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Asymmetric transamination from amino acids (II) asymmetric synthesis of amines by chemical transamination of optically active amino acids to ketones
TetrahedronLetters No. 13, pp 1001 - 1004. 1976. Pergamon Press. Printed in Great Britain.
ASYMMETRIC ASYMMETRIC
TRANSAMINATION
SYNTHESIS
FROM AMINO ACIDS
OF AMINCS BY CHEKTCAL
(IT)
TRANSAMINATION
OF OPTICALLY Shun-ichi Faculty
ACTIVE AMINO ACIDS TO KETONES * Yamada, Kobuo Ikota, and Kazuo Achiwa
of Pharmaceutical
Sciences,
Hongo, Bunkyo-ku,
University
of Tokyo,
Tokyo 113, Japan
(Receivedin Japan 27 December 1975; received in UK for publication17 February1976) In an extension
of a previous
paper, 1) in which
of a new amino acid by transamination
of amine by
ketone
a similar
synthesis
of the amino group from an optically
amino acid to :t-keto acid has been reported, sis
the asymmetric
ca+nation trarr,..~.
we now report the asymmetric
from ooticallv
active synthe-
active amino acid to
instead of to a-keto acid.
The Schiff Bases(II1) amino acid esters(I) apparatus.
with ketones(II)
The amino acid esters(I)
ethyl esters of L-alanine, glutamic
L-phenylalanine,
of L-alaninc
of optically
active
benzene using a Dean-Stark
used were the methyl
ester of L-valine,
L-aspartic
acid, and L-
The ketones(I1)
and L-valine.
were reduced by catalytic
Treatment
and the subsequent
hydrolysis
of the intermediate
hydrogenation
active amines(VII1) _
optical
5% Pd on
and sodium ethoxide with 58
In some cases, VPC analysis peaks which
yields were calculated
correspond
to each
from the ratio Of
the peak areas of this VPC data. Results Tables
of asymmetric
I and II.
used
as a diastereo-
of the newly formed Schiff bases(V1)
IV, showed two well separated
Therefore,
with
amino acid esters(IV)
of IV with t-butyl hypochlorite
acid gave optically
diastereoisomer.
in sefluxlnq
to give the N-alkylated
in C2H50H
merit mixture.
from the reaction
and phenyiacetone.
Schiff bases(III)
sulfuric
L-valine,
acid and t-butyl esters
were acetophenone
charcoal
were prepared
synthesis
When L-amino
by catalytic
hydrogenation
are shown in
acid esters are used as chiral reaqents,
1001
the
i40.13
1002
Scheme
I
H
I
R3-C-CH3 R3-?-CH3 ; II
-H20
R3-&II3
: +
AH
Pa-C/H2 -3
Rl-f-COOR2
NH I2 Rl-C-COOR2
Rl-C-COOR2
H
I:
I:
III
IV
I HP;
7”
R3-C-CH3 ButOCl
_~.
R3-;-CH
I
Base
LCl
----_ 3
3
N
3
VIII
-~-H2° -__+
Rl-&CR2
Rl-&COOR2 A,
RlCOCOOR2
V Rl:
a) C6H5CH2-,
R: 2
CH 3, C2H5-,
absolute
VII CH3, d)CH,CH-
VI
b) C2H50COCH2t Bu -,
R3:
confiqurations
c) C2H50COCH2CH2-
3
C6H5-, C6H5CH2-
of the amines obtained
always belong
to the S-series.
The steric effect by the side chain of the amino acid esters sterically
larger ester groups of amino acids give better
means
of IV agree very closely with
that no epimerization The process
Formation
and racemization
of this reaction
of VI, instead of VI',
optical yields yields
the experimental
(runs
calculated This
value.
occur in the whole process.
is sliqhtly
different
from the previous
one.
1)
from V with a base is due to the fact that HCY
in V is more acidic than is Ha because the u position
is not clear, but
Optical
1,2 and 3,4 in Table I, and runs 2,3,4 in Table II). from the VPC analysis
c) CH3-
of the ester qroup.
Ha is located
Treatment
at
of
R3-C-CH 1, 3 N R$-COOR2
V with a base gives exclusively transamination
reaction
VI.
