CuAAC Synthesis and Anion Binding Properties of Bile Acid Derived Tripodal Ligands

Article abstract of DOI:10.1002/ejoc.201500835

The copper-catalyzed azide-alkyne cycloaddition reaction was used for the preparation of a series of bis- and tris-3- and 24-5β-cholanetriazolyl derivatives of phosphorus acids, which contained anion-binding triazolium sites and hydrophobic cholane residues. The influence of the location of the triazolium moiety (in 3α-, 3β-position) on fluoride-ion complexation was investigated. The anion-binding properties of tris(triazolium) ligands were studied for a series of inorganic and organic anions and high complexation constants were observed with fluoride, hydrosulfate, and benzoate anions. A series of bile acid derived pincer and tripodal ligands that contain anion-binding triazolium and phosphoramide sites were prepared. These compounds efficiently bind inorganic and organic anions to give 1:2 ligand/anion complexes.

Full text of DOI:10.1002/ejoc.201500835

FULL PAPER
DOI: 10.1002/ejoc.201500835
CuAAC Synthesis and Anion Binding Properties of Bile Acid Derived Tripodal
Ligands
Dmitry A. Erzunov,[a] Gennadij V. Latyshev,[a] Alexey D. Averin,[a] Irina P. Beletskaya,[a] and
Nikolay V. Lukashev*[a]
Keywords: Supramolecular chemistry / Receptors / Anions / Bile acids / Steroids / Azides
The copper-catalyzed azide–alkyne cycloaddition reaction
was used for the preparation of a series of bis- and tris-3-
and 24-5β-cholanetriazolyl derivatives of phosphorus acids,
triazolium moiety (in 3α-, 3β-position) on fluoride-ion com-
plexation was investigated. The anion-binding properties of
tris(triazolium) ligands were studied for a series of inorganic
which contained anion-binding triazolium sites and hydro- and organic anions and high complexation constants were
phobic cholane residues. The influence of the location of the
observed with fluoride, hydrosulfate, and benzoate anions.
Specific properties of bile acids are largely associated
with their facial amphiphilicity, which is to say the hydro-
philic cavity and the hydrophobic outer side. Besides, in
solutions the hydroxy and carboxy groups of bile acids can
form intermolecular hydrogen bonds that lead to aggrega-
tion and gel formation.[10] The combination of a rigid
curved skeleton and amphiphilicity make them very attract-
ive as building blocks for synthesis of macrocycles[11] and
for supramolecular chemistry.[12] Hydroxy groups situated
on the α-face of bile-acid molecules are suitable for further
modification, which suggests their use for attaching various
binding residues. There are many examples of such conju-
gates of bile acids with various fragments, which include
crown ethers,[13] polyaromatics,[14] and peptides.[15] So, in-
corporation of bile-acid fragments into an anion receptor
can provide a rigid framework for H-bond donors in a
binding site and the possibility for further derivatization.
The lipophilic nature of bile acids also makes such a recep-
tor compatible with non-polar environments, such as ste-
roid-based amide receptors that are an important class of
anion receptors capable of selectively transporting anions
through lipid membranes. In some cases, the ion flux can
be detected at as low as a 1:250000 receptor/lipid ratio.[16]
Molecules that contain several bile acid residues exhibit
self-assembly properties to form hydrophilic or hydrophobic
“molecular pockets” as a function of the polarity of the
media.[17] Thus, reversible cholamide-calix[4]arene-based
molecular switches can respond to the changes in solvent
polarity by changing between hydrophilic face-in and
hydrophilic face-out conformations.[18] Positively charged
ammonium derivatives with hydrophobic exteriors and cat-
ionic highly polar interiors are extremely effective as anion
transporters.[19] Bile-derived “molecular umbrellas” conju-
gated with nucleosides are able to penetrate through phos-
pholipid liposomal bilayers.[20]
Introduction
Ion receptors and transporters are important classes of
compounds for supramolecular chemistry, especially in
light of their potential biological applications.[1] The disrup-
tion of anion current through a cell membrane is often con-
sidered as a main cause of many disorders.[2] Recently, a
monograph[3] and several reviews[4] have been devoted to
the chemistry of anion receptors. The most important
classes of anion receptors are positively charged polyam-
monium salts – linear, macrocyclic, cryptands, as well as
closely related guanidinium, amidinium, and imidazolium
derivatives. Many proteins could participate in anion bind-
ing not only by ammonium groups but also by hydrogen
bonding of anions with neutral amide groups. Amides of
1,3-arene(hetarene)-dicarboxylic acids are among the most
popular molecules for anion binding.[5]
Essential problems in construction of artificial ion re-
cognition systems are the preorganization of a polar bind-
ing site and maintenance of some physical properties (e.g.
solubility) for the desired medium (e.g. cell membrane).[6] It
is known that various steroid molecules can be integrated
in lipid membranes and form ion channels. In this way, bile
acids activate the bile acid-sensitive ion channel (epithelial
sodium channel) by alteration of its membrane environ-
ment.[7] The first bile acid derived anionophores were pre-
pared by Davis.[8] To date different derivatives of bile acids
were proposed as ion channels or chemosensors for cations
and anions.[9]
[a] Chemistry Department, Moscow Lomonosov University,
Vorobievy Gory 1, 119991 Moscow, Russian Federation
E-mail: nvluk@org.chem.msu.ru
nvlukashev@gmail.com
http://www.chem.msu.ru
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500835.
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N. V. Lukashev et al.
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Since the discovery of the copper-catalyzed azide-alkyne obtained from the corresponding phosphoryl chlorides and
cycloaddition (CuAAC) reaction[21] it has become a very propargylamine in the presence of triethylamine in 58–73%
convenient method for the construction of bile-acid conju- yields (Scheme 1).
gates. In 2005, it was applied for the syntheses of several
bile-acid dimers linked at the C-3 and C-24 positions by
triazole units.[22] Moreover, this reaction provided an easy
route to bile-acid containing macrocycles.[23] It should be
noted that the 1,2,3-triazole moiety is not just a passive
linker, because it readily associates with biological targets
Scheme 1. Preparation of phosphorus-containing propargyl deriva-
through hydrogen bonding and dipole interactions.[24] The
tives. 1a–1c (X = O); (a) n = 1, 68%; (b) n = 2, 90%; (c) n = 3,
ability of 1,2,3-triazoles to mimic topological and electronic
features of the amide bond can be used for the design of
peptidomimetics,[25] cation receptors,[26] and steroid mol-
ecules with potential biological activity.[24] Recently, the
CuAAC synthesis of various bile acid containing tripodal
ligands to form “pockets” was proposed, and dynamic in-
version between two conformations by a simple change of
the media polarity was demonstrated.[27]
1,2,3-Triazolium salts are a class of charged anion recep-
tors first introduced by Pandey et. al.[28] Their ability to
bind anions is associated with a combination of the rela-
tively high acidity of the CH bond and electrostatic factors.
