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The influence of α-aryl ethers on the asymmetric reduction of carbonyls
Tetrahedron Letters,Vol.27,No.27,pp Printed in Great Britain
THE INFLUENCE
OF a-ARYL
3091-3094,1986
ETHERS ON THE ASYMMETRIC
0040-4039/86 $3.00 + .OO Perqamon Journals Ltd.
REDUCTION
OF CARBONYLS
William
D. Samuels, David A. Nelson*, and Richard T. Hallen Chemical Technology Department Pacific Northwest Laboratory, Richland Washington 99352
Summary
The asymmetric reduction of a-aryl ethers 1 was found to be strongly influenced bv the uresence of ortho substituents on tFe arvl rina. tirouos (methoxv or hydroxy) that chelate metal cations tend to stabilize-a "1ockkd"'bicycl;c 4 which, intermediate when reduced, yielded preferentially the erytho isomer.
Uuring
our investigation
lignocellulosic senting
materials,
the various
preparation plished
into the mechanistic
we had anticipated
types of bonds within
of Z-aryloxyphenylpropanols
by the reduction
lignin.
2.
of the appropriate
details
The latter
reference
either oxygen hydrides,
Our initial
yroups metal
ketone Lwith
NaBH4[1,2].
and 8-esters[ll].
reduction, souyht
selectivity
to determine
alcohols
The phenoxy
nitroyen
[5], alcohols
to the carbonyl
the reasons
atmosphere.
for this loss of selectivity which produce
the reducing
A sufficient
the
oxygen
ethers
prepared
results bearing
with a variety
[7j, and sulfoxides
enhanced
[9], a-alkoxy
containing
of metal
[tlj
had
functional
stereoselectivity
for
LlOj, and a-phenoxy to NaBH4 (in ethanol)
(see Table
in the preparation
1).
Thus, we
of some of the
stereoselectivity.
used in this work were prepared
Typically,
of ketones,
Further,
have also exhibited
These
riyid models
when the ketones -la-h were SubJected
the conditions
ketones, 1,
phenol.
[4] with cyclic
[63, epoxides
induction.
they include a-alcohols However,
toward
has been accom-
isomer ratio of 9:1[2].
was not found for all of the alcohols
and to establish
respective
an erthro to threo
a hiyh degree of asymmetric
reduction;
was directed
compounds
of repre-
2
Work by others on the reduction
to a-alkoxyethers
in the a position hydride
ethers
or nitrogen.
interest
of similar
by the work of Cram [3j and Karabatsos
adJacent
also indicated
indicated
decomposition
of a series of compounds
The synthesis
1
can be explained
of the thermal
the preparation
from Z-bromopropiophenone
and the
agent was added to a flame dried flask under a
volume of anhydrous
3091
solvent was added to dissolve
the
3092
TABLE 1:
Reduction
of Z-Phenoxypropiophenones.
Aryloxy Substitution
Reducing Agenta (erythro:threo)
Z-methoxy 2,5-dimethoxy 2-hydroxy none 4-methoxy 3-methoxy 2-methyl 2-t-butyl a b
c reduciny
ayent.
of reduciny 1.25:1.
NaBHab
LiAIHnC
Zn(BH4)2C
89:ll 77~23 92:8 42:58 55:45 45:55 26~74
9ll:lO 92:8 92:8 72:28 77:23 70:30 46:54
>YY:l Y2:8 >YY:l >YY:l >Y9:1 91:Y 72~28
Isomer ratios were determined by yas chromatoyraphy and confirmed by integration (NMR) of the methyl absorbences. Reductions were performed in ethanol. Reductions were performed in ether.
Then the a-phenoxy
ketone was added via a syrinye
agent to ketone was l:l, except
to the flask.
for ketone -lc where the ratio was increased
The ratio of solvent to ketone was kept at 25mL to 1.0 mmole.
was stirred
at 23OC for 3 hours before a minimal
This mixture obtained
was extracted
in quantitative
with ether, dried,
yield
The molar
and exhibited
amount
of saturated
and stripped NMR, IR,
The reaction
NH4C1 solution
of solvent.
