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Synthetic studies on Rabdosia diterpene lactones I: The preparation of a key tricyclic intermediate
Tetrahedron Printed in
Letters,Vo1.27,No.33,pp Great Britain
0040-4039/86 $3.00 + .OO Pergamon JournaPs Ltd.
3923-3926,1986
SYNTHETICSTUDIESON RABDOSIADITERPENE LACTONES I: THE PREPARATION OF INTERMRDIATE
A KEY
TRICYCLIC
Martin J. Kenny, Lewis N. Mander* and S. Paul Sethi Research School
of Chemistry,
Australian
National University, Australia
GPOBox 4, Canberra, ACT, 2601,
Summary: A strategy is proposed for the synthesis of Rabdosia diterpene lactones, eg. effusin 2 and the preparation of a suitable tricyclic intermedia= 6 described. More than 100 highly c(6)-C(7)
in the B-ring
completed
by E. Fujita
promising
antineoplastic
the following
Letter5
A relay
from the
et a1.,4
but otherwise
properties, we describe
these structurally
have received the first
arrangements typified
total
little synthesis
many with
In this
attention.
of a derivative
at
has been
complex molecules,
synthetic
fission
by enmein l2 and
of 1, encompassing 40 or so steps,
synthesis
that of (+)-15-desoxy-effusin
lactones,
have been isolated
number of these compounds have undergone oxidative
to form one of two new skeletal
23. respectively
effusin
oxygenated kaurane derivatives
A significant
Rabdosia genus.’
and
of these diterpene
3. 12
OH
HO’
z
3
OH
A summary of the synthetic synthetic
equivalence
ring and associated reactions
plan is given in Scheme 1.
hydrolytic
of the B-ring fission
moieties hemi-acetal
of the lactone
(o.f.(5+3)3.
The preparation
details
elaboration
of its
The key features
4
R=O
5
R=H, are (a) the
between the methoxyenone 6 and enone T6, (b) the construction lactone
by sequential
(8+9) modelled on our earlier
utilization
R=H2
into
syntheses function
intramolecular of gibberellins
A,, A4 and A38)7, induced fission
in Scheme 2 and described
(+)-15-desoxy-effusin
3923
of the A-
(7+8) and alkylation (c)
the
in 10 as a thermodynamic sink following
ring in 9, (d) the periodate
of 6 is outlined
Michael
3 are disclosed
of the B-ring
below,
while the
in the following
Letter -*
3924
Scheme
1
o&&MM
q!.pp
3 -5-
,
WOH b02H
o/”/
OR
IO
Reduction by in situ
of
alkylation
129-130°c,8
which
formylation
followed
ethyl
which
ester
yellow
solid,
catalytic m.p.
3,5-dimethoxybenzoic with
was not
hydrogenation
131.5-133OC,
which acid
The methoxy thereby
allowing
which
afforded
trans
isomer,
fusion
to
clearly
at
relative interactions
to
m.p.
21,
identical
with
to
give
would
crystal
X-ray
that
(6 25.7
bond
mixture
(6 24.2
and 26.5)
15 with
its
15 as a pale to
saturated
and cyclized
towards
acid,
in
most
reagents,
aluminum hydride,
(88% yield)
with
assignment
showed,
its
of
inter
and 22.6,
was obtained,
of
that
the
were
additional
however,
hydrogenation)
B,C-
a B,C -cis-
alia,
respectively)
as a consequence
and further
m.p
184.5-185.5°C.12
bond by lithium
Confirmation
B-elimination,
acid
94-95’C
m.p.
which
acid
ammonia to
The stereochemical
and C(12)
isomer.l’l
lOl-102°C
as
its
methoxymethyl
and then
The assignment the
convexity
alkylation
structure
We are
olefinic
double
as a 5:2:2
20.13
C(11)
m.p. 17,
12,
15 was resistant
in liquid
16,
acid
Vilsmeier
l3,g. of
followed
Y-
by reduction
which
was
sample.15
m.p.
of
A(6)
A(9)
Acid
‘3C-NMR spectrum
isomer
former
102-103’C.