In some cases anion–π interactions play an important role
in anion recognition.[29] Anion receptors that bear two tri-
azolium subunits separated by rigid spacer display high af-
finity and selectivity towards various anions.[30] These com-
plexes were used as starting point for the anion-templated
synthesis of rotaxanes and pseudorotaxanes.[31] Hybrid re-
ceptors that contain both amide and triazolium fragments
often have enhanced complexation properties.[32] They were
also employed as organocatalysts for asymmetric alkylation
of oxindole.[33]
34%. 2a–2c (X = NH); (a) n = 1, 64%; (b) n = 2, 73%; (c) n = 3,
58%.
Bile azides 3a–3c and 4 were synthesized by using a stan-
dard route by nucleophilic substitution of the correspond-
ing α- and β-mesylates with sodium azide in dimethyl sulf-
oxide (DMSO; Scheme 2).[22,40] A previously reported syn-
thesis of 24-azidocholane derivatives relied upon the rather
unselective mesylation of 3,24-cholanediols (75:25 ratio for
mono/dimesylate).[41] To avoid a tedious separation of
mono- and dimesylates the 3-OH was protected with a trityl
group. Subsequent reduction with LiAlH4, mesylation,
nucleophilic substitution with NaN3, and removal of the
protective group afforded azides 5a and 5b (Scheme 3).
The ability of aminophosphoryl and aminothiophos-
phoryl groups to efficiently coordinate anions has been
known for a long time,[34] but was almost ignored until re-
cently.[35] Nevertheless the high hydrogen bond donor prop-
erties of these groups promoted their use as core structures
within new organocatalysts for ionic [4+2] cycloaddition[36]
and asymmetric Michael reactions.[37]
Recently, some of us described synthesis of tripodal bile
acid architectures with a triarylphosphine oxide core by
copper catalyzed [3+2] dipolar cycloaddition reaction.[38]
However, high hydrophobicity of the phosphine oxide core
that results from the phenyl rings at the P atom required
additional modification of the tripods by taurine to obtain
water-soluble compounds. Here we describe the synthesis Scheme 2. Synthesis of 3α- and 3β-azidocholane derivatives;
DEAD = diethyl azodicarboxylate.
and anion complexation properties of a series of tris-chol-
anetriazolyl derivatives of phosphorus acids that include
anion binding triazolium sites in different positions (3α- or
3β-) of hydrophobic cholane residues.
“Extended 3α-” bile azide 6 that contains an azido group
separated by a flexible acetate linker from the steroid core
was prepared by a simple two-step procedure from methyl
lithocholate (Scheme 4).[42]
CuAAC reaction of 5a with hydrophobic amide 2a in the
presence of CuSO4 and sodium ascorbate in a tetra-
Results and Discussion
Propargyl esters 1a–1c and propargyl amides 2a–2c of hydrofuran (THF)/H2O system (conditions A) afforded 7 in
various hydrophilicity were chosen as precursors for the 80% yield within 15 min (Scheme 5). The reaction proved
core of our tripodal ligands. Preparation of esters 1a–1c was to be insensitive to the nature of the copper(I) precursor.
described previously in the literature.[39] Amides 2a–2c were Similar yields and reaction times were observed for other
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Synthesis and Properties of Bile Acid Derived Tripodal Ligands
In contrast, dipropargyl derivative 2b appeared to be sig-
nificantly less reactive, and only traces of products 10 and
11 were observed after stirring at room temperature for pro-
longed times under conditions A. However, excellent yields
(80–88%) were obtained when the temperature was raised
to 60 °C (conditions B; Scheme 6).
Scheme 3. Synthesis of 24-azidocholane derivatives 5; DCE = 1,2-
dichloroethane.
Scheme 6. Synthesis of pincer-like bile-acid conjugates. Conditions:
B: CuSO4·5H2O (5 mol-%), NaAsc (40 mol-%), THF/H2O (4:1),
60 °C, 24 h; C: CuSO4·5H2O (5 mol-%), NaAsc (40 mol-%), THF/
H2O (4:1), TBTA (5 mol-%), room temp., 2 h.
Scheme 4. Preparation of 3α-azidoacetoxy derivative 6.
It is well known that polytriazolyl ligands accelerate
CuAAC reactions. This effect is probably related to stabili-
zation of the CuI oxidation state and the decomposition
of polynuclear copper acetylide clusters.[43] For pincer-like
compounds 10 and 11 the use of tris(benzyltriazolyl-
methyl)amine (TBTA) allowed the CuAAC reaction to be
conducted at room temperature in 2 h and significantly in-
creases the yield of 11. Unfortunately, phosphonate-based
pincer 12a was labile even under such mild conditions and
the obtained product was contaminated by ≈ 10% of 24-(4-
hydroxymethyltriazolyl)-5-β-cholan-3-ol (12b), which could
not be separated from the major product (Scheme 6).
Both conditions B and C were successfully applied to the
preparation of the bile acid based tripods 13–18 (Scheme
7). However, up to 24 h were required for complete disap-
pearance of the copper acetylides in method B. Good yields
were obtained for 3β- (13–15), 3α- (16), and 24- (18) chol-
anetriazolyl derivatives (Scheme 7). Slightly higher yields
were observed for lithocholic acid based tripods relative to
deoxycholic and cholic acid based products. Also, we ob-
tained click adduct 17 with 3-azidoacetoxycholane deriva-
tive 6, because derivatives that contain a longer triazolyl-
acetoxy linker may have a bigger cavity and be capable of
effective complexation with anions.[28] Surprisingly, CuAAC
reaction of tripropargyl phosphate 1c with steroidal azides
gave complex mixture of products, which were insoluble in
most organic solvents including DMSO.
copper catalysts such as CuI or Cu(phen)(PPh3)Br. There-
fore, we use the most popular CuSO4-ascorbate system as
the most convenient one. The progress of reactions was
monitored by TLC, and by disappearance of the character-
istic yellowish color of the copper acetylides. Similarly, 3-
and 24-azidocholane derivatives 3c and 5a readily react
with propargyl ester 1a at room temperature to afford
cycloadducts 8 and 9 in 15 min in 75–77% yield.
Scheme 5. Synthesis of mono bile-acid phosphorus(V) conjugates.
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N. V. Lukashev et al.
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Scheme 8. Preparation of triazolium derivatives 20a–20c.
(Table 1). The highest binding constant, K = 1.9ϫ105 m–2,
with fluoride was observed for compound 20b with a β-
orientation of the triazolium moiety. A change of orienta-
tion at C-3 of bile acid fragment to α instead of β led to
a decrease in the binding constant by more than 5 times.
Introduction of an acetoxy bridge in 20c could enhance the
binding constant as a result of additional hydrogen bond-
ing.[42] However, the observed binding constant for 20c was
approximately two times lower than 20b.
