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Total synthesis of (−) altholactone (goniothalenol) from D-glucose
Tetrahedron Letters,Vol.28,No.34,pp Printed in Great Britain
TOTAL SYNTHESIS
0~ (-) ALTHOLACTONE
Jean-Pierre
GESSON:
Laboratoire "Synthese 40, Avenue
ABSTRACT
3945-3948,1987
(GONIOTHALENOL)
Jean-Claude
de Chimie
JACQUESY
and Martine
de Produits
isolated
MONDON
Naturels"
Pineau - 86022 POITIERS,
: A ten steps total synthesis of (-) altholactone, pyrone
FROM D-GLUCOSE
XII - U.A. CNRS N" 489
et Reactivite
du Recteur
QO40-4039/87 $3.00 + .OO Pergamon Journals Ltd.
from Goniothahw
species,
France
enantiomer
is described
of an antitumor
starting
from D-
glucose. (+) Altholactone known PotyaZthea species. rano-2
pyrone structure
zation. nalysis)
Recently,
1 has been isolated This substance
proposed
MCLAUGHLIN
in 1977 by LODER et al? from an un-
is characterized
on the basis of spectral
et d?
have extracted
by a cis-fused
data and chemical
1 (structure
from the stem bark of Goniothubmus giganteus Annonceae
shown that it is cytotoxic
tetrahydrofu-
confirmed
derivati-
by X-Ray a-
and subsequently
in vitro (BS, 9 KB) and active in aiuo against P 388 leuke-
mia.
phm 4
\3
2
HO/’
9
O
Ii
(+) 1 Altholactone (Goniothalenol)
ZR=H
Goniodiol
3 R = OH
Goniotriol
Ph H
4 Goniothalamin
2 Dihydrokawain-5
3945
01
3946
It is worthy figuration
of note that other bioactive
have been isolated
the more oxygenated
from other Goniothdms
goniodiol
red as a non cyclized
1 and goniotrio134
The interesting
biological
asperlin7
activities
nes (with either a 6R or a 6s configuration) of (+) and (-) altholactone
Retrosynthetic
arylation
analysis
may be obtained
of D-glucose)
found in related
demonstrated
by most of these pyro-
that we propose
two enantiodiver-
from D-glucose'.
from a carbohydrate
and that construction
pyro-
(i.e. respectively
5R, 6s and 7s C-4, C-3 and C-2
of the pyrone ring from 5 to give -11 followed
by
at C-8 should give (-) 1.
11
PREPARATION
6 successively.
OF PYRONE 11 Reformatsky
tate affords
condensation
of the readily
a major oily compound 1,
is thought
enolate1°'12. ethyl acetate)
hydrolysis
pyridine)
The axial orientation tion about the relative (J H-4/H-5 Finally, is obtained
from g
is then converted
and to acetate I&
of the acetoxy
of the zinc (H2,PdK,
to lactone 2 (1.2
m.p. 85-86'C,
group, confirming
of z, is demonstrated
= 2.2 Hz) of triplets
in CH2C12 at room temperature
addition
by hydrogenolysis
[aID = + 22"
78% from @I'.
stereochemistry
the requested
10 fj with ethyl bromoace-
chelation-controlled
of ester 1 followed
gives ,11, m.p. 142°C (85%) which
(CHC13, c = 1.2), (Ac20, pyridine,
available
IaID = -22" (CHC13, c = 2), 85% isolated yield"
to result from the favored
Base catalyzed
eq. dicyclohexylcarbodiimide,
CHCl,+I
is however
justify
These two points will be discussed
doublet
43 and
and analogues8.
of (-) 1 shows that the requested
(-) 1
which
6s con-
: goniothalamin
(this latter compound may be conside-
of (+) altholactone olguin6,
nes such as dihydrokawainol-55,
configurations
species
form of (-) altholactone).
The 6R configuration
gent syntheses
pyrones with the opposite
(J H-5/H-6
(87%).
assumpof a
= 8.8 Hz) at 6 = 5.32 ppm for H-4.
pyrone 11, m.p. 70-71"C,
on treatment
the previous
by the presence
[aID = + 33" (c = 1.5,
with 1.1 eq. of diazabicyclouhdecene
(DBU)
3947
Ii
zR=H &I R = COCH3 ARYLATION
OF PYRONE u The conversion
logous to the synthesis
of C-aryl nucleosides
ting groups and reaction arylation
of pyrone 11 to (-) altholactone
with 40 eq. of benzene
from carbohydrates.
