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Total synthesis of (+)- and (−)-norsecurinine
Tetrahedron Printed in
Letters,Vol.30,No.51,pp Great Britain
TOTAL
7173-7176,1989
SYNTHESIS
+ -00
OF (+)- AND (-)-NORSECURININE
Peter A. Jacobi,* Charles A. Blum, Robert W. DeSimone Hall-Atwater
0040-4039,‘89 $3.00 Pergamon Press plc
Laboratories,
Middletown,
and LJko E. S. Udodong
Wesleyan University
Connecticut
06457
Summary: (-)-Norsecurinine (lo) has been prepared in a stereospecific fashion beginning with the acetylenic oxazole 18. Disk-Alder cyclization of 18 afforded the furanoketone 19, which was transformed in five steps to the butetwlide mesylate 24. Transannular alkylation of 24 then afforded la. In identical fashion, ent-18 gave (+)-norsecurinine (lb).
(1) is a member of the Securinega
Norsecurinine
form lb from Phylanthus
niruri by Rouffiac
activity exhibited
by securinine
acetylcholinesterase
system?
possessing
lower toxicity.4
solids, 1 Polymerizes approaches efficient
which
was initially
and Parello. * Interest in 1 derives
itself @iperidine ring replaces pyrrolidine
isolated
in the
in the dextrorotatory
mainly from the physiological
in la), which acts as an inhibitor of the
and produces a stimulant effect in the central nervous system similar to strychnine but In contrast
to the securinine
type alkaloids,
which are generally
stable, crystalline
readily and is unstable as the free base. This lack of stability restricts the number of synthetic
available,
syntheses
previously
class of alkaloids
form la from Securinega virosa by Iketubosin and Mathiesen, la and subsequently
levorotatory
and to date only one successful
synthesis
of ~$1 has appeared.sa
of both la and lb which make use of the oxazole Diels-Alder
employed for the synthesis of furanoterpenes
In this note we describe
methodology
which we have
and related materials.6
Me H
A --* -MaoN
N ti
As indicated was expected
above,
the key intermediate
for our synthesis
the correct relative and absolute stereochemistry to give the methoxyfuran
= leaving group).
The feasibility
H
Y
l-i
(-)-Norsecurinine (la)
3
incorporates
0
0
of la was the acetylenic
oxazole
at C;! and C7 found in la. Diels-Alder
3,6 which upon hydrolysis
and transannular
alkylation
2, which
cyclization
of 2
would afford la (X
of this approach was initially tested with the model system 9, which was readily
prepared from the known proline derivative
47 (Scheme 1; initial experiments
7173
were carried out with 4 derived from
7174
the more readily
available
L-proline.
For convenience,
structures
axe represented
as those derived
Me
from the
Me
Ok
LibC
SC-TMS
,’
c
NH
5
7
Me
9
10
Scheme 1 enantiomeric followed
D-Proline*).
by catalytic hydrogenation,9
3-bromopropionyl
routinely
the furanoketone
by a sequence hydrolysis
to the oxazole pyrrolidine
derivative
and 5 was directly alkylated with the bromoamide
chloride with N,O-dimethylhydroxylamine.
(8) then proceeded provided
Thus, 4 was first converted
to afford the acetylenic
Condensation
involving
gave 14 as a mixture
reduction
of epimers
6 prepared by reaction of
of 7 with lithiotrimethylsilylacetylide
ketone 9, 10 which upon brief thermolysis
II in 55% overall yield from 7. Finally, 11 was converted
of operations
5 by cyclodehydration
and elimination
to afford the methoxyfuran
at C9 (R = H, TMS).
Little effort
(PhEt, 1360 C)
to the butenolide
alkene 14
13, which upon acid
was made to optimize
these
1) 2) Burgess 12, 30% 11
transformations. unexpectedly
13
It is worth noting, however, difficult,
that the elimination
and of a variety of conditions
the only reagent which afforded 13 in moderately Extrapolation furanoketone diagrammed
of these
of general in Scheme
dimethylhydroxylamine, 16 in -50% overall yield.
studies
structure
explored,
with lithiotrimethylsilylacetylide
of (-)-norsecurinine
(la)
This was readily achieved,
page).
and the resulting E-amidoacid Silylation
step in the sequence
Et3N+S02-NC02Me
11 ---> 13 proved to be
(12, Burgess’s reagentll)
was
acceptable yields.
to the synthesis
3 (vide supru).
