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Intramolecular [4 + 1] pyrroline annulation approach to pyrrolizidine alkaloids. Formal total synthesis of (±)-supinidine.
Tetrahedron Letters,Vo1.26,No.30,pp Printed in Great Britain
INTRAMOLECULAR
0040-4039/85 $3.00 + .OO 61985 Pergamon Press Ltd.
3523-3526,1985
[4 + l] PYRROLINE ANNULATION APPROACH TO PYRROLIZIDINE FORMAL TOTAL SYNTHESIS OF (+)-SUPINIDINE.~
ALKALOIDS.
Tomas Hudlicky*2, James 0. Frazier and Lawrence 0. Kwart Dept. of Chem., Virginia Polytechnic Institute & State Univ., Blacksburg,
The synthetic of a carbenoid
utility
species
rearrangement
sesquiterpenes.3 union
24061
Dienic azide 7 was found to yield dehydropyrrolizidines 10 and 11 on thermolysis. The synthesis-of these compounds is described and the mezanist?? implications as well as synthetic utility of this new annulation sequence is discussed.
Abstract:
pentene
VA
of a carbocyclic
with a conjugated
diene and a subsequent
has been demonstrated
The heterocyclic
and subsequent
[4 + l] annulation
by the generalized
equivalent
rearrangements
of this reaction
lrklichentails
the interaction
vinylcyclopropane synthesis involves
- cyclo-
of several the intramolecular
of an azide and a diene as depicted
in eq. 1.
R = H, alkyl, C02R Whereas predictable anologues
the outcome
based on the stability can undergo
diradical,4
3 _*
a variety
involving
An electronically
by displacement
species,
transformations
In this report we describe
azide -1 produced
pyrrolizidines
marginal
evidence
system was thus envisioned
by ozonolysis
with sodium
the corresponding
diverse
of functionalized
more suitable
The aldehyde 4, prepared followed
of diradical
processes.6
to the synthesis unsubstituted
such as 1+2+3 in the carbocyclic
of mechanistically
ionic,5 or concerted
this strategy's7 studies
of the sequence
of bromopent-4-ene
azide (NaN3/DMF/R.T.,
series
nitrogenous involving
BrCH2CHCHC02Et
either
the application
11 -10 and _*
of pyrroline
in acrylate 7 (Scheme (CH2C12/-78"C,
of
Initial model
of formation
1).
Me2S workup)
12 hours) was subjected
OR
-4
is quite
to the CO,Et
Co2Et
;,5.R=H 5, R = AC 3523
-7 Scheme
1
3524
"a-conditions" obtained hours)
of the vinylogous
in 90% yield,
Reformatsky
was filtered
through
silica
(Scheme
(2:l mixture
Exposure (82%)."
Flash pyrolysis
of imine fi gave similar
From these observations these rearrangements.
intermediates
presumably
300"-400",
bond 2 or b. supported is subject analogous
was detected
That the diradical
easily manipulated
synthesis
of 8, lo,
and -11 (approx.50:40:10)
conclusions
in 86%
of either
about the mechanism
of reactions
of
2 have been and they
are
and 11.
depending
from the scission
of pyrrolizidine
l&
exo
3,
endo
-10.
The utility
In addition,
imine -8.13
is obtained
on the scission
the endo isomer 12b
This behavior
by the preparation
is entirely
and its reversibility in high yield and which
of these transformations
alkaloids
of either
of bond _a is the more stable one is
alkyl vinylcyclopropanes,
of pyrrolizidine
has been achieved
z.ll
C02Et
from imine -8 which
to the synthesis
to triazoline
aziridine -12 nor triazoline
shift which produces
than azide -7."~~~
to imine 4
as did a sealed tube thermolysis
in 1H-NMR monitoring
derived
formation
to that of cis-disposed pyrrolizidines
(DME, DBU, O"C, 5 min.)
in a clean conversion
of 8, &J,
-12 can form two sets of diradicals,
to a1,5-homodienyl
applicability
resulted
to draw certain
vinyl
in the formation
by the predominant
manufacture
to diene I
DMAP, 12
2 hours)."
neither
-10
Vinylaziridine
results
it is possible
Although
their existence
adduct 5,
(Ac20, pyridine,
at 0°C + R.T. (4-6 days) azide 1 was transformed
azide 7 or imine fi (toluene,
isolated,
THF (4 hours)
nf 1 at 450" or 500" gave a mixture
Pyrolysis
yield.
