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Rearrangements of 32-oxygenated lanostanes
Tetrahedron Letters
No.10,
1967. Pergamon Press Ltd.
PP. 925-930,
REARRANGEMENTS
OF 32 -OXYGENATED
Josef Fried and James W.
Printed in Great Britain.
LANGSTANESl
Brown
Ben May Laboratory for Cancer Research and Department of Biochemistry University of Chicago Chicago, Ill. 60637 (Received 22 Pecernber 1966) Lanosterol this2,3>4
derivatives
bearing
and other laboratories.
of previously
reported
dimethylcholestene
acetate, sample. result
acetate,
m.p. 11
with particular
(VD4 on pyrolysis
on their conversion
into 4,4-
in a stream
of He for 30 min.
at 250-255”
115-16”;
[a],
34 [cY], t27.5O;
112-13.5”;
-cholestene-38-01 reported:
10
+2.3“;
6-membered
transition
state A is sufficiently
partial m.p.
5.82-5.88~;
(C=Cg);
[a]:
acetate VII,
The aldehydes rolysis
+25’; m.p.
VII,
3.00,
142-44”;
energetically
VIIb,
15
m. p.
s. 577 cps (CHO), m. 330 cps (C=C_H),
5.85~; [(Y]:
n.m.r.,
s.
+32O; reported:
577 cps (CEO), 5
VIIa and VIIb were decarbonylated
of VIIb at 250” for 75 min.
[aID +15’;
to
12,13
n. m. r.,
AZ:
138-41°;
with an authentic
favored
reduction with NaBH4 in 70% aqueous dioxane at 22O for 40 min. 131-133”;
m. p.
142 -43“;
identified by i. r. and g. 1. c. comparison
+28’,
Cope rearrangement.
hXB;
(VIIIa),
m. p.
Jones oxidation of VI at -15O l4 afforded the 3-keto-32-aldehyde [a]:
additional transformations
emphasis
8(14)
yield 4,4-dimethyl-A
m.p.
The cyclic
in facile
We now wish to describe
from
derivatives.
in quantitative
+14”;’
t(l1;
5,6,7,8
compounds
A7-Lanostene-38,32-diol furnished
oxygen on carbon atom 32 have been reported
gave the A 8(14) -3-ketone
925
m. p.
144-45”;
by 3 different VIIIb,
130-30.5O;
which on
gave the 38-01 VIIa, m.
327 cps
[cu], +24”, procedures.
m. p. 98-99’;
[IY]~
Py-5”;
926
No.10
II R=Ac IIa R=H
1) GO3
I
2) NaBH4
250” t
VII All
compounds
or b=3-keto.
hv have Jo-acetoxy
substituent
except
when
designated
a=3P-hydroxy
No. 10
927
XKBr max 5.88p,
probably
via a cyclic
VIIIa.
Photolytic
decarbonylation,
acetate
IX,
132-36°;17
m.p.
fied by g. 1. c. comparison ation product
revealed
tions by Jeger this reaction
et al.
14
transition fluxing hours
21
furnished
Application facile
CH3CO), -
5.80,
which
and 3570 cm
Recent
-1
14
bonding cleaved
m.p.
201-203”;
[(Y]:
of the latter V,
m.p.
-27”; AZ:
260-63’;
formyl
group
m. p.
152-154”;
((CH2j2). -
in 25% yield 5.80-5.85~;
to the 3p-01.
Further
AKmB3 2.90,
of III with [a]~
of the crude
ethylene
-38O; A::$
glycol 5.79,
m.p.
II,
202-205”;
5.87,
the hemiketal
of III with Jones
resulted
selective
instead
5.88; n.m.r.,
Re-
and IX as shown by g. 1. c. diacetate
I afforded
in a
m. p. 215-17O; [Q]:
34 max [o$, +13”,, vcc14
-1 22
+24O;
in acetic sh.
reagent
3630
because AS a -cis-
.
acid to form
5.93p; n.m.r.,
IV4 by oxidation
592 cps (32-C_HO),
Attempted
the
for several
as the 7P,32P-cis-diol -
by lead tetraacetate
S.
sense
122.5 and 126 cps (3- and 32-
-38”; AKmB3 3.00,
n.m. r.,
5.79p.
to which
19,20
reactions.
