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Introduction of functional groups into 6 position of pyridoxal
TetrahedronLettersNo. 28, pp 2603 - 2606. QPergamon Press Ltd. 1979. Printed in Great Britain.
0040-4039/79/0708-260?$02.00/0
INTRODUCTION OF FUNCTIONAL GROUPS INTO 6 POSITION OF PYRIDOXAL Yasuhiro Yamada*, Toshio Hayashi, Yuichi Fusho and Hirosuke Okada Department of Fermentation Technology, Faculty of Engineering, Osaka University, Yamadakami, Suita-shi, Osaka, Japan
Summary: The synthesis of 6-acylpyridoxal, 6-carboxyethylpyridoxal and 6-(3'aminopropyl)pyridoxal derivatives are described. Pyridoxal-5'-phosphate
(2), the active form of vitamin B6, is a coenzyme of
many enzymes which catalyze transamination, decarboxylation, deamination, $elimination and B-substitution of amino acids. Pyridoxal activities. 1)
(l), (2) and their derivatives also show some physiological These facts have stimulated studies on the relation of their
structure and activities.
Although many derivatives of V.B6 were reported, of
which greater part were modified in position other than 6 position of their pyridine ring and only a few of them have a substituent on 6 position. lb, 2) In order to obtain variants of pyridoxal or pyridoxal-5'-phosphate which retain their coenzyme activities and are applicable to immobilized coenzymes, the introduction of carbon functional groups into open 6 position of pyridoxal and elongation of them to appropriate spacers is a promising method. In this communication, we wish to describe an acylation of 6 position of appropriately protected pyridoxal via its lithium compound and preparation of some 6-substituted pyridoxal derivatives. Bromination of pyridoxal with pyridinium hydrobromide perbromide in CHC13 at room temperature with vigorous stirring for 3 h gave 6-bromopyridoxal
(3) in
57% yield, [mp 138' (dp); mass, 247, 245 (M+); NMR (in d-DMSO) 6, 2.40 (CH3), 4.85 (5'-CH2-,d), 6.50 (4'-CH-); W (in MeOH) nm, 225 (9,500), 288 (6,600)]. (3)
was transformed to 6-bromo methylacetal
2603
(4) (mp 149O) by HCl in dry methanol
QR
ZHO
H.-O,
h
Ho
/
H3C
‘N
(1)
R=H
(3)
R=H
(2)
RzP03H2
(4)
RXH3
I
CH2 6r
QCH3
(5)
R=Br
(12)
Rl=CH3,
R2 =COOH
(6)
R=Li
(13)
Rl=H,
R2=COOH
(7)
R=CHO
(14)
Rl= CH3,
R2=CH2NH2
(8)
R = COCH3
(9)
R z CO(CH2CH20)3CH2CgH5
(10)
R= CH=CHCOOH
(11)
R = CH=CHCN (4) was benzylated
in 92% yield. in ethanol
in the presence
methylacetal (OCH3), MeOH)
4.95
nm, 225
Bromine butyllithium
with
of sodium
dimethylphenylbenzylammonium
ethoxide
(5) in 82% yield,
[mp 110"; NMR
(5'-CH2-,d),
(Ar-CH2-),
(sh), 285
atom
in
5.10
to give
3)
6-bromo-3-0-benzyl
(in CDC13)
6.18
chloride
(4'-CH-),
6, 2.46 7.33
(CH3), 3.45
(Ar-H); UV
(in
(6,770)1.
(5) was
substituted
in THF at -78' under
with
argon.
lithium
by treating
To the lithium
compound
(5) with
n-
(6) colored
29
No.
dark
red, was added
After
treating
benzyl
1.5 equiv.
reaction
6, 2.60 6.30
(ArCH20),
275
(9,620),
Reaction
with
dil.
