An easy access to asymmetrically substituted oligoethylene glycols from 18-crown-6

Article abstract of DOI:10.1016/j.tetlet.2013.06.065

A new route for the preparation of multi-gram quantities of the heterobifunctional oligoethylene glycol (OEG) derivatives (n = 6, 7) is reported based on decyclization of 18-crown-6.

Full text of DOI:10.1016/j.tetlet.2013.06.065

Tetrahedron Letters 54 (2013) 4533–4535
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An easy access to asymmetrically substituted oligoethylene glycols
from 18-crown-6
⇑
Polina I. Abronina, Alexander I. Zinin, Anna V. Orlova, Sergey L. Sedinkin, Leonid O. Kononov
N.D. Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences, Leninsky prosp., 47, Moscow 119991, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
A new route for the preparation of multi-gram quantities of the heterobifunctional oligoethylene glycol
(OEG) derivatives (n = 6, 7) is reported based on decyclization of 18-crown-6.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 27 April 2013
Revised 28 May 2013
Accepted 14 June 2013
Available online 24 June 2013
Keywords:
Crown ethers
Ring cleavage
Oligoethylene glycols
Desymmetrization
Asymmetrically functionalized poly- and oligoethylene glycols
[PEG and OEG, respectively, R1 (OCH2CH2)nOR2] have found wide-
spread use in a variety of applied areas due to their hydrophilic,1,2
nonimmunogenic,3 and nontoxic4 properties. They are used as
spacers for (bio)molecules, as good anchors for ligands of recep-
tors, and they are known to reduce the nonspecific binding of pro-
teins and other bioactive molecules.5
Heterobifunctional OEG derivatives can generally be prepared
from commercially available H(OCH2CH2)nOH diols.6 The key step
involves the differentiation of two chemically equivalent terminal
hydroxyl groups. This desymmetrization can usually be achieved
by preparation of monosubstituted derivatives from symmetrical
diols, which was until recently considered a rather ineffective pro-
cess. This situation changed when an efficient method for selective
mono-tosylation of diols in the presence of silver(I) oxide was
introduced7 (note that mesylation proceeds somewhat less selec-
tively5,8). This approach is also applicable to benzylation and trity-
lation and has been used for multigram syntheses of
heterobifunctional OEG chains.9,10
The ring-opening reaction of 18-crown-6 (1) with ZrCl4 in a
toluene–THF mixture at 100 °C is known to lead (in 25% yield) to
the
formation
of
a
complex
with
a
formula
[ZrCl2ꢀ(OCH2CH2)5OCH2CH2Cl+][ZrCl5(THF)ꢁ].12–15
After considerable experimentation we developed a preparative
version of this process which provided reliable access to gram
quantities of H(OCH2CH2)6Cl (2)16 (Scheme 1). The key to the suc-
cess was the use of nitrobenzene as the solvent, which enabled the
reaction temperature to be increased to 135 °C. Product 2 was iso-
lated in 88% yield and further transformed by reaction with NaN3,
(DMF, 75 °C) into the corresponding azide H(OCH2CH2)6N3 (3)5 in
81% yield, which was purified by silica gel chromatography. The
purity of the isolated azide 3 was sufficient for further chemical
transformations including syntheses of valuable and difficult to ac-
cess targets, such as hexa(hepta)ethylene glycols
8 and 10
(Scheme 2) and N-acetylglucosamine derivative 16 with a hexaeth-
ylene glycol-based spacer (Scheme 3).
In order to introduce a carboxyl group into hexaethylene glycol
azide 3 we examined two different approaches. The first was based
on oxidation of the primary hydroxy group in 3 by treatment with
(PyH)2Cr2O7 in tert-butyl alcohol,17 which resulted in the forma-
tion of hexaethylene glycol-derived tert-butyl ester 4, which was
purified by silica gel chromatography (27%). Ester 4 was treated
with KOH in aq. EtOH to give after acidification the corresponding
However, penta- and hexaethylene glycols (n = 5, 6) are much
more expensive in contrast to shorter analogs.11 For this reason,
we propose an alternative route for the preparation of multigram
quantities of the heterobifunctional OEG derivatives (n = 6, 7)
based on decyclization of crown-ethers, which are several times
cheaper than the corresponding OEGs of similar chain length.
x
-azidocarboxylic acid 6.18–21 Staudinger reduction of the azido
group (Ph3P/H2O) in 6 followed by ion-exchange chromatography
gave hexaethylene glycol-derived acid 8 in 77% yield (from 4).
A more efficient alternative route for the introduction of a
carboxy group was based on alkylation of the hydroxy group in
⇑
Corresponding author. Tel.: +7 495 943 2946; fax: +7 499 135 5328.
E-mail
addresses:
kononov@ioc.ac.ru,
leonid.kononov@gmail.com
(L.O. Kononov).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.065

