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Elucidation of the absolute configurations of amino acids and amines by the modified mosher's method
0040-4039191 93.00 + .oo Pcrgamon hss plc
Tetrahedron Letters, Vo1.32, No.25. pp 2939-2942. 1991 Printed in Great Britain
ELUCIDATION
OF THE
ABSOLUTE
AMINES
Takenori
Kusumi,
CONFIGURATIONS
BY THE MODIFIED
Toshiro
Fukushima,
OF AMINO
MOSHER’S
Ikuko
ACIDS
AND
METHOD
Ohtani,
and Hiroshi
Kakisawa*
Department of Chemistry, University of Tsukuba, Tsukuba, Ibaraki 305, Japan
Application of the modified Mosher’s method to the N-MTPA derivatives of Abstract: several amino acid esters and acyclic amines indicates that this method may be generally used to determine the absolute configurations of the a-carbons of amino compounds of less than 0.1 mg amount.
We have reported (summarized organic
in Figure
compounds
accepted
These
Similar
methodologies
possible
to assign
techniques another
such
MTPA these
acids
plane,
are
positive. l),
and
amines
a secondary
applied
to elucidation
method
using
depend
on
of the
and
prepared
all negative, These
they
the
findings
have
With respect
Mosher’s
to elucidate
the absolute
configurations
alcohol
high-field
method
while
those
are in good revealed
method
configurations been
molecules
developed
are
employed.
the We
configurations
natural
by Trost.9
which when
of
is widely
of some
spectroscopy,
to the absolute
(+) and (-)-MTPA 9 The
and L-amino
values
This
method
has
made
modern herein
alcohols
for the protons located
on
the
A.6
describe
of amines.
chlorides values
right
or the
(6s - 6~) obtained in Figure
2.
for As
on the left side of the MTPA side
of
the
MTPA
from
Model
agreement
with
the prediction
that
idea
of MTPA
plane
we have noticed
other
the
de-
in pyridine1°
are summarized
oriented
it
pulse
(2-methoxy-2-phenyl-2-trifluoromethylacetyl) with
A6
1-5
has
big
spectra
in dichloromethane.
eventually
moiety.
NMR
of even
or HMBC
acid esters
as it is for secondary
the modified
of the absolute
protons
by treatment
the Figure,
method,
O-methylmandelates
(-)-(S)-MTPA
and DCC-DMAP
from
can
of the modified
N-MTPA-L-amino
is obvious
be used
which
as H,H-COSY
The N-(+)-(R) were
I),
most
application
rivatives
and reliable
possessing
and has been
products.6-*
the convenient
was
also
plane
are
A (Figure valid
for
alcohols.
to the amino
acid derivatives,
2939
features
of the
A6
2940
1 Mode/Al
Figure 1. MTPA plane and Model A to predict the absolute configurations alcohols (X = 0) or primary amines (X = NH). A6 = 6s - 6~.
values:
(1) The values
methoxyl
groups
negative.
for
a-protons
of the MTPA
Because
it should
configuration
of the a-carbon
ester
watched
procedures
(100 ug) in pyridine
microtube.
syringe,
and
the
(+)-MTPA mixture
Dimethyl-1,3_propanediamine chloride,
and
subjected
to prep
the MTPA
the
amides
(1.5
pyridine
TLC (Merck, are visible
(R) and (S)-MTPA-L-valine Preparation
urea was concentrated (31 mg; 86 %).
amide
and the residue
ester:
protons
rule
inclinations
the are
tenden-
to tell the Sof the protons
20 equivalent)
was
of L-valine
CaH2;
The
DCC
The reaction was separated
was
50 nL) added for
added
rH-NMR
by prep
6 : 4).
are shown A mixture
the hydroxyl
containing TLC, group
via
a lo-uL N,N-
the
The
excess
residue
(The
(500
was
bands
MHz)
in Figure
of
of N-
3.
of L-phenylalaninol
(25 mg) and (+)-MTPA mixture
was put in
to quench
spectra
methyl
10 min.
evaporator.
hexane-EtOAc,
(ca 200 ug each)
conditions
A solution
temperature
a vacuum
60 F254,
with
are as follows:
20 equivalent) at room
on
derivatives
from
of L-phenylalaninol:
treated
for 30 min.
these
uL;
254 nm light.) esters
these
for
on these
as a general
and distilled
to stand
Kieselgel
(1 mL) was
Under
(2.2
uL;
methyl
was stirred
(dried
evaporated
under
of (R)-MTPA
(15 mg) and CH2C12 and the mixture
was
although
methyl
allowed
the amide
interpretation
of the N-MTPA
chloride
was
for
values
works.
of the preparation
hydrochloride
those
properties
acids,
in future
of N-(R)-MTPA-L-valine
a I-mL
amide
to take these
Preparation
and
to put a reasonable
of amino
(2) The
in all cases.”
are positive
unable
be too risky
have to be consecutively Typical
moieties
we have been
cies thus far,
are positive
of secondary
acid
(28 mg),
the precipitates
affording
of
the (R)-MTPA
was not esterified
at all.
