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Synthesis of the forskolin skeleton via anionic oxy-cope rearrangement
Tetrahedron printed in
Letters,Vo1.28,No.45,pp Great Britain
SYNTHESIS
OF THE FORSKOLIN
Jeffrey Evans
Chemical
SKELETON
A. Oplinger
Laboratories,
oo40-4039/87 $3.00 + .OO Pergamon Journals Ltd.
5441-5444,1987
VIA ANIONIC
OKY-COPE
REARRANGEMENT
and Leo A. Paquette*
The Ohio State University,
Columbus,
Ohio 43210
Summary: The forskolin prototype 14 has been elaborated in 9 steps from 2,4,4-trimethylcyclohexenone (5), the entire ring system materializing during oxyanionic Cope rearrangement of alcohol 10.
The intense diterpene
scrutiny
isolated
adenylate
chemists worldwide.
utility
Preliminary
and nitrile
interested
of oxyanionic
and reduce
pharmacological
tion, a a tandem Michael-aldol We became
and inotropic
cyclase4
of 1 and its fascinating
lar Diels-Alder6
experiments
labdane
pressure
in man. 5
have appeared having Strategies
ability
The unique
structure
the attention
of synthetic
as their basis
intramolecu-
involving
radical
cycliza-
sequence, 9 and ring C annulation lo have also shown promise.
reported
designed
As part of the relevant
(or equivalent)
alkoxide
of a program
a route to ketone
3, to explore
to this substrate,
of 2 for Cope rearrangement.
pure 4 should allow for kinetic
The prototype
oxygenated
as well as its demonstrated
have elicited
oxide cycloadditions.7
[3,3] sigmatropy.ll
clivity of the potassium
properties
(l),l a highly
stems in large part from its broncho-
activity,3
in 1 in the context
a 2-lithiodihydropyran
optically
forskolin
intraocular
approaches
(eq l), the need arose to develop joining
being accorded
from the roots of Coleus forskolii,2
antihypertensive,
spasmolytic, to activate
presently
herein
5441
a successful
the synthetic
retrosynthetic
analysis
the feasibility
of con-
and to elucidate
Furthermore,
resolution llg and arrival provide
to expand
the
pro-
the use of
at natural
forskolin.
test of the overall
process.
5442
Scheme
I shows the synthetic (89%) to 6. "hose
5 led smoothly carbonyl
protection
7 was a mixture
when
orientation
treated with RuCl3 in the presence
was required
highly hindered
environment
potassium addition
are readily
about
Scheme
cleaved without
of NaIO4
(92%). l3
since subsequent
The steric driving
group in 8 is obvious.
Conversion
this proton.
in 62% yield a 7:l mixture
exe
more stable enolate
perhaps
The best conditions containing
by means
of 8 to the desired
The actual course of events
in 1,2-dimethoxyethane afforded
deprotonation
The fact that
force underlying
the latter step proved easy to accomplish, regioselective
need for
cyclization
to give the thermodynamically
of the base and the solvent.
triflate
separable
only 8 (91%).
to achieve
hexamethyldisilazide of methyl
inconsequential
enolization
While
experimentation
to the nature
methyl
selective
followed by 0-methylation.
linked
proved
acid furnished
of the secondary
en01 ether 3 mandates
Thus, application of the Sakurai reaction 12 to
to 3.
double bond could be oxidatively
of diastereomers
of hot PPA in acetic
route
considerable due to the is intimately
involved use of
HMPA at -2O'C. of 3 and 9.
Subsequent
These
isomers
chromatographically.
I
TlC14, CHzC12 CH3CN
-70°C 6
PPA HOAc IOO”C
0
OCH, 9
Exposure
of 3 to 2. lithiodihydropyran14
in a ratio of 1.5:1
(90% ).
Although
0
2.CH30Tf 8
resulted
this product
in the formation
distribution
of 10 and its epimer
is lower than desired,
a more
5443
bulky nucleophile less sterically Oxy-Cope solution
encumbered
completely16
formed.
