Reaction of monensin silver salt with methyl iodide: Smooth alkylation of a tightly hydrogen-bonded carboxylate

Article abstract of DOI:10.1080/10610278.2010.506550

Despite its structural similarity to the sparingly reactive sodium salt of monensin, the silver salt of monensin was smoothly alkylated with methyl iodide on the carboxyl group to give the methyl ester of monensin.

Full text of DOI:10.1080/10610278.2010.506550

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Reaction of monensin silver salt with methyl iodide:
smooth alkylation of a tightly hydrogen-bonded
carboxylate
a
a
Yoshio Inagaki & Tadao Shishido
a
Synthetic Organic Chemistry Laboratories, Fujifilm Corporation , 577 Ushijima, Kaisei-
Machi, Ashigarakami-Gun, Kanagawa, 258-8577, Japan
Published online: 27 Aug 2010.
To cite this article: Yoshio Inagaki & Tadao Shishido (2011) Reaction of monensin silver salt with methyl iodide:
smooth alkylation of a tightly hydrogen-bonded carboxylate, Supramolecular Chemistry, 23:01-02, 19-21, DOI:
10.1080/10610278.2010.506550
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Supramolecular Chemistry
Vol. 23, Nos. 1–2, January–February 2011, 19–21
Reaction of monensin silver salt with methyl iodide: smooth alkylation of a tightly
hydrogen-bonded carboxylate
Yoshio Inagaki* and Tadao Shishido
Synthetic Organic Chemistry Laboratories, Fujifilm Corporation, 577 Ushijima, Kaisei-Machi, Ashigarakami-Gun,
Kanagawa 258-8577, Japan
(
Received 28 May 2010; final version received 28 June 2010)
Despite its structural similarity to the sparingly reactive sodium salt of monensin, the silver salt of monensin was smoothly
alkylated with methyl iodide on the carboxyl group to give the methyl ester of monensin.
Keywords: monensin; ionophore; ion selective electrode; esterification; intramolecular hydrogen bond
Introduction
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) for 4 days at
room temperature gave monensin methyl ester 2 in 75%
yield (21), and the reaction of monensin 1 with methanol
in the presence of 1,3-dicyclohexylcarbodiimide (DCC)
and a catalytic amount of 4-pyrrolidinopyridine gave 2 in
Monensin 1 (Figure 1) is a polyether ionophore that forms
lipophilic complexes with metal cations and is capable of
controlling the transport of cations across cell membranes
(
1). With these properties, monensin exhibits antibiotic
8
8% yield (22). Monensin sodium salt 4 was esterified
activity and has been used as a coccidiostat for poultry. In
the search for more efficient and selective cation-binding
substances, the ionophoric properties of monensin
derivatives, including esters and amides, have been
investigated (2–12). The ionophoric properties of
monensin esters have been studied in ion-selective
electrodes (13, 14), and the methyl ester 2 has been
employed in a clinical system for the quantitative analysis
of sodium cations in human blood (15–17). For this
purpose, the methyl ester 2 must be free from
contamination by sodium cations.
with 1-bromoacetylpyrene in the presence of dicyclo-
hexyl-18-crown-6 in 30.6% yield (23), and with benzyl
bromide in the presence of cryptand[2.2.2] for 1 day at
room temperature in 98% yield (24).
In this paper, we report on our findings that the silver
salt of monensin 3, though it has a pseudocyclic structure
very similar to that of the sodium salt of monensin 4, was
smoothly alkylated with methyl iodide on the carboxyl
group to produce the methyl ester 2 (Scheme 1).
Monensin 1 is susceptible to direct esterification under
acidic conditions. Under neutral to basic conditions, the
carboxyl group on monensin must be activated. Unlike
O(25)- or O(26)-protected monensins (10), however, the
carboxyl group of monensin 1 or its sodium salt 4 is only
sparingly reactive because its pseudocyclic structure is
locked by two intramolecular hydrogen bonds between the
carboxyl group and O(25) and O(26) atoms as demon-
strated by X-ray crystallographic analyses (Figure 2)
Results and discussion
The silver salt of monensin monohydrate 3 was prepared
by the reaction of monensin sodium salt 4 with an aqueous
solution of silver nitrate (24, 25). We prepared the silver
salt using the reaction of monensin (free acid, mono-
hydrate) 1 and wet silver oxide in order to eliminate
contamination by sodium cations. The analytical data were
consistent with those previously reported for 3.
(
18–20). The esterification of monensin has, therefore,
A tetrahydrofuran solution of the monensin silver salt
dihydrate 3 (24) and an excess amount of methyl iodide
were mixed and heated under reflux for 3 h. Powdery
crystals of silver iodide, AgI, precipitated out and were
filtered off. The filtrate was chromatographed on silica gel
to give monensin methyl ester 2 in 66% yield. The
structure of the methyl ester, free from complex formation
been facilitated by disrupting the hydrogen-bond-enforced
pseudocyclic complex by generating a naked carboxylate.
This can be accomplished by either the combined use
of the free acid form of monensin plus bulky organic
bases or using the sodium salt of monensin plus
stronger ionophores as crown ethers or cryptands to
capture the sodium cation. For example, the reaction
of monensin 1 with methyl iodide in the presence of
1
13
with AgI, was confirmed by H, C NMR and IR
spectroscopies, mass spectrometry and elemental analysis.
*Corresponding author. Email: yoshio_inagaki@fujifilm.co.jp
ISSN 1061-0278 print/ISSN 1029-0478 online
q 2011 Taylor & Francis
DOI: 10.1080/10610278.2010.506550
http://www.informaworld.com

