3
04
T. Pospieszny et al. / Tetrahedron Letters 53 (2012) 301–305
The synthesis of the cholic acid dimer 7 linked by a 1,2,3-tria-
zole ring is shown in Scheme 1. The structure of the oligomeric
compound 8 is shown in Figure 1.
final heat of formation (ꢁ1287.0911 kcal/mol) than cyclic com-
pound (ꢁ664.5813 kcal/mol). Furthermore, the presence of addi-
tional groups –OCHO in positions 7
a and 12a of the steroid ring
Compound 2 was prepared from cholic acid 1 according to the
causes steric hindrance and increases the repulsive interaction
between two steroid units.
1
4
1
literature procedure.
The H NMR spectrum showed three
characteristic signals at 8.02, 8.10, and 8.16 ppm assigned to the
In conclusion, five new compounds, propargyl 7
ormyloxy-3 -hydroxy-5b-cholan-24-oate (4), propargyl 3
roacetoxy-7 ,12 -diformyloxy-5b-cholan-24-oate (5), propargyl
-azidoacetoxy-7 ,12 -diformyloxy-5b-cholan-24-oate (6), di-
mer (7), and tetramer (8) linked by 1,2,3-triazole ring were pre-
a
,12
a-dif-
1
4
–
OCHO groups.
Alcohol 3 was obtained by a selective hydrolysis of the 3
a
a
a-chlo-
a
-
a
OCHO group of compound 2. Our attempts to carry out the reaction
according to the literature procedure failed.14 Carrying out the
hydrolysis in acetone in the presence of 0.2 or 0.1 M NaOH aqueous
solutions led to mixtures containing small amounts of product, but
containing mostly unreacted substrate. Changing the solvent to
methanol and using 0.1 M aqueous NaOH gave compound 3 in high
3a
a
a
1
7,18
pared from cholic acid.
Acknowledgment
1
yield. The H NMR spectrum confirmed the loss of the signal at
This work was supported by the Ministry of Science and Higher
Education (Project No. N N204 166 836).
8
.02 ppm assigned to the 3a-OCHO group and the appearance of
a signal at 3.51 ppm due to the 3b-H proton.
The synthesis of compound 4 presented difficulties as well.
Esterification in the presence of propargyl alcohol and a catalytic
amount of p-toluenesulfonic acid caused hydrolysis of the –OCHO
Supplementary data
1
5
groups. Compound 4 was synthesized in the presence of DCC,
16
DMAP, and propargyl alcohol in good yield. The structure of the
product obtained was confirmed by 1H NMR spectroscopy which
showed two characteristic signals at 2.46 and 4.61 ppm assigned
References and notes
to the –C„CH and –O–CH
Compound 5 was easily obtained from ester 4 in high yield by
reaction with chloroacetyl chloride in the presence of CaH and tri-
2
protons of the propargyl group.
1. (a) Kirson, I.; Glotter, E. J. Nat. Prod. 1981, 44, 633–647; (b) Gao, H.; Dias, J. R.
Org. Prep. Proced. Int. 1999, 32, 145–166; (c) Fetizon, M.; Kakis, F. J.; Ignatiadou-
Ragoussis, V. J. Org. Chem. 1973, 38, 4308–4311; (d) Okamura, W. H.; Midland,
M. M.; Hammond, M. W.; Rahman, N. A.; Dormanen, M. C.; Nemere, I.; Norman,
A. W. J. Steroid Biochem. Mol. Biol. 1995, 53, 603–613.
2
ethylbenzylammonium chloride. The structure of the product was
1
confirmed by H NMR spectroscopy which showed a characteristic
2.
(a) Salunke, D. B.; Hazra, B. G.; Pore, V. S. Curr. Med. Chem. 2006, 13, 813–847;
b) Davis, A. P. Molecules 2007, 12, 2106–2122.
2
signal at 4.03 ppm assigned to the –CH –Cl group.
(
Compound 5 was transformed into azide 6 via a substitution
3.
(a) Willimann, P.; Marti, T.; Fürer, A.; Diederich, F. Chem. Rev. 1997, 97,
1567–1608; (b) Davis, A. P. Chem. Soc. Rev. 1993, 22, 243–253; (c) Li, Y.; Dias, R.
Chem. Rev. 1997, 97, 283–304; (d) Tamminen, J.; Kolehmainen, E. Molecules
1
3
reaction carried out in DMF in the presence of NaN . The H NMR
spectrum showed a signal at 3.85 ppm protons of the –CH
group.
2 3
–N
2001, 6, 21–46.
4
.
.
(a) Gao, H.; Dias, J. R. J. Prakt. Chem. 1997, 339, 187–190; (b) Li, Y. X.; Dias, J. R.
Org. Prep. Proced. Int. 1996, 28, 203–209; (c) Hsieh, H. P.; Muller, J. G.; Burrows,
C. J. J. Am. Chem. Soc. 1994, 116, 12077–12078; (d) Guthrie, J. P.; Cullimore, P. A.;
McDonald, R. S.; O’Leary, S. Can. J. Chem. 1982, 60, 747–764.
(a) Willemen, H. M.; Vermonden, T.; Marcelis, A. T. M.; Sudhölter, E. J. R. Eur. J.
Org. Chem. 2001, 2329–2335; (b) Willemen, H. M.; Vermonden, T.; Marcelis, A.
T. M.; Sudhölter, E. J. R. Langmuir 2002, 18, 7102–7106; (c) Valkonen, A.;
Lahtinen, M.; Virtanen, E.; Kaikkonen, S.; Kolehmainen, E. Biosens. Bioelectron.
