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Synthesis of β,γ-unsaturated amino acids as potential catalytic irreversible enzyme inhibitors
Tetrahedron Letters No. qlr pp 3689 - 3692, 1977.
SYNTHESIS OF B,y-UNSATURATED
Pergmon Press. Printed in Great Britain.
AFINO ACIDS AS POTENTIAL CATALYTIC
IRREVERSIBLE
ENZYME
Brian W. METCALFand
INHIBITORS
Karin JUND
Centre de Recherche Merrell International 16, rue d'Ankara, 67000 Strasbourg - France
(Recejved in UK 11 August, 1977; accepted for publication 25 August 1977) As a continuation inhibitors: DOPA)
(1)s
of our work on the design and synthesis
we wish to
a-bromovinyl
of the pyridoxal
The proposed
present
(PyCHO)
- dependent
of inhibition,
irreversible
enzyme
of a-vinyl-3,4_dihydroxyphenylalanine
DOPA (2) and a-acetylenic
phosphate
mechanism
the synthesis
of catalytic
DOPA (3), potential
irreversible
(a-vinyl inhibitors
DOPA-decarboxylase.
illustrated
follows:
+
NHI
I
3689
with a-vinyl
DOPA (l), is outlined
as
36~0
Yc* 41
Thus loss of CO2 from the Schiff's substrate
-1 would
lead to formation
could then occur -via the Michael to the conjugated
imine.
may also be expected
The synthesis alkylation
base formed between
and acylation
addition
active
irreversible
inhibition
phosphate
and the unnatural
site of a vinyl imine.
of a nucleophilic
In a similar manner a-bromovinyl
to produce
of a-vinyl
in the enzyme
pyridoxal
residue
(Nu) in the active
OOPA (2) and a-acetylenic
2
of this enzyme
from the appropriately
site
OOPA (2)
.
DOPA (1) is shown below and relies on the consecutive of anions derived
Inactivation
activated
regioselective
propargyl-
TMS I
I. PhNHNH, 2.
Treatment
6
I
of the anion derived
imine -5
4
bromide
, some dialkylation
from the aldimine 4 was essential
(0.9 eq., 30 min. -70°C) led mainly
occurring.
The use of LDA to generate
in order to avoid the extensive
n-BuLi was used as base. -5 was treated second propargylic
-7
from the aldimine -4 Ia (1 eq. lithium diisopropylamide
THF, -70°C) with 3,4_dimethoxybenzyl monoalkylated
in situ (1 eq. n-BuLi,
the protected
detected
by n.m.r.
amino acid -6
4
at either
the anion
observed
(1 eq., 30 min.,
stage of the synthesis
ation of 4 and acylation
of 5 thus appear to be regioselective
Owing
to the instability
of intermediates
after
isolation
liberate
to the
when a
-7O"C),
. It is to be noted that no allenic products were
or i.r. spectroscopy
by ether extraction,
dialkylation
(LDA),
-70°C) so as to generate
anion. This anion, when trapped with C1COOCH3
afforded
KOH
the amine, which when subjected
processes.
5 and 5 to chromatography
was treated with PhNHNH2 to aqueous
of 5. The alkyl-
and distillation,
crude 6,
(1 eq., 2 hours, 25'C) to
KOH (5 eq. in aq.CH30H
, 1 hour) afforded
IT@. 41
the stable amino acid 1 4y5 (m.p. 225°C). 50 % overall yield
isation,
groups
by treatment
a-vinyl
DOPA i(260"
in 85 % yield.
decomp.,
62 %)
435
= 3 HZ) 7 was isolated
in 24 "6 overall yield
benzyl bromide -10
in 31 % yield when the
We have observed
analog 2 8
4
of 1, prepared
in a similar
DOPA 2 4y5 (m.p. 21O"C,
gave a-acetylenic
from -10.
-9
10 -
a-vinyl
of the methyl ether
.
(HCl 6N) of the 3,4_isopropylidene
from 3,4_isopropylidene
decomp.)
6 to
amino acid -7 was treated with 47 % HBr (reflux 4 hours).
