, 32.4, 32.3, 28.3, 27.2, 26.8, 26.4, 25.3, 24.4, 23.4
(19-CH3), 20.9, 18.6 (21-CH3), 12.0 (18-CH3).
Cyclic 3a,3¢a-(Isophthaloyloxy)bis(5b-cholan-24-yloxy)oxalate
(7a)
Yield: 33 mg (45%).
1H NMR (500 MHz, CDCl3): d = 8.47 (t, 4J = 1.7 Hz, 1 H, ArH-2),
8.28 (dd, 3J1 = 7.8 Hz, 4J2 = 1.7 Hz, 2 H, ArH-4,6), 7.53 (t, 3J = 7.8
Hz, 1 H, ArH-5), 4.96 (m, 2 H, 3b-H, 3b¢-H), 4.40–4.20 (m, 4 H,
24-CH2, 24¢-CH2), 0.99 (s, 6 H, 19-CH3, 19¢-CH3), 0.93 (d, 3J = 6.5
Hz, 6 H, 21-CH3, 21¢-CH3), 0.68 (s, 6 H, 18-CH3, 18¢-CH3).
13C NMR (126 MHz, CDCl3): d = 165.6 (ArC=O), 158.1 (C=O),
134.4 (ArC-4,6), 131.2 (ArC-1,3), 128.9 (ArC-2), 128.6 (ArC-5),
76.3 (3-CH), 66.8 (24-CH2), 56.5, 56.4, 42.8, 42.3, 40.6, 40.3, 35.9,
35.5, 35.2, 34.8, 32.5, 31.8, 28.8, 27.2, 26.9, 26.4, 25.6, 24.3, 23.5
(19-CH3), 21.0, 18.7 (21-CH3), 12.0 (18-CH3).
MS (ESI-TOF): m/z [M + Na]+ calcd for C64H88O8Na: 1007.64;
found: 1007.57.
Cyclic 3a,3¢a-(Isophthaloyloxy)bis(5b-cholan-24-yloxy)-2,6-py-
ridinedicarboxylate (7e)
Yield: 21 mg (27%).
1H NMR (500 MHz, CDCl3): d = 8.44 (t, 4J = 1.7 Hz, 1 H, ArH-2),
8.27 (d, 3J = 7.8 Hz, 2 H, Ar¢H-3,5), 8.24 (dd, 3J1 = 7.8 Hz, 4J2 = 1.7
Hz, 2 H, ArH-4,6), 7.97 (t, 3J = 7.8 Hz, 1 H, Ar¢H-4), 7.52 (t,
3J = 7.8 Hz, 1 H, ArH-5), 4.93 (m, 2 H, 3b-H, 3b¢-H), 4.54–4.31 (m,
4 H, 24-CH2, 24¢-CH2), 0.97 (s, 6 H, 19-CH3, 19¢-CH3), 0.94 (d,
3J = 6.5 Hz, 6 H, 21-CH3, 21¢-CH3), 0.63 (s, 6 H, 18-CH3, 18¢-CH3).
MS (ESI-TOF): m/z [M + Na]+ calcd for C58H84O8Na: 931.61;
found: 931.64.
13C NMR (126 MHz, CDCl3): d = 165.7 (ArC=O), 165.2 (Ar¢C=O),
148.6 (Ar¢C-2,6), 137.9 (Ar¢C-4), 134.2 (ArC-4,6), 131.3 (ArC-
1,3), 129.0 (ArC-2), 128.6 (ArC-5), 127.8 (Ar¢C-3,5), 76.3 (3-CH),
66.5 (24-CH2), 56.5, 56.4, 42.8, 42.2, 40.6, 40.3, 35.9, 35.2, 35.1,
34.8, 32.4, 32.2, 28.3, 27.2, 26.8, 26.4, 25.4, 24.4, 23.4 (19-CH3),
20.9, 18.6 (21-CH3), 12.0 (18-CH3).
Cyclic 3a,3¢a-(Isophthaloyloxy)bis(5b-cholan-24-yloxy)-2,5-
thiophenedicarboxylate (7b)
Yield: 9 mg (11%).
