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Complexes of amine cations with lasalocid A, a microbial ionophore
0064OiW85 S3.00+.00 Q 1985Pcrgaa~x1 RedaLtd.
Temhedim Vol. 41, No. 20. pp. 4437 to 4442, 1985 Printed in GreatBritin.
Caplexes
of Amine Cations with
Lasalocid A. a Ulcrobial IomplWe Rafaelita C.R. Cueco and Grover W. Everett* Department of Chemistry. Laurence,
of Kansas
University
Kansas
66045
(Received in USA 26 April 1985)
- Complexes
Abstract prepared diverse
steric
solvents
of
molecular
weight
Lasalocid
as chloroform
A-1 have
of organic canplexes
dissolve
and are characterized NMR data
and 13C nmr spectroscopy.
that
a carboxylic
di-,
lonophore
and trivalent
metal
solvent
across
natural
by bind
data show
by microorganisms,
produced
cations
in
the cations
weight -via hydrogen bonds to 03, 06, and OB. Molecular complexes are appreciably dissociated in chloroform solution.
A (I)‘, mono-,
with
readily
in this
indicate
been
substituents
A anion
none of these
transporting
such
CR-NH;l[lasalocid
a series
The crystalline
properties.
low polarity data
the stoichiometry
where R represents
and electronic
the lasalocid that
having
and characterized,
is
capable
of
qembranes.2-4
and artificial
I Crystallographic abbreviated
studies5-9
LAS, reveal
that
each of
which has a cyclic
oxygens
lie
on the inside
04,
06,
07’
05’
oxygen
of
of the lasalocid
the cations
are sandwiched
in all
but one case,
conformation of
stabilized
the
cation
cation
in all
in only
by intramolecular
leaving
the complex,
and OB bind
is bound to the
the Na+, Ag+, and Ba2+ complexes
a hydrophobic
six
of
hydrogen
outer
The five
structures.
and in no case
is
hereafter
0’
Most of
bonds.
surface.
the published
two structures,
A anion,
by two LAS ligands, the
oxygen.3
A carboxylate
involved
in cation
binding. In the solution differs
Prom that
laboratory
phase
in which
determined
remaining
having
attached
the general
Mn2+, Cd3’,
their
reported
lsolatfon
result
of
crystallographic that
the
amine
conformation CWIplSXeS
cation
of
of metal
the
is
several of
binds
two ligands
ability
well
chiral
crystallization the LAS-cation
used
Another solution
“take
are
involving
intramolecular
via
04.
06’
crystalline
and characterized
to bind and transport and the existence
and 07
complexes for
established.2-4*‘2-‘4 of
crystalline
ones for of complex
In 1:'
amine cations.
of 1:l
complexes
1977,
M - Ca2+,
Host of the
in solution
Westley
et --
LAS-amine complexes.
which resolution
of
one diastereomer
the racemic of
the
and
a1.15
first
A number of amine occurred
complex.
An x-ray
of R-(*I-1-amino-1-(4-brcmophenyllethane
showed The overall
LAS -via hydrogen bonds Prom -NH3+ to 03’ 06’ and Og’ in this complex was Pound to be the same as that
LAS backbone
cations.
binding
study”
binding
studies,
clearly Prom this
cation
recent a dynamic,
turns”
In both these
for
ligation paper”
or half-integer.
amines,
and characterlzatlon
study15
charge.
in chloroform
at 03 and OB.
its
biogenic
preferential
LAS oxygens
cation
of
in a recent
Hn+(LASjn . X CHC13 were prepared
known for
amines were used including as the
in which at least
in membrane transport
the
that
where the pattern
are summarized
the specific
Here X 1s an integer
A is also
instances
These
and the
to the cation
work has involved
role
that
polarity
stolchianetry
and La3+.
Lasalocid prevlous
a number of state.
of LAS indicates
donor exchange occurs
while
are
we demonstrate
by both the solvent
Ca2+ and La 3+ complexes ligand
there
Pound in the solid
However,
unlike
the dlmeric
monomeric. 4437
Na+ and Ag’
complexes,
in
the amine complex
LAS is
4438
R. C. R.
of our work concerned
As an extension
cations in the solution
and G. W. EVERETT
GUECO
the
with
ligating
phase, it seemed appropriate
properties
to attempt
of LAS toward inorganic
to establish
how the lasalocid
anion binds organic amine cations in the solution phase. Thus we have prepared and characterized a series of complexes varied
of LAS having
systematically
over
the general
stoichiometry
a range of organic
(R-NHS)(LASl. where the R-group
substituents
varying
in steric
properties
is and
functional groups. RESULTS AND DISCDSSICU The procedure used for preparing LAS complexes described in this paper and in previous reports from this laboratory'"~" elemental
analyses
is designed
are consistent
to ensure
saturation
of the ionophore.
with the 1:l stoichiometry
(cationl(LAS).
In all
stoichianetric amount of water is associated with the complex. Results of elemental melting points of the complexes are given in Table I.
Effective molecular
cases,
In some cases a analyses and
weights in chloroform
solution are shown in Table II. The complexes are very soluble in organic solvents of low polarity such as chloroform and qethylene chloride and have moderate solubilities
in cyclohexane and carbon
tetrachloride.
Table
s
rn4+ %O
%O
c8p3+ + CZ”5-m3 pC4H9-NH,+
+ 'b"S-NH) lad-nr mahe
CC’)
of
(Catiml”+)w3), * 8 ComplaM
w.
zc found
2
*.
found
cakd. --
E
found
170-172(d)
67.18
66.72
9.45
9.25
2.30
1.97
187-189
66.64
66.50
9.59
9.84
2.22
2.19
202-204
68.00
67.61
9.67
9.60
2.20
2.15
196-198
68.74
68.86
9.87
10.10
2.11
2.07
158-160
69.33
69.05
9.02
9.10
2.02
1.95
201-203
71.22
71.00
9.64
9.56
1.89
1.84
70.85
70.99
9.20
9.48
1.97
1.80
112
69.97
70.17
9.23
9.50
1.94
1.70
158-159
66.17
66.00
9.25
9.50
1.98
1.68
67.80
67.48
8.81
9.00
1.88
1.81
69.51
69.40
9.92
10.01
2.03
1.82
l-
*
IJ
R-(+)a--thy1 bauylanina*H+ 4H20
characrsriz~timl
1.