ensure
The elaboration Acknowledgement:
from
B,C-trans
19,
expectation
the molecule
on its
18 was protectedI
based
on the
and enone
an authentic
ester
the
162-163’C
(hydrogenation,
6, m.p.
the
of
18 m.p.
initially
intermediate
single
17 deactivates reduction
in the
Methoxyenone C(10)
diazoketone
ester
furnishing
metal
ammonia,
dihydroaromatic
a mixture
directly,
by sodium
in liquid
to
88-89’C).
methoxydienone
resonances
92-93OC,
m.p.
give
to
the
gave
into
in
the
hydrolysed
ester,
was reduced
95.5-96.5OC
to
gauche
condensation
-20°C10s11
methoxyenone m.p.
but
afforded
decarboxylation
was converted
group
18 was based
ethoxide
(methyl it
selective
identifiable
upfield
so
11 by 1 ith ,ium metal
acid
oxidative
separated
310-314OC
OR
9
4-bromobutanoate
underwent
by potassium
m.p.
trifluoroacetic
ethyl
readily
0
on this
determination
6 into indebted
alkylated of
imposed
out
(+)-15-desoxyeffusin to Bruce
Twitchin
m.p.
ally1
stereochemistry by the
C-acylated
to
give
at C(10)
in
ester
on the
was ultimately
described
technical
66-67OC,
bromide
fusion
at a later
3 is for
B,C-cis This
same side.l7 carried
ether, with
stage
in the
in the support.
top
the
at key
10 was face
confirmed
Of by a
synthesis.5
following
better.
3925
Scheme 2
16
g
15
14
88%
19
18
17
(a) Li(2.3 equiv), NH3, -33“C; Br(CH213C02Et, lh. CuIOAcJ2, PhH, 25"C, 10 min; 4O"C, lh; aq. NaOAc, ice.
(bl PblOAcl4(1.2 equivl,
ICH~~HI~. (cl POCZ3(2 equiv), DMF, 25'C, 4h;
(dl NaOEt, THF, 24'C, lh; NaOH, EtOH-H20, ZO"C, lh.
(e/ Na(3 equiu), NH3, t-BuOH, -33V, 45 min, 97% yield.
Cfl(COC112(3.0equiv),
CH2C12, 2O"C, 45 min; 11lh; CH2N2(3 equivl, Et20, -3O'C. CH2CZ2(7:l), -25oc, 5 min. Et20, O"C, lh.
(hl substrate/THF+filteredsolution of LiAlH4 in
li) CICH2OMe, iPr2NEt, CH2C12, 25“C, 12h.
THF, 25"C, 30 min; CZC02Et(3 equivl, -78'C, 5 min. 25"C, 15 min;
(f) CF3C02H,
CH2=CHCH2Br(3 equiv), 25"C, 3h.
Cj) LDA(2.5 equiv),
Ikl NaH(2.S equiv), DMF,
3926
References and Footnotes 1.
E. Fujita and M. Node, Progress in the Chemistry of Natural Products, Vol. 46, Springer Verlag, New York, 1984, pp.77-157.
2.
E. Fujita, T. Fujita, and M. Shibuya, J. Chem. Sot. Chem. Commun., 1966, 297.
3.
I. Kubo, T. Kamikawa, T. Isobe, and T. Kubota, J. Chem. Sot. Chem. Commun., 1980, 1206.
4.
E. Fujita, M. Shibuya, S. Nakamura, Y. Okada, and T. Fujita, J. Chem. Sot. Perkin Trans. I, 1974, 165.
5.
M.J. Kenny, L.N. Mander, and S.P. Sethi, Tetrahedron Lett., 1986, 27
6.
cf. G. Stork and R.L. Danheiser, J. Org. Chem., 1973, 38, 1775.
7.
L. Lombardo, L.N. Mander, and J.V. Turner, J. Am. Chem. Sot., 1980, 102, 6626;
A.L.
Cossey. L. Lombardo, and L.N. Mander, Tetrahedron Lett., 1980, 4383; L. Lombard0 and L.N. Mander, J. Org. Chem., 1983, 48, 2298. 0.