Hydroxy
of E/Z).
of azide 1 to refluxing
On standing
1).
and acetylated
to afford 85% yield of acetate 6 which was converted
in 96% yield
total
reaction'$'
such as supinidine
of g,14
serves
to
is more
lies in their 13, whose formal
and of the unusual
ant venoms
3525
such as -1415 which could become
through
this sequence
It should be noted that the regioselectivity
azide 4. plays
available
an extraordinary
functionalized isolated,
role in the design
at either
the previously
produce -11 selectively under different
l- or 3- position reported
precursors
as indicated
in eq. 2.
of heterogeneous
and under mild conditions.
conditions,
of the vinylogous
of appropriate
conditions
via modification
of precursory
Reformatsky
reaction
to afford pyrrolizidines If vinylaziridine
cleavage5
-12 can be
will be applied
to
Thus both -10 and 11 will be accessible,
from the a-regioisomer
of 1,
as well as from the y-regioisomer.
cq -c6°H P?
eq. 2
N
C02R
We will report
-13
on these and any further
Acknowledgements:
The authors
Petroleum
Fund (AC-16617),
support
Research
C7H15
-14 applications
thank the Chemistry
of this new methodology
Department
and the National
at Virginia
Institutes
of Health
in due course.
Tech, the donors
of
(AI-00564)for the
of this work.
References: 1.
Presented in part at the ACS Southeastern Abstract no. 431.
2.
Fellow of the Alfred P. Sloan Foundation, 1981-85; Development Award (NIH-AI-00564), 1984-89.
3.
For recent applications see 6. C. Ranu, M. Kavka, L. A. Higgs, Tetrahedron Lett., 2447 (1984), and references therein.
4.
R. S. Atkinson and C. W. Rees, J. Chem. Sot. Chem. Comm., 1232 (1967); 0. Borel, Y. Gelas-Mialhe, and R. Vessiere, Can. 3. Chem., 54, 1590 11976).
5.
2,
Regional
Meeting,
Recipient
Raleigh,
NC, October
of the Research
1986,
Career
and T. Hudlicky,
2528 (1967); A. G. Hortmann, Ja-Young Koo, J. Org. Chem., J. Am. Chem. Sot., 87, 749 (1965).
6.
Concerted mechanisms are favored in 1,5-homodienyl shift reactions of vinylaziridines (ref. 13), whereas the majority of other rearranqements is explained on the basis of diradical or ionic intermediates. Some photolytic decompositions have been considered as concerted (P. Scheiner, J. Am. Chem. Sot., 90, 968 (1968) and such a possible pathway has not been excluded from further considerations.
7.
We have been made aware of a similar study in progress by Prof. William H. Pearson, University of Michigan. Cycloadditions of azides and enones have previously led to the formation of pyrrolines: A. G. Schultz, J. P. Pittami, S. 0. Myong, and Chin-Kang Sha, J. Am. Chem. Sot., 105, 3273 (1982); A. G. Schultz and W. G. McMahon, J. Org. Chem., 2, 1676 (1984).
3526
8. L. E. Rice, M. C. Boston, H. 0. Finklea, B. J. Suder, J. 0. Frazier, and T. Hudlicky, JOrg. Chem., 49,
1845 (1984).
9. T. Hudlicky, M. G. Natchus, L. D. Kwart, and B. Colwell, J. Am. Chem. Sot., submitted. The conditions
yielding
a-regiochemistry
10. Monitoring
of this reaction and vinylaziridine -12.
11. The triazoline
by TLC and 1H-NMR revealed
was not characterized
of pyrrolizidineno --
13. Vinylcyclopropanes: Vinylaziridines: 1590 (1976).
Et20,
the intermediacy
of triazoline
-9
due to its rapid decomposition.
The sealed tube reactions produced and 11 than the flash vacuum pyrolyses of -7.
12. The formation of 8 from 12b is reversible. content
involve Zn/Cu couple,
higher
T. Hudlicky and F. J. Koszyk, Tetrahedron Lett., 2487 (1980). and R. Vessiere, Can. J. Chem., 54_, 1582, D. Borel, Y. Gelas-Mialhe,
14. For recent svntheses of supinidine see:
T. Kametani, K. Higashiyama, H. Otomasu, and T. 729 (1984); D. J. Hart and T. K. Yang, Tetrahedron Lett., 2761 Honda, Heterocycles, 2, (1982); D. J. Robins and S. Sakdarat, J. Chem. Sot. Perkin I, 1734 (1979); J. J. For a review of pyrrolizidine Tufariello and J. P. Tette, J. Org. Chem., 40, 3866 (1975). D. J. Robins, Adr. Heterocycl. Chem., 24, 247 (1979). alkaloids see: Chemical and Biological Perspectives, S. W. Pelletier, ed., vol. l., 33 (1983); H. Stetler, W. Basse, H. Kuhlman, A. Landscheidt, W. Schlenker, Chem. Berr., 110, I007 (1977).