H.P.
CatlO”
196-196 (lit.15 198-199)
w-;~~:hYY
sthyl-t-alaninate . II+
216-218 wt.‘5 220) 189-191
w
C&Xi.
rarnd
613
591
1
608
620
3 I( 6
636 664
622
142
126
8
712
100
10
744
132
Y&As
652
Complexes of amine cations with lasakid
Organic
amlnes with
diverse
ability
primary
but we were unable
amines,
eplnephrine amlnes
by the usual
having
complexes 4Table
II).
both
dlamlne,
or
complexes hydrogen
ccmp1e.l
-5
enantlomers
similar
2 and s
in
which
of
the chlral
assessed the
% -_.Y
- C4
cg
3-L
L
&_
121.5
N.U.5
176.5
118.1
160.8
123.0
131.3
119.9
m4sb
175.4
116.0
161.3
123.2
131.7
119.7
1
175.9
116.2
161.5
123.1
131.9
119.9
143.9
2
176.1
116.5
161.7
123.3
131.9
119.9
144.1
70.5
3
175.9
116.1
162.0
123.4
131.9
119.9
144.3
70.4
4
175.1
116.2
161.9
123.4
131.8
119.8
144.4
70.5
5
175.9
115.4
161.9
123.6
132.5
120.2
144.5
70.5
6
175.7
116.4
162.0
123.4
131.8
119.7
144.5
7
175.9
116.0
162.3
123.6
132.2
120.1
a
175.8
116.0
162.2
123.5
132.1
9
175.9
116.1
162.1
123.6
10
176.2
115.8
161.4
11
176.0
116.2
162.1
products
absorbances 1020(w);
occur
1048(s),
weight
groups
with 1:l
determinations were easily III).
one at each end.
’ 3C nmr data)
and/or
c1)
capable
%a ---
of
The No are
forming
?9
c22
86.4
70.9
73.2
82.7
87.2
68.3
71.0
04.7
87.7
69.7
71.6
56.0
a2.a
87.2
70.0
71.5
218.2
56.2
83.1
87.6
69.6
71.2
218.3
56.4
83.0
87.7
70.1
71.0
218.2
56.3
83.2
81.2
70.0
70.9
217.8
51.2
83.5
87.7
70.4
71.5
56.3
83.2
87.3
70.1
70.7
56.5
83.1
87.7
70.3
71.1
56.6
81.0
87.5
68.9
71.0
210.7
56.7
83.1
87.7
70.1
71.2
48.6
218.0
56.2
03.4
87.9
70.1
71.5
49.2
21a.2
56.5
83.1
87.7
70.3
71.1
214.6
55.3
84.1
143.3
70.4
48.6
218.5
55.b
143.7
70.5
48.2
216.2
56.4
70.4
49.0
217.3
49.0 49.2 48.9 49.2
70.7
48.9
217.8
144.6
70.6
49.3
218.4
119.9
144.5
70.4
49.5
219.2
132.2
120.0
144.5
70.7
49.4
123.6
132.4
120.3
144.8
70.8
123.5
132.0
120.0
144.4
70.5
110.3(s),
144.3
complex
in order
The spectra
at the following 1048(s);
_%_
49.1
of NaLAS and of in 2.
L
72.)
CH3CH2NH2, were compared
reaction
weight
Cl3 and C,9 (Table
has functional
135.2
spectra
even
of monomeric.
-two LAS anions,
all
amine R-(-j-
a-methylbenxylamlne for
assess
with
bonds.
124.4
Infrared
except
by molecular
161.8
amlnes,
of molecular
to
obtained
The existence
binds
cation
the secondary
were readily
amine,
shifts
113.4Ill.3
“IA.9
of LAS with
by the results
apparently (as
obtained
complexes
13C nmr chemical
structures
in order
were readily
and l-adamantyl.
demonstrated
1,12-diaminododecane,
stoichiometrles for
as t-butyl
is
were chosen
complexes
a complex
Stolchlometrlc
such
4439
properties
Crystalline
to isolate
procedure.
of
and electronic
lonophore.
solution
Complexes
add1 tlonal
the
R-groups
These have very
long-chain found
large
in chloroform
prepared. unusual
of
steric
the coordinating
A
are
formed frax test
for
virtually
frequencies 1103(s);
1, to
(in
the cation
the
identical. cd’)
1248(w),
for 1254(w);
of one of the more reactive
occurrence
of
In the
Schlff
base
1000-2000
cm-’
2 and NaLAS. resPectlveIY: 1281(s),
1275(a);
1321(s),
or amide region, 1022(w), 1321(s);
4440
R. C. R. Gusto and G. W. EVERETT
1385(vs),
1383(vs);
Thus there
is
1429(vs),
no evidence
Binding ---Sites (4-br~~henyl)athane also
bind
of
complexes
the complexes
shifts
of
Spectra
III.
of
Chemical
III.
signals
It generally
closer
complexes
of
solution
binding
cation
Prom Table of
cation-bound
shifts
for
implies
near
C,2s
C2, C3, Cll,
Clg,
chemical
diFPerences
shift
Sfmilarly, the 05’ diPPerently with 06. relatively
small
13C nmr data
indicate
Chemical
very
for
Sites
solution
COmpariBOn. are
that
LAS
StrUctUres
in
POr Na+ in the
at Lou temperatures
which Strongly at 0,.
indicates
similar
T%+
Oqr and 07.
