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Studies on a biomimetic approach to aerothionin and psammaplysin-A
Tetrahedron Letters,Vo1.28,No.42,pp Printed in Great Britain
4969-4972,1987
0040-4039/87 $3.00 + .oo Pergamon Journals Ltd.
STUDIES ON A BIOMIMETIC APPROACH AEROTHIONIN AND PSAMMAPLYSIN-A
TO
Kelvin T. Okamoto and Jon Clardy* Department of Chemistry - Baker Laboratory Cornell University Ithaca, NY 14853-1301 USA
Summary: Oxidation and psammaplysin-A
of a plausible biological (2) is described.
In the last two decades,
precursor
for the spirocyclic
a number of natural products
have been isolated
order Verongida.
Most of them can be formulated
as products generated
dibromotyrosine.
Aerophobin-1,’
and psammaplysin-A
While the natural antibacterial
aerothionin
role of these
testing.
A recent
compounds
is unknown,
report on the related
ATPase and myosin Ca ATPase and activation
Me0
(l),*
0
compound
(2)s are pertinent
all have some purealin
from sponges
by the aromatic
(1)
of the
oxidation
of
examples.
biological
showed
inhibition
activity
in
of Na/K
OMe
u
OMe Br
they
of aerothionin
of myosin WEDTA ATPase.4 Br
Me0
systems
OMe
Br’
Br
NHR’
H2N-o Br 4
4969
4970
OMe Br
NOH
6
Scheme 1 The most interesting system.
Compounds
Verongida.
structural
aspect
with this spirocyclic
The purported
precursor
(Scheme
[5,3] spirocyclic
alcohol
bond
the
to yield
1).
could be formed
ketal
isoxazoline
only from the sponges
of dibromotyrosine.
by nucleophilic
can open by breaking
analogous
spirocyclic
is the spirocyclic
system have been isolated
The epoxide
in a reaction
[6,3]
molecules
is the oxime 5, a derivative
to arene oxide 6, the final spirocycles on the epoxide
of these
in a mechanism
a carbon-oxygen
similar
to the
of order
Were 5 oxidized
attack of the oxime
to the NIH shifts or by breaking
ring
hydroxyl
bond to give the the carbon-carbon
arene
oxide-oxepin
tautomerism.s A synthetic retrosynthetically acetyl
protected
overall
yield
approach
incorporating
disconnected
this proposed
at the carbon-nitrogen
amine 4 (R’=Ac) was synthesized
of 17%.
The carboxyl
portion
oxime 5. Ethyl ester 9 was synthesized
scheme amide
Compound
bond into two pieces.
from tyramine
retrosynthetically
was explored.
hydrochloride was envisioned
from p-hydroxybenzaldehyde
2 was
The mono-N-
in five steps with an as arising
from the
(8) in six steps with an overall
yield of 25%. Four methods
i.
The porphyrin
hydroxylation platinum
worked
were used to oxidize compound oxidation
eq), 2.5 ~JL N-methyl
of the oxime was performed
out by Tabushi
in polyvinylpyrollidine imidazole
9:
and
(PtPVP, (0.22 eq),
Morimitsu. 7
using conditions In a typical
6.6 PM, 4.1 x 10-T eq),* 1.80 mg TPP.MnCI
conducive
experiment,lO.O
3.80 mg benzoic
(0.018 eq),
to aromatic uL colloidal
anhydride
(0.12
and 55.0 mg 9 (1.00 eq)
4971
were stirred in 1.5 mL dry ethanol trace of non-starting
ii.
Oxime
9 was
dodecacarbonyl ethanol
material also
heated
as a solvent,
oxidized
the oxidation
after several
identified.
Two products
aldehyde
was obtained
atmosphere
after HPLC purification,
using
a system
of t-butyl
for several days.
but no identification hydroperoxide
Only a
was possible.
and
molybdenum
to 930 in a sealed tube9 for times ranging from 14 hours to 37 days.
recovered
12 was the result
under a 1 :l hydrogen:oxygen
days.
proceeded
Numerous
extremely
oxidation
hydroxylation
13 was an intermediate
Over 50% of starting
products were isolated
11.
and the last was the benzaldehyde
on the pathway
material
and four compounds
10 and the benzyl cyanide
were the nitro compound
of aromatic
slowly.
to oxime 5; HPLC purification
With was were
The third product 13.
Although
of 5 prior to oxidation
showed that 13 was not a contaminant.