That methyl
convincingly
solving metal axially
be subject
reduction
The cis nature
can be achieved
double bond
HZ O.IN KOH C,H,OH 25’ C
to our objec-
13 (39%) and 14
back to 12 with
Me-Me
10% hydrochloric
interaction
methyl
as it is
group
being
face as desired was
in 14 cannot be accomplished
hydrogenation
SePh
10% Pd-C
of 12 furnished
by dis-
its Cg-0 bond to be
under these conditions.
-
!J
suited
only of unidirectional
of the B/C ring fusion causes
by catalytic
formed enolate
at 300 MHz.
THF, 7O’C 2. PhSeCl
capable
on the convex
to more rapid cleavage
to 70°C in THF
the fact that the new angular
1,3-diaxial
NOE studies
of the conjugated
and subject
high chemoselectivity
to reflect
to serious
by difference
reduction.
disposed
from the
of 11 (79%) following
to be highly
easily converted
capture had indeed occurred
established
Selective
a substrate
the deprotonation-methylation
(100%). is presumed
in 14 must necessarily
in the isolation
This finding proved
of 13, a compound
heating
this time, the initially
for example,
chloride.
In actuality,
acid in THF at 25OC
During
to give 12 provided
The co-formation
levels of 1,2-addition
salt of 10 required
for 20 min.
as reflected,
of phenylselenenyl
enolization. (52%).
of the potassium
18-crown-6
tives, since elimination
to foster greater
direction.15
rearrangement
containing
equilibrated addition
such as 4 is expected
In contrast,
over 10% Pd-C in 0.1
N
5444
KOH solution. l7
ethanolic analyses
at 500 MHz.18
relationship
between
imparts considerable Epimerization
Dreiding
conformational
at C-9 is, of course,
fication will permit
Acknowledgment. Institutes
derived
appropriate
was shown to be 15 (84%) by COSY and NOE
models
reveal
that prior establishment
at C-8 and C-9 (see 14) as demanded rigidity
and predisposes
critically therefrom.
control
This research of Health
product
molecular
the substituents
uent in 2 and the compounds
National
The exclusive
dependent
The likelihood
was made possible
by forskolin
to C8-0 bond equatorially.
on the presence
of stereochemistry
of a trans
of an OR substit-
that this structural
is currently
by financial
being
support
modi-
assessed.
provided
by the
(Grant GM-28468).
References
and Notes
(1) de Souza, N. J.; Dohadwalla, A. N.; Reden, J. Medicin. Res. Revs. 1983, 3, 201. (b) Seamon, K. B. Ann. Rep. Medicin. Chem. 1984, 19, 293. (2) (a) Bhat, S. V.; Bajwa, B. S.; Dornauer, H.; de Souza, N. J.; Fehlhaber, H.-W. (b) Bhat, S. V.; Bajwa, B. S.; Dornauer, H.; de Souza, N. J. Tetrahedron Lett 1977, 1669. J. Chem. Sot., Perkin Trans. I 1982, 767. (3) (a) Lichey, A.; Friedrich, T.; Priesnitz, M.; Biamino, G.; Usinger, P.; Huckauf, H. The Lancet 1984, 2, 167. (b) Bhat, S. V.; Dohadwalla, A. N.; Bajwa, B. S.; Dadkar, N. K.; Dornauer, H.; de Souza, N. J. J.Med. Chem. 1983, 26, 486. (4) Seamon, K. B.; Padgett, W.; Daly, J. W. Proc. Natl. Acad. Sci. 1981, 78, 3363. (5) Caprioli, J.; Sears, M. The Lancet 1983, 1, 958. (6) (a) Jenkins, P. R.; Menear, K. A.; Barraclough, P.; Nobbs, M. S. J. Chem. Sot., (c) Ziegler, F. Chem. Camnun. 1984, 1423. (b) Nicolaou, K. C.; Li, W. S. Ibid. 1985, 421. (d) Bold, G.; Chao, S.; E.; Jaynes, B. H.; Saindane, M. T. Tetrahedron Lett. 1985, 3307. Bhide, R.; Wu, S.-H.; Patel, D. V.; Shih, C. J. Ibid. 1987, 1973. (7) Baraldi, P. G.; Barco, A., Benetti, S.; Pollini, G. P.; Polo, E.; Simoni, D. J. Chem. Sot., Chem. Commun. 