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Stereoisomers of coleonol (forskolin) and related diterpenoids
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TetrahedronLetters,Vo1.31,No.51.pp 7493-7494.1990 P&ted in GreatBritain
STEREOISOMERS OF COLEONOL (FORSKOLIN) AND RELATED DITEwENOIDS R.A. Vishwakarmaa iCentral Central
Institute of Medicinal & Aromatic Drug Research Institute, Lucknow
Abstracts Regioselective new, unnatural epimers Coleonol a labdane
diterpenoid
in unique
226016
13-epoxy-labd-14-en-1
la, 68, Ya-trihydroxy-7B-acetoxy-8,
isolated’
from the Indian medicinal
congestive
manner
Plants, Lucknow 226001;India
Mitsunobu inversion of the hydroxyl groups of coleonol (forskolin) led to as potential adenylate cyclase stimulant and pharmacodynamic agents.
(Forskolin,
drug for glaucoma,
and J.S. Tandonb
by direct
of guanine
nucleotide
and novel
pharmacodynamic
heart-failure
and reversible
stimulating
action
protein2.
action,
plant
and bronchial on catalytic
Forskolin,
has emerged
Coleus forskohlii
asthma,
activates
subunit
I),
and a potential
adenylate
of the enzyme
owing to its highly
as a highly
l-one,
cyclase
in absence
oxygenated
structure
target
synthetic
attractive
for
investigations2. During we decided activity
our studies
with
the synthesis using
the
new and unnatural
stereochemical
of various
versatile
l-e&
Mitsunobu
stereochemical hydroxyl
on the physiological
to prepare
outcome
centres.
azodiacarboxylate
orientation and 7-a
reaction3
2 after
assigned
to l-a-axial
(Ac20,
was assigned A recently using
Py,
Mitsunobu
acid
7a-axial
reaction
acetylcoleonol showed’
7-@equatorial 7-+coleonol
at
epimer
5.50
in MeOH
(7).
NaOBz
gave
report
in
dry
(TPP,
with
of secondary
3 mmol),
diethyl-
THF at room temperature
as lg-benzoyloxy-l-deoxy= 10 Hz, J
C-2ax and C-2eq protons.
= 2Hz) axleq Debenzoy-
(3) which on selective
(4). The stereochemistry
of Cl-OH
of 4
to obtain
as nucleophile
equatorial
and
sodium
= 9.5 & J = 2.0 Hz). ax/eq vs axial-hydroxyl selectivity
benzoate
(5) prepared
as catalyst
was
by deacetylation
and NaOBz afforded
used
of 1, on
7-deacetyl-7-&trifluoro-
The PMR 2
Hz) for
The hydrolysis led to 7-deacetyl-
The reaction
complex
we
synthesis
of configuration
at 6 5.75 (Jax,ax
of 1. The 7-deacetylcoleonol
(J =
(6-acetyl-7-deacetylcoleonol, TPP-DEAD
in organic
I-e&-7-deacetylcoleonol
using TFA (1.1 mole equivalent)
CH_ proton.
of 6 by refluxing
procedure6
(TFA)
(6) in 60% yield. 4
mmol)
and characterized
coleonol
Herein
by PMR5 which showed & at 3.95 (Jax,ax
Mitsunobu
trifluoroacetic
i-ee
tool
inversion
with two neighbouring
gave
groups.
biological
and 6,7-epoxy-6,7-dideoxycoleonol
triphenylphosphine
of 2 showed4 g
and its analogues,
of 1 to correlate
hydroxyl
a useful
acid (1.1
NaOMe at r.t. yielded O-5’)
as E-equatorial modified
to synthesize
of 6
coupled
of 2 with methanolic
various
a clean
chromatography
(yield 45%). The PMR spectra
acetylation
invariably
(Forskolin)
(epimers)
(forskolins)
of 1 (I mmol) with
coleonol
proton
of Coleonol
has become
(DEAD, 3 mmol) and benzoic
for 36 h gave compound
lation
of
coleonols
which
being almost
The reaction
effects
stereoisomers
using
of coleonol-B 8)
with
TFA
and
/+?&!+
6-acetyl-7-deacetyL7-e&-
trif luoroacetyfcoleonol
(9)
which
on selective 7493
hydrolysis
(reflux
in
MeOH)
gave
7494
7-M coleonol-B (10). Further hydrolysis (NaOMe in MeOH at r.t.) 9 gave 7. An interesting product, 6,7-epoxy-6,7-dideoxycoleonol (11) was formed when 7-deacetylcoleonol (5) was reacted with TPP-DEAD complex in dry II-IF in absence of acidic component. The result indicated
~l~~~~
1, R’ = a-OH,
R* = AC
5, R’ = H, R2 = B-OH
2, R’ = f3-OBz, R* = AC
6, Rl = H, R* = a-OCOCF3
3, R’ = B-OH, R* = H
7, R1 = H, R* = a-OH
4, R’ = B-OH, R* = AC
8, Rl = AC, R* = &OH
I1
9, R’ = AC, R* = a-0COCF3 10, R1 = AC, R* = a-OH the inversion at C-7 being successful but followed by an intramolecular nucleophilic dpplaceto be ment by free hydroxyl at C-6. The stereochemistry of epoxide ring was ascertained 6B-7f3-oriented as determined by PMR spectrum of Il. Conclusively, it is possible to regioselectively invert the configuration of l- and 7-OH of forskolin using Mitsunobu reaction to prepare new and unnatuml epimeric compounds as potential pharmacodynamic agents. The 6- and 9-hydroxyl groups being much more hindered did not react. The biological activity of the epimeric forskolins will be published separately. References and Notes 1.