CO2 Et
$.
i-iii
*BrGBr
iv,v
NOH
Lrdyy
’
rco2Et
Br OH
OMe
I OMe
i) NBS, 90% ii) Mel. K&O,. v) NaH, CH,(COOEt),, 75%
90% iii) NaBH,,65% iv) Nal, BF,.Et,O, vi) BuONO, NaOEt. 70%
75%
Br
Ho-NH2 i) A+O,
Br&Et
-
NaOAc, 75%
ii) Br,, 60%
H2N-oY-NHAc
iii) Br(CH2)3Br, NaH, 60%
Br
iv) K+Pth-,60%
BrJBI($yE;r$Br
v) H,NNH,,
Br$;
OMe
OMe
OMe
Ok
OMe
10
11
12
13
14
60%
4972
iii.
Oxidation
of 9 proceeded
Recovery
of starting
material
products
were isolated
oxidation
product in 3-4% yield.
much faster in benzene was
negligible
and identified.
after
Furthermore,
Compound
using the oxidizing
24 hours
and the same
the spirocycle
14 was identified
conditions
of method ii.
four major
14 was also isolated
oxidation
as an minor
using 1H NMR and chemical
ionization
MS;10 the NMR spectrum was similar to that reported for the methyl ester.” The last method
iv.
by Jerina
of oxidation
and Daly.12.13
products.
Recovered
in ethanol. experiments
Efforts
Oxidations
starting
no oxime was isolated.
aromatic
or less.l*.ts
acid in a biphasic system as reported
proceeded
with longer
cleanly
reaction
could
not successful.
be conclusively
few
times; after 37 days, virtually
products were the same four reported 14 were
and gave relatively
isolated from the reaction
Furthermore,
identified
throughout
as the spirocyclic
the
system
3
(2). oxidations
are run for only a few minutes
are performed
to prevent
The isolation
proposed
bio-oxidation
sponges.
Synthesis
of the methyl
biomimetic
synthesis
of aerothionin
generating
the necessary
AcknowledamentS:
decreased
to find the spirocycle
(R=Et) of psammaplysin-A
percent
material
compound
trifluoroperacetic
using this system
The identified
no isolated
Typically,
employed
on simple
secondary
and identification
of 9 to the spirocyclic
reactions.
seen in natural
of 14 would
(1). 11 Further oxidation
arene oxide and subsequently
This work was supported
Yields
the desired
by the National
are ususally ten
oxidation
products
complete
studies
and anisole--and
of products
of 14 from the peroxide
systems
ester analogue
systems--benzene
the
from the Verongida
a formal,
may reveal
supports
albeit
better
low-yield,
methods
for
spirocycles.
Institutes of Health (CA24487).
REFERENCES
3 4. 5.
;: 8. 9.
10. 11. 12. 13.
P.D. Bartlett and T.G. Traylor. J. Am. Chem. Sot. 83, 856 (1961). Tetrahedron Lett., 22, 39.42(1981) and references J.A. McMillan, I.C. Paul, Y.M. Goo. and K.L. Rinehart, Jr. therein. D.M. Roll. C.W.J. Chang. P.J. Scheuer, G.A. Gray, J.N. Shoolery, G.K. Matsumoto. G.D. VanDuyne, and J. Clardy. J. Am. Chem. Sot. 107, 2916-20(1985) and references therein. H. Nakamura, H. Wu, J. Kobayashi, Y. Nakamura, and Y. Ohizumi. Tetrahedron Left 26, 4517.20(1985). D.M. Jerina and J.W. Daly. Science. 165, 573~82(1974) and references therein, E. Vogel and H. Gunther. Angew. Chemie Int. Ed. 6, 385-401(1967). I. Tabushi and K. Morimitsu. Tetwhderon Lett. 27,51-4(1986). H. Hirai, Y. Nakao, and N. Toshima. J. Macromol. Sci.-Chem. A13. 727.50(1979). M.N. Sheng and J.G. Zajacek. Advan. Cbem. Series. 1968.418-32. Spectral data for 14: CIMS, m/z= 412(M++3, trace); ‘H NMR(CDC13, 400 MHz) 6 6.47 (IH, s), 5.24 (lH, d, J=5.9 Hz), 4.30 (IH, d, J=6.0), 3.94 (lH, d. J=7.7). 3.10 (lH, d, J-7.8) 4.17 (2H, q, 8.2) 1.22, (3H. 1, 8.2) and 3.81 (3H. s) ppm. S. Nishiyama and S. Yamamura. Bull. Chem. Sot. Jpn. 56,3453-6(1965). D.M. Jerina, J.W. Daly, and 8. Witkop. Biochemistry. 10, 366-72(1971). D. Jerina, G. Guroff, and J. Daly. Arch. Biochem. Biopbys. 124. 612-15(1968).
