- Email: [email protected]
Mechanism of the rearrangement of dopachrome to 5,6-dihydroxyindole
0040.J039/91 5300+ oc PergarnonF?essplc
Tetrahedron Letters,Vo1.32, No 31.~~ 3849-3850, 1991 Printed in Great Braam
MECHANISM
OF THE REARRANGEMENT
C. Costantini, Dlpartimento Napoli,
OF DOPACHROME
0. Crescenzi,
TO 5,6-DINYDROXYINDOLE
G. Prota*
di Chimica Organica e Biologica, Universita Via Mezzocannone 16, I-80134 Napoli, Italy.
di
Abstract. Kinetic and isotopic labelling studies provide for the first time evidence that at physiological pH the rearrangement of dopachrome (1) to 5,6_dihydroxyindole (2) involves abstraction of the proton at position 3 and formation of the intermediate quinone-methide 4.
Dopachrome tyroslne
(1)
a
to melanin,l
man.
Once
generated
of
dopa,
key
the
intermediate
major
Since
it
was
conversion
to
of
tautomerization
to
position
3
reported
dopachrome
by
could
have
decarboxylation
2
to
(Pathway a
the
of
differences
in
chemical
cxidation undergoes
as
a):
to 2 [Pathway
the
the
major
proposed
1):
the
of
3
one6
and
its
hydrogen
which
would
the
several
to account first
alternatively,7 (4),
twenties,
object
indolenine
quinone-methide
for the involves
subsequent shift
than
from
undergo
b).
HO
3
0 OOH -0
conversion
give
in
the
been
(Scheme
dopachrome
give
color or
to
Raper' been
has
5,6-dihydroxyindole
decarboxylation
skin
enzymic
decarboxylation
4, 5 Two mechanisms
investigations.3'
of
by
oxidative
(2).
first
of
the
2,3-dihydroindole-5,6-quinone
concomitant
5,6_dihydroxyindole
rearrangement
solution
unstable
with
in
determinant
in aqueous
this
rearrangement product
is
HO
H
H
H
2
HO
1
0
SCHEME 1 However,
substantiated between
up
to the present by detailed
the two
Recently,
4
kinetic
alternatives
we have
found
such
has that
t!
hypothethical and mechanistic
remained
studies,
essentially
the rearrangement 3849
pathways
have and
never any
been
choice
speculative.
of a-methyldopachrome
3850
methyl ester
(5) leads to a relatively stable quinone-methide
(6);8 this
finding, leading apparently support to the general pathway b, prompted us itself.
to re-examine the mechanism of rearrangement of dopachrome
CHs COOCH3
"I=
_;~Z,,,
6
5
Dopachrome was prepared by ferricyanide oxidation of dopa, and diluted to 0.05 mH with pH 7.0 phosphate 0.088
buffer
(resulting buffer
concentration
M).
The rearrangement
of dopachrome was followed spectrophotometrically at 475 nm, at 30-C under nitrogen, and was found first order in dopachrome, with
an
apparent
rate
5,6_dihydroxyindole,
constant
of
0.060
The
min-I.
yield
as determined by HPLC analysis of the mixtures
complete rearrangement,
of
after
exceeds 96%.
Under identical conditions, the rate constants for the rearrangement
of
[2-'HI- and [3,3- 2H2]dopachromeg are 0.055 and 0.0073 mine', respectively. The primary isotope effect (k,/k D = 8.2) observed for [3,3-ZH2Jdopachrome indicates
that
reaction.
Accordingly,
base
5,6_dihydroxyindole
catalyzed
removal
the mechanisms
of H-3
is the
first
of rearrangement
step
of the
of dopachrome
to
at neutral pH can be formulated as depicted ln pathway
b of scheme 1. It
should
disappearance the subsequent
be
noted
that
of dopachrome,
appears
that
kinetic
data
refes
and afford no information
steps. However,
intermediate quinone-methide
the
since no significant
a5
only
to
to the rate of
accumulation
of the
4 can be detected spectrophotometrically,
decarboxylation
of
4
is
rapid
in
the
comparison
to
it Its
generation. Acknowledgments. Research Foundation
We thank the C.N.R.
(Rome) and the Lawrence
M. Gelb
(Stanford, CT) for financial support.
References and notes. 1. Prota, G.: Medicinal Research Reviews, 1988, 8, 525. 2. Raper, H.S.; Biochem .I., 1927, 21, 89. 3. Mason, H.S.; J.BLol.Chem , 1948, 172, 83 4. Bu'Lock, J.D., Harley-Mason, J.; J.Chem Sot , 1951, 2248. 5. Mason, H.S., Wright, C.I.; J Biol Chem , 1949, 180, 235. 6. Brown, R.K. in Houlihan, W.J., ed.; Indoles, part I, Wiley, 1972, 446. 7. Sobotka, H., Barsel, N., Chanely, J.D. in Zechmeister, L., ed.; Fortschr.Chem.Org.Naturstcffe, 1957, 14, 229. 8. Crescenzi, O., Costantini, C., Prota, G.; Tetrahedron Lett., 1990, 31, 6095. 9. Binns, F., King, J.A.G., Percival, A., Robson, N.C., Swan, G.A.; J Chem Sot (C), 1970, 1134. (Received inUK 9 May 1991)
Tetrahedron Letters,Vo1.32, No 31.~~ 3849-3850, 1991 Printed in Great Braam
MECHANISM
OF THE REARRANGEMENT
C. Costantini, Dlpartimento Napoli,
OF DOPACHROME
0. Crescenzi,
TO 5,6-DINYDROXYINDOLE
G. Prota*
di Chimica Organica e Biologica, Universita Via Mezzocannone 16, I-80134 Napoli, Italy.