Although
many activa-
have been reported to promote the formation and 13 onium ion , we anticipated that anhydrous HF will cata-
and arylation
of 11 to 1. As a matter
in HF at 0°C for 10 min. affords
of fact treatment
three compounds
to retain even after
ties (not detected
Florisil
by NMR and TLC) which
this sample affords
material,
chromatography
preclude
quantitatively
(m.p. 142°C) and spectral
cept for the sign of optical
14, m.p. 141"C, data"
rotation
[aID
are similar
J H-7/H-8
is however
trast with the usual respectivevalues
(FLitt
of impuri= 75'C,[a]B
[al0
smaller
by the occurrence
both exhibit
angles
by LOOER' ex-
(EtOH, c = 1)).
= 266" (EtOH, c = 0.5)11.
This mate-
at C-8 with 1. The observed
for -12 than for 1 (see Table
) in conrings
of conformations
in agreement
14
R = H
12
R = COCH3
13 Table
no Ph
AA (1)
3J (Hz)
1
-12
H5-H6
5
5
H6-H7
2
0
H7-H8
5.5
3.5
n Ph--
14
.
A for 1 and B for 11 which -3 with the experimental J values (see Table).
n (-) 1
of
= - 200' (EtOH, c = 1) whose
for cis and trans 3J in five membered
This may be explained dihedral
trace amounts
to those reported
([al0 = + 208"C,
. 12 (18%), m.p. 190-192”C, constant
14
crystallization
rial must be, on the basis of MS and NMR data, epimeric coupling
are iden-
[a]B = - 166" (c = 0.5,
. = llO"C, [alo = + 184.7" (EtOH)2 for (+) 1). Acetylation
+ 188" (EtOH)l and FLitt
physical
This oily synthetic
of -11
:
. (-) 1 (48%) whose TLC behaviour, IR, ‘H and 13C NMR spectra tical with those of (+) LIy2. EtOH) appears
as ana-
conditions
of the intermediate
lyze both ketal cleavage
1 may be considered
=
3948
. 13 (3%), m.p. 201-202°C,[aID This minor
compound
results
= + 53" (EtOH, c = 0.5)11.
from
diarylation
as shown by MS and NMR spec-
tra. As expected
(-) 1 resulting
from arylation
12 (2.7 ratio) and under these conditions promise
for HF-catalyzed
arylation
anti to theC-7/OHis
diarylation
of suitably
is minimized15.
protected
favored
over
This result holds
carbohydrates
to C-nucleosi-
des.
In conclusion, cose using an efficient
(-) altholactone HF catalyzed
1 has been prepared
arylation
ty of these new pyrones will be reported ACKNOWLEDGMENTS
: We are grateful to Prof.McLAUGHLIN
(Paris) for financial
antitumor
activi-
later.
viding a sample of (+) 1 as well as copies of res HOECHST
in 10 steps from O-glu-
as the last step.The
(Purdue U., USA) for kindly pro-
IR and NMR. We thank CNRS and Laboratoi-
support.
REFERENCES 1 - J.W. LOOER and R.M. NEARN, Heterocycles, A. EL-ZAYAT,
2-
N.R. FERRIGNI,
1, 113 (1977).
T.G. MC CLOUD, A.T. MC KENZIE, S.R. BYRN, J.M.
C.J. CHANG and J.L. MC LAUGHLIN,Tetrahedron K. JEWERS,
3-
Letters, 2&, 955 (1985).
J.8. DAVIS, J. OOUGAN, A.H. MANCHAOA,
PINAN, Phytochemistry, 4 - S.K. TALAPATRA,
CASSIOY,
G. BLUNOEN,
A. KYE and S. WETCHA-
11, 2025 (1972).
0. BASU, T. DEB, S. GOSWANI
and B. TALAPATRA,
Ind.J.Chen., 24-8, 29,
(1985). H. ACHENBACH
5-
6 - A. ALEMANY,
and G. WITTMANN, C. MARQUEZ,
TINEZ RIPOLL, 7-
Tetrahedron
MARTINEZ,
C. MARQUEZ,
Tetrahedron
9 - The synthesis
and M.P. KUNSTMANN,
c - K. KAKINUMA,
Tetrahedron
internal
Letters,
A. PERALES,
1791 (1969).