3P-acetoxy-lanostane-7-one-32-al
oxidation
5.65,
s.
irradi-
in line with observa-
by the i. r. band at 3570 cm
from
identi-
on the use of certain
of VIII
derivative
17
in that both reactions
to the 7-keto
formulated
in 10 min.
to form
[a]:
reaction4
indicated
cess
216-18”;
has focused
of
142-43’,
of 19 -formyl-A5-steroids,
a 50:50 mixture
the trio1 IIa,
which was also prepared
reagent
VIIIa,
and decarbonylation
yield
592 cps (32-C_Ho), Jones
-isomer
s. 341 cps (32~C_HOAc),
furnished
IIa was quantitatively IIIa,
interest
s. 279 cps (32-CHOH), -
hydrogen
the keto aldehyde
m. p.
G. 1. c. analysis
32-demethylation
40% of the cyclobutanediol
5.85~; n.m.r.,
; n. m. r.,
Ma,
of VII with chloro-tris-(triphenylphosphin)-rhodium
on hydrolysis
of intramolecular glycol,
10
t. 1. c. in small
(35 min.)
8(14)
furnished
oxidation
It should be noted that in a formal
the biochemical
of the 7,32 -photocyclization
reaction
XKBr max 2.91,
after
18
for hydrogenation
solution
11
specimen.
by Jones
and 134-36O, respectively,
of the decarbonylation
analogous.
resembles
10 min.
143-46.5’
of 5% of the A
in the case
complexes
a benzene
m. p.
with an authentic
double bond shift.
metal
state B, also prepared
of VIIa for
10
reported,
is mechanistically
without
14,16
the presence
photo decarbonylation proceed
transition
(III), followed
in the 7-ethylene
S. 607 cps (32-C_HO),
with exm.p.
by hydrolysis
furnished
acetalization
s.
the lactol of the 32 -
ketal-32-aldehyde, m.
232 cps
928
No.10
The cyclopropane of this ring orphous 5.79,
system
XI appeared
among natural
products.
7-keto-32-mesylate
5.85 (sh.),
(J=lO)
derivative
7.40,
(32-CHZO).
followed
Treatment
by reacetylation,
furnished
was performed
a 1:l mixture 167.5-8.5”; protons; with well. rise
6.00~; A;;, instead
of XI (3-ol),
in 55% yield
[~-$7+173~;
structures
Rearrangement to XIII.
Additional
by methanol
as the acetate,
information
reaction
(but not by DMSO),
kg:
in DMSO at 25”,
ketone
XI,
is required
of rearrangement in DMSO, thereby
5.97,
to decide
25
m. p.
192-940;
there
no vinyl
grounds
path b would
these
over
as
give
alternative
to cyclopropane
to shielding
rearrangement
m. p.
data are compatible
while
between
in competition
was formed ketone,
for on mechanistic XII,
When the’re-
6.20~; n. m. r.,
and analytical
may be ascribed favoring
methoxide
and an cr$-unsaturated
X) would yield
23 XKBr max
XIII
sodium
accounted
into the am-
at 50°,
M+ peak at -m/e 484.
26
occurence
249 and 271 cps
carbanion24
3.00,
spectral
are readily
by path a (structure
The intervention
is the exclusive
methanolic
The above
which
Qart.
the cyclopropyl
216mp (e 5,500);
Asm’;x 263mp (E 8,500);
XII or XIII,
chloride
XII
in boiling
isolated
M+ peak at _m/e 442.
structures. which
5.77,
IV was converted
181.5 cps (CH3S02), -
XI
-20”; LK$;
of the possible
and methanesulfonyl
of X with methylsulfinyl
X
action
s.
because
The hemiketal
X with pyridine
8.51~; n.m.r.,
of interest
formation,
of the enolate internal
anion
alkylation.
No. 10
929
REFERENCES 1.
This
was supported by Public Health Service Research
investigation
and by Research of Arthritis
Career
Program
and Metabolic
Award 5-K6-AM-21840
Tetrahedron
J , Fried,
J. W.
Brown and M.
Applebaum,
3.
J. Fried,
J. W.
Brown and L.
Borkenhagen,
4.
J. Fried
5.
T. J.
6.
C.
Bentley,
W.
Brown,
J. F.
Shoppee,
from the National Institute
Diseases.
2.
and J. W.