1, and it might
and induce
Were
in Table
amine Complexes
Similar
binding
coupling.
shifts
for
This
The ionic
be expected,
conformations
difference
C, 5 and Cl 8, ” NH: binds
hydrogen
2
in the
the observed ring
particular
interest,
shifts
assumed that
for
this
manner as its
to
cationslO, of 0.2-1.4
test could
and fc)
unlike
C.,5 implies
(b)
is
at 03,
08,
the
bromlnated
nmr spectrum whether
the unexplained
Tt+
LAS at 03 Larger
and NHI(+ in
large
large
ions
and probably are rather
diPference
is
is the only
cation
shift
view
diPPerenoea
differences
It
interact
OP (a)
cannot
the
in TP-C in
bound at 06.10n2’.
06.
g).
capable
differences
is
similar
at Cl3 for
electronic
cation
spin-
Overall,
be ascertained
are attributed
analog
in the
binds
solid
of
to
the
the
effects
of 1 is
Rf+)-1-amino-l-(4state.”
complexes.
If
solution
nmr data
be
bonds.
Canplex
and 08 in the solid
the other
only
might
to steric!
LAS in chloroform
state,
differ
Pour hydrogen
of the R-group.
related
from those
ammonium cation
and in general Some differences
of forming
influences
closely
deviations
imply
it
is
in the same
binding
at 03,
Complexes. of
1C2H5NH3)(LAS), 1,
solvent
be discerned.
ppm were observed
in chemical binds
T%+, NH&+ is not bound to
that
the unexpectedly
except
the possible
resonance.)
questionable
by paramagnetlc
carbons
differences
by the solvent
which has been shown to bind LAS at 03, 06,
the amine Cation
The carbon-13 (DMF) solution
at C,8,
and other
1 show no unusual
(4-phenyl)
for
all
the NH4+ cation
that,
implication
chemical
the R-(+I-a-methylbenzyl
061 and 08 for $&
Tt+,
1s obscured
amine complexes
currents, since
cation
The smaller
like
for
manner with
bond.
ainoe
the R-group,
braaophenyllethane
latter
of NH4LAS (largest
-2-l-*1 araaatic
that,
dfPPerence
this
that
by 0.5 ppm or less LAS in a similar
(05 and 06).
of Cl5 and Cl8 induced
the NH{ complex,
bind
Por Cl2 and C,3 suggest
among the other
Prom those
differ
ions
and C,5
shift
Among canplexes
changes
the
of Tf.+ binding
sites
(The C23 signal
shift
between rates
metal
given
for
signals
listed
of HLAS, indicating
have the
not
of the nmr data of the amine complexes.
and C22 indicate
However,
relaxatlon
Chemical
probably
Purpose. in Table
The latter
for
than to those
no evidence
these
C13,
chemical
whether NH; Porms a fourth
of
observed
A and 1.66 A, respectively2’
that
observed
chemical
coup1 ing constants
expected
shifts
203*205T%-‘3C
is
of the T%+ and NH4+ complexes
at 01, 04, or 07.
slightly
1).
this
are given
Of NaLAS except
but are
OP TLLAS In chloroform
interpretation
and 08 but not
the
that
Fig.
known regarding
due to
(1.54
(see
procedures
cations
seek the same LAS binding
This
0P oxygens Par Ct.
lattice
metal
There
to
NatAS, and T$LAS are also
chemical
definitely
splitting,
point
C12, C13, and C15. exception
similar
for
13C
oP LAS
ionophore.
Chemical
shifts
very
decoupling
the ‘3C nmr spectrum
signal
they would
are
phase,
nmr spectra
resolved assignments 7.16-18
firm
the Na* and T11* complexes is
Proton
insufficiently
having
acid),
and monovalent
Houever,
a starting that
(80 MHz) are
111 that
of Tt* and NH; are similar
priori
of R(+l-l-amino-l-
in the solution
were examined.
off-resonance
nothing
of
solution
complexes
at OS, OS, 06, and 08.l’
provides radii
1705(s).
in Solution.
from the amine substltuent
amine cations
shows a pattern
bonding
routine
those
to
phase,
1707(s).
the cation
the amine-LAS interaction
13C signals
Por HLAS(lasalocid seen
Virtually
solution.
1597fvs);
has shown that
arising
of
shifts
is readily
of
spectrometer
amine
with the aid
hydrogen
in chloroform
read1 ly-observed
oP the
superposition assigned
used for the nature
the Bruker up-80
on
Chemical
1593(va),
between the amine and LAS.
LAS -via hydrogen bonds CO 03* 06, and 08.‘= Other amine Cations maY manner in the solid state, but as pointed out in the Introduction. tha same
to establish
of
1458(vs);
Crystallography
Amine Cations.
are not necessarily
1n an effort nmr spectra
1456(vs),
bond formation
binds
LAS in this
LAS oxygens
1429(s);
Por covalent
polarity On going
for
was also
ePfects fran
most carbons
chloroform oP 2.
examined in N,N-dimethylformamfde
on ligation,
such
as those
to DffF solutions,
Similar
changes
observed chemical
are observed
also
for shift uith
Complexes of amine cations with lasalocid A
7
13
15 16
6
120
160
4441
80
40
&
20-l4Hz carbon-l 3 nmr spectrum ,&~,,cO~GYg klm (tlhe in chloroform SolutlOn. k&k?ylk!ine~H)kA.S). adamantyl grou are assigned as follows: Al, Cl(52.1 PPm); A c2 + C8 + C9 (41.1 ppm); B 3, C3 + C5 + C7 (29.2 PP~); Aq, CQ + hj + Cl0 ( 3’5.8 PPm).
and do not necessarily
NaLAS”
of 2.3 ppm found and x
indicate
found for
for
Summary.
the
08 does
not bind
Crystalline,
1:l
changes (the
in ligation.
