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The relation between cd spectra of n-dithioethoxycarbonyl derivatives of β-amino acids and their configurations
Tetrahedron Letters No. 21, pp 1813 - 1816, 1978. @
oO~O-4O3y/78/Oj15-1813. $X.00/0.
PergamonPressLtd. Printedin Great Britain.
THE RELATION BETWEEN CD SPECTRA OF N-DITHIOETHOXYCARBONYL DERIVATIVES OF B-AMINO ACIDS AND THEIR CONFIGURATIONS
Takashi YAMADA, Shigeru KUWATA,
and Hiroshi WATANABE
Laboratory of Chemistry, Faculty of Science, Kbnan University Okamoto, Higashinada-ku, Kobe 658, Japan (Receivedin Japan 3 March.1978; receivedin UK for Publication30 March 1978) There have been only few reports on the relationship between the configural-3) and the relationships are
tions of B-amino acids and their optical behaviors,
not always satisfactory to be used as empirical rules for determining the configurations of various B-amino acids.
I
,:
,:
‘.
B-HLE
..,
i
A relation-
ship suggested by Sjijberg et al. 2) that the di-
I‘... :
thiocarbamate of a L-$-amino acid shows negative
3.
Cotton effect had been considered useful, but we pointed out an exceptional case to it. 4,
At
the same time, we proposed an empirical rule, similar to that of Balenovic, 1) for the assign-
6-HPR
ment of the configuration of a B-amino acid from pH-dependence of its ORD curve. 4) However, two
2.
i
,'
%; :
i :
B-HME 6-HLY
(Z)
exceptional cases to it have recently been observed. 5,6) We report here the results of our reinvestigations on the relation between CD spectra of B-amino acid derivatives and their configurations.
Optically active B-amino acids
used for this purpose, summarized in Table 3, 0
:: ::::: ::-I ...........................)~~............~...""" ... 4oom / ./.' B-HAL / ... ,,z : ;:
were prepared from the corresponding L-cl-amino acids, except L-8-Phe 7,8) and L-8-Hpr, ') by the Arndt-Eistert reaction.
These B-amino acids
were converted into N-dithioethoxycarbonyl (DTEC) derivatives, and their Cotton effects, especially influences of solvents on them, 10)
-1 '
6-tiPH B-PHE
PHIL 6-LEU
.
-2.
were examined in detail. Every N-DTEC-L-B-amino acid (DTEC-L-B-AA-OH) showed a CD maximum in the region of 330-350 run. Unexpectedly, no definite relationship between
FIG.~.
CD SPECTRA
OF
DTEC-L-AA-OH
IN MEOH.
the sign of the Cotton effect in methanol and 1813
I?o. 21
configuration of the parent B-amino acid could be recognized, as is seen in Fig. 1. Moreover, in chloroform or benzene most of the compounds showed positive the
Cotton effects, just contrary to the SjBberg's suggestion, though a fairly definite So, solvent effects upon the Cotton effect
relationship was recognized (Table 1).
TABLE
1,
COTTON
EFFECTS
DTEC-R-A&OH
DTEC-L-B-AA-OH
OF
MeOH
CHC13
+ + + +
+ + + + + + +
CgH6 + + + + + + +
+
+
+
B-Hal B-Leu B-Hi1 B-Ale f3-Hme 6-Hly(Z) B-Hgu fi-Phe O-Hph B-Hpr
FIG.~.
cc+
./--.
OF ADDED
CD SPECTRA
“..,
,:’ ,;’
EFFECTS
SOLVENTS
ON MAXIMA
OF DTEC-L-a-HIL-OH
OF
IN CCI4.
-
‘..,
,:
:
l-
!!
NONE
/~'---%.. '.., ,<..' *.., ,,>" 'k.,
i ,."
'..., y, “... ‘---___..
o:,
,
400 "Ill
350
'... \
‘x,, ‘,.,..., .,,“..:‘, ‘...
,, ‘..
. . . . .,:..
. .._.._,_
‘., .._.