2 (following
14
Thus,
maleic
anhydride
required
the preparation
in a highly convergent (15) was
was reduced with NaBH&lC@Et
reacted
of a
fashion, as with
N,O-
to afford the E-alcohol
of 16 (t-butyldimethylsilyl
chloride,
Cl-E, 78%) followed
(8) then gave the protected
enynone
17 (98%),to
by condensation
which proved
to be an
7175
exceedingly pyrrolidine
reactive Michael acceptor.
In protic solvents
(i-PrOH) 17 underwent
5 to afford the acetylenic ketone 18, 12 which without purification
by brief thermolysis
in mesitylene
c 0
to the furanoketone
19
(-50% overall yield from 17, 5 - 17 g scales based on 18). The material thus TMS
0th
0
I
a rapid addition of the oxazole
was converted
Me-N’
1) MeNHOMe
1) Cl -z 0
2) N&l., / ClCqEt
0
0 2) Li-CPC-TMS
\
-50%
8 r OH
- 75%
16
15
17
O=
ox
c
NH
A -M&N
5
-% (17 -> 19) H
Ox
18 (1.8 : 1)
Scheme 2 obtained consisted initial condensation epimerization
of 5 and 17.
In addition,
the undesired
with Na2CO3 in MeOH, which effected
isomer
19s
could be conveniently
a Michael-retro-Michael
of the enone 20 (see below; 19 : 19s f;i 50 : 50 at thermodynamic
intermediacy
this interconversion Cls.
of an - 2 : 1 mixture of 19 together with its C7 epimer 19S, which reflects the kinetic bias in the
An alternative
was established mechanism,
by deuterium involving
incorporation
sequence
equilibrium).
C2 proton abstraction,
Furanoketone Deprotection
19 was next converted
with Martin’s reagent of 22 (90%), followed
23 as a single isomer,t‘Q tmnsannular
which
to the furanoalkene
by hydrolysis was converted
with NaI/TiQ to the mesylate
by
through the
incorporation
for at
would have yielded en?-19 from 19s and has series (vide infra).
22 by initial reduction
([CgHgC(CF3)20]2S[CgH5]2,
recycled
The mechanism
studies, which showed exclusive
been ruled out on the basis of specific rotations obtained in both the D- and L-proline
by elimination
proceeding
with NaBa
21, 65%) (Scheme (75%), 14a then afforded 24 in virtually
alkylation of 24 with K-HMDS gave a 69% yield of (-)-norsecurinine
(90%) followed
3, following the butenolide
quantitative
yield.
page).t3 alcohol Finally,
(la), isolated as its HCl salt (mp
7176
228-300 d. lit.lb mp 223-250 d), the free base of which had identical spectral data (NMR, IR, UV, mass spectrum) as that published
for the naturally
[EtOH], natural).lb
Repetition
afforded (+)-norsecurinine
occurring
substance
([a]~ = -2620, c = 0.06 [EtOH], synthetic;
of the identical reaction sequence
(lb), also in homochiral
described
for la, but beginning
-2720, c = 6.9 with L-proline,
form ([a]~ = +2680, c = 0.085 [EtOH]).ls
24
(-)-Norsecurinine (la)
Scheme 3
References 1.
2. 3. 4. 5.
6. 7.
8. 9.
10 11. 12. 13. 14.
