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Total synthesis of cyclosativene
TetrahedronLetters No.1, pp. 55-58, 1969,
PergamonPress, Printed in Great Britain,
TOTAL SYNTHESIS
OF CYCLOSATIVENE
John E. MC Murr'y Division
of Natural
Sciences, University
Santa Cruz, California (Received
Longifolene, both because
in USA 17
l_, occupies
tricyclic
reactions
(2).
starting material
For example
3,
might
exhibits
(1) of
is
of interesting
is heated with
longicyclene,
2,
(4)
along with much recovered
2
sesquiterpene
in 1965
also reasonably reported
sativene
available,
hydrocarbon,
(5) and, because be expected
of its structural
the first total synthesis (7), were
interested
(8) as well as its isomerization
interesting of sativene
similarity
(6) and, with
55
We have synthetic
it might undergo.
of the tetracyclic
red fir (Abies magnifica,
into sativene.
to longifolene,
chemistry.
in the transformations
the isolation
& , from California
3
sativene, 5, was isolated by de Mayo
to display
this work was in progress,
CYclOSativene,
longifolene
(3) when longifolene
(15%), are obtained
chemistry
(51%).
recently
While
November 1968)
of the complexity
allows for a number
1
and Williams
and because
chemistry which
skeleton which
29
place in sesquiterpene
in acetic acid, two isomeric hydrocarbons,
(29%), and isolongifolene,
The tricyclic
95060
in u( for publication
of its structure
Much of this remarkable
due to its compact
cupric acetate
receih
a most interesting
of the uniqueness
its chemistry.
transannular
October 1968;
o.f California
sesquiterpene
Murray) was reported
We are thus prompted
to record
No.1
56
our own similar results, Under conditions 100 mg -dl-sativene glacial acetic
and to comment
analogous
Following
r15% on 60/80 Chromosorb
of the isomerization.
+ longicyclene
interconversion,
for two days with 25 mg Cu(OAc)2.H20 work-up,
Examination
gave 85 mg of material. column
to the longifolene
was refluxed
acid.
on the mechanism
micro-distillation
in 3 ml
of the crude product
of the product mixture
by VPC using
W; 5' x y'; llO"; 60 cc/min]
indicated
an FFAP
that three
. isomeric hydrocarbons
were present
and that the following
equilibrium
had been
established: Peak 1, 32%, was assigned Zavarin,
by spectral
[tricyclene 9.12
nucleus
the structure 2, denoted
data: ir, (CC14) 3055 cm -' (cyclopropane (9)l; nmr (CC14) 7 9.01 (s, 3 H), 9.24
(pair of doublets,
204'(100,
gave an nmr spectrum natural material constitutes
by Smedman and
C-H), 860, 840
(s, 3 H), 9.10 and
6 H, J = 6 Hz), 9.22 (s, 1 H, cyclopropane
(d, 1 H, J = 5 Hz, cyclopropane intensity),
cyclosativene
C-H); mass spectrum
C-H), 9.34
(10) (80 ev), m/e
M+), 189 (27), 161 (91), 133 (36), 94 (88). identical with
and kindly provided
a total synthesis
that produced. by an authentic by Dr. L. Smedman.
of this naturally
Peak 2, 7%, was recovered dl-sativene,
(relative
dl-Cyclosativene sample of the
This reaction
therefore
occurring material.
6, identified
spectroscopically
and gas
chromatographically. Peak 3, 61%, was a third isomeric hydrocarbon
which we denote dl-isosativene
and to which we assign structure -10 on the basis of spectral measurements: ir (CC14), 3065 cm-l, 1655, 875 (terminal methylene); 5.52 (s, 1 H), 7.39 (broad doublet, mass
spectrum
(80 ev), m/e
nmr
(CC14), 7 5.24
1 H), 9.01 (s, 3 H), 9.10
(relative intensity),
(s, 1 H),
(d, 6 H, J = 6 Hz);
204 (22, M+), 189 (9), 161 (25),
133 (13), 94 (100). That a true equilibrium demonstrated acetatemixture
by subjecting
exists between samples
acetic acid treatment
these three isomeric
of pure cyclosativene
and observing
sesquiterpenes
and isosativene
the formation
was
to cupric
of the same equilibrium
of products.
The mechanism "Iongifolene longibornyl
of the isomerization
and longicyclene cation" 2.
is not clear.
get interconverted,
Dev has suggested in all likelihood
(il) that
through the
57
NO.1
Although
this is a possibility,
we see no compelling
3O to 2O carbonium
unfavorable
the path shown below for the analogous tiith classical
carbonium
sativene + cyclosativene
loses a proton
ion analogous
9
of two directions deprotonation,
to generate
it for the forward process there are marked
longifolene
a new tertiary
[cyclosativene
and sativene.
Under
to a 2O
cation 2, or to regenerate
Certainly
+ sativenel
between
innaediately
can then open by protonation
also, in disagreement
differences
of sativene
rather than isomerize
Cyclosativene
9 then gives isosativene.
choice for the reverse
Thus
to cyclosativene,
to 5.
interconversion,
0
the cation 1 formed by protonation
and closes
instead
ions for convenience:
10 -
In this pathway,
We prefer
ion rearrangement.
