Efficient enantiomeric synthesis of pyrrolidine and piperidine alkaloids from tobacco

Article abstract of DOI:10.1021/jo010386b

An enantiomeric synthesis of six piperidine and pyrrolidine alkaloids, (S)-nornicotine 1, (S)-nicotine 2, (S)-anatabine 3, (S)-N-methylanatabine 4, (S)-anabasine 5, and (S)-N-methylanabasine 6, known as natural products in tobacco, was established from a common chiral homoallylic (S)-3-(1-azidobut-3-enyl)-pyridine 15. An intramolecular hydroboration-cycloalkylation of the homoallylic azide intermediate 15 served as the key step in the pyrrolidine ring formation. A ring closing metathesis reaction (RCM) of a diethylenic amine intermediate (S)-allyl-(1-pyridin-3-yl-but-3-enyl)-carbamic acid benzyl ester 20 served as the key step in the piperidine ring formation. From the commercially available 3-pyridinecarboxaldehyde 13, a short and convenient enantiomeric synthesis of tobacco alkaloids is described: (S)-nornicotine I (5 steps, with an overall yield of 70%), (S)-hicotine 2 (6 steps, 65%), (S)-anatabine 3 (8 steps, 30%), (S)-N-methylanatabine 4 (8 steps, 25%), (S)-anabasine 5 (8 steps, 35%), and (S)-N-methylanabasine 6 (8 steps, 25%).

Full text of DOI:10.1021/jo010386b

J . Org. Chem. 2001, 66, 6305-6312
6305
Efficien t En a n tiom er ic Syn th esis of P yr r olid in e a n d P ip er id in e
Alk a loid s fr om Toba cco
Franc¸ois-Xavier Felpin,† Sandrine Girard,†,‡ Giang Vo-Thanh,† Richard J . Robins,‡
J ean Villie´ras,† and J acques Lebreton*,†
Laboratoire de Synthe`se Organique, CNRS UMR 6513, and Laboratoire d'Analyse Isotopique et
Electrochimique de Me´tabolismes, CNRS UMR 6006, Faculte´ des Sciences et des Techniques,
2 rue de la Houssinie`re, BP 92208, 44322 Nantes Cedex 3, France
lebreton@chimie.univ-nantes.fr
Received April 16, 2001
An enantiomeric synthesis of six piperidine and pyrrolidine alkaloids, (S)-nornicotine 1, (S)-nicotine
2, (S)-anatabine 3, (S)-N-methylanatabine 4, (S)-anabasine 5, and (S)-N-methylanabasine 6, known
as natural products in tobacco, was established from a common chiral homoallylic (S)-3-(1-azido-
but-3-enyl)-pyridine 15. An intramolecular hydroboration-cycloalkylation of the homoallylic azide
intermediate 15 served as the key step in the pyrrolidine ring formation. A ring closing metathesis
reaction (RCM) of a diethylenic amine intermediate (S)-allyl-(1-pyridin-3-yl-but-3-enyl)-carbamic
acid benzyl ester 20 served as the key step in the piperidine ring formation. From the commercially
available 3-pyridinecarboxaldehyde 13, a short and convenient enantiomeric synthesis of tobacco
alkaloids is described: (S)-nornicotine 1 (5 steps, with an overall yield of 70%), (S)-nicotine 2 (6
steps, 65%), (S)-anatabine 3 (8 steps, 30%), (S)-N-methylanatabine 4 (8 steps, 25%), (S)-anabasine
5 (8 steps, 35%), and (S)-N-methylanabasine 6 (8 steps, 25%).
In tr od u ction
There are many biologically important compounds that
have a pyrrolidine or piperidine heterocyclic ring in their
structure, and it was recently reported in the literature
that during the past 10 years over 12 000 piperidine
derivatives have been mentioned in clinical or preclinical
studies.1 The development of new methods for the
synthesis of pyrrolidine-2 or piperidine-based compounds3
is therefore of considerable importance, particularly
approaches leading to chiral derivatives of these ring
skeletons.4 In this context, the enantiomeric synthesis
of piperidine and pyrrolidine alkaloids, known as natural
products from tobacco, provides convenient and excellent
templates for the development of new strategies in this
field.
