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Observations regarding eschenmoser sulfide contractions of β-oxygenated thiolactams
T~rrnhdron
Lefrers,
Vol
36. No
43, pp. 7787.7790, 1995 Elsevier Science Ltd Printed in Great Britain cow-4039/95 $9.50+0.00
0040-4039(95)01648-l
OBSERVATIONS
REGARDING
ESCHENMOSER
SULFIDE
CONTRACTIONS
OF
P-OXYGENATED
THIOLACTAMS
David Department
of Chemistry,
The Ohio
J Hart’ State
and
Li-Qlang
University,
120
Alan Georgetown
University
Application
Abstract:
was complicated retarded
During the
task
the
Eschenmoser
of a protect
of converting sulfide
azomethine such
5 and
carbon
directed
a deprotonation,
followed
toward
1 to pyrrolidine
contraction
2
6 (Scheme
under
sulhde
Road,
Eschenmoser by a-elimination
the
this
it is known
contraction
could be obtained.
of potential We
met with
and
cocaine
hoped
failure
as treatment and
it was
uptake
to do this
that thioalkyliminium
conditions,
bearing
products
by tnphenylphosphine
Since
Ohio
43210
DC 20007-2197
the p-subsfiluent
3.’
presumed
that
can
group group
antagonists
we were
via vinylogous
urethane
of 1 with
carbomethoxymethyl
triethylamine salts
a P-acyloxy to an alkoxy
in dichloromethane
gave
be deprotonated
pyrroles
5 and
faced 2 using
adjacent 6 were
a
to the
the result
of
aromatization.5 Scheme
0
N. W., Washington,
Changing
synthesis
derivative
Unfortunately followed
1). 3,4
Columbus,
to a rhiolactam
contracfion reachon.
such that su/fide contraction
in acetonitrile
of pyrroles
Reservoir
/3-elimination
thiolactam
Ave.,
P. Kozikowski
3900
of an Eschenmoser
the rate of elimination
trifluoromethanesulfonate mixture
School,
by a competitive
the course
with
Medical
Sun W. 18th
1
0
S
CHzC02Me 3
1 TfOCHaCOaMe
c
,CH$OsH N-Me
SCHaCOaMe
’
SCHaCOaMe
4
5
7787
CH3 c N-Me
SCHzCOzMe 6
7788
In an attempt Thus,
thiolactams
Although
thus problem,
7 and 8 were
this did not completely
reasonable
yield.
For example,
In dichloromethane similar
to elimmate
gave
manner
changing
from
undesired
aromatization.7
prepared
and subjected
eliminate
the aromatization
treatment
vinylogous
as vinylogous 8-acyloxy
to replace
problem,
sulfide
followed
to a 8-alkoxy
group
11 were turned
produced
with a worse
contraction
it did afford
triflate
group
vinylogous
by triphenylphosphine 11.
contraction
Thiolactam
pathway
group.
(Scheme
2).6
urethanes
in a
and triethylamine
in 65% and 30% yields,
on the sulfide
leaving
conditions
the desired
9 in 66% yield along with 17% of pyrrole
10 and pyrrole
Scheme R2
the j3-acyloxy
to Eschenmoser
of 7 with the appropriate
urethane
urethane
group
it was decided
8 behaved
in a
respectively.
Thus,
at the expense
of the
2
CH2COzMe 1. TfOCHaCOsMe,
R,..“’
CHsCN
N-Me 2. Ph3P, Et3N, CH2C12 c S
7 R, =OMe R2=H 8 R1 =H R2=OMe
It was possible Scheme
to use this observation
3. Thus, sequential
(94%).