However.
corresponding
change
the amine In the more polar
remain
closely
complexes
prepared.
than to Porm hydrogen ions
fran
the chemical is only
solvent.
A
shift
change
0.6 ppm for
NaLAS)
Similar
SltUatiOn
was
the Un2+ cation”.
primary amines are readily other
result
C22 of 3 is exceptional
bonds.
associated.
of
IR spectra Moleoular Carbon-13
the lasalocid show that weight
A anion
data demonstrate
nmr data
A anion are involved ‘a1 and probably 06 of the lasalocld been found for a related complex in the solid state.
with
cations
the amine3 do not react in chloroform
that
of a
Variety
in chloroform
solution
in hydrogen bonding
of
with lasalocid indicate
to the cations
A
solution that
03,
as has
4442
R. C. R. Gueco and G.
W.
EVEXETT
Materials. NqI,ASwas purchased Prom Aldrich Chemical Company and used wlthoyt,,fur\h;; puriPl?XlZon 8l C nmr chemicalshifts were in good agreementwith reportedvalues, @ signals attribut%e to impuritiescould be detected. Some of the amine8 used are available as their hydrochloridesalts and, with the exceptionof Anlline*HClwas recrystallizedseveral times the exceptionof Rin ethyl ether. The ether then dried in vacua. ution of the amine Pono~ -The procedureused to prepare LAS complexesof amine cations ~:;Io~~~E~~a~~~~~t~d3~ev~ously for p reparatlon of LAS complexes of metal . ml aqueousso ut on containing10 mm01 of the amine hydrochloride is divided into three lo-ml portions. Each portion,in turn, la stirred vi orcusly for 2-3 hr with 25 ml of a chloroformor meth lene chloridesolution containing1 mm01 NaLf S. The non-aqueous layer is then washed several % imea with water and dried over molecular sieves. Subsequentfiltrationfollowed by removal of the solvent -in vacua affordsa crystallineproduct. Instrumentation. Carbon-13 nmr spectra were obtained on a Bruker WP-80 FT spectrometer ac Cu m Spectra were run at the ambient probe temperature of 39OC using 8~ data lemental inal sea were carried out on a Hewlett Packard Model 1858 C, H, N analyzer ocated in the Departmen f.of Medicinal Chemistry. Repeatedanalyses of the same instrumentspanneda ran e of 0.51 for C and 0.4sfor H and N. Nltro en analyadS-%lB Molecular weight determfnations were made in chloroformsolution a& 37°C using a Hewlettl&&% Model 302 vapor reaaure oamometer. The oamometerwas calibratedusing recrystallizedbenzil, and solutions were Pn the concentration range OP 1 to 10 mmolar. Infrared s ectra were run on KBr elleta using an IBM InstrumentsIR 32 FT apectrophotometer. All melting poPnta were measuredon a fhomas Hoover capillarymelting point apparatusand are uncorrected.
1.
The numberingscheme used here is that roposed earlier: Weatley. J.W.J. Antibiot.1976, 29. 584. Oxygen numbers are shown in parenPheses.
2.
Weatley. J.W. "Pal ether Antibiotics: Naturally OccurringAcid Icnophorea";Vol. I and II; Marcel Dekker:Base 1, 1982. Ovchinnikov,Y.A. in "Frontiersin Bioor anic Chemistryand,y7\ecularBiology";Ovchinnikov, Y.A.and Kolosov, M.N.,Eda. Chapter 8: &sevier:Amsterdam, .
3. 4.
Poonia, N.S.:Bajaj, A.V. Chem. Rev. 1979, 79, 389.
5.
Smith, G.D.;Daux, W.L.;Fortier. S. J. Am. Chem. Sot. 1978, 100. 6725.
6.
Chiang, C.C.;Paul, I.C.Science (Washington,D.C.)1977, 196, 1441.
7.
Schmidt, P.G.;Wang, A.H.-J.;Paul, I.C.J. Am. Chem. Sot. 1974, 96, 6189. Maier, C.A.:Paul, I.C.J. Chem. Sot. Chem. Commun. 1971, 181.
a. 9. 10.
Johnson. S.H.;Herrin, J.; Liu. S.J.:Paul, I.C.J. Am. Chem. Sot. 1970, 92, 4428. Hanna, D.A.;Yeh, C; Shaw, J.; Everett, C.W.Biochem. 1983, 22, 5619.
11. Everett, C.W.;Parker, S.B.;Wllllama, R.J.P.Biochem. 1983, 22, 6149. 12.
Melnik E I . Lindenbaum. S.; Sternaon. L.A.;Ovchinnlkov, ~::;~:.&~:i;~, 684. 2.33:
Y.A.
Bicchlm. et
13. ~:~",~:~.",~F~a1MsBS:11i~~~,EjIjj.Sternson. L.A.; Lindanbaum. S; Ovchinnikov, Y.A. Biochim. et 14. Kinael Pharmac&%
Melnik E.1 * Lindenbaum, S.; Sternson, L.A.;Ovchinnikov, Y.A. Internat. J. 1982, 13. 97:'
15. Weatley, J.W.;Evans, R.H.,Jr.: Blount, J.F.J. Am. Chem. Sot. 1977, 99, 6057. 16. Seto. H.; Westley, J.W.;Pitcher, R.G.J. Antlbiot. 1978, 31. 289. 17. Anteunis, M.J.O.Bioorg. Chem.w,
5, 327.
18. Patel, D.J.:Shen. C. Proc.Natl. Acad. Sci. USA 1976, 73, 1786, 4277. 19. Lallemand, J.-Y.:Michon, V.J.Chem.Rea.. miniprint 1978, 2081. 20. Cotton, F.A.;Wilkinson,G. "AdvancedInorganicChemistry";4th Ed.: John Wiley and Sons: New York, 1980. 21. Lallemand, J.-Y.;Rao, R.; Prange, T. Nouv. J. Chlm. 1980, 4, 315.