Freshly obtained compound 6 was used as a substrate in the
click’ reaction in the presence of CuSO O and sodium ascor-
ꢀ5H
bate. Application of two different mixtures of solvents: t-BuOH/
O (9:1) and DMF/H O (4:1) gave the same results. The mixture
of unreacted substrate 6, acyclic dimer 7 and oligomeric compound
was obtained and separated by column chromatography.
‘
4
2
5
H
2
2
8
2004, 20, 1233–1241.
1
The H NMR spectrum of compound 7 in CDCl
3
showed a char-
6. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 2004–
acteristic, diagnostic singlet at 7.73 ppm assigned to the triazole
ring. Moreover, the spectrum also showed singlets in the range
2021.
7.
(a) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B.
Angew. Chem. Int. Ed. 2005, 44, 3275; (b) Kolb, H. C.; Finn, M. G.; Sharpless, K. B.
Angew. Chem. 2001, 113, 2056.
8
.11–8.18 ppm assigned to the protons of the four –OCHO groups.
Three diagnostic singlets for compound 7 at 3.85, 5.12, and
.22 ppm were assigned to the –CH –N , –CH –C-triazole ring,
and –CH –N-triazole ring. The methylene doublet resonance at
.67 ppm was assigned to the –O–CH
The oligomerization reaction occurred unexpectedly and spon-
taneously at reduced temperature without additional external fac-
8. Tron, G. C.; Pirali, T.; Billington, R. A.; Canonico, P. L.; Sorba, G.; Genazzani, A. A.
Med. Res. Rev. 2008, 28, 278–307.
9. Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2003, 8, 1128–1137.
5
2
3
2
2
1
0. (a) Moses, J. E.; Moorhouse, A. D. Chem. Soc. Rev. 2007, 36, 1249–1262; (b) Wu,
P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel, A.; Voit, B.; Pyun, J.;
Fréchet, J. M. J.; Sharpless, K. B.; Fokin, V. V. Angew. Chem., Int. Ed. 2004, 43,
4
2
.
3928–3932.
1
1. (a) Casas-Solvas, J. M.; Vargas-Berenguel, A.; Capitán-Vallvey, L. F.; Santoyo-
González, F. Org. Lett. 2004, 6, 3687–3690; (b) Chittepu, P.; Sirivolu, V. R.; Seela,
F. Bioorg. Med. Chem. 2008, 16, 8427–8439; (c) Kacprzak, K. M.; Maier, N. M.;
Lindner, W. Tetrahedron Lett. 2006, 47, 8721–8726; (d) Gajewski, M.; Seaver, B.;
Esslinger, C. S. Bioorg. Med. Chem. Lett. 2007, 17, 4163–4166.
1
3
tors. The H NMR spectrum of tetramer 8 in CDCl showed singlets
at 7.73–7.70 ppm assigned to the three protons of the triazole
rings. Moreover, the 8 exhibited singlets in the range 8.17–
8
.08 ppm assigned to the protons of the eight –OCHO groups.
12. (a) Latyshev, G. V.; Baranov, M. S.; Kazantsev, A. V.; Averin, A. D.; Lukashev, N.
V.; Beletskaya, I. P. Synthesis 2009, 2605–2615; (b) Pore, V. S.; Aher, N. G.;
Kumar, M.; Shukla, P. K. Tetrahedron 2006, 62, 11178–11186; (c) Zhang, J.; Luo,
J.; Zhu, X. X.; Junk, M. J. N.; Hinderberger, D. Langmuir 2010, 26, 2958–2962; (d)
Kumar, A.; Pandey, P. S. Org. Lett. 2008, 10, 165–168; (e) Kumar, A.; Chhatra, R.
K.; Pandey, P. S. Org. Lett. 2010, 12, 24–27; (f) Vatmurge, N. S.; Hazra, B. G.;
Pore, V. S.; Shirazi, F.; Deshpande, M. V.; Kadreppa, S.; Chattopadhyay, S.;
The diagnostic singlet at 3.85 ppm and triplet at 2.47 ppm were as-
2 3
signed to the –CH –N and –C„CH protons, respectively.
The 1 C NMR and FT-IR spectra of compounds 4–7 were in
3
agreement with the assigned structures.
PM5 semiempirical calculations were preformed using the
WinMopac 2003 program. Compound 7 can exist in both syn and
anti conformations as shown in Figure 2. In solution the equilibrium
between the two conformers is expected to depend on the polarity
of the solvent. The anti conformer is almost a linear structure. The
final heat of formation for the anti conformer is ꢁ617.9462 kcal/
mol, and that of the syn conformer is ꢁ620.6547 kcal/mol. The olig-
omeric compound 8 is formed preferentially because it has a lower
Borodina, Y. V.; Lagunin, A. A.; Kos, A. J. Chem. Inf. Comput. Sci. 2000, 40, 1349–
1
8
355; (c) Poroikov, V. V.; Filimonov, D. A. J. Comput. Aided Mol. Des. 2003, 16,
19–824; (d) Poroikov, V. V.; Filimonov, D. A. In Predictive Toxicology; Helma,
Christopher, Eds.; Taylor and Francis, 2005; pp 459–478; (e) Stepanchikova, A.
V.; Lagunin, A. A.; Filimonov, D. A.; Poroikov, V. V. Curr. Med. Chem. 2003, 10,
225–233.
14. Tserng, K.-Y.; Klein, P. D. Steroids 1977, 29, 635–648.