1986, 757. (8) Hutchinson, J. H.; Pattenden, G.; Myers, P. L. Tetrahedron Lett. 1987, 1313. (9) Koft, E. R.; Kotnis, A. S.; Broadbent, T. A. Tetrahedron Lett. 1987, 2799. (10) Hashimoto, S.; Sonegawa, M.; Sakata, S.; Ikegami, S. J. Chem. SOC., Chem. Commun. 1987, 24. (11) (a) Paquette, L. A.; Andrews, D. R.; Springer, J. P. J. Org. Chem. 1983, 48, 1147. (c) Paquette, L. (b) Paquette, L. A.; Colapret, J. A.; Andrews, D. R. Ibid. 1985, 50, 201. A.; Learn, K. S. J. Am. Chem. Sot. 1986, 108, 7873. (d) Paquette, L. A.; Romine, J. L.; Lin, H.-S. Tetrahedron Lett. 1987, 31. (e) Paquette, L. A.; Learn, K. S.; Romine, J. L. Synth. Commun. 1987, 17, 369. (f) Paquette, L. A.; Pierre, F.; Cottrell, C. E. J. Am. Chem. Sot. 1987, 109, in press. (g) Paquette, L. A.; DeRussy, D. T.; Cottrell, C. E. submitted for publication. (12) Hosomi, A.; Sakurai, H. J. Am. Chem. Sot. 1977, 99, 1673. (13) Carlsen, P. H. J.; Sharpless, K. 8. J. Org. Chem. 1981, 46, 3936. (14) Boeckman, R. K., Jr., Bruza, K. J. Tetrahedron Lett. 1977, 4187. (15) The smaller vinylmagnesium bromide adds to 3 predominantly (2:l) from the direction syn to the gem-dimethyl group. (16) This phenomenon has been observed reviously under less forcing conditions, although not with such striking exclusivety. Pig (17) McQuillin, F. J.; Ord, W. 0. J. Chem. Sot. 1959, 2902. (18) We thank Dr. C. E. Cottrell for these measurements. (Received
in
USA
6 August
1987)
Letters,Vo1.28,No.45,pp Great Britain
SYNTHESIS
OF THE FORSKOLIN
Jeffrey Evans
Chemical
SKELETON
A. Oplinger
Laboratories,
oo40-4039/87 $3.00 + .OO Pergamon Journals Ltd.
5441-5444,1987
VIA ANIONIC
OKY-COPE
REARRANGEMENT
and Leo A. Paquette*
The Ohio State University,
Columbus,
Ohio 43210
Summary: The forskolin prototype 14 has been elaborated in 9 steps from 2,4,4-trimethylcyclohexenone (5), the entire ring system materializing during oxyanionic Cope rearrangement of alcohol 10.
The intense diterpene
scrutiny
isolated
adenylate
chemists worldwide.
utility
Preliminary
and nitrile
interested
of oxyanionic
and reduce
pharmacological
tion, a a tandem Michael-aldol We became
and inotropic
cyclase4
of 1 and its fascinating
lar Diels-Alder6
experiments
labdane
pressure
in man. 5
have appeared having Strategies
ability
The unique
structure
the attention
of synthetic
as their basis
intramolecu-
involving
radical
cycliza-
sequence, 9 and ring C annulation lo have also shown promise.
reported
designed
As part of the relevant
(or equivalent)
alkoxide
of a program
a route to ketone
3, to explore
to this substrate,
of 2 for Cope rearrangement.
pure 4 should allow for kinetic
The prototype
oxygenated
as well as its demonstrated
have elicited
oxide cycloadditions.7
[3,3] sigmatropy.ll
clivity of the potassium
properties
(l),l a highly
stems in large part from its broncho-
activity,3
in 1 in the context
a 2-lithiodihydropyran
optically
forskolin
intraocular
approaches
(eq l), the need arose to develop joining
being accorded
from the roots of Coleus forskolii,2
antihypertensive,
spasmolytic, to activate
presently
herein
5441
a successful
the synthetic
retrosynthetic
analysis
the feasibility
of con-
and to elucidate
Furthermore,
resolution llg and arrival provide
to expand
the
pro-
the use of
at natural
forskolin.
test of the overall
process.
