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Epimerisation of vitamin D3. The cholecalciferyl ion
Tetrahedron
Letters
No. 22, pp 1913 - 1916, 1976.
EPIMERISATION
OF VITAMIN
Mordechai Department
(Received
necessitated
the preparation
been previously our objective
described
Chemistry,
of Science,
equilibria
of vitamin
for
of their C3-epimers. I"
D3 tosylate4
(a)
(15%), for-mate (12%) and vitamin
superimposable
with
was a distortion
that this material europium signals
induced
shifted
'H-nmr
for each epimer.
and the others were
C3-epivitamin
assigned
03 derivatives
D3 (3%) fractions.
the C 18-methyl
in which
less shifted
to its C3-epimer
Ja_ and swas
signals
R*
b
R = CH3aS0,
C
R - HCO
1913
The fact
indicated
identified
a.
e
was almost
in this spectrum
D3 (&).l"
by the
and H at C7 showed were
(70%),
spectrum
H
a
of sodium
hydrocarbon
RO
RO’*
had D3,3
The 3,5-dinitrobenzoate
to H at C3 in vitamin
spectrum,
The paramagentically
of vitamin
in the presence
alcohols
systems
alcohol.
into an unsaturated
of the C3-epimeric
thus assigned
and related
hydrolysis gave material whose IH-nmr 03 (la). 192 The only observable difference
line pattern
is a mixture
1976)
and total synthesis
on basic
that of vitamin
of the seven
was separated
23 April
D3 (cholecalciferol)
in dimethylformamide
3,5-dinitrobenzoate
([aID + 29' in CHC13),
publication
of the parent
gave a mixture
fraction
which
Israel
Although
3,5_dinitrobenzoate
ION
The Weirmann
in the partial
by epimerization
in Great Britain.
Mazur
Rehovot,
in vitamin
as intermediates
was their preparation
Solvolysis
and Yehuda
in UK 4 March 19761 accepted
The study of conformational
Printed
03. THE CHOLECALCIFERYL
Sheves
of Organic
Institute
Pergamon Press.
R = NQjjCO
separate
as those of -la
NO. 22
1914
Hydrolysis -Za
(PI,
+
of the formate
40' in C6H6).
of C3-epimeric was performed benzoate
formates
to its
addition
to these,
vitamin
respective
esters
yield
with
triphenylphosphine
esters
The p-nitrobenzoate
ester obtained
which was established &
D3. The IH-nmr
spectrum
esters
formed
considering
ring A chair
observed
in the solvolysis
two indeoendent
having
different
reactions
in the
also in a mixture
of the
([a], - 29', CHC13),
proportion
reaction
spectrum
of the C3-inverted
was recrystallized -lo, benzene)
from methanol
the purity
of the hydrolysis
product,
the H at C3 appeared (J=8.2 Hz instead &
OH - in either
population.
of the shift
of the
and a
also as a
of J=7.6
Hz).lS2
exist as a
axial or equatorial
pathways
for the formation
leading
mainly
to a complete
retention
involves
a homoallylic
cation,
unsymmetrically
of -3A and 35. The intermediacy
The larger
reagent
conformer.
shifts
of C18-methyl
are consistent Using
the relative
the
ratios
with
[alo values
their for the
of the C3-epimeric
(Table).
of configurational
leading
the formation
of
-lb solvolysis.
constant
ion in the OH-axial
high proportion
of a SN2 character
charge
and 2
that the C3-epimers
conformers
on addition
to the europium
reaction
positive
Treatment
that the OH-axial and OH-equatorial conformers of -la 1 H nmr spectra and the minor differences in the coupling have identical
suggests
route
isolated.
in tetrahydrofuran5
acid resulted
to that of &,
coupling
_2a and its esters we have calculated
03
The relative
route,
was very similar
of H at C3 are due to their
proximity
epivitamin
'H-nmr
In
hydrocarbon
We stipulate'
and of H- at C7 in 2, closer
an unsaturated
before were
([a], - 44', CHC13,
shifted
with a larger
may be explained,
and -2a respectively constants
of 3
however
equilibrating
3
- 45', CHC13) lacking the signals of Cl8 -methyl and H at C7 of vitamin
([a],
conformation.ly2
(15%) which
a higher
in the latter
117-118'
by the europium
C3-epivitamin,
iine pattern,
&mp
p-nitro-
+ lo; CHCl3) or k
from tosylate
mixture &
of sodium
and diethylazocarboxylate
products
of the tosylate
&and
&Z and &and
indicated
and
of the p-nitroesters
to that obtained
values
k
A similar
nmr spectrum.
