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Regiospecific michael additions to α-methylene cyclopentenones
Tetrahedron Letters,Vol.25,No.3,pp Printed in Great Britain
REGIOSPECIFIC
TIWA Department
MICHAEL
ADDITIONS
SIWAPINYOYOS
of Chemistry,
Nucleophiles
Faculty
cisoid-enone
unsymmetrical formation
1
has demonstrated
enedione
of enolate
to the less strained uniformly
derived
difference
addition
fashion
to a-methylene
at the exocyclic
that the direction by strain
It is extremely
of Michael
in the developing
2 is attack
interesting
in the addition
at the bridgehead
to the endocyclic
at 2 yielding
University,
bond.
1 is governed
from 2.
attack
Mahidol
Thailand.
additions enolate,
to the
-2 with an SP2 bridgehead carbon being inhibited compared Thus products from such reactions are enolate 2.
in regiochemistry
Nucleophilic
10400,
regiospecifically
double
CYCLOPENTENONES
THEBTARANONTH*
of Science,
Bangkok
add in a Michael
cyclopentenones
Danishefsky
TO a-METHYLENE
AND YODHATHAI
Rama 6 Road,
Abstract:
0040-4039/84 $3.00 + .OO 01984 Pergamon Press Ltd.
353-356,1984
carbon
transoid-enone
as depicted
the in 4.
5 to give 2 is, in fact,
double
at the exocyclic
to consider
reaction
bond,
cisoid-enone
while
an
the same process
double
bond.
endocyclic:transoid-enone
exocyclic:cisoid-enone
Michael examples occurring
additions
being
to both
the in V&O
types
Michael
additions
o-methylene-r-butyrolactones
(endocyclic:transoid),3
which
of enones
explain
are well documented,
of L-cysteine
(exocyclic:cisoid)2 the biological
353
specific
to naturally and cyclopentenones
activities
of these
354
compounds. direct
However,
competition
to assess
this,
enones
system
give
should
rise
Michael
two Michael Michael
intermediates
the convenient
3-carbon
model
with
steric
reasons.
Inspection
indicated
almost
no strain
in either
on the In order
endocyclic
enedione
comparable
strain.
method
for the this
of the regiospecificity for its stability5
of molecular
1, the
of such a study.
annelation
5 was selected
following
both
(eg. zJ4 we have perceived
for the study
Hence compound
bearing
the bicyclic
the results
cyclopentenones
a report
is not precedented.
molecule
and unlike
like to present
to be a suitable
additions.
investigation,
pathways
acceptor
to enolate
we would
of a-methylene
of dienone
Danishefsky's
must be employed,
Since developing synthesis
from
of these
a suitable
and exocyclic
In this Letter
apart
models
of the transition
of
and the
of molecule
states
type
6 to the
leading
attack at the two trigonal -7 or 8, which are expected from nucleophilic Nevertheless, nucleophilic addition to the (see arrows in 2).
enolate centres
endocyclic
double
electronically
bond of the acceptor
more
of the reactions
stable
were
enolate
molecule
2, yet,
not controlled
5 should
as will
lead
to an
be seen later,
by this predicted
effect
the products
at all.
0
a-Methylene
cyclopentenone 6 described method.
previously smoothly
in THF solution
of two molar
equivalents
the NMR spectra easily
The Michael
in very good
addition
yield
reactions
bond
protonation
Michael
exocyclic
adducts
vinyl
showed
proton,
H) were
As the TABLE
of the cisoid-enone. we were
able to trap
complete
originally
indicates,
the intermediate
This is demonstrated
electrophiles.
proceeded
a solution of 5 was added to a solution 7 It was very interesting to find that of nucleophile.
in entries
enolate
absence
of the
a quartet
at 6 6.76 8 identified as 2,
Purification of these crude materials gave products in -6 which proves that the Michael addition specifically occurred double
by our
at -78O when
of the crude
distinguishable
2 was prepared
at the exocyclic
apart
from
S with
i and -ii where
other
products
2
(E f
obtained.