“‘...,,
;o ,,..” ..““‘,...$y ,.I’
‘.. .,., ,,,.,,3 ‘..
‘_....”
.._(
,,..
i”
.,;
‘.
-l-
.
NH3
400nm
,,..
“Q.., ." ,j,,: '.., '.......,....,' ,$$; .,;:., <; i '.:. :'. 3 !
::..
ETHER 03-M.?
(4.5)
ONH*
(5.7)
DIOXANE -2-
-3-
‘%,, ;,.”
u
:
MEOH
..c
L
FIG,~.
CD SPECTRA
OF DTEC-L-+HIL-OH
ACETONE
IN VARIOUS
SOLVENTS.
FIG.~.
EFFECTS
OF ADDED
AMINES
ON COTTON
OF DTEC-L-E-HIL-OH IN CHCI3. (Numbers Indicate molar equivalents amines t0 DTEC-L-B-Hil-OH)
EFFECT Of
No.
21
were
further
(Fig. 2).
investigated Marked
derivative.
the B-Hi1
Cotton
for the
2
It should be noted that effects were
observed
common in such oxygen-containing
in
Figure 3
shows that, in a mixed solvent the strength and even the signofthecotton
effect change
dependent upon the mixing ratio of the solThe change was
remarkable
region of the lowconcentrationof containing solvent.
1
solvents as
alcohol, ester, ether, or ketone.
vents.
3
were obtained
This was also the case
B-Leu derivative. negative
using
results
in the
anoxygen-
0 m I 0 rl x
-1
;
-2
These results suggest
that the solvent effect isdueto action of a carboxyl group
of
the inter-
with the oxygen-containing solvent. fore, a base can be expected
-3
DTEC-B-AA-OH There-
to be a more
-4
effective cause of the change of the Cotton effect than these solvents, as Fig. 4 shows.
-5
As the dicyclohexylamine (DCHA) was the most effective, the DCHA salts of DTEC-L-B-AA-OH were prepared and their CDspectra
ured.
were meas-
Strikingly, all the DCHA salts, with
theonly
exception oftheL-S-Hpr
showed negative Cottoneffects (Fig. 5)
-6
-1
derivative,
in chloroform
FIG.~,CD SPECTRA OF DTEC-L-d-AA-OH,DCHA INCHCl3
with scarcely any solvent effects
(Table 2), in contrast with the case of the free DTEC-L-B-AA-OH. the DCHAsalts
be applied to The relationship found here could successfully __. ofy-ethyl D-B-glutamatell' (positive Cotton
of theN-DTECderivatives
effect in methanol, chloroform, or benzene) and (+)-S-(2-thiazolyl)-S-alanine which had been assigned to the L-series 12) TABLE 2.
COTTON EFFECTS OF DTEC-L-B-AA-OH'DCHA
DTEC-B-?+A-OH.DCHA
MeOH
CHC12
'sH6
B-Hal B-Leu
(negative Cotton effect in methanol, chloroform, or benzene). Consequently, the following rule is thought useful to determine the configurations of B-amino acids, with
@-Hi1
the exception of such an imino (or a +-
E-Hle
cyclic imino) acid as B-Hpr:
B-Hme
If the Cotton effect of the DCHA salt of a
B-Hly(Z) B-Hgu(
$-Phe B-Hph B-Hpr
N-DTEC-B-amino acid in chloroform or benzene
ZDCHA)
in the region of 330-350 runis negative, the configuration of the &amino acid is assigned
+
+
+
to the L-series.
1816
No. 21
Further investigations on 8-imino acids are in progress. Acknowledgment:
We thank Dr. Toshio Wakabayashi in Teijin Institute for Biomedi-
cal Research for his kind supplying of L-B-homoproline, and Mr. Koichi Niwa for preparing of some 8-amino acids.
This work was supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education
(14703, 1976).