Acid hydrolysis manner
Cleavage
(Na/(NH4)2S04/NH3)
in
of 8 with 47 % HBr (reflux 2 hours) then gave, after neutral-
cl-Bromovinyl DOPA 2 4y5 (m.p. 280°c, J(c=cH,) acetylenic
amino acid 1 is thus available
bromide. l was reduced
from 3,4_dimethoxybenzyl
the vinyl amino acid 8 4y5 (m.p. 250°C) protecting
The acetylenic
an irreversible
DOPA 1 and a-acetylenic
component DOPA 3,
3
in the inhibition which
of DOPA decarboxylase
will be reported
with both
elsewhere.
References 1.
a) B.W. Metcalf
and P. Casara,
b) M.J. Jung and B.W. Metcalf, c) B. Lippert, 2.
Rando has proposed irreversible Science, 185,
3.
B.W. Metcalf,
J.E.
M.J.
Letters,
Biophys.
3337-3340
Res. Comm., 67,
Jung and P. Casara,
of pyridoxal
(1975). 301-306
Eur. J. Biochem.,
(1975). _, 74
441 (1977).
amino acids may prove to be generally
phosphate-dependent
enzymes.
useful as
See R.R. Rando,
320 (1974). a to an aldimine
extensively
Dolfini
Biochem.
that B,y-unsaturated
inhibitors
Anion formation described
Tetrahedron
function,
in recent years,
and J.Z. Gougoutas,
acting as amaskedprimary
amine,
e.g. E.H.W. Biihm, H.E. Applegate,
J. Amer. Chem. Sot., 93, 4324 (1971);
has been
B. Toeplitz,
No.
3692
R.A. Firestone,
N. Schelechow,
D.B.R. Johnston
and B.G. Christensen,
Tetrahedron
Letters,
375 (1972); W.A. Spitzer,
T. Goodson,
R.J. Smithey
and I.G. Wright,
J. Chem. Sot. Chem. Conm.,
1138
(1972). 4.
N.m.r.
5.
Satisfactory
6.
A.L. Henne and G.W. Greenlee,
J. Amer. Chem. Sot., 65, 2020 (1943).
7.
L,M.Jackman
"Applications
and i.r. spectra were consistentwith
in Organic 8.
elemental
analyses
and S. Sternhell, Chemistry",
were obtained
2nd Edition,
K. Ogura and G. Tsuchihashi,
the proposed
structure.
for this compound.
of Nuclear
Magnetic
p, 277.
Tetrahedron
Letters,
3151 (1971).
Resonance
41
Spectroscopy
SYNTHESIS OF B,y-UNSATURATED
Pergmon Press. Printed in Great Britain.
AFINO ACIDS AS POTENTIAL CATALYTIC
IRREVERSIBLE
ENZYME
Brian W. METCALFand
INHIBITORS
Karin JUND
Centre de Recherche Merrell International 16, rue d'Ankara, 67000 Strasbourg - France
(Recejved in UK 11 August, 1977; accepted for publication 25 August 1977) As a continuation inhibitors: DOPA)
(1)s
of our work on the design and synthesis
we wish to
a-bromovinyl
of the pyridoxal
The proposed
present
(PyCHO)
- dependent
of inhibition,
irreversible
enzyme
of a-vinyl-3,4_dihydroxyphenylalanine
DOPA (2) and a-acetylenic
phosphate
mechanism
the synthesis
of catalytic
DOPA (3), potential
irreversible
(a-vinyl inhibitors
DOPA-decarboxylase.
illustrated
follows:
+
NHI
I
3689
with a-vinyl
DOPA (l), is outlined
as
36~0
Yc* 41
Thus loss of CO2 from the Schiff's substrate
-1 would
lead to formation
could then occur -via the Michael to the conjugated
imine.
may also be expected
The synthesis alkylation
base formed between
and acylation
addition
active
irreversible
inhibition
phosphate
and the unnatural
site of a vinyl imine.
of a nucleophilic
In a similar manner a-bromovinyl
to produce
of a-vinyl
in the enzyme
pyridoxal
residue
(Nu) in the active
OOPA (2) and a-acetylenic
2
of this enzyme
from the appropriately
site
OOPA (2)
.
DOPA (1) is shown below and relies on the consecutive of anions derived
Inactivation
activated
regioselective
propargyl-
TMS I
I. PhNHNH, 2.
Treatment
6
I
of the anion derived
imine -5
4
bromide
, some dialkylation
from the aldimine 4 was essential
(0.9 eq., 30 min. -70°C) led mainly
occurring.
