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The selective in vitro oxidation of the terminal double bonds in squalene
Tetrahedron Letters in Great Britain.
No.
3,
pp.
121-124,
1962.
Pergamon
Press
Ltd.
Printed
THE SELECTIVE IN VITRO OXIDATION OF TEE TERMINAL DOUBLE BONDS IN SQUALENE E.E.
van
Department
Tamelen
of Chemistry,
as
a precursor
steroids of
and
the
this
not
availability
of
such
carbon
1
For
experiments
have
demonstrated
that
lanosterol
and
as
the
of
cholesterol
the
the
terminus,
a recent
review,
shown
(I
laboratory
(and
Not is
the
II).l
has
the
least
selective
of
L. Ruzicka,
Proc. 121
acts
doubtless
but
also
the
problems
in
of
other
duplicating
in
certain
because
Sot.
of
which
the
that
Chem,
vivo
oxidation-cyclization
interest
of
in
many
The prospect
oxidation challenge
squalene
involves
occasioned
aspects
an uncommon
see
which
+
theoretical
squalene.
an undertaking at
Wisconsin 1962)
in
because
of Wisconsin
30 January
system,
only
in
6,
triterpenoids), in a process
phenomenon
Curphey
(Received
of
polyene
T.J.
University
Madison
EXTENSIVE tracer
and
all
the must
starting of
341
circles,
the
(1959).
abundant be faced
hydrodouble
,122
In vitro
bonds
oxidation
in the s.ystem are
of
the terminal
trisubstituted
double
bonds
and more or less
encumbered.
Wdreport
herein
selectivity,
utilizing
means which we believe
a solution
to this
No.3
equally
problem
sterically
in chemical
to be novel
and also
of wider
applicability. In studying gated:
the nature
The results
of
successful carried
ether
concentration
gel. For
epoxide, perchloric
oxidations,
oxidizing
experiments
conversion
that
bromohydrin
of
with
fractions
(along
agent are
be separated with
of
start
of into
unreacted
of
in Table
to a mixture
such conditions at the
variables
and the nature
summarized
squalene
the solution could
two major
N-bromosuccinimide
under
Product
were investithe solvent.2
1.
In the most
of halohydrins
was
in aqueous
ethylene
temperature
(23’)
the reaction mono-,
squalene)
glycol and
was saturated
di-
and higher
by chromatography
over
3
further
chemical
work,
halohydrin
which was then converted aci.d in glyme.
and measurement strated
the
(glyme),
squalene.
silica
of
these
case,
in vitro
out by oxidation
dimethyl
with
such
that
of
acetone
the periodate
to
Combination
material
1,2-glycol of
was ring
by treatment
quantitative
closed with
periodate
to aqueous
oxidation
formation
on lead
tetraacetate
oxidation,
cleavable
material
consisted
predominantly
demonof
In regard to the latter factor, it seemed to us that the very feature which was responsible for this problem of selectivity, viz. the elongated, in partially olefinic hydrocarbon system, could be turned toadvantage, that the conformation of this large hydrocarbon might be sufficiently More precisesolvent-dependent to affect markedly its chemical behavior. ly, in a solvent of low polarity there is no reason to suppose that squalene would not exist for the most part in an uncoiled, fully extended state, with all of the double bonds equally vulnerable to attack by an oxidizing agent. On the other hand, in a more polar medium (such as that offered by a hydroxylic solvent) it appears possible that squalene would assume a more highly coiled, compact conformation, such that the tritersolvated”, and the system of hydrogen bonds penoid would be “internally Should this be in the medium would be disrupted as little as possible. the case, the internal double bonds in this coiled conformation might be sterically shielded and thus chemically less reactive, whereas the terminal olefinis links would remain exposed. Unpublished
results
secured
by Dr. A. Storni
in this
Laboratory.
In vitro
No.3
terminal
1,2-glycol
glycol)
amount
3,2-glycol
- as high
of
(DNP) from simple
of
acetone
material,
objective,
oxidation
under models
a completely
squalene,
(as
seemingly
of
the
terminal
as 81% of
the
double
theoretical
(e.g.,
was
where the actual
oxidation
all
terminal from
produced
yield
C6H5CHOHCOH(CH3)2)was 81%.
selective
123
(i.e.,
dinitrophenylhydrazone)
conditions
bonds
at the terminal
of
acetone
Thus,
the
double
bonds
had been achieved.