Conversion
15 (95%).
treatment
to accomplish
of (S)-maiic
reduction
then provided
17 in 96% yreld.9
(81%)
by benzylatron
of the resulting
which was converted
to thiolactam
contraction
procedure
to 22 did afford
pyrrolidrne
25 (77%)
along
afforded
lactone
Treatment
22 (90%) vinylogous
with 14% of 24. I3
borohydride
to provide
using Lawesson’s urethane Finally,
gave
20 (90%).
reagent,tt,t2
23 in 51% yield.
and titanium
Application
Borch reduction of the benzyl
gave
and a Williamson
tetrachloride
gave 18
protecting
Ozonolysis
in
gave imide 13
of the alcohol
16 (84%)8
of the tert-butyldimethylsilyl
ether
hydrogenolysis
of 3, as outlined
HCI and reprotection
of 17 with allytrimethylsilane
19 (98%)
a synthesis
and acetyl chloride
in methanol
trans isomer. 19 Removal
alcohol
objective,
methylamine,
group
of 20 gave ester 21
01 the Eschemoser
sulfide
of 23 gave the desired
all-cis
ether
using
rhodium
on alumina
3 in 80% yield.
In summary was complicated
synthetic
in 98% yteld using ethanolic
of the amide using sodium
in 72% yield along with 12% of the corresponding was followed
the original
acid with acetyl chloride,
of the 13 to 14 was accomplished
Regioselective
ether synthesis
11 (17%) 11 (30%)
9 RI =OMe Ra=H (66%) 10 RI = H Ra= OMe (65%)
it was found that a Eschenmoser by a competitive
substttuent
to an alkoxy
oxygenated
substrates.t5
group.
p-elimination This tactic
sufide contraction reaction
should
I4
expand
on a thiolactam
Thus problem the scope
substrate
was overcome,
of the sulfide
carrying
however,
contraction
a P-acyloxy by changing
process
group the p-
to include
p-
7789
Scheme
3 X
0 HO..,,
C02H
a, b, a *
N-Me
r MeOaC
BnO,, ‘,
I
_
r,
mlt *,
CHaCOaMe i
BnO,,
N-Me
j
: N-Me c
x
0
h < 18 R = TBS (78%) i (19 R = H (98%) 20 R = Bn (90%)
n
N-Me c
c CH$ZOaMe
CHaC02Me
24 (14%)
CH2C02Me
25 (77%)
3 (80%)
AcCl (b) MeNH2, CHaCia (c) HCI, EtOH (d) TBSCI, rmidazole. DMF (e) NaBH4, MeOH NaH. Mel, THF (g) TMSCHaCH=CHa, TiCId, CHaCl2, -78’C --f rt (h) rrBu4NF, THF (i) NaH, BnBr, THF 03, MeOH-H20-NaOH, CHaCIa (k) (MeOCeH4PS2)a, CH2C12 (I) TfOCHaC02Me; PhaP, EtaN, CHeCla NaBHaCN, MeOH. pH4 (n) Ha, Pd(OH)e
References
Kozikowski, Med.
RO., *,
CHaCOaMe f
‘,
+
(84%) (96%)
CHaCH=CHa
k < 21 X = 0 (81%) 22 x = s (90%)
23 (51%)
0
f < 16 X = OH 17 X=OMe
N-Me
\
c
CH2C02Me T
CHaC02Me
(a) (f) (j) (m)
-
c
i
‘I
,, N-Me
0 c (13 R = AC (94%) d (14 R=H (98%) 15 R = TBS (95%)
12
BnO,,
e
N-Me
C02H
BnO,,
TBSO.,
RO., *,
A. P
Chem.
Roberti,
1992,
Ball, R G. J. Med. 2.
Roth, M.. Dubs,
3
The synthesis reaction
Chem.
LetI
1981,
Bergmann,
J S.; Callahan,
D ; Stoelwmder,
E ; Eschenmoser,
thiolactam
below
P Anna/en
L
Slmoni,
Notes
P. M ; Cunningham,
M : Kozikowski,
A. P.; Johnson,
K. A.; Johnson,
K. M. J.
K M.; Bergmann,
J. S.;
1993, 36, 3975.
P.; Goschi, of startrng
as described
Tetrahedron Russkamp,
M., Xiang,
35, 4764.
and
For other 22. 719
1983,
529
A He/v.