1H NMR (500 MHz, CDCl3): d = 8.46 (t, 3J = 1.7 Hz, 1 H, ArH-2),
3
4
8.25 (dd, J1 = 7.8 Hz, J2 = 1.7 Hz, 2 H, ArH-4,6), 7.77 (s, 2 H,
3
Ar¢H-3,4), 7.53 (t, J = 7.8 Hz, 1 H, ArH-5), 4.95 (m, 2 H, 3b-H,
MS (ESI-TOF): m/z [M + Na]+ calcd for C63H87NO8Na: 1008.63;
found: 1008.59.
3b¢-H), 4.40–4.20 (m, 4 H, 24-CH2, 24¢-CH2), 0.98 (s, 6 H, 19-CH3,
19¢-CH3), 0.93 (d, 3J = 6.5 Hz, 6 H, 21-CH3, 21¢-CH3), 0.66 (s, 6 H,
18-CH3, 18¢-CH3).
Preparation of Macrocycles 7f–g; General Procedure
A mixture of 6b (46 mg, 0.05 mmol), DMAP (3 mg, 0.02 mmol),
the corresponding dichloroanhydride (0.05 mmol), and Et3N (0.5
mL) in anhyd CH2Cl2 (8 mL) was stirred at r.t. until TLC analysis
revealed the end of the reaction (24 h). The solvent was removed
under reduced pressure and the residue was purified by chromatog-
raphy on silica gel (CH2Cl2–MeOH, 48:2; Rf = ~0.20) to give 7f,g
as white crystalline solids.
13C NMR (126 MHz, CDCl3): d = 165.7 (ArC=O), 161.5 (Ar¢C=O),
138.5 (Ar¢C-2,5), 134.2 (ArC-4,6), 133.2 (Ar¢C-3,4), 131.3 (ArC-
1,3), 129.0 (ArC-2), 128.6 (ArC-5), 76.1 (3-CH), 65.2 (24-CH2),
56.6, 56.5, 42.8, 42.2, 40.6, 40.3, 35.9, 35.1, 35.0, 34.8, 32.4, 31.7,
28.6, 27.2, 26.8, 26.4, 25.3, 24.4, 23.4 (19-CH3), 20.9, 18.5 (21-
CH3), 12.0 (18-CH3).
MS (ESI-TOF): m/z [M + Na]+ calcd for C62H86O8SNa: 1013.59;
found: 1013.65.
Cyclic 3a,3¢a-(Isophthaloyloxy)bis(7a,12a-dihydroxy-5b-
cholan-24-yloxy)-2,6-pyridinedicarboxylate (7f)
Yield: 9 mg (17%).
Cyclic 3a,3¢a-(Isophthaloyloxy)bis(5b-cholan-24-yloxy)tereph-
thalate (7c)
Yield: 17 mg (21%).
1H NMR (400 MHz, CDCl3): d = 8.55 (t, 4J = 1.6 Hz, 1 H, ArH-2),
8.30 (d, 3J = 7.8 Hz, 2 H, Ar¢H-3,5), 8.20 (dd, 3J1 = 7.8 Hz, 4J2 = 1.7
Hz, 2 H, ArH-4,6), 7.98 (t, 3J = 7.8 Hz, 1 H, Ar¢H-4), 7.50 (t,
3J = 7.8 Hz, 1 H, ArH-5), 4.79 (m, 2 H, 3b-H, 3b¢-H), 4.56–4.31 (m,
4 H, 24-CH2, 24¢-CH2), 4.01 (br s, 2 H, 12b-H, 12b¢-H), 3.85 (br s,
1H NMR (500 MHz, CDCl3): d = 8.41 (t, 4J = 1.7 Hz, 1 H, ArH-2),
3
4
8.20 (dd, J1 = 7.8 Hz, J2 = 1.7 Hz, 2 H, ArH-4,6), 8.08 (s, 4 H,
Ar¢H-2,3,5,6), 7.50 (t, 3J = 7.8 Hz, 1 H, ArH-5), 4.86 (m, 2 H, 3b-
H, 3b¢-H), 4.39–4.26 (m, 4 H, 24-CH2, 24¢-CH2), 0.97 (s, 6 H, 19-
Synthesis 2009, No. 24, 4175–4182 © Thieme Stuttgart · New York

4182
N. V. Lukashev et al.
PAPER
(8) Bhattarai, K. M.; Davis, A. P.; Perry, J. J.; Walter, C. J.
J. Org. Chem. 1997, 62, 8463.
(9) Rasmussen, B. S.; Elezcano, U.; Skrydstrup, T. J. Chem.