J. FAYOS and M.
in the accompanying
J. Org. Chem., 2,
Letters,
communication.
Chem. Ber., 61, 1735 (1928). 1800 (1962).
4413 (1977).
have been characterized
'H and eventually
by elemental
analysis
or High Resolu-
13C NMR (BRUKER WP 200 SY) in COC13 using TMS as
standard.
12 - For a review of addition see
is described
W. OURR and H. Von HOCHSTETTER,
and S. HANESSIAN,
tion MS, IR,
Tetrahedron
S. VALVEROE,
Letters, 20, 3583 (1979).
b - M.L. WOLFROM
11 - All new compounds
J. FAYOS and M. MAR-
3579 (1979).
C. PASCUAL,
of (+) altholactone
10 a - K. FREUOENBERG,
3259 (1970).
A. PERALES,
Can. J. Chem., 56, 2889 (1978).
R.H. EVANS, G.A. ELLESTAO
b - A. ALEMANY,
Letters,
S. VALVEROE,
Letters, 3,
S. LESAGE and A.S. PERLIN,
8a-
Tetrahedron
C. PASCUAL,
reactions
to chiral
a- and B- alkoxy carbonyl compounds
: M.T. REETZ, Angew. Chem. Int. Ed. Engl., 23, 556 (1984).
13 - S. HANESSIAN
and 6. PERNET, Adv. Carbohydr.
Chem. Biochem.,
2,
111 (1976).
6. DOYLE OAVES and C.C. CHENG, Progress in Medicinal Chemistry, Vol. 13, 303, G.P. ELLIS and G.B. WEST Ed., North-Holland Publishing Company (1976). 14 - A. GAUOEMER in Stereochemistry : Fundamentals and Methods, Vol. 1, 44, H.B. KAGAN Ed., Georg Thieme Verlag Ed. (1977). 15 - F. MICHEEL
and J. STANEK,
Tetrahedron
(Received in France 30 May
1987)
Letters,
1609 (1970).
TOTAL SYNTHESIS
0~ (-) ALTHOLACTONE
Jean-Pierre
GESSON:
Laboratoire "Synthese 40, Avenue
ABSTRACT
3945-3948,1987
(GONIOTHALENOL)
Jean-Claude
de Chimie
JACQUESY
and Martine
de Produits
isolated
MONDON
Naturels"
Pineau - 86022 POITIERS,
: A ten steps total synthesis of (-) altholactone, pyrone
FROM D-GLUCOSE
XII - U.A. CNRS N" 489
et Reactivite
du Recteur
QO40-4039/87 $3.00 + .OO Pergamon Journals Ltd.
from Goniothahw
species,
France
enantiomer
is described
of an antitumor
starting
from D-
glucose. (+) Altholactone known PotyaZthea species. rano-2
pyrone structure
zation. nalysis)
Recently,
1 has been isolated This substance
proposed
MCLAUGHLIN
in 1977 by LODER et al? from an un-
is characterized
on the basis of spectral
et d?
have extracted
by a cis-fused
data and chemical
1 (structure
from the stem bark of Goniothubmus giganteus Annonceae
shown that it is cytotoxic
tetrahydrofu-
confirmed
derivati-
by X-Ray a-
and subsequently
in vitro (BS, 9 KB) and active in aiuo against P 388 leuke-
mia.
phm 4
\3
2
HO/’
9
O
Ii
(+) 1 Altholactone (Goniothalenol)
ZR=H
Goniodiol
3 R = OH
Goniotriol
Ph H
4 Goniothalamin
2 Dihydrokawain-5
3945
01
3946
It is worthy figuration
of note that other bioactive
have been isolated
the more oxygenated
from other Goniothdms
goniodiol
red as a non cyclized
1 and goniotrio134
The interesting
biological
asperlin7
activities
nes (with either a 6R or a 6s configuration) of (+) and (-) altholactone
Retrosynthetic
arylation
analysis
may be obtained
of D-glucose)
found in related
demonstrated
by most of these pyro-
that we propose
two enantiodiver-
from D-glucose'.
from a carbohydrate
and that construction
pyro-
(i.e. respectively
5R, 6s and 7s C-4, C-3 and C-2
of the pyrone ring from 5 to give -11 followed
by
at C-8 should give (-) 1.