1 was accomplished intramolecular
Flitsch,
W
C/urn. Acta 1971,
54, 710.
from imide 14 (v/de sup@ Wittig
Russkamp.
reactrons
of imides
P ; Anna/en
1983,
using an intramolecular
see Flitsch, 521.
Wittig
W.; Wernsmann,
Flitsch,
W.; Pandl,
P.; K.;
7790
0 RO.
**,
d
N-Me
N-Me
95%
c
a( bc
R=H R = C02C02Br R = C02CH21
(a) BrCHsCOCI. pyridine, CHsCla (e) (pMeOC+U’Sa)a, CHaCl2
4.
Petersen,
5.
Gompper,
x=0 x=s
e<
(86%) (100%)
J. S.: Fels, G
(b) Nat acetone
Rapoport,
H. J. Am
R.; Elser, W J. L Ann.
(c) PhsP, CHsCN;
Chem
1969,
Chem.
1984,
Sot.
725. 64
then EtsN (d) Ha, RhlAlaOs,
EtOAc
706. 4539.
Hart, D J.; Hong,
W.-P.;
Hsu, L.-Y. J. Org. Chem.
1987,
52, 4665. 6.
Thiolactams
7 and 8 were prepared
will be described 7
8.
search
P-oxygenated
2thiopyrrolidinone.
9.
Kuzmich, 1994,
10.
116,
1982. 55, 1406.
W.-J , van Grnkel,
Marshall, Scheibye, Borch,
Acetylation
A.: Micheli,
22 in Scheme
3. Details
of an Eschenmoser
1975, 34, 179.
J. Chem.
S.; Alarashi,
Sot.,
sulfide
Chamberlin,
Chem.
contraction
of a
A. R.; Chung,
J. Y.
1983,
Commun.
135.
S.; Choi, J.-K.; Hart, D. J. J. Am. Chem.
Sot.
a thiolactam
We thank
Interneuron
Instrumentation
USA 26
support
June
G A.; Neuenschwander, see Thaning,
D , Scolastico.
M ; Hiemstra,
Sedrani,
B. S
Lawesson,
R C Synlert S.-O.
Chem.
of 19 followed
gave
contraction
C.; Villa, R. Tetrahedron
H.; Louwrier,
only
Chum.
L.-G. Left.
S.; Moolenaar,
Sot.
Sot.,
Chem.
J. Org.
Chem.
1990,
M. J.; Speckamp,
31, 4949.
W. N.
Thus,
Pharmaceuticals from the Campus
revised
22
Chemical
pyrrole
gift that
accepted
with Lawesson’s
yield
upon
that the elimination thiolactam
supported Center
23
lactam
in 95%
in bicyclic
Instrumentation
August 1995:
87, 229.
of the derived
we are confident
for a generous
1978,
1971, 93, 2897.
by treatment
the corresponding
conditions.
Be/g.
and not ring strain that might be present
1995;
K. J. Chem.
M.; Wistrand,
1992, 643.
Bull. Sot.
Durst. H. D J Am group
which
of the P-substltuent
Kraus,
of relevance
F ; Potenza,
A. W
M D
of the hydroxyl
sulfide
studies
401.
32,
Pederson,
aforementioned
in
Ramesh,
1981, 22, 1567.
Letf.
R ; Kranenburg,
1991,
R. F.; Bernstein,
provided
nature
Bernardi,
Lelt.
S
14
an example
W N Tetrahedron
Ha, D -C ; Lee, C -S
J. A.; Garofaio,
13.
to uncover
Han, D J ; Yang, T.-K
3653.
For stereochemical
Koot,
12.
105.
Tetrahedron
134
1990,
11.
for thiolactam
6943.
Hart, D. J., Tsar, Y-M
Tetrahedron
(Received
J B P A : Speckamp,
1983,
Sot.
D ; Wu, S C
Commun.
15.
using CAS REACT failed
J. C.. Wijnberg,
J. Am. Chem.
similar to that described
elsewhere
A substructure
Hubert,
by a procedure
this
exposure
problem
to the
is due to the
1. research
and acknowledge
at The Ohio State University.