Structures 10 and 14-19 represent racemic compounds and are fully consistent with their 'H-NMR, IR and mass spectra. All crystalline compounds gave satisfactory microanalytical data (+<0.3%).
Atoms are numbered throughout on the basis of the
full kaurane structure. 9.
cf. A.J. Birch and J. Slobbe, Tetrahedron Lett., 1976, 2079.
10.
cf. D.J. Beames, T.R. Klose, and L.N. Mander, Aust. J. Chem., 1974, 27, 1269.
11.
cf. D.W. Johnson, L.N. Mander, and T.J. Masters, Aust. J. Chem., 1981, 34, 1243.
12.
This intermediate had been prepared earlier by D.W. Johnson (Ph.D Thesis, University of Adelaide, 1975). In this case, however, 6,8-dimethoxy-1,2,3,4-tetrahydro-2naphthoic acid was prepared (47% yield) from 6,7,8-trimethoxy-4-oxo-1,2,3,4tetrahydro-2-naphthoicacidto by Birch reduction (Na, liq.NH3) followed by Clemmensen reduction (Zn-Hg, HCl, PhMe).
13.
Catalytic hydrogenation under a variety of conditions or lithium-liquid ammonia reduction also allowed selective reduction of the A(9) olefinic bond, but strongly favoured formation of the trans isomer.
14.
NMR Spectroscopy", Academic Press, New York, 1972, pp.52-69. J.B. Stothers, ffCarbon-13
15.
A.L. Cossey, L.N. Mander, and S.G. Pyne, Aust. J. Chem; 1979, 32, 817.
16.
G. Stork and T. Takahashi, J. Am. Chem. Sot., 1977, 99, i275.
17.
Steric factors are often outweighed by stereoelectronicones in the alkylation of conformationallyrestricted B-keto esters, but the incorporationof the a',R' olefinic bond allows the substrate to adopt a quasi-boat conformation for a minimal energy penalty and maintain good orbital overlap with an incoming reagent on the g-face. cr. A. Afonso, J. Org. Chem., 1970, 35, 1949. (Received
in UK 14 May
1986)
Letters,Vo1.27,No.33,pp Great Britain
0040-4039/86 $3.00 + .OO Pergamon JournaPs Ltd.
3923-3926,1986
SYNTHETICSTUDIESON RABDOSIADITERPENE LACTONES I: THE PREPARATION OF INTERMRDIATE
A KEY
TRICYCLIC
Martin J. Kenny, Lewis N. Mander* and S. Paul Sethi Research School
of Chemistry,
Australian
National University, Australia
GPOBox 4, Canberra, ACT, 2601,
Summary: A strategy is proposed for the synthesis of Rabdosia diterpene lactones, eg. effusin 2 and the preparation of a suitable tricyclic intermedia= 6 described. More than 100 highly c(6)-C(7)
in the B-ring
completed
by E. Fujita
promising
antineoplastic
the following
Letter5
A relay
from the
et a1.,4
but otherwise
properties, we describe
these structurally
have received the first
arrangements typified
total
little synthesis
many with
In this
attention.
of a derivative
at
has been
complex molecules,
synthetic
fission
by enmein l2 and
of 1, encompassing 40 or so steps,
synthesis
that of (+)-15-desoxy-effusin
lactones,
have been isolated
number of these compounds have undergone oxidative
to form one of two new skeletal
23. respectively
effusin
oxygenated kaurane derivatives
A significant
Rabdosia genus.’
and
of these diterpene
3. 12
OH
HO’
z
3
OH
A summary of the synthetic synthetic
equivalence
ring and associated reactions
plan is given in Scheme 1.
hydrolytic
of the B-ring fission
moieties hemi-acetal
of the lactone
(o.f.(5+3)3.