We also looked additions
cleanly
preferentially
at the simpler
produced
only 3,
at the exocyclic
(but not as good) showing
site.
model
molecule
that nucleophiles
-10.
reacted
Again,
355
Nucleophile
Ph
A,R=Me
&R=Me
~,R=H
ll_,~=H
(-COOMe
-
iii.
~,R=H
% of 9"
% of 12Q
H30+
91
90
a5
76
c. H2C=CH-CH2-Br
82
74
d. Ph-CH2-Br
64
73
a. H30+
90
71
85
b
- (-COOMe
c.
H2C=CH-CH2-Br
81
b
OMe
d.
Ph-CH2-Br
58
6
a.
H30+
- (-COOMe Ph
-e
iv.
z,R=Me
b. CH31
OMe
ii.
Nu
b. CH31
a. 1.
R
or alkyl halide
Electrophile
Nucleophile
H
Ph
Ph
a4
73
b. CH31
6
68
c. H2C=CH-CH2-Br
b
77
a. Ph-CH2-Br
b
78
H30+
86
72
H30+
82'
94c
H30+
95c
97c
Ph
COOMe
COOMe V.
-(
-S-Ph
vi.
a
COOMe
The yields
hexane).
shown are isolated
predominated 12-iii-c, assign
yields
where several diastereomers (indicated by NMR).
after purification were possible
Separation
by Prep. TLC (Silica gel, 7:3 CH2C12:
it was found that one isomer always
of isomers were performed
and 12-iii-d,
each of which afforded 6. their stereochemistry. This reaction
conducted
either
the yield
shown being from the latter reaction
in cases 12-iii-b,
two stereomers,
but no attempt was made to C has not been performed. The reaction can be
in THF (LDA as base) at -78O or in MeOH condition.
(NaOt?e as base) at room temperature,
356
The regiospecificity was subjected competition
of the reaction
to the same reaction
of the exocyclic
double
was confirmed
conditions bond,
found
to add to the enone 13 to give, almost quantitatively.
when cyclopentenone
as described
above.
13' the
Without
nucleophiles
(i ii 1, and vi) were -1 _I protonation, the pentanone -14
after
0 Ph --& \ !?
while
In conclusion, 1_ is governed
by steric
with monocyclic bond despite formed
factors
addition
in the resulting
in the bicyclic
enolates,
enedione
the same reaction
dienones
5 and 10 occur specifically at the exocyclic double that an electronically more favourable enolate could be
the fact
from endocyclic
specificity
the site of Michael
attack.
is viable
Acknowledgement:
These
results
in the biological
We thank support
the National
suggest
that the same
type of
system.
Research
Council
of Thailand
for
of this work.
References
1.
S.Danishefsky,
2.
S.M.Kupchan,
M.Kahn,
3.
I.H.Hall,
4.
T.Siwapinyoyos,
5.
Aryl substituted
6.
Compound
Tetrahedron
D.C.Fessler,
K.H.Lee,
Lett.,
M.A.Eakin,
E.C.Mar,
C.O.Starnes,
Y.Thebtaranonth, a-methylene
1981, 2,
485.
T.J.Giacobbe,
Science,
J.Med.Chem.,
J.Org.Chem.,
1977,
1982, 47,
cyclopentenones
are quite
1970, 168, g,
376.
333.
598. stable
while
others
are not.
described 7.
Lower
6 and its geometrical isomer were prepared in ref. 4 with nearly quantitative yields
yields
employed.
the emerging
8.
of -9 were observed when equimolar is probably due to competition
This
enolate
concentration
8 for the acceptor was required.
All compounds
described
in this
Letter
-6.
in each
to the method step.
amounts
of reactants
between
the nucleophile
Hence
display
according
were and
a high nucleophile
quite
satisfactory
physical
data. 9.