5442
Scheme
I shows the synthetic (89%) to 6. "hose
5 led smoothly carbonyl
protection
7 was a mixture
when
orientation
treated with RuCl3 in the presence
was required
highly hindered
environment
potassium addition
are readily
about
Scheme
cleaved without
of NaIO4
(92%). l3
since subsequent
The steric driving
group in 8 is obvious.
Conversion
this proton.
in 62% yield a 7:l mixture
exe
more stable enolate
perhaps
The best conditions containing
by means
of 8 to the desired
The actual course of events
in 1,2-dimethoxyethane afforded
deprotonation
The fact that
force underlying
the latter step proved easy to accomplish, regioselective
need for
cyclization
to give the thermodynamically
of the base and the solvent.
triflate
separable
only 8 (91%).
to achieve
hexamethyldisilazide of methyl
inconsequential
enolization
While
experimentation
to the nature
methyl
selective
followed by 0-methylation.
linked
proved
acid furnished
of the secondary
en01 ether 3 mandates
Thus, application of the Sakurai reaction 12 to
to 3.
double bond could be oxidatively
of diastereomers
of hot PPA in acetic
route
considerable due to the is intimately
involved use of
HMPA at -2O'C. of 3 and 9.
Subsequent
These
isomers
chromatographically.
I
TlC14, CHzC12 CH3CN
-70°C 6
PPA HOAc IOO”C
0
OCH, 9
Exposure
of 3 to 2. lithiodihydropyran14
in a ratio of 1.5:1
(90% ).
Although
0
2.CH30Tf 8
resulted
this product
in the formation
distribution
of 10 and its epimer
is lower than desired,
a more
5443
bulky nucleophile less sterically Oxy-Cope solution
encumbered
completely16
formed.
That methyl
convincingly
solving metal axially
be subject
reduction
The cis nature
can be achieved
double bond
HZ O.IN KOH C,H,OH 25’ C
to our objec-
13 (39%) and 14
back to 12 with
Me-Me
10% hydrochloric
interaction
methyl
as it is
group
being
face as desired was
in 14 cannot be accomplished
hydrogenation
SePh
10% Pd-C
of 12 furnished
by dis-
its Cg-0 bond to be
under these conditions.
-
!J
suited
only of unidirectional
of the B/C ring fusion causes
by catalytic
formed enolate
at 300 MHz.
THF, 7O’C 2. PhSeCl
capable
on the convex
to more rapid cleavage
to 70°C in THF
the fact that the new angular
1,3-diaxial
NOE studies
of the conjugated
and subject
high chemoselectivity
to reflect
to serious
by difference
reduction.
disposed
from the
of 11 (79%) following
to be highly
easily converted
capture had indeed occurred
established
Selective
a substrate
the deprotonation-methylation
(100%). is presumed
in 14 must necessarily
in the isolation
This finding proved
of 13, a compound
heating
this time, the initially
for example,
chloride.
In actuality,
acid in THF at 25OC
During
to give 12 provided
The co-formation
levels of 1,2-addition
salt of 10 required
for 20 min.
as reflected,
of phenylselenenyl
enolization. (52%).
of the potassium
18-crown-6
tives, since elimination
to foster greater
direction.15
rearrangement
containing
equilibrated addition
such as 4 is expected
In contrast,
over 10% Pd-C in 0.1
N
5444
KOH solution. l7
ethanolic analyses
at 500 MHz.18
relationship
between
imparts considerable Epimerization
Dreiding
conformational
at C-9 is, of course,
fication will permit
Acknowledgment. Institutes
derived
appropriate
was shown to be 15 (84%) by COSY and NOE
models
reveal
that prior establishment
at C-8 and C-9 (see 14) as demanded rigidity
and predisposes
critically therefrom.
control
This research of Health
product
molecular
the substituents
uent in 2 and the compounds
National
The exclusive
dependent
The likelihood
was made possible
by forskolin
to C8-0 bond equatorially.
on the presence
of stereochemistry
of a trans
of an OR substit-
that this structural
is currently
by financial
being
support
modi-
assessed.
provided
by the
(Grant GM-28468).
