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New synthetic methods: a general and efficient approach to ring-fused cycloheptadienes
TetrahedronImttersHo. 40, pp 3975 - 3978, 1973.
Psrgamon Prere.
Printed in mat
Britain.
A GENERAL AND EFFICIENT
NEW SYNTHETIC METHODS:
APPROACH TO RING-FUSED
CYCLOHEPTADIENESl
J. P. Marina* and Takushi Kaneko Department
of Chemistry, University
48104
Ann Arbor, Michigan (Received in USA 13 -at The widespread cycloheptane
1973; reoeived in UK for publioation
occurrence
of functionalized
ring systems in numerous
cycloheptane
and ring-fused
2
has made them
Despite recent advances
cycloheptadienes
ous labile functionalities.
which would also allow for incorporation
sesquiterpene
is reinforced by the isolation
lactones which show significant
cycloheptadienes.
of an eneone sulfoxonium
and a Wittig reagent to ultimately
I
of numer-
of many highly
antitumor
In this paper we wish to present a general and unique approach structing ring-fused
Our approach combines
methylide
(I), an
activity.
the three carbon
a, B-unsaturated
aldehyde
form the skeleton of the cycloheptadiene
0
II
4
for con-
R4
R3
ring
5
OR1 \
R4R5C=Pp13 .
to
The compelling need for new and efficient method-
ology in this area of synthesis
backbone
in
syntheses, 3 there are almost no general and direct approaches
hydroasulene
oxygenated
28 August 1973)
classes of natural products
the synthetic targets of many investigators.
ring-fused
of Michigan
II
cc-
\
R2 R3
3975
3976
No. 40
In the accompanying
communication,
ion of a cyclohexenone
sulfoxonium
vinyl cyclopropanes. 5
To illustrate
we described a new and efficient react-
methylide
to produce highly functionalized
the practicality
above scheme, we have utilized the cyclopropane previously
and efficiency
of the
adduct from acrolein
(III),
When a 4:l trans:cis mixture of this cyclopropane
described.5
hyde was treated with one equivalent
of either triphenylphosphonium
(IVa) or carbethoxy-triphenylphosphonium a selective Wittig reaction
methylide
(Va and b).6
methylide
(IVb) at room temperature,
occurred at the aldehyde
ducts from both reactions were the corresponding
alde-
carbonyl.
trans-divinyl
The major procyclopropanes
The minor product in each case was the isomeric rearranged[5.4.0]-
bicycloundecadienering
system
(Via and b).
THF >
RCH=P03 IVa, R=H b, R=C02Et The structure
of Via was confirmed by partial hydrogenation The well-documented
[5.4.0]-bicycloundeceneone.7 divinyl cyclopropanes8
once again revealed
ducts derived from thie cis-aldehyde rearrangement
at room temperature,
form the conjugated
enenone
to the known
thermal instability
itself in the cis-divinyl
of III.
of cisWittig pro-
In addition to the inital Cope
a subsequent
1,3 hydrogen
shift occurred to
(VI).
To complete the final phase of our synthetic scheme all that remained was to convert the trans-divinyl adienes VI.
This
cyclopropanes
(V) to the same rearranged
was expected to be quite straight
work of Baldwin' and Pettus"
cyclopropanes
when cyclopropanes
IIIa and IIIb were subjected
at temperatures
converted
time study of the rearrangement t1/2 of eight hours at 140°C. can be quantitatively
forward in view of the recent
who observed facile thermal rearrangements
ious trans-divinyl
they were quantitatively
cyclohept-
converted
In fact,
well below 200°C. to vpc analysis,
at 18O'C (111,
to isomers Via and b respectively.
of the trans-divinyl
cyclopropanes
products.
An NMR
showed a
Thus, both cis and trans-cyclopropane to the same rearranged
of var-
isomers
The overall
.
