- Email: [email protected]
Synthesis of the spirocyclic center of fredericamycin a by phenoxy-enoxy radical coupling
Tetrahedron Letters,Vo1.26,No.26,pp Printed in Great Britain
SYNTHESIS FREDERICAMYCIN
OF THE SPIROCYCLIC
Summary:
Ferricyanide
oxidation
radical
of Chemistry,
or ortho to the phenolic
COUPLING
of Rochester
University NY
of the dianions
coupling
RADICAL
S. Kende*, Frank H. Ebetino 1 and Toshiharu Ohta
Rochester,
ular phenoxy-enoxy
0040-4039/85 $3.00 + .OO 01985 Pergamon Press Ltd.
CENTER OF
A BY PHENOXY-ENOKY
Andrew
Department
3063-3066,1985
14627
of phenolic
to form Spiro systems
8-diketones
derived
2 effects
intramolec-
from C-C bond formation
para
oxygen.
The intramolecular
coupling
of two phenoxy
radicals
to form a new carbon-carbon
bond
has been long recognized
as a major biosynthetic and important synthetic route to certain 2 We are unaware of the related coupling between a phenoxy alkaloids and polyketide substances. 3 We now report this possibly bioradical and an enoxy radical in natural products synthesis.
mimetic
model
antitumor
for the facile construction
antibiotic
fredericamycin
of the spirocyclic
diketone
center of the unique
A (1).4
1
The phenolic phenol
B-diketone
in 18% overall
O'C, then 1.2 eqts of n-BuLi followed
:a5 was prepared
yield as in Scheme 1. in hexane
in 3 hours by quenching
3-(4'-butenyl)-5-methylphenol. H202 gave the corresponding to the arylbutyric phthalate7
The dianion
Reaction
acid, mp 54-56°C.
chloromethyl
with excess BH3'SMe2
which was directly The corresponding
2a __ as colorless
3063
flakes
operations
of 3,5-dimethylphenol
at O"C, 20 m)6 was reacted
at 0°C with methyl
alcohol
to yield the diketone
in five synthetic
from 3,5-dimethyl(KH in THF at
at -78°C with ally1 chloride, ether to give O-methoxymethyl-
(O"C, 4 h) then with alkaline
oxidized
(PDC, 3.5 eqt, DMF, O'C, 18 h)
ester was condensed from methanol,
with dimethyl 8 mp 123-124°C.
3064
Scheme
1
L
(55%)
(71%)
(80%)
Treatment after
56%
of ?a at 0°C in 0.5 M Na2C03 with 6 eqts of 0.5 M K3Fe(CN)2'g
and workup
10 min using citric acid gave in 67% yield the pale yellow para-coupling product 2, 11 10 and 8% of the desired colorless ortho-coupling product $5, mp 221-113°C.
mp 253-254'C,
Differentiation the Ar-CH3
between
signal of para product
as a result
of shielding
Attempts oxidants2b either
acid
was condensed Oxidative assigned
to modify
2 (6 1.73) relative
the cyclization
FeC13, VOF3-TFA, We therefore
product.
by the 0.5 ppm upfield
to either
regiochemistry
aryl ring
(cf. Scheme
by the use of higher
pH or other
VOC13, T1(CF3C02j2, reacted
structure
phthalate
as described
CUCKOO),
our phenolic
$b because
1704 cm -I; 'H-NMR(CDC13): 8.02(2H,m)]
p-iodo
2.47(2H,t,J=7.6
with that of the minor product
ester with ICl 12 This ester.
_2!, mp 159-161°C
46% of a single spirodiketone,
of the close correspondence
2.36(3H,s),
2).
failed to produce
arylbutyrate
to give 45% of iodo diketone
produced
shift of
2% (6 2.23) or +a (6 2.26)
perpendicular
(1.0 eqt, 8"C, 30 m) to give 93% of the corresponding with dimethyl
coupling
7.88(2H,m),
was facilitated
in 3 by the newly proximate,
(e.g., Mn02,
cyclization
in acetic
these regioisomers
(dec).
13
mp 157-160°C
(dec),
[IR(CDC13):
1740,
of its spectra
Hz), 3.27(2H,t,J=7.6 4a from the earlier
Hz), 6.43(1H,s), cyclization
3065
Scheme
2
OH
d OH
0
)
0
X
+
22 (X=H) 2b (X=1)
because
Deiodination
of $b could not be selectively
of competing
reduction 14
under the usual conditions, Thus irradiation source
of the 1,3-dione selective
of _4b in isopropanol
in a Pyrex reaction
coupled
$9 (X=H) $b (X=1)
3
spirodiketone
from appropriate
studies
containing
(a) "Oxidative
Coupling
of Phenols,"
(b) Dhingra,
of enoxy radicals
using a 140 W. Hanovia
15
UV
ortho-
4b. coupling
could
of fredericamycin
A
For structure,
see Misra,
A recent
and Footnotes
Sciences,
of Tokyo.