P.Prempree, s.,
(Received
T.Siwapinyoyos,
1980, 21,
1169.
in UK 7 November
1983)
C.Thebtaranonth,
Y.Thebtaranonth,
Tetrahedron
REGIOSPECIFIC
TIWA Department
MICHAEL
ADDITIONS
SIWAPINYOYOS
of Chemistry,
Nucleophiles
Faculty
cisoid-enone
unsymmetrical formation
1
has demonstrated
enedione
of enolate
to the less strained uniformly
derived
difference
addition
fashion
to a-methylene
at the exocyclic
that the direction by strain
It is extremely
of Michael
in the developing
2 is attack
interesting
in the addition
at the bridgehead
to the endocyclic
at 2 yielding
University,
bond.
1 is governed
from 2.
attack
Mahidol
Thailand.
additions enolate,
to the
-2 with an SP2 bridgehead carbon being inhibited compared Thus products from such reactions are enolate 2.
in regiochemistry
Nucleophilic
10400,
regiospecifically
double
CYCLOPENTENONES
THEBTARANONTH*
of Science,
Bangkok
add in a Michael
cyclopentenones
Danishefsky
TO a-METHYLENE
AND YODHATHAI
Rama 6 Road,
Abstract:
0040-4039/84 $3.00 + .OO 01984 Pergamon Press Ltd.
353-356,1984
carbon
transoid-enone
as depicted
the in 4.
5 to give 2 is, in fact,
double
at the exocyclic
to consider
reaction
bond,
cisoid-enone
while
an
the same process
double
bond.
endocyclic:transoid-enone
exocyclic:cisoid-enone
Michael examples occurring
additions
being
to both
the in V&O
types
Michael
additions
o-methylene-r-butyrolactones
(endocyclic:transoid),3
which
of enones
explain
are well documented,
of L-cysteine
(exocyclic:cisoid)2 the biological
353
specific
to naturally and cyclopentenones
activities
of these
354
compounds. direct
However,
competition
to assess
this,
enones
system
give
should
rise
Michael
two Michael Michael
intermediates
the convenient
3-carbon
model
with
steric
reasons.
Inspection
indicated
almost
no strain
in either
on the In order
endocyclic
enedione
comparable
strain.
method
for the this
of the regiospecificity for its stability5
of molecular
1, the
of such a study.
annelation
5 was selected
following
both
(eg. zJ4 we have perceived
for the study
Hence compound
bearing
the bicyclic
the results
cyclopentenones
a report
is not precedented.
molecule
and unlike
like to present
to be a suitable
additions.
investigation,
pathways
acceptor
to enolate
we would
of a-methylene
of dienone
Danishefsky's
must be employed,
Since developing synthesis
from
of these
a suitable
and exocyclic
In this Letter
apart
models
of the transition
of
and the
of molecule
states
type
6 to the
leading
attack at the two trigonal -7 or 8, which are expected from nucleophilic Nevertheless, nucleophilic addition to the (see arrows in 2).
enolate centres
endocyclic
double
electronically
bond of the acceptor
more
of the reactions
stable
were
enolate
molecule
2, yet,
not controlled
5 should
as will
lead
to an
be seen later,
by this predicted
effect
the products
at all.
0
a-Methylene
cyclopentenone 6 described method.
previously smoothly
in THF solution
of two molar
equivalents
the NMR spectra easily
The Michael
in very good
addition
yield
reactions
bond
protonation
Michael
exocyclic
adducts
vinyl
showed
proton,
H) were
As the TABLE
of the cisoid-enone. we were
able to trap
complete
originally
indicates,
the intermediate
This is demonstrated
electrophiles.
proceeded
a solution of 5 was added to a solution 7 It was very interesting to find that of nucleophile.
in entries
enolate
absence
of the
a quartet
at 6 6.76 8 identified as 2,
Purification of these crude materials gave products in -6 which proves that the Michael addition specifically occurred double
by our
at -78O when
of the crude
distinguishable
2 was prepared
at the exocyclic
apart
from
S with
i and -ii where
other
products
2
(E f
obtained.