All alcohols
and MS data consistent
ratio
to
mixture was added. were
with the expected
products. The initial
reduction
atom at the ortho position control
of ketones -la-c with NaBH4 suyyested in the phenoxy
than had been previously
riny had a yreater
reported[1,2].
in Table 1 have been used in accordance
that the presence
influence
The isomer desiynations
with the results
of the previous
of 1-(4'-benzyloxyphenyl,3'-methoxy-)-2-(2"-methoxyphenoxy)-l-propanone ratio of Y:l was found for the reduction The five-membered adequately
describe
of an oxygen
on the stereochemical of erythro
and threo
work on the reduction [2], where an isomer
run with NaBH4 in ethanol.
riny rigid model 2,
similar
the course of the reduction
to tnat proposed
of the ketones L,
by Cram [3J, miyht
but for several
exceptions
3093
which
are apparent
both oxygen
in Table
methoxy
and hydroxy
substituted
1 indicate
substituted
rings which
modification
The erytho-selectivity
a non-hindering
approach
in a manner
[12] allows the propanone
direct
comparisons
of the results
ferent
solvents
consistent
since reductions
81:1Y(LiA1H4),
while g
The predominance attributed the t-butyl
obtained
were used due to synthetic of la,
cation chela-
groups.
Molecular
noted with & "locked"
However,
away from the
to a hindrance
The erythro-threo
lithium,
the trends
in THF gave erytro:threo
the
or zinc; i.e., hard-
We do caution
reductions
from the ratios
Apparently,
structure.
methyl to predominate.
necessity.
a con-
can be held in
attack to occur predominately
by NaBH4 and LiAlH4
preformed
involves
aryloxy-group
does not form as rigid a ring structure _3_as either
ness of the cation
rings which
suggest that some
to its alternative,
of -2b may be attributed
unity in -2d-f due to the lack of the bicyclic
sodium cation
substituted groups
or hydroxy
structure {the
which allows metal hydride
group, that is not chelated,
the
ortho-
(Za-c), non-ortho --
from NaBH4 probably
such as 4 is preferred
The lower erythro-selectivity
group.
0-methoxy
structure
Rather,
is necessary.
and A-methoxy
aryloxy,
With the presumed
ring.
position
ring 2
shown by -2a-c prepared
suggest that a bicyclic
selectivity
These distinct
-h).
with the
groups of compounds:
(2d-f), and ortho-alkyl --
(&and
chelate
in the carbonyl,
eight-membered
Id-f using NaBH4. --
show erythro
chelates
phenylpropanone
phenoxypropriophenones
rings which
selectivity
of Z-methoxy
This was not observed
that there are at least three
of the five membered
tion of the oxyyens
in the reduction
cation effectively
9:l was observed.
show no selectivity
show a threo or "reverse"
n-methyl
and ketone groups
of the non ortho-substituted
found in Table
voluted,
[6] has shown that the sodium
ratio of approximately
results
models
Glass
atoms of the alkoxy
and that an isomer reductions
1.
against
in Table 1 since difdo appear
of 73:27(NaBH4)
somewhat and
gave ratios of 50:50 for both reagents. of the threo-diastereomers
to steric hindrance
of the z-toluoxy
group is overwhelming
after NaBH4 reduction and -o-t-butyl-phenoxy
even when strong Zn++ chelation
of
a and,
groups.
$_
can be
The presence
of
can occur.
Acknowledgment This work was supported under Contract
DE-ACU6-76RLO
by the U.S. Department
of Energy,
Office
of Basic Energy Sciences,
1830.
References 1.
A.F.A.
2.
G. Brunow,
3.
U.J. Cram, And U.R. Wilson,
4.