August 1995)
reagent
Lefrers,
Vol
36. No
43, pp. 7787.7790, 1995 Elsevier Science Ltd Printed in Great Britain cow-4039/95 $9.50+0.00
0040-4039(95)01648-l
OBSERVATIONS
REGARDING
ESCHENMOSER
SULFIDE
CONTRACTIONS
OF
P-OXYGENATED
THIOLACTAMS
David Department
of Chemistry,
The Ohio
J Hart’ State
and
Li-Qlang
University,
120
Alan Georgetown
University
Application
Abstract:
was complicated retarded
During the
task
the
Eschenmoser
of a protect
of converting sulfide
azomethine such
5 and
carbon
directed
a deprotonation,
followed
toward
1 to pyrrolidine
contraction
2
6 (Scheme
under
sulhde
Road,
Eschenmoser by a-elimination
the
this
it is known
contraction
could be obtained.
of potential We
met with
and
cocaine
hoped
failure
as treatment and
it was
uptake
to do this
that thioalkyliminium
conditions,
bearing
products
by tnphenylphosphine
Since
Ohio
43210
DC 20007-2197
the p-subsfiluent
3.’
presumed
that
can
group group
antagonists
we were
via vinylogous
urethane
of 1 with
carbomethoxymethyl
triethylamine salts
a P-acyloxy to an alkoxy
in dichloromethane
gave
be deprotonated
pyrroles
5 and
faced 2 using
adjacent 6 were
a
to the
the result
of
aromatization.5 Scheme
0
N. W., Washington,
Changing
synthesis
derivative
Unfortunately followed
1). 3,4
Columbus,
to a rhiolactam
contracfion reachon.
such that su/fide contraction
in acetonitrile
of pyrroles
Reservoir
/3-elimination
thiolactam
Ave.,
P. Kozikowski
3900
of an Eschenmoser
the rate of elimination
trifluoromethanesulfonate mixture
School,
by a competitive
the course
with
Medical
Sun W. 18th
1
0
S
CHzC02Me 3
1 TfOCHaCOaMe
c
,CH$OsH N-Me
SCHaCOaMe
’
SCHaCOaMe
4
5
7787
CH3 c N-Me
SCHzCOzMe 6
7788
In an attempt Thus,
thiolactams
Although
thus problem,
7 and 8 were
this did not completely
reasonable
yield.
For example,
In dichloromethane similar
to elimmate
gave
manner
changing
from
undesired
aromatization.7
prepared
and subjected
eliminate
the aromatization
treatment
vinylogous
as vinylogous 8-acyloxy
to replace
problem,
sulfide
followed
to a 8-alkoxy
group
11 were turned
produced
with a worse
contraction
it did afford
triflate
group
vinylogous
by triphenylphosphine 11.
contraction
Thiolactam
pathway
group.
(Scheme
2).6
urethanes
in a
and triethylamine
in 65% and 30% yields,
on the sulfide
leaving
conditions
the desired
9 in 66% yield along with 17% of pyrrole
10 and pyrrole
Scheme R2
the j3-acyloxy
to Eschenmoser
of 7 with the appropriate
urethane
urethane
group
it was decided
8 behaved
in a
respectively.
Thus,
at the expense
of the
2
CH2COzMe 1. TfOCHaCOsMe,
R,..“’
CHsCN
N-Me 2. Ph3P, Et3N, CH2C12 c S
7 R, =OMe R2=H 8 R1 =H R2=OMe
It was possible Scheme
to use this observation
3. Thus, sequential
(94%).