REFERENCES AND NOTES 1) K. Balenovic, "Chiba Foundation Symposium on Amino Acids and Peptides with Antimetabolic Activity," J. & A. Churchill, London (1958), p.5. 2) B. SjSberg, B. Hansson, and R. Dahlbom, Acta Chem. Seand., 16, 1057 (1962). 3) H. Yonehara and N. btake, Tetrahedron Lett., 3785 (1966). 4) Y. Seto, T. Yamada, K. Niwa, S. Miwa, F. Tanaka, S. Kuwata. and H. Watanabe, Chem. Lett., 151 (1973). 5) H. Nakamura, T. Yoshioka, T. Takita, H. Umezawa, Y. Muraoka, and Y. Iitaka, J. Antibiot., 29, 762 (1976). 6) J. M. Cassel, A. Fiirst, and W. Meier, HeZv. Chim. Acta, 59, 1917 (1976). with ephedrin; 7) This was prepared by the resolution of the N-phthalyl%-compound cf. E. Graf and H. Boeddeker, Justus Liebigs Ann. Chem., 613, 111 (1958). 8) Abbreviations according to the IUPAC-IUB Commission (J. BioZ. Chem., 247, 977 (1972)) are used. Hal, homoalanine; Hil, homoisoleucine; Hle, homoleucine; Hme, homomethionine; Hly(Z), w-N-benzyloxycarbonyl homolysine; Hgu, homoglutamic acid: Hph, homophenylalanine; Hpr, homoproline; Bzl, benzyl. See T. Wakabayashi, K. Watanabe, 9) This was presented from Dr. T. Wakabayashi. and Y. Kato, Synth. Connmcn.,1, 239 (1977). 10) Drastic solvent effects on the Cotton effects of DTEC-c-AA-OH were found by Yamada, et al.; K. Ishikawa, K. Achiwa, and S. Yamada, Chem. Pharm. Bulk, 2, 912 (1971). 11) This was derived from Z-L-Asp(OBzl)-OH via Z-L-8-Glu(OBzl)-OEt (E Z-D-8-Glu(OEt)' OBzl) by the Arndt-Eistert reaction. 8-Glu means 8-glutamic acid, i.e., B-aminoglutaric acid. 12) Y. Seto, K. Torii, K. Bori, K. Inabata, S. Kuwata, and H. Watanabe, BUZZ. Chem. Sot. Jpn;, 47, 151. (1974). 13) K. Balenovz, D. Cerar, and Z. Fuks, J. Chem. Sot., 3316 (1952). E. Fischer and H. Scheibler, Justus Liebigs Ann. Chem., 383, 337 (1911). 14) D-isomer: K. Balenovid and D. Dvornik, J. Chem. Sot., 2976 (lS“4). 15) K. Balenovid and D. Brovet-Keglevid, Chem. Abstr., 46, 10104f (1952).
TABLE 3. B-AA
R'
B-Hal
H
B-Leu
H
R2 CH3 CH(CH3)2
L-B-AMINO ACIDS Mp(dec)
R'R2 ( HNCHCH~COOH
1
(“C)
211 - 212
+34.8O
(c 0.48, 19°C)
13
201
+55.2O
(c 1.0
, 22OC)
14
- 202.5
B-Hi1
H
CH(CH3)C2H5
190 - 191
+46.0"
(c 1.0
, 22°C)
-
B-Hle
H
CH2CH(CH3)2
216
- 217.5
+34.70
(c 1.0
, 22OC)
15
B-Hme
H
(CH~)~SCH~
190
- 191.5
-33.8"
(c 0.5
, 22OC)
-
B-Hly(Z)
H
(CH~J~NH-Z
191 - 193
+16.5O
(c 1.0
, 2OOC)
-
B-Hgu
H
(CH2)2COOH
187 - 188.5
+70.2O
(c 0.5
, 24OC)
-
B-Phe
H
B-Hph
H
B-Hpr
'gH5
CH2C6H5 -CH2CH2CH2-
236
- 237
+ 6.2"
(c 0.65,
224
- 224.5
+ 1.30
(c 7,N-HC1,20"C)
-
182
- 184
+43.70
cc 1,
9
19OC)
3N-HCl)
7
oO~O-4O3y/78/Oj15-1813. $X.00/0.