G.J. Karabatsos,
Willis,
Cellulose
L. Koskinen,
Chem. Tech.,
and P. Urpilainen,
Acta Chem. Scand.,B,
J. Amer. Chem. Sot.,
J. Amer. Chem. Sot.,
5a. K. Koga and S.-I. Yamada, b. L.E. Overman
1976,x,345.
1967, e,
Chem. Pharm. Bull.,
and R.J. McCready,
Tetrahedron
1963,*,
1245.
1641. 1972,g,
Lett.,
526.
1982, 2355.
1981, 35,
53.
3094
c. C. Still and J.H. McDonald, d. T. Tokuyama,
K. Shimado,
6a. J.H. Stocker, U_, 3913. b. R.S. Glass,
Tetrahedron
Lett.,
and M. Uemura,
P. Sidisunthorn,
O.H. Ueardorff,
Tetrahedron
B.M. Benjamin,
and K. Henegar,
b. A. Amouroux,
Tetrahedron
and T. Oishi, Tetrahedron
B. Gerin,
and M. Chartrette,
8.
ti. Sollaedie,
C. Greek,
9.
T. Nakata and T Oishi, Tetrahedron
11.
G.E. Miksche,
Acta Chem. Stand.,
12.
R.G. Pearson,
J. Amer. Chem. Sot., 1963,g, USA
28
February
1981, 4723. Lett.,
Lett.,
1982, 4341. 1982, 5047.
1980, 1641.
1966, 1038.
1986)
1980, 4723.
Lett.,
and T. Matsumota,
M. Yanagiya,
in
K. Hasegawa,
Lett.,
J. Amer. Chem. SOC., 1960,
1983, 2653.
Tetrahedron
Lett.,
1980, 4723.
Lett.,
Tetrahedron
10.
(Received
F. Matsuda,
and G. Oemailly,
Lett.,
and C.S. Collins,
c. T. Nakata, T. Tanaka, and T. Oishi, Tetrahedron 7a. T. Nakata, T. Tanaka,
lY82, 2121.
3533.
Tetrahedron
Lett.,
1982, 4039.
THE INFLUENCE
OF a-ARYL
3091-3094,1986
ETHERS ON THE ASYMMETRIC
0040-4039/86 $3.00 + .OO Perqamon Journals Ltd.
REDUCTION
OF CARBONYLS
William
D. Samuels, David A. Nelson*, and Richard T. Hallen Chemical Technology Department Pacific Northwest Laboratory, Richland Washington 99352
Summary
The asymmetric reduction of a-aryl ethers 1 was found to be strongly influenced bv the uresence of ortho substituents on tFe arvl rina. tirouos (methoxv or hydroxy) that chelate metal cations tend to stabilize-a "1ockkd"'bicycl;c 4 which, intermediate when reduced, yielded preferentially the erytho isomer.
Uuring
our investigation
lignocellulosic senting
materials,
the various
preparation plished
into the mechanistic
we had anticipated
types of bonds within
of Z-aryloxyphenylpropanols
by the reduction
lignin.
2.
of the appropriate
details
The latter
reference
either oxygen hydrides,
Our initial
yroups metal
ketone Lwith
NaBH4[1,2].
and 8-esters[ll].
reduction, souyht
selectivity
to determine
alcohols
The phenoxy
nitroyen
[5], alcohols
to the carbonyl
the reasons
atmosphere.
for this loss of selectivity which produce
the reducing
A sufficient
the
oxygen
ethers
prepared
results bearing
with a variety
[7j, and sulfoxides
enhanced
[9], a-alkoxy
containing
of metal
[tlj
had
functional
stereoselectivity
for
LlOj, and a-phenoxy to NaBH4 (in ethanol)
(see Table
in the preparation
1).
Thus, we
of some of the
stereoselectivity.
used in this work were prepared
Typically,
of ketones,
Further,
have also exhibited
These
riyid models
when the ketones -la-h were SubJected
the conditions
ketones, 1,
phenol.