Temhedim Vol. 41, No. 20. pp. 4437 to 4442, 1985 Printed in GreatBritin.
Caplexes
of Amine Cations with
Lasalocid A. a Ulcrobial IomplWe Rafaelita C.R. Cueco and Grover W. Everett* Department of Chemistry. Laurence,
of Kansas
University
Kansas
66045
(Received in USA 26 April 1985)
- Complexes
Abstract prepared diverse
steric
solvents
of
molecular
weight
Lasalocid
as chloroform
A-1 have
of organic canplexes
dissolve
and are characterized NMR data
and 13C nmr spectroscopy.
that
a carboxylic
di-,
lonophore
and trivalent
metal
solvent
across
natural
by bind
data show
by microorganisms,
produced
cations
in
the cations
weight -via hydrogen bonds to 03, 06, and OB. Molecular complexes are appreciably dissociated in chloroform solution.
A (I)‘, mono-,
with
readily
in this
indicate
been
substituents
A anion
none of these
transporting
such
CR-NH;l[lasalocid
a series
The crystalline
properties.
low polarity data
the stoichiometry
where R represents
and electronic
the lasalocid that
having
and characterized,
is
capable
of
qembranes.2-4
and artificial
I Crystallographic abbreviated
studies5-9
LAS, reveal
that
each of
which has a cyclic
oxygens
lie
on the inside
04,
06,
07’
05’
oxygen
of
of the lasalocid
the cations
are sandwiched
in all
but one case,
conformation of
stabilized
the
cation
cation
in all
in only
by intramolecular
leaving
the complex,
and OB bind
is bound to the
the Na+, Ag+, and Ba2+ complexes
a hydrophobic
six
of
hydrogen
outer
The five
structures.
and in no case
is
hereafter
0’
Most of
bonds.
surface.
the published
two structures,
A anion,
by two LAS ligands, the
oxygen.3
A carboxylate
involved
in cation
binding. In the solution differs
Prom that
laboratory
phase
in which
determined
remaining
having
attached
the general
Mn2+, Cd3’,
their
reported
lsolatfon
result
of
crystallographic that
the
amine
conformation CWIplSXeS
cation
of
of metal
the
is
several of
binds
two ligands
ability
well
chiral
crystallization the LAS-cation
used
Another solution
“take
are
involving
intramolecular
via
04.
06’
crystalline
and characterized
to bind and transport and the existence
and 07
complexes for
established.2-4*‘2-‘4 of
crystalline
ones for of complex
In 1:'
amine cations.
of 1:l
complexes
1977,
M - Ca2+,
Host of the
in solution
Westley
et --
LAS-amine complexes.
which resolution
of
one diastereomer
the racemic of
the
and
a1.15
first
A number of amine occurred
complex.
An x-ray
of R-(*I-1-amino-1-(4-brcmophenyllethane
showed The overall
LAS -via hydrogen bonds Prom -NH3+ to 03’ 06’ and Og’ in this complex was Pound to be the same as that
LAS backbone
cations.
binding
study”
binding
studies,
clearly Prom this
cation
recent a dynamic,
turns”
In both these
for
ligation paper”
or half-integer.
amines,
and characterlzatlon
study15
charge.
in chloroform
at 03 and OB.
its
biogenic
preferential
LAS oxygens
cation
of
in a recent
Hn+(LASjn . X CHC13 were prepared
known for
amines were used including as the
in which at least
in membrane transport
the
that
where the pattern
are summarized
the specific
Here X 1s an integer
A is also
instances
These
and the
to the cation
work has involved
role
that
polarity
stolchianetry
and La3+.
Lasalocid prevlous
a number of state.
of LAS indicates
donor exchange occurs
while
are
we demonstrate
by both the solvent
Ca2+ and La 3+ complexes ligand
there
Pound in the solid
However,
unlike
the dlmeric
monomeric. 4437
Na+ and Ag’
complexes,
in
the amine complex
LAS is
4438
R. C. R.
of our work concerned
As an extension
cations in the solution
and G. W. EVERETT
GUECO
the
with
ligating
phase, it seemed appropriate
properties
to attempt
of LAS toward inorganic
to establish
how the lasalocid
anion binds organic amine cations in the solution phase. Thus we have prepared and characterized a series of complexes varied
of LAS having
systematically
over
the general
stoichiometry
a range of organic
(R-NHS)(LASl. where the R-group
substituents
varying
in steric
properties
is and
functional groups. RESULTS AND DISCDSSICU The procedure used for preparing LAS complexes described in this paper and in previous reports from this laboratory'"~" elemental
analyses
is designed
are consistent
to ensure
saturation
of the ionophore.
with the 1:l stoichiometry
(cationl(LAS).
In all
stoichianetric amount of water is associated with the complex. Results of elemental melting points of the complexes are given in Table I.
Effective molecular
cases,
In some cases a analyses and
weights in chloroform
solution are shown in Table II. The complexes are very soluble in organic solvents of low polarity such as chloroform and qethylene chloride and have moderate solubilities
in cyclohexane and carbon
tetrachloride.
Table
s
rn4+ %O
%O
c8p3+ + CZ”5-m3 pC4H9-NH,+
+ 'b"S-NH) lad-nr mahe
CC’)
of
(Catiml”+)w3), * 8 ComplaM
w.
zc found
2
*.
found
cakd. --
E
found
170-172(d)
67.18
66.72
9.45
9.25
2.30
1.97
187-189
66.64
66.50
9.59
9.84
2.22
2.19
202-204
68.00
67.61
9.67
9.60
2.20
2.15
196-198
68.74
68.86
9.87
10.10
2.11
2.07
158-160
69.33
69.05
9.02
9.10
2.02
1.95
201-203
71.22
71.00
9.64
9.56
1.89
1.84
70.85
70.99
9.20
9.48
1.97
1.80
112
69.97
70.17
9.23
9.50
1.94
1.70
158-159
66.17
66.00
9.25
9.50
1.98
1.68
67.80
67.48
8.81
9.00
1.88
1.81
69.51
69.40
9.92
10.01
2.03
1.82
l-
*
IJ
R-(+)a--thy1 bauylanina*H+ 4H20
characrsriz~timl
1.