15. T. H. Jones and M. S. Blum, Alkaloids:
(Received in USA 25 March 1985)
and
INTRAMOLECULAR
0040-4039/85 $3.00 + .OO 61985 Pergamon Press Ltd.
3523-3526,1985
[4 + l] PYRROLINE ANNULATION APPROACH TO PYRROLIZIDINE FORMAL TOTAL SYNTHESIS OF (+)-SUPINIDINE.~
ALKALOIDS.
Tomas Hudlicky*2, James 0. Frazier and Lawrence 0. Kwart Dept. of Chem., Virginia Polytechnic Institute & State Univ., Blacksburg,
The synthetic of a carbenoid
utility
species
rearrangement
sesquiterpenes.3 union
24061
Dienic azide 7 was found to yield dehydropyrrolizidines 10 and 11 on thermolysis. The synthesis-of these compounds is described and the mezanist?? implications as well as synthetic utility of this new annulation sequence is discussed.
Abstract:
pentene
VA
of a carbocyclic
with a conjugated
diene and a subsequent
has been demonstrated
The heterocyclic
and subsequent
[4 + l] annulation
by the generalized
equivalent
rearrangements
of this reaction
lrklichentails
the interaction
vinylcyclopropane synthesis involves
- cyclo-
of several the intramolecular
of an azide and a diene as depicted
in eq. 1.
R = H, alkyl, C02R Whereas predictable anologues
the outcome
based on the stability can undergo
diradical,4
3 _*
a variety
involving
An electronically
by displacement
species,
transformations
In this report we describe
azide -1 produced
pyrrolizidines
marginal
evidence
system was thus envisioned
by ozonolysis
with sodium
the corresponding
diverse
of functionalized
more suitable
The aldehyde 4, prepared followed
of diradical
processes.6
to the synthesis unsubstituted
such as 1+2+3 in the carbocyclic
of mechanistically
ionic,5 or concerted
this strategy's7 studies
of the sequence
of bromopent-4-ene
azide (NaN3/DMF/R.T.,
series
nitrogenous involving
BrCH2CHCHC02Et
either
the application
11 -10 and _*
of pyrroline
in acrylate 7 (Scheme (CH2C12/-78"C,
of
Initial model
of formation
1).
Me2S workup)
12 hours) was subjected
OR
-4
is quite
to the CO,Et
Co2Et
;,5.R=H 5, R = AC 3523
-7 Scheme
1
3524
"a-conditions" obtained hours)
of the vinylogous
in 90% yield,
Reformatsky
was filtered
through
silica
(Scheme
(2:l mixture
Exposure (82%)."
Flash pyrolysis
of imine fi gave similar
From these observations these rearrangements.
intermediates
presumably
300"-400",
bond 2 or b. supported is subject analogous
was detected
That the diradical
easily manipulated
synthesis
of 8, lo,
and -11 (approx.50:40:10)
conclusions
in 86%
of either
about the mechanism
of reactions
of
2 have been and they
are
and 11.
depending
from the scission
of pyrrolizidine
l&
exo
3,
endo
-10.
The utility
In addition,
imine -8.13
is obtained
on the scission
the endo isomer 12b
This behavior
by the preparation
is entirely
and its reversibility in high yield and which
of these transformations
alkaloids
of either
of bond _a is the more stable one is
alkyl vinylcyclopropanes,
of pyrrolizidine
has been achieved
z.ll
C02Et
from imine -8 which
to the synthesis
to triazoline
aziridine -12 nor triazoline
shift which produces
than azide -7."~~~
to imine 4
as did a sealed tube thermolysis
in 1H-NMR monitoring
derived
formation
to that of cis-disposed pyrrolizidines
(DME, DBU, O"C, 5 min.)
in a clean conversion
of 8, &J,
-12 can form two sets of diradicals,
to a1,5-homodienyl
applicability
resulted
to draw certain
vinyl
in the formation
by the predominant
manufacture
to diene I
DMAP, 12
2 hours)."
neither
-10
Vinylaziridine
results
it is possible
Although
their existence
adduct 5,
(Ac20, pyridine,
at 0°C + R.T. (4-6 days) azide 1 was transformed
azide 7 or imine fi (toluene,
isolated,
THF (4 hours)
nf 1 at 450" or 500" gave a mixture
Pyrolysis
yield.
