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Selenium dioxide oxidation of vitamin D3 acetate to a dimer of 1-oxotransvitamin D3 acetate
883
SELENIUH
DIOXIDE OXIDATION
OF VITANIN
TO A DIMER OF I-OXOTRANSVITAMIN Glenn
F. Reynolds,
D3 ACETATE
D.3 ACETATE
Robert A. Reamer and Gary H. Rasmusson
Merck, Sharp and Dohme Research Laboratories Box 2000, Rahway, New Jersey 07065-0900 10-25-85 ABSTRACT 2-3-86)
Received (Revised
The treatment of vitamin D3 acetate with hydroperoxide leads to a mixture from which oxotransvitamin D3 acetate was isolated.
selenium dioxide and a Diels-Alder dimer
t-butyl of l-
INTRODUCTION The report
by Pelt on the selenium
a low yield of the I-hydroxy to attempt sumably
this oxidation milder
acetateAwas
reacted
hydroperoxide more
polar
primary
materials
component
uniformity
D3 acetatefvusing
described
by Umbreit
with selenium
and followed were among
by two high
until
dioxide
the
which shows a molecular
is clearly
a dimer
carbonyl
frequencies
Thin
liquid
vitamin
and Sharpless
layer This
(1) prompted
acetate
(1738
was consumed,
chromatography component
revealed was
saturated
(1712
a maximum
at 256nm with a shoulder
spectrum
indicate
November
1985
that
this material
(CDC13) shows two acetate
1.95 and 2.04 ppm and two pairs of doublets,
October,
to
(KBr) has cm”),
and
spectrum
has
at 300nm.
13C NMR spectra
The proton
purified
spectrum
(1670 and 1640 cm-‘) ketone groups, while the ultraviolet
type of dimer.
one
mass spectrum,
unsaturated
The 1H and
a series of
The non-crystalline
The infrared
cm”),
and pre-
of an excess of pbutyl
chromatographies.
D3 acetate.
us
(2). Thus, when the
ion at 880 in its field desorption
of an oxovitamin
D3 to give
the more selective
material
products.
pressure
of vitamin
in the presence
the starting
formed.
material,
for
oxidation
isomers of the & and m
on vitamin
conditions
dioxide
Steroids
split
11 and
is a Diels-Alder methyl
signals
IO Hz respectively,
Volume
46, Numbers
at at
4, 5
3.64, 4.59; 5.69 and 6.31 ppm.
The latter
pair can be assigned
C6 and C7 of one half of the dimer, while in the former shielded
and C6 has a deshielded The natural
saturated,
one
substituted
sp2
the
Cg carbons,
correspond
abundance
unsaturated carbons, the
aliphatic
carbonyl,
three mono protonated shifts
for
the
closely to those reported
protons of
pair the C7 vinyl proton is
proton.
13C spectrum ketone
to vinylic
carbons
for vitamin
(CDC13) shows the presence two
acetate
sp2 carbons, of
the
methyls,
fully
and, except for one of
C-D rings
D3 acetate
five
of one
and
side-chain
(3).
R= -$H
0
L
2 EXPERIHENTAL
The IR spectrum was obtained with a Perkin-Elmer ~421 spectrophotometer, 1 ‘H NMR spectra in CDCl with a Varian SC-300 spectrometer, 1% NMR spectra in UV spectrum in MeOH with a Perkin CDC13 with a Varian C E T-20 spectrometer, Elmer #202 visible/ultraviolet spectraphotometer and the mass spectrum on a Finnigan Mat #731 spectrometer using field desorption (F.D.). A suspension of selenium dioxide (130 mg) (1.18 mmole) in methylene chloride (2.0 ml) was treated with t-butyl hydroperoxide (0.51 ml) (4.70 mmole) and stirred under nitrogen atmosphere for one hour. The suspension was treated with a solution of vitamin D3 acetate (1.0 g) (2.35 mmole) in methylene chloride (4.0 ml); additional methylene chloride (2.0 ml) was used as a rinse. The suspension totally dissolved upon completion of the addition and the pale yellow color intensified as the reaction proceeded. Progress was followed by thin layer chromatography on silica gel eluting with ethyl acetate:toluene (5:95) and showed only a trace amount
of starting material after four hours. The reaction was diluted with benzene and evaporated to dryness. The resulting glass was dissolved in ether and washed successively with aqueous potassium hydroxide (lo%), saturated sodium chloride solution, then dried over magnesium sulfate and evaporated. The resulting glass was dissolved in a mixture of acetic acid:methyl sulfide (1:l) (4.0 ml) and allowed to stand overnight. The solution was neutralized with aqueous potassium carbonate (20%) and extracted with ether. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to a thick oil (1.03 g). The crude mixture was filtered through silica by eluting with ethyl acetate:methylene chloride (28) and evaporated to an orange foam (832 mg). The crude dimer was initially purified on a Waters Prep 500 liquid chromatograph, normal phase, eluting with ethyl acetate:methylene chloride (575) to give a strongly UV absorbing peak which yielded 175 mg of material containing two distinct acetates by NMR. The material was further purified by HPLC using a Waters M6000A pump and Waters 440 UV detector, eluting through a porsil column (4*x3/8”) at 2.0 ml/min with ethyl acetate:hexane (4:6). The major peak afforded the dimer 3 (73 mg); JR (KBr) (cm-l) 1738 (acetyl C-O), 1712 (saturated ketone C-O), 1670 and 1640 (unsaturated ketone C=O); UV: (MeOH) (nm) 256 and 300; MS: (F.D.) 880; proton NMR: (300 MHz,CDCI3 in ppm) 0.50(3H,s.C-18), 0.54(3H,s,C-18), 1.95(3H,s,acetate), 2.04(3H,s,acetate), 3.64(1H,d,JlOHz,6-CH), 4.59(1H,d,JlOHz,7-CH), 5.69(1H,d,Jl lHz,7’-CH), 6.31(lH,d,Jl lHz,6’-CH); carbon-13 NMR: (20 MHz,CDC13 in ppm).