A. R.; Taylor,
in Organic
Press, New York
Chemistry,"
1982, and references
(a) Ito, Y.; Konoike,
(b) Frazier,
R. H., Jr.; Harlow,
W. I.; Dekker,
New
Ed. Trahanovsky, therein.
T.; Saegusa, R. L.
T.
.I. Org. Chem.
therein.
R.; Pandey,
synthetic
University
Eds. Battersby,
are reported:
1980, 41, 5408, and references
R. C.; Silverton,
approach
J. V.
to the spirocyclic
is by Rao, A. V. R.; Reddy, D. R.; Deshpande, 1119.
photochemically.
gave 59% of the desired
in a total synthesis
0. P. in "Oxidations
.I. Am. Chem. Sot. 1975, 97, 649
104, 4478.
$b was inert to Bu3SnH
that such mild phenoxy-enoxy
center
of Pharmaceutical
w. s.; Part D, Ch. IV, Academic Couplings
excess NaOAc,
systems
precursors.16
On leave from Faculty
1967
Although
for 10 hours,
References
York,
out using H2-catalyst
of iodine was achieved
by 25% of recovered
suggest
the spirodiketone
unit.
reduction
at 60-70°C
$9 accompanied
These preliminary serve to construct
vessel
carried
V. H.
J. Am. Chem. Sot. 1982,
dione system of fredericamycin
.I. Chem. Sot., Chem. Commun.
1984,
3066
5. All compounds
for which mp are given gave satisfactory
C, H, or mass spectrometric
analyses. to Dr. Lee Latimer
6. We are indebted
(Eastman Kodak Co.) for providing
these reaction
condi-
tions from his laboratories. 7. Koelsch,
C. F.; Byers, D. J.
8. -2a: 'H-NMPx(CDC13,6): J=6.0),
5.28(1H,bs),
9. E&, Day, A. C. 10. 94 6;;(C;;;;;";;)
.
.
,
J. Am. Chem. Sot. 1940, 62, 560.
2.23 (3H,s), 2.24(2H,dt,J=6.0, 6.50(1H,s),
6.53(1H,s),
J. Chem. Sot. 1964, 3001. -1 ; UV(CH30H, 1740, 1702, 1595 cm
; 'H-NMR(CDC13,6):
(lH,bs), 6.39(1H,s), 36.8, 66.0, 109.6,
6.63(1H,s), 115.8,
6.74(1H,s),
7.86(2H,m),
X, log E): 382(2.33),
2.46(2H,t,J=7.5),
8.08(2H,m);
302(3.21),
3.19(2H,t,J=7.5),
13C NMR(DMSO-d6,6):
278 4.98
19.9, 32.1,
In the 134.4, 137.2, 141.5, 148.8, 158.5, 203.0. 13 C NMR are at 6 68.2 and 201.5, respeccarbons in the
on rechromatography. -1 ; UV(CH30H, X, log E):
1740, 1700, 1595 cm 2.26(3H,s),
7.87(2H,m),
3.04(1H,t,
7.98(2H,m).
123.8, 130.7,
Rao diketone the Spiro and carbonyl 4 tively. The UV of 3 was unchanged 11. 4a: IR(CHC13,v): iH-NMR(CDC13,B):
1.73(3H,s),
7.93(2H,m),
7.8). 2.76(2H,t,J=7.8),
6.58(1H,s),
2.46(2H,t,J=7.8),
8.02(wH,m).
3.22(2H,t,J=7.8),
In fredericamycin
275(3.58),
246(4.06);
4.79(1H,bs),
A the two adjacent
6.27(1H,s),
methylenes
are
at 6 2.55 (t,J=6) and 3.22(t,J=6).4 12. Papa, D.; Ginsberg,
H. F.; Lederman,
13. -2b: 'H-NMR(CDC13,6): 6.66(2H,s),
7.87(2H,m),
14. Brown, H. C.; Liu, K.-T. 15. cr. Friedman,
I.; DeCamp,
2.24(2H,q,J=8.0),
P., Abst.
V.