The preparation
details
elaboration
of its
The key features
4
R=O
5
R=H, are (a) the
between the methoxyenone 6 and enone T6, (b) the construction lactone
by sequential
(8+9) modelled on our earlier
utilization
R=H2
into
syntheses function
intramolecular of gibberellins
A,, A4 and A38)7, induced fission
in Scheme 2 and described
(+)-15-desoxy-effusin
3923
of the A-
(7+8) and alkylation (c)
the
in 10 as a thermodynamic sink following
ring in 9, (d) the periodate
of 6 is outlined
Michael
3 are disclosed
of the B-ring
below,
while the
in the following
Letter -*
3924
Scheme
1
o&&MM
q!.pp
3 -5-
,
WOH b02H
o/”/
OR
IO
Reduction by in situ
of
alkylation
129-130°c,8
which
formylation
followed
ethyl
which
ester
yellow
solid,
catalytic m.p.
3,5-dimethoxybenzoic with
was not
hydrogenation
131.5-133OC,
which acid
The methoxy thereby
allowing
which
afforded
trans
isomer,
fusion
to
clearly
at
relative interactions
to
m.p.
21,
identical
with
to
give
would
crystal
X-ray
that
(6 25.7
bond
mixture
(6 24.2
and 26.5)
15 with
its
15 as a pale to
saturated
and cyclized
towards
acid,
in
most
reagents,
aluminum hydride,
(88% yield)
with
assignment
showed,
its
of
inter
and 22.6,
was obtained,
of
that
the
were
additional
however,
hydrogenation)
B,C-
a B,C -cis-
alia,
respectively)
as a consequence
and further
m.p
184.5-185.5°C.12
bond by lithium
Confirmation
B-elimination,
acid
94-95’C
m.p.
which
acid
ammonia to
The stereochemical
and C(12)
isomer.l’l
lOl-102°C
as
its
methoxymethyl
and then
The assignment the
convexity
alkylation
structure
We are
olefinic
double
as a 5:2:2
20.13
C(11)
m.p. 17,
12,
15 was resistant
in liquid
16,
acid
Vilsmeier
l3,g. of
followed
Y-
by reduction
which
was
sample.15
m.p.
of
A(6)
A(9)
Acid
‘3C-NMR spectrum
isomer
former
102-103’C.
ensure
The elaboration Acknowledgement:
from
B,C-trans
19,
expectation
the molecule
on its
18 was protectedI
based
on the
and enone
an authentic
ester
the
162-163’C
(hydrogenation,
6, m.p.
the
of
18 m.p.
initially
intermediate
single
17 deactivates reduction
in the
Methoxyenone C(10)
diazoketone
ester
furnishing
metal
ammonia,
dihydroaromatic
a mixture
directly,
by sodium
in liquid
to
88-89’C).
methoxydienone
resonances
92-93OC,
m.p.
give
to
the
gave
into
in
the
hydrolysed
ester,
was reduced
95.5-96.5OC
to
gauche
condensation
-20°C10s11
methoxyenone m.p.
but
afforded
decarboxylation
was converted
group
18 was based
ethoxide
(methyl it
selective
identifiable
upfield
so
11 by 1 ith ,ium metal
acid
oxidative
separated
310-314OC
OR
9
4-bromobutanoate
underwent
by potassium
m.p.
trifluoroacetic
ethyl
readily
0
on this
determination
6 into indebted
alkylated of
imposed
out
(+)-15-desoxyeffusin to Bruce
Twitchin
m.p.
ally1
stereochemistry by the
C-acylated
to
give
at C(10)
in
ester
on the
was ultimately
described
technical
66-67OC,
bromide
fusion
at a later
3 is for
B,C-cis This
same side.l7 carried
ether, with
stage
in the
in the support.
top
the
at key
10 was face
confirmed
Of by a
synthesis.5
following
better.
3925
Scheme 2
16
g
15
14
88%
19
18
17
(a) Li(2.3 equiv), NH3, -33“C; Br(CH213C02Et, lh. CuIOAcJ2, PhH, 25"C, 10 min; 4O"C, lh; aq. NaOAc, ice.
(bl PblOAcl4(1.2 equivl,
ICH~~HI~. (cl POCZ3(2 equiv), DMF, 25'C, 4h;
(dl NaOEt, THF, 24'C, lh; NaOH, EtOH-H20, ZO"C, lh.