PergamonPressLtd. Printedin Great Britain.
THE RELATION BETWEEN CD SPECTRA OF N-DITHIOETHOXYCARBONYL DERIVATIVES OF B-AMINO ACIDS AND THEIR CONFIGURATIONS
Takashi YAMADA, Shigeru KUWATA,
and Hiroshi WATANABE
Laboratory of Chemistry, Faculty of Science, Kbnan University Okamoto, Higashinada-ku, Kobe 658, Japan (Receivedin Japan 3 March.1978; receivedin UK for Publication30 March 1978) There have been only few reports on the relationship between the configural-3) and the relationships are
tions of B-amino acids and their optical behaviors,
not always satisfactory to be used as empirical rules for determining the configurations of various B-amino acids.
I
,:
,:
‘.
B-HLE
..,
i
A relation-
ship suggested by Sjijberg et al. 2) that the di-
I‘... :
thiocarbamate of a L-$-amino acid shows negative
3.
Cotton effect had been considered useful, but we pointed out an exceptional case to it. 4,
At
the same time, we proposed an empirical rule, similar to that of Balenovic, 1) for the assign-
6-HPR
ment of the configuration of a B-amino acid from pH-dependence of its ORD curve. 4) However, two
2.
i
,'
%; :
i :
B-HME 6-HLY
(Z)
exceptional cases to it have recently been observed. 5,6) We report here the results of our reinvestigations on the relation between CD spectra of B-amino acid derivatives and their configurations.
Optically active B-amino acids
used for this purpose, summarized in Table 3, 0
:: ::::: ::-I ...........................)~~............~...""" ... 4oom / ./.' B-HAL / ... ,,z : ;:
were prepared from the corresponding L-cl-amino acids, except L-8-Phe 7,8) and L-8-Hpr, ') by the Arndt-Eistert reaction.
These B-amino acids
were converted into N-dithioethoxycarbonyl (DTEC) derivatives, and their Cotton effects, especially influences of solvents on them, 10)
-1 '
6-tiPH B-PHE
PHIL 6-LEU
.
-2.
were examined in detail. Every N-DTEC-L-B-amino acid (DTEC-L-B-AA-OH) showed a CD maximum in the region of 330-350 run. Unexpectedly, no definite relationship between
FIG.~.
CD SPECTRA
OF
DTEC-L-AA-OH
IN MEOH.
the sign of the Cotton effect in methanol and 1813
I?o. 21
configuration of the parent B-amino acid could be recognized, as is seen in Fig. 1. Moreover, in chloroform or benzene most of the compounds showed positive the
Cotton effects, just contrary to the SjBberg's suggestion, though a fairly definite So, solvent effects upon the Cotton effect
relationship was recognized (Table 1).
TABLE
1,
COTTON
EFFECTS
DTEC-R-A&OH
DTEC-L-B-AA-OH
OF
MeOH
CHC13
+ + + +
+ + + + + + +
CgH6 + + + + + + +
+
+
+
B-Hal B-Leu B-Hi1 B-Ale f3-Hme 6-Hly(Z) B-Hgu fi-Phe O-Hph B-Hpr
FIG.~.
cc+
./--.
OF ADDED
CD SPECTRA
“..,
,:’ ,;’
EFFECTS
SOLVENTS
ON MAXIMA
OF DTEC-L-a-HIL-OH
OF
IN CCI4.
-
‘..,
,:
:
l-
!!
NONE
/~'---%.. '.., ,<..' *.., ,,>" 'k.,
i ,."
'..., y, “... ‘---___..
o:,
,
400 "Ill
350
'... \
‘x,, ‘,.,..., .,,“..:‘, ‘...
,, ‘..
. . . . .,:..
. .._.._,_
‘., .._.
“‘...,,
;o ,,..” ..““‘,...$y ,.I’
‘.. .,., ,,,.,,3 ‘..