Scheme 7. Synthesis of tripodal derivatives. Conditions:
B: CuSO4·5H2O (5 mol-%), NaAsc (40 mol-%), THF/H2O (4:1),
60 °C, 24 h; C: CuSO4·5H2O (5 mol-%), NaAsc (40 mol-%), THF/
H2O (4:1), TBTA (5 mol-%), room temp., 24 h.
Triazolium salts are more attractive for anion detection
than the original triazole compound.[30f] This prompted us
to investigate the anion recognition behavior of tris-triazol-
ium tripods 20a–20c. These compounds were prepared in
two steps: iodomethylation of 13, 16, or 17 by CH3I with
subsequent anion exchange of 19a–19c with AgBF4
(Scheme 8).
The fluoride anion binding properties were investigated
for triazolium salts with different positions for the cholane
residue – [3α-, 3β- or in a 3α-triazolylacetoxy group (com-
pounds 20a–20c)]. Complexation was examined by moni-
toring the 1H NMR spectral changes that resulted from ad-
dition of tetrabutylammonium fluoride to a CDCl3 solution
of tripod. Upon addition of aliquots of a solution of
Bu4NF, significant downfield shifts were observed for the
C–H protons of the triazolium groups, which suggests inter-
action between the anion and triazolium C(5) protons
through a C–H···F– hydrogen bond (Figure 1). Moreover,
Figure 1. NMR titration of 20b with Bu4NF.
The observed 1:2 composition of the complexes seems to
the strong downfield shift observed for the NH group indi- be quite unexpected for the triple-charged cation. However,
cates their participation in hydrogen bonding with anions. similar 1:2 complexes were described for analogous neutral
A Job’s plot analysis showed the formation of 1:2 mol ratio phosphoramide-based receptors.[35a] The high association
(tripod to fluoride) complexes in all cases. The association constants and NMR spectroscopic data suggest chelate
constants were calculated by using WinEQNMR software binding of F– with both N–H and triazolium C–H bonds
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Synthesis and Properties of Bile Acid Derived Tripodal Ligands
Table 1. Binding properties of 20a–20c to F– in CDCl3.
Table 2. Anion-binding properties of 20b in CDCl3.
Receptor
K, m–2
(3.7Ϯ0.7)ϫ104
(1.9Ϯ0.1)ϫ105
(9.7Ϯ0.3)ϫ104
Composition
Anion
F–
K, m–2
Composition
20a
20b
20c
1:2
1:2
1:2
(1.9Ϯ0.1)ϫ105
(6.8Ϯ0.7)ϫ104
(6.6Ϯ0.7)ϫ104
(3.9Ϯ0.6)ϫ104
(3.1Ϯ0.6)ϫ104
(2.7Ϯ0.3)ϫ104
(2.7Ϯ0.5)ϫ104
(1.8Ϯ0.3)ϫ104
55Ϯ3
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:1
–
HSO4
PhCOO–
Cl–
Br–
CH3COO–
–
H2PO4
of tripods 20a–20c. The observed stoichiometry is likely due
to coordination of two anions from opposite sides of the
phosphoramide moiety (Scheme 9). The coordination of the
third equivalent of F– is unfavorable because of charge re-
pulsion with another anion on the same side.
I–
ClO4
–
Conclusions
We proposed a convenient protocol based on CuAAC
reactions for the preparation of a phosphorus-centered
pincer and tripodal derivatives with bile acid derived tenta-
cles. Binding of the triple-charged triazolium tripods with
anions in CDCl3 afforded 1:2 complexes with single-
–
charged anions except for ClO4 . The different facial orien-
tation of cholane residues and the additional acetoxy linker
in the ligands obtained were found to exert a negligible ef-
fect on the binding affinity of the ligands. The binding con-
stants, as expected, decreased from F– (1.9ϫ105 m–2) to I–
(1.8ϫ104 m–2). However, rather high binding constants with
oxoanions with delocalized negative charge were measured.
Overall, binding constants measured decrease along the
–
series: F– Ͼ HSO4 Ն PhCOO– Ͼ Cl– Ͼ Br– Ͼ AcO– Ͼ
Scheme 9. Possible coordination mode of tripods 20a–20c with
anions.
–
–
H2PO4 Ͼ I– ϾϾ ClO4 .
Compound 20b was found to be moderately selective for
binding fluoride ions relative to other halide anions. The
observed binding trend F– Ͼ Cl– Ͼ Br– Ͼ I– (Table 2) was
expected: the very high binding ability of fluorine anions is
well documented.[44] The higher selectivity of this receptor
toward fluoride ions is obviously related to the smaller ion-
radius and higher charge-density of the anion in spite of its
hydration. The increase in binding constants for oxoanions
with delocalized negative charge was observed for other
anion-binding receptors,[35a] and is likely to be associated
with coordination of ligands with two or more oxygen
atoms on the anion. The preferential binding of perchlorate
anion with respect to tetrafluoroborate anion, which serves
as an initial counterion for the cationic ligand deserves
mention, as commonly both these anions are regarded as
extremely weak bases and nucleophiles, and both possess
the same tetrahedral structure with the charge equally delo-
Experimental Section
General Information: The 1H NMR (400 MHz), 13C NMR
(100.6 MHz), and 31P NMR (161.9 MHz) spectra were recorded
with a Bruker Avance 400 spectrometer and an Agilent 400MR
spectrometer at ambient temperature in CDCl3 and [D6]DMSO.
Chemical shifts are referenced to hexamethyldisiloxane (δ =
1
0.05 ppm) in the H NMR spectra and to the solvent signal in the
1
13C NMR spectra. H NMR spectroscopic data are presented for
key protons only in the steroid-containing substrates. MALDI-
TOF spectra were recorded with a Bruker Daltonics UltraFlex in-
strument in dithranol matrix with PEG 1500 as internal standard.
Elemental analyses were performed with an Elementar Vario
MICRO cube apparatus. Column chromatographic separations
were carried out on Macherey–Nagel silica gel 60 (0.040–
0.063 mm). NMR titrations were performed by adding aliquots of
the corresponding tetrabutylammonium salts solutions (0.01–0.1 m)
to a solution of ligand (0.01 m) in CDCl3.