(e/ Na(3 equiu), NH3, t-BuOH, -33V, 45 min, 97% yield.
Cfl(COC112(3.0equiv),
CH2C12, 2O"C, 45 min; 11lh; CH2N2(3 equivl, Et20, -3O'C. CH2CZ2(7:l), -25oc, 5 min. Et20, O"C, lh.
(hl substrate/THF+filteredsolution of LiAlH4 in
li) CICH2OMe, iPr2NEt, CH2C12, 25“C, 12h.
THF, 25"C, 30 min; CZC02Et(3 equivl, -78'C, 5 min. 25"C, 15 min;
(f) CF3C02H,
CH2=CHCH2Br(3 equiv), 25"C, 3h.
Cj) LDA(2.5 equiv),
Ikl NaH(2.S equiv), DMF,
3926
References and Footnotes 1.
E. Fujita and M. Node, Progress in the Chemistry of Natural Products, Vol. 46, Springer Verlag, New York, 1984, pp.77-157.
2.
E. Fujita, T. Fujita, and M. Shibuya, J. Chem. Sot. Chem. Commun., 1966, 297.
3.
I. Kubo, T. Kamikawa, T. Isobe, and T. Kubota, J. Chem. Sot. Chem. Commun., 1980, 1206.
4.
E. Fujita, M. Shibuya, S. Nakamura, Y. Okada, and T. Fujita, J. Chem. Sot. Perkin Trans. I, 1974, 165.
5.
M.J. Kenny, L.N. Mander, and S.P. Sethi, Tetrahedron Lett., 1986, 27
6.
cf. G. Stork and R.L. Danheiser, J. Org. Chem., 1973, 38, 1775.
7.
L. Lombardo, L.N. Mander, and J.V. Turner, J. Am. Chem. Sot., 1980, 102, 6626;
A.L.
Cossey. L. Lombardo, and L.N. Mander, Tetrahedron Lett., 1980, 4383; L. Lombard0 and L.N. Mander, J. Org. Chem., 1983, 48, 2298. 0.
Structures 10 and 14-19 represent racemic compounds and are fully consistent with their 'H-NMR, IR and mass spectra. All crystalline compounds gave satisfactory microanalytical data (+<0.3%).
Atoms are numbered throughout on the basis of the
full kaurane structure. 9.
cf. A.J. Birch and J. Slobbe, Tetrahedron Lett., 1976, 2079.
10.
cf. D.J. Beames, T.R. Klose, and L.N. Mander, Aust. J. Chem., 1974, 27, 1269.
11.
cf. D.W. Johnson, L.N. Mander, and T.J. Masters, Aust. J. Chem., 1981, 34, 1243.
12.
This intermediate had been prepared earlier by D.W. Johnson (Ph.D Thesis, University of Adelaide, 1975). In this case, however, 6,8-dimethoxy-1,2,3,4-tetrahydro-2naphthoic acid was prepared (47% yield) from 6,7,8-trimethoxy-4-oxo-1,2,3,4tetrahydro-2-naphthoicacidto by Birch reduction (Na, liq.NH3) followed by Clemmensen reduction (Zn-Hg, HCl, PhMe).
13.
Catalytic hydrogenation under a variety of conditions or lithium-liquid ammonia reduction also allowed selective reduction of the A(9) olefinic bond, but strongly favoured formation of the trans isomer.
14.
NMR Spectroscopy", Academic Press, New York, 1972, pp.52-69. J.B. Stothers, ffCarbon-13
15.
A.L. Cossey, L.N. Mander, and S.G. Pyne, Aust. J. Chem; 1979, 32, 817.
16.
G. Stork and T. Takahashi, J. Am. Chem. Sot., 1977, 99, i275.
17.
Steric factors are often outweighed by stereoelectronicones in the alkylation of conformationallyrestricted B-keto esters, but the incorporationof the a',R' olefinic bond allows the substrate to adopt a quasi-boat conformation for a minimal energy penalty and maintain good orbital overlap with an incoming reagent on the g-face. cr. A. Afonso, J. Org. Chem., 1970, 35, 1949. (Received
in UK 14 May
1986)