207.93
c-1 ’
195.67
C-1
28.01
56.73 56.65 c-14,14:17,17’
C-25.25’
27.63 C-16.16’
56.39 56.08 1
27.48 l23.88
45.96
C-23.23’
c-13.13’ 45.41 1 43.89
C-6
142.94F
42.98
C-2.2’
22.82
132.75
40.38
C-12.12’
22.57
131.64
39.50
C-24.24 ’
22.23
C-II.1 1’
124.51 C-6’
36.12 C-20.20:22,22
21.11
cH3 of Acetates
116.64
29.18
145.07
-8,8’ C-26,26’27,27’ c-5,10
C-9,9 ’
18.85 C-21.21’
-7.7’
115.64lC
12.05 C-18.18’ 11.48 )_
70.66 -3,3 ’ 68.49 I-C 58.89
C-IO’
00.00
TMS
ss
886
TBROIDm
DISCUSSI0N These data are consistent acetate
which
methylene
spontaneously
with
carbons
is such that each
other
Irradiation
the
is ascribed
groups.
allowing
the respective
irradiation
This indicates
of each portion
AX patterns
seen
to the acetates,
can only be coupled
in the
NMR
5.17 ppm) reduces
methylene
that the oxidation
C2 p rotons
to couple
of another
an initially
pattern.
pairs adjacent
occurred only
spectrum.
This
to ketone
at C, of each portion,
with
each
other
under
the
conditions.
stable previtamin
case, the dimeric
(4) that
D skeleton
Since the corresponding
compound
for a Diels-Alder
D3 isomerizes
in the presence
be expected
spontaneously
of manganese
to behave
above must derive
similarly
instead,
from
to a
dioxide. in this 1-0x0-5,6-
It has been shown that cis-trans
isomerization
D3 occurs readily
of selenium
dioxide
is more sterically
exposed
in the presence
system of the I-oxotransvitamin
dimerization
shift found
would
described
D3 acetate& bond of vitamin
I-oxovitamin
when generated
f-acetate
(1). The 5,6,10(19)-diene
and is of the wrong
geometry
of the
for the facile
1,7-
with the I-oxovitamin.
The novel spirohydronaphthalenone Presented.
of the C,O-C,9
2.80 and 3.05 ppm to a simple four-peak
It has been shown
transvitamin
addition
D3
In this case the substitution
together.
to one proton each from two distinct
carbonyl
hydrogen
simple
at C3 (a
between
of a I-oxovitamin
across the diene system C,9-C,O-C5-C6
the C6 and C7 protons
to give
formation
by Diels-Alder
are attached
of the protons
complex multiplet
5,6-double
dimerizes
group of one molecule
such that the Cl9 pattern
with the initial
Because of the flexibility
Spiro moiety at Clot and the adjacent ring cannot be determined.
structure&is
in accord
of the system the exact substituent
with the data
orientation
of the
at C6 on the hydronaphthalenone
S
TEII&OTDI
887
ACKNOWLEDGMENTS
spectra, infrared
We are indebted to Herman Flynn for obtaining the 300 MHz 1H NMR to Jack L. Smith for the mass spectra and to Robert Walker for the spectra. REFERENCES
1. 2. 3. 4.
Pelt, B., STEROIDS 29, 193 (1977). Umbreit, M. A. and Sharpless, K. B., J. AM. CHEM. SOC. s, 5526 (1977). Tsukida, K., Akutsu, K. and Saiki, K., J. NUTR. SCI. VITAMINOL. & 411 (1975). Sheves, M., Friedman, N. and Mazur, Y., J. ORG. CHEM. Q, 3597 (1977).