the solvolysis
) contained more of the inverted ester -* 2e
3
formates
([a],
rotational
alcohols
hand in the presence
or p-nitrobenzoic
(ca 25%) -Id and 2d
than in the respective
rapidly
in CHCI
mixture
of the C3-epimeric
shifted
when
On the other
of C3-epimeric
3,5-dinitrobenzoic
the more negative
This similarity
alone.
and composition
to give the pure C3-epiester
seven
from their europium
(20%) was obtained
(-2.5',
a mixture
of either
gave also a mixture
led to the C3-epimeric
[cx],value
in similar
03 (a)
However
and &
in dimethylformamlde
according
presence
as evidenced &
the solvolysis
fraction,
fraction
retention
of these esters.
to inversion
of configuration
the cholecalciferyl
distributed
mainly
of this cation
of both C3- and C6-methylethers
in the solvolys~s
(k5-type)
One - a displacement
and the other,
(kD-type).6
reactions
We assume
ion 3. We describe
an assisted
that the latter
it as having
at C3 and C6 being
has recently
the
thus a resonance hybride 437 to explain been postulated by us
on the solvolysis
of -lb in methanol.
No. 22
1915
Table.
Comparison
of percentage
Na-3,5dinitrobenroate + dimethylformamide
ld+Zd -lc+Zc --
+29'(CHC13) +43°(C6H6)
Na-p-nitrobenzoate + dimethylformamide
le+2e -lc+2c --
-2.8°(cHc13)
68
+43
(C6H61
33e
-lb
dimethylformamide
lc+2c --
+45'
(C6H6)
33e
lab
3,5-dinitrobenzoic
ld+2d --
+l"
(CHC13)
64'
lab -
p-nitrobenzoic
le+2e --
-29' (CHC13)
8gd
-lb
-lb
%he
error
in these
in tetrahydrofuran. Calculated
using
Since CC13CH20H
the protic - a protic
3,Minitrobenzoic The Purity
estimations
ca. t88.
'Calculated
using
product
solvents
favour
or p-nitrobenzoic
those of the corresponding a-electrons
inaccessibility
the formation
products
derivative
of the C6-position
(C6H6) for &
and g
sodium
shifted
03 triphenylphosphonium reveals
a weaker
proportion
to the comparatively
at c3.
mp 124-125' of their hydrolysis
D3 were
absent.
p-nitrobenzoate8
participation
of the C3 inverted
of vitamin
of la in -
salt of
of configuration
spectra
with
of the products.
D3 may be explained
large aryloxy
from
respectively,
ion, the solvolysis
of either
retention
induced
products
eCalculated
t 80°, CHC13) and &,
([a],
thus to a larger
and triphenylphosphine
respectively.
and H at C7 of the epivitamin
of vitamin
among the solvolysis
41C 33e
(CHC13) for Id and 2d respectively
of a carbonium
in the presence
by the europium
of C18 -methyl
leading
and &
acids gave a complete
cholesteryl
in the former,
of the C6-esters
&
[a], t 60° and 0"
esters I.&, mp 130-131'
the signals
of the solvolysis
(CHC13)for
solvent,
% Inversiona
b. With diethylazocarboxylate
[a], t 80° and -44O
(+40°) using
non-nucleophilic
Of the resulting
in which
Comparison
steric
acid
+ 85', CHC13), was established
products
acid
[a], + 85O and -44O
[a],, of hydrolyzed
absence
03.
["ID
Nucleophile
(id,
at C3 in vitamin
Product
Substance
d
of inversion
by the
substituents.
The
1916
No. 22
Using
triphenylphosphine,
we have also epimerized (mp 104-105°
diethylazocarboxylate
transvitamin CHC13)
[a], - 95',
D3 (G)
and 2
b
and p-nitrobenzoic
and dihydrotachysterol
(mp 100-lOlo,
(3)
to the esters J&
[a], - 141°, CHC13).
R =ac-N02&C0,
We are indebted to Dr. A. Furst and Hoffman-La Dr. M.P. Rappoldt
acid in tetrahydrofuran
and Philips-Duphar
Roche
for the gift of vitamin
for the sample of dihydrotachysterol
D3 and to
.
References 1.
