Application of HPLC for the screening of separation of new macrocyclic systems

Article abstract of DOI:10.1080/10426507.2016.1255622

The efficient synthesis of new macrocyclic systems via nucleophilic ring opening reaction of epoxides by thiols was described. Initially new macrocyclic compounds were obtained as a mixture of diastereomers. Preparative thin layer chromatography was applied to separate meso and pairs of enantiomer. The identification of products using a chiral HPLC column and mass spectroscopy was utilized.

Full text of DOI:10.1080/10426507.2016.1255622

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Application of HPLC for the screening of
separation of new macrocyclic systems
Monika Stefaniak & Jarosław Romański
To cite this article: Monika Stefaniak & Jarosław Romański (2017) Application of HPLC for the
screening of separation of new macrocyclic systems, Phosphorus, Sulfur, and Silicon and the
Related Elements, 192:2, 245-248, DOI: 10.1080/10426507.2016.1255622
To link to this article: http://dx.doi.org/10.1080/10426507.2016.1255622
Accepted author version posted online: 10
Nov 2016.
Published online: 10 Nov 2016.
Submit your article to this journal
Article views: 17
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=gpss20
Download by: [University of Newcastle, Australia]
Date: 15 March 2017, At: 23:48

PHOSPHORUS, SULFUR, AND SILICON
, VOL. , NO. , –
http://dx.doi.org/./..
Application of HPLC for the screening of separation of new macrocyclic systems
Monika Stefaniak and Jarosław Roman´ski
´
´
Department of Organic and Applied Chemistry, University of Łódz, Łódz, Poland
ABSTRACT
ARTICLE HISTORY
Received  October 
Accepted  October 
The efficient synthesis of new macrocyclic systems via nucleophilic ring opening reaction of epoxides by
thiols was described. Initially new macrocyclic compounds were obtained as a mixture of diastereomers.
Preparative thin layer chromatography was applied to separate meso and pairs of enantiomer. The identifi-
cation of products using a chiral HPLC column and mass spectroscopy was utilized.
KEYWORDS
Macrocyclic compounds;
nucleophilic ring-opening;
epoxides; click chemistry
GRAPHICAL ABSTRACT
described elsewhere.12 According to literature procedure,13 in
which cyclopentadiene in a Diels-Alder cycloaddition with
benzoquinone gives a cycloadduct followed by [2 + 2] photo-
cycloaddition, we obtained diketone 6 in excellent yields. Next,
reaction of 6 with two equivalents of Grignard’s reagent and next
forms an oxygen bridge in the presence of PTSA, provide to allyl
derivate 7, which after standard oxidation led to bis-epoxide 8.
The first experiment was performed using a methanolic solu-
tion of potassium or sodium hydroxide and after 24 h new com-
pounds with poor yields were obtained. For that reason the use
of a different method starting from epoxides and dithiols in the
presence of potassium carbonate in methanol was applied. The
reaction was carried out in 1 mmol scale and under high dilu-
tion conditions (1 mg/mL) to avoid the formation of linear or
polymeric side products.
A mixture of products 9a and 9b in 40% yield was obtained.
The application of thin layer preparative chromatography to sep-
arate diastereoisomers (meso 9a and pair of enantiomers 9b) was
successfully performed. Furthermore, for both separated frac-
tions the MS spectra showed the same molecular mass peak,
which confirmed our expectations. The isomers 9a and 9b were
subjected for examination using HPLC method with a chiral
column. The result of this investigation is not perfectly clear
and it needs to be revised, however for the preliminary indi-
cate the similar composition of both separated fractions which
is depicted on Figure 1.
Introduction
Epoxides derivatives are very powerful compounds and consti-
tute an important point for the preparation of optically active
amino alcohols,1 sulfides,2 azido alcohols,3 and hydroxy nitrates
derivatives.4 In many cases epoxides provide very easy and quick
way to lead a series of very useful linkers which can be used to
create libraries of diverse compounds.5
In our hands application of nucleophilic ring-opening reac-
tion give a possibility to use it as tools for synthesis of novel
macrocyclic systems with two unsubstituted hydroxy groups.
The syntheses of starting materials were performed accord-
ing to literature protocols, however, the allyl compounds were
described only by boiling point without spectroscopic data.6
Only bis-epoxides derivatives7 were known in contrast to their
sulfur analogues. The dithiols were obtained according to
known procedure via their tosyl derivatives.8
Results and discussion
Following a classic protocol,9 the di-, tri-, and tetraethylene gly-
cols 1a-c were reacted with allyl bromide, to give, after standard
chromatographic purification, corresponding bis-allyl deriva-
tives 2a-c in good yields of 71–95% as shown at Scheme 1.
Derivatives 2a-c were converted to bis-epoxide derivatives 4a-c
using m-chloroperbenzoic acid in methylene chloride.10 Also we
prepared sulfur bis-epoxides 5a-c using epichlorohydrin under
phase-transfer catalysis conditions. 11
The further examination using different methods of HPLC
such as, refractive index detection or derivatization of macrocy-
cles to investigate the obtained isomers is in progress.
Cookson’s birdcage 6 was also used to introduce a rigid
and lipophilic motif to our macrocyclic system, which is well
CONTACT Monika Stefaniak
monika_stefaniak@o.pl
Department of Organic and Applied Chemistry, University of Łódz´, Tamka , - Łódz´, Poland.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
©  Taylor & Francis Group, LLC

´
M. STEFANIAK AND J. ROMANSKI
246
Scheme . Synthesis of bis-epoxide derivatives.
Scheme . Synthesis of Cookson’s birdcage derivatives.
Scheme . Synthesis of new macrocyclic systems with free hydroxy groups.
Scheme . Proposed synthesis of new C-cryptands with triazole rings.
Scheme . First attempt to synthesis of new C-bridgehead cryptand.

