Formation of hybrid polymethylene-poly(oxyethylene) macrocycles

Article abstract of DOI:10.1016/S0040-4039(00)02231-0

Macrocyclisations, particularly those forming crown ethers, normally require high dilution conditions. However, treatment of 1,9-bis(sarcosylamino)nonane with α,ω-bis(oxiranylmethyl) ethers derived from oligomeric poly(ethyleneglycol)s of MW 400-600 Da under high concentration conditions was found to give excellent yields of 1:1 hybrid polymethylene-poly(oxyethylene) macrocyclic crown ether derivatives. The corresponding α,ω-bis(oxiranylmethyl) ether derived from poly(ethyleneglycol) of mean M W 1500 Da gave polymeric material only. The macrocycles were characterised by NMR, GPC and MS.

Full text of DOI:10.1016/S0040-4039(00)02231-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1355–1357
Formation of hybrid polymethylene–poly(oxyethylene)
macrocycles
Susan E. Matthews,a Colin W. Poutonb and Michael D. Threadgillb,*
aInorganic Chemistry Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QR, UK
bDepartment of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK
Received 29 November 2000; accepted 5 December 2000
Abstract—Macrocyclisations, particularly those forming crown ethers, normally require high dilution conditions. However,
treatment of 1,9-bis(sarcosylamino)nonane with a,v-bis(oxiranylmethyl) ethers derived from oligomeric poly(ethyleneglycol)s of
MW 400–600 Da under high concentration conditions was found to give excellent yields of 1:1 hybrid polymethylene–poly-
(oxyethylene) macrocyclic crown ether derivatives. The corresponding a,v-bis(oxiranylmethyl) ether derived from poly(ethyleneg-
lycol) of mean MW 1500 Da gave polymeric material only. The macrocycles were characterised by NMR, GPC and MS. © 2001
Elsevier Science Ltd. All rights reserved.
Currently, routes to macrocyclic polyethers, such as
crown ethers, and hybrid hydrocarbon–polyether
macrocycles require high dilution (or pseudo high dilu-
tion) conditions to avoid polymerisation.1,2 There is
strong interest in the development of new high-yielding
methods avoiding very low concentration conditions
for formation of large macrocyclic crown ether deriva-
acylate nonane-1,9-diamine 3 to give 1,9-bis(Cbz-sar-
cosinamido)nonane 414 (Scheme 1). Deprotection by
hydrogenolysis afforded 1,9-bis(sarcosylamino)nonane
5.14 The chain length of 5 corresponds closely to the
typical dimensions of our tetrapeptide derivatives. We
have previously described12 the conversion of PEG
1500 6c into the corresponding electrophilic a,v-
bis(oxiranylmethoxy) derivative 7c by treatment with
epichlorohydrin and sodium hydroxide, in a modifica-
tion of the general method of Gu et al.15 This process
has now been extended to the lower oligomers PEG 400
6a and 3,6,9,12,15-pentaoxaheptadecane-1,17-diol 6b,
giving 7a and 7b, respectively.16 In this process, the
polyether acts as both phase-transfer catalyst and sub-
strate enabling conversion of the end-groups with >97%
efficiency, as determined by 13C NMR.
tives.3–6
Adventitious
macrocyclisations
during
attempted polymerisations are also being studied.7 As
part of a programme of preparation and evaluation of
biodegradable polymers for applications in delivery of
therapeutic and diagnostic agents to tumours,8–11 we
developed a polymerisation strategy for the synthesis
of alternating co-polymers of peptide and poly-
(oxyethylene) (PEG) units.12 For this polymerisation,
we proposed the reaction of nucleophilic peptide a,v-
secondary amines with electrophilic PEG a,v-diglycidyl
ethers. The elegance of this approach is that the chem-
istry is an addition reaction, obviating the formation of
co-products that have to be removed from the polymer.
This method proved successful in polymerisation of
a,v-bis(methylamino)peptides10 with PEG derivatives.
However, as part of our model studies on this poly-
merisation process, the reactions of a simple a,v-sec-
ondary amine, 1,9-bis(sarcosylamino)nonane 4, with
PEG a,v-diglycidyl ethers were also investigated.
In our typical polymerisation procedure, a high concen-
tration (10% w/v) of the two bifunctional reagents are
stirred in refluxing ethanol for ca. 15 h. Surprisingly,
reaction of a,v-bis(oxiranylmethyl) PEG 400 7a with
the diamine 5 under these conditions17 gave a mixture
of 1:1 macrocycles 8a in excellent yield (Scheme 1).
GPC analysis18 (Fig. 1A) showed only material in the
MW range 600–1000 Da for 8a. However, the 1H NMR
spectrum19 (Fig. 1B) demonstrated complete reaction of
all end-groups as shown by the absence of epoxide
resonances. The sarcosine CH2 resonances appeared as
a pair of doublets, reporting an asymmetric environ-
ment. Such an asymmetric environment is created when
the oxirane is opened by the secondary amine, forming
a secondary alcohol.
To provide
a
model for the a,v-bis(methyl-
amino)peptides, Cbz-sarcosine 113 was firstly converted
to its 2,4,5-trichlorophenyl ester 2, which was used to
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02231-0

