Though commonly used as a reference in the study of new
nAChRs, it is currently expensive and available only in small
quantities commercially. In addition, of the two possible
enantiomeric forms, only the (-)-antipode is available from
natural sources.
Scheme 1. Retrosynthetic Analysis
In the past few years, a number of cytisine derivatives
were prepared in order to modify the pharmacological profile
of the natural alkaloid so as to obtain compounds of potential
therapeutic interest.8 The first total syntheses of racemic
cytisine were reported 40 years ago,9 while quite recently,
three new different approaches were developed,10 underscor-
ing current interest in this field. All the same, to the best of
our knowledge, no enantioselective routes to this alkaloid
have been published to date.
As part of our ongoing work concerning the stereoselective
synthesis of natural nitrogen-containing compounds,11 we
report here our successful approach to enantiopure (-)-
cytisine and, formally, to its (+)-antipode.
From a chemical point of view, (-)-cytisine is a quino-
lizidine alkaloid with a tricyclic skeleton, consisting of the
bispidine framework (B- and C-rings) fused to a 2-pyridone
moiety (A-ring). It bears two stereogenic centers, which were
established to be 7R,9S.
To ensure a formal access to either enantiomer of the target
compound, our retrosynthetic plan (Scheme 1) features the
cis-piperidine-3,5-dimethanol monoacetate 2 as a suitable
starting material. In fact, both this compound and its
enantiomeric form (ent-2) are readily available by means of
biocatalytic asymmetrization of the appropriate Cs-symmetric
forms.12
ring A) in the retrosynthetic pathway reveals that 3 could in
principle be obtained by a key ring-closing metathesis
reaction on the N-but-3-enylacrylamide moiety of 4. Various
studies in recent years have demonstrated the usefulness of
RCM for constructing N-heterocycles. In some cases, the
ring-closing reactions are problematic because the catalysts
are inhibited by the complex-forming properties of amines
and amides and, for the R,â-unsaturated compounds, by the
intramolecular interaction with the carbonyl group.13 We
reasoned that, if necessary, an additional blocking of the
nitrogen (N1) in 4 with a suitable protecting group could
overcome such problems, enabling us to carry out the RCM
reaction more advantageously. Finally, intermediate 4 could
in turn be fashioned by selective functional group modifica-
tion of the chiral cis-piperidine-3,5-dimethanol monoacetate
2.
The key intermediate N-but-3-enylacrylamide 4 was
constructed as follows (Scheme 2). Oxidation of the diol
monoacetate 2 (98% ee) afforded the configurationally stable
aldehyde 5, which was used directly in the next step of
allylation. BF3‚Et2O-mediated reaction of allyltrimethylsilane
on 5 produced the homoallylic alcohol 6a,b, in 85% yield,
as an inseparable 1:1 mixture of diastereoisomers.
The first dissection of ring B (N1-C10 bond) in (-)-
cytisine 1, along with an adjustment of the oxidation level
for ring A, yields the 6-piperidinyl-5,6-dihydropyridin-2-one
3, which in turn could be accessed from the key intermediate
4. In fact, the cleavage of the C3-C4 bond (dissection of
This lack of diastereofacial selectivity on the carbonyl
group of 5 does not represent a problem in our synthetic
plan. In fact, to assemble the skeleton of cytisine, a later
oxidation step had been envisaged, which destroys this
additional stereogenic center. At any rate, we wanted to
examine more closely this allylation step, also in view of
applying this strategy to the enantiosynthesis of non aromatic
tricyclic quinolizidine alkaloids, in which the stereogenic
center at C6 is retained. We observed that when 5 was treated
with (-)-allyldiisopinocampheylborane, according to Brown’s
procedure,14 the homoallylic alcohol 6a was obtained, with
a diastereoisomeric ratio of 10:1, as determined by 1H NMR
(8) O’Neill, B. T. PCT Int. Appl. WO98 18,798, 1998; Chem. Abstr.
1998, 119, 4774k. Canu Boido, C.; Sparatore, F. Farmaco 1999, 54, 438-
451. Marrie`re, E.; Rouden, J.; Tadino, V.; Lasne, M.-C. Org. Lett. 2000, 2,
1121-1124. Imming, P.; Klaperski, P.; Stubbs, M. T.; Seitz, G.; Gu¨ndisch,
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Sparatore, F.; Carotti, A. Farmaco 2002, 57, 469-478. Canu Boido, C.;
Tasso, B.; Boido, V.; Sparatore, F. Farmaco 2003, 58, 265-277.
(9) Van Tamelen, E. E.; Baran, J. S. J. Am. Chem. Soc. 1955, 77, 4944-
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D.; Bundesmann, M. W.; Arnold, E. P. Org. Lett. 2000, 2, 4201-4204.
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(11) Consonni, A.; Danieli, B.; Lesma, G.; Passarella, D.; Piacenti, P.;
Silvani, A. Eur. J. Org. Chem. 2001, 1377-1383. Danieli, B.; Lesma, G.;
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