A
transamination
typical
procedure
(2.14 g, 18.3 mmoles) were rcfluxed
I!I,
This miqration
pattern
scheme than is the previous is as follows.
and phenylacetone
A solution 11(2.44g,
for 48 hr usinq a Dean-Stark
(Rl=CH3, R2=C2H5,
VI'
is built up by the migration
of the double bond from III to VI. biological
This
R3=C6H5CH2).
is more
t0
pattern.l'
of L-alanine
18.3 mmolcs)
apparatus
similar
ethyl ester(I)
in benzene(60
ml)
to give the Schiff hase(III)
The solvent was evaporated
and the residual
oil
No.
1003
17
Table I
Asymmetric
Synthesis
of 2-Amino-3-phenyl
propane(vII1,
2-Amino-3-phenylpropane(VII1,
R~'C~H~CH~)
L-Amino Acid Run i
2)
; Ala-OBut
3
: Val-0C2H5
4
,5 '6
Optical yield based on VPC Analysis of IV(%) ~-
Confign.
2
3)
Val-OBut
j
Phe-OC2H5
~
yc2"5 Asp-0C2H5
R~=c~H~CH~)
37
85(89)
56
50(53)
48
63
87(83)
81
25
21(23)
S
40
49(53)
S
I
7
17
i
I ~I----a) Based on II, determined b) Optically
pure
in parentheses benzoate:
lytically
(S)-VIII(R3=C6~5~~2 are optical
[al;5+72o(c=l
was dissolved
H2 at room temperature
gel(200
wi th 5% Pd on charcoal After
for 16 hr.
of the N-alkylated
then an alcoholic
0.012 atom) and absolute for one hour at 40°C(bath
The reaction mixture
solution
Optically
pure
the catalyst,
chromatoqraphically
pressure
with silica
solvent to give a diastereo-
g, 9 mmole)
g, 59% based on II). in dry ether(5 ml) was
of sodium ethoxidc prepared ml) were added.
under
from Na(0.275
q,
The reaction was continued
After evaporation
of the solvent,
and the whole was kept at room temperature
was worked
of
the alcohol
(10 ml) of purified rV(2.0 g, 8.5 mmole)
temperature).
(S)-
(50 ml) of III was cata-
amino acid ester(IV)(2.56
alcohol(l0
Numbers
C2H50H).
(1.0 g) at a 60Kg/cmL
as the elutinq
solution
H2S04 was added to the residue
standard.
Ber. 65, 660(1932)).
filtering
of t-butyl hypochlorite(0.98
added to a dry ether solution
hr.
An alcoholic
The crude product was purified
A solution
cooling,
[a]15+34.5"(c=10.62, D
14, CH30H) (W. Leithe,
g) and ether-n-hexane(2:3)
merit mixture
),
as the internal
yields based on the benzoate.
in alcohol( 50 ml).
hydrogenated
was removed.
by VPC using naphthalene
up as usual to give 2-amino-3-phenyl
5% for 2
No. lj
1004
Table II
Asymmetric
Synthesis
of a-Phenethylamine
Chiral Reagents used7
Product ~~-_
4.
J
_____
u a --.-
7-m Chemical
L-Amino Acid Esters
yield(%
Ala-OC2H5 Val-OCH
(VIII, R,=C,H,)
20
3
12
30(36)
14
50(59)
56
10
-_(85)
88
13
50(55)
48
~
Val-OC2H5
I ! I
Val-OBu t3) Phe-0C2H5 TC2H5
- (45)
Asp-oC2Hs a) based Optically Chem.,
on II, determined pure
by VPC using durene
CR)-VIII(R3=C6H5)
121, 86,
on the benzoate.
: [a]~"+31c(c=2.0844,
c) Numbers
284(1912). Optically
pure
R3=CsH5CH2,
method.
C2H5OH)(K. are optical
b)
Parck, J. Prak yields based
: [a1~0-52.50(c=0.7947,
C6H6) (W.
444(1913)).
mmHg),
[ali5+
66%).
derivative
of VIII(R3=CsH5CH._,) was obtained
The product was purified
ether-n-hexane(l:l)
standard.
0.72 g, 37% based on II), bp 83-86'(15
22.7"(C2H50H) (Optical yield The N-Benzoyl
in parentheses
(S)-benzoate
J. Pope and J. Read, J. Chem. Sot., x,
propane(VIII,
as the internal
by the usual
by silica gel column chromatography
as the eluting
solvent,
(yield 86%),
with
[a]25+45 l'(CH OH) D ' 3
(Optical yield 63%). The application
of this reaction
active amines will be reported
to the synthesis
of various optically
in the near future. REFERENCES
1) S. Yamada,
S. Hashimoto,
2) R. W. Roeske, Chem. 3) G. W. Anderson
T. L. in press.
& Ind., 1959,
and F. M. Callahan,
1121. J. Am. Chem. Sot., 2,
3359(1959).
