A new approach to steroid dimers and macrocycles by the reaction of 3-chlorocarbonyl derivatives of bile acids with O,O-, N,N-, and S,S-dinucleophiles

Article abstract of DOI:10.1016/j.tetlet.2012.08.151

The reaction of 3-chlorocarbonyl derivatives of bile acid esters with O,O-, N,N-, and S,S-dinucleophiles provides a general and efficient entry into steroid dimers with bis-carbamate, bis-carbonate, and bismonothiocarbonate moieties in the linker fragment. The macrocyclization of the bis-carbamate 10 afforded the dimeric and tetrameric cholaphanes, 15 and 16, respectively.

Full text of DOI:10.1016/j.tetlet.2012.08.151

Tetrahedron Letters 53 (2012) 6212–6215
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new approach to steroid dimers and macrocycles by the reaction
of 3-chlorocarbonyl derivatives of bile acids with O,O-, N,N-, and
S,S-dinucleophiles
⇑
Zdzisław Paryzek , Roman Joachimiak, Monika Piasecka, Tomasz Pospieszny
´
Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of 3-chlorocarbonyl derivatives of bile acid esters with O,O-, N,N-, and S,S-dinucleophiles
provides a general and efficient entry into steroid dimers with bis-carbamate, bis-carbonate, and bis-
monothiocarbonate moieties in the linker fragment. The macrocyclization of the bis-carbamate 10 affor-
ded the dimeric and tetrameric cholaphanes, 15 and 16, respectively.
Received 17 July 2012
Revised 17 August 2012
Accepted 31 August 2012
Available online 7 September 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Steroid dimers
Bile acids
Cholaphanes
Chloroformates
Steroids display various biological functions in living organisms
and form complexes with steroid receptors, similar to antibodies,
enzymes, and proteins. The diverse functionalized steroids them-
selves can act as molecular receptors and the importance of ste-
roids in molecular recognition has been reviewed.1
Bile acids are readily available scaffolds9 and frequent building
blocks for supramolecular hosts.9,10 Since the first acyclic cleft-type
dimer of cholic acid was reported by McKenna,11 compounds of
similar structure have been synthesized as potential supramolecu-
lar hosts or as substrates for the construction of macrocyclic
assemblies. Tail-to-tail dimers of bile acids, in which the linker
forms a bridge between the side chains of the two bile acid mole-
cules (C24–C240 connection) have been frequently reported.12
These include bis-amides,12–14 bis-hydrazides,15 and bis-esters.16
Some of these dimers show interesting biological,13 ionophoric,14
and metal-complexing12 properties and have also been used as
substrates in macrocyclizations to afford cholaphanes.17–21
The advantages of click chemistry have resulted in the prepara-
tion of dimers with a 1,2,3-triazole ring unit as the linker and the
synthesis of head-to-head and head-to-tail dimers of bile acids
using this methodology has been reported.22–26 Also, olefin
metathesis of unsaturated bile acid esters has been applied for
the preparation of 24–240 dimers.27
Dimeric steroids are a special group of compounds which have
recently received significant attention.2 Steroid dimers with or
without a spacer group are both natural and synthetic com-
pounds.2,3 Natural products such as the steroidal pyrazines, ceph-
alostatins, and ritterazines, are dimeric steroids of potent
cytotoxicity and have been investigated as potential anticancer
agents.3,4 The biological activity of dimeric steroid esters has
shown considerable prolongation of hormonal effects compared
to the respective monomer.5 Moreover, dimerization of the steroid
skeleton provides an entry into compounds with unique properties
and numerous applications in supramolecular chemistry.2,3
The synthesis of dimeric steroids in which two steroid units are
directly linked has been reported previously.2,6–8 However, by far
more frequently reported are dimeric steroids in which the two ri-
gid steroid frameworks are linked by various types of spacer
groups.2,3 Precise control of the host cavity for guest recognition
may be achieved by using a dedicated spacer which may possibly
modify the molecular recognition properties of the dimer or mac-
rocycle derived from it, due to the shape, size, and polarity of the
molecular cavity.
Dimers of bile acids have been synthesized by linking the hy-
droxyl groups on C(3) of the steroid skeleton by a spacer having
two ester or ether groups.16,28 The 3,30-dimerization in the reaction
of the 3-hydroxy group of lithocholic acid with m-xylylenediisocy-
anate has been reported and the resulting dimer having a m-xylyl-
ene dicarbamate linker was used for supramolecular channel
construction.29
The alkyl and aryl chloroformates are reactive compounds
which react with O-, N-, and S-nucleophiles to produce carbonates,
carbamates, and monothiocarbonates, respectively.30 Since
reactions of the chlorocarbonyl derivatives of cholesterol,31 and
⇑
Corresponding author. Tel.: +48 61 8291324; fax: +48 61 8658008.
E-mail address: zparyzek@amu.edu.pl (Z. Paryzek).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.151