7
carbonium
to invoke an
+ P+ P P
energetically
illustrated
reason
this mechanism
reaction,
7.
Upon
is the obvious
and we therefore
favor
with Dev's suggestion.
the acid catalyzed
the conditions
in either
described
here,
rearrangements
of
sativene undergoes
No.1
58
no deep seated skeletal change analogous rearrangement. z
A possible
is a presumed
sativene
reason
in the longifolene
unlikely.
strained due to the decreased
It therefore
appears
some interesting
such a path
12
f?
that sativene,
in analogy with
longifolene,
and we are continuing
Acknowledgement:
We wish
to thank the Petroleum
Chemical
and the Division
Santa Cruz, for their support
In the
+
transformations
Society,
ion
intermediates
ring size, making
11
I
carbonium
isomerization.
ion 12, and all succeeding
the analogous
+ P
would be much more
•t isolongifolene
for this is that the bridgehead
(2) intermediate
case however,
to the longifolene
of Natural
of
the study.
Research
Sciences,
is capable
Fund of the American
University
of California,
of this work. References
(1)
For a review of the early chemistry of longifolene, see J. S. Simonsen and D. H. R. Barton, "The Terpenes," Vol. III, Cambridge University Press, Cambridge, England, 1952, pp. 92-98.
(2)
For a review of the molecular rearrangements which longifolene undergoes, see G. Ourisson, Simonsen Lecture, Proc. Chem. Sot., 274 (1964).
(3)
U. R. Nayak and S. Dev, Tetrahedron Letters, 243 (1963). U. R. Nayak and S. Dev, Tetrahedron, 24, 4099 (1968).
(4)
Longicyclene is the first naturally occurring tetracyclic sesquiterpene and occurs as a minor portion of the oil from the oleoresin of Pinus longifolia; see ref. 3.
(5)
P. de Mayo and R. E. Williams,
(6)
J. E. MC Murry, J. Am. Chem. Sot., in the press.
(7)
a-Sativene is far more readily available than is the natural material which occurs only in very small amounts in helminthosporium sativum; see ref. 5.
(8)
L. Smedman
(9)
M. Hanack
and E. Zavarin,
J. Am. Chem. Sot., 87, 3275 (1965).
Tetrahedron
and H. Eggensperger,
(10) The mass spectra were recorded
Letters,
3833 (1968).
Liebigs Ann., 648, 1 (1961). on an Hitachi-Perkin-Elmer
(11) U. R. Nayak and S. Dev, Tetrahedron,
24, 4102
(1968).
RMU-6E
instrument.
PergamonPress, Printed in Great Britain,
TOTAL SYNTHESIS
OF CYCLOSATIVENE
John E. MC Murr'y Division
of Natural
Sciences, University
Santa Cruz, California (Received
Longifolene, both because
in USA 17
l_, occupies
tricyclic
reactions
(2).
starting material
For example
3,
might
exhibits
(1) of
is
of interesting
is heated with
longicyclene,
2,
(4)
along with much recovered
2
sesquiterpene
in 1965
also reasonably reported
sativene
available,
hydrocarbon,
(5) and, because be expected
of its structural
the first total synthesis (7), were
interested
(8) as well as its isomerization
interesting of sativene
similarity
(6) and, with
55
We have synthetic
it might undergo.
of the tetracyclic
red fir (Abies magnifica,
into sativene.
to longifolene,
chemistry.
in the transformations
the isolation
& , from California
3
sativene, 5, was isolated by de Mayo
to display
this work was in progress,
CYclOSativene,
longifolene
(3) when longifolene
(15%), are obtained
chemistry
(51%).
recently
While
November 1968)
of the complexity
allows for a number
1
and Williams
and because
chemistry which
skeleton which
29
place in sesquiterpene
in acetic acid, two isomeric hydrocarbons,
(29%), and isolongifolene,
The tricyclic
95060
in u( for publication
of its structure
Much of this remarkable
due to its compact
cupric acetate
receih
a most interesting
of the uniqueness
its chemistry.
transannular
October 1968;
o.f California
sesquiterpene
Murray) was reported
We are thus prompted
to record
No.1
56
our own similar results, Under conditions 100 mg -dl-sativene glacial acetic
and to comment
analogous
Following
r15% on 60/80 Chromosorb
of the isomerization.
+ longicyclene
interconversion,
for two days with 25 mg Cu(OAc)2.H20 work-up,
Examination
gave 85 mg of material. column
to the longifolene
was refluxed
acid.
on the mechanism
micro-distillation
in 3 ml
of the crude product
of the product mixture
by VPC using
W; 5' x y'; llO"; 60 cc/min]
indicated
an FFAP
that three
. isomeric hydrocarbons
were present
and that the following
equilibrium
had been
established: Peak 1, 32%, was assigned Zavarin,
by spectral
[tricyclene 9.12
nucleus
the structure 2, denoted
data: ir, (CC14) 3055 cm -' (cyclopropane (9)l; nmr (CC14) 7 9.01 (s, 3 H), 9.24
(pair of doublets,
204'(100,
gave an nmr spectrum natural material constitutes
by Smedman and
C-H), 860, 840
(s, 3 H), 9.10 and
6 H, J = 6 Hz), 9.22 (s, 1 H, cyclopropane
(d, 1 H, J = 5 Hz, cyclopropane intensity),
cyclosativene
C-H); mass spectrum
C-H), 9.34
(10) (80 ev), m/e
M+), 189 (27), 161 (91), 133 (36), 94 (88). identical with
and kindly provided
a total synthesis
that produced. by an authentic by Dr. L. Smedman.
of this naturally
Peak 2, 7%, was recovered dl-sativene,
(relative
dl-Cyclosativene sample of the
This reaction
therefore
occurring material.