SELENIUH
DIOXIDE OXIDATION
OF VITANIN
TO A DIMER OF I-OXOTRANSVITAMIN Glenn
F. Reynolds,
D3 ACETATE
D.3 ACETATE
Robert A. Reamer and Gary H. Rasmusson
Merck, Sharp and Dohme Research Laboratories Box 2000, Rahway, New Jersey 07065-0900 10-25-85 ABSTRACT 2-3-86)
Received (Revised
The treatment of vitamin D3 acetate with hydroperoxide leads to a mixture from which oxotransvitamin D3 acetate was isolated.
selenium dioxide and a Diels-Alder dimer
t-butyl of l-
INTRODUCTION The report
by Pelt on the selenium
a low yield of the I-hydroxy to attempt sumably
this oxidation milder
acetateAwas
reacted
hydroperoxide more
polar
primary
materials
component
uniformity
D3 acetatefvusing
described
by Umbreit
with selenium
and followed were among
by two high
until
dioxide
the
which shows a molecular
is clearly
a dimer
carbonyl
frequencies
Thin
liquid
vitamin
and Sharpless
layer This
(1) prompted
acetate
(1738
was consumed,
chromatography component
revealed was
saturated
(1712
a maximum
at 256nm with a shoulder
spectrum
indicate
November
1985
that
this material
(CDC13) shows two acetate
1.95 and 2.04 ppm and two pairs of doublets,
October,
to
(KBr) has cm”),
and
spectrum
has
at 300nm.
13C NMR spectra
The proton
purified
spectrum
(1670 and 1640 cm-‘) ketone groups, while the ultraviolet
type of dimer.
one
mass spectrum,
unsaturated
The 1H and
a series of
The non-crystalline
The infrared
cm”),
and pre-
of an excess of pbutyl
chromatographies.
D3 acetate.
us
(2). Thus, when the
ion at 880 in its field desorption
of an oxovitamin
D3 to give
the more selective
material
products.
pressure
of vitamin
in the presence
the starting
formed.
material,
for
oxidation
isomers of the & and m
on vitamin
conditions
dioxide
Steroids
split
11 and
is a Diels-Alder methyl
signals
IO Hz respectively,
Volume
46, Numbers
at at
4, 5
3.64, 4.59; 5.69 and 6.31 ppm.
The latter
pair can be assigned
C6 and C7 of one half of the dimer, while in the former shielded
and C6 has a deshielded The natural
saturated,
one
substituted
sp2
the
Cg carbons,
correspond
abundance
unsaturated carbons, the
aliphatic
carbonyl,
three mono protonated shifts
for
the
closely to those reported
protons of
pair the C7 vinyl proton is
proton.
13C spectrum ketone
to vinylic
carbons
for vitamin
(CDC13) shows the presence two
acetate
sp2 carbons, of
the
methyls,
fully
and, except for one of
C-D rings
D3 acetate
five
of one
and
side-chain
(3).
R= -$H
0
L
2 EXPERIHENTAL
The IR spectrum was obtained with a Perkin-Elmer ~421 spectrophotometer, 1 ‘H NMR spectra in CDCl with a Varian SC-300 spectrometer, 1% NMR spectra in UV spectrum in MeOH with a Perkin CDC13 with a Varian C E T-20 spectrometer, Elmer #202 visible/ultraviolet spectraphotometer and the mass spectrum on a Finnigan Mat #731 spectrometer using field desorption (F.D.). A suspension of selenium dioxide (130 mg) (1.18 mmole) in methylene chloride (2.0 ml) was treated with t-butyl hydroperoxide (0.51 ml) (4.70 mmole) and stirred under nitrogen atmosphere for one hour. The suspension was treated with a solution of vitamin D3 acetate (1.0 g) (2.35 mmole) in methylene chloride (4.0 ml); additional methylene chloride (2.0 ml) was used as a rinse. The suspension totally dissolved upon completion of the addition and the pale yellow color intensified as the reaction proceeded. Progress was followed by thin layer chromatography on silica gel eluting with ethyl acetate:toluene (5:95) and showed only a trace amount
of starting material after four hours. The reaction was diluted with benzene and evaporated to dryness. The resulting glass was dissolved in ether and washed successively with aqueous potassium hydroxide (lo%), saturated sodium chloride solution, then dried over magnesium sulfate and evaporated. The resulting glass was dissolved in a mixture of acetic acid:methyl sulfide (1:l) (4.0 ml) and allowed to stand overnight. The solution was neutralized with aqueous potassium carbonate (20%) and extracted with ether. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to a thick oil (1.03 g). The crude mixture was filtered through silica by eluting with ethyl acetate:methylene chloride (28) and evaporated to an orange foam (832 mg). The crude dimer was initially purified on a Waters Prep 500 liquid chromatograph, normal phase, eluting with ethyl acetate:methylene chloride (575) to give a strongly UV absorbing peak which yielded 175 mg of material containing two distinct acetates by NMR. The material was further purified by HPLC using a Waters M6000A pump and Waters 440 UV detector, eluting through a porsil column (4*x3/8”) at 2.0 ml/min with ethyl acetate:hexane (4:6). The major peak afforded the dimer 3 (73 mg); JR (KBr) (cm-l) 1738 (acetyl C-O), 1712 (saturated ketone C-O), 1670 and 1640 (unsaturated ketone C=O); UV: (MeOH) (nm) 256 and 300; MS: (F.D.) 880; proton NMR: (300 MHz,CDCI3 in ppm) 0.50(3H,s.C-18), 0.54(3H,s,C-18), 1.95(3H,s,acetate), 2.04(3H,s,acetate), 3.64(1H,d,JlOHz,6-CH), 4.59(1H,d,JlOHz,7-CH), 5.69(1H,d,Jl lHz,7’-CH), 6.31(lH,d,Jl lHz,6’-CH); carbon-13 NMR: (20 MHz,CDC13 in ppm).