G.N.
Mar,
La
M.R. Pirio,
and D.L. Budd,
Chem.
S.M. Sine and A.W. Norman,
A. Rego, M.R. Pirio 2.
E. Berman,
3.
I.T. Harrison, H.H.
J. Amer.
and A.W. Norman,
Science,
J. Amer.
Z. Luz, Y. ~azur and M. Sheves, R.A.A.
Inhoffen,
Hurst,
B. Lythqoe
7314
186,
939
(1974); R.N. Wing, (1974); R.M. Winq,
Chom. Sot., 97, 4980
W.H. Okamuta, W.H. Okamura,
(1975).
to be published.
and D.H. Williams,
H. Hirschfeld,
K. Irmscher,
Sot., z,
J. them.
Sot.,
and A. Kreutzer,
U. Stache
5176
Chem.
(1960);
Ber., 91, 2309
(1958) * 4. 5.
M. Sheves
and Y. Mazur,
a. o. Mitsunobu M. Eguchi,
7.
Letters,
C.J. Lancelot, P.v.R.
M.
Yamada,
1619
8.
p-nitrobenzoic previously
(1975). 40, 2380
acid results
with
A.P. Davies
(1967); 0. Mitsunobu
in "Carbonium
with C5-Cl0
ibid.,
lo33
III, G-A. Olah and
erronously
in a mixture acid
triphenyl
of p-nitrobenzoates, (Ref. SC).
in Ref. 4. The C6-H bond
and not with C3-C5 bond.
diethylazocarboxylate,
with benzoic
and J.A. KnaqgS, Ions" Vol.
and
and M.S. Manhas,
N.Y. 1972, pp. 1347-1483.
cation was drawn
relationship
of cholesterol
in reaction
Schleyer
New York,
of cyclopropylcarbinyl
The reaction
Sot. Japan,
(1973); c. R. Aneja,
Ed., Wiley,
should be in antiparallel
Sot., 97, 6249
Bull. Chem.
D.J. Cram and P.v.R.
Schleyer
The formula
Chem.
(1971); b. A.K. Bose, B. Lal, W.A. Hoffman
ibid., 44, 3427
Tetrahedron 6.
and
J. Amer.
phosphine
analogous
and
to that
reported
(1975)
Letters
No. 22, pp 1913 - 1916, 1976.
EPIMERISATION
OF VITAMIN
Mordechai Department
(Received
necessitated
the preparation
been previously our objective
described
Chemistry,
of Science,
equilibria
of vitamin
for
of their C3-epimers. I"
D3 tosylate4
(a)
(15%), for-mate (12%) and vitamin
superimposable
with
was a distortion
that this material europium signals
induced
shifted
'H-nmr
for each epimer.
and the others were
C3-epivitamin
assigned
03 derivatives
D3 (3%) fractions.
the C 18-methyl
in which
less shifted
to its C3-epimer
Ja_ and swas
signals
R*
b
R = CH3aS0,
C
R - HCO
1913
The fact
indicated
identified
a.
e
was almost
in this spectrum
D3 (&).l"
by the
and H at C7 showed were
(70%),
spectrum
H
a
of sodium
hydrocarbon
RO
RO’*
had D3,3
The 3,5-dinitrobenzoate
to H at C3 in vitamin
spectrum,
The paramagentically
of vitamin
in the presence
alcohols
systems
alcohol.
into an unsaturated
of the C3-epimeric
thus assigned
and related
hydrolysis gave material whose IH-nmr 03 (la). 192 The only observable difference
line pattern
is a mixture
1976)
and total synthesis
on basic
that of vitamin
of the seven
was separated
23 April
D3 (cholecalciferol)
in dimethylformamide
3,5-dinitrobenzoate
([aID + 29' in CHC13),
publication
of the parent
gave a mixture
fraction
which
Israel
Although
3,5_dinitrobenzoate
ION
The Weirmann
in the partial
by epimerization
in Great Britain.
Mazur
Rehovot,
in vitamin
as intermediates
was their preparation
Solvolysis
and Yehuda
in UK 4 March 19761 accepted
The study of conformational
Printed
03. THE CHOLECALCIFERYL
Sheves
of Organic
Institute
Pergamon Press.