Conversion
15 (95%).
treatment
to accomplish
of (S)-maiic
reduction
then provided
17 in 96% yreld.9
(81%)
by benzylatron
of the resulting
which was converted
to thiolactam
contraction
procedure
to 22 did afford
pyrrolidrne
25 (77%)
along
afforded
lactone
Treatment
22 (90%) vinylogous
with 14% of 24. I3
borohydride
to provide
using Lawesson’s urethane Finally,
gave
20 (90%).
reagent,tt,t2
23 in 51% yield.
and titanium
Application
Borch reduction of the benzyl
gave
and a Williamson
tetrachloride
gave 18
protecting
Ozonolysis
in
gave imide 13
of the alcohol
16 (84%)8
of the tert-butyldimethylsilyl
ether
hydrogenolysis
of 3, as outlined
HCI and reprotection
of 17 with allytrimethylsilane
19 (98%)
a synthesis
and acetyl chloride
in methanol
trans isomer. 19 Removal
alcohol
objective,
methylamine,
group
of 20 gave ester 21
01 the Eschemoser
sulfide
of 23 gave the desired
all-cis
ether
using
rhodium
on alumina
3 in 80% yield.
In summary was complicated
synthetic
in 98% yteld using ethanolic
of the amide using sodium
in 72% yield along with 12% of the corresponding was followed
the original
acid with acetyl chloride,
of the 13 to 14 was accomplished
Regioselective
ether synthesis
11 (17%) 11 (30%)
9 RI =OMe Ra=H (66%) 10 RI = H Ra= OMe (65%)
it was found that a Eschenmoser by a competitive
substttuent
to an alkoxy
oxygenated
substrates.t5
group.
p-elimination This tactic
sufide contraction reaction
should
I4
expand
on a thiolactam
Thus problem the scope
substrate
was overcome,
of the sulfide
carrying
however,
contraction
a P-acyloxy by changing
process
group the p-
to include
p-
7789
Scheme
3 X
0 HO..,,
C02H
a, b, a *
N-Me
r MeOaC
BnO,, ‘,
I
_
r,
mlt *,
CHaCOaMe i
BnO,,
N-Me
j
: N-Me c
x
0
h < 18 R = TBS (78%) i (19 R = H (98%) 20 R = Bn (90%)
n
N-Me c
c CH$ZOaMe
CHaC02Me
24 (14%)
CH2C02Me
25 (77%)
3 (80%)
AcCl (b) MeNH2, CHaCia (c) HCI, EtOH (d) TBSCI, rmidazole. DMF (e) NaBH4, MeOH NaH. Mel, THF (g) TMSCHaCH=CHa, TiCId, CHaCl2, -78’C --f rt (h) rrBu4NF, THF (i) NaH, BnBr, THF 03, MeOH-H20-NaOH, CHaCIa (k) (MeOCeH4PS2)a, CH2C12 (I) TfOCHaC02Me; PhaP, EtaN, CHeCla NaBHaCN, MeOH. pH4 (n) Ha, Pd(OH)e
References
Kozikowski, Med.
RO., *,
CHaCOaMe f
‘,
+
(84%) (96%)
CHaCH=CHa
k < 21 X = 0 (81%) 22 x = s (90%)
23 (51%)
0
f < 16 X = OH 17 X=OMe
N-Me
\
c
CH2C02Me T
CHaC02Me
(a) (f) (j) (m)
-
c
i
‘I
,, N-Me
0 c (13 R = AC (94%) d (14 R=H (98%) 15 R = TBS (95%)
12
BnO,,
e
N-Me
C02H
BnO,,
TBSO.,
RO., *,
A. P
Chem.
Roberti,
1992,
Ball, R G. J. Med. 2.
Roth, M.. Dubs,
3
The synthesis reaction
Chem.
LetI
1981,
Bergmann,
J S.; Callahan,
D ; Stoelwmder,
E ; Eschenmoser,
thiolactam
below
P Anna/en
L
Slmoni,
Notes
P. M ; Cunningham,
M : Kozikowski,
A. P.; Johnson,
K. A.; Johnson,
K. M. J.
K M.; Bergmann,
J. S.;
1993, 36, 3975.
P.; Goschi, of startrng
as described
Tetrahedron Russkamp,
M., Xiang,
35, 4764.
and
For other 22. 719
1983,
529
A He/v.