Hydroxy
of E/Z).
of azide 1 to refluxing
On standing
1).
and acetylated
to afford 85% yield of acetate 6 which was converted
in 96% yield
total
reaction'$'
such as supinidine
of g,14
serves
to
is more
lies in their 13, whose formal
and of the unusual
ant venoms
3525
such as -1415 which could become
through
this sequence
It should be noted that the regioselectivity
azide 4. plays
available
an extraordinary
functionalized isolated,
role in the design
at either
the previously
produce -11 selectively under different
l- or 3- position reported
precursors
as indicated
in eq. 2.
of heterogeneous
and under mild conditions.
conditions,
of the vinylogous
of appropriate
conditions
via modification
of precursory
Reformatsky
reaction
to afford pyrrolizidines If vinylaziridine
cleavage5
-12 can be
will be applied
to
Thus both -10 and 11 will be accessible,
from the a-regioisomer
of 1,
as well as from the y-regioisomer.
cq -c6°H P?
eq. 2
N
C02R
We will report
-13
on these and any further
Acknowledgements:
The authors
Petroleum
Fund (AC-16617),
support
Research
C7H15
-14 applications
thank the Chemistry
of this new methodology
Department
and the National
at Virginia
Institutes
of Health
in due course.
Tech, the donors
of
(AI-00564)for the
of this work.
References: 1.
Presented in part at the ACS Southeastern Abstract no. 431.
2.
Fellow of the Alfred P. Sloan Foundation, 1981-85; Development Award (NIH-AI-00564), 1984-89.
3.
For recent applications see 6. C. Ranu, M. Kavka, L. A. Higgs, Tetrahedron Lett., 2447 (1984), and references therein.
4.
R. S. Atkinson and C. W. Rees, J. Chem. Sot. Chem. Comm., 1232 (1967); 0. Borel, Y. Gelas-Mialhe, and R. Vessiere, Can. 3. Chem., 54, 1590 11976).
5.
2,
Regional
Meeting,
Recipient
Raleigh,
NC, October
of the Research
1986,
Career
and T. Hudlicky,
2528 (1967); A. G. Hortmann, Ja-Young Koo, J. Org. Chem., J. Am. Chem. Sot., 87, 749 (1965).
6.
Concerted mechanisms are favored in 1,5-homodienyl shift reactions of vinylaziridines (ref. 13), whereas the majority of other rearranqements is explained on the basis of diradical or ionic intermediates. Some photolytic decompositions have been considered as concerted (P. Scheiner, J. Am. Chem. Sot., 90, 968 (1968) and such a possible pathway has not been excluded from further considerations.
7.
We have been made aware of a similar study in progress by Prof. William H. Pearson, University of Michigan. Cycloadditions of azides and enones have previously led to the formation of pyrrolines: A. G. Schultz, J. P. Pittami, S. 0. Myong, and Chin-Kang Sha, J. Am. Chem. Sot., 105, 3273 (1982); A. G. Schultz and W. G. McMahon, J. Org. Chem., 2, 1676 (1984).
3526
8. L. E. Rice, M. C. Boston, H. 0. Finklea, B. J. Suder, J. 0. Frazier, and T. Hudlicky, JOrg. Chem., 49,
1845 (1984).
9. T. Hudlicky, M. G. Natchus, L. D. Kwart, and B. Colwell, J. Am. Chem. Sot., submitted. The conditions
yielding
a-regiochemistry
10. Monitoring
of this reaction and vinylaziridine -12.
11. The triazoline
by TLC and 1H-NMR revealed
was not characterized
of pyrrolizidineno --
13. Vinylcyclopropanes: Vinylaziridines: 1590 (1976).
Et20,
the intermediacy
of triazoline
-9
due to its rapid decomposition.
The sealed tube reactions produced and 11 than the flash vacuum pyrolyses of -7.
12. The formation of 8 from 12b is reversible. content
involve Zn/Cu couple,
higher
T. Hudlicky and F. J. Koszyk, Tetrahedron Lett., 2487 (1980). and R. Vessiere, Can. J. Chem., 54_, 1582, D. Borel, Y. Gelas-Mialhe,
14. For recent svntheses of supinidine see:
T. Kametani, K. Higashiyama, H. Otomasu, and T. 729 (1984); D. J. Hart and T. K. Yang, Tetrahedron Lett., 2761 Honda, Heterocycles, 2, (1982); D. J. Robins and S. Sakdarat, J. Chem. Sot. Perkin I, 1734 (1979); J. J. For a review of pyrrolizidine Tufariello and J. P. Tette, J. Org. Chem., 40, 3866 (1975). D. J. Robins, Adr. Heterocycl. Chem., 24, 247 (1979). alkaloids see: Chemical and Biological Perspectives, S. W. Pelletier, ed., vol. l., 33 (1983); H. Stetler, W. Basse, H. Kuhlman, A. Landscheidt, W. Schlenker, Chem. Berr., 110, I007 (1977).
15. T. H. Jones and M. S. Blum, Alkaloids:
(Received in USA 25 March 1985)
and