R = NQjjCO
separate
as those of -la
NO. 22
1914
Hydrolysis -Za
(PI,
+
of the formate
40' in C6H6).
of C3-epimeric was performed benzoate
formates
to its
addition
to these,
vitamin
respective
esters
yield
with
triphenylphosphine
esters
The p-nitrobenzoate
ester obtained
which was established &
D3. The IH-nmr
spectrum
esters
formed
considering
ring A chair
observed
in the solvolysis
two indeoendent
having
different
reactions
in the
also in a mixture
of the
([a], - 29', CHC13),
proportion
reaction
spectrum
of the C3-inverted
was recrystallized -lo, benzene)
from methanol
the purity
of the hydrolysis
product,
the H at C3 appeared (J=8.2 Hz instead &
OH - in either
population.
of the shift
of the
and a
also as a
of J=7.6
Hz).lS2
exist as a
axial or equatorial
pathways
for the formation
leading
mainly
to a complete
retention
involves
a homoallylic
cation,
unsymmetrically
of -3A and 35. The intermediacy
The larger
reagent
conformer.
shifts
of C18-methyl
are consistent Using
the relative
the
ratios
with
[alo values
their for the
of the C3-epimeric
(Table).
of configurational
leading
the formation
of
-lb solvolysis.
constant
ion in the OH-axial
high proportion
of a SN2 character
charge
and 2
that the C3-epimers
conformers
on addition
to the europium
reaction
positive
Treatment
that the OH-axial and OH-equatorial conformers of -la 1 H nmr spectra and the minor differences in the coupling have identical
suggests
route
isolated.
in tetrahydrofuran5
acid resulted
to that of &,
coupling
_2a and its esters we have calculated
03
The relative
route,
was very similar
of H at C3 are due to their
proximity
epivitamin
'H-nmr
In
hydrocarbon
We stipulate'
and of H- at C7 in 2, closer
an unsaturated
before were
([a], - 44', CHC13,
shifted
with a larger
may be explained,
and -2a respectively constants
of 3
however
equilibrating
3
- 45', CHC13) lacking the signals of Cl8 -methyl and H at C7 of vitamin
([a],
conformation.ly2
(15%) which
a higher
in the latter
117-118'
by the europium
C3-epivitamin,
iine pattern,
&mp
p-nitro-
+ lo; CHCl3) or k
from tosylate
mixture &
of sodium
and diethylazocarboxylate
products
of the tosylate
&and
&Z and &and
indicated
and
of the p-nitroesters
to that obtained
values
k
A similar
nmr spectrum.
the solvolysis
) contained more of the inverted ester -* 2e
3
formates
([a],
rotational
alcohols
hand in the presence
or p-nitrobenzoic
(ca 25%) -Id and 2d
than in the respective
rapidly
in CHCI
mixture
of the C3-epimeric
shifted
when
On the other
of C3-epimeric
3,5-dinitrobenzoic
the more negative
This similarity
alone.
and composition
to give the pure C3-epiester
seven
from their europium
(20%) was obtained
(-2.5',
a mixture
of either
gave also a mixture
led to the C3-epimeric
[cx],value
in similar
03 (a)
However
and &
in dimethylformamlde
according
presence
as evidenced &
the solvolysis
fraction,
fraction
retention
of these esters.
to inversion
of configuration
the cholecalciferyl
distributed
mainly
of this cation
of both C3- and C6-methylethers
in the solvolys~s
(k5-type)
One - a displacement
and the other,
(kD-type).6
reactions
We assume
ion 3. We describe
an assisted
that the latter
it as having
at C3 and C6 being
has recently
the
thus a resonance hybride 437 to explain been postulated by us
on the solvolysis
of -lb in methanol.
No. 22
1915
Table.
Comparison
of percentage
Na-3,5dinitrobenroate + dimethylformamide
ld+Zd -lc+Zc --
+29'(CHC13) +43°(C6H6)
Na-p-nitrobenzoate + dimethylformamide
le+2e -lc+2c --
-2.8°(cHc13)
68
+43
(C6H61
33e
-lb
dimethylformamide
lc+2c --
+45'
(C6H6)
33e
lab
3,5-dinitrobenzoic
ld+2d --
+l"
(CHC13)
64'
lab -
p-nitrobenzoic
le+2e --
-29' (CHC13)
8gd
-lb
-lb
%he
error
in these
in tetrahydrofuran. Calculated
using
Since CC13CH20H
the protic - a protic
3,Minitrobenzoic The Purity
estimations
ca. t88.
