A short and efficient total synthesis of (+)-ferruginine using the CN(R,S) method

Full text of DOI:10.1021/jo971122l

6704
J . Org. Chem. 1997, 62, 6704-6705
A Sh or t a n d Efficien t Tota l Syn th esis of
(+)-F er r u gin in e Usin g th e CN(R,S) Meth od
Isabelle Gauthier, J acques Royer,* and
Henri-Philippe Husson*
Institut de Chimie des Substances Naturelles, CNRS,
91198 Gif-sur-Yvette, France
Received J une 20, 1997
F igu r e 1.
(+)-Ferruginine ((+)-1a ), a potent neurotoxin contain-
ing an 8-azabicyclo[3.2.1]octane ring system, was isolated
from the arboreal species Darlingiana ferruginea1 and
D. darlingiana.2 Its biological activity has not been fully
studied, unlike its unnatural (-) enantiomer which has
been prepared from cocaine.1 (-)-Ferruginine ((-)-1a )
and (-)-norferruginine ((-)-1b) were found to be good
agonists for the nicotinic acetylcholine receptor (nAchR)
although they appear to be only 2.7 × 10-3 and 1.2 ×
10-3 times as potent, respectively, as (+)-anatoxin a
(Figure 1).3
Due to the intense interest in its potent nicotinic
agonist activity, several syntheses of ferruginine have
been reported, mainly as a racemate,4 but two asym-
metric syntheses of the (+)-enantiomer have also ap-
peared recently in the literature.5 Campbell et al. first
reported a racemic synthesis from cocaine,4a then Davies
et al. reported the preparation of racemic material via
the reaction of vinylcarbenoids with N-(alkoxycarbonyl)-
pyrroles.4b,c Synthesis of racemic ferruginine has also
been described by Pd-catalyzed intramolecular amino-
carbonylation.4d More recently Rigby et al. achieved the
first asymmetric synthesis of (+)-ferruginine by metal-
promoted [6π + 2π] cycloaddition of azepines followed by
ring contraction.5a In a more classical approach, Rapo-
port et al. reported an asymmetric synthesis via intramo-
lecular cyclization of an iminium ion derived from
L-pyroglutamic acid,5b leading to (+)-ferruginine in 15
steps and 1% yield.
Sch em e 1
It can thus be considered as a chiral nonracemic equiva-
lent of the pyrrolinium salts involved in the biosynthesis
of tropane alkaloids.8a,b According to the CN(R,S)
method,7b it is possible to introduce at will a 2-pentanone
chain in an R or an S absolute configuration. Mannich
type cyclization onto the oxazolidine ring of such a
compound might be possible, but the creation of the
double bond would require several tedious steps using
standard methods.5b Our intention was to take advan-
tage of a compound of type 5 (Scheme 1) already contain-
ing a double bond and which could also cyclize to a
tropane system.
The cyclization of an R,â-unsaturated ketone onto an
acyliminium ion, reported by Speckamp9 for the synthesis
of elaeokanine B, appeared an attractive means of
achieving our objective. The synthesis of the required
pyrrolidine 5 is described in Scheme 2.
The anion of 2-cyano-5-oxazolopyrrolidine 2 was alkyl-
ated with bromoacetaldehyde diethyl acetal in the pres-
ence of HMPA to afford 3 as a diastereomeric mixture in
86% yield.10 Decyanation of 3 was achieved using Li/
NH3,7 to give compound 4 in 66% yield as a single
stereomer. Previous studies from this laboratory have
shown this reduction step to be completely stereoselective
and to furnish pyrrolidine 4 with the 2R configuration.7,10
Careful cleavage of the acetal function of compound 4
with dilute hydrochloric acid was effected without open-
ing the oxazolidine, to furnish the aldehyde which was
not isolated but immediately converted into the trans
enone 5 by treatment with dimethyl (2-oxopropyl)phos-
phonate under Horner-Wadsworth-Emmons condi-
tions11 (iPr2NEt, LiCl, MeCN) in 86% overall yield.
Cyclization of 5 to the bicyclic enone 6 was then carried
out using the experimental conditions described by
Speckamp, i.e., by treatment with hydrogen chloride gas
in methanol at -50 °C.9 The desired tropane 6 was thus
obtained in 66% yield, accompanied by the chlorinated
We undertook an asymmetric synthesis of (+)-ferrugi-
nine 1a based on a similar bond disconnection strategy,
but starting from 2-cyano-5-oxazolopyrrolidine 2 which
we designed, some years ago, for the preparation of R-
(and R′-) substituted pyrrolidine derivatives.6,7a
2-Cyano-5-oxazolopyrrolidine 2, easily prepared in one
step from phenylglycinol, dimethoxytetrahydrofuran, and
potassium cyanide,6 appeared as an ideal starting mate-
rial for the construction of the 8-azabicyclo[3.2.1]octane
skeleton since it possesses two potential iminium systems
permitting substitutions R and R′ to the nitrogen atom.