In fresh Nicotina tabacum, the species most commonly
used for the production of cigarette tobacco, the alkaloid
F igu r e 1.
mixture typically consists of 93% (S)-nicotine 2, 3.9% (S)-
anatabine 3, 2.4% (S)-nornicotine 1, and 0.5% (S)-
anabasine 5 (Figure 1).5 Other pyridine alkaloids such
as (S)-N-methylanatabine 4, (S)-N-methylanabasine 6,
myosmine 7, and anabaseine 8 are also detected.
Nicotinic acetylcholine receptors (nAChR) are a group
of channel receptors that play an important role in many
biological processes related to a number of nervous
system disorders.6 Several studies have demonstrated
that the naturally occurring alkaloids (S)-nicotine 2 and
(S)-epibatidine 9 and many analogues of 2 and 9 display
potent biological activity in mammals by modulation of
nAChR (Figure 2).7 In particular, (S)-nicotine 2 has
attracted much attention because of its important phar-
macological effects on central nervous system (CNS)
diseases. (S)-Nicotine 2 may have beneficial effects in the
treatment of Parkinson’s disease, Alzheimer’s disease,
* Ph: + 33 2 51 12 54 03. Fax: + 33 2 51 12 54 02.
† Laboratoire de Synthe`se Organique.
‡ Laboratoire d'Analyse Isotopique et Electrochimique de Me´tabo-
lismes.
(1) Watson, P. S.; J iang, B.; Scott, B. Org. Lett. 2000, 2, 3679-3681.
(2) For representative papers on the pyrrolidine series, see: (a) Xu,
Y-z.; Choi, J .; Calaza, M. I.; Turner, S. C.; Rapoport, H. J . Org. Chem.
1999, 64, 4069-4078. (b) Turner, S. C.; Zhai, H.; Rapoport, H. J . Org.
Chem. 2000, 65, 861-870. (c) Knight, D. W.; Salter, R. Tetrahedron
Lett. 1999, 40, 5915-5918.
(3) For representative papers on the piperidine series, see: (a)
Takahata H.; Kubota, M.; Ikota, N. J . Org. Chem. 1999, 64, 8594-
8601. (b) Kumareswaran, R.; Balasubramanian, T.; Hassner, A.
Tetrahedron Lett. 2000, 41, 8157-8162. (c) Agami, C.; Couty, F.; Evano,
G. Tetrahedron: Asymmetry 2000, 11, 4639-4643. (d) Eskici, M.;
Gallagher, T. Synlett 2000, 1360-1362. (e) Cossy, J .; Willis, C.;
Bellosta, V.; Bouzbouz, S. Synlett 2000, 1461-1463. (f) Lindstro¨m, S.;
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I.; Meyer, C. Synlett 2000, 122-124.
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see: (a) Bailey, P. D.; Millwood, P. A.; Smith, P. D. J . Chem. Soc.,
Chem. Commun. 1998, 633-640. (b) Laschat, S.; Dickner, T. Synthesis
2000, 1781-1813.
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6444.
(6) Galzi, J . L.; Changeux, J . P. Neuropharmacology 1995, 34, 563-
579.
10.1021/jo010386b CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/23/2001

6306 J . Org. Chem., Vol. 66, No. 19, 2001
Felpin et al.
nately, several unsuccessful attempts at enantioselective
hydrogenation or reduction of myosmine 7 (or analogues)
have been reported in the literature. For example,
Buchwald16 and co-workers reported that, while 2-phenyl-
1-pyrroline underwent enantioselective hydrogenation
(>99% ee) in the presence of chiral titanocene catalyst,
to give the corresponding 2-phenyl-1-pyrrolidine, the
same conditions when applied to myosmine 7 failed to
give any reaction. In the key step in the synthesis of SIB-
1508Y 11, 5-bromo-3-(2-pyrrolin-1-yl)pyridine was re-
duced with chiral (acyloxy)borohydride reagent (derived
from Cbz-D-proline) in high yields but with poor enanti-
oselectivity (at best 30% ee). Thus, pure (S)-SIB-1508Y
11 (ee >99%) was obtained by recrystallization as the
dibenzoyl-L-tartrate salt of its enantiomerically enriched
material. In general, the most popular approach to the
preparation of these chiral alkaloids or their analogues
is the classical resolution using inexpensive resolving
agents, such as tartaric acid.17
F igu r e 2.