2941
-0.089
-".23
(-0.080) -
kH,
-0.327
&BZ
-0.076
-0.36
(-0.071)
L -isoleucine
L -1eucine
L -valine
-0.07
_ _-
L-methionine (du?B)(~ -0.07
-0.037
-0.05
L-threonine
L -serine
(-0.056)
-0.126
-+0.014
-0.082 -0.095
-0.252
m
y;:;;m;i -0.315
&Qgj
L-glutamic
L -phenylalanine
acid -0.073
-0.21
-0.117
________---_______-------I
I
1
::ip~i.$i
/ -0.02
pjfq--q
H -0.162 I I_______,__-____----______I
L-tryptophan 0
-“.042 & H,_.*cH3
-0.056
-0.027 -0.001
-0.134
jJL7
-
I
d&z &_@j A
CH3?ixAc~H -0.09
i-i- -NH-MTPA -0.02
-0.142
-0.01
/
dd8.t
rV,V-."
TV.lLC
+0.072
L-phenylalaninol
L-isoleucinol
Figure 2. A6 values (ppm) obtained for (R) and (S)-MTPA amides of amino compounds. protons which could be interchanged
with other protons (e.g. a-CO,Et
two possible values, one in parenthesis, on a Bruker AM 500 spectrometer experiments
acid),
The data are obtained from the spectra measured
using CDCIs as a solvent.
and H,H COSY spectra.
and L-tryptophan
are assigned.
For the
vs y-CO,Et in L-glutamic
For the assignments
The assignments
are based on decoupling
of the aromatic protons of L-phenylalanine
MTPA amides, NOESY spectra were used.
2942
---A6>0 -Ac3<0 NH-MTPA
MTPA-OMe C02Me 1
H3-4, 5
H20
TPA amide
Figure 3. ‘H NMR (CDCI-,; 500 MHz) spectra of 2 mM solutions of the N-(S)-MTPA (above) and (R)-MTPA (below)-L-valine methyl esters.
References
1
2
Kusumi,
T.; Ohtani,
I.; Inouye,
International
Symposium
1988,
Pa17.
Abstr.
Kusumi,
T.; Ohtani,
and
Notes
Y.; Ishitsuka,
on the Chemistry
I.; Inouye,
0. M.; Kakisawa,
of Natural
Y.; Kakisawa,
H.
H. 16th IUPAC
Products
(Kyoto),
Tetrahedron
Lett.
May-June,
1988,
29,
Letf.
1989,
4731. 3
Ohtani,
I.; Kusumi,
T.; Ishitsuka,
0. M.; Kakisawa,
H.
Tetrahedron
30,
3147. Ohtani,
I.; Kusumi,
T.; Kashman,
Y; Kakisawa,
H.
J. Org. Chem.
1991,
Olitani,
I.; Kusumi,
T.; Kashman,
Y; Kakisawa,
H.
J. Am.
Sot.
Kobayashi,
8
M.; Kawazoe,
Kitagawa,
I.; Kobayashi,
T.
Chem.
J. Am.
Hundt,
9
Trost, 1986,
Lett.
1990,
112,
I.
Tetrahedron
T.; Yamashita,
Lett.
1989,
M.; Tanaka,
56,
1296.
in press.
30, 4149.
J.; Doi,
M.; Ishida,
3710.
J. F. W.; Steynberg,
1990,
B. M.; Curran,
Belletire,
M.; Katori,
Sot.
A. F.; Burger,
Tetrahedron
K.; Kitagawa,
Chem.
J. P.; Steenkamp,
J. A.; Ferreira,
D.
31, 5073. D. P.
J. L.; Godleski,
Tetrahedron
Lett.
S.; McDougal,
1981,
22, 4929.
P. G.; Balkovec,
J. M.
Trost,
B. M. ;
J. Org. Chem.
51, 2370.
IO
Dale,
11
The chemical
J. A.; Mosher,
be affected
shift more
H. S.
J. Am.
of the proton by the carbonyl
group.
(Received in Japan 22 January 1991)
Chem.