2.
3. 4.
5.
6. 7.
8.
(a) J.S. Tandon, M.M. Dhar, S. Ramakumar and K. Venkatesan, Indian J. Chem., 15B, 880 (1977): (b) S.V. Bhat, B.S. Bajwa, H. Dornauer, N.J. deSouza and H.W. Fehlhaber, Tetrahedron Lett., 1669 (1977). ’ For a review, See: K.B. Seamon and J.W. Daly, Adv. Cyclic Nucleotide Res., 20, 1 (1986). For total syntheses of Forskolin, See: (a) F.E. Ziegler, B.H. Jaynes, M.T. Saindane, S. Sakata, M. Sonegawa, J. Am. Chem. Sot., 109, 8115 (1987); (b) S .-i. Hashimoto, S. Ikegami, J. Am. Chem. Sot., 110, 3670 (1988); k) E.J. Corey, P.D.S. Jardine, J-C. reactions, see (a) R.W. Rohloff, J. Am. Chem. Sot., 110, 3672 (1988). For regiocontrolled Kosley and R.J. Cherill, J. Org. Chem., 54, 2972 (1989); (b) G.I. O’Malley, B. Spat-4 d( 17), 5.75 (dd, lH, H-l% J = 10 & 2), 5.50 (fi, lH, H-7, J q 4), 5.24 (dd lH, H-15, J q 17 d( 1.5), 4.48 (3 lH, H-6), 4.93 (dd, lH, H-15’, J = 10 & 1.5), 3.18-7-& lH, H-12, J q 17), 2.50 (4 lH, H-12, 3 = 17), 2.15 (3 3H, COCI-13), 1.00, 1.10, 1.27, 1.30, 1.60 (all% 5 x CH3). PMR data of 4. 6.13 (dd, lH, H-14, J = 10 & 17)), 5.21 (dd, lH, H-15, J = 17 d( 1.5)~ 4.99 (dd, IH, H-15, J = 10 & 1.5), 3.95 (dd, IH, H-lax- J = 9.5 & 2), 4.40 (3 lH, H-6), 5.50 (3 lH, H-7, J = 4), 3.18 (c, lH, H-12, J = 17), 2.50 (c& lH, H-12, J = 17), 2.10 (3 lH, H-5, J I 3), 2.15 (3 3H, COCH ), 1.0, 1.05, 1.25, 1.40, 1.60 (all 3 5 x CH ). M. Varasi, K.A.M. Walker and d .L. Maddox, J. Or)g. Che(m., 52, 4235 (198% PMR data of 6. 6.00 (dd, lH, H-14, J = 10 & 17, 5.21 dd lH, H-15, J = 17 6r l-5), 4.99 (G, lH, H-15, J = 10 & 1.5), 5.50 (a lH, H-7, J = $4.55 (3 lH, H-l), 4.48 (3 IH, H-6), 3.15 (4 lH, H-12, J = 17), 2.50 (3 lH, H-12, J = 17), 2.30 (& lH, H-5), 0.95, 1.05, 1.25, 1.30, 1.55 (all 3 5 x CH ). PMR data of 11. 6.00 (dd, &I, H-14, J = 10 & 17), 5.15 (dd, lH, H-15, J = 17 6( 1.5), 5.00 (dd, lH, H-15, J = lo), 4.20 (-m lH, H-l), 3.30 (c& lH, .H-12, J = 15), 2.40 (d lH, H-12; J = 15), 2.55 (I& lH, H-7, J = 3.5), 2.15 (dd, lH, H-6, J = 3.5 & 1.9), 2.05 ($ lH, H-5, J = 1.9), 1.20, 1.21, 1.40, 1.50, 1.60 (all3 5 x CH3). CDRI Communication
No. 4720
(Received in UK 24 October 1990)
TetrahedronLetters,Vo1.31,No.51.pp 7493-7494.1990 P&ted in GreatBritain
STEREOISOMERS OF COLEONOL (FORSKOLIN) AND RELATED DITEwENOIDS R.A. Vishwakarmaa iCentral Central
Institute of Medicinal & Aromatic Drug Research Institute, Lucknow
Abstracts Regioselective new, unnatural epimers Coleonol a labdane
diterpenoid
in unique
226016
13-epoxy-labd-14-en-1
la, 68, Ya-trihydroxy-7B-acetoxy-8,
isolated’
from the Indian medicinal
congestive
manner
Plants, Lucknow 226001;India
Mitsunobu inversion of the hydroxyl groups of coleonol (forskolin) led to as potential adenylate cyclase stimulant and pharmacodynamic agents.