calized between four terminal atoms. However, apart from Prop-2-yn-1-yl Diphenylphosphinate (1a): This compound was pre-
pared[39c] from diphenylphosphinic acid chloride (1.186 g, 5 mmol)
these apparent similarities, the perchlorate anion is signifi-
and propargyl alcohol (0.3 mL, 5 mmol). The product was purified
cantly more nucleophilic, most probably a result of the
by column chromatography (CH2Cl2/CH3OH, 50:1) to give title
higher polarizability of the oxygen atom relative to fluorine,
which is extensively documented in various areas of physi-
compound 1a (0.866 g, 68%) as a colorless oil, which rapidly crys-
tallized, m.p. 59–62 °C. 1H NMR (400 MHz, CDCl3): δ = 7.90–
cal organic chemistry, e.g. the so-called specific salt ef-
7.38 [m, 10 H, CH(Ar)], 4.68 (dd, J = 8.3, 2.4 Hz, 2 H, CH2), 2.46
fect.[45]
(t, J = 2.4 Hz, 1 H, CH) ppm. 13C NMR (100 MHz, CDCl3): δ =
Thus, the tricationic anion receptors based on phos-
phorus amide derivatives show moderate selectivity but very
high association constants with anions, especially with
132.5 [CH(Ar)], 131.7 [d, J = 11.0 Hz, CH(Ar)], 130.8 [d, J =
136.6 Hz, C(Ar)-P], 128.6 [d, J = 13.5 Hz, CH(Ar)], 78.0 (d, J =
9.3 Hz, –Cϵ), 75.7 (CH), 52.3 (CH2) ppm. 31P NMR (161.9 MHz,
fluoride, hydrosulfate, and benzoate, to give 1:2 complexes. CDCl3): δ = 34.2 ppm.
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Diprop-2-yn-1-yl Phenylphosphonate (1b): This compound was pre-
pared[39b] from phenylphosphonic acid dichloride (1.375 g, 7 mmol)
and propargyl alcohol (0.9 mL, 15.5 mmol). The product was iso-
lated as described for 1a, yield 1.487 g (90%), yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 7.90–7.79 (m, 2 H, Ar), 7.61–7.54 (m, 1 H,
Ar), 7.52–7.42 (m, 2 H, Ar), 4.81–4.65 (m, 4 H, CH2), 2.52 (t, J =
2.5 Hz, 2 H, CH) ppm. 13C NMR (100 MHz, CDCl3): δ = 133.0
[CH(Ar)], 131.8 [d, J = 11.0 Hz, CH(Ar)], 128.5 [d, J = 15.2 Hz,
CH(Ar)], 126.7 [d, J = 193.0 Hz, C(Ar)-P], 77.6 (d, J = 6.8 Hz,
–Cϵ), 75.9 (2CH), 53.6 (CH2) ppm. 31P NMR (161.9 MHz,
CDCl3): δ = 21.1 ppm.
2.5 Hz, 3 H, CH) ppm. 13C NMR (100 MHz, CDCl3): δ = 82.0
(–Cϵ), 71.3 (CH), 30.5 (CH2) ppm. 31P NMR (161.9 MHz,
CDCl3): δ = 15.6 ppm.
Methyl 3α-(Azidoacetoxy)-5β-cholan-24-oate (6): A suspension of
methyl lithocholate (4 g, 10.3 mmol), calcium oxide (0.862 g,
15.4 mmol) and chloroacetic anhydride (1.916 g, 11.27 mmol) was
stirred overnight. After, chloroacetic anhydride (0.348 g, 2 mmol)
was added and stirring was continued for an additional 24 h. The
reaction mixture was quenched by addition of 10% HCl, the or-
ganic layer was washed with satd. NaHCO3 (3 ϫ 50 mL) and water
(3ϫ50 mL). The organic layer was dried with Na2SO4 and the sol-
vents evaporated. The residue was purified by column chromatog-
raphy (CH2Cl2/hexanes, 1:1) to give a white powder, yield 3.852 g
(80%). 1H NMR (400 MHz, CDCl3): δ = 4.83 (tt, J = 11.3, 4.6 Hz,
1 H, 3-CH), 3.82 (s, 2 H, ClCH2CO), 3.65 (s, 3 H, COOCH3), 0.92
Triprop-2-yn-1-yl Phosphate (1c): This compound was prepared[39a]
from propargyl alcohol (11.37 g, 0.203 mol) and POCl3 (6.3 mL,
0.067 mol), yield 4.83 g (34%), yellow oil; b.p. 112–115 °C, 0.1 mm.
1
Hg. H NMR (400 MHz, CDCl3): δ = 4.72 (m, 6 H, CH2), 2.61 (t,
J = 2.5 Hz, 3 H, CH) ppm. 13C NMR (100 MHz, CDCl3): δ = (s, 3 H, 19-CH3), 0.90 (d, J = 6.4 Hz, 21-CH3), 0.63 (s, 3 H, 18-
76.9 (–Cϵ), 76.5 (CH), 55.6 (CH2) ppm. 31P NMR (161.9 MHz, CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.7 (COOCH3),
CDCl3): δ = –1.17 ppm.
167.7 (COCH2Cl), 76.4, 56.4, 56.0, 51.4, 42.7, 41.9, 41.2, 40.4, 40.1,
35.7, 35.3, 34.9, 34.5, 32.0, 31.0, 31.0, 28.1, 27.0, 26.4, 26.3, 24.1,
23.3, 20.8, 18.2, 12.0 ppm. Methyl 3α-(chloroacetoxy)-5β-cholan-
24-oate (3.802 g, 8.14 mmol) was dissolved in DMSO (30 mL) and
sodium azide (0.794 g, 12.21 mmol) added. The mixture was stirred
for 24 h at 60 °C, diluted with CH2Cl2 (100 mL) and washed with
water (5ϫ100 mL). The organic layer was dried with Na2SO4 and
the solvents evaporated. The obtained product was purified by col-
umn chromatography (CH2Cl2/hexanes, 1:1) to give a white solid,
yield 3.007 g (76%), m.p. 105–106 °C. 1H NMR (400 MHz,
CDCl3): δ = 4.83 (tt, J = 11.4, 4.7 Hz, 1 H, 3-CH), 3.82 (s, 2 H,
N3CH2CO), 3.65 (s, 3 H, COOCH3), 0.92 (s, 3 H, 19-CH3), 0.90
(d, J = 6.4 Hz, 3 H, 21-CH3), 0.63 (s, 3 H, 18-CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 174.7 (COOCH3), 167.7 (COCH2N3), 76.4,
56.4, 56.0, 51.4, 50.6, 42.7, 41.9, 40.4, 40.1, 35.8, 35.3, 34.9, 34.5,
32.1, 31.0, 31.0, 28.1, 26.9, 26.6, 26.3, 24.1, 23.3, 20.8, 18.2,
12.0 ppm.