Grant CA 07445
Tetrahedron
McGhie
J. C. Coll,
N. W.
Tetrahedron
Letters,
and D. H. R.
Letters,
849 (1965).
Letters,
2499 (1965).
1677 (1966).
Barton,
Tetrahedron
Hughes and R. E.
Lack,
Letters,
2497 (1965).
Tetrahedron
Letters,
3249
Letters,
4343 (1965).
(1965). 7.
D. H. R. Barton,
8.
C
9.
All rotations
W.
Shoppee,
analyses
A. Hameed N
W.
Hughes,
in CHC13.
F. McGhie,
R. E.
N. m. r.
were performed
Diatoport
and J.
Lack,
spectra
Tetrahedron
and K.
Letters,
in CDC13 on a Varian
on an F and M model 400 instrument
S column at a He flow of 100 ml/min.
Gautschi
Tetrahedron
10.
F.
Bloch,
11.
We wish to thank Professor
J. Biol. K.
Chem.,
5235 (1966).
A-60
G. 1. c.
instrument.
using a 3.8% SE 30 on
at 250-280”.
233, 1343 (1958).
-
Bloch of Harvard
University
for kindly supplying these
samples. 12.
62% of the theoretical
13.
A similarly
facile
Chem -*
2033 (1965)
) g, -
methyl polygalate.
amount of formaldehyde
reaction
has been observed
in the conversion
14.
J. Hill,
by J. J. Dugan and P.
of the dimethyl
5(10)
ester
K. Schaffner
and 0.
Jeger,
Helv.
de Mayo,
of presenegenin
-19-norandrostene-3P-ol-17-one
J. H. Fried of the Syntex Laboratories
J. Iriarte,
as the dimedon derivative.
On the other hand, A5-androstene-3g,19-diol-17-one
only to the extent of 25% to A to thank Dr.
was isolated
Can b
to di-
was converted in one hour.
We wish
for these two compounds. chim.
Acta,
J.
g, -
292 (1966).
930
15.
16.
No.10
All new compounds
gave correct
Metuchen,
New Jersey.
Irradiation
was effected
elemental
Analyses
analyses.
by J. Alicino,
at 25O with a 200 W Hanovia quartz high pressure
mercury
lamp without filter in ethanol. 17.
Taken on Kofler
18.
M.
Akhtar,
19.
M.
A.
20.
J. Tsuji
21.
Tetrahedron
Bennett and P.
and E.
All other m. p. ‘s in capillaries.
block.
Letters,
A.
4227 (1965).
Longstaff,
and K. Ohno, Tetrahedron
Caspi,
The reaction
Tetrahedron (0.01
mmole
Chem. Letters,
Letters,
22.
M.
Tich;,
1965, 23.
846 (1965).
3969 (1965);
Y.
Shimizu,
of VII and 0.02 mmole
of rhodium complex,
Additional
amounts of complex
changed. zation.
produced
in Organic
Chemistry”
Vol.
had to be
5, Interscience
Publishers,
a mixture
The very difficultly Yield
of X,
E. J. Corey and M.
25.
The two protons
X and the isomeric
cyclic
n. m. r.
from the mixture
protons
Chaykovsky,
of 7-keto
J. Am.
Chem.
evidence
Sot.,
87, =
ring at C-32
1345 (1965). are sufficiently
group to be hidden under the methyl peaks,
for such a structure.
in small
yield.
at 23 and 36 cps (J=3.5); -7-ketones
Reviews,
53 -
by crystalli-
70%.
Reduction
NaBH4 in aqueous dioxane for 48 hours at 25O gave a mixture could be isolated
mesylate.
from the latter leaving X un-
soluble IV was removed
attached to the cyclopropane
due to the proximity precluding
of the mesylate
with aqueous dioxane at 25” regeneratedlV
24.
A
in
page 172.
Hydrolysis
26.
refluxed
the reaction.
in “Advances
This procedure
8(14)
H. Mitsuhashi
4113 (1966).
benzene for 1 hour) was followed by g. 1. c. added to complete
and Ind.,
absorb
117 (1953).
Its n. m. r. 7aI& m.
at 260-263mp
spectrum
centered
clearly
deshielded thereby
of the keto group with from which the 78-alcohol shows the cyclopropyl
at 213 cps.
(E, 8,000-10,000).
Cf.