H.P.
CatlO”
196-196 (lit.15 198-199)
w-;~~:hYY
sthyl-t-alaninate . II+
216-218 wt.‘5 220) 189-191
w
C&Xi.
rarnd
613
591
1
608
620
3 I( 6
636 664
622
142
126
8
712
100
10
744
132
Y&As
652
Complexes of amine cations with lasakid
Organic
amlnes with
diverse
ability
primary
but we were unable
amines,
eplnephrine amlnes
by the usual
having
complexes 4Table
II).
both
dlamlne,
or
complexes hydrogen
ccmp1e.l
-5
enantlomers
similar
2 and s
in
which
of
the chlral
assessed the
% -_.Y
- C4
cg
3-L
L
&_
121.5
N.U.5
176.5
118.1
160.8
123.0
131.3
119.9
m4sb
175.4
116.0
161.3
123.2
131.7
119.7
1
175.9
116.2
161.5
123.1
131.9
119.9
143.9
2
176.1
116.5
161.7
123.3
131.9
119.9
144.1
70.5
3
175.9
116.1
162.0
123.4
131.9
119.9
144.3
70.4
4
175.1
116.2
161.9
123.4
131.8
119.8
144.4
70.5
5
175.9
115.4
161.9
123.6
132.5
120.2
144.5
70.5
6
175.7
116.4
162.0
123.4
131.8
119.7
144.5
7
175.9
116.0
162.3
123.6
132.2
120.1
a
175.8
116.0
162.2
123.5
132.1
9
175.9
116.1
162.1
123.6
10
176.2
115.8
161.4
11
176.0
116.2
162.1
products
absorbances 1020(w);
occur
1048(s),
weight
groups
with 1:l
determinations were easily III).
one at each end.
’ 3C nmr data)
and/or
c1)
capable
%a ---
of
The No are
forming
?9
c22
86.4
70.9
73.2
82.7
87.2
68.3
71.0
04.7
87.7
69.7
71.6
56.0
a2.a
87.2
70.0
71.5
218.2
56.2
83.1
87.6
69.6
71.2
218.3
56.4
83.0
87.7
70.1
71.0
218.2
56.3
83.2
81.2
70.0
70.9
217.8
51.2
83.5
87.7
70.4
71.5
56.3
83.2
87.3
70.1
70.7
56.5
83.1
87.7
70.3
71.1
56.6
81.0
87.5
68.9
71.0
210.7
56.7
83.1
87.7
70.1
71.2
48.6
218.0
56.2
03.4
87.9
70.1
71.5
49.2
21a.2
56.5
83.1
87.7
70.3
71.1
214.6
55.3
84.1
143.3
70.4
48.6
218.5
55.b
143.7
70.5
48.2
216.2
56.4
70.4
49.0
217.3
49.0 49.2 48.9 49.2
70.7
48.9
217.8
144.6
70.6
49.3
218.4
119.9
144.5
70.4
49.5
219.2
132.2
120.0
144.5
70.7
49.4
123.6
132.4
120.3
144.8
70.8
123.5
132.0
120.0
144.4
70.5
110.3(s),
144.3
complex
in order
The spectra
at the following 1048(s);
_%_
49.1
of NaLAS and of in 2.
L
72.)
CH3CH2NH2, were compared
reaction
weight
Cl3 and C,9 (Table
has functional
135.2
spectra
even
of monomeric.
-two LAS anions,
all
amine R-(-j-
a-methylbenxylamlne for
assess
with
bonds.
124.4
Infrared
except
by molecular
161.8
amlnes,
of molecular
to
obtained
The existence
binds
cation
the secondary
were readily
amine,
shifts
113.4Ill.3
“IA.9
of LAS with
by the results
apparently (as
obtained
complexes
13C nmr chemical
structures
in order
were readily
and l-adamantyl.
demonstrated
1,12-diaminododecane,
stoichiometrles for
as t-butyl
is
were chosen
complexes
a complex
Stolchlometrlc
such
4439
properties
Crystalline
to isolate
procedure.
of
and electronic
lonophore.
solution
Complexes
add1 tlonal
the
R-groups
These have very
long-chain found
large
in chloroform
prepared. unusual
of
steric
the coordinating
A
are
formed frax test
for
virtually
frequencies 1103(s);
1, to
(in
the cation
the
identical. cd’)
1248(w),
for 1254(w);
of one of the more reactive
occurrence
of
In the
Schlff
base
1000-2000
cm-’
2 and NaLAS. resPectlveIY: 1281(s),
1275(a);
1321(s),
or amide region, 1022(w), 1321(s);
4440
R. C. R. Gusto and G. W. EVERETT
1385(vs),
1383(vs);
Thus there
is
1429(vs),
no evidence
Binding ---Sites (4-br~~henyl)athane also
bind
of
complexes
the complexes
shifts
of
Spectra
III.
of
Chemical
III.
signals
It generally
closer
complexes
of
solution
binding
cation
Prom Table of
cation-bound
shifts
for
implies
near
C,2s
C2, C3, Cll,
Clg,
chemical
diFPerences
shift
Sfmilarly, the 05’ diPPerently with 06. relatively
small
13C nmr data
indicate
Chemical
very
for
Sites
solution
COmpariBOn. are
that
LAS
StrUctUres
in
POr Na+ in the
at Lou temperatures
which Strongly at 0,.
indicates
similar
T%+
Oqr and 07.