N-Prop-2-yn-1-yl-P,P-diphenylphosphinic Amide (2a): A mixture of
propargylamine (0.4 mL, 6.23 mmol) and triethylamine (1.58 mL,
11.3 mmol) in dry CH2Cl2 (10 mL) was cooled to 0 °C. To this
mixture a solution of diphenylphosphinic acid chloride (1.335 g,
5.66 mmol) in dry CH2Cl2 (10 mL) was added dropwise and the
reaction mixture was stirred overnight at room temp. Then, the
solvent was removed in vacuo and the product was purified by
column chromatography (CH2Cl2/CH3OH, 20:1) to give a white
powder, yield 0.924 g (64%), m.p. 115–117 °C. C15H14NOP
(255.26): calcd. C 70.58, H 5.53, N 5.49; found C 70.40, H 5.55, N
5.50. 1H NMR (400 MHz, CDCl3): δ = 7.96–7.86 (m, 4 H, Ar),
7.55–7.39 (m, 6 H, Ar), 3.78–3.70 (m, 2 H, CH2), 3.28–3.15 (m, 1
H, NH), 2.26 (t, J = 2.4 Hz, 1 H, CH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 132.2 [CH(Ar)], 132.1 [CH(Ar)], 131.6 [d, J =
129.0 Hz, C(Ar)-P], 128.6 [d, J = 12.6 Hz, CH(Ar)], 81.3 [d, J =
10.1 Hz, C(prop)], 71.7 (CH), 30.1 (CH2) ppm. 31P NMR
(161.9 MHz, CDCl3): δ = 24.5 ppm.
General Procedure A for the Synthesis of Monotriazolyl Click Ad-
ducts: Propargyl diphenylphosphinate (0.2 mmol), corresponding
azidocholane derivative (0.2 mmol), CuSO4·5H2O (10 mol-%) and
sodium ascorbate (40 mol-%) were stirred under Ar for 15 min at
room temp. in a THF/H2O mixture (4:1, 1 mL). The obtained solu-
tion was diluted with CH2Cl2 (100 mL), washed with water
(3ϫ50 mL), dried with Na2SO4 and the solvents evaporated. The
product was purified by column chromatography (CH2Cl2/MeOH,
20:1).
N,NЈ-Diprop-2-yn-1-yl-P-phenylphosphonic Diamide (2b): A mix-
ture of propargylamine (0.93 mL, 14.5 mmol) and triethylamine
(3.85 mL, 27.6 mmol) in dry CH2Cl2 (10 mL) was cooled to 0 °C.
To this mixture a solution of phenylphosphonic acid dichloride
(1.345 g, 6.9 mmol) in dry CH2Cl2 (10 mL) was added dropwise
and the reaction mixture was stirred overnight at room temp. Then,
the solvent was removed in vacuo and the residue was purified by
column chromatography (CH2Cl2/CH3OH, 20:1) to give yellowish
crystals, yield 1.169 g (73%), m.p. 83–85 °C. C12H13N2OP (232.22): (1-[3α-Hydroxy-5β-cholan-24-yl]-1H-1,2,3-triazol-4-yl)-methyl-
calcd. C 62.07, H 5.64, N 12.06; found C 62.41, H 5.79, N 12.14.
diphenylphosphinate (8): Yield 75%, white powder. C39H54N3O3P
(643.85): calcd. C 72.75, H 8.45, N 6.53; found C 72.50, H 8.28, N
1H NMR (400 MHz, CDCl3): δ = 7.91–7.81 [m, 2 H, CH(Ar)],
7.57–7.40 [m, 3 H, CH(Ar)], 3.90–3.68 (m, 4 H, CH2), 3.05–2.90 6.48. 1H NMR (400 MHz, CDCl3): δ = 7.86–7.76 (m, 4 H, Ar),
(m, 2 H, NH), 2.20 (t, J = 2.53 Hz, 2 H, CH) ppm. 13C NMR 7.62 [s, 1 H, CH(triaz)], 7.54–7.47 (m, 2 H, Ar), 7.46–7.39 (m, 4 H,
(100 MHz, CDCl3): δ = 132.0 [CH(Ar)], 131.7 [d, J = 10.1 Hz,
CH(Ar)], 131.2 [d, J = 144.1 Hz, C(Ar)-P], 128.4 [d, J = 13.5 Hz,
CH(Ar)], 81.5 [d, J = 6.8 Hz, C(prop.)], 71.4 [CH(prop.)], 30.1
[CH2(prop)] ppm. 31P NMR (161.9 MHz, CDCl3): δ = 20.1 ppm.
Ar), 5.19 (d, J = 9.1 Hz, 2 H, POCH2), 4.31–4.17 (m, 2 H, 24-
CH2), 3.60 (tt, J = 11.0, 4.6 Hz, 1 H, 3-CH), 0.91–0.86 (m, 6 H, 21-
CH3+19-CH3), 0.61 (s, 3 H, 18-CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 143.4 [C(triaz)], 132.2 [CH(Ar)], 131.6 [d, J = 11 Hz,
CH(Ar)], 131.1 [d, J = 135.7 Hz, C(Ar)-P], 128.5 [d, J = 12.7 Hz,
CH(Ar)], 123.5 [CH(triaz)], 71.6 (3-CH), 58.1 (d, J = 5.1 Hz,
POCH2), 56.4, 55.8, 50.7, 42.6, 42.0, 40.3, 40.1, 36.3, 35.7, 35.3,
35.2, 34.5, 32.5, 30.4, 28.1, 27.1, 26.8, 26.3, 24.1, 23.3, 20.7, 18.5,
11.9 ppm. 31P NMR (161.9 MHz, CDCl3): δ = 33.3 ppm.
N,NЈ,NЈЈ-Triprop-2-yn-1-ylphosphoric Triamide (2c): A mixture of
propargylamine (2.17 mL, 33.9 mmol) and triethylamine (9.14 mL,
65.5 mmol) in dry CH2Cl2 (10 mL) was cooled to 0 °C. Phosphoryl
chloride (1 mL, 10.9 mmol) in dry CH2Cl2 (10 mL) was added
dropwise and mixture was stirred overnight. The solvent was re-
moved in vacuo and the residue was purified by column
chromatography (CH2Cl2/CH3OH, 10:1) to give a dark yellow oil,
yield 1.33 g (58%). C9H12N3OP (209.19): calcd. C 51.68, H 5.78,
Methyl (3β,7α,12α)-3-(4-[Diphenylphosphoryloxymethyl]-1H-1,2,3-
triazol-1-yl)-7,12-dihydroxy-5β-cholan-24-oate (9): Yield 71 %,
white powder. C40H54N3O6P (703.86): calcd. C 68.26, H 7.73, N
N 20.09; found C 51.62, H 5.81, N 20.19. 1H NMR (400 MHz, 5.97; found C 68.19, H 7.77, N 5.82. 1H NMR (400 MHz, CDCl3):
CDCl3): δ = 3.76 (m, 6 H, CH2), 3.13 (m, 3 H, NH), 2.27 (t, J = δ = 7.85–7.76 (m, 4 H, Ar), 7.62 [s, 1 H, CH(triaz)], 7.53–7.46 (m,
6294
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Eur. J. Org. Chem. 2015, 6289–6297

Synthesis and Properties of Bile Acid Derived Tripodal Ligands
2 H, Ar), 7.46–7.38 (m, 4 H, Ar), 5.21 (d, 2 H, POCH2), 4.51 (br. = 5.9 Hz, C(triaz)], 131.3 [d, J = 9.3 Hz, CH(Ar)], 130.8 [CH(Ar)],
s, 1 H, 3-CH), 4.00 (br. s, 1 H, 12-CH), 3.87 (br. s, 1 H, 7-CH),
3.65 (s, 3 H, COOCH3), 2.91 (td, J = 13.7, 4.6 Hz, 1 H, 4-CH),
0.97 (d, J = 6.3 Hz, 3 H, 21-CH3), 0.85 (s, 3 H, 19-CH3), 0.69
(s, 3 H, 18-CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.7
(COOCH3), 142.8 [C(triaz)], 132.3 [CH(Ar)], 131.6 [d, J = 10.1 Hz,
CH(Ar)], 131.1 [d, J = 137.4 Hz, C(Ar)-P], 128.5 [d, J = 12.7 Hz,
CH(Ar)], 123.1 [CH(triaz)], 72.8, 68.1, 58.1 (d, J = 4.2 Hz,
POCH2), 56.8, 51.5, 47.2, 46.5, 41.8, 39.4, 36.7, 35.1, 34.8, 33.9,
32.4, 31.0, 30.8, 30.5, 28.4, 27.4, 26.6, 24.7, 23.2, 22.7, 17.3,
12.5 ppm. 31P NMR (161.9 MHz, CDCl3): δ = 33.3 ppm.