L.
Dorfman,
Chem.
No.10,
1967. Pergamon Press Ltd.
PP. 925-930,
REARRANGEMENTS
OF 32 -OXYGENATED
Josef Fried and James W.
Printed in Great Britain.
LANGSTANESl
Brown
Ben May Laboratory for Cancer Research and Department of Biochemistry University of Chicago Chicago, Ill. 60637 (Received 22 Pecernber 1966) Lanosterol this2,3>4
derivatives
bearing
and other laboratories.
of previously
reported
dimethylcholestene
acetate, sample. result
acetate,
m.p. 11
with particular
(VD4 on pyrolysis
on their conversion
into 4,4-
in a stream
of He for 30 min.
at 250-255”
115-16”;
[a],
34 [cY], t27.5O;
112-13.5”;
-cholestene-38-01 reported:
10
+2.3“;
6-membered
transition
state A is sufficiently
partial m.p.
5.82-5.88~;
(C=Cg);
[a]:
acetate VII,
The aldehydes rolysis
+25’; m.p.
VII,
3.00,
142-44”;
energetically
VIIb,
15
m. p.
s. 577 cps (CHO), m. 330 cps (C=C_H),
5.85~; [(Y]:
n.m.r.,
s.
+32O; reported:
577 cps (CEO), 5
VIIa and VIIb were decarbonylated
of VIIb at 250” for 75 min.
[aID +15’;
to
12,13
n. m. r.,
AZ:
138-41°;
with an authentic
favored
reduction with NaBH4 in 70% aqueous dioxane at 22O for 40 min. 131-133”;
m. p.
142 -43“;
identified by i. r. and g. 1. c. comparison
+28’,
Cope rearrangement.
hXB;
(VIIIa),
m. p.
Jones oxidation of VI at -15O l4 afforded the 3-keto-32-aldehyde [a]:
additional transformations
emphasis
8(14)
yield 4,4-dimethyl-A
m.p.
The cyclic
in facile
We now wish to describe
from
derivatives.
in quantitative
+14”;’
t(l1;
5,6,7,8
compounds
A7-Lanostene-38,32-diol furnished
oxygen on carbon atom 32 have been reported
gave the A 8(14) -3-ketone
925
m. p.
144-45”;
by 3 different VIIIb,
130-30.5O;
which on
gave the 38-01 VIIa, m.
327 cps
[cu], +24”, procedures.
m. p. 98-99’;
[IY]~
Py-5”;
926
No.10
II R=Ac IIa R=H
1) GO3
I
2) NaBH4
250” t
VII All
compounds
or b=3-keto.
hv have Jo-acetoxy
substituent
except
when
designated
a=3P-hydroxy
No. 10
927
XKBr max 5.88p,
probably
via a cyclic
VIIIa.
Photolytic
decarbonylation,
acetate
IX,
132-36°;17
m.p.
fied by g. 1. c. comparison ation product
revealed
tions by Jeger this reaction
et al.
14
transition fluxing hours
21
furnished
Application facile
CH3CO), -
5.80,
which
and 3570 cm
Recent
-1
14
bonding cleaved
m.p.
201-203”;
[(Y]:
of the latter V,
m.p.
-27”; AZ:
260-63’;
formyl
group
m. p.
152-154”;
((CH2j2). -
in 25% yield 5.80-5.85~;
to the 3p-01.
Further
AKmB3 2.90,
of III with [a]~
of the crude
ethylene
-38O; A::$
glycol 5.79,
m.p.
II,
202-205”;
5.87,
the hemiketal
of III with Jones
resulted
selective
instead
5.88; n.m.r.,
Re-
and IX as shown by g. 1. c. diacetate
I afforded
in a
m. p. 215-17O; [Q]:
34 max [o$, +13”,, vcc14
-1 22
+24O;
in acetic sh.
reagent
3630
because AS a -cis-
.
acid to form
5.93p; n.m.r.,
IV4 by oxidation
592 cps (32-C_HO),
Attempted
the
for several
as the 7P,32P-cis-diol -
by lead tetraacetate
S.
sense
122.5 and 126 cps (3- and 32-
-38”; AKmB3 3.00,
n.m. r.,
5.79p.
to which
19,20
reactions.