2.42(3H,s),
J. Am. Chem. Sot. 1953, 75, 1107. 2.98(2H,t,J=8.0),
3.08(1H,t,J=8.0),
8.01(2H,m). J. Am, Chem. Sot. 1970, 92, 3502 and references 148th American
Chemical
Society Meeting
(Chicago,
therein. 1964), Orgn.
p. 275. 16. Partial
support
(USPHS, DHEW) (Received
in
of this research
is gratefully USA
11 March
by grant CA-11326
acknowledged. 1985)
from the National
Cancer
Institute
SYNTHESIS FREDERICAMYCIN
OF THE SPIROCYCLIC
Summary:
Ferricyanide
oxidation
radical
of Chemistry,
or ortho to the phenolic
COUPLING
of Rochester
University NY
of the dianions
coupling
RADICAL
S. Kende*, Frank H. Ebetino 1 and Toshiharu Ohta
Rochester,
ular phenoxy-enoxy
0040-4039/85 $3.00 + .OO 01985 Pergamon Press Ltd.
CENTER OF
A BY PHENOXY-ENOKY
Andrew
Department
3063-3066,1985
14627
of phenolic
to form Spiro systems
8-diketones
derived
2 effects
intramolec-
from C-C bond formation
para
oxygen.
The intramolecular
coupling
of two phenoxy
radicals
to form a new carbon-carbon
bond
has been long recognized
as a major biosynthetic and important synthetic route to certain 2 We are unaware of the related coupling between a phenoxy alkaloids and polyketide substances. 3 We now report this possibly bioradical and an enoxy radical in natural products synthesis.
mimetic
model
antitumor
for the facile construction
antibiotic
fredericamycin
of the spirocyclic
diketone
center of the unique
A (1).4
1
The phenolic phenol
B-diketone
in 18% overall
O'C, then 1.2 eqts of n-BuLi followed
:a5 was prepared
yield as in Scheme 1. in hexane
in 3 hours by quenching
3-(4'-butenyl)-5-methylphenol. H202 gave the corresponding to the arylbutyric phthalate7
The dianion
Reaction
acid, mp 54-56°C.
chloromethyl
with excess BH3'SMe2
which was directly The corresponding
2a __ as colorless
3063
flakes
operations
of 3,5-dimethylphenol
at O"C, 20 m)6 was reacted
at 0°C with methyl
alcohol
to yield the diketone
in five synthetic
from 3,5-dimethyl(KH in THF at
at -78°C with ally1 chloride, ether to give O-methoxymethyl-
(O"C, 4 h) then with alkaline
oxidized
(PDC, 3.5 eqt, DMF, O'C, 18 h)
ester was condensed from methanol,
with dimethyl 8 mp 123-124°C.
3064
Scheme
1
L
(55%)
(71%)
(80%)
Treatment after
56%
of ?a at 0°C in 0.5 M Na2C03 with 6 eqts of 0.5 M K3Fe(CN)2'g
and workup
10 min using citric acid gave in 67% yield the pale yellow para-coupling product 2, 11 10 and 8% of the desired colorless ortho-coupling product $5, mp 221-113°C.
mp 253-254'C,
Differentiation the Ar-CH3
between
signal of para product
as a result
of shielding
Attempts oxidants2b either
acid
was condensed Oxidative assigned
to modify
2 (6 1.73) relative
the cyclization
FeC13, VOF3-TFA, We therefore
product.
by the 0.5 ppm upfield
to either
regiochemistry
aryl ring
(cf. Scheme
by the use of higher
pH or other
VOC13, T1(CF3C02j2, reacted
structure
phthalate
as described
CUCKOO),
our phenolic
$b because
1704 cm -I; 'H-NMR(CDC13): 8.02(2H,m)]
p-iodo
2.47(2H,t,J=7.6
with that of the minor product
ester with ICl 12 This ester.
_2!, mp 159-161°C
46% of a single spirodiketone,
of the close correspondence
2.36(3H,s),
2).
failed to produce
arylbutyrate
to give 45% of iodo diketone
produced
shift of
2% (6 2.23) or +a (6 2.26)
perpendicular
(1.0 eqt, 8"C, 30 m) to give 93% of the corresponding with dimethyl
coupling
7.88(2H,m),
was facilitated
in 3 by the newly proximate,
(e.g., Mn02,
cyclization
in acetic
these regioisomers
(dec).
13
mp 157-160°C
(dec),
[IR(CDC13):
1740,
of its spectra
Hz), 3.27(2H,t,J=7.6 4a from the earlier
Hz), 6.43(1H,s), cyclization
3065
Scheme
2
OH
d OH
0
)
0
X
+
22 (X=H) 2b (X=1)
because
Deiodination
of $b could not be selectively
of competing
reduction 14
under the usual conditions, Thus irradiation source
of the 1,3-dione selective
of _4b in isopropanol
in a Pyrex reaction
coupled
$9 (X=H) $b (X=1)
3
spirodiketone
from appropriate
studies
containing
(a) "Oxidative
Coupling
of Phenols,"
(b) Dhingra,
of enoxy radicals
using a 140 W. Hanovia
15
UV
ortho-
4b. coupling
could
of fredericamycin
A
For structure,
see Misra,
A recent
and Footnotes
Sciences,
of Tokyo.