di
Abstract. Kinetic and isotopic labelling studies provide for the first time evidence that at physiological pH the rearrangement of dopachrome (1) to 5,6_dihydroxyindole (2) involves abstraction of the proton at position 3 and formation of the intermediate quinone-methide 4.
Dopachrome tyroslne
(1)
a
to melanin,l
man.
Once
generated
of
dopa,
key
the
intermediate
major
Since
it
was
conversion
to
of
tautomerization
to
position
3
reported
dopachrome
by
could
have
decarboxylation
2
to
(Pathway a
the
of
differences
in
chemical
cxidation undergoes
as
a):
to 2 [Pathway
the
the
major
proposed
1):
the
of
3
one6
and
its
hydrogen
which
would
the
several
to account first
alternatively,7 (4),
twenties,
object
indolenine
quinone-methide
for the involves
subsequent shift
than
from
undergo
b).
HO
3
0 OOH -0
conversion
give
in
the
been
(Scheme
dopachrome
give
color or
to
Raper' been
has
5,6-dihydroxyindole
decarboxylation
skin
enzymic
decarboxylation
4, 5 Two mechanisms
investigations.3'
of
by
oxidative
(2).
first
of
the
2,3-dihydroindole-5,6-quinone
concomitant
5,6_dihydroxyindole
rearrangement
solution
unstable
with
in
determinant
in aqueous
this
rearrangement product
is
HO
H
H
H
2
HO
1
0
SCHEME 1 However,
substantiated between
up
to the present by detailed
the two
Recently,
4
kinetic
alternatives
we have
found
such
has that
t!
hypothethical and mechanistic
remained
studies,
essentially
the rearrangement 3849
pathways
have and
never any
been
choice
speculative.
of a-methyldopachrome
3850
methyl ester
(5) leads to a relatively stable quinone-methide
(6);8 this
finding, leading apparently support to the general pathway b, prompted us itself.
to re-examine the mechanism of rearrangement of dopachrome
CHs COOCH3
"I=
_;~Z,,,
6
5
Dopachrome was prepared by ferricyanide oxidation of dopa, and diluted to 0.05 mH with pH 7.0 phosphate 0.088
buffer
(resulting buffer
concentration
M).
The rearrangement
of dopachrome was followed spectrophotometrically at 475 nm, at 30-C under nitrogen, and was found first order in dopachrome, with
an
apparent
rate
5,6_dihydroxyindole,
constant
of
0.060
The
min-I.
yield
as determined by HPLC analysis of the mixtures
complete rearrangement,
of
after
exceeds 96%.
Under identical conditions, the rate constants for the rearrangement
of
[2-'HI- and [3,3- 2H2]dopachromeg are 0.055 and 0.0073 mine', respectively. The primary isotope effect (k,/k D = 8.2) observed for [3,3-ZH2Jdopachrome indicates
that
reaction.
Accordingly,
base
5,6_dihydroxyindole
catalyzed
removal
the mechanisms
of H-3
is the
first
of rearrangement
step
of the
of dopachrome
to
at neutral pH can be formulated as depicted ln pathway
b of scheme 1. It
should
disappearance the subsequent
be
noted
that
of dopachrome,
appears
that
kinetic
data
refes
and afford no information
steps. However,
intermediate quinone-methide
the
since no significant
a5
only
to
to the rate of
accumulation
of the
4 can be detected spectrophotometrically,
decarboxylation
of
4
is
rapid
in
the
comparison
to
it Its
generation. Acknowledgments. Research Foundation
We thank the C.N.R.
(Rome) and the Lawrence
M. Gelb
(Stanford, CT) for financial support.
References and notes. 1. Prota, G.: Medicinal Research Reviews, 1988, 8, 525. 2. Raper, H.S.; Biochem .I., 1927, 21, 89. 3. Mason, H.S.; J.BLol.Chem , 1948, 172, 83 4. Bu'Lock, J.D., Harley-Mason, J.; J.Chem Sot , 1951, 2248. 5. Mason, H.S., Wright, C.I.; J Biol Chem , 1949, 180, 235. 6. Brown, R.K. in Houlihan, W.J., ed.; Indoles, part I, Wiley, 1972, 446. 7. Sobotka, H., Barsel, N., Chanely, J.D. in Zechmeister, L., ed.; Fortschr.Chem.Org.Naturstcffe, 1957, 14, 229. 8. Crescenzi, O., Costantini, C., Prota, G.; Tetrahedron Lett., 1990, 31, 6095. 9. Binns, F., King, J.A.G., Percival, A., Robson, N.C., Swan, G.A.; J Chem Sot (C), 1970, 1134. (Received inUK 9 May 1991)