3P-acetoxy-lanostane-7-one-32-al
oxidation
5.65,
s.
irradi-
in line with observa-
by the i. r. band at 3570 cm
from
identi-
on the use of certain
of VIII
derivative
17
in that both reactions
to the 7-keto
formulated
in 10 min.
to form
[a]:
reaction4
indicated
cess
216-18”;
has focused
of
142-43’,
of 19 -formyl-A5-steroids,
a 50:50 mixture
the trio1 IIa,
which was also prepared
reagent
VIIIa,
and decarbonylation
yield
592 cps (32-C_Ho), Jones
-isomer
s. 341 cps (32~C_HOAc),
furnished
IIa was quantitatively IIIa,
interest
s. 279 cps (32-CHOH), -
hydrogen
the keto aldehyde
m. p.
G. 1. c. analysis
32-demethylation
40% of the cyclobutanediol
5.85~; n.m.r.,
; n. m. r.,
Ma,
of VII with chloro-tris-(triphenylphosphin)-rhodium
on hydrolysis
of intramolecular glycol,
10
t. 1. c. in small
(35 min.)
8(14)
furnished
oxidation
It should be noted that in a formal
the biochemical
of the 7,32 -photocyclization
reaction
XKBr max 2.91,
after
18
for hydrogenation
solution
11
specimen.
by Jones
and 134-36O, respectively,
of the decarbonylation
analogous.
resembles
10 min.
143-46.5’
of 5% of the A
in the case
complexes
a benzene
m. p.
with an authentic
double bond shift.
metal
state B, also prepared
of VIIa for
10
reported,
is mechanistically
without
14,16
the presence
photo decarbonylation proceed
transition
(III), followed
in the 7-ethylene
S. 607 cps (32-C_HO),
with exm.p.
by hydrolysis
furnished
acetalization
s.
the lactol of the 32 -
ketal-32-aldehyde, m.
232 cps
928
No.10
The cyclopropane of this ring orphous 5.79,
system
XI appeared
among natural
products.
7-keto-32-mesylate
5.85 (sh.),
(J=lO)
derivative
7.40,
(32-CHZO).
followed
Treatment
by reacetylation,
furnished
was performed
a 1:l mixture 167.5-8.5”; protons; with well. rise
6.00~; A;;, instead
of XI (3-ol),
in 55% yield
[~-$7+173~;
structures
Rearrangement to XIII.
Additional
by methanol
as the acetate,
information
reaction
(but not by DMSO),
kg:
in DMSO at 25”,
ketone
XI,
is required
of rearrangement in DMSO, thereby
5.97,
to decide
25
m. p.
192-940;
there
no vinyl
grounds
path b would
these
over
as
give
alternative
to cyclopropane
to shielding
rearrangement
m. p.
data are compatible
while
between
in competition
was formed ketone,
for on mechanistic XII,
When the’re-
6.20~; n. m. r.,
and analytical
may be ascribed favoring
methoxide
and an cr$-unsaturated
X) would yield
23 XKBr max
XIII
sodium
accounted
into the am-
at 50°,
M+ peak at -m/e 484.
26
occurence
249 and 271 cps
carbanion24
3.00,
spectral
are readily
by path a (structure
The intervention
is the exclusive
methanolic
The above
which
Qart.
the cyclopropyl
216mp (e 5,500);
Asm’;x 263mp (E 8,500);
XII or XIII,
chloride
XII
in boiling
isolated
M+ peak at _m/e 442.
structures. which
5.77,
IV was converted
181.5 cps (CH3S02), -
XI
-20”; LK$;
of the possible
and methanesulfonyl
of X with methylsulfinyl
X
action
s.
because
The hemiketal
X with pyridine
8.51~; n.m.r.,
of interest
formation,
of the enolate internal
anion
alkylation.
No. 10
929
REFERENCES 1.
This
was supported by Public Health Service Research
investigation
and by Research of Arthritis
Career
Program
and Metabolic
Award 5-K6-AM-21840
Tetrahedron
J , Fried,
J. W.
Brown and M.
Applebaum,
3.
J. Fried,
J. W.
Brown and L.
Borkenhagen,
4.
J. Fried
5.
T. J.
6.
C.
Bentley,
W.
Brown,
J. F.
Shoppee,
from the National Institute
Diseases.
2.
and J. W.