PHOSPHORUS, SULFUR, AND SILICON
247
Figure . Mass spectra and HPLC data of compounds 9a and 9b.
In the next step of our investigation to modify the hydroxyl reaction catalyzed by copper(I) ions, in a so-called click chem-
groups the reaction with propargyl bromide was performed. In istry concept.
this manner, we obtained previously undescribed bis-propargyl
Recently, the literature is focused on the preparation of
derivative 10 in 55% yield. This product will be applied for cryptands with the bridgehead nitrogen atom which are
reaction with organic azides using 1,3-dipolar cycloaddition called N-cryptands.14 The first attempt to obtain a new, rare

´
M. STEFANIAK AND J. ROMANSKI
248
class of C-bridgehead cryptands using reaction of new macro-
cycles with ditosylate derivatives failed and unfortunately, the
desired product was not obtained.
Brown, F.; Bahamontes-Rosa, N.; Wu, B.; Beitz, E.; Kun, J. F. J.; Flitsch,
S. L. J. Med. Chem. 2007, 50, 4243-4249.
2. (a) Fringuelli, F.; Pizzo, F.; Tortoioli, S.; Vaccaro, L. Green Chem.,
2003, 5, 436-440; (b) De, S.; Khan, A. Chem. Commun. 2012, 48,
3130-3132.
3. Arya, A.; Kumar, V.; Mathur, D.; Singh, S.; Brahma, R.; Singh, R. J.
Heterocycl. Chem. 2015, 52, 1-3.
Conclusions
4. Fan, Y.; Shang, X.; Liu, Z.; Wu, L. Synth. Commun. 2006, 36, 3149-3152.
5. (a) Amantini, D.; Fringuelli, F.; Rermath, O.; Tortoidi, S.; Vaccaro, L.
ARKIVOC, 2002, 293-311; (b) Azizi, N., Batebi, E. Catal. Sci. Technol.
2012, 2, 2445-2448.
6. (a) Monfette, S.; Crane, A. K.; Duarte Silva, J. A.; Facey, G. A.;
dos Santos, E. N.; Araujo, M. H., Fogg, D. E. Inorg. Chim. Acta,
2010, 363, 481-486; (b) Riemschneider, K. Monatsh. Chem. 1959, 90,
787-790.
7. (a) Guo, Q.; Liu, Y.; Xun, M.; Zhang, J.; Huang, Z.; Zhou, X.; Yu, X.
J. Mater. Chem. B., 2015, 3, 2660-2670; (b) Xue-Ping, G.; Ikeda, I.;
Okahara, M. Synthesis 1985, 6, 649-651.
8. Kumar Roy, R.; Ramakrishnan, S. J. Polym. Sci. A Polym. Chem. 2013,
51, 4125-4136.
9. Chujo, Y.; Tomita, J.; Hashiguchi, Y.; Tanigawa, H.; Ihara, E.; Saegusa,
T. Macromolecules 1991, 24, 345-348.
10. Wu, X.; Lipinski, T.; Carrel, F. R.; Bailey, J. J.; Bundle, D. R. Org. Biomol.
Chem. 2007, 5, 3477-3485.
11. Peng, W.; Liu, P.; Jiang, N.; Lin, H.; Zhang, G.; Liu, Y.; Yu, X. Bioorg.
Chem. 2005, 33, 374-385.
The application of nucleophilic ring-opening reaction of bis-
epoxides using dithiols leads to a series of new macrocycles
with unsubstituted hydroxy groups. The successful separation
of diastereoisomers via preparative thin layer chromatography
was utilized. HPLC investigation is ambiguous and needs to be
performed again under different HPLC conditions using various
methods of detections or derivatization of macrocycles.
The hydroxy group can be modified by reaction with, e.g.,
ditosylate compounds lead to new group of cryptands with the
bridgehead carbon atom. First attempts to modify the hydroxyl
groups have been carried out using propargyl bromide and
the bis-propargyl derivative was obtained as new compound.
All obtained new macrocyclic compounds will be explored for
screening their complexing properties toward various metal
cations.
12. (a) Levitskaia, T.; Moyer, B.; Bonnesen, P.; Marchand, A. P.;
Krishnudu, K.; Chen, Z.; Huang, Z.; Kruger, H.; McKim, A. S. J. Am.
Chem. Soc. 2001, 123, 12099-12100; (b) Govender, T.; Haripraksha,
H.; Kruger, H. K.; Marchand, A. P. Tetrahedron: Asymmetry 2003, 14,
1553-1557.
13. (a) Marchand, A. P.; Huang, Z.; Haripraksha, Z. H.; Namboothiri, I. N.
N.; J. Heterocycl. Chem. 2001, 38, 1361; (b) Marchand, A. P.; Kumar, K.
A.; McKim, A. S. Tetrahedron 1997, 53, 3467.
Funding
The authors thank the National Science Centre (Poland) for
financial support (Grant no.DEC-2015/17/N/ST5/03028).
References
14. (a) Sarkar, B.; Mukhopadhyay, P.; Bharadwaj, P. K. Coord.
Chem. Rev. 2003, 236, 1-13; (b) Naguib, Y. Molecules 2009, 14,
3600-3609.
1. (a) Fu, X.; Wu, S. Synth. Commun. 1997, 27, 1677-1683; (b) Azoulay, S.;
Manabe, K.; Kobayashi, S. Org. Lett. 2005, 7, 4593-4595; (c) Robin, A.;