Sot.
on the carbon group
1973, bearing
of the MTPA
95, 512. an MTPA moiety
amide
than from
group
should
the phenyl
Tetrahedron Letters, Vo1.32, No.25. pp 2939-2942. 1991 Printed in Great Britain
ELUCIDATION
OF THE
ABSOLUTE
AMINES
Takenori
Kusumi,
CONFIGURATIONS
BY THE MODIFIED
Toshiro
Fukushima,
OF AMINO
MOSHER’S
Ikuko
ACIDS
AND
METHOD
Ohtani,
and Hiroshi
Kakisawa*
Department of Chemistry, University of Tsukuba, Tsukuba, Ibaraki 305, Japan
Application of the modified Mosher’s method to the N-MTPA derivatives of Abstract: several amino acid esters and acyclic amines indicates that this method may be generally used to determine the absolute configurations of the a-carbons of amino compounds of less than 0.1 mg amount.
We have reported (summarized organic
in Figure
compounds
accepted
These
Similar
methodologies
possible
to assign
techniques another
such
MTPA these
acids
plane,
are
positive. l),
and
amines
a secondary
applied
to elucidation
method
using
depend
on
of the
and
prepared
all negative, These
they
the
findings
have
With respect
Mosher’s
to elucidate
the absolute
configurations
alcohol
high-field
method
while
those
are in good revealed
method
configurations been
molecules
developed
are
employed.
the We
configurations
natural
by Trost.9
which when
of
is widely
of some
spectroscopy,
to the absolute
(+) and (-)-MTPA 9 The
and L-amino
values
This
method
has
made
modern herein
alcohols
for the protons located
on
the
A.6
describe
of amines.
chlorides values
right
or the
(6s - 6~) obtained in Figure
2.
for As
on the left side of the MTPA side
of
the
MTPA
from
Model
agreement
with
the prediction
that
idea
of MTPA
plane
we have noticed
other
the
de-
in pyridine1°
are summarized
oriented
it
pulse
(2-methoxy-2-phenyl-2-trifluoromethylacetyl) with
A6
1-5
has
big
spectra
in dichloromethane.
eventually
moiety.
NMR
of even
or HMBC
acid esters
as it is for secondary
the modified
of the absolute
protons
by treatment
the Figure,
method,
O-methylmandelates
(-)-(S)-MTPA
and DCC-DMAP
from
can
of the modified
N-MTPA-L-amino
is obvious
be used
which
as H,H-COSY
The N-(+)-(R) were
I),
most
application
rivatives
and reliable
possessing
and has been
products.6-*
the convenient
was
also
plane
are
A (Figure valid
for
alcohols.
to the amino
acid derivatives,
2939
features
of the
A6
2940
1 Mode/Al
Figure 1. MTPA plane and Model A to predict the absolute configurations alcohols (X = 0) or primary amines (X = NH). A6 = 6s - 6~.
values:
(1) The values
methoxyl
groups
negative.
for
a-protons
of the MTPA
Because
it should
configuration
of the a-carbon
ester
watched
procedures
(100 ug) in pyridine
microtube.
syringe,
and
the
(+)-MTPA mixture
Dimethyl-1,3_propanediamine chloride,
and
subjected
to prep
the MTPA
the
amides
(1.5
pyridine
TLC (Merck, are visible
(R) and (S)-MTPA-L-valine Preparation
urea was concentrated (31 mg; 86 %).
amide
and the residue
ester:
protons
rule
inclinations
the are
tenden-
to tell the Sof the protons
20 equivalent)
was
of L-valine
CaH2;
The
DCC
The reaction was separated
was
50 nL) added for
added
rH-NMR
by prep
6 : 4).
are shown A mixture
the hydroxyl
containing TLC, group
via
a lo-uL N,N-
the
The
excess
residue
(The
(500
was
bands
MHz)
in Figure
of
of N-
3.
of L-phenylalaninol
(25 mg) and (+)-MTPA mixture
was put in
to quench
spectra
methyl
10 min.
evaporator.
hexane-EtOAc,
(ca 200 ug each)
conditions
A solution
temperature
a vacuum
60 F254,
with
are as follows:
20 equivalent) at room
on
derivatives
from
of L-phenylalaninol:
treated
for 30 min.
these
uL;
254 nm light.) esters
these
for
on these
as a general
and distilled
to stand
Kieselgel
(1 mL) was
Under
(2.2
uL;
methyl
was stirred
(dried
evaporated
under
of (R)-MTPA
(15 mg) and CH2C12 and the mixture
was
although
methyl
allowed
the amide
interpretation
of the N-MTPA
chloride
was
for
values
works.
of the preparation
hydrochloride
those
properties
acids,
in future
of N-(R)-MTPA-L-valine
a I-mL
amide
to take these
Preparation
and
to put a reasonable
of amino
(2) The
in all cases.”
are positive
unable
be too risky
have to be consecutively Typical
moieties
we have been
cies thus far,
are positive
of secondary
acid
(28 mg),
the precipitates
affording
of
the (R)-MTPA
was not esterified
at all.