Bo. 40
3977
isolated yields for the synthesis (j-oxo-1-cyclohexenyl)
of compounds Via and VIb from the starting
dimethyl-sulfoxonium
methylide
were in excess of 60% for
Via and 70% for VIb, making the overall scheme quite efficient. In order to introduce diene ring, phenylthio with the cyclopropane
a potential
oxygen functionality
triphenylphosphonium aldehyde
III.
methylide
IVc (R=SPh) was reacted
The expected trans-divinylcyclopropane
in 65% yield, along with a small amount *
was isolated
vc
after the Cope rearrangement,
facile elimination aluminum hydride in quantitative VIIIb
of the benzenethiol,
All attempts
and VIIIb have resulted
it was selectively
assists the
reduced with lithium
The allylic alcohol VIIIa
(R=H) was produced
so far to thermally rearrange
in partial or total elimination
While it was not possible
arrangement
undoubtedly
yield and was easily converted to its t-butyldimethylsilyl
(R=t-BuSiMe2).
our synthetic
was again eliminated
was produced.
of the ketone functionality
in ether at -78’.
was eliminated
When the divinylcyclo-
even at room temperature.
propane Vc was heated at 120° for six hours, benzenethiol
Since the presence
to retain the phenylthio
scheme, the reduction
VII.
VIII
leaving group of benzenethiol
of isomeric ketotrienes
Vc
(15%) of the ketotriene
VII
Thus, it appears that the excellent
and a mixture
in the cyclohepa-
ether
compounds VIIIa
of the phenylthio
moiety
moiety in the final step of
of the enone carbonyl prior to thermal re-
should prove to be a valuable
step towards preventing
the migration
of the double bond in the original cycloheptadiene. In summary, our synthetic wide spectrum of substitution cyclic enenone utilization
containing
approach to ring-fused patterns
in the cycloheptadiene
the initial sulfoxonium
of both cis and trans cyclopropane
the methodology
outlined above quite efficient
applying the above approach to the synthesis and tricyclic
cycloheptadienes.
cycloheptadienes
methylide.
offers a
ring and in the In addition,
the
isomers for the same end makes and convenient.
of functionalized
We are currently hydroazulenes
3978
No. 40
Acknowledgements: We are pleased to acknowledge partial support of this work in a Dow-Britton Fellowship to Takushi Kaneko and Rackham Faculty research grant to J. P. Marino. References 1.
Present in part at the 165th National Meeting of the American Chemical Society, Dallas, Texas, April, 1973, Orgn. #35.
2.
a) F. Sorm and L. Doljs, "Guainanolides and Germacranoaides", Hermann Press, Paris, 1965, b) J. S. Roberts, Chap. 2, Vol. 2, Terpenodis and Steroids, Specialist Periodical Reports, The Chemical Society of London, 1972. c) J. S. Roberts, Vol. 1, ibid., 1971. -d) T. K. Devon and A. I. Scott, "Handbook of Naturally Occurring Compounds," Vol. II, Terpenes, Academic Press, New York, 1972.
3.
a) J. A. Mar&hall and J. J. Partridge, Tetrahedron, 3,
2159 (1969).
b) C. Heathcock and R. Ratcliffe, J. Org. Chem., 31, 1796, (1972). c) J. B. Henderickson and R. K. Boeckman Jr., J. Amer. Chem. Sot., 93, 1307 (1971). d) P. T. Landsbury, P. M. Woukulich and P. E. Gallagher, Tetrahedron Letters, 65 (1973). e) Niels H. Anderson and Hong-sun Uh, w.,
2079 (1973).
4.
a) see ref. la.
5.
J. P. Marino and Takushi Kaneko, Tetrahedron Letters, 0000 (1973).
6.
All new compounds gave satisfactory elemental analysis and NMR, U.V. and IR spectra compatible with the assigned structures.
7.
D. Kimchi and S. Bien, J. Chem. Sot., 5345 (1961).
0.
E. Vogel, K-H Ott and K. Gajek, &,
9.
E. Vogel and D. Erb, Angew. Chem. Int. Ed., 1, 53 (1962). C. Ullenius,
6114,172 (1961).
P. W. Ford and J. E. Baldwin, J. Amer. Chem. Sot., 94, 5910 (1972). 93, 3087 (1971).
10.