127.9 [d, J = 12.7 Hz, CH(Ar)], 121.8 [CH(triaz)], 55.9, 55.6, 55.5,
51.2, 42.3, 36.8, 35.7, 35.2, 34.8, 34.3, 30.6, 30.4, 30.3, 29.2, 27.7,
26.1, 25.7, 24.3, 23.8, 23.6, 20.6, 18.1, 11.8 ppm. 31P NMR
(161.9 MHz, [D6]DMSO): δ = 20.6 ppm.
Trimethyl (3β,3Јβ,3ЈЈβ)-3,3Ј,3ЈЈ-[Phosphoryl-tris(iminomethylene-
1H-1,2,3-triazole-4,1-diyl)]tris(5β-cholan-24-oate) (13): Procedure
B, yield 64 %, white solid. C84H135N12O7P (1456.04): calcd. C
1
69.29, H 9.35, N 11.54; found C 69.12, H 9.13, N 11.35. H NMR
(400 MHz, CDCl3): δ = 7.62 [s, 3 H, CH(triaz)], 4.61 (br. s, 3 H,
3-CH), 4.28–4.16 (m, 6 H, NHCH2), 3.65 (s, 9 H, COOCH3), 3.56
(br. s, 3 H, PONH), 0.90 (d, J = 6.4 Hz, 9 H, 21-CH3), 0.87 (s, 9
H, 19-CH3), 0.64 (s, 9 H, 18-CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 174.7 (COOCH3), 146.8 [C(triaz)], 120.7 [CH(triaz)],
56.6, 56.5, 56.0, 51.5 (OCH3), 42.7, 40.4, 40.1, 37.2, 36.6, 35.6, 35.3,
34.7, 31.0, 30.9, 30.6, 29.8, 28.1, 26.4, 26.1, 24.8, 24.1, 23.7, 20.9,
18.2, 12.0 ppm. 31P NMR (161.9 MHz, CDCl3): δ = 15.8 ppm.
General Procedure B for the Synthesis of Pincer and Tripodal Chol-
anetriazolyl Derivatives: N,NЈ-dipropargylamide of phenylphos-
phonic acid (0.22 mmol) or tripropargylphosphamide (0.12 mmol),
corresponding azidocholane derivative (2.15 or 3.25 equiv.),
CuSO4·5H2O (10 mol-%) and sodium ascorbate (40 mol-%) were
mixed in an evacuated and argon-filled tube. To the mixture THF/
H2O (4:1, 1 mL) was added and the reaction tube heated at 60 °C
overnight. Next, the reaction mixture was diluted with CH2Cl2
(100 mL), washed with water (3ϫ50 mL), dried with Na2SO4, and
solvent was removed on a rotary evaporator. The resulting solid
was purified by column chromatography (CH2Cl2/CH3OH, 20:1)
to afford 10, 11, and 13.
Trimethyl (3β,3Јβ,3ЈЈβ)-3,3Ј,3ЈЈ-[Phosphoryl-tris(iminomethylene-
1H-1,2,3-triazole-4,1-diyl)]tris(12α-hydroxy-5β-cholan-24-oate)
(14): Procedure C, yield 61%, white solid. 1H NMR (400 MHz,
[D6]DMSO): δ = 7.97 [s, 3 H, CH(triaz)], 4.63 (br. s, 3 H, 3-CH),
4.47–4.36 (m, 3 H, NHCH2), 4.21 (d, J = 3.4 Hz, 3 H, 12-OH),
4.00–3.90 (m, 6 H, NHCH2), 3.78 (br. s, 3 H, 12-CH), 3.56 (s, 9 H,
COOCH3), 0.90 (d, J = 6.2 Hz, 9 H, 21-CH3), 0.78 (s, 9 H, 19-
CH3), 0.59 (s, 9 H, 18-CH3) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 174.2 (COOCH3), 147.7 [C(triaz)], 122.1 [CH(triaz)],
71.5, 56.1, 51.6, 47.9, 46.6, 46.5, 37.3, 36.8, 35.9, 35.4, 34.3, 33.1,
31.2, 30.9, 30.9, 29.8, 29.1, 27.6, 26.6, 26.1, 24.7, 23.9, 23.8, 17.4,
12.9 ppm. 31P NMR (161.9 MHz, [D6]DMSO): δ = 16.7 ppm.
HRMS (MALDI-TOF): calcd. for C84H135N12O10P [M + Na]+
1526.0059; found 1526.0055.
General Procedure (C) for the Synthesis of Pincer and Tripodal
Cholanetriazolyl Derivatives: N,NЈ-dipropargylamide of phenyl-
phosphonic acid (0.22 mmol) or tripropargylphosphamide
(0.12 mmol), corresponding azidocholane derivative (2.15 or
3.25 equiv.), Cu(OAc)2·H2O (5 mol-%), TBTA (5 mol-%) and so-
dium ascorbate (40 mol-%) were mixed in an evacuated and argon-
filled tube. To the mixture THF/H2O (4:1, 1 mL) was added and
the reaction was stirred overnight at room temp. Next, the reaction
mixture was diluted with CH2Cl2 (100 mL), washed with water
(3ϫ50 mL), dried with Na2SO4 and the solvent was removed on
a rotary evaporator. The resulting solid was purified by column
chromatography (CH2Cl2/CH3OH, 20:1) to afford 14–18.