1, and it might
and induce
Were
in Table
amine Complexes
Similar
binding
coupling.
shifts
for
This
The ionic
be expected,
conformations
difference
C, 5 and Cl 8, ” NH: binds
hydrogen
2
in the
the observed ring
particular
interest,
shifts
assumed that
for
this
manner as its
to
cationslO, of 0.2-1.4
test could
and fc)
unlike
C.,5 implies
(b)
is
at 03,
08,
the
bromlnated
nmr spectrum whether
the unexplained
Tt+
LAS at 03 Larger
and NHI(+ in
large
large
ions
and probably are rather
diPference
is
is the only
cation
shift
view
diPPerenoea
differences
It
interact
OP (a)
cannot
the
in TP-C in
bound at 06.10n2’.
06.
g).
capable
differences
is
similar
at Cl3 for
electronic
cation
spin-
Overall,
be ascertained
are attributed
analog
in the
binds
solid
of
to
the
the
effects
of 1 is
Rf+)-1-amino-l-(4state.”
complexes.
If
solution
nmr data
be
bonds.
Canplex
and 08 in the solid
the other
only
might
to steric!
LAS in chloroform
state,
differ
Pour hydrogen
of the R-group.
related
from those
ammonium cation
and in general Some differences
of forming
influences
closely
deviations
imply
it
is
in the same
binding
at 03,
Complexes. of
1C2H5NH3)(LAS), 1,
solvent
be discerned.
ppm were observed
in chemical binds
T%+, NH&+ is not bound to
that
the unexpectedly
except
the possible
resonance.)
questionable
by paramagnetlc
carbons
differences
by the solvent
which has been shown to bind LAS at 03, 06,
the amine Cation
The carbon-13 (DMF) solution
at C,8,
and other
1 show no unusual
(4-phenyl)
for
all
the NH4+ cation
that,
implication
chemical
the R-(+I-a-methylbenzyl
061 and 08 for $&
Tt+,
1s obscured
amine complexes
currents, since
cation
The smaller
like
for
manner with
bond.
ainoe
the R-group,
braaophenyllethane
latter
of NH4LAS (largest
-2-l-*1 araaatic
that,
dfPPerence
this
that
by 0.5 ppm or less LAS in a similar
(05 and 06).
of Cl5 and Cl8 induced
the NH{ complex,
bind
Por Cl2 and C,3 suggest
among the other
Prom those
differ
ions
and C,5
shift
Among canplexes
changes
the
of Tf.+ binding
sites
(The C23 signal
shift
between rates
metal
given
for
signals
listed
of HLAS, indicating
have the
not
of the nmr data of the amine complexes.
and C22 indicate
However,
relaxatlon
Chemical
probably
Purpose. in Table
The latter
for
than to those
no evidence
these
C13,
chemical
whether NH; Porms a fourth
of
observed
A and 1.66 A, respectively2’
that
observed
chemical
coup1 ing constants
expected
shifts
203*205T%-‘3C
is
of the T%+ and NH4+ complexes
at 01, 04, or 07.
slightly
1).
this
are given
Of NaLAS except
but are
OP TLLAS In chloroform
interpretation
and 08 but not
the
that
Fig.
known regarding
due to
(1.54
(see
procedures
cations
seek the same LAS binding
This
0P oxygens Par Ct.
lattice
metal
There
to
NatAS, and T$LAS are also
chemical
definitely
splitting,
point
C12, C13, and C15. exception
similar
for
13C
oP LAS
ionophore.
Chemical
shifts
very
decoupling
the ‘3C nmr spectrum
signal
they would
are
phase,
nmr spectra
resolved assignments 7.16-18
firm
the Na* and T11* complexes is
Proton
insufficiently
having
acid),
and monovalent
Houever,
a starting that
(80 MHz) are
111 that
of Tt* and NH; are similar
priori
of R(+l-l-amino-l-
in the solution
were examined.
off-resonance
nothing
of
solution
complexes
at OS, OS, 06, and 08.l’
provides radii
1705(s).
in Solution.
from the amine substltuent
amine cations
shows a pattern
bonding
routine
those
to
phase,
1707(s).
the cation
the amine-LAS interaction
13C signals
Por HLAS(lasalocid seen
Virtually
solution.
1597fvs);
has shown that
arising
of
shifts
is readily
of
spectrometer
amine
with the aid
hydrogen
in chloroform
read1 ly-observed
oP the
superposition assigned
used for the nature
the Bruker up-80
on
Chemical
1593(va),
between the amine and LAS.
LAS -via hydrogen bonds CO 03* 06, and 08.‘= Other amine Cations maY manner in the solid state, but as pointed out in the Introduction. tha same
to establish
of
1458(vs);
Crystallography
Amine Cations.
are not necessarily
1n an effort nmr spectra
1456(vs),
bond formation
binds
LAS in this
LAS oxygens
1429(s);
Por covalent
polarity On going
for
was also
ePfects fran
most carbons
chloroform oP 2.
examined in N,N-dimethylformamfde
on ligation,
such
as those
to DffF solutions,
Similar
changes
observed chemical
are observed
also
for shift uith
Complexes of amine cations with lasalocid A
7
13
15 16
6
120
160
4441
80
40
&
20-l4Hz carbon-l 3 nmr spectrum ,&~,,cO~GYg klm (tlhe in chloroform SolutlOn. k&k?ylk!ine~H)kA.S). adamantyl grou are assigned as follows: Al, Cl(52.1 PPm); A c2 + C8 + C9 (41.1 ppm); B 3, C3 + C5 + C7 (29.2 PP~); Aq, CQ + hj + Cl0 ( 3’5.8 PPm).
and do not necessarily
NaLAS”
of 2.3 ppm found and x
indicate
found for
for
Summary.
the
08 does
not bind
Crystalline,
1:l
changes (the
in ligation.