Soc., Perkin Trans. 1 2002, 1723.
(10) Chattopadhyay, P.; Pandey, P. S. Bioorg. Med. Chem. Lett.
2007, 17, 1553.
(11) Chattopadhyay, P.; Pandey, P. S. Tetrahedron 2006, 62,
8620.
(12) Kikuchi, J.-I.; Murakami, Y. J. Inclusion Phenom. Mol.
Recognit. Chem. 1998, 32, 209.
(13) Gao, H.; Dias, J. R. Synth. Commun. 1997, 27, 757.
(14) Dias, J. R.; Pascal, R. A.; Morrill, J.; Holder, A. J.; Gao, H.;
Barnes, C. J. Am. Chem. Soc. 2002, 124, 4647.
(15) Gao, H.; Dias, J. R. Croat. Chem. Acta 1998, 71, 827.
(16) Davis, A. P.; Walsh, J. J. Chem. Commun. 1996, 449.
(17) Bonar-Law, R. P.; Davis, A. P. Tetrahedron 1993, 49, 9829.
(18) Tian, Z.; Cui, H.; Wang, Y. Synth. Commun. 2002, 32, 3821.
(19) Albert, D.; Feigel, M.; Benet-Buchholz, J.; Boese, R.
Angew. Chem. Int. Ed. 1998, 37, 2727.
(20) Albert, D.; Fiegel, M. Tetrahedron Lett. 1994, 35, 565.
(21) Rivera, D. G.; Wessjohann, L. Molecules 2007, 12, 1890.
(22) Wessjohann, L. A.; Rivera, D. G.; Coll, F. J. Org. Chem.
2006, 71, 7521.
3
2 H, 7b-H, 7b¢-H), 1.01 (d, J = 6.4 Hz, 6 H, 21-CH3, 21¢-CH3),
0.93 (s, 6 H, 19-CH3, 19¢-CH3), 0.68 (s, 6 H, 18-CH3, 18¢-CH3).
13C NMR (100 MHz, CDCl3): d = 165.5 (ArC=O), 165.1 (Ar¢C=O),
148.5 (Ar¢C-2,6), 138.0 (Ar¢C-4), 133.8 (ArC-4,6), 131.1 (ArC-
1,3), 130.3 (ArC-2), 128.4 (ArC-5), 127.9 (Ar¢C-3,5), 75.4 (3-CH),
73.1 (12-CH), 68.1 (7-CH), 66.5 (24-CH2), 47.6, 46.6, 41.8, 41.3,
39.7, 35.1, 34.9, 34.8, 34.5, 32.3, 29.6, 28.4, 27.5, 26.8, 26.6, 25.7,
23.4 (19-CH3), 22.5, 17.9 (21-CH3), 12.6 (18-CH3).
MS (MALDI-TOF): m/z [M + H]+ calcd for C63H88NO12: 1050.63;
found: 1050.55.
Anal. Calcd for C63H87NO12: C, 72.04; H, 8.35; N, 1.33. Found: C,
71.81; H, 8.43; N, 1.29.
Cyclic 3a,3¢a-(Isophthaloyloxy)bis(7a,12a-dihydroxy-5b-
cholan-24-yloxy)-3-oxaglutarate (7g)
Yield: 9 mg (18%).
1H NMR (400 MHz, CDCl3): d = 8.54 (t, 4J = 1.6 Hz, 1 H, ArH-2),
8.21 (dd, 3J1 = 7.8 Hz, 4J2 = 1.7 Hz, 2 H, ArH-4,6), 7.51 (t, 3J = 7.8
Hz, 1 H, ArH-5), 4.79 (m, 2 H, 3b-H, 3b¢-H), 4.27–4.12 (m, 8 H,
24-CH2, 24¢-CH2, OCH2), 4.02 (br s, 2 H, 12b-H, 12b¢-H), 3.87 (br
s, 2 H, 7b-H, 7b¢-H), 0.98 (d, 3J = 6.4 Hz, 6 H, 21-CH3, 21¢-CH3),
0.95 (s, 6 H, 19-CH3, 19¢-CH3), 0.71 (s, 6 H, 18-CH3, 18¢-CH3).