4534
P. I. Abronina et al. / Tetrahedron Letters 54 (2013) 4533–4535
Alkaline hydrolysis of benzyl ester in 9 followed by Staudinger
reduction of the azido group (Ph3P/H2O) and subsequent ion-ex-
change chromatography gave heptaethylene glycol-derived amino
acid 10 in 97% yield (from 9).
The overall yields of hexa(hepta)ethylene glycol-derived acids
824 and 10 were 17% and 26%, respectively, from inexpensive and
commercially available 18-crown-6 (1),25 which makes our ap-
proach economically useful and competitive.
Straightforward protection of the amino group in 10 as the N-
trifluoroacetyl derivative and transformation of the carboxy func-
tion into an activated N-oxysuccinimidyl ester gave the protected
derivative of heptaethylene glycol-derived acid 11 in 91% yield,
which was recently applied in the synthesis of spacer-armed glyco-
sides of a hexaarabinofuranoside fragment of Mycobacterium tuber-
culosis lipoarabinomannan, which after conjugation with the
recombinant mycobacterial proteins MPB-64 and Rv0934 were
transformed into artificial antigens useful for tuberculosis
diagnosis.26
Scheme 1. Reagents and conditions: (a) ZrCl4, PhNO2, 135 °C, 36 h, 88%; (b) NaN3,
DMF, 75 °C, 15 h, 81%.
hexaethylene glycol azide 3 with tert-butyl bromoacetate in DMF
in the presence of NaH,22 which led to the heptaethylene glycol-
derived tert-butyl ester 5 with a longer chain.5,8,10 Unlike in refer-
ence 5, in our case, product 5 was contaminated with the corre-
sponding carboxylic acid salt, apparently formed by cleavage of
the tert-butyl ester 5.23 For this reason, the crude mixture contain-
ing partially hydrolyzed 5 was treated with KOH in aq EtOH to
ensure complete hydrolysis into salt 718 followed by benzylation
with PhCH2Br in DMF in the presence of K2CO3 with subsequent
SiO2 chromatography to give benzyl ester 9 in 38% yield (from 3).
To demonstrate the synthetic potential of our approach toward
hexaethylene glycol-based azide 3, we also present here the prep-
aration of N-acetylglucosamine derivative 16 with a hexaethylene
glycol-based aglycon-spacer (Scheme 3). Crude
was glycosylated using known selectively protected 2-deoxy-2-
phthalimido-b-
-glucopyranoside (12)27 to give N-acetylglucos-
x-azidoalcohol 3
D
aminide 13 with a hexaethylene glycol azide spacer in 56% yield
after column chromatography. After replacement of the N-phthal-
oyl with an N-acetyl group (13?14) and modification of the
Scheme 2. Reagents and conditions: (a) (PyH)2Cr2O7, t-BuOH, Ac2O, CH2Cl2, 1 h, 27%; (b) KOH (aq), EtOH; (c) (1). Ph3P, EtOH–25% aq NH3–THF, (2) ion-exchange
chromatography (Dowex 50 W ꢂ 4 (H+), 1 M py (aq)), 86% from 4, 23% from 3, 17% from 1; (d) NaH, DMF, BrCH2CO2-t-Bu; (e) KOH (aq), EtOH; (f) BnBr, K2CO3,DMF, 38%; (g) (1)
KOH, MeOH; (2). Ph3P, 25% aq NH3, THF, (3) ion-exchange chromatography (Dowex 50 W ꢂ 4(H+), 1 M py (aq)), 97% from 9, 37% from 3, 26% from 1; (h) (1) CF3CO2Et, Et3N,
MeOH, 5 h, (2) N-hydroxysuccinimide, DMAP, DCC, DMF, 0 °C ? rt, 91%.