‘_....”
.._(
,,..
i”
.,;
‘.
-l-
.
NH3
400nm
,,..
“Q.., ." ,j,,: '.., '.......,....,' ,$$; .,;:., <; i '.:. :'. 3 !
::..
ETHER 03-M.?
(4.5)
ONH*
(5.7)
DIOXANE -2-
-3-
‘%,, ;,.”
u
:
MEOH
..c
L
FIG,~.
CD SPECTRA
OF DTEC-L-+HIL-OH
ACETONE
IN VARIOUS
SOLVENTS.
FIG.~.
EFFECTS
OF ADDED
AMINES
ON COTTON
OF DTEC-L-E-HIL-OH IN CHCI3. (Numbers Indicate molar equivalents amines t0 DTEC-L-B-Hil-OH)
EFFECT Of
No.
21
were
further
(Fig. 2).
investigated Marked
derivative.
the B-Hi1
Cotton
for the
2
It should be noted that effects were
observed
common in such oxygen-containing
in
Figure 3
shows that, in a mixed solvent the strength and even the signofthecotton
effect change
dependent upon the mixing ratio of the solThe change was
remarkable
region of the lowconcentrationof containing solvent.
1
solvents as
alcohol, ester, ether, or ketone.
vents.
3
were obtained
This was also the case
B-Leu derivative. negative
using
results
in the
anoxygen-
0 m I 0 rl x
-1
;
-2
These results suggest
that the solvent effect isdueto action of a carboxyl group
of
the inter-
with the oxygen-containing solvent. fore, a base can be expected
-3
DTEC-B-AA-OH There-
to be a more
-4
effective cause of the change of the Cotton effect than these solvents, as Fig. 4 shows.
-5
As the dicyclohexylamine (DCHA) was the most effective, the DCHA salts of DTEC-L-B-AA-OH were prepared and their CDspectra
ured.
were meas-
Strikingly, all the DCHA salts, with
theonly
exception oftheL-S-Hpr
showed negative Cottoneffects (Fig. 5)
-6
-1
derivative,
in chloroform
FIG.~,CD SPECTRA OF DTEC-L-d-AA-OH,DCHA INCHCl3
with scarcely any solvent effects
(Table 2), in contrast with the case of the free DTEC-L-B-AA-OH. the DCHAsalts
be applied to The relationship found here could successfully __. ofy-ethyl D-B-glutamatell' (positive Cotton
of theN-DTECderivatives
effect in methanol, chloroform, or benzene) and (+)-S-(2-thiazolyl)-S-alanine which had been assigned to the L-series 12) TABLE 2.
COTTON EFFECTS OF DTEC-L-B-AA-OH'DCHA
DTEC-B-?+A-OH.DCHA
MeOH
CHC12
'sH6
B-Hal B-Leu
(negative Cotton effect in methanol, chloroform, or benzene). Consequently, the following rule is thought useful to determine the configurations of B-amino acids, with
@-Hi1
the exception of such an imino (or a +-
E-Hle
cyclic imino) acid as B-Hpr:
B-Hme
If the Cotton effect of the DCHA salt of a
B-Hly(Z) B-Hgu(
$-Phe B-Hph B-Hpr
N-DTEC-B-amino acid in chloroform or benzene
ZDCHA)
in the region of 330-350 runis negative, the configuration of the &amino acid is assigned
+
+
+
to the L-series.
1816
No. 21
Further investigations on 8-imino acids are in progress. Acknowledgment:
We thank Dr. Toshio Wakabayashi in Teijin Institute for Biomedi-
cal Research for his kind supplying of L-B-homoproline, and Mr. Koichi Niwa for preparing of some 8-amino acids.
This work was supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education
(14703, 1976).