Z. Paryzek et al. / Tetrahedron Letters 53 (2012) 6212–6215
6213
O
O
O
OCH2Ph
PhH2CO
O
O
Py, THF
HO OH
O
O
2
+
O
O
OCH2Ph
O
O
PhH2CO
O
O
4
5
Scheme 1.
of cholic32,33 or deoxycholic34 acids with nucleophiles have been
reported, reactions of the chlorocarbonyl derivatives of hydroxys-
teroids with dinucleophiles appear to be an interesting and prom-
ising approach to novel steroidal architectures. In particular, a
large family of dimeric and macrocyclic supramolecular hosts can
be prepared by this approach, provided the readily accessible chlo-
rocarbonyl derivatives of bile acids are used as substrates.
Herein, we report the synthesis of a series of representative bile
acid dimers possessing a carbonate, monothiocarbonate, or ure-
thane group in the spacer fragment.
Lithocholic and cholic acid methyl or benzyl esters were se-
lected as building blocks for the synthesis of dimers, as potential
supramolecular hosts and substrates for the preparation of macro-
cyclic compounds. The 3-chlorocarbonyl derivatives 1, 2, and 3, of
lithocholic and cholic acid esters respectively, were prepared by
reactions of the respective 3-alcohols with triphosgene (CCl3O-
COOCCl3) in methylene chloride in the presence of catalytic
amounts of pyridine. The chloroformates were purified by chroma-
tography. It was also found that the crude chloroformates could be
used as substrates in the reactions with nucleophiles.
By an appropriate selection of the dinucleophilic reagent (1,2-,
1,3- or 1,4-isomers), dimers of variable length and predicted geom-
etries of the spacer groups were synthesized. Particularly effective
were dimerizations in which disubstituted benzene derivatives
were used affording relatively rigid spacer groups. The reactions
of the above chloroformates afforded bis-carbonates, bis-mono-
thiocarbonates, and bis-carbamates.
The reaction of chloroformate 2 with 1,3-dihydroxybenzene in
THF with pyridine, sodium hydride, and 4-dimethylaminopyridine
(DMAP) as the base gave dimer 4 in increasing yields of 32%, 49%,
and 92%, respectively. In the reaction of 2 catalyzed by pyridine
(Scheme 1) the carbonate 5 (33% yield) was also obtained along
with the traces of the parent 3-hydroxy compound. The DMAP-
catalyzed reaction of methyl 3-chlorocarbonyloxy-7a,12a-diacet-
oxy-5b-cholan-24-oate (3) with 1,2-dihydroxybenzene gave the
bis-carbonate 6 in 90% yield.
For the preparation of bis-carbamoyl-oxa-bridged bile acid
derivatives, N,N0-dinucleophiles with a two, three, or four unit lin-
ker, which also varied in terms of the hybridization, (i.e., C-sp3 and
C-sp2), were considered. The dimeric bis-carbamates 7–11 were
formed via the reactions of chloroformates 1 and 3 with aliphatic
and aromatic diamines. Again, the best results were obtained when
the reactions were carried out in tetrahydrofuran as the solvent
and in the presence of DMAP as the base in equimolar quantities.
The bile acid ester dimers having ethylene-,35 diethylene-, m-,
and p-phenylenedicarbamate linkers were obtained in high
yields.36 Under these conditions, neither hydrolysis of the chloro-
O
R2
OR3
O
R1
Cl
O
H
formate nor formation of the respective bis(cholan-3a-yl) carbon-
ate was observed.
1 R1 = R2 = H, R3 = Me
1 = R2 = H, R3 = Bn
3 R1 = R2 = OAc, R3 = Me
2
R
O
OMe
OAc
O
R2
O
O
OAc
R3O
R3O
OAc
O
R1
O
OAc
O
MeO
MeO
O
O
O
O
O
O
NH
O
N
N
L
O
NH
O
OAc
O
R1
OAc
OAc
O
R2
OMe
O
OAc
O
6
7
linker L
8 R1 = R2 = OAc, R3 = Me, ethylene
1 = R2 = H, R3 = Bn,
10 R1 = R2 = OAc, R3 = Me, m-phenylene
11
m-phenylene
9
R
R
1 = R2 = OAc, R3 = Me, p-phenylene
12 R1 = R2 = OAc, R3 = H, m-phenylene