H
cl9 ‘x” \
I-
Br
33
I
/A#\
I
\ \0
HO
(\
Br
CH:
CHO
I
Iv
III
In order degradation of
its
to confirm
product
acetonide,
of
the C24-dialdehyde
6.36;
m.p.
N, 15.66, It
is
terminal
94-108’; 15.10,
isolated AZ13
the oxidation
tetrol
on a preparative (IV),
interesting
of
1,2-glycol
the regenerated
sodium metaperiodate
hydrazone,
the course
was sought. (III)
scale.
fraction The product
and characterized
Calc.:
to note
that
C, 60.15; when squalene
After
a definitive chromatography
was cleaved was found
with to be
as the bis-dinitrophenyl-
358 rnp (E = 43,800)
15.57.
reaction,
(Found:
H, 6.45;
C, 59.98;
H,
N, 15.59).
was oxidized
with
other
In vitro
124
agents
in dilute,
preferential
o:tidation
usually
reaction
of
the
non-aqueous
terminal
double
solution
at the end double
(Table
bonds
bonds
l),
No.3
very
was observed.
little
In each
case
TABLE 1
Oxidizing agent
Yield (%) acetone (DNP) from squalene glycol
Equiv. oxidant/mole squalene
Solvent -
Osmium tetroxidepyridine
Ether
1
26,
27
Monoperphthali: acids
Chloroform
2
32,
39
Potassium permanganate
Acetonewater (15:l)
l&
26
Iodine-silver acetate
Acetic
acid
1
40
N-bromosuccinimide
Glyme-water
1
78
Glyme-water
2
81
N-bromosuccinimide -
A In ether and dimethylformamide solutions the second order rate plots were linear up to at least four mo:.es of peracid per mole of squalene. ’
the
total
initial
converted and then
tetrol
oxidation
to suc:h material analyzed
relationships are under
In experiments with less farther from completion. product,
if
not
acetone
between
solvent,
oxidation
already
by the appropriate
for
continuing
reagent,
a vicinal
sequence
by the method described oxidizing
investigation,
agent
as are
the
was
of
chemical
above.
and conformation further
glycol,
was reactions
The precise of
transformations
squalene of
(III).
Acknowledoements - These studies were aided by a grant from the National Sciencs Foundation (G19515) and by a contract between the Office of Naval Research, Department of the Navy, and the University of Wisconsin, NR 108-389.
No.
3,
pp.
121-124,
1962.
Pergamon
Press
Ltd.
Printed
THE SELECTIVE IN VITRO OXIDATION OF TEE TERMINAL DOUBLE BONDS IN SQUALENE E.E.
van
Department
Tamelen
of Chemistry,
as
a precursor
steroids of
and
the
this
not
availability
of
such
carbon
1
For
experiments
have
demonstrated
that
lanosterol
and
as
the
of
cholesterol
the
the
terminus,
a recent
review,
shown
(I
laboratory
(and
Not is
the
II).l
has
the
least
selective
of
L. Ruzicka,
Proc. 121
acts
doubtless
but
also
the
problems
in
of
other
duplicating
in
certain
because
Sot.
of
which
the
that
Chem,
vivo
oxidation-cyclization
interest
of
in
many
The prospect
oxidation challenge
squalene
involves
occasioned
aspects
an uncommon
see
which
+
theoretical
squalene.
an undertaking at
Wisconsin 1962)
in
because
of Wisconsin
30 January
system,
only
in
6,
triterpenoids), in a process
phenomenon
Curphey
(Received
of
polyene
T.J.
University
Madison
EXTENSIVE tracer
and
all
the must
starting of
341
circles,
the
(1959).
abundant be faced
hydrodouble
,122
In vitro
bonds
oxidation
in the s.ystem are
of
the terminal
trisubstituted
double
bonds
and more or less
encumbered.
Wdreport
herein
selectivity,
utilizing
means which we believe
a solution
to this
No.3
equally
problem
sterically
in chemical
to be novel
and also
of wider
applicability. In studying gated:
the nature
The results
of
successful carried
ether
concentration
gel. For
epoxide, perchloric
oxidations,
oxidizing
experiments
conversion
that
bromohydrin
of
with
fractions
(along
agent are
be separated with
of
start
of into
unreacted
of
in Table
to a mixture
such conditions at the
variables
and the nature
summarized
squalene
the solution could
two major
N-bromosuccinimide
under
Product
were investithe solvent.2
1.