(1) Bick, I. R. C.; Gillard, J . W.; Leow, H.-M. Aust. J . Chem. 1979,
32, 2537-2543.
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32, 2523-2536.
(3) Swanson, K. L.; Albuquerque, E. X. Handbook of Expt. Phar-
macology, Vol. 102. Selective Neurotoxicity; Herken, H., Hucho, F., Eds.;
Springer-Verlag: Berlin, Heidelberg, 1992; pp 620-621.
(4) (a) Campbell, H. F.; Edwards, O. E.; Kolt, R. Can J . Chem. 1977,
55, 1372-1379. (b) Davies, H. M. L.; Saikali, E.; Huby, N. J . S.; Gilliatt,
V. J .; Matasi, J . J .; Sexton, T.; Childers, S. R. J . Med. Chem. 1994, 37,
1262. (c) Davies, H. M. L.; Saikali, E.; Young, W. B. J . Org. Chem.
1991, 56, 5696-5700. (d) Ham, W.-H.; J ung, Y. H.; Lee, K.; Oh, C.-Y.;
Lee, K.-Y. Tetrahedron Lett. 1997, 38, 3247-3248.
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(b) Hernandez, A. S.; Thaler, A.; Castells, J .; Rapoport, H. J . Org.
Chem. 1996, 61, 314-323.
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(7) (a) Huang, P. Q.; Arseniyadis, S.; Husson, H.-P. Tetrahedron Lett.
1987, 28, 547-550. (b) Husson, H.-P.; Royer, J . in Advances in the
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S0022-3263(97)01122-5 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 20, 1997 6705
Sch em e 2
Sch em e 3
yield. This transformation was totally stereoselective:
only one stereomer was found in the crude mixture as
1
proved by H and 13C NMR and chromatographic analy-
ses. The configuration of this compound was deduced
from 1H NMR: the diagnostic proton H-2 exhibited
coupling constants of 10.1 and 2.5 Hz with H-3 and H-1,
respectively, which clearly indicated that H-2 and H-3
occupy axial positions. Hydrogenolysis (H2, Pd(OH)2/C)
of the N-benzylic bond of 8 afforded the free amine (TLC
analysis), not isolated but immediately converted into 9
in the presence of CH2O, NaCNBH3 (62% yield for the
two steps).4c Alternatively, treatment of 8 with aque-
ous formaldehyde under hydrogenation conditions (H2,
Pd(OH)2/C) gave the N-methyl derivative 9 in an im-
proved 73% yield. Elimination of methanol was achieved
by treatment of compound 9 with p-toluenesulfonic acid
in benzene at 80 °C15 to give (+)-ferruginine in 68% yield
([R]D ) +36 (CHCl3, c 0.27); lit.1 [R]D ) +37 (CHCl3).
In conclusion, we have performed a new, short, and
efficient synthesis of (+)-ferruginine in seven steps and
20% overall yield, starting from a versatile chiral non-
racemic starting material, via the intramolecular cycliza-
tion of an R,â-unsaturated ketone onto a potential
iminium system. Such a stereospecific intramolecular
cyclization should allow easy access to a range of ana-
logues. This strategy, starting from commercially avail-
able material, compares favorably to previously described
synthetic routes.
product 7 in 15% yield. The latter could be transformed
easily into 6.9a Removal of the chiral appendage to afford
the corresponding free amine was usually carried out
under hydrogenolytic conditions; the presence of the
enone function of 6, however, precluded this method.
N-Debenzylation using a chloroformate12 (ethyl, vinyl,
(trimethylsilyl)ethyl, or benzyl chloroformate) or dissolv-
ing metal conditions (Li/NH3)13 could not be achieved,
even after the protection of the keto group of 6 using
Noyori’s reagent.14
We therefore decided to examine the possibilities of
preparing a related compound in which the double bond
was protected. Product 7 was a potential candidate, but
unfortunately it underwent elimination too quickly to
give 6, and the presence of the chlorine atom was also
incompatible with hydrogenolytic conditions. We thus
decided to use the more stable methoxy group and
repeated the iminium ion cyclization by treatment of 5
(Scheme 3) with sulfuric acid in methanol (15 h, 60 °C).
Under these conditions compound 8 was obtained in 84%
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and 1H NMR and 13C NMR spectra of all new
compounds (17 pages).
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39, 2302-2312.
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J O971122L
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