J. A. Pettus and R. E. Moore, s.,
11.
vPc-column-5'xl/4", 10% FFAP on 60/80 Chrom W.
Psrgamon Prere.
Printed in mat
Britain.
A GENERAL AND EFFICIENT
NEW SYNTHETIC METHODS:
APPROACH TO RING-FUSED
CYCLOHEPTADIENESl
J. P. Marina* and Takushi Kaneko Department
of Chemistry, University
48104
Ann Arbor, Michigan (Received in USA 13 -at The widespread cycloheptane
1973; reoeived in UK for publioation
occurrence
of functionalized
ring systems in numerous
cycloheptane
and ring-fused
2
has made them
Despite recent advances
cycloheptadienes
ous labile functionalities.
which would also allow for incorporation
sesquiterpene
is reinforced by the isolation
lactones which show significant
cycloheptadienes.
of an eneone sulfoxonium
and a Wittig reagent to ultimately
I
of numer-
of many highly
antitumor
In this paper we wish to present a general and unique approach structing ring-fused
Our approach combines
methylide
(I), an
activity.
the three carbon
a, B-unsaturated
aldehyde
form the skeleton of the cycloheptadiene
0
II
4
for con-
R4
R3
ring
5
OR1 \
R4R5C=Pp13 .
to
The compelling need for new and efficient method-
ology in this area of synthesis
backbone
in
syntheses, 3 there are almost no general and direct approaches
hydroasulene
oxygenated
28 August 1973)
classes of natural products
the synthetic targets of many investigators.
ring-fused
of Michigan
II
cc-
\
R2 R3
3975
3976
No. 40
In the accompanying
communication,
ion of a cyclohexenone
sulfoxonium
vinyl cyclopropanes. 5
To illustrate
we described a new and efficient react-
methylide
to produce highly functionalized
the practicality
above scheme, we have utilized the cyclopropane previously
and efficiency
of the
adduct from acrolein
(III),
When a 4:l trans:cis mixture of this cyclopropane
described.5
hyde was treated with one equivalent
of either triphenylphosphonium
(IVa) or carbethoxy-triphenylphosphonium a selective Wittig reaction
methylide
(Va and b).6
methylide
(IVb) at room temperature,
occurred at the aldehyde
ducts from both reactions were the corresponding
alde-
carbonyl.
trans-divinyl
The major procyclopropanes
The minor product in each case was the isomeric rearranged[5.4.0]-
bicycloundecadienering
system
(Via and b).
THF >
RCH=P03 IVa, R=H b, R=C02Et The structure
of Via was confirmed by partial hydrogenation The well-documented
[5.4.0]-bicycloundeceneone.7 divinyl cyclopropanes8
once again revealed
ducts derived from thie cis-aldehyde rearrangement
at room temperature,
form the conjugated
enenone
to the known
thermal instability
itself in the cis-divinyl
of III.
of cisWittig pro-
In addition to the inital Cope
a subsequent
1,3 hydrogen
shift occurred to
(VI).
To complete the final phase of our synthetic scheme all that remained was to convert the trans-divinyl adienes VI.
This
cyclopropanes
(V) to the same rearranged
was expected to be quite straight
work of Baldwin' and Pettus"
cyclopropanes
when cyclopropanes
IIIa and IIIb were subjected
at temperatures
converted
time study of the rearrangement t1/2 of eight hours at 140°C. can be quantitatively
forward in view of the recent
who observed facile thermal rearrangements
ious trans-divinyl
they were quantitatively
cyclohept-
converted
In fact,
well below 200°C. to vpc analysis,
at 18O'C (111,
to isomers Via and b respectively.
of the trans-divinyl
cyclopropanes
products.
An NMR
showed a
Thus, both cis and trans-cyclopropane to the same rearranged
of var-
isomers
The overall
.