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S. E. Matthews et al. / Tetrahedron Letters 42 (2001) 1355–1357
Scheme 1. Synthesis of the hybrid polymethylene–poly(oxyethylene) macrocycles 8a,b. Reagents and conditions: i, 2,4,5-
trichlorophenol, dicyclohexylcarbodiimide, EtOAc, 0°C, 4 h, 85%; ii. Pri2NEt, DMAP, CH2Cl2, 7 days, 91%; iii, H2, Pd/C, MeOH,
2 days, 99%; iv, epichlorohydrin, NaOH, water (trace), 65°C, 2 h, 68% (7a), 90% (7b), 76% (7c); v, EtOH (10% w/v solution), 15
h, reflux, 99% (8a), 97% (8b).
Electrospray and FAB mass spectroscopic analysis rec-
onciled this apparent dichotomy. Ions corresponding to
[M+H]+, [M+Na]+ and [M+K]+ for the oligomeric
macrocycles 8a were observed (Fig. 1C). The relative
abundances of these pseudomolecular ions fitted well
with the oligomeric composition of the starting PEG
400 diglycidyl ether 7a.
This interesting macrocyclisation prompted us to inves-
tigate the reaction of the monodisperse oligomer 7b (a
component of the PEG 400 derivative 7a) and of the
much longer polydisperse 7c. Similar treatment of the
defined-length oligomer 7b afforded the corresponding
1:1 macrocycle 8b in high yield as confirmed by 1H
NMR and MS. However, the analogous reaction of
1
Figure 1. GPC trace (A), part of H NMR spectrum (B) and electrospay MS (C) of 8a. In B, signals marked ꢀ are assigned to
the Sar-CH2. In C, peaks marked ꢁ are [M+H]+, peaks marked * are [M+Na]+ and peaks marked
are [M+K]+.