1 was accomplished intramolecular
Flitsch,
W
C/urn. Acta 1971,
54, 710.
from imide 14 (v/de sup@ Wittig
Russkamp.
reactrons
of imides
P ; Anna/en
1983,
using an intramolecular
see Flitsch, 521.
Wittig
W.; Wernsmann,
Flitsch,
W.; Pandl,
P.; K.;
7790
0 RO.
**,
d
N-Me
N-Me
95%
c
a( bc
R=H R = C02C02Br R = C02CH21
(a) BrCHsCOCI. pyridine, CHsCla (e) (pMeOC+U’Sa)a, CHaCl2
4.
Petersen,
5.
Gompper,
x=0 x=s
e<
(86%) (100%)
J. S.: Fels, G
(b) Nat acetone
Rapoport,
H. J. Am
R.; Elser, W J. L Ann.
(c) PhsP, CHsCN;
Chem
1969,
Chem.
1984,
Sot.
725. 64
then EtsN (d) Ha, RhlAlaOs,
EtOAc
706. 4539.
Hart, D J.; Hong,
W.-P.;
Hsu, L.-Y. J. Org. Chem.
1987,
52, 4665. 6.
Thiolactams
7 and 8 were prepared
will be described 7
8.
search
P-oxygenated
2thiopyrrolidinone.
9.
Kuzmich, 1994,
10.
116,
1982. 55, 1406.
W.-J , van Grnkel,
Marshall, Scheibye, Borch,
Acetylation
A.: Micheli,
22 in Scheme
3. Details
of an Eschenmoser
1975, 34, 179.
J. Chem.
S.; Alarashi,
Sot.,
sulfide
Chamberlin,
Chem.
contraction
of a
A. R.; Chung,
J. Y.
1983,
Commun.
135.
S.; Choi, J.-K.; Hart, D. J. J. Am. Chem.
Sot.
a thiolactam
We thank
Interneuron
Instrumentation
USA 26
support
June
G A.; Neuenschwander, see Thaning,
D , Scolastico.
M ; Hiemstra,
Sedrani,
B. S
Lawesson,
R C Synlert S.-O.
Chem.
of 19 followed
gave
contraction
C.; Villa, R. Tetrahedron
H.; Louwrier,
only
Chum.
L.-G. Left.
S.; Moolenaar,
Sot.
Sot.,
Chem.
J. Org.
Chem.
1990,
M. J.; Speckamp,
31, 4949.
W. N.
Thus,
Pharmaceuticals from the Campus
revised
22
Chemical
pyrrole
gift that
accepted
with Lawesson’s
yield
upon
that the elimination thiolactam
supported Center
23
lactam
in 95%
in bicyclic
Instrumentation
August 1995:
87, 229.
of the derived
we are confident
for a generous
1978,
1971, 93, 2897.
by treatment
the corresponding
conditions.
Be/g.
and not ring strain that might be present
1995;
K. J. Chem.
M.; Wistrand,
1992, 643.
Bull. Sot.
Durst. H. D J Am group
which
of the P-substltuent
Kraus,
of relevance
F ; Potenza,
A. W
M D
of the hydroxyl
sulfide
studies
401.
32,
Pederson,
aforementioned
in
Ramesh,
1981, 22, 1567.
Letf.
R ; Kranenburg,
1991,
R. F.; Bernstein,
provided
nature
Bernardi,
Lelt.
S
14
an example
W N Tetrahedron
Ha, D -C ; Lee, C -S
J. A.; Garofaio,
13.
to uncover
Han, D J ; Yang, T.-K
3653.
For stereochemical
Koot,
12.
105.
Tetrahedron
134
1990,
11.
for thiolactam
6943.
Hart, D. J., Tsar, Y-M
Tetrahedron
(Received
J B P A : Speckamp,
1983,
Sot.
D ; Wu, S C
Commun.
15.
using CAS REACT failed
J. C.. Wijnberg,
J. Am. Chem.
similar to that described
elsewhere
A substructure
Hubert,
by a procedure
this
exposure
problem
to the
is due to the
1. research
and acknowledge
at The Ohio State University.
August 1995)
reagent