207.93
c-1 ’
195.67
C-1
28.01
56.73 56.65 c-14,14:17,17’
C-25.25’
27.63 C-16.16’
56.39 56.08 1
27.48 l23.88
45.96
C-23.23’
c-13.13’ 45.41 1 43.89
C-6
142.94F
42.98
C-2.2’
22.82
132.75
40.38
C-12.12’
22.57
131.64
39.50
C-24.24 ’
22.23
C-II.1 1’
124.51 C-6’
36.12 C-20.20:22,22
21.11
cH3 of Acetates
116.64
29.18
145.07
-8,8’ C-26,26’27,27’ c-5,10
C-9,9 ’
18.85 C-21.21’
-7.7’
115.64lC
12.05 C-18.18’ 11.48 )_
70.66 -3,3 ’ 68.49 I-C 58.89
C-IO’
00.00
TMS
ss
886
TBROIDm
DISCUSSI0N These data are consistent acetate
which
methylene
spontaneously
with
carbons
is such that each
other
Irradiation
the
is ascribed
groups.
allowing
the respective
irradiation
This indicates
of each portion
AX patterns
seen
to the acetates,
can only be coupled
in the
NMR
5.17 ppm) reduces
methylene
that the oxidation
C2 p rotons
to couple
of another
an initially
pattern.
pairs adjacent
occurred only
spectrum.
This
to ketone
at C, of each portion,
with
each
other
under
the
conditions.
stable previtamin
case, the dimeric
(4) that
D skeleton
Since the corresponding
compound
for a Diels-Alder
D3 isomerizes
in the presence
be expected
spontaneously
of manganese
to behave
above must derive
similarly
instead,
from
to a
dioxide. in this 1-0x0-5,6-
It has been shown that cis-trans
isomerization
D3 occurs readily
of selenium
dioxide
is more sterically
exposed
in the presence
system of the I-oxotransvitamin
dimerization
shift found
would
described
D3 acetate& bond of vitamin
I-oxovitamin
when generated
f-acetate
(1). The 5,6,10(19)-diene
and is of the wrong
geometry
of the
for the facile
1,7-
with the I-oxovitamin.
The novel spirohydronaphthalenone Presented.
of the C,O-C,9
2.80 and 3.05 ppm to a simple four-peak
It has been shown
transvitamin
addition
D3
In this case the substitution
together.
to one proton each from two distinct
carbonyl
hydrogen
simple
at C3 (a
between
of a I-oxovitamin
across the diene system C,9-C,O-C5-C6
the C6 and C7 protons
to give
formation
by Diels-Alder
are attached
of the protons
complex multiplet
5,6-double
dimerizes
group of one molecule
such that the Cl9 pattern
with the initial
Because of the flexibility
Spiro moiety at Clot and the adjacent ring cannot be determined.
structure&is
in accord
of the system the exact substituent
with the data
orientation
of the
at C6 on the hydronaphthalenone
S
TEII&OTDI
887
ACKNOWLEDGMENTS
spectra, infrared
We are indebted to Herman Flynn for obtaining the 300 MHz 1H NMR to Jack L. Smith for the mass spectra and to Robert Walker for the spectra. REFERENCES
1. 2. 3. 4.
Pelt, B., STEROIDS 29, 193 (1977). Umbreit, M. A. and Sharpless, K. B., J. AM. CHEM. SOC. s, 5526 (1977). Tsukida, K., Akutsu, K. and Saiki, K., J. NUTR. SCI. VITAMINOL. & 411 (1975). Sheves, M., Friedman, N. and Mazur, Y., J. ORG. CHEM. Q, 3597 (1977).