P. I. Abronina et al. / Tetrahedron Letters 54 (2013) 4533–4535
4535
3. Boeckler, C.; Frisch, B.; Muller, S.; Schuber, F. J. Immunol. Methods 1996, 191, 1–
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11. A cost-effective route to OEG oligomers (n = 6, 10 and 12) has recently been
proposed (Ref. 6).
12. Prinz, H.; Bott, S. G.; Atwood, J. L. J. Am. Chem. Soc. 1986, 108, 2113–2114.
13. Alvanipour, A.; Atwood, J. L.; Bott, S. G.; Junk, P. C.; Kynast, U. H.; Prinz, H. J. J.
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14. A similar reaction of 18-crown-6 with PtCl4 in anhydrous aprotic solvents
(MeNO2, MeCN) was also reported to give related ionic complexes with
oligoethylene glycols (Ref. 15).
15. Guseva, E. V.; Khasanshin, R. A.; Zinkicheva, T. T.; Yarkova, E. G.; Polovnyak, V.
K. Russ. J. Gen. Chem. 2007, 11, 1864–1873.
Scheme 3. Reagents and conditions: (a) 3, NIS, Et3SiOTf, CH2Cl2, ꢁ20 °C, 4 Å MS, 1 h,
SiO2, 56%; (b) (1) NH2(CH2)2NH2, i-C5H11OH, reflux (bath temperature 140 °C), 4 h,
(2) Ac2O, py, 1.5 h, SiO2, (20?60 vol % Me2CO in benzene), 82%; (c) (1) MeONa,
MeOH, 16 h, (2) Ph3P, 25% aq NH3–THF–MeOH, 40 °C, 5 h, (3) CF3CO2Et, Et3N, MeOH,
3 h, (4) Ac2O, py, 16 h, 78%; (d) NaBH3CN, MsOH, THF, 4 Å MS, 4 h, SiO2, 90%.
16. Pedersen, C. J.U.S. Patent 3,562,295; Chem. Abstr. 1970, 73, 66642.
17. Classon, B.; Samuelsson, B. Acta Chem. Scand. 1985, B39, 501–504.
18. The exceptional ease of cleavage of tert-butyl esters 4 and 5 under basic
conditions, which is rare (cf. Refs. 19–21), in our case may be attributed to
complexation of K+-ion by OEG polyether chain. It is noteworthy that K-salts of
x
-azidocarboxylic acids 6 and 7 are soluble in CH2Cl2 and could be easily
aglycon (14?15), compound 15 was obtained in 78% yield. The
benzylidene group in N-acetylglucosamine 15 was opened selec-
tively by NaBH3CN–MsOH28 in anhydrous THF to afford new glyco-
syl acceptor 16 in 90% yield containing an N-trifluoroacetamido
hexaethylene glycol spacer.
In summary, new routes to asymmetrically substituted OEGs
starting from cheap and commercially available 18-crown-6 have
been developed.
extracted with this solvent from aqueous solutions.
19. (a) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups In Organic Synthesis,
4th ed.; John Wiley & Sons: Hoboken, New Jersey, 2007; pp 582–588; (b)
Kocien´ ski, P. J. Protecting Groups, 3rd ed.; Georg Thieme: Stuttgart, 2004; pp
403–409; (c) Sambri, L.; Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Curr. Org.
Synth. 2012, 9, 137–148.
20. Paul, S.; Schmidt, R. R. Synlett 2002, 1107–1108.
21. Filali, E.; Lloyd-Jones, G. C.; Sale, D. A. Synlett 2009, 205–208. and references
cited therein.
22. For other methods of alkylation of OEG azidoalcohols with tert-butyl
bromoacetate see Refs. 8,10.
23. Although tert-butyl esters are usually considered to be stable under mild basic
conditions (Ref. 19), their cleavage by NaH in DMF (Refs. 20,21) or KOH in THF
(Ref. 21) has been reported and studied.
Acknowledgement
24. Tanaka, A.; Terada, T.; Tamura, T.; Ichiyama, T.; Yamazaki, A.; Furuya, M.;
Haramura, M. U.S. Patent 7,919,653; Chem. Abstr. 2004, 140, 283950.
25. The known synthesis (Ref. 24) of hexaethylene glycol-derived amino acid 8
starts from ꢃ5 times more expensive pentaethylene glycol (comparison with
Sigma–Aldrich prices for 18-crown-6) and gives the same yield of 8 (19%) as in
our case. Although heptaethylene glycol-derived amino acid 10 is unknown to
the best of our knowledge, the respective precursor 5 has been obtained from
ꢃ3 times more expensive hexaethylene glycol in 33% (Ref. 8) and 81% (Ref. 10)
yields. These yields should be compared with the yield of the corresponding
benzyl ester 9 (27% from 1).
This work was supported financially by the Russian Foundation
for Basic Research (Projects 10-03-01019 and 13-03-00666).
Supplementary data
Supplementary data (experimental procedures and character-
ization data) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2013.06.065.
26. Abronina, P. I.; Podvalnyy, N. M.; Melnikova, T. M.; Zinin, A. I.; Fedina, K. G.;
Kachala, V. I.; Torgov, V. I.; Kononov, L. O.; Panferzev, E. A.; Baranova, E. V.;
Mochalov, V. V.; Dyatlova, V. I.; Biketov, S. F. Russ. Chem. Bull. 2010, 59, 2333–
2337.
References and notes
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