15.
and Notes
(a) Iketubosin, G. 0.; Mathieson, D. W, J. Pharm. Pharmacol. 1963,15, 810. See also (b) Saito, S.; Tanaka, T.; Kotera, K.; Nakai, H.; Sugimoto, N.; Horii, 2.; Ikeda, M.; Tamura, Y. Chem. Pharm. Bull. 1965,13,786; (c) Snieckus, V. in “The Alkaloids”; Manske, R. H., Ed., Academic Press: New York, 1973, Vol. 14, p. 425. Rouffiac, R.; Parello, J. Plant. Med. Phytorher. 1969,3, 220. Friess, S. L.; Durant, R. C.; Whitcomb, E. R.; Reber, L. J.; Thommesen, W. C. Toxicol. Appl. Pharmacol. 1961,3,347; CA 1961,55, 25053b. Turova, A. D.; Aleshkina, Y. A. Farmakol. Toksikol. (Moscow) 1956,19, 11; CA 1956,50, 17201a. (a) Heathcock, C. H.; von Geldem, T. W. Hererocycles 1987,25, 75, and references cited therein. For an unsuccessful approach to (+)-1, see (b) Kucerovy, A. Ph.D. Thesis, Pennsylvania State University, University Park, 1984; Diss. Abstr. Int. B. 1984,45(6), 1780. For a partial listing, see Reference 1 in Jacobi, P. A.; Armacost, L. M.; Kravitz, J. I.; Martinelli, M. I.; Selnick, H. G. Tetrahedron LRtc. 1988,29, 6865. Savige, W. E. Aust. J. Chem. 1961,14, 664. Satisfactory spectral and analytical data were obtained for all new compounds reported Likhan, R.; Ternai, B. Adv. Heterocycl. Chem. 1974,17,99. Nahm, S.; Weinreb, S. M. Tetrahedron L&t. 1981,22, 3815. Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Org. Chem. 1973,38, 26. The TMS protecting group in 17 served to prevent Michael addition to the normally more reactive triple bond. Arhart, R. J.; Martin, J. C. J. Amer. Chem. Sot. 1972,94, 5003. (a) Mandal, A. K.; Mahajan, S. W. Tetrahedron 1988, 44. 2293. Direct hydrolysis of 22, prior to desilylation, gave much lower yields of butenolides. The hydroxyl group may facilitate this reaction by initial ligand exchange with Tick, followed by intramolecular complexation at C9. (b) We are grateful to Ms. Gail Schulte, of Yale University, for carrying out an X-ray analysis of 23. Financial support of this work by the National Science Foundation, Grant No. CHE-8711922, is gratefully acknowledged.
(Received
in
USA 5 September
1989)
Letters,Vol.30,No.51,pp Great Britain
TOTAL
7173-7176,1989
SYNTHESIS
+ -00
OF (+)- AND (-)-NORSECURININE
Peter A. Jacobi,* Charles A. Blum, Robert W. DeSimone Hall-Atwater
0040-4039,‘89 $3.00 Pergamon Press plc
Laboratories,
Middletown,
and LJko E. S. Udodong
Wesleyan University
Connecticut
06457
Summary: (-)-Norsecurinine (lo) has been prepared in a stereospecific fashion beginning with the acetylenic oxazole 18. Disk-Alder cyclization of 18 afforded the furanoketone 19, which was transformed in five steps to the butetwlide mesylate 24. Transannular alkylation of 24 then afforded la. In identical fashion, ent-18 gave (+)-norsecurinine (lb).
(1) is a member of the Securinega
Norsecurinine
form lb from Phylanthus
niruri by Rouffiac
activity exhibited
by securinine
acetylcholinesterase
system?
possessing
lower toxicity.4
solids, 1 Polymerizes approaches efficient
which
was initially
and Parello. * Interest in 1 derives
itself @iperidine ring replaces pyrrolidine
isolated
in the
in the dextrorotatory
mainly from the physiological
in la), which acts as an inhibitor of the
and produces a stimulant effect in the central nervous system similar to strychnine but In contrast
to the securinine
type alkaloids,
which are generally
stable, crystalline
readily and is unstable as the free base. This lack of stability restricts the number of synthetic
available,
syntheses
previously
class of alkaloids
form la from Securinega virosa by Iketubosin and Mathiesen, la and subsequently
levorotatory
and to date only one successful
synthesis
of ~$1 has appeared.sa
of both la and lb which make use of the oxazole Diels-Alder
employed for the synthesis of furanoterpenes
In this note we describe
methodology
which we have
and related materials.6
Me H
A --* -MaoN
N ti
As indicated was expected
above,
the key intermediate
for our synthesis
the correct relative and absolute stereochemistry to give the methoxyfuran
= leaving group).