13C NMR (100 MHz, CDCl3): d = 169.9 (ArC=O), 165.5 (C=O),
133.8 (ArC-4,6), 131.1 (ArC-1,3), 130.0 (ArC-2), 128.5 (ArC-5),
75.6 (3-CH), 73.1 (12-CH), 68.4 (7-CH), 68.1 (OCH2), 66.3 (24-
CH2), 47.5, 46.5, 41.7, 41.3, 39.7, 35.1, 34.9, 34.8, 34.6, 32.0, 29.7,
28.5, 27.5, 26.8, 26.5, 25.5, 23.4 (19-CH3), 22.5, 17.7 (21-CH3),
12.7 (18-CH3).
(23) Tamminen, J.; Kolehmainen, E.; Haapala, M.; Linnanto, J.
Synthesis 2000, 1464.
(24) Pandey, P. S.; Rai, R.; Singh, R. B. J. Chem. Soc., Perkin
Trans. 1 2002, 918.
(25) Kolehmainen, E.; Tamminen, J.; Lappalainen, K.; Torkkel,
T.; Seppälä, R. Synthesis 1996, 1082.
(26) Pandey, P. S.; Rai, R.; Singh, R. B. Tetrahedron 2002, 58,
355.
(27) Ra, C. S.; Cho, S. W.; Choi, J. W. Bull. Korean Chem. Soc.
2000, 21, 342.
(28) Łotowski, Z.; Guzmański, D. Monatsh. Chem. 2005, 136,
153.
MS (MALDI-TOF): m/z [M + Na]+ calcd for C60H88NaO13:
1039.61; found: 1039.53.
Anal. Calcd for C60H88O13: C, 70.84; H, 8.72. Found: C, 70.57; H,
8.51.
(29) Nair, V.; Prabhakaran, J.; Eigendorf, G. K. Synth. Commun.
1997, 27, 3095.
(30) Averin, A. D.; Ranyuk, E. R.; Lukashev, N. V.; Beletskaya,
I. P. Chem. Eur. J. 2005, 11, 7030.
(31) Averin, A. D.; Ranyuk, E. R.; Lukashev, N. V.; Golub, S. L.;
Buryak, A. K.; Beletskaya, I. P. Tetrahedron Lett. 2008, 49,
1188.
Acknowledgment
We are grateful to the Russian Foundation for Basic Research (grant
08-03-91308-INDa and 07-03-00619a) and the Academy of Finland
(project 105950) for financial support.
(32) Czajkowska, D.; Morzycki, J. W. Tetrahedron Lett. 2007,
48, 2851.
(33) Latyshev, G. V.; Baranov, M. S.; Kazantsev, A. V.; Averin,
A. D.; Lukashev, N. V.; Beletskaya, I. P. Synthesis 2009,
2605.
(34) Valkonen, A.; Sievänen, E.; Ikonen, S.; Lukashev, N. V.;
Donez, P. A.; Averin, A. D.; Lahtinen, M.; Kolehmainen, E.
J. Mol. Struct. 2007, 846, 65.
(35) Kohmoto, S.; Fukui, D.; Nagashima, T.; Kishikawa, K.;
Yamamoto, M.; Yamada, K. Chem. Commun. 1996, 1869.
(36) Li, Y.; Dias, J. R. Synthesis 1997, 425.
(37) Vijayalakshmi, N.; Maitra, U. Macromolecules 2006, 39,
7931.
References
(1) Bonar-Law, R. P.; Sanders, J. K. M. Tetrahedron Lett. 1992,
33, 2071.
(2) Virtanen, E.; Koivukorpi, J.; Tamminen, J.; Mänttäri, P.;
Kolehmainen, E. J. Organomet. Chem. 2003, 668, 43.
(3) Khatri, V. K.; Upreti, S.; Pandey, P. S. Org. Lett. 2006, 8,
1755.
(4) Maitra, U.; D’Souza, L. J.; Kumar, P. V. Supramol. Chem.
1998, 10, 97.
(5) Ghosh, S.; Choudhury, A. R.; Row, T. N. G.; Maitra, U. Org.
Lett. 2005, 7, 1441.
(6) Bonar-Law, R. P.; Mackay, L. G.; Sanders, J. K. M. J. Chem.
Soc., Chem. Commun. 1993, 456.
(38) Li, H.; Wang, L. X. Org. Biomol. Chem. 2003, 1, 3507.
(7) Davis, A. P. Chem. Soc. Rev. 1993, 22, 243.
Synthesis 2009, No. 24, 4175–4182 © Thieme Stuttgart · New York