(CH3), 3.49
(4'-CH-),
6.25,
(OCH3),
7.40
(Ar-H),
10.0
of lithium
compound
(6) with
(8) and
(M+); NMR
3.88
(-CO-CH2-CW2-0-,
J=12
Hz)]. cases,
7.39
of these
a-methylene
proton
All attempts allylbromide, fact
t,
a-lithiumpyridine of piericidin
Similarly of
(10) under
CH-) r UV
nm, 293 nm
6.40
form.
(in MeOH)
HZ),
acid
yield,
(-CH3),
5.42
3.42
(5'-CH2-,
as a main
(OCH3), d,
product. of
6-H compound.
alkylhalides
such as
reagents
were unseccessful. et air.5) successfully
several
prenylbromides
intermediate
we have
in their
acid
(=CH-cN,
(20,900),
over
HZ),
Pd-C
285
UV
(in MeOH)
[mp 125O;
mass,
219; NMR 6.44
nm, 285
(4'-CH-), (6,920)].
by condensation -1 (Nujol) 2,200 cm
IR
5.1-5.5
(-CH=, J=16
223
for 3 h to give
3.30
(M+), 310,
(11) was obtained
(ArCH2-,
HZ),
5'-CH2-),
7.39
(Ar-H); uv
(2:l) at room
temperature
(sh)].
(5%) in MeOH-THF
Imp (dp) 170-180"; (-CH2CH2-CO),
341
(OCH3),
7.15
(13,000),
(7).
of a trace
(ArCH2,5'-CH2-),
methylacetal
J=16 272
pressure
5.1-5.3
(CH3), 3.46
6-carboxy-
(15) from
in the presence
(-CH=, Ar-H);
in 65% yield.
synthesized
6-carboxyvinyl-3-0-benzyl
[mp 192O; mass, (OCH3),
for the synthesis
derivative
in pyridine
7.24-7.5
6, 2.52
nm,
(5'-CH2-, 260
due to the release
(6) with
that Rapoport with
3.2-3.5
(11,200),
(6) to give
alkylating
compound
(CH3), 3.38
(CH3), 2.5-2.8
(12) was easily
compound
6-acylpyridoxal
6, 2.48
probably
with
at 80" for 2 h to give
cyanoacetic
an atmospheric
6, 2.36
lithium
with malonic
was hydrogenated
crystalline
5.34
and N,N-dimethyl-
(-0CH3),
5.18,
6-(3'-aminopropyl)pyridoxal
d, J=16
nm, 320
(9) were
For example,
6, 2.42
(4'-CH-),
(in EtOH)
Hz),
(8) [mp 95"; mass,
was obtained
derivatives.
(C-N), NMR (in CDC13) 6.24
(in MeOH)
nm, 294
(in CDC13)
reacted
6-cyanovinyl-3-0-benzyl
(7) with
CM+), 268; NMR
analogues.
(10) in 79.5%
(=CH-CO,
3.45
(in EtOH)
(7) is an useful
of piperidine
(in d-DMSO)
(-CH3),
derivative
(13) and
methylacetal
(8) and
considering
synthesis
6.60
for 4 h.
6-formyl-3-0-
d, J=12
corresponding
(ArCH2-0-3-C),
and other
is interesting
(7) was condensed
5.28
which
to alkylate
alkylated
amount
UV
respectively.
6-H compound
products
6-Formylpyridoxal
2.66
(M+); NMR
J=6),
allyliodide
ethylpydoxal
521
of amids
of 6-alkylpyridoxal
gave
(Ar-H), UV
debrominated
Low yields
This
6, 2.56,
(4'-CH-),
(9) [oil; mass,
In both
299
(4'-CH2-,
(-CH=O),
(9) in 18 and 6% yields
(in CDC13)
6.26
(8,320)1.