[4] with cyclic
[63, epoxides
induction.
they include a-alcohols However,
toward
has been accom-
isomer ratio of 9:1[2].
was not found for all of the alcohols
and to establish
respective
an erthro to threo
a hiyh degree of asymmetric
reduction;
was directed
compounds
of repre-
2
Work by others on the reduction
to a-alkoxyethers
in the a position hydride
ethers
or nitrogen.
interest
of similar
by the work of Cram [3j and Karabatsos
adJacent
also indicated
indicated
decomposition
of a series of compounds
The synthesis
1
can be explained
of the thermal
the preparation
from Z-bromopropiophenone
and the
agent was added to a flame dried flask under a
volume of anhydrous
3091
solvent was added to dissolve
the
3092
TABLE 1:
Reduction
of Z-Phenoxypropiophenones.
Aryloxy Substitution
Reducing Agenta (erythro:threo)
Z-methoxy 2,5-dimethoxy 2-hydroxy none 4-methoxy 3-methoxy 2-methyl 2-t-butyl a b
c reduciny
ayent.
of reduciny 1.25:1.
NaBHab
LiAIHnC
Zn(BH4)2C
89:ll 77~23 92:8 42:58 55:45 45:55 26~74
9ll:lO 92:8 92:8 72:28 77:23 70:30 46:54
>YY:l Y2:8 >YY:l >YY:l >Y9:1 91:Y 72~28
Isomer ratios were determined by yas chromatoyraphy and confirmed by integration (NMR) of the methyl absorbences. Reductions were performed in ethanol. Reductions were performed in ether.
Then the a-phenoxy
ketone was added via a syrinye
agent to ketone was l:l, except
to the flask.
for ketone -lc where the ratio was increased
The ratio of solvent to ketone was kept at 25mL to 1.0 mmole.
was stirred
at 23OC for 3 hours before a minimal
This mixture obtained
was extracted
in quantitative
with ether, dried,
yield
The molar
and exhibited
amount
of saturated
and stripped NMR, IR,
The reaction
NH4C1 solution
of solvent.
All alcohols
and MS data consistent
ratio
to
mixture was added. were
with the expected
products. The initial
reduction
atom at the ortho position control
of ketones -la-c with NaBH4 suyyested in the phenoxy
than had been previously
riny had a yreater
reported[1,2].
in Table 1 have been used in accordance
that the presence
influence
The isomer desiynations
with the results
of the previous
of 1-(4'-benzyloxyphenyl,3'-methoxy-)-2-(2"-methoxyphenoxy)-l-propanone ratio of Y:l was found for the reduction The five-membered adequately
describe
of an oxygen
on the stereochemical of erythro
and threo
work on the reduction [2], where an isomer
run with NaBH4 in ethanol.
riny rigid model 2,
similar
the course of the reduction
to tnat proposed
of the ketones L,
by Cram [3J, miyht
but for several
exceptions
3093
which
are apparent
both oxygen
in Table
methoxy
and hydroxy
substituted
1 indicate
substituted
rings which
modification
The erytho-selectivity
a non-hindering
approach
in a manner
[12] allows the propanone
direct
comparisons
of the results
ferent
solvents
consistent
since reductions
81:1Y(LiA1H4),
while g
The predominance attributed the t-butyl
obtained
were used due to synthetic of la,
cation chela-
groups.
Molecular
noted with & "locked"
However,
away from the
to a hindrance
The erythro-threo
lithium,
the trends
in THF gave erytro:threo
the
or zinc; i.e., hard-
We do caution
reductions
from the ratios
Apparently,
structure.
methyl to predominate.
necessity.
a con-
can be held in
attack to occur predominately
by NaBH4 and LiAlH4
preformed
involves
aryloxy-group
does not form as rigid a ring structure _3_as either
ness of the cation
rings which
suggest that some
to its alternative,
of -2b may be attributed
unity in -2d-f due to the lack of the bicyclic
sodium cation
substituted groups
or hydroxy
structure {the
which allows metal hydride
group, that is not chelated,
the
ortho-
(Za-c), non-ortho --
from NaBH4 probably
such as 4 is preferred
The lower erythro-selectivity
group.