(Forskolin,
drug for glaucoma,
and J.S. Tandonb
by direct
of guanine
nucleotide
and novel
pharmacodynamic
heart-failure
and reversible
stimulating
action
protein2.
action,
plant
and bronchial on catalytic
Forskolin,
has emerged
Coleus forskohlii
asthma,
activates
subunit
I),
and a potential
adenylate
of the enzyme
owing to its highly
as a highly
l-one,
cyclase
in absence
oxygenated
structure
target
synthetic
attractive
for
investigations2. During we decided activity
our studies
with
the synthesis using
the
new and unnatural
stereochemical
of various
versatile
l-e&
Mitsunobu
stereochemical hydroxyl
on the physiological
to prepare
outcome
centres.
azodiacarboxylate
orientation and 7-a
reaction3
2 after
assigned
to l-a-axial
(Ac20,
was assigned A recently using
Py,
Mitsunobu
acid
7a-axial
reaction
acetylcoleonol showed’
7-@equatorial 7-+coleonol
at
epimer
5.50
in MeOH
(7).
NaOBz
gave
report
in
dry
(TPP,
with
of secondary
3 mmol),
diethyl-
THF at room temperature
as lg-benzoyloxy-l-deoxy= 10 Hz, J
C-2ax and C-2eq protons.
= 2Hz) axleq Debenzoy-
(3) which on selective
(4). The stereochemistry
of Cl-OH
of 4
to obtain
as nucleophile
equatorial
and
sodium
= 9.5 & J = 2.0 Hz). ax/eq vs axial-hydroxyl selectivity
benzoate
(5) prepared
as catalyst
was
by deacetylation
and NaOBz afforded
used
of 1, on
7-deacetyl-7-&trifluoro-
The PMR 2
Hz) for
The hydrolysis led to 7-deacetyl-
The reaction
complex
we
synthesis
of configuration
at 6 5.75 (Jax,ax
of 1. The 7-deacetylcoleonol
(J =
(6-acetyl-7-deacetylcoleonol, TPP-DEAD
in organic
I-e&-7-deacetylcoleonol
using TFA (1.1 mole equivalent)
CH_ proton.
of 6 by refluxing
procedure6
(TFA)
(6) in 60% yield. 4
mmol)
and characterized
coleonol
Herein
by PMR5 which showed & at 3.95 (Jax,ax
Mitsunobu
trifluoroacetic
i-ee
tool
inversion
with two neighbouring
gave
groups.
biological
and 6,7-epoxy-6,7-dideoxycoleonol
triphenylphosphine
of 2 showed4 g
and its analogues,
of 1 to correlate
hydroxyl
a useful
acid (1.1
NaOMe at r.t. yielded O-5’)
as E-equatorial modified
to synthesize
of 6
coupled
of 2 with methanolic
various
a clean
chromatography
(yield 45%). The PMR spectra
acetylation
invariably
(Forskolin)
(epimers)
(forskolins)
of 1 (I mmol) with
coleonol
proton
of Coleonol
has become
(DEAD, 3 mmol) and benzoic
for 36 h gave compound
lation
of
coleonols
which
being almost
The reaction
effects
stereoisomers
using
of coleonol-B 8)
with
TFA
and
/+?&!+
6-acetyl-7-deacetyL7-e&-
trif luoroacetyfcoleonol
(9)
which
on selective 7493
hydrolysis
(reflux
in
MeOH)
gave
7494
7-M coleonol-B (10). Further hydrolysis (NaOMe in MeOH at r.t.) 9 gave 7. An interesting product, 6,7-epoxy-6,7-dideoxycoleonol (11) was formed when 7-deacetylcoleonol (5) was reacted with TPP-DEAD complex in dry II-IF in absence of acidic component. The result indicated
~l~~~~
1, R’ = a-OH,
R* = AC
5, R’ = H, R2 = B-OH
2, R’ = f3-OBz, R* = AC
6, Rl = H, R* = a-OCOCF3
3, R’ = B-OH, R* = H
7, R1 = H, R* = a-OH
4, R’ = B-OH, R* = AC
8, Rl = AC, R* = &OH
I1
9, R’ = AC, R* = a-0COCF3 10, R1 = AC, R* = a-OH the inversion at C-7 being successful but followed by an intramolecular nucleophilic dpplaceto be ment by free hydroxyl at C-6. The stereochemistry of epoxide ring was ascertained 6B-7f3-oriented as determined by PMR spectrum of Il. Conclusively, it is possible to regioselectively invert the configuration of l- and 7-OH of forskolin using Mitsunobu reaction to prepare new and unnatuml epimeric compounds as potential pharmacodynamic agents. The 6- and 9-hydroxyl groups being much more hindered did not react. The biological activity of the epimeric forskolins will be published separately. References and Notes 1.