2941
-0.089
-".23
(-0.080) -
kH,
-0.327
&BZ
-0.076
-0.36
(-0.071)
L -isoleucine
L -1eucine
L -valine
-0.07
_ _-
L-methionine (du?B)(~ -0.07
-0.037
-0.05
L-threonine
L -serine
(-0.056)
-0.126
-+0.014
-0.082 -0.095
-0.252
m
y;:;;m;i -0.315
&Qgj
L-glutamic
L -phenylalanine
acid -0.073
-0.21
-0.117
________---_______-------I
I
1
::ip~i.$i
/ -0.02
pjfq--q
H -0.162 I I_______,__-____----______I
L-tryptophan 0
-“.042 & H,_.*cH3
-0.056
-0.027 -0.001
-0.134
jJL7
-
I
d&z &_@j A
CH3?ixAc~H -0.09
i-i- -NH-MTPA -0.02
-0.142
-0.01
/
dd8.t
rV,V-."
TV.lLC
+0.072
L-phenylalaninol
L-isoleucinol
Figure 2. A6 values (ppm) obtained for (R) and (S)-MTPA amides of amino compounds. protons which could be interchanged
with other protons (e.g. a-CO,Et
two possible values, one in parenthesis, on a Bruker AM 500 spectrometer experiments
acid),
The data are obtained from the spectra measured
using CDCIs as a solvent.
and H,H COSY spectra.
and L-tryptophan
are assigned.
For the
vs y-CO,Et in L-glutamic
For the assignments
The assignments
are based on decoupling
of the aromatic protons of L-phenylalanine
MTPA amides, NOESY spectra were used.
2942
---A6>0 -Ac3<0 NH-MTPA
MTPA-OMe C02Me 1
H3-4, 5
H20
TPA amide
Figure 3. ‘H NMR (CDCI-,; 500 MHz) spectra of 2 mM solutions of the N-(S)-MTPA (above) and (R)-MTPA (below)-L-valine methyl esters.
References
1
2
Kusumi,
T.; Ohtani,
I.; Inouye,
International
Symposium
1988,
Pa17.
Abstr.
Kusumi,
T.; Ohtani,
and
Notes
Y.; Ishitsuka,
on the Chemistry
I.; Inouye,
0. M.; Kakisawa,
of Natural
Y.; Kakisawa,
H.
H. 16th IUPAC
Products
(Kyoto),
Tetrahedron
Lett.
May-June,
1988,
29,
Letf.
1989,
4731. 3
Ohtani,
I.; Kusumi,
T.; Ishitsuka,
0. M.; Kakisawa,
H.
Tetrahedron
30,
3147. Ohtani,
I.; Kusumi,
T.; Kashman,
Y; Kakisawa,
H.
J. Org. Chem.
1991,
Olitani,
I.; Kusumi,
T.; Kashman,
Y; Kakisawa,
H.
J. Am.
Sot.
Kobayashi,
8
M.; Kawazoe,
Kitagawa,
I.; Kobayashi,
T.
Chem.
J. Am.
Hundt,
9
Trost, 1986,
Lett.
1990,
112,
I.
Tetrahedron
T.; Yamashita,
Lett.
1989,
M.; Tanaka,
56,
1296.
in press.
30, 4149.
J.; Doi,
M.; Ishida,
3710.
J. F. W.; Steynberg,
1990,
B. M.; Curran,
Belletire,
M.; Katori,
Sot.
A. F.; Burger,
Tetrahedron
K.; Kitagawa,
Chem.
J. P.; Steenkamp,
J. A.; Ferreira,
D.
31, 5073. D. P.
J. L.; Godleski,
Tetrahedron
Lett.
S.; McDougal,
1981,
22, 4929.
P. G.; Balkovec,
J. M.
Trost,
B. M. ;
J. Org. Chem.
51, 2370.
IO
Dale,
11
The chemical
J. A.; Mosher,
be affected
shift more
H. S.
J. Am.
of the proton by the carbonyl
group.
(Received in Japan 22 January 1991)
Chem.
Sot.
on the carbon group
1973, bearing
of the MTPA
95, 512. an MTPA moiety
amide
than from
group
should
the phenyl