S. E. Matthews et al. / Tetrahedron Letters 42 (2001) 1355–1357
1357
a,v-bis(oxiranylmethyl) PEG 1500 7c with 5 was shown
by GPC to give predominantly polymeric material.
4. Chenevert, R.; D’Astous, L. J. Heterocycl. Chem. 1986,
23, 1785–1787.
5. Vitali, C. A.; Masci, B. Tetrahedron 1989, 45, 2201–2212.
6. Gibson, H. W.; Bheda, M. C.; Engen, P.; Shen, Y. X.;
Sze, J.; Zhang, H.; Gibson, M. D.; Delaviz, Y.; Lee,
S.-H.; Liu, S.; Wang, L.; Nagvekar, D.; Rancourt, J.;
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7. Zhang, Y.; Wada, T.; Sasabe, H. Chem. Commun. 1996,
621–622.
8. Matthews, S. E.; Pouton, C. W.; Threadgill, M. D. J.
Chem. Soc., Chem. Commun. 1995, 1809–1811.
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Drug Delivery Rev. 1996, 18, 219–267.
The reaction proceeds by an initial addition of one
secondary amine to one oxirane. Subsequently, it may
be postulated that macrocyclisation occurs only when
the polyether is pre-organised. It may be speculated
that complexation to a sodium cation facilitates the
movement of the remaining oxirane and secondary
amine into close proximity. Such traces of sodium ions
may be adventitiously present as a minor contaminant
in 7a,b. In this context, it is notable that the [M+Na]
peaks are highly abundant for all oligomers of 7a in the
electrospray MS, whereas the [M+K] ions are of low
abundance and are absent for the lower oligomers. In
the case of 7c, an analogous complexation would not
bring about this favourable conformation.
10. Matthews, S. E.; Pouton, C. W.; Threadgill, M. D. New
J. Chem. 1999, 23, 1087–1096.
11. Garrett, S. W.; Davies, O. R.; Milroy, D. A.; Wood, P.
J.; Pouton, C. W.; Threadgill, M. D. Bioorg. Med. Chem.
2000, 8, 1779–1797.
12. Matthews, S. E.; Pouton, C. W.; Threadgill, M. D. J.
This straightforward method of preparing hybrid
polyether–hydrocarbon macrocycles opens avenues of
approach to a wide range of functionalised hybrid
macrocycles. Our continuing investigations are explor-
ing the detail and the generality of the process.
Controlled Release 2000, 67, 129–139.
13. Aggen, J. B.; Humphrey, J. M.; Gauss, C.-M.; Huang,
H.-B.; Nairn, A. C.; Chamberlain, A. R. Bioorg. Med.
Chem. 1999, 7, 543–564.
14. New compounds were characterized by 1H NMR and
high resolution MS.
15. Gu, X.-P.; Ikeda, I.; Okahara, M. Synthesis 1985, 649–
651.
Acknowledgements
16. Synthesis of 7a. PEG 400 6a (5.00 g, 12.5 mmol) was
added dropwise to epichlorohydrin (6.75 g, 75 mmol),
NaOH (3.0 g, 7.5 mmol) and water (0.3 mL) and was
stirred at 65°C for 2 h. The cooled suspension was filtered
and the solids were washed with CH2Cl2. Drying and
evaporation gave 7a (4.49 g, 71%).
We thank Mr. R. R. Hartell and Mr. D. Wood (Uni-
versity of Bath) for NMR spectra, Dr. G. J. Price
(Bath) for GPC analyses, Mr. C. Cryer (Bath) and Dr.
J. A. Ballantine (EPSRC Mass Spectrometry Centre,
Swansea) for mass spectra. We also thank Sanofi
Winthrop Pharmaceuticals for financial support.
S.E.M. held a University of Bath Research Bursary.
17. Synthesis of 8a. Compounds 5 (500 mg, 1.66 mmol) and
7a (806 mg, 1.66 mmol) were heated at reflux in EtOH
(10 mL) for 15 h. Evaporation gave 8a (1.30 g, 99%) as a
colourless gum.
18. Bruker LC 21/41 system; THF eluant at 1 mL min−1; ‘PL
Gel’ (Polymer Laboratories).
19. 1H NMR data for 8a: l (CDCl3) 1.29 (10 H, brs,
CH2CH2(CH2)5CH2CH2), 1.49 (4 H, br, 2×NCH2CH2),
2.34 (6 H, s, 2×NMe), 2.42 (2 H, dd, J=13, 4 Hz) and
2.50 (2 H, dd, J=13, 8 Hz) (2×NCH2CHOH), 3.05 (2 H,
d, J=16 Hz) and 3.10 (2 H, d, J=16 Hz) (2×Sar-H2),
3.23 (4 H, q, J=7 Hz, 2×NCH2CH2), 3.35–3.55 (4 H, m,
2×OCH2CHOH), 3.62 (ca. 35 H, br, 9×OCH2CH2O),
3.91 (2 H, m, 2×CHOH), 7.45 (2 H, br, 2×NH).
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