2.
3. 4.
5.
6. 7.
8.
(a) J.S. Tandon, M.M. Dhar, S. Ramakumar and K. Venkatesan, Indian J. Chem., 15B, 880 (1977): (b) S.V. Bhat, B.S. Bajwa, H. Dornauer, N.J. deSouza and H.W. Fehlhaber, Tetrahedron Lett., 1669 (1977). ’ For a review, See: K.B. Seamon and J.W. Daly, Adv. Cyclic Nucleotide Res., 20, 1 (1986). For total syntheses of Forskolin, See: (a) F.E. Ziegler, B.H. Jaynes, M.T. Saindane, S. Sakata, M. Sonegawa, J. Am. Chem. Sot., 109, 8115 (1987); (b) S .-i. Hashimoto, S. Ikegami, J. Am. Chem. Sot., 110, 3670 (1988); k) E.J. Corey, P.D.S. Jardine, J-C. reactions, see (a) R.W. Rohloff, J. Am. Chem. Sot., 110, 3672 (1988). For regiocontrolled Kosley and R.J. Cherill, J. Org. Chem., 54, 2972 (1989); (b) G.I. O’Malley, B. Spat-4 d( 17), 5.75 (dd, lH, H-l% J = 10 & 2), 5.50 (fi, lH, H-7, J q 4), 5.24 (dd lH, H-15, J q 17 d( 1.5), 4.48 (3 lH, H-6), 4.93 (dd, lH, H-15’, J = 10 & 1.5), 3.18-7-& lH, H-12, J q 17), 2.50 (4 lH, H-12, 3 = 17), 2.15 (3 3H, COCI-13), 1.00, 1.10, 1.27, 1.30, 1.60 (all% 5 x CH3). PMR data of 4. 6.13 (dd, lH, H-14, J = 10 & 17)), 5.21 (dd, lH, H-15, J = 17 d( 1.5)~ 4.99 (dd, IH, H-15, J = 10 & 1.5), 3.95 (dd, IH, H-lax- J = 9.5 & 2), 4.40 (3 lH, H-6), 5.50 (3 lH, H-7, J = 4), 3.18 (c, lH, H-12, J = 17), 2.50 (c& lH, H-12, J = 17), 2.10 (3 lH, H-5, J I 3), 2.15 (3 3H, COCH ), 1.0, 1.05, 1.25, 1.40, 1.60 (all 3 5 x CH ). M. Varasi, K.A.M. Walker and d .L. Maddox, J. Or)g. Che(m., 52, 4235 (198% PMR data of 6. 6.00 (dd, lH, H-14, J = 10 & 17, 5.21 dd lH, H-15, J = 17 6r l-5), 4.99 (G, lH, H-15, J = 10 & 1.5), 5.50 (a lH, H-7, J = $4.55 (3 lH, H-l), 4.48 (3 IH, H-6), 3.15 (4 lH, H-12, J = 17), 2.50 (3 lH, H-12, J = 17), 2.30 (& lH, H-5), 0.95, 1.05, 1.25, 1.30, 1.55 (all 3 5 x CH ). PMR data of 11. 6.00 (dd, &I, H-14, J = 10 & 17), 5.15 (dd, lH, H-15, J = 17 6( 1.5), 5.00 (dd, lH, H-15, J = lo), 4.20 (-m lH, H-l), 3.30 (c& lH, .H-12, J = 15), 2.40 (d lH, H-12; J = 15), 2.55 (I& lH, H-7, J = 3.5), 2.15 (dd, lH, H-6, J = 3.5 & 1.9), 2.05 ($ lH, H-5, J = 1.9), 1.20, 1.21, 1.40, 1.50, 1.60 (all3 5 x CH3). CDRI Communication
No. 4720
(Received in UK 24 October 1990)