(Received
in USA 16 June
1987)
4969-4972,1987
0040-4039/87 $3.00 + .oo Pergamon Journals Ltd.
STUDIES ON A BIOMIMETIC APPROACH AEROTHIONIN AND PSAMMAPLYSIN-A
TO
Kelvin T. Okamoto and Jon Clardy* Department of Chemistry - Baker Laboratory Cornell University Ithaca, NY 14853-1301 USA
Summary: Oxidation and psammaplysin-A
of a plausible biological (2) is described.
In the last two decades,
precursor
for the spirocyclic
a number of natural products
have been isolated
order Verongida.
Most of them can be formulated
as products generated
dibromotyrosine.
Aerophobin-1,’
and psammaplysin-A
While the natural antibacterial
aerothionin
role of these
testing.
A recent
compounds
is unknown,
report on the related
ATPase and myosin Ca ATPase and activation
Me0
(l),*
0
compound
(2)s are pertinent
all have some purealin
from sponges
by the aromatic
(1)
of the
oxidation
of
examples.
biological
showed
inhibition
activity
in
of Na/K
OMe
u
OMe Br
they
of aerothionin
of myosin WEDTA ATPase.4 Br
Me0
systems
OMe
Br’
Br
NHR’
H2N-o Br 4
4969
4970
OMe Br
NOH
6
Scheme 1 The most interesting system.
Compounds
Verongida.
structural
aspect
with this spirocyclic
The purported
precursor
(Scheme
[5,3] spirocyclic
alcohol
bond
the
to yield
1).
could be formed
ketal
isoxazoline
only from the sponges
of dibromotyrosine.
by nucleophilic
can open by breaking
analogous
spirocyclic
is the spirocyclic
system have been isolated
The epoxide
in a reaction
[6,3]
molecules
is the oxime 5, a derivative
to arene oxide 6, the final spirocycles on the epoxide
of these
in a mechanism
a carbon-oxygen
similar
to the
of order
Were 5 oxidized
attack of the oxime
to the NIH shifts or by breaking
ring
hydroxyl
bond to give the the carbon-carbon
arene
oxide-oxepin
tautomerism.s A synthetic retrosynthetically acetyl
protected
overall
yield
approach
incorporating
disconnected
this proposed
at the carbon-nitrogen
amine 4 (R’=Ac) was synthesized
of 17%.
The carboxyl
portion
oxime 5. Ethyl ester 9 was synthesized
scheme amide
Compound
bond into two pieces.
from tyramine
retrosynthetically
was explored.
hydrochloride was envisioned
from p-hydroxybenzaldehyde
2 was
The mono-N-
in five steps with an as arising
from the
(8) in six steps with an overall
yield of 25%. Four methods
i.
The porphyrin
hydroxylation platinum
worked
were used to oxidize compound oxidation
eq), 2.5 ~JL N-methyl
of the oxime was performed
out by Tabushi
in polyvinylpyrollidine imidazole
9:
and
(PtPVP, (0.22 eq),
Morimitsu. 7
using conditions In a typical
6.6 PM, 4.1 x 10-T eq),* 1.80 mg TPP.MnCI
conducive
experiment,lO.O
3.80 mg benzoic
(0.018 eq),
to aromatic uL colloidal
anhydride
(0.12
and 55.0 mg 9 (1.00 eq)
4971
were stirred in 1.5 mL dry ethanol trace of non-starting
ii.
Oxime
9 was
dodecacarbonyl ethanol
material also
heated
as a solvent,
oxidized
the oxidation
after several
identified.
Two products
aldehyde
was obtained
atmosphere
after HPLC purification,
using
a system
of t-butyl
for several days.
but no identification hydroperoxide
Only a
was possible.
and
molybdenum
to 930 in a sealed tube9 for times ranging from 14 hours to 37 days.
recovered
12 was the result
under a 1 :l hydrogen:oxygen
days.
proceeded
Numerous
extremely
oxidation
hydroxylation
13 was an intermediate
Over 50% of starting
products were isolated
11.
and the last was the benzaldehyde
on the pathway
material
and four compounds
10 and the benzyl cyanide
were the nitro compound
of aromatic
slowly.
to oxime 5; HPLC purification
With was were
The third product 13.
Although
of 5 prior to oxidation
showed that 13 was not a contaminant.