5.60
gave
N,N-dimethylacetamide
4,7,10-trioxa-11-phenylundecanoyl-l-amide
Ar-CH2-),
workup
(sh)].
derivatives 322
in dry THF and kept
HCl, usual
[mp 103O; mass,
(7) in 72% yield, 4,
methylacetal
(in CDCl3)
dimethylformamide
mixture
(12) in 56% yield
221
(-CH30H),
(OCH3),
4.96
in a pure
176; NMR
(5'-CH2-),
(in d-DMSO) 6.16
(4'-
(6,920)].
hydrolyzed
to
(13) with
1 N HCl at 50' for 1 h quantita-
2606
No. 20
tively. The unsaturated nitrile (11) was also hydrogenated to saturated amine (14) over Pd-C (15%) in ethanol in the presence of small amount of CHC13 6) under 1 atm of H2 at room temperature.
This amine (14) was purified and identified
in the form of diacetate in 52% yield, [oil, NMR (in CDC13) 6, 1.94, 2.34, 2.42 (CH3), 1.75-2.15 (C-CH2-C), 2.71 (6C-CH2-, t), 3.2-3.5 (-CH,-N), 5.10 L
(5'-CH2-, d, d), 6.12 (4'-CH-), 6.40 (NH)]. Acknowledgment A part of this work was carried out under the support of a grant No. 347094 from the Ministry of Education, Science and Culture, Japanese Government. References 1. a) M.J. Modak, Biochemistry, 15, 3620 (1976). b) W. Koryntnyk, M. Ikawa, Methods in Enzymology, Is, 524 (1970). 2. S. Ikeda, S. Fukui, Biochem. Biophys. Res. Commun., 52, 482 (1973). 3. W. Korytnyk, S.C. Srivastava, N. Angelino, P.G.G. Potti, B. Paul, J. Med. Chem., 5,
1096 (1973).
4. J.E. Parks, B.E. Wagner, R.H. Holm, J. Organometal. Chem., 56, 53 (1973). 5. E.P. Schmidtchen, H. Rapoport, J. Am. Chem. Sot., 2,
7014 (1977).
6. J.A. Secrist, DI, M.W. Logue, J. Org. Chem., 37, 335 (1972).
(Receivedin Japan 7 April 1979)
0040-4039/79/0708-260?$02.00/0
INTRODUCTION OF FUNCTIONAL GROUPS INTO 6 POSITION OF PYRIDOXAL Yasuhiro Yamada*, Toshio Hayashi, Yuichi Fusho and Hirosuke Okada Department of Fermentation Technology, Faculty of Engineering, Osaka University, Yamadakami, Suita-shi, Osaka, Japan
Summary: The synthesis of 6-acylpyridoxal, 6-carboxyethylpyridoxal and 6-(3'aminopropyl)pyridoxal derivatives are described. Pyridoxal-5'-phosphate
(2), the active form of vitamin B6, is a coenzyme of
many enzymes which catalyze transamination, decarboxylation, deamination, $elimination and B-substitution of amino acids. Pyridoxal activities. 1)
(l), (2) and their derivatives also show some physiological These facts have stimulated studies on the relation of their
structure and activities.