Bo. 40
3977
isolated yields for the synthesis (j-oxo-1-cyclohexenyl)
of compounds Via and VIb from the starting
dimethyl-sulfoxonium
methylide
were in excess of 60% for
Via and 70% for VIb, making the overall scheme quite efficient. In order to introduce diene ring, phenylthio with the cyclopropane
a potential
oxygen functionality
triphenylphosphonium aldehyde
III.
methylide
IVc (R=SPh) was reacted
The expected trans-divinylcyclopropane
in 65% yield, along with a small amount *
was isolated
vc
after the Cope rearrangement,
facile elimination aluminum hydride in quantitative VIIIb
of the benzenethiol,
All attempts
and VIIIb have resulted
it was selectively
assists the
reduced with lithium
The allylic alcohol VIIIa
(R=H) was produced
so far to thermally rearrange
in partial or total elimination
While it was not possible
arrangement
undoubtedly
yield and was easily converted to its t-butyldimethylsilyl
(R=t-BuSiMe2).
our synthetic
was again eliminated
was produced.
of the ketone functionality
in ether at -78’.
was eliminated
When the divinylcyclo-
even at room temperature.
propane Vc was heated at 120° for six hours, benzenethiol
Since the presence
to retain the phenylthio
scheme, the reduction
VII.
VIII
leaving group of benzenethiol
of isomeric ketotrienes
Vc
(15%) of the ketotriene
VII
Thus, it appears that the excellent
and a mixture
in the cyclohepa-
ether
compounds VIIIa
of the phenylthio
moiety
moiety in the final step of
of the enone carbonyl prior to thermal re-
should prove to be a valuable
step towards preventing
the migration
of the double bond in the original cycloheptadiene. In summary, our synthetic wide spectrum of substitution cyclic enenone utilization
containing
approach to ring-fused patterns
in the cycloheptadiene
the initial sulfoxonium
of both cis and trans cyclopropane
the methodology
outlined above quite efficient
applying the above approach to the synthesis and tricyclic
cycloheptadienes.
cycloheptadienes
methylide.
offers a
ring and in the In addition,
the
isomers for the same end makes and convenient.
of functionalized
We are currently hydroazulenes
3978
No. 40
Acknowledgements: We are pleased to acknowledge partial support of this work in a Dow-Britton Fellowship to Takushi Kaneko and Rackham Faculty research grant to J. P. Marino. References 1.
Present in part at the 165th National Meeting of the American Chemical Society, Dallas, Texas, April, 1973, Orgn. #35.
2.
a) F. Sorm and L. Doljs, "Guainanolides and Germacranoaides", Hermann Press, Paris, 1965, b) J. S. Roberts, Chap. 2, Vol. 2, Terpenodis and Steroids, Specialist Periodical Reports, The Chemical Society of London, 1972. c) J. S. Roberts, Vol. 1, ibid., 1971. -d) T. K. Devon and A. I. Scott, "Handbook of Naturally Occurring Compounds," Vol. II, Terpenes, Academic Press, New York, 1972.
3.
a) J. A. Mar&hall and J. J. Partridge, Tetrahedron, 3,
2159 (1969).
b) C. Heathcock and R. Ratcliffe, J. Org. Chem., 31, 1796, (1972). c) J. B. Henderickson and R. K. Boeckman Jr., J. Amer. Chem. Sot., 93, 1307 (1971). d) P. T. Landsbury, P. M. Woukulich and P. E. Gallagher, Tetrahedron Letters, 65 (1973). e) Niels H. Anderson and Hong-sun Uh, w.,
2079 (1973).
4.
a) see ref. la.
5.
J. P. Marino and Takushi Kaneko, Tetrahedron Letters, 0000 (1973).
6.
All new compounds gave satisfactory elemental analysis and NMR, U.V. and IR spectra compatible with the assigned structures.
7.
D. Kimchi and S. Bien, J. Chem. Sot., 5345 (1961).
0.
E. Vogel, K-H Ott and K. Gajek, &,
9.
E. Vogel and D. Erb, Angew. Chem. Int. Ed., 1, 53 (1962). C. Ullenius,
6114,172 (1961).
P. W. Ford and J. E. Baldwin, J. Amer. Chem. Sot., 94, 5910 (1972). 93, 3087 (1971).
10.
J. A. Pettus and R. E. Moore, s.,
11.
vPc-column-5'xl/4", 10% FFAP on 60/80 Chrom W.