A. R.; Taylor,
in Organic
Press, New York
Chemistry,"
1982, and references
(a) Ito, Y.; Konoike,
(b) Frazier,
R. H., Jr.; Harlow,
W. I.; Dekker,
New
Ed. Trahanovsky, therein.
T.; Saegusa, R. L.
T.
.I. Org. Chem.
therein.
R.; Pandey,
synthetic
University
Eds. Battersby,
are reported:
1980, 41, 5408, and references
R. C.; Silverton,
approach
J. V.
to the spirocyclic
is by Rao, A. V. R.; Reddy, D. R.; Deshpande, 1119.
photochemically.
gave 59% of the desired
in a total synthesis
0. P. in "Oxidations
.I. Am. Chem. Sot. 1975, 97, 649
104, 4478.
$b was inert to Bu3SnH
that such mild phenoxy-enoxy
center
of Pharmaceutical
w. s.; Part D, Ch. IV, Academic Couplings
excess NaOAc,
systems
precursors.16
On leave from Faculty
1967
Although
for 10 hours,
References
York,
out using H2-catalyst
of iodine was achieved
by 25% of recovered
suggest
the spirodiketone
unit.
reduction
at 60-70°C
$9 accompanied
These preliminary serve to construct
vessel
carried
V. H.
J. Am. Chem. Sot. 1982,
dione system of fredericamycin
.I. Chem. Sot., Chem. Commun.
1984,
3066
5. All compounds
for which mp are given gave satisfactory
C, H, or mass spectrometric
analyses. to Dr. Lee Latimer
6. We are indebted
(Eastman Kodak Co.) for providing
these reaction
condi-
tions from his laboratories. 7. Koelsch,
C. F.; Byers, D. J.
8. -2a: 'H-NMPx(CDC13,6): J=6.0),
5.28(1H,bs),
9. E&, Day, A. C. 10. 94 6;;(C;;;;;";;)
.
.
,
J. Am. Chem. Sot. 1940, 62, 560.
2.23 (3H,s), 2.24(2H,dt,J=6.0, 6.50(1H,s),
6.53(1H,s),
J. Chem. Sot. 1964, 3001. -1 ; UV(CH30H, 1740, 1702, 1595 cm
; 'H-NMR(CDC13,6):
(lH,bs), 6.39(1H,s), 36.8, 66.0, 109.6,
6.63(1H,s), 115.8,
6.74(1H,s),
7.86(2H,m),
X, log E): 382(2.33),
2.46(2H,t,J=7.5),
8.08(2H,m);
302(3.21),
3.19(2H,t,J=7.5),
13C NMR(DMSO-d6,6):
278 4.98
19.9, 32.1,
In the 134.4, 137.2, 141.5, 148.8, 158.5, 203.0. 13 C NMR are at 6 68.2 and 201.5, respeccarbons in the
on rechromatography. -1 ; UV(CH30H, X, log E):
1740, 1700, 1595 cm 2.26(3H,s),
7.87(2H,m),
3.04(1H,t,
7.98(2H,m).
123.8, 130.7,
Rao diketone the Spiro and carbonyl 4 tively. The UV of 3 was unchanged 11. 4a: IR(CHC13,v): iH-NMR(CDC13,B):
1.73(3H,s),
7.93(2H,m),
7.8). 2.76(2H,t,J=7.8),
6.58(1H,s),
2.46(2H,t,J=7.8),
8.02(wH,m).
3.22(2H,t,J=7.8),
In fredericamycin
275(3.58),
246(4.06);
4.79(1H,bs),
A the two adjacent
6.27(1H,s),
methylenes
are
at 6 2.55 (t,J=6) and 3.22(t,J=6).4 12. Papa, D.; Ginsberg,
H. F.; Lederman,
13. -2b: 'H-NMR(CDC13,6): 6.66(2H,s),
7.87(2H,m),
14. Brown, H. C.; Liu, K.-T. 15. cr. Friedman,
I.; DeCamp,
2.24(2H,q,J=8.0),
P., Abst.
V.
2.42(3H,s),
J. Am. Chem. Sot. 1953, 75, 1107. 2.98(2H,t,J=8.0),
3.08(1H,t,J=8.0),
8.01(2H,m). J. Am, Chem. Sot. 1970, 92, 3502 and references 148th American
Chemical
Society Meeting
(Chicago,
therein. 1964), Orgn.
p. 275. 16. Partial
support
(USPHS, DHEW) (Received
in
of this research
is gratefully USA
11 March
by grant CA-11326
acknowledged. 1985)
from the National
Cancer
Institute