However.
corresponding
change
the amine In the more polar
remain
closely
complexes
prepared.
than to Porm hydrogen ions
fran
the chemical is only
solvent.
A
shift
change
0.6 ppm for
NaLAS)
Similar
SltUatiOn
was
the Un2+ cation”.
primary amines are readily other
result
C22 of 3 is exceptional
bonds.
associated.
of
IR spectra Moleoular Carbon-13
the lasalocid show that weight
A anion
data demonstrate
nmr data
A anion are involved ‘a1 and probably 06 of the lasalocld been found for a related complex in the solid state.
with
cations
the amine3 do not react in chloroform
that
of a
Variety
in chloroform
solution
in hydrogen bonding
of
with lasalocid indicate
to the cations
A
solution that
03,
as has
4442
R. C. R. Gueco and G.
W.
EVEXETT
Materials. NqI,ASwas purchased Prom Aldrich Chemical Company and used wlthoyt,,fur\h;; puriPl?XlZon 8l C nmr chemicalshifts were in good agreementwith reportedvalues, @ signals attribut%e to impuritiescould be detected. Some of the amine8 used are available as their hydrochloridesalts and, with the exceptionof Anlline*HClwas recrystallizedseveral times the exceptionof Rin ethyl ether. The ether then dried in vacua. ution of the amine Pono~ -The procedureused to prepare LAS complexesof amine cations ~:;Io~~~E~~a~~~~~t~d3~ev~ously for p reparatlon of LAS complexes of metal . ml aqueousso ut on containing10 mm01 of the amine hydrochloride is divided into three lo-ml portions. Each portion,in turn, la stirred vi orcusly for 2-3 hr with 25 ml of a chloroformor meth lene chloridesolution containing1 mm01 NaLf S. The non-aqueous layer is then washed several % imea with water and dried over molecular sieves. Subsequentfiltrationfollowed by removal of the solvent -in vacua affordsa crystallineproduct. Instrumentation. Carbon-13 nmr spectra were obtained on a Bruker WP-80 FT spectrometer ac Cu m Spectra were run at the ambient probe temperature of 39OC using 8~ data lemental inal sea were carried out on a Hewlett Packard Model 1858 C, H, N analyzer ocated in the Departmen f.of Medicinal Chemistry. Repeatedanalyses of the same instrumentspanneda ran e of 0.51 for C and 0.4sfor H and N. Nltro en analyadS-%lB Molecular weight determfnations were made in chloroformsolution a& 37°C using a Hewlettl&&% Model 302 vapor reaaure oamometer. The oamometerwas calibratedusing recrystallizedbenzil, and solutions were Pn the concentration range OP 1 to 10 mmolar. Infrared s ectra were run on KBr elleta using an IBM InstrumentsIR 32 FT apectrophotometer. All melting poPnta were measuredon a fhomas Hoover capillarymelting point apparatusand are uncorrected.
1.
The numberingscheme used here is that roposed earlier: Weatley. J.W.J. Antibiot.1976, 29. 584. Oxygen numbers are shown in parenPheses.
2.
Weatley. J.W. "Pal ether Antibiotics: Naturally OccurringAcid Icnophorea";Vol. I and II; Marcel Dekker:Base 1, 1982. Ovchinnikov,Y.A. in "Frontiersin Bioor anic Chemistryand,y7\ecularBiology";Ovchinnikov, Y.A.and Kolosov, M.N.,Eda. Chapter 8: &sevier:Amsterdam, .
3. 4.
Poonia, N.S.:Bajaj, A.V. Chem. Rev. 1979, 79, 389.
5.
Smith, G.D.;Daux, W.L.;Fortier. S. J. Am. Chem. Sot. 1978, 100. 6725.
6.
Chiang, C.C.;Paul, I.C.Science (Washington,D.C.)1977, 196, 1441.
7.
Schmidt, P.G.;Wang, A.H.-J.;Paul, I.C.J. Am. Chem. Sot. 1974, 96, 6189. Maier, C.A.:Paul, I.C.J. Chem. Sot. Chem. Commun. 1971, 181.
a. 9. 10.
Johnson. S.H.;Herrin, J.; Liu. S.J.:Paul, I.C.J. Am. Chem. Sot. 1970, 92, 4428. Hanna, D.A.;Yeh, C; Shaw, J.; Everett, C.W.Biochem. 1983, 22, 5619.
11. Everett, C.W.;Parker, S.B.;Wllllama, R.J.P.Biochem. 1983, 22, 6149. 12.
Melnik E I . Lindenbaum. S.; Sternaon. L.A.;Ovchinnlkov, ~::;~:.&~:i;~, 684. 2.33:
Y.A.
Bicchlm. et
13. ~:~",~:~.",~F~a1MsBS:11i~~~,EjIjj.Sternson. L.A.; Lindanbaum. S; Ovchinnikov, Y.A. Biochim. et 14. Kinael Pharmac&%
Melnik E.1 * Lindenbaum, S.; Sternson, L.A.;Ovchinnikov, Y.A. Internat. J. 1982, 13. 97:'
15. Weatley, J.W.;Evans, R.H.,Jr.: Blount, J.F.J. Am. Chem. Sot. 1977, 99, 6057. 16. Seto. H.; Westley, J.W.;Pitcher, R.G.J. Antlbiot. 1978, 31. 289. 17. Anteunis, M.J.O.Bioorg. Chem.w,
5, 327.
18. Patel, D.J.:Shen. C. Proc.Natl. Acad. Sci. USA 1976, 73, 1786, 4277. 19. Lallemand, J.-Y.:Michon, V.J.Chem.Rea.. miniprint 1978, 2081. 20. Cotton, F.A.;Wilkinson,G. "AdvancedInorganicChemistry";4th Ed.: John Wiley and Sons: New York, 1980. 21. Lallemand, J.-Y.;Rao, R.; Prange, T. Nouv. J. Chlm. 1980, 4, 315.