Although many derivatives of V.B6 were reported, of
which greater part were modified in position other than 6 position of their pyridine ring and only a few of them have a substituent on 6 position. lb, 2) In order to obtain variants of pyridoxal or pyridoxal-5'-phosphate which retain their coenzyme activities and are applicable to immobilized coenzymes, the introduction of carbon functional groups into open 6 position of pyridoxal and elongation of them to appropriate spacers is a promising method. In this communication, we wish to describe an acylation of 6 position of appropriately protected pyridoxal via its lithium compound and preparation of some 6-substituted pyridoxal derivatives. Bromination of pyridoxal with pyridinium hydrobromide perbromide in CHC13 at room temperature with vigorous stirring for 3 h gave 6-bromopyridoxal
(3) in
57% yield, [mp 138' (dp); mass, 247, 245 (M+); NMR (in d-DMSO) 6, 2.40 (CH3), 4.85 (5'-CH2-,d), 6.50 (4'-CH-); W (in MeOH) nm, 225 (9,500), 288 (6,600)]. (3)
was transformed to 6-bromo methylacetal
2603
(4) (mp 149O) by HCl in dry methanol
QR
ZHO
H.-O,
h
Ho
/
H3C
‘N
(1)
R=H
(3)
R=H
(2)
RzP03H2
(4)
RXH3
I
CH2 6r
QCH3
(5)
R=Br
(12)
Rl=CH3,
R2 =COOH
(6)
R=Li
(13)
Rl=H,
R2=COOH
(7)
R=CHO
(14)
Rl= CH3,
R2=CH2NH2
(8)
R = COCH3
(9)
R z CO(CH2CH20)3CH2CgH5
(10)
R= CH=CHCOOH
(11)
R = CH=CHCN (4) was benzylated
in 92% yield. in ethanol
in the presence
methylacetal (OCH3), MeOH)
4.95
nm, 225
Bromine butyllithium
with
of sodium
dimethylphenylbenzylammonium
ethoxide
(5) in 82% yield,
[mp 110"; NMR
(5'-CH2-,d),
(Ar-CH2-),
(sh), 285
atom
in
5.10
to give
3)
6-bromo-3-0-benzyl
(in CDC13)
6.18
chloride
(4'-CH-),
6, 2.46 7.33
(CH3), 3.45
(Ar-H); UV
(in
(6,770)1.
(5) was
substituted
in THF at -78' under
with
argon.
lithium
by treating
To the lithium
compound
(5) with
n-
(6) colored
29
No.
dark
red, was added
After
treating
benzyl
1.5 equiv.
reaction
6, 2.60 6.30
(ArCH20),
275
(9,620),
Reaction
with
dil.
(CH3), 3.49
(4'-CH-),
6.25,
(OCH3),
7.40
(Ar-H),
10.0
of lithium
compound
(6) with
(8) and
(M+); NMR
3.88
(-CO-CH2-CW2-0-,
J=12
Hz)]. cases,
7.39
of these
a-methylene
proton
All attempts allylbromide, fact
t,
a-lithiumpyridine of piericidin
Similarly of
(10) under
CH-) r UV
nm, 293 nm
6.40
form.
(in MeOH)
HZ),
acid
yield,
(-CH3),
5.42
3.42
(5'-CH2-,
as a main
(OCH3), d,
product. of
6-H compound.
alkylhalides
such as
reagents
were unseccessful. et air.5) successfully
several
prenylbromides
intermediate
we have
in their
acid
(=CH-cN,
(20,900),
over
HZ),
Pd-C
285
UV
(in MeOH)
[mp 125O;
mass,
219; NMR 6.44
nm, 285
(4'-CH-), (6,920)].
by condensation -1 (Nujol) 2,200 cm
IR
5.1-5.5
(-CH=, J=16
223
for 3 h to give
3.30
(M+), 310,
(11) was obtained
(ArCH2-,
HZ),
5'-CH2-),
7.39
(Ar-H); uv
(2:l) at room
temperature
(sh)].
(5%) in MeOH-THF
Imp (dp) 170-180"; (-CH2CH2-CO),
341
(OCH3),
7.15
(13,000),
(7).
of a trace
(ArCH2,5'-CH2-),
methylacetal
J=16 272
pressure
5.1-5.3
(CH3), 3.46
6-carboxy-
(15) from
in the presence
(-CH=, Ar-H);
in 65% yield.
synthesized
6-carboxyvinyl-3-0-benzyl
[mp 192O; mass, (OCH3),
for the synthesis
derivative
in pyridine
7.24-7.5
6, 2.52
nm,
(5'-CH2-, 260
due to the release
(6) with
that Rapoport with
3.2-3.5
(11,200),
(6) to give
alkylating
compound
(CH3), 3.38
(CH3), 2.5-2.8
(12) was easily
compound
6-acylpyridoxal
6, 2.48
probably
with
at 80" for 2 h to give
cyanoacetic
an atmospheric
6, 2.36
lithium
with malonic
was hydrogenated
crystalline
5.34
and N,N-dimethyl-
(-0CH3),
5.18,
6-(3'-aminopropyl)pyridoxal
d, J=16
nm, 320
(9) were
For example,
6, 2.42
(4'-CH-),
(in EtOH)
Hz),
(8) [mp 95"; mass,
was obtained
derivatives.