6, identified
spectroscopically
and gas
chromatographically. Peak 3, 61%, was a third isomeric hydrocarbon
which we denote dl-isosativene
and to which we assign structure -10 on the basis of spectral measurements: ir (CC14), 3065 cm-l, 1655, 875 (terminal methylene); 5.52 (s, 1 H), 7.39 (broad doublet, mass
spectrum
(80 ev), m/e
nmr
(CC14), 7 5.24
1 H), 9.01 (s, 3 H), 9.10
(relative intensity),
(s, 1 H),
(d, 6 H, J = 6 Hz);
204 (22, M+), 189 (9), 161 (25),
133 (13), 94 (100). That a true equilibrium demonstrated acetatemixture
by subjecting
exists between samples
acetic acid treatment
these three isomeric
of pure cyclosativene
and observing
sesquiterpenes
and isosativene
the formation
was
to cupric
of the same equilibrium
of products.
The mechanism "Iongifolene longibornyl
of the isomerization
and longicyclene cation" 2.
is not clear.
get interconverted,
Dev has suggested in all likelihood
(il) that
through the
57
NO.1
Although
this is a possibility,
we see no compelling
3O to 2O carbonium
unfavorable
the path shown below for the analogous tiith classical
carbonium
sativene + cyclosativene
loses a proton
ion analogous
9
of two directions deprotonation,
to generate
it for the forward process there are marked
longifolene
a new tertiary
[cyclosativene
and sativene.
Under
to a 2O
cation 2, or to regenerate
Certainly
+ sativenel
between
innaediately
can then open by protonation
also, in disagreement
differences
of sativene
rather than isomerize
Cyclosativene
9 then gives isosativene.
choice for the reverse
Thus
to cyclosativene,
to 5.
interconversion,
0
the cation 1 formed by protonation
and closes
instead
ions for convenience:
10 -
In this pathway,
We prefer
ion rearrangement.
7
carbonium
to invoke an
+ P+ P P
energetically
illustrated
reason
this mechanism
reaction,
7.
Upon
is the obvious
and we therefore
favor
with Dev's suggestion.
the acid catalyzed
the conditions
in either
described
here,
rearrangements
of
sativene undergoes
No.1
58
no deep seated skeletal change analogous rearrangement. z
A possible
is a presumed
sativene
reason
in the longifolene
unlikely.
strained due to the decreased
It therefore
appears
some interesting
such a path
12
f?
that sativene,
in analogy with
longifolene,
and we are continuing
Acknowledgement:
We wish
to thank the Petroleum
Chemical
and the Division
Santa Cruz, for their support
In the
+
transformations
Society,
ion
intermediates
ring size, making
11
I
carbonium
isomerization.
ion 12, and all succeeding
the analogous
+ P
would be much more
•t isolongifolene
for this is that the bridgehead
(2) intermediate
case however,
to the longifolene
of Natural
of
the study.
Research
Sciences,
is capable
Fund of the American
University
of California,
of this work. References
(1)
For a review of the early chemistry of longifolene, see J. S. Simonsen and D. H. R. Barton, "The Terpenes," Vol. III, Cambridge University Press, Cambridge, England, 1952, pp. 92-98.
(2)
For a review of the molecular rearrangements which longifolene undergoes, see G. Ourisson, Simonsen Lecture, Proc. Chem. Sot., 274 (1964).
(3)
U. R. Nayak and S. Dev, Tetrahedron Letters, 243 (1963). U. R. Nayak and S. Dev, Tetrahedron, 24, 4099 (1968).
(4)
Longicyclene is the first naturally occurring tetracyclic sesquiterpene and occurs as a minor portion of the oil from the oleoresin of Pinus longifolia; see ref. 3.
(5)
P. de Mayo and R. E. Williams,
(6)
J. E. MC Murry, J. Am. Chem. Sot., in the press.
(7)
a-Sativene is far more readily available than is the natural material which occurs only in very small amounts in helminthosporium sativum; see ref. 5.
(8)
L. Smedman
(9)
M. Hanack
and E. Zavarin,
J. Am. Chem. Sot., 87, 3275 (1965).
Tetrahedron
and H. Eggensperger,
(10) The mass spectra were recorded
Letters,
3833 (1968).
Liebigs Ann., 648, 1 (1961). on an Hitachi-Perkin-Elmer
(11) U. R. Nayak and S. Dev, Tetrahedron,
24, 4102
(1968).
RMU-6E
instrument.