11
PREPARATION
6 successively.
OF PYRONE 11 Reformatsky
tate affords
condensation
of the readily
a major oily compound 1,
is thought
enolate1°'12. ethyl acetate)
hydrolysis
pyridine)
The axial orientation tion about the relative (J H-4/H-5 Finally, is obtained
from g
is then converted
and to acetate I&
of the acetoxy
of the zinc (H2,PdK,
to lactone 2 (1.2
m.p. 85-86'C,
group, confirming
of z, is demonstrated
= 2.2 Hz) of triplets
in CH2C12 at room temperature
addition
by hydrogenolysis
[aID = + 22"
78% from @I'.
stereochemistry
the requested
10 fj with ethyl bromoace-
chelation-controlled
of ester 1 followed
gives ,11, m.p. 142°C (85%) which
(CHC13, c = 1.2), (Ac20, pyridine,
available
IaID = -22" (CHC13, c = 2), 85% isolated yield"
to result from the favored
Base catalyzed
eq. dicyclohexylcarbodiimide,
CHCl,+I
is however
justify
These two points will be discussed
doublet
43 and
and analogues8.
of (-) 1 shows that the requested
(-) 1
which
6s con-
: goniothalamin
(this latter compound may be conside-
of (+) altholactone olguin6,
nes such as dihydrokawainol-55,
configurations
species
form of (-) altholactone).
The 6R configuration
gent syntheses
pyrones with the opposite
(J H-5/H-6
(87%).
assumpof a
= 8.8 Hz) at 6 = 5.32 ppm for H-4.
pyrone 11, m.p. 70-71"C,
on treatment
the previous
by the presence
[aID = + 33" (c = 1.5,
with 1.1 eq. of diazabicyclouhdecene
(DBU)
3947
Ii
zR=H &I R = COCH3 ARYLATION
OF PYRONE u The conversion
logous to the synthesis
of C-aryl nucleosides
ting groups and reaction arylation
of pyrone 11 to (-) altholactone
with 40 eq. of benzene
from carbohydrates.
Although
many activa-
have been reported to promote the formation and 13 onium ion , we anticipated that anhydrous HF will cata-
and arylation
of 11 to 1. As a matter
in HF at 0°C for 10 min. affords
of fact treatment
three compounds
to retain even after
ties (not detected
Florisil
by NMR and TLC) which
this sample affords
material,
chromatography
preclude
quantitatively
(m.p. 142°C) and spectral
cept for the sign of optical
14, m.p. 141"C, data"
rotation
[aID
are similar
J H-7/H-8
is however
trast with the usual respectivevalues
(FLitt
of impuri= 75'C,[a]B
[al0
smaller
by the occurrence
both exhibit
angles
by LOOER' ex-
(EtOH, c = 1)).
= 266" (EtOH, c = 0.5)11.
This mate-
at C-8 with 1. The observed
for -12 than for 1 (see Table
) in conrings
of conformations
in agreement
14
R = H
12
R = COCH3
13 Table
no Ph
AA (1)
3J (Hz)
1
-12
H5-H6
5
5
H6-H7
2
0
H7-H8
5.5
3.5
n Ph--
14
.
A for 1 and B for 11 which -3 with the experimental J values (see Table).
n (-) 1
of
= - 200' (EtOH, c = 1) whose
for cis and trans 3J in five membered
This may be explained dihedral
trace amounts
to those reported
([al0 = + 208"C,
. 12 (18%), m.p. 190-192”C, constant
14
crystallization
rial must be, on the basis of MS and NMR data, epimeric coupling
are iden-
[a]B = - 166" (c = 0.5,
. = llO"C, [alo = + 184.7" (EtOH)2 for (+) 1). Acetylation
+ 188" (EtOH)l and FLitt
physical
This oily synthetic
of -11
:
. (-) 1 (48%) whose TLC behaviour, IR, ‘H and 13C NMR spectra tical with those of (+) LIy2. EtOH) appears
as ana-
conditions
of the intermediate
lyze both ketal cleavage
1 may be considered
=
3948
. 13 (3%), m.p. 201-202°C,[aID This minor
compound
results
= + 53" (EtOH, c = 0.5)11.
from
diarylation
as shown by MS and NMR spec-
tra. As expected
(-) 1 resulting
from arylation
12 (2.7 ratio) and under these conditions promise
for HF-catalyzed
arylation
anti to theC-7/OHis
diarylation
of suitably
is minimized15.
protected
favored
over
This result holds
carbohydrates
to C-nucleosi-
des.