'Calculated
using
product
solvents
favour
or p-nitrobenzoic
those of the corresponding a-electrons
inaccessibility
the formation
products
derivative
of the C6-position
(C6H6) for &
and g
sodium
shifted
03 triphenylphosphonium reveals
a weaker
proportion
to the comparatively
at c3.
mp 124-125' of their hydrolysis
D3 were
absent.
p-nitrobenzoate8
participation
of the C3 inverted
of vitamin
of la in -
salt of
of configuration
spectra
with
of the products.
D3 may be explained
large aryloxy
from
respectively,
ion, the solvolysis
of either
retention
induced
products
eCalculated
t 80°, CHC13) and &,
([a],
thus to a larger
and triphenylphosphine
respectively.
and H at C7 of the epivitamin
of vitamin
among the solvolysis
41C 33e
(CHC13) for Id and 2d respectively
of a carbonium
in the presence
by the europium
of C18 -methyl
leading
and &
acids gave a complete
cholesteryl
in the former,
of the C6-esters
&
[a], t 60° and 0"
esters I.&, mp 130-131'
the signals
of the solvolysis
(CHC13)for
solvent,
% Inversiona
b. With diethylazocarboxylate
[a], t 80° and -44O
(+40°) using
non-nucleophilic
Of the resulting
in which
Comparison
steric
acid
+ 85', CHC13), was established
products
acid
[a], + 85O and -44O
[a],, of hydrolyzed
absence
03.
["ID
Nucleophile
(id,
at C3 in vitamin
Product
Substance
d
of inversion
by the
substituents.
The
1916
No. 22
Using
triphenylphosphine,
we have also epimerized (mp 104-105°
diethylazocarboxylate
transvitamin CHC13)
[a], - 95',
D3 (G)
and 2
b
and p-nitrobenzoic
and dihydrotachysterol
(mp 100-lOlo,
(3)
to the esters J&
[a], - 141°, CHC13).
R =ac-N02&C0,
We are indebted to Dr. A. Furst and Hoffman-La Dr. M.P. Rappoldt
acid in tetrahydrofuran
and Philips-Duphar
Roche
for the gift of vitamin
for the sample of dihydrotachysterol
D3 and to
.
References 1.
G.N.
Mar,
La
M.R. Pirio,
and D.L. Budd,
Chem.
S.M. Sine and A.W. Norman,
A. Rego, M.R. Pirio 2.
E. Berman,
3.
I.T. Harrison, H.H.
J. Amer.
and A.W. Norman,
Science,
J. Amer.
Z. Luz, Y. ~azur and M. Sheves, R.A.A.
Inhoffen,
Hurst,
B. Lythqoe
7314
186,
939
(1974); R.N. Wing, (1974); R.M. Winq,
Chom. Sot., 97, 4980
W.H. Okamuta, W.H. Okamura,
(1975).
to be published.
and D.H. Williams,
H. Hirschfeld,
K. Irmscher,
Sot., z,
J. them.
Sot.,
and A. Kreutzer,
U. Stache
5176
Chem.
(1960);
Ber., 91, 2309
(1958) * 4. 5.
M. Sheves
and Y. Mazur,
a. o. Mitsunobu M. Eguchi,
7.
Letters,
C.J. Lancelot, P.v.R.
M.
Yamada,
1619
8.
p-nitrobenzoic previously
(1975). 40, 2380
acid results
with
A.P. Davies
(1967); 0. Mitsunobu
in "Carbonium
with C5-Cl0
ibid.,
lo33
III, G-A. Olah and
erronously
in a mixture acid
triphenyl
of p-nitrobenzoates, (Ref. SC).
in Ref. 4. The C6-H bond
and not with C3-C5 bond.
diethylazocarboxylate,
with benzoic
and J.A. KnaqgS, Ions" Vol.
and
and M.S. Manhas,
N.Y. 1972, pp. 1347-1483.
cation was drawn
relationship
of cholesterol
in reaction
Schleyer
New York,
of cyclopropylcarbinyl
The reaction
Sot. Japan,
(1973); c. R. Aneja,
Ed., Wiley,
should be in antiparallel
Sot., 97, 6249
Bull. Chem.
D.J. Cram and P.v.R.
Schleyer
The formula
Chem.
(1971); b. A.K. Bose, B. Lal, W.A. Hoffman
ibid., 44, 3427
Tetrahedron 6.
and
J. Amer.
phosphine
analogous
and
to that
reported
(1975)