6214
Z. Paryzek et al. / Tetrahedron Letters 53 (2012) 6212–6215
O
O
OCH3
O
H3CO
H3CO
O
O
S
Py, Ar
SH
O
O
1
+
S
S
HS
O
HS
O
14
13
Scheme 2.
Figure 1. The two low energy syn and anti conformations of dimer 9.
O
O
O
OAc
O
O
AcO
AcO
HN
HN
NH
NH
OAc
O
1. KOH, THF/H2O
2. ClCO2Et,1,4-dioxane,
N-methylmorpholine
15
10
3. p-phenylenediamine
H
N
H
N
OAc
OAc
O
O
OAc
OAc
AcO
AcO
O
O
O
O
O
O
O
O
HN
NH
HN
NH
OAc
OAc
O
O
N
H
N
H
16
Scheme 3.
The dimerization of chlorocarbonyl derivatives with S,S-dinucle-
ophiles was less effective. The reaction of 1 with 1,2-ethanedithiol
in pyridine resulted in the formation of bis-monothiocarbonate
13 (55% yield) along with monothiocarbonate 14 (15%) (Scheme 2).
The attempted reaction of 1 with 2,20-(ethylenedioxy)diethanethiol
gave a product which decomposed during isolation.
The dimers with a bis-carbamoyl-oxa bridge were relatively
stable under basic conditions and were hydrolyzed selectively to
afford dicarboxylic derivatives (see later).
Two low energy conformations, syn and anti, are possible for the
dimers as a consequence of the free rotation of bonds in the linker
fragment. Semiempirical calculations (PM3, CAChe Fujitsu) on the
bis-carbamate 9 showed that the syn conformer was more stable
than the anti conformer by 5.58 kcal/mol (Fig. 1). In the syn con-
All the dimers37 synthesized were characterized spectroscopi-
cally using IR and 1H, 13C NMR, and by ESI- or MALDI-TOF mass
spectrometry experiments.36
former p–p stacking sandwich type interactions between two aro-