In conclusion, cose using an efficient
(-) altholactone HF catalyzed
1 has been prepared
arylation
ty of these new pyrones will be reported ACKNOWLEDGMENTS
: We are grateful to Prof.McLAUGHLIN
(Paris) for financial
antitumor
activi-
later.
viding a sample of (+) 1 as well as copies of res HOECHST
in 10 steps from O-glu-
as the last step.The
(Purdue U., USA) for kindly pro-
IR and NMR. We thank CNRS and Laboratoi-
support.
REFERENCES 1 - J.W. LOOER and R.M. NEARN, Heterocycles, A. EL-ZAYAT,
2-
N.R. FERRIGNI,
1, 113 (1977).
T.G. MC CLOUD, A.T. MC KENZIE, S.R. BYRN, J.M.
C.J. CHANG and J.L. MC LAUGHLIN,Tetrahedron K. JEWERS,
3-
Letters, 2&, 955 (1985).
J.8. DAVIS, J. OOUGAN, A.H. MANCHAOA,
PINAN, Phytochemistry, 4 - S.K. TALAPATRA,
CASSIOY,
G. BLUNOEN,
A. KYE and S. WETCHA-
11, 2025 (1972).
0. BASU, T. DEB, S. GOSWANI
and B. TALAPATRA,
Ind.J.Chen., 24-8, 29,
(1985). H. ACHENBACH
5-
6 - A. ALEMANY,
and G. WITTMANN, C. MARQUEZ,
TINEZ RIPOLL, 7-
Tetrahedron
MARTINEZ,
C. MARQUEZ,
Tetrahedron
9 - The synthesis
and M.P. KUNSTMANN,
c - K. KAKINUMA,
Tetrahedron
internal
Letters,
A. PERALES,
1791 (1969).
J. FAYOS and M.
in the accompanying
J. Org. Chem., 2,
Letters,
communication.
Chem. Ber., 61, 1735 (1928). 1800 (1962).
4413 (1977).
have been characterized
'H and eventually
by elemental
analysis
or High Resolu-
13C NMR (BRUKER WP 200 SY) in COC13 using TMS as
standard.
12 - For a review of addition see
is described
W. OURR and H. Von HOCHSTETTER,
and S. HANESSIAN,
tion MS, IR,
Tetrahedron
S. VALVEROE,
Letters, 20, 3583 (1979).
b - M.L. WOLFROM
11 - All new compounds
J. FAYOS and M. MAR-
3579 (1979).
C. PASCUAL,
of (+) altholactone
10 a - K. FREUOENBERG,
3259 (1970).
A. PERALES,
Can. J. Chem., 56, 2889 (1978).
R.H. EVANS, G.A. ELLESTAO
b - A. ALEMANY,
Letters,
S. VALVEROE,
Letters, 3,
S. LESAGE and A.S. PERLIN,
8a-
Tetrahedron
C. PASCUAL,
reactions
to chiral
a- and B- alkoxy carbonyl compounds
: M.T. REETZ, Angew. Chem. Int. Ed. Engl., 23, 556 (1984).
13 - S. HANESSIAN
and 6. PERNET, Adv. Carbohydr.
Chem. Biochem.,
2,
111 (1976).
6. DOYLE OAVES and C.C. CHENG, Progress in Medicinal Chemistry, Vol. 13, 303, G.P. ELLIS and G.B. WEST Ed., North-Holland Publishing Company (1976). 14 - A. GAUOEMER in Stereochemistry : Fundamentals and Methods, Vol. 1, 44, H.B. KAGAN Ed., Georg Thieme Verlag Ed. (1977). 15 - F. MICHEEL
and J. STANEK,
Tetrahedron
(Received in France 30 May
1987)
Letters,
1609 (1970).