(C-N), NMR (in CDC13) 6.24
(in MeOH)
nm, 294
(in CDC13)
reacted
6-cyanovinyl-3-0-benzyl
(7) with
CM+), 268; NMR
analogues.
(10) in 79.5%
(=CH-CO,
3.45
(in EtOH)
(7) is an useful
of piperidine
(in d-DMSO)
(-CH3),
derivative
(13) and
methylacetal
(8) and
considering
synthesis
6.60
for 4 h.
6-formyl-3-0-
d, J=12
corresponding
(ArCH2-0-3-C),
and other
is interesting
(7) was condensed
5.28
which
to alkylate
alkylated
amount
UV
respectively.
6-H compound
products
6-Formylpyridoxal
2.66
(M+); NMR
J=6),
allyliodide
ethylpydoxal
521
of amids
of 6-alkylpyridoxal
gave
(Ar-H), UV
debrominated
Low yields
This
6, 2.56,
(4'-CH-),
(9) [oil; mass,
In both
299
(4'-CH2-,
(-CH=O),
(9) in 18 and 6% yields
(in CDC13)
6.26
(8,320)1.
5.60
gave
N,N-dimethylacetamide
4,7,10-trioxa-11-phenylundecanoyl-l-amide
Ar-CH2-),
workup
(sh)].
derivatives 322
in dry THF and kept
HCl, usual
[mp 103O; mass,
(7) in 72% yield, 4,
methylacetal
(in CDCl3)
dimethylformamide
mixture
(12) in 56% yield
221
(-CH30H),
(OCH3),
4.96
in a pure
176; NMR
(5'-CH2-),
(in d-DMSO) 6.16
(4'-
(6,920)].
hydrolyzed
to
(13) with
1 N HCl at 50' for 1 h quantita-
2606
No. 20
tively. The unsaturated nitrile (11) was also hydrogenated to saturated amine (14) over Pd-C (15%) in ethanol in the presence of small amount of CHC13 6) under 1 atm of H2 at room temperature.
This amine (14) was purified and identified
in the form of diacetate in 52% yield, [oil, NMR (in CDC13) 6, 1.94, 2.34, 2.42 (CH3), 1.75-2.15 (C-CH2-C), 2.71 (6C-CH2-, t), 3.2-3.5 (-CH,-N), 5.10 L
(5'-CH2-, d, d), 6.12 (4'-CH-), 6.40 (NH)]. Acknowledgment A part of this work was carried out under the support of a grant No. 347094 from the Ministry of Education, Science and Culture, Japanese Government. References 1. a) M.J. Modak, Biochemistry, 15, 3620 (1976). b) W. Koryntnyk, M. Ikawa, Methods in Enzymology, Is, 524 (1970). 2. S. Ikeda, S. Fukui, Biochem. Biophys. Res. Commun., 52, 482 (1973). 3. W. Korytnyk, S.C. Srivastava, N. Angelino, P.G.G. Potti, B. Paul, J. Med. Chem., 5,
1096 (1973).
4. J.E. Parks, B.E. Wagner, R.H. Holm, J. Organometal. Chem., 56, 53 (1973). 5. E.P. Schmidtchen, H. Rapoport, J. Am. Chem. Sot., 2,
7014 (1977).
6. J.A. Secrist, DI, M.W. Logue, J. Org. Chem., 37, 335 (1972).
(Receivedin Japan 7 April 1979)