ASYMMETRIC ASYMMETRIC
TRANSAMINATION
SYNTHESIS
FROM AMINO ACIDS
OF AMINCS BY CHEKTCAL
(IT)
TRANSAMINATION
OF OPTICALLY Shun-ichi Faculty
ACTIVE AMINO ACIDS TO KETONES * Yamada, Kobuo Ikota, and Kazuo Achiwa
of Pharmaceutical
Sciences,
Hongo, Bunkyo-ku,
University
of Tokyo,
Tokyo 113, Japan
(Receivedin Japan 27 December 1975; received in UK for publication17 February1976) In an extension
of a previous
paper, 1) in which
of a new amino acid by transamination
of amine by
ketone
a similar
synthesis
of the amino group from an optically
amino acid to :t-keto acid has been reported, sis
the asymmetric
ca+nation trarr,..~.
we now report the asymmetric
from ooticallv
active synthe-
active amino acid to
instead of to a-keto acid.
The Schiff Bases(II1) amino acid esters(I) apparatus.
with ketones(II)
The amino acid esters(I)
ethyl esters of L-alanine, glutamic
L-phenylalanine,
of L-alaninc
of optically
active
benzene using a Dean-Stark
used were the methyl
ester of L-valine,
L-aspartic
acid, and L-
The ketones(I1)
and L-valine.
were reduced by catalytic
Treatment
and the subsequent
hydrolysis
of the intermediate
hydrogenation
active amines(VII1) _
optical
5% Pd on
and sodium ethoxide with 58
In some cases, VPC analysis peaks which
yields were calculated
correspond
to each
from the ratio Of
the peak areas of this VPC data. Results Tables
of asymmetric
I and II.
used
as a diastereo-
of the newly formed Schiff bases(V1)
IV, showed two well separated
Therefore,
with
amino acid esters(IV)
of IV with t-butyl hypochlorite
acid gave optically
diastereoisomer.
in sefluxlnq
to give the N-alkylated
in C2H50H
merit mixture.
from the reaction
and phenyiacetone.
Schiff bases(III)
sulfuric
L-valine,
acid and t-butyl esters
were acetophenone
charcoal
were prepared
synthesis
When L-amino
by catalytic
hydrogenation
are shown in
acid esters are used as chiral reaqents,
1001
the
i40.13
1002
Scheme
I
H
I
R3-C-CH3 R3-?-CH3 ; II
-H20
R3-&II3
: +
AH
Pa-C/H2 -3
Rl-f-COOR2
NH I2 Rl-C-COOR2
Rl-C-COOR2
H
I:
I:
III
IV
I HP;
7”
R3-C-CH3 ButOCl
_~.
R3-;-CH
I
Base
LCl
----_ 3
3
N
3
VIII
-~-H2° -__+
Rl-&CR2
Rl-&COOR2 A,
RlCOCOOR2
V Rl:
a) C6H5CH2-,
R: 2
CH 3, C2H5-,
absolute
VII CH3, d)CH,CH-
VI
b) C2H50COCH2t Bu -,
R3:
confiqurations
c) C2H50COCH2CH2-
3
C6H5-, C6H5CH2-
of the amines obtained
always belong
to the S-series.
The steric effect by the side chain of the amino acid esters sterically
larger ester groups of amino acids give better
means
of IV agree very closely with
that no epimerization The process
Formation
and racemization
of this reaction
of VI, instead of VI',
optical yields yields
the experimental
(runs
calculated This
value.
occur in the whole process.
is sliqhtly
different
from the previous
one.
1)
from V with a base is due to the fact that HCY
in V is more acidic than is Ha because the u position
is not clear, but
Optical
1,2 and 3,4 in Table I, and runs 2,3,4 in Table II). from the VPC analysis
c) CH3-
of the ester qroup.
Ha is located
Treatment
at
of
R3-C-CH 1, 3 N R$-COOR2
V with a base gives exclusively transamination
reaction
VI.
A
transamination
typical
procedure
(2.14 g, 18.3 mmoles) were rcfluxed
I!I,
This miqration
pattern
scheme than is the previous is as follows.
and phenylacetone
A solution 11(2.44g,
for 48 hr usinq a Dean-Stark
(Rl=CH3, R2=C2H5,
VI'
is built up by the migration
of the double bond from III to VI. biological
This
R3=C6H5CH2).
is more
t0
pattern.l'
of L-alanine
18.3 mmolcs)
apparatus
similar
ethyl ester(I)
in benzene(60
ml)
to give the Schiff hase(III)
The solvent was evaporated
and the residual
oil
No.