0-methoxy
structure
Rather,
is necessary.
and A-methoxy
aryloxy,
With the presumed
ring.
position
ring 2
shown by -2a-c prepared
suggest that a bicyclic
selectivity
These distinct
-h).
with the
groups of compounds:
(2d-f), and ortho-alkyl --
(&and
chelate
in the carbonyl,
eight-membered
Id-f using NaBH4. --
show erythro
chelates
phenylpropanone
phenoxypropriophenones
rings which
selectivity
of Z-methoxy
This was not observed
that there are at least three
of the five membered
tion of the oxyyens
in the reduction
cation effectively
9:l was observed.
show no selectivity
show a threo or "reverse"
n-methyl
and ketone groups
of the non ortho-substituted
found in Table
voluted,
[6] has shown that the sodium
ratio of approximately
results
models
Glass
atoms of the alkoxy
and that an isomer reductions
1.
against
in Table 1 since difdo appear
of 73:27(NaBH4)
somewhat and
gave ratios of 50:50 for both reagents. of the threo-diastereomers
to steric hindrance
of the z-toluoxy
group is overwhelming
after NaBH4 reduction and -o-t-butyl-phenoxy
even when strong Zn++ chelation
of
a and,
groups.
$_
can be
The presence
of
can occur.
Acknowledgment This work was supported under Contract
DE-ACU6-76RLO
by the U.S. Department
of Energy,
Office
of Basic Energy Sciences,
1830.
References 1.
A.F.A.
2.
G. Brunow,
3.
U.J. Cram, And U.R. Wilson,
4.
G.J. Karabatsos,
Willis,
Cellulose
L. Koskinen,
Chem. Tech.,
and P. Urpilainen,
Acta Chem. Scand.,B,
J. Amer. Chem. Sot.,
J. Amer. Chem. Sot.,
5a. K. Koga and S.-I. Yamada, b. L.E. Overman
1976,x,345.
1967, e,
Chem. Pharm. Bull.,
and R.J. McCready,
Tetrahedron
1963,*,
1245.
1641. 1972,g,
Lett.,
526.
1982, 2355.
1981, 35,
53.
3094
c. C. Still and J.H. McDonald, d. T. Tokuyama,
K. Shimado,
6a. J.H. Stocker, U_, 3913. b. R.S. Glass,
Tetrahedron
Lett.,
and M. Uemura,
P. Sidisunthorn,
O.H. Ueardorff,
Tetrahedron
B.M. Benjamin,
and K. Henegar,
b. A. Amouroux,
Tetrahedron
and T. Oishi, Tetrahedron
B. Gerin,
and M. Chartrette,
8.
ti. Sollaedie,
C. Greek,
9.
T. Nakata and T Oishi, Tetrahedron
11.
G.E. Miksche,
Acta Chem. Stand.,
12.
R.G. Pearson,
J. Amer. Chem. Sot., 1963,g, USA
28
February
1981, 4723. Lett.,
Lett.,
1982, 4341. 1982, 5047.
1980, 1641.
1966, 1038.
1986)
1980, 4723.
Lett.,
and T. Matsumota,
M. Yanagiya,
in
K. Hasegawa,
Lett.,
J. Amer. Chem. SOC., 1960,
1983, 2653.
Tetrahedron
Lett.,
1980, 4723.
Lett.,
Tetrahedron
10.
(Received
F. Matsuda,
and G. Oemailly,
Lett.,
and C.S. Collins,
c. T. Nakata, T. Tanaka, and T. Oishi, Tetrahedron 7a. T. Nakata, T. Tanaka,
lY82, 2121.
3533.
Tetrahedron
Lett.,
1982, 4039.