In the most
of halohydrins
was
in aqueous
ethylene
temperature
(23’)
the reaction mono-,
squalene)
glycol and
was saturated
di-
and higher
by chromatography
over
3
further
chemical
work,
halohydrin
which was then converted aci.d in glyme.
and measurement strated
the
(glyme),
squalene.
silica
of
these
case,
in vitro
out by oxidation
dimethyl
with
such
that
of
acetone
the periodate
to
Combination
material
1,2-glycol of
was ring
by treatment
quantitative
closed with
periodate
to aqueous
oxidation
formation
on lead
tetraacetate
oxidation,
cleavable
material
consisted
predominantly
demonof
In regard to the latter factor, it seemed to us that the very feature which was responsible for this problem of selectivity, viz. the elongated, in partially olefinic hydrocarbon system, could be turned toadvantage, that the conformation of this large hydrocarbon might be sufficiently More precisesolvent-dependent to affect markedly its chemical behavior. ly, in a solvent of low polarity there is no reason to suppose that squalene would not exist for the most part in an uncoiled, fully extended state, with all of the double bonds equally vulnerable to attack by an oxidizing agent. On the other hand, in a more polar medium (such as that offered by a hydroxylic solvent) it appears possible that squalene would assume a more highly coiled, compact conformation, such that the tritersolvated”, and the system of hydrogen bonds penoid would be “internally Should this be in the medium would be disrupted as little as possible. the case, the internal double bonds in this coiled conformation might be sterically shielded and thus chemically less reactive, whereas the terminal olefinis links would remain exposed. Unpublished
results
secured
by Dr. A. Storni
in this
Laboratory.
In vitro
No.3
terminal
1,2-glycol
glycol)
amount
3,2-glycol
- as high
of
(DNP) from simple
of
acetone
material,
objective,
oxidation
under models
a completely
squalene,
(as
seemingly
of
the
terminal
as 81% of
the
double
theoretical
(e.g.,
was
where the actual
oxidation
all
terminal from
produced
yield
C6H5CHOHCOH(CH3)2)was 81%.
selective
123
(i.e.,
dinitrophenylhydrazone)
conditions
bonds
at the terminal
of
acetone
Thus,
the
double
bonds
had been achieved.
H
cl9 ‘x” \
I-
Br
33
I
/A#\
I
\ \0
HO
(\
Br
CH:
CHO
I
Iv
III
In order degradation of
its
to confirm
product
acetonide,
of
the C24-dialdehyde
6.36;
m.p.
N, 15.66, It
is
terminal
94-108’; 15.10,
isolated AZ13
the oxidation
tetrol
on a preparative (IV),
interesting
of
1,2-glycol
the regenerated
sodium metaperiodate
hydrazone,
the course
was sought. (III)
scale.
fraction The product
and characterized
Calc.:
to note
that
C, 60.15; when squalene
After
a definitive chromatography
was cleaved was found
with to be
as the bis-dinitrophenyl-
358 rnp (E = 43,800)
15.57.
reaction,
(Found:
H, 6.45;
C, 59.98;
H,
N, 15.59).
was oxidized
with
other
In vitro
124
agents
in dilute,
preferential
o:tidation
usually
reaction
of
the
non-aqueous
terminal
double
solution
at the end double
(Table
bonds
bonds
l),
No.3
very
was observed.
little
In each
case
TABLE 1
Oxidizing agent
Yield (%) acetone (DNP) from squalene glycol
Equiv. oxidant/mole squalene
Solvent -
Osmium tetroxidepyridine
Ether
1
26,
27
Monoperphthali: acids
Chloroform
2
32,
39
Potassium permanganate
Acetonewater (15:l)
l&
26
Iodine-silver acetate
Acetic
acid
1
40
N-bromosuccinimide
Glyme-water
1
78
Glyme-water
2
81
N-bromosuccinimide -
A In ether and dimethylformamide solutions the second order rate plots were linear up to at least four mo:.es of peracid per mole of squalene. ’
the
total
initial
converted and then
tetrol
oxidation
to suc:h material analyzed
relationships are under
In experiments with less farther from completion. product,
if
not
acetone
between
solvent,
oxidation
already
by the appropriate
for
continuing
reagent,
a vicinal
sequence
by the method described oxidizing
investigation,
agent
as are
the
was
of
chemical
above.
and conformation further
glycol,
was reactions
The precise of
transformations
squalene of
(III).
Acknowledoements - These studies were aided by a grant from the National Sciencs Foundation (G19515) and by a contract between the Office of Naval Research, Department of the Navy, and the University of Wisconsin, NR 108-389.