Trimethyl (3β,3Јβ,3ЈЈβ)-3,3Ј,3ЈЈ-[Phosphoryl-tris(iminomethylene-
1H-1,2,3-triazole-4,1-diyl)]tris(7α,12α-dihydroxy-5β-cholan-24-oate)
(15): Procedure C, yield 65 %, white solid. C84H135N12O13
P
(1552.04): calcd. C 65.01, H 8.77, N 10.83; found C 64.72, H 8.79,
N 10.61. 1H NMR (400 MHz, [D6]DMSO): δ = 7.93 [s, 3 H,
CH(triaz)], 4.53 (br. s, 3 H, 3-CH), 4.47–4.38 (m, 3 H, NHCH2),
4.21 (d, J = 3.4 Hz, 3 H, OH), 4.16 (d, J = 3.3 Hz, 3 H, OH), 4.00–
3.90 (m, 6 H, NHCH2), 3.78 (br. s, 3 H, 12-CH), 3.62 (br. s, 3 H,
7-CH), 3.56 (s, 9 H, COOCH3), 2.98–2.85 (m, 3 H, 4-CH), 0.91 (d,
J = 6.1 Hz, 9 H, 21-CH3), 0.73 (s, 9 H, 19-CH3), 0.57 (s, 9 H, 18-
CH3 ) ppm. 1 3C NMR (100 MHz, [D6 ]DMSO): δ = 173.8
(COOCH3), 147.2 [d, J = 6.9 Hz, C(triaz)], 121.5 [CH(triaz)], 71.0,
66.2, 55.7, 51.2, 51.2, 46.0, 45.8, 41.3, 39.4, 36.8, 36.3, 35.0, 34.4,
34.0, 32.1, 30.7, 30.4, 28.6, 27.2, 26.1, 24.3, 22.9, 22.7, 16.9,
12.3 ppm. 31P NMR (161.9 MHz, [D6]DMSO): δ = 16.4 ppm.
N,NЈ-Bis({1-[(3α,7α,12α)-3,7,12-trihydroxy-5β-cholan-24-yl]-1H-
1,2,3-triazol-4-yl}methyl)-P-phenylphosphonic Diamide (10): Pro-
cedure B, yield 80%, white solid. C60H95N8O7P (1071.43): calcd. C
1
67.26, H 8.94, N 10.46; found C 67.12, H 9.12, N 10.30. H NMR
(400 MHz, [D6]DMSO): δ = 7.80 [d, J = 2.1 Hz, 2 H, CH(triaz)],
7.77–7.70 (m, 2 H, Ar), 7.52–7.45 (m, 1 H, Ar), 7.45–7.37 (m, 2 H,
Ar), 5.05–4.94 (m, 2 H, PONH), 4.31 (d, J = 4.2 Hz, 2 H, OH),
4.27–4.16 (m, 4 H, NHCH2), 4.10 (d, J = 3.2 Hz, 2 H, OH), 4.04–
3.96 (m, 6 H, 24-CH2, OH), 3.76 (br. s, 2 H, 12-CH), 3.59 (br. s, 2
H, 7-CH), 3.15 (m, 2 H, 3-CH), 0.91 (d, J = 6.3 Hz, 6 H, 21-
CH3), 0.79 (s, 6 H, 19-CH3), 0.57 (s, 6 H, 18-CH3) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 147.2 [d, J = 5.9 Hz, C(triaz)], 131.3
[d, J = 9.3 Hz, CH(Ar)], 130.9 [CH(Ar)], 127.9 [d, J = 12.6 Hz,
CH(Ar)], 122.4 [CH(triaz)], 71.0, 70.4, 66.2, 49.7, 46.0, 45.7, 41.5,
41.3, 35.6, 35.3, 34.9, 34.4, 32.2, 30.4, 28.5, 27.3, 26.6, 26.2, 22.8,
22.6, 17.2, 12.3 ppm. 31P NMR (161.9 MHz, [D6]DMSO): δ =
19.8 ppm.
Trimethyl (3α,3Јα,3ЈЈα)-3,3Ј,3ЈЈ-[Phosphoryl-tris(iminomethylene-
1H-1,2,3-triazole-4,1-diyl)]tris(5β-cholan-24-oate) (16): Procedure
C, yield 77 %, white solid. C84H135N12O7P (1456.04): calcd. C
1
69.29, H 9.35, N 11.54; found C 69.26, H 9.07, N 11.47. H NMR
(400 MHz, CDCl3): δ = 7.56 [s, 3 H, CH(triaz)], 4.38 (td, J = 11.1,
4.5 Hz, 3 H, 3-CH), 4.28–4.12 (m, 6 H, NHCH2), 3.65 (s, 9 H,
COOCH3), 3.47 (broad s, 3 H, PONH), 0.99 (s, 9 H, 19-CH3), 0.90
(d, J = 6.4 Hz, 9 H, 21-CH3), 0.64 (s, 9 H, 18-CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 174.6 (COOCH3), 146.7 [C(triaz)], 119.5
[CH(triaz)], 61.0 (3-C), 56.2, 55.9, 51.4 (COOCH3), 42.7, 40.5, 39.9,
36.7, 35.8, 35.8, 35.3, 34.7, 34.0, 31.0, 30.9, 28.1, 28.0, 27.0, 26.2,
24.1, 23.4, 20.9, 18.2, 12.0 ppm. 31P NMR (161.9 MHz, CDCl3): δ
= 15.8 ppm.
Dimethyl (3β,3Јβ)-3,3Ј-[(Phenylphosphoryl)bis(iminomethylene-1H-
1,2,3-triazol-4,1-diyl)]bis(5β-cholan-24-oate) (11): Procedure B,
yield 88%, white solid. C62H95N8O5P (1063.46): calcd. C 70.02, H
9.00, N 10.54; found C 70.08, H 9.05, N 10.16. 1H NMR
(400 MHz, [D6]DMSO): δ = 7.85 [d, J = 2.8 Hz, 2 H, CH(triaz)],
7.77–7.69 (m, 2 H, Ar), 7.50–7.44 (m, 1 H, Ar), 7.43–7.36 (m, 2 H,
Ar), 5.05–4.96 (m, 2 H, PONH), 4.59 (br. s, 2 H, 3-CH), 4.05–3.96
(m, 4 H, NHCH2), 3.56 (s, 6 H, COOCH3), 0.86 (d, J = 6.4 Hz, 6 Trimethyl (3α,3Јα,3ЈЈα)-3,3Ј,3ЈЈ-{Phosphoryl-tris[iminomethylene-
H, 21-CH3), 0.82 (s, 6 H, 19-CH3), 0.61 (s, 6 H, 18-CH3) ppm. 13C 1H-1,2,3-triazole-4,1-diyl(2-oxoethane-2,1-diyl)oxy]}tris(5β-cholan-
NMR (100 MHz, [D6]DMSO): δ = 173.7 (COOCH3), 147.0 [d, J 24-oate) (17): Procedure C, yield 66%, white solid. C90H141N12O13P
Eur. J. Org. Chem. 2015, 6289–6297
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6295

N. V. Lukashev et al.
FULL PAPER
(1630.15): calcd. C 66.31, H 8.72, N 10.31; found C 66.55, H 8.79,
(161.9 MHz, CDCl3): δ = 17.2 ppm. HRMS (MALDI-TOF): calcd.