Grant CA 07445
Tetrahedron
McGhie
J. C. Coll,
N. W.
Tetrahedron
Letters,
and D. H. R.
Letters,
849 (1965).
Letters,
2499 (1965).
1677 (1966).
Barton,
Tetrahedron
Hughes and R. E.
Lack,
Letters,
2497 (1965).
Tetrahedron
Letters,
3249
Letters,
4343 (1965).
(1965). 7.
D. H. R. Barton,
8.
C
9.
All rotations
W.
Shoppee,
analyses
A. Hameed N
W.
Hughes,
in CHC13.
F. McGhie,
R. E.
N. m. r.
were performed
Diatoport
and J.
Lack,
spectra
Tetrahedron
and K.
Letters,
in CDC13 on a Varian
on an F and M model 400 instrument
S column at a He flow of 100 ml/min.
Gautschi
Tetrahedron
10.
F.
Bloch,
11.
We wish to thank Professor
J. Biol. K.
Chem.,
5235 (1966).
A-60
G. 1. c.
instrument.
using a 3.8% SE 30 on
at 250-280”.
233, 1343 (1958).
-
Bloch of Harvard
University
for kindly supplying these
samples. 12.
62% of the theoretical
13.
A similarly
facile
Chem -*
2033 (1965)
) g, -
methyl polygalate.
amount of formaldehyde
reaction
has been observed
in the conversion
14.
J. Hill,
by J. J. Dugan and P.
of the dimethyl
5(10)
ester
K. Schaffner
and 0.
Jeger,
Helv.
de Mayo,
of presenegenin
-19-norandrostene-3P-ol-17-one
J. H. Fried of the Syntex Laboratories
J. Iriarte,
as the dimedon derivative.
On the other hand, A5-androstene-3g,19-diol-17-one
only to the extent of 25% to A to thank Dr.
was isolated
Can b
to di-
was converted in one hour.
We wish
for these two compounds. chim.
Acta,
J.
g, -
292 (1966).
930
15.
16.
No.10
All new compounds
gave correct
Metuchen,
New Jersey.
Irradiation
was effected
elemental
Analyses
analyses.
by J. Alicino,
at 25O with a 200 W Hanovia quartz high pressure
mercury
lamp without filter in ethanol. 17.
Taken on Kofler
18.
M.
Akhtar,
19.
M.
A.
20.
J. Tsuji
21.
Tetrahedron
Bennett and P.
and E.
All other m. p. ‘s in capillaries.
block.
Letters,
A.
4227 (1965).
Longstaff,
and K. Ohno, Tetrahedron
Caspi,
The reaction
Tetrahedron (0.01
mmole
Chem. Letters,
Letters,
22.
M.
Tich;,
1965, 23.
846 (1965).
3969 (1965);
Y.
Shimizu,
of VII and 0.02 mmole
of rhodium complex,
Additional
amounts of complex
changed. zation.
produced
in Organic
Chemistry”
Vol.
had to be
5, Interscience
Publishers,
a mixture
The very difficultly Yield
of X,
E. J. Corey and M.
25.
The two protons
X and the isomeric
cyclic
n. m. r.
from the mixture
protons
Chaykovsky,
of 7-keto
J. Am.
Chem.
evidence
Sot.,
87, =
ring at C-32
1345 (1965). are sufficiently
group to be hidden under the methyl peaks,
for such a structure.
in small
yield.
at 23 and 36 cps (J=3.5); -7-ketones
Reviews,
53 -
by crystalli-
70%.
Reduction
NaBH4 in aqueous dioxane for 48 hours at 25O gave a mixture could be isolated
mesylate.
from the latter leaving X un-
soluble IV was removed
attached to the cyclopropane
due to the proximity precluding
of the mesylate
with aqueous dioxane at 25” regeneratedlV
24.
A
in
page 172.
Hydrolysis
26.
refluxed
the reaction.
in “Advances
This procedure
8(14)
H. Mitsuhashi
4113 (1966).
benzene for 1 hour) was followed by g. 1. c. added to complete
and Ind.,
absorb
117 (1953).
Its n. m. r. 7aI& m.
at 260-263mp
spectrum
centered
clearly
deshielded thereby
of the keto group with from which the 78-alcohol shows the cyclopropyl
at 213 cps.
(E, 8,000-10,000).
Cf.
L.
Dorfman,
Chem.