1003
17
Table I
Asymmetric
Synthesis
of 2-Amino-3-phenyl
propane(vII1,
2-Amino-3-phenylpropane(VII1,
R~'C~H~CH~)
L-Amino Acid Run i
2)
; Ala-OBut
3
: Val-0C2H5
4
,5 '6
Optical yield based on VPC Analysis of IV(%) ~-
Confign.
2
3)
Val-OBut
j
Phe-OC2H5
~
yc2"5 Asp-0C2H5
R~=c~H~CH~)
37
85(89)
56
50(53)
48
63
87(83)
81
25
21(23)
S
40
49(53)
S
I
7
17
i
I ~I----a) Based on II, determined b) Optically
pure
in parentheses benzoate:
lytically
(S)-VIII(R3=C6~5~~2 are optical
[al;5+72o(c=l
was dissolved
H2 at room temperature
gel(200
wi th 5% Pd on charcoal After
for 16 hr.
of the N-alkylated
then an alcoholic
0.012 atom) and absolute for one hour at 40°C(bath
The reaction mixture
solution
Optically
pure
the catalyst,
chromatoqraphically
pressure
with silica
solvent to give a diastereo-
g, 9 mmole)
g, 59% based on II). in dry ether(5 ml) was
of sodium ethoxidc prepared ml) were added.
under
from Na(0.275
q,
The reaction was continued
After evaporation
of the solvent,
and the whole was kept at room temperature
was worked
of
the alcohol
(10 ml) of purified rV(2.0 g, 8.5 mmole)
temperature).
(S)-
(50 ml) of III was cata-
amino acid ester(IV)(2.56
alcohol(l0
Numbers
C2H50H).
(1.0 g) at a 60Kg/cmL
as the elutinq
solution
H2S04 was added to the residue
standard.
Ber. 65, 660(1932)).
filtering
of t-butyl hypochlorite(0.98
added to a dry ether solution
hr.
An alcoholic
The crude product was purified
A solution
cooling,
[a]15+34.5"(c=10.62, D
14, CH30H) (W. Leithe,
g) and ether-n-hexane(2:3)
merit mixture
),
as the internal
yields based on the benzoate.
in alcohol( 50 ml).
hydrogenated
was removed.
by VPC using naphthalene
up as usual to give 2-amino-3-phenyl
5% for 2
No. lj
1004
Table II
Asymmetric
Synthesis
of a-Phenethylamine
Chiral Reagents used7
Product ~~-_
4.
J
_____
u a --.-
7-m Chemical
L-Amino Acid Esters
yield(%
Ala-OC2H5 Val-OCH
(VIII, R,=C,H,)
20
3
12
30(36)
14
50(59)
56
10
-_(85)
88
13
50(55)
48
~
Val-OC2H5
I ! I
Val-OBu t3) Phe-0C2H5 TC2H5
- (45)
Asp-oC2Hs a) based Optically Chem.,
on II, determined pure
by VPC using durene
CR)-VIII(R3=C6H5)
121, 86,
on the benzoate.
: [a]~"+31c(c=2.0844,
c) Numbers
284(1912). Optically
pure
R3=CsH5CH2,
method.
C2H5OH)(K. are optical
b)
Parck, J. Prak yields based
: [a1~0-52.50(c=0.7947,
C6H6) (W.
444(1913)).
mmHg),
[ali5+
66%).
derivative
of VIII(R3=CsH5CH._,) was obtained
The product was purified
ether-n-hexane(l:l)
standard.
0.72 g, 37% based on II), bp 83-86'(15
22.7"(C2H50H) (Optical yield The N-Benzoyl
in parentheses
(S)-benzoate
J. Pope and J. Read, J. Chem. Sot., x,
propane(VIII,
as the internal
by the usual
by silica gel column chromatography
as the eluting
solvent,
(yield 86%),
with
[a]25+45 l'(CH OH) D ' 3
(Optical yield 63%). The application
of this reaction
active amines will be reported
to the synthesis
of various optically
in the near future. REFERENCES
1) S. Yamada,
S. Hashimoto,
2) R. W. Roeske, Chem. 3) G. W. Anderson
T. L. in press.
& Ind., 1959,
and F. M. Callahan,
1121. J. Am. Chem. Sot., 2,
3359(1959).