Z. Paryzek et al. / Tetrahedron Letters 53 (2012) 6212–6215
6215
4. Moser, B. R. J. Nat. Prod. 2008, 71, 487–491.
5. Kuhl, H.; Taubert, H. D. Steroids 1974, 24, 613–626.
6. Templeton, J. F.; Majgier-Baranowska, H.; Marat, K. Steroids 2000, 65, 219–223.
7. DellaGreca, M.; Iesce, M. R.; Previtera, L.; Temussi, F.; Zarrelli, A. J. Org. Chem.
2002, 67, 9011–9015.
matic rings were observed and their interplanar separation of ap-
prox. 3.8 Å was calculated. Similar values have been observed for
p–p
stack arrangements.38 For other dimers, the energy differences
between the syn/anti conformers were lower, by 1.1 and 1.6 kcal/
mol for 7 and 8, respectively.
ˇ
´
ˇ
8. Harmatha, J.; Budešínsky, M.; Vokáac, K. Steroids 2002, 67, 127–135.
9. Davis, A. P. Molecules 2007, 12, 2106–2122.
The dimers synthesized are potential substrates for the prepara-
tion of macrocyclic compounds with predicted cavities. An inter-
esting approach to the synthesis of a new cholaphane was
demonstrated by cyclization of the dimeric bis-carbamate 10.
Selective hydrolysis of 10 (KOH, THF/H2O 4:1) afforded the dimeric
diacid 12. Activation of the carboxyl groups in 12 by the formation
of the mixed anhydride via reaction with ethyl chloroformate (1,4-
dioxane, N-methylmorpholine) followed by treatment with p-
phenylenediamine resulted in the formation of two macrocyclic
compounds: dimer 15 and tetramer 16. The macrocyclization
was fairly effective affording 15 and 16 in isolated yields of 35%
and 19%, respectively (Scheme 3).
In summary, we have developed an efficient procedure for the
preparation of the head-to-head bile acid dimers bearing a bis-car-
bamate, bis-carbonate, or bis-monothiocarbonate moieties in the
spacer group from the readily available 3-chlorocarbonyl deriva-
tives of bile acid esters. Macrocyclization of the dimer 10 afforded
highly functionalized dimeric and tetrameric cholaphanes, 15 and
16, respectively. These acyclic and macrocyclic dimers may find
applications in molecular recognition, supramolecular chemistry,
and in pharmacology.
10. Tamminen, J.; Kolehmainen, E. Molecules 2001, 6, 21–46.
11. McKenna, J. M.; Thornthwaite, D. W. J. Chem. Soc., Chem. Commun. 1977, 809–
811.
12. Virtanen, E.; Tamminen, J.; Haapala, M.; Mänttäri, P.; Kauppinen, R.;
Kolehmainen, E. Magn. Reson. Chem. 2003, 41, 567–576.
13. Salunke, D. B.; Hazra, B. G.; Pore, V. S.; Bhat, M. K.; Nahar, P. B.; Deshpande, M.
V. J. Med. Chem. 2004, 47, 1591–1594.
14. Salunke, D. B.; Hazra, B. G.; Pore, V. S. Arkivoc 2003, ix, 115–125.
15. Łotowski, Z.; Guzman´ ski, D. Monatsh. Chem. 2006, 137, 117–124.
16. Gouin, S.; Zhu, X. X. Steroids 1996, 61, 664–669.
17. Pandey, P. S.; Singh, R. B. Tetrahedron Lett. 1997, 38, 5045–5046.
18. Pandey, P. S.; Rai, R.; Singh, R. B. J. Chem. Soc., Perkin Trans. 1 2002, 918–923.
19. Tamminen, J.; Lappalainen, K.; Torkkel, T.; Seppälä, R. Synthesis 1996, 1082–
1084.
20. Haapala, M.; Kolehmainen, E.; Tamminen, J.; Kauppinen, R.; Linnanto, J.;
Virtanen, E.; Suontamo, R.; Vainiotalo, P. Mater. Sci. Eng., C 2001, 18, 21–23.
21. Tamminen, J.; Kolehmainen, E.; Haapala, M.; Linnanto, J. Synthesis 2000, 1464–
1468.
22. Aher, N. G.; Pore, V. S.; Patil, S. P. Tetrahedron 2007, 63, 12927–12934.
23. Aher, N. G.; Pore, V. S. Synlett 2005, 2155–2158.
24. Zhang, Z.; Ju, Y.; Zhao, Y. Chem. Lett. 2007, 36, 1450–1451.
25. Vatmurge, N. S.; Hazra, B. G.; Pore, V. S.; Shirazi, F.; Deshpande, M. V.;
Kadreppa, S.; Chattopadhyay, S.; Gonnade, R. G. Org. Biomol. Chem. 2008, 6,
3823–3830.
26. Pospieszny, T.; Małecka, I.; Paryzek, Z. Tetrahedron Lett. 2012, 53, 301–305.
27. Dallstream, C.; Dias, J. R. Org. Prep. Proced. Int. 2006, 38, 337–340.
28. Lukashev, N. V.; Kazantsev, A. V.; Averin, A. D.; Donez, P. A.; Baranov, M. S.;
Sievänen, E.; Kolehmainen, E. Synthesis 2009, 4175–4182.
29. Yoshii, M.; Yamamura, M.; Satake, A.; Kobuke, Y. Org. Biol. Chem. 2004, 2, 2619–
2623.
Acknowledgment
30. Matzner, M.; Kurkjy, R. P.; Cotter, R. J. Chem. Rev. 1964, 64, 645–687.
31. Schadendorff, E.; Verdino, A. Monatsh. Chem. 1935, 65, 338–347.
32. Verdino, A.; Schadendorff, E. Monatsh. Chem. 1935, 65, 169–175.
33. Janout, V.; Lanier, M.; Regen, S. L. J. Am. Chem. Soc. 1997, 119, 640–647.
34. Sokolova, T. V.; Maslov, M. A.; Serebrennikova, G. A. Russ. J. Bioorg. Chem. 2004,
30, 477–481.
This investigation was supported by the Ministry of Science and
Higher Education (Project No. N N204 166836).
Supplementary data
35. Paryzek, Z.; Piasecka, M.; Joachimiak, R.; Luks, E.; Radecka-Paryzek, W. J. Rare
Earths 2010, 28, 56–60.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.
151.
36. See Supplementary data.
37. Typical procedure for the preparation of dimers: To a solution of methyl 3
a-
chlorocarbonyloxy-7 ,12 -diacetoxy-5b-cholan-24-oate (569 mg, 1 mmol) in
a
a
THF (10 mL) were added 1,3-diaminobenzene (54.1 mg, 0.5 mmol) and DMAP
(122 mg, 1 mmol) and the mixture was stirred at room temperature until all
the substrates had reacted (2 h). Addition of H2O followed by extraction of the
product with toluene/Et2O gave the crude product which was
chromatographed on silica gel column to give dimer 10 (528 mg, 90%) as a
white solid.36
References and notes
1. Wallimann, P.; Marti, T.; Fürer, A.; Diederich, F. Chem. Rev. 1997, 97, 1567–
1608.
2. Li, Y.; Dias, J. R. Chem. Rev. 1997, 97, 283–304.
3. Nahar, L.; Sarker, S. D.; Turner, A. B. Curr. Med. Chem. 2007, 14, 1349–1370.
38. (a) Hunter, C. A.; Sanders, J. K. M. J. Am. Chem. Soc. 1990, 112, 5525–5534; (b)
Bloom, J. W. G.; Wheeler, S. E. Angew. Chem. 2011, 123, 7993–7995.