N 10.15. 1H NMR (400 MHz, CDCl3): δ = 7.68 [br. s, 3 H, for C93H150B2F8N12O13P [M – BF4]+ 1848.2171; found 1848.1225.
CH(triaz)], 5.07 (s, 6 H, NCH2CO), 4.78 (td, J = 11.1, 4.2 Hz, 3
H, 3-CH), 4.16 (br. s, 6 H, NHCH2), 3.65 (s, 9 H, COOCH3), 0.93–
0.88 (m, 18 H, 21-CH3, 19-CH3), 0.63 (s, 9 H, 18-CH3) ppm. 13C
NMR (100 MHz, CDCl3 ): δ = 173.6 (COOCH3 ), 166.7
(NCH2COO), 147.9 [C(triaz)], 124.1 [CH(triaz)], 75.4 (3-C), 55.8,
55.4, 51.1, 50.3, 42.2, 41.1, 39.8, 36.2, 35.3, 34.7, 34.3, 34.1, 31.7,
30.6, 30.3, 27.6, 26.5, 26.1, 25.9, 23.8, 22.9, 20.4, 18.0, 11.8 ppm.
31P NMR (161.9 MHz, CDCl3): δ = 15.9 ppm.
Acknowledgments
This work was supported by the Russian Foundation for Basic Re-
search (grant number 11-03-00265-a) and by the M. V. Lomonosov
Moscow State University (Program of Development).
N,NЈ,NЈЈ-Tris-{[1-(3α-hydroxy-5β-cholan-24-yl)-1H-1,2,3-triazol-4-
yl]methyl}phosphoramide (18): Procedure C, yield 63%, white solid.
1H NMR (400 MHz, CDCl3): δ = 7.61 [s, 3 H, CH(triaz)], 4.31–
4.18 (m, 6 H, NHCH2), 4.18–4.06 (m, 6 H, 24-CH2), 3.88–3.71 (m,
3 H, NH), 3.65–3.52 (m, 3 H, 3-CH), 0.92–0.84 (m, 18 H, 21-CH3,
19-CH3), 0.61 (br. s, 9 H, 18-CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ = 147.1 [C(triaz)], 121.6 [CH(triaz)], 71.4, 56.3, 55.9,
50.6, 42.6, 42.0, 40.3, 40.0, 36.3 (2 C), 35.7, 35.2 (2 C), 34.5, 32.6,
30.4, 28.2, 27.1, 27.0, 26.3, 24.1, 23.3, 20.7, 18.5, 11.9 ppm. 31P
NMR (161.9 MHz, CDCl3): δ = 16.2 ppm. HRMS (MALDI–
TOF): calcd. for C81H135N12O4P [M + Na]+ 1394.0365; found
1394.0339.
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Trimethyl (3α,3Јα,3ЈЈα)-3,3Ј,3ЈЈ-[Phosphoryl-tris(iminomethylene-3-
methyl-1H-1,2,3-triazolium-4,1-diyl)]tris(5β-cholan-24-oate) Tris-
(tetrafluoroborate) (20a): Yield 97 %, white powder. 1H NMR
(400 MHz, CDCl3): δ = 8.53 [br. s, 3 H, CH(triaz)], 4.85–4.35 (m,
9 H, 3-CH, CH2NH), 4.22 (s, 9 H, NCH3), 3.65 (s, 9 H, COOCH3),
0.97 (s, 9 H, 19-CH3), 0.91 (d, J = 5.7 Hz, 9 H, 21-CH3), 0.64 (s,
9 H, 18-CH3 ) ppm. HRMS (MALDI-TOF): calcd. for
C87H144B2F8N12O7P [M – BF4]+ 1674.1061; found 1674.2464.
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Trimethyl (3β,3Јβ,3ЈЈβ)-3,3Ј,3ЈЈ-[Phosphoryl-tris(iminomethylene-3-
methyl-1H-1,2,3-triazolium-4,1-diyl)]tris(5β-cholan-24-oate) Tris-
(tetrafluoroborate) (20b): Yield 98 %, white powder. 1H NMR
(400 MHz, CDCl3): δ = 8.48 [s, 3 H, CH(triaz)], 4.85 (br. s, 3 H,
3-CH), 4.60–4.35 (m, 9 H, NHCH2, NHCH2), 4.18 (s, 9 H, NCH3),
3.65 (s, 9 H, COOCH3), 0.90 (br. s, 18 H, 21CH3, 19CH3), 0.63 (s,
9 H, 18CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.7 (CO-
OCH3), 143.5 [C(triaz)], 128.4 [CH(triz)], 61.6 (3-C), 56.5, 56.0,
51.4, 42.7, 40.4, 40.1, 37.8, 36.6, 35.5, 35.4, 34.6, 34.4, 31.1, 31.0,
30.0, 29.7, 28.7, 28.1, 26.0, 24.2, 24.0, 23.4, 21.0, 18.3, 12.0 ppm.
31P NMR (161.9 MHz, CDCl3): δ = 17.4 ppm. HRMS (MALDI-
TOF): calcd. for C87H144B2F8N12O7P [M – BF4]+ 1674.1061; found
1674.1158.
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Trimethyl (3α,3Јα,3ЈЈα)-3,3Ј,3ЈЈ-{Phosphoryl-tris[iminomethylene-3-
methyl-1H-1,2,3-triazole-4,1-diyl(2-oxoethane-2,1-diyl)oxy]}tris-
(5β-cholan-24-oate) Tris(tetrafluoroborate) (20c): 1H NMR
(400 MHz, CDCl3): δ = 8.50 [s, 3 H, CH(triaz)], 5.24 (s, 6 H,
NCH2CO), 4.87–4.65 (m, 6 H, 3-CH, NHCH2), 4.52–4.32 (m, 6 H,
NHCH2), 4.20 (s, 9 H, NCH3), 3.65 (s, 9 H, COOCH3), 0.95–0.86
(m, 18 H, 21-CH3, 19CH3), 0.64 (s, 3 H, 18CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 174.7 (COOCH3), 164.4 (NCH2COO),
144.6 [C(triaz)], 130.4 [CH(triaz)], 77.7 (3-C), 56.3, 55.9, 53.5, 51.4,
42.7, 41.9, 40.4, 40.0, 37.9, 35.7, 35.3, 34.9, 34.5, 34.1, 31.9, 31.0,
30.9, 28.1, 27.0, 26.3, 24.2, 23.3, 20.8, 18.2, 12.0 ppm. 31P NMR
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6289–6297

Synthesis and Properties of Bile Acid Derived Tripodal Ligands
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Received: June 23, 2015
Published Online: August 18, 2015
Eur. J. Org. Chem. 2015, 6289–6297
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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