The use of LDA to generate
in order to avoid the extensive
n-BuLi was used as base. -5 was treated second propargylic
-7
from the aldimine -4 Ia (1 eq. lithium diisopropylamide
THF, -70°C) with 3,4_dimethoxybenzyl monoalkylated
in situ (1 eq. n-BuLi,
the protected
detected
by n.m.r.
amino acid -6
4
at either
the anion
observed
(1 eq., 30 min.,
stage of the synthesis
ation of 4 and acylation
of 5 thus appear to be regioselective
Owing
to the instability
of intermediates
after
isolation
liberate
to the
when a
-7O"C),
. It is to be noted that no allenic products were
or i.r. spectroscopy
by ether extraction,
dialkylation
(LDA),
-70°C) so as to generate
anion. This anion, when trapped with C1COOCH3
afforded
KOH
the amine, which when subjected
processes.
5 and 5 to chromatography
was treated with PhNHNH2 to aqueous
of 5. The alkyl-
and distillation,
crude 6,
(1 eq., 2 hours, 25'C) to
KOH (5 eq. in aq.CH30H
, 1 hour) afforded
IT@. 41
the stable amino acid 1 4y5 (m.p. 225°C). 50 % overall yield
isation,
groups
by treatment
a-vinyl
DOPA i(260"
in 85 % yield.
decomp.,
62 %)
435
= 3 HZ) 7 was isolated
in 24 "6 overall yield
benzyl bromide -10
in 31 % yield when the
We have observed
analog 2 8
4
of 1, prepared
in a similar
DOPA 2 4y5 (m.p. 21O"C,
gave a-acetylenic
from -10.
-9
10 -
a-vinyl
of the methyl ether
.
(HCl 6N) of the 3,4_isopropylidene
from 3,4_isopropylidene
decomp.)
6 to
amino acid -7 was treated with 47 % HBr (reflux 4 hours).
Acid hydrolysis manner
Cleavage
(Na/(NH4)2S04/NH3)
in
of 8 with 47 % HBr (reflux 2 hours) then gave, after neutral-
cl-Bromovinyl DOPA 2 4y5 (m.p. 280°c, J(c=cH,) acetylenic
amino acid 1 is thus available
bromide. l was reduced
from 3,4_dimethoxybenzyl
the vinyl amino acid 8 4y5 (m.p. 250°C) protecting
The acetylenic
an irreversible
DOPA 1 and a-acetylenic
component DOPA 3,
3
in the inhibition which
of DOPA decarboxylase
will be reported
with both
elsewhere.
References 1.
a) B.W. Metcalf
and P. Casara,
b) M.J. Jung and B.W. Metcalf, c) B. Lippert, 2.
Rando has proposed irreversible Science, 185,
3.
B.W. Metcalf,
J.E.
M.J.
Letters,
Biophys.
3337-3340
Res. Comm., 67,
Jung and P. Casara,
of pyridoxal
(1975). 301-306
Eur. J. Biochem.,
(1975). _, 74
441 (1977).
amino acids may prove to be generally
phosphate-dependent
enzymes.
useful as
See R.R. Rando,
320 (1974). a to an aldimine
extensively
Dolfini
Biochem.
that B,y-unsaturated
inhibitors
Anion formation described
Tetrahedron
function,
in recent years,
and J.Z. Gougoutas,
acting as amaskedprimary
amine,
e.g. E.H.W. Biihm, H.E. Applegate,
J. Amer. Chem. Sot., 93, 4324 (1971);
has been
B. Toeplitz,
No.
3692
R.A. Firestone,
N. Schelechow,
D.B.R. Johnston
and B.G. Christensen,
Tetrahedron
Letters,
375 (1972); W.A. Spitzer,
T. Goodson,
R.J. Smithey
and I.G. Wright,
J. Chem. Sot. Chem. Conm.,
1138
(1972). 4.
N.m.r.
5.
Satisfactory
6.
A.L. Henne and G.W. Greenlee,
J. Amer. Chem. Sot., 65, 2020 (1943).
7.
L,M.Jackman
"Applications
and i.r. spectra were consistentwith
in Organic 8.
elemental
analyses
and S. Sternhell, Chemistry",
were obtained
2nd Edition,
K. Ogura and G. Tsuchihashi,
the proposed
structure.
for this compound.
of Nuclear
Magnetic
p, 277.
Tetrahedron
Letters,
3151 (1971).
Resonance
41
Spectroscopy