The feasibility
H
Y
l-i
(-)-Norsecurinine (la)
3
incorporates
0
0
of la was the acetylenic
oxazole
at C;! and C7 found in la. Diels-Alder
3,6 which upon hydrolysis
and transannular
alkylation
2, which
cyclization
of 2
would afford la (X
of this approach was initially tested with the model system 9, which was readily
prepared from the known proline derivative
47 (Scheme 1; initial experiments
7173
were carried out with 4 derived from
7174
the more readily
available
L-proline.
For convenience,
structures
axe represented
as those derived
Me
from the
Me
Ok
LibC
SC-TMS
,’
c
NH
5
7
Me
9
10
Scheme 1 enantiomeric followed
D-Proline*).
by catalytic hydrogenation,9
3-bromopropionyl
routinely
the furanoketone
by a sequence hydrolysis
to the oxazole pyrrolidine
derivative
and 5 was directly alkylated with the bromoamide
chloride with N,O-dimethylhydroxylamine.
(8) then proceeded provided
Thus, 4 was first converted
to afford the acetylenic
Condensation
involving
gave 14 as a mixture
reduction
of epimers
6 prepared by reaction of
of 7 with lithiotrimethylsilylacetylide
ketone 9, 10 which upon brief thermolysis
II in 55% overall yield from 7. Finally, 11 was converted
of operations
5 by cyclodehydration
and elimination
to afford the methoxyfuran
at C9 (R = H, TMS).
Little effort
(PhEt, 1360 C)
to the butenolide
alkene 14
13, which upon acid
was made to optimize
these
1) 2) Burgess 12, 30% 11
transformations. unexpectedly
13
It is worth noting, however, difficult,
that the elimination
and of a variety of conditions
the only reagent which afforded 13 in moderately Extrapolation furanoketone diagrammed
of these
of general in Scheme
dimethylhydroxylamine, 16 in -50% overall yield.
studies
structure
explored,
with lithiotrimethylsilylacetylide
of (-)-norsecurinine
(la)
This was readily achieved,
page).
and the resulting E-amidoacid Silylation
step in the sequence
Et3N+S02-NC02Me
11 ---> 13 proved to be
(12, Burgess’s reagentll)
was
acceptable yields.
to the synthesis
3 (vide supru).
2 (following
14
Thus,
maleic
anhydride
required
the preparation
in a highly convergent (15) was
was reduced with NaBH&lC@Et
reacted
of a
fashion, as with
N,O-
to afford the E-alcohol
of 16 (t-butyldimethylsilyl
chloride,
Cl-E, 78%) followed
(8) then gave the protected
enynone
17 (98%),to
by condensation
which proved
to be an
7175
exceedingly pyrrolidine
reactive Michael acceptor.
In protic solvents
(i-PrOH) 17 underwent
5 to afford the acetylenic ketone 18, 12 which without purification
by brief thermolysis
in mesitylene
c 0
to the furanoketone
19
(-50% overall yield from 17, 5 - 17 g scales based on 18). The material thus TMS
0th
0
I
a rapid addition of the oxazole
was converted
Me-N’
1) MeNHOMe
1) Cl -z 0
2) N&l., / ClCqEt
0
0 2) Li-CPC-TMS
\
-50%
8 r OH
- 75%
16
15
17
O=
ox
c
NH
A -M&N
5
-% (17 -> 19) H
Ox
18 (1.8 : 1)
Scheme 2 obtained consisted initial condensation epimerization
of 5 and 17.
In addition,
the undesired
with Na2CO3 in MeOH, which effected
isomer
19s
could be conveniently
a Michael-retro-Michael
of the enone 20 (see below; 19 : 19s f;i 50 : 50 at thermodynamic
intermediacy
this interconversion Cls.
of an - 2 : 1 mixture of 19 together with its C7 epimer 19S, which reflects the kinetic bias in the
An alternative
was established mechanism,
by deuterium involving
incorporation
sequence
equilibrium).
C2 proton abstraction,
Furanoketone Deprotection
19 was next converted
with Martin’s reagent of 22 (90%), followed
23 as a single isomer,t‘Q tmnsannular
which
to the furanoalkene
by hydrolysis was converted
with NaI/TiQ to the mesylate
by
through the
incorporation
for at
would have yielded en?-19 from 19s and has series (vide infra).