and Tourette’s syndrome.8 (R)-Epibatidine 9, isolated
from the skin of an Ecuadorian frog, is a powerful
analgesic agent (>200-500 times more potent than
morphine) that acts via neuronal nAChR.9 Recent ad-
vances in the synthesis of analogues have led to the
discovery of new compounds, such as ABT-418 10 and
SIB-1508Y 11, which have improved pharmacotherapeu-
tic properties.10 SIB-1508Y 11 is in clinical trials for the
treatment of Parkinson’s disease. Other piperidine to-
bacco alkaloids, anabaseine 8, (S)-anabasine 5, (S)-
anatabine 3, and analogues display similar activities.11
Lobeline 12 is under development as an aid to alieviate
nicotine addiction.12
It has been shown that the (S) enantiomer of nicotine
2 is more active than the (R),13 a tendency also estab-
lished for many analogues. This clear stereoselectivity
of biological activity has recently stimulated considerable
efforts in the synthesis of enantiopure pyrrolidine and
piperidine analogues of these natural products. While
many racemic syntheses of these alkaloids have been
described, only a few individual and specific asymmetric
syntheses have been reported.14 It should be noted that
the well-documented enantioselective hydrogenation or
reduction of the imine functionality15 of myosmine 7 or
anabaseine 8 constitutes an obvious and straightforward
route to (S)-nornicotine 1 or (S)-anabasine 5. Unfortu-
Resu lts a n d Discu ssion
In this paper, we report a flexible and general strategy
for both families of these alkaloids from a common chiral
intermediate.18 Our retrosynthetic route for the natural
alkaloids 1-6 is depicted in Scheme 1. In a single step,
enantioselective allylation of the 3-pyridinecarboxalde-
hyde 13 affords the corresponding chiral homoallylic
alcohol (R)-14, introducing both the chiral center with
an unambiguous absolute configuration, as well as a
suitable double bond to prepare all the target molecules.
The chiral alcohol (R)-14 was converted into the chiral
homoallylic azide (S)-15, with complete inversion of the
carbon chiral center. We anticipated that this key
intermediate would give rise to the pyrrolidine and
piperidine rings. Thus, the elaboration of the pyrrolidine
ring relies on an intramolecular hydroboration-cyclo-
alkylation19 of azido-olefin (S)-15 providing a rapid and
convenient access to (S)-nornicotine 1 in a one-pot multi-
step process, thence to (S)-nicotine 2 by N-methylation.
(14) To the best of our knowledge only four asymmetric syntheses
of (S)-nicotine (or (S)-nornicotine) have been reported in the literature;
see: (a) Loh, T.-P.; Zhou, J .-R.; Li, X.-R.; Sim, K.-Y. Tetrahedron Lett.
1999, 40, 7847-7850. (b) Swango, J . H.; Bhatti, B. S.; Quershi, M. M.;
Crooks, P. A. Chirality 1999, 11, 316-318. (c) Swango, J . H.; Quershi,
M. M.; Crooks, P. A. Pharm. Res. 1997, 14, 695. (d) Chavdarian, C.
G.; Sanders, E. B.; Bassfield, R. L. J . Org. Chem. 1982, 47, 1069-
1073. For asymmetric synthesis of (S)-anabasine, see: (e) Pfrengle W.;
Kunz, H. J . Org. Chem. 1989, 54, 4261-4263. (f) Hattori, K.; Yama-
moto, H. Tetrahedron 1993, 49, 1749-1760. For (S)-anatabine, see:
(g) Balasubramanian, T.; Hassner, A. Tetrahedron: Asymmetry 1998,
9, 2201-2205. (h) Mehmandoust, M.; Marazano, C.; Das, B. C. J . Chem.