We also looked additions
cleanly
preferentially
at the simpler
produced
only 3,
at the exocyclic
(but not as good) showing
site.
model
molecule
that nucleophiles
-10.
reacted
Again,
355
Nucleophile
Ph
A,R=Me
&R=Me
~,R=H
ll_,~=H
(-COOMe
-
iii.
~,R=H
% of 9"
% of 12Q
H30+
91
90
a5
76
c. H2C=CH-CH2-Br
82
74
d. Ph-CH2-Br
64
73
a. H30+
90
71
85
b
- (-COOMe
c.
H2C=CH-CH2-Br
81
b
OMe
d.
Ph-CH2-Br
58
6
a.
H30+
- (-COOMe Ph
-e
iv.
z,R=Me
b. CH31
OMe
ii.
Nu
b. CH31
a. 1.
R
or alkyl halide
Electrophile
Nucleophile
H
Ph
Ph
a4
73
b. CH31
6
68
c. H2C=CH-CH2-Br
b
77
a. Ph-CH2-Br
b
78
H30+
86
72
H30+
82'
94c
H30+
95c
97c
Ph
COOMe
COOMe V.
-(
-S-Ph
vi.
a
COOMe
The yields
hexane).
shown are isolated
predominated 12-iii-c, assign
yields
where several diastereomers (indicated by NMR).
after purification were possible
Separation
by Prep. TLC (Silica gel, 7:3 CH2C12:
it was found that one isomer always
of isomers were performed
and 12-iii-d,
each of which afforded 6. their stereochemistry. This reaction
conducted
either
the yield
shown being from the latter reaction
in cases 12-iii-b,
two stereomers,
but no attempt was made to C has not been performed. The reaction can be
in THF (LDA as base) at -78O or in MeOH condition.
(NaOt?e as base) at room temperature,
356
The regiospecificity was subjected competition
of the reaction
to the same reaction
of the exocyclic
double
was confirmed
conditions bond,
found
to add to the enone 13 to give, almost quantitatively.
when cyclopentenone
as described
above.
13' the
Without
nucleophiles
(i ii 1, and vi) were -1 _I protonation, the pentanone -14
after
0 Ph --& \ !?
while
In conclusion, 1_ is governed
by steric
with monocyclic bond despite formed
factors
addition
in the resulting
in the bicyclic
enolates,
enedione
the same reaction
dienones
5 and 10 occur specifically at the exocyclic double that an electronically more favourable enolate could be
the fact
from endocyclic
specificity
the site of Michael
attack.
is viable
Acknowledgement:
These
results
in the biological
We thank support
the National
suggest
that the same
type of
system.
Research
Council
of Thailand
for
of this work.
References
1.
S.Danishefsky,
2.
S.M.Kupchan,
M.Kahn,
3.
I.H.Hall,
4.
T.Siwapinyoyos,
5.
Aryl substituted
6.
Compound
Tetrahedron
D.C.Fessler,
K.H.Lee,
Lett.,
M.A.Eakin,
E.C.Mar,
C.O.Starnes,
Y.Thebtaranonth, a-methylene
1981, 2,
485.
T.J.Giacobbe,
Science,
J.Med.Chem.,
J.Org.Chem.,
1977,
1982, 47,
cyclopentenones
are quite
1970, 168, g,
376.
333.
598. stable
while
others
are not.
described 7.
Lower
6 and its geometrical isomer were prepared in ref. 4 with nearly quantitative yields
yields
employed.
the emerging
8.
of -9 were observed when equimolar is probably due to competition
This
enolate
concentration
8 for the acceptor was required.
All compounds
described
in this
Letter
-6.
in each
to the method step.
amounts
of reactants
between
the nucleophile
Hence
display
according
were and
a high nucleophile
quite
satisfactory
physical
data. 9.
P.Prempree, s.,
(Received
T.Siwapinyoyos,
1980, 21,
1169.
in UK 7 November
1983)
C.Thebtaranonth,
Y.Thebtaranonth,
Tetrahedron