22 by initial reduction
([CgHgC(CF3)20]2S[CgH5]2,
recycled
The mechanism
studies, which showed exclusive
been ruled out on the basis of specific rotations obtained in both the D- and L-proline
by elimination
proceeding
with NaBa
21, 65%) (Scheme (75%), 14a then afforded 24 in virtually
alkylation of 24 with K-HMDS gave a 69% yield of (-)-norsecurinine
(90%) followed
3, following the butenolide
quantitative
yield.
page).t3 alcohol Finally,
(la), isolated as its HCl salt (mp
7176
228-300 d. lit.lb mp 223-250 d), the free base of which had identical spectral data (NMR, IR, UV, mass spectrum) as that published
for the naturally
[EtOH], natural).lb
Repetition
afforded (+)-norsecurinine
occurring
substance
([a]~ = -2620, c = 0.06 [EtOH], synthetic;
of the identical reaction sequence
(lb), also in homochiral
described
for la, but beginning
-2720, c = 6.9 with L-proline,
form ([a]~ = +2680, c = 0.085 [EtOH]).ls
24
(-)-Norsecurinine (la)
Scheme 3
References 1.
2. 3. 4. 5.
6. 7.
8. 9.
10 11. 12. 13. 14.
15.
and Notes
(a) Iketubosin, G. 0.; Mathieson, D. W, J. Pharm. Pharmacol. 1963,15, 810. See also (b) Saito, S.; Tanaka, T.; Kotera, K.; Nakai, H.; Sugimoto, N.; Horii, 2.; Ikeda, M.; Tamura, Y. Chem. Pharm. Bull. 1965,13,786; (c) Snieckus, V. in “The Alkaloids”; Manske, R. H., Ed., Academic Press: New York, 1973, Vol. 14, p. 425. Rouffiac, R.; Parello, J. Plant. Med. Phytorher. 1969,3, 220. Friess, S. L.; Durant, R. C.; Whitcomb, E. R.; Reber, L. J.; Thommesen, W. C. Toxicol. Appl. Pharmacol. 1961,3,347; CA 1961,55, 25053b. Turova, A. D.; Aleshkina, Y. A. Farmakol. Toksikol. (Moscow) 1956,19, 11; CA 1956,50, 17201a. (a) Heathcock, C. H.; von Geldem, T. W. Hererocycles 1987,25, 75, and references cited therein. For an unsuccessful approach to (+)-1, see (b) Kucerovy, A. Ph.D. Thesis, Pennsylvania State University, University Park, 1984; Diss. Abstr. Int. B. 1984,45(6), 1780. For a partial listing, see Reference 1 in Jacobi, P. A.; Armacost, L. M.; Kravitz, J. I.; Martinelli, M. I.; Selnick, H. G. Tetrahedron LRtc. 1988,29, 6865. Savige, W. E. Aust. J. Chem. 1961,14, 664. Satisfactory spectral and analytical data were obtained for all new compounds reported Likhan, R.; Ternai, B. Adv. Heterocycl. Chem. 1974,17,99. Nahm, S.; Weinreb, S. M. Tetrahedron L&t. 1981,22, 3815. Burgess, E. M.; Penton, H. R., Jr.; Taylor, E. A. J. Org. Chem. 1973,38, 26. The TMS protecting group in 17 served to prevent Michael addition to the normally more reactive triple bond. Arhart, R. J.; Martin, J. C. J. Amer. Chem. Sot. 1972,94, 5003. (a) Mandal, A. K.; Mahajan, S. W. Tetrahedron 1988, 44. 2293. Direct hydrolysis of 22, prior to desilylation, gave much lower yields of butenolides. The hydroxyl group may facilitate this reaction by initial ligand exchange with Tick, followed by intramolecular complexation at C9. (b) We are grateful to Ms. Gail Schulte, of Yale University, for carrying out an X-ray analysis of 23. Financial support of this work by the National Science Foundation, Grant No. CHE-8711922, is gratefully acknowledged.
(Received
in
USA 5 September
1989)