CO2 Et
$.
i-iii
*BrGBr
iv,v
NOH
Lrdyy
’
rco2Et
Br OH
OMe
I OMe
i) NBS, 90% ii) Mel. K&O,. v) NaH, CH,(COOEt),, 75%
90% iii) NaBH,,65% iv) Nal, BF,.Et,O, vi) BuONO, NaOEt. 70%
75%
Br
Ho-NH2 i) A+O,
Br&Et
-
NaOAc, 75%
ii) Br,, 60%
H2N-oY-NHAc
iii) Br(CH2)3Br, NaH, 60%
Br
iv) K+Pth-,60%
BrJBI($yE;r$Br
v) H,NNH,,
Br$;
OMe
OMe
OMe
Ok
OMe
10
11
12
13
14
60%
4972
iii.
Oxidation
of 9 proceeded
Recovery
of starting
material
products
were isolated
oxidation
product in 3-4% yield.
much faster in benzene was
negligible
and identified.
after
Furthermore,
Compound
using the oxidizing
24 hours
and the same
the spirocycle
14 was identified
conditions
of method ii.
four major
14 was also isolated
oxidation
as an minor
using 1H NMR and chemical
ionization
MS;10 the NMR spectrum was similar to that reported for the methyl ester.” The last method
iv.
by Jerina
of oxidation
and Daly.12.13
products.
Recovered
in ethanol. experiments
Efforts
Oxidations
starting
no oxime was isolated.
aromatic
or less.l*.ts
acid in a biphasic system as reported
proceeded
with longer
cleanly
reaction
could
not successful.
be conclusively
few
times; after 37 days, virtually
products were the same four reported 14 were
and gave relatively
isolated from the reaction
Furthermore,
identified
throughout
as the spirocyclic
the
system
3
(2). oxidations
are run for only a few minutes
are performed
to prevent
The isolation
proposed
bio-oxidation
sponges.
Synthesis
of the methyl
biomimetic
synthesis
of aerothionin
generating
the necessary
AcknowledamentS:
decreased
to find the spirocycle
(R=Et) of psammaplysin-A
percent
material
compound
trifluoroperacetic
using this system
The identified
no isolated
Typically,
employed
on simple
secondary
and identification
of 9 to the spirocyclic
reactions.
seen in natural
of 14 would
(1). 11 Further oxidation
arene oxide and subsequently
This work was supported
Yields
the desired
by the National
are ususally ten
oxidation
products
complete
studies
and anisole--and
of products
of 14 from the peroxide
systems
ester analogue
systems--benzene
the
from the Verongida
a formal,
may reveal
supports
albeit
better
low-yield,
methods
for
spirocycles.
Institutes of Health (CA24487).
REFERENCES
3 4. 5.
;: 8. 9.
10. 11. 12. 13.
P.D. Bartlett and T.G. Traylor. J. Am. Chem. Sot. 83, 856 (1961). Tetrahedron Lett., 22, 39.42(1981) and references J.A. McMillan, I.C. Paul, Y.M. Goo. and K.L. Rinehart, Jr. therein. D.M. Roll. C.W.J. Chang. P.J. Scheuer, G.A. Gray, J.N. Shoolery, G.K. Matsumoto. G.D. VanDuyne, and J. Clardy. J. Am. Chem. Sot. 107, 2916-20(1985) and references therein. H. Nakamura, H. Wu, J. Kobayashi, Y. Nakamura, and Y. Ohizumi. Tetrahedron Left 26, 4517.20(1985). D.M. Jerina and J.W. Daly. Science. 165, 573~82(1974) and references therein, E. Vogel and H. Gunther. Angew. Chemie Int. Ed. 6, 385-401(1967). I. Tabushi and K. Morimitsu. Tetwhderon Lett. 27,51-4(1986). H. Hirai, Y. Nakao, and N. Toshima. J. Macromol. Sci.-Chem. A13. 727.50(1979). M.N. Sheng and J.G. Zajacek. Advan. Cbem. Series. 1968.418-32. Spectral data for 14: CIMS, m/z= 412(M++3, trace); ‘H NMR(CDC13, 400 MHz) 6 6.47 (IH, s), 5.24 (lH, d, J=5.9 Hz), 4.30 (IH, d, J=6.0), 3.94 (lH, d. J=7.7). 3.10 (lH, d, J-7.8) 4.17 (2H, q, 8.2) 1.22, (3H. 1, 8.2) and 3.81 (3H. s) ppm. S. Nishiyama and S. Yamamura. Bull. Chem. Sot. Jpn. 56,3453-6(1965). D.M. Jerina, J.W. Daly, and 8. Witkop. Biochemistry. 10, 366-72(1971). D. Jerina, G. Guroff, and J. Daly. Arch. Biochem. Biopbys. 124. 612-15(1968).
(Received
in USA 16 June
1987)