REFERENCES AND NOTES 1) K. Balenovic, "Chiba Foundation Symposium on Amino Acids and Peptides with Antimetabolic Activity," J. & A. Churchill, London (1958), p.5. 2) B. SjSberg, B. Hansson, and R. Dahlbom, Acta Chem. Seand., 16, 1057 (1962). 3) H. Yonehara and N. btake, Tetrahedron Lett., 3785 (1966). 4) Y. Seto, T. Yamada, K. Niwa, S. Miwa, F. Tanaka, S. Kuwata. and H. Watanabe, Chem. Lett., 151 (1973). 5) H. Nakamura, T. Yoshioka, T. Takita, H. Umezawa, Y. Muraoka, and Y. Iitaka, J. Antibiot., 29, 762 (1976). 6) J. M. Cassel, A. Fiirst, and W. Meier, HeZv. Chim. Acta, 59, 1917 (1976). with ephedrin; 7) This was prepared by the resolution of the N-phthalyl%-compound cf. E. Graf and H. Boeddeker, Justus Liebigs Ann. Chem., 613, 111 (1958). 8) Abbreviations according to the IUPAC-IUB Commission (J. BioZ. Chem., 247, 977 (1972)) are used. Hal, homoalanine; Hil, homoisoleucine; Hle, homoleucine; Hme, homomethionine; Hly(Z), w-N-benzyloxycarbonyl homolysine; Hgu, homoglutamic acid: Hph, homophenylalanine; Hpr, homoproline; Bzl, benzyl. See T. Wakabayashi, K. Watanabe, 9) This was presented from Dr. T. Wakabayashi. and Y. Kato, Synth. Connmcn.,1, 239 (1977). 10) Drastic solvent effects on the Cotton effects of DTEC-c-AA-OH were found by Yamada, et al.; K. Ishikawa, K. Achiwa, and S. Yamada, Chem. Pharm. Bulk, 2, 912 (1971). 11) This was derived from Z-L-Asp(OBzl)-OH via Z-L-8-Glu(OBzl)-OEt (E Z-D-8-Glu(OEt)' OBzl) by the Arndt-Eistert reaction. 8-Glu means 8-glutamic acid, i.e., B-aminoglutaric acid. 12) Y. Seto, K. Torii, K. Bori, K. Inabata, S. Kuwata, and H. Watanabe, BUZZ. Chem. Sot. Jpn;, 47, 151. (1974). 13) K. Balenovz, D. Cerar, and Z. Fuks, J. Chem. Sot., 3316 (1952). E. Fischer and H. Scheibler, Justus Liebigs Ann. Chem., 383, 337 (1911). 14) D-isomer: K. Balenovid and D. Dvornik, J. Chem. Sot., 2976 (lS“4). 15) K. Balenovid and D. Brovet-Keglevid, Chem. Abstr., 46, 10104f (1952).
TABLE 3. B-AA
R'
B-Hal
H
B-Leu
H
R2 CH3 CH(CH3)2
L-B-AMINO ACIDS Mp(dec)
R'R2 ( HNCHCH~COOH
1
(“C)
211 - 212
+34.8O
(c 0.48, 19°C)
13
201
+55.2O
(c 1.0
, 22OC)
14
- 202.5
B-Hi1
H
CH(CH3)C2H5
190 - 191
+46.0"
(c 1.0
, 22°C)
-
B-Hle
H
CH2CH(CH3)2
216
- 217.5
+34.70
(c 1.0
, 22OC)
15
B-Hme
H
(CH~)~SCH~
190
- 191.5
-33.8"
(c 0.5
, 22OC)
-
B-Hly(Z)
H
(CH~J~NH-Z
191 - 193
+16.5O
(c 1.0
, 2OOC)
-
B-Hgu
H
(CH2)2COOH
187 - 188.5
+70.2O
(c 0.5
, 24OC)
-
B-Phe
H
B-Hph
H
B-Hpr
'gH5
CH2C6H5 -CH2CH2CH2-
236
- 237
+ 6.2"
(c 0.65,
224
- 224.5
+ 1.30
(c 7,N-HC1,20"C)
-
182
- 184
+43.70
cc 1,
9
19OC)
3N-HCl)
7