2
0
Y. Inagaki and T. Shishido
because the use of the silver salt eliminates contamination
by sodium cations.
OH
O
Me
OMe
Me
H
O
Me
Et
Me
Me
H
OH
R
O
O
Conclusions
H
O
O
O
Me Me
H
OH
H
We have found that the silver salt of monensin, in contrast
to the sparingly reactive sodium salt of monensin, was
smoothly alkylated with methyl iodide on the carboxyl
group to give the methyl ester of monensin. Although the
yield (66%) was lower than those of previously reported
reactions of monensin 1 with methyl iodide and DBU
(75%) (21) or with methanol and DCC (88%) (22), this
silver salt method nevertheless has practical advantages as
follows: (1) short reaction time (3 h vs. 4 days); (2) simple
work-up (AgI, the only non-volatile by-product, was easily
removed by filtration); (3) the stable precursor, the silver
salt of monensin 3, was storable for a longer period than
the free acid 1 and (4) recyclable by-product, AgI (as
useful elements, silver and iodine). In view of the
presumed reaction mechanism, this silver salt method is
potentially applicable to other ionophoric carboxylic acids
with monensin-like structures, including nigericin and
salinomycin and alkyl iodides other than methyl iodide
may be well employed.
1
: R = H; 2: R = Me; 3: R = Ag; 4: R = Na
Figure 1. Structural formula of monensin and its derivatives.
The elevated reactivity of the silver salt is rather
surprising in view of the following facts implying that
monensin binds a silver cation more firmly than a sodium
cation. According to an X-ray crystallographic analysis by
Pinkerton and Steinrauf (20), monensin silver salt has a
rigid structure in which a silver cation is confined in a
pseudocyclic structure locked by two hydrogen bonds
between the terminal carboxylate and O(25) and O(26)
(
Figure 2). This structure is very similar to that of the
sparingly reactive sodium salt (18), and moreover, the
formation constant for the silver salt 3 (log K ¼8.2 ^ 0.2)
f
(
26) is larger by more than two orders of magnitude than
that of the sodium salt 4 (log K ¼ 6.7 ^ 0.05) (26).
f
The low solubility of AgI most likely drove the esteri-
fication to completion by enhancing the irreversibility of
the reaction.
Experimental
The reaction of a silver salt of an acid with an alkyl
halide is used infrequently for the preparation of simple
aliphatic esters, but is sometimes valuable in making esters
from acids that are unstable towards direct esterification
General
13
1
Melting points were uncorrected. C and H NMR spectra
were recorded on Bruker WH-90 and Varian EM-390
spectrometers, respectively. Mass spectra were measured
with a JEOL JMS-01SG spectrometer, and IR spectra were
obtained with a JASCO IR-S grating double-beam
spectrophotometer.
(
27). This is also the case for monensin, which is
susceptible to esterification under acidic conditions (1).
Silver iodide, a by-product, is recyclable and free from
disposal problems owing to the established recycling
system for silver halides in the photographic industry. In
addition, this transformation has an advantage in preparing
the methyl ester for sodium-cation selective electrodes
Materials
Monensin sodium salt (Carbiochem, 4) was purchased
and used without further purification. Methyl iodide
(Wako Pure Chemical Industries, Osaka, Japan) was
OH
Me
O
Me
H
O
OMe
Me
Et
Me
OH
Me
H
O
Ag
OH
O
O
O
O
H
O
O
O
O
Me Me
H
M
H
O
O
MeI/THF, reflux 3h
7
O
H
O
OH
Me
OMe
Me
Me
H
Me
25
O
26
Me
H
Et
H
OH
+ AgI
1
Me
O
O
O
O
H
O
H
O
O
O
Me Me
H
OH
Figure 2. Schematic illustration of the pseudocyclic structure
for a metal salt of monensin.
Scheme 1. Reaction of monensin silver salt with methyl iodide.

Supramolecular Chemistry
21
passed through a short column of Al O before use. Silver
2
107.80, 176.16; [a ] ¼ 518 (AcOEt); Anal. calcd. for
3
D
oxide was prepared according to a reported procedure (28).
Monensin monohydrate 1 was prepared from the
corresponding sodium salt as described previously (29):
Milky white crystals, mp 113–1168C [117–1228C (29)];
C H O : C 64.89, H 9.42; Found: C 65.16, H 9.51%.
37 64 11
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IR (Nujol): 3540, 3330 and 1705 cm
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13
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(
(
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(
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(
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