References
and Notes
(1) de Souza, N. J.; Dohadwalla, A. N.; Reden, J. Medicin. Res. Revs. 1983, 3, 201. (b) Seamon, K. B. Ann. Rep. Medicin. Chem. 1984, 19, 293. (2) (a) Bhat, S. V.; Bajwa, B. S.; Dornauer, H.; de Souza, N. J.; Fehlhaber, H.-W. (b) Bhat, S. V.; Bajwa, B. S.; Dornauer, H.; de Souza, N. J. Tetrahedron Lett 1977, 1669. J. Chem. Sot., Perkin Trans. I 1982, 767. (3) (a) Lichey, A.; Friedrich, T.; Priesnitz, M.; Biamino, G.; Usinger, P.; Huckauf, H. The Lancet 1984, 2, 167. (b) Bhat, S. V.; Dohadwalla, A. N.; Bajwa, B. S.; Dadkar, N. K.; Dornauer, H.; de Souza, N. J. J.Med. Chem. 1983, 26, 486. (4) Seamon, K. B.; Padgett, W.; Daly, J. W. Proc. Natl. Acad. Sci. 1981, 78, 3363. (5) Caprioli, J.; Sears, M. The Lancet 1983, 1, 958. (6) (a) Jenkins, P. R.; Menear, K. A.; Barraclough, P.; Nobbs, M. S. J. Chem. Sot., (c) Ziegler, F. Chem. Camnun. 1984, 1423. (b) Nicolaou, K. C.; Li, W. S. Ibid. 1985, 421. (d) Bold, G.; Chao, S.; E.; Jaynes, B. H.; Saindane, M. T. Tetrahedron Lett. 1985, 3307. Bhide, R.; Wu, S.-H.; Patel, D. V.; Shih, C. J. Ibid. 1987, 1973. (7) Baraldi, P. G.; Barco, A., Benetti, S.; Pollini, G. P.; Polo, E.; Simoni, D. J. Chem. Sot., Chem. Commun. 1986, 757. (8) Hutchinson, J. H.; Pattenden, G.; Myers, P. L. Tetrahedron Lett. 1987, 1313. (9) Koft, E. R.; Kotnis, A. S.; Broadbent, T. A. Tetrahedron Lett. 1987, 2799. (10) Hashimoto, S.; Sonegawa, M.; Sakata, S.; Ikegami, S. J. Chem. SOC., Chem. Commun. 1987, 24. (11) (a) Paquette, L. A.; Andrews, D. R.; Springer, J. P. J. Org. Chem. 1983, 48, 1147. (c) Paquette, L. (b) Paquette, L. A.; Colapret, J. A.; Andrews, D. R. Ibid. 1985, 50, 201. A.; Learn, K. S. J. Am. Chem. Sot. 1986, 108, 7873. (d) Paquette, L. A.; Romine, J. L.; Lin, H.-S. Tetrahedron Lett. 1987, 31. (e) Paquette, L. A.; Learn, K. S.; Romine, J. L. Synth. Commun. 1987, 17, 369. (f) Paquette, L. A.; Pierre, F.; Cottrell, C. E. J. Am. Chem. Sot. 1987, 109, in press. (g) Paquette, L. A.; DeRussy, D. T.; Cottrell, C. E. submitted for publication. (12) Hosomi, A.; Sakurai, H. J. Am. Chem. Sot. 1977, 99, 1673. (13) Carlsen, P. H. J.; Sharpless, K. 8. J. Org. Chem. 1981, 46, 3936. (14) Boeckman, R. K., Jr., Bruza, K. J. Tetrahedron Lett. 1977, 4187. (15) The smaller vinylmagnesium bromide adds to 3 predominantly (2:l) from the direction syn to the gem-dimethyl group. (16) This phenomenon has been observed reviously under less forcing conditions, although not with such striking exclusivety. Pig (17) McQuillin, F. J.; Ord, W. 0. J. Chem. Sot. 1959, 2902. (18) We thank Dr. C. E. Cottrell for these measurements. (Received
in
USA
6 August
1987)