Soc., Chem. Commun. 1989, 1185-1187. (i) Barco, A.; Benetti, S.; De
Risi, Carmela.; Marchetti, P.; Pollini, G. P.; Zanirato, V. Eur. J . Org.
Chem. 2001, 975-986.
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L. S.; Cosford, N. D. P. J . Org. Chem. 1999, 64, 5299-5300.
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(a) Girard, S.; Robins, R. J .; Villie´ras, J .; Lebreton, J . Tetrahedron Lett.
2000, 41, 9245-9249. (b) Felpin, F.-X.; Vo-Thanh, G.; Robins, R. J .;
Villie´ras, J .; Lebreton, J . Synlett 2000, 1646-1648.
(19) For a review of this field, see: Carboni, B.; Vaultier, M. Bull.
Soc. Chim. Fr. 1995, 132, 1003-1008 and literature cited therein. For
significant examples, see: (a) Salmon, A.; Carboni, B. J . Organome-
tallic Chem. 1998, 567, 6614-6617. (b) Waid, P. P.; Flynn, G. A.,
Huber, Sabol, J . S. Tetrahedron Lett. 1996, 37, 4091-4094. (c) Evans,
D. A.; Weber, A. E. J . Am. Chem. Soc. 1987, 109, 7151-7157.
(7) For recent reviews on structure-activity relationships for nAChR
ligands, see: (a) Lloyd, G. K.; Williams, M. J . Pharmacol. Exp. Ther.
2000, 292, 461-467. (b) Holladay, M. W.; Dart, M. J .; Lynch, J . K. J .
Med. Chem. 1997, 40, 4169-4194. (c) Latli, B.; D’Amour, K.; Casida,
J . E. J . Med. Chem. 1999, 42, 2227-2234. (d) Nielsen, S. F.; Nielsen,
E. O.; Olsen, G. M.; Liljefors, T.; Peters, D. J . Med. Chem. 2000, 43,
2217-2226. (e) Mullen, G.; Napier, J .; Balestra, M.; DeCory, T.; Hale,
G.; Macor, J .; Mack, R.; Loch, J ., III; Wu, E.; Kover, A.; Verhoest, P.;
Sampognaro, A.; Phillips, E.; Zhu, Y.; Murray, R.; Griffith, R.; Blosser,
J .; Gurley, D.; Machulskis, A.; Zongrone, J .; Rosen, A.; Gordon, J . J .
Med. Chem. 2000, 43, 4045-4050.
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Noriega, L.; Correa, L. D.; Crona, J . H.; Mahaffy, L. S.; Menzaghi, F.;
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J . Med. Chem. 1979, 22, 174-177.

Synthesis of Pyrrolidine and Piperidine Alkaloids
J . Org. Chem., Vol. 66, No. 19, 2001 6307
Sch em e 1
Sch em e 2
80%) and accompanied by starting aldehyde 13. We were
quite disappointed by these results compared to those
reported (this reaction is described on 15 mmol scale:
85% yield and >96% ee).
First, this failure led us to check the quality of the
B-allyldiisopinocampheylborane, which was checked by
allylation of benzaldehyde, to afford the corresponding
homoallylic alcohol with comparable yields and slightly
reduced enantioselectivities relative to those previously
reported. Considering the contrasting behavior of 3-pyri-
dinecarboxaldehyde 13 versus benzaldehyde, we specu-
lated that the pyridine nitrogen was somehow responsible
for our problems. To overcome these difficulties, allylation
of 3-pyridinecarboxaldehyde 13 with B-allyldiisopinocam-
pheylborane was carefully reinvestigated through a range
of different reaction temperatures and stoichiometries.
As already observed in the enantioselective reduction of
acetylpyridines with oxazaborolidines,24 we found that
the complexation of the nitrogen of the pyridine is crucial
for a high yield and ee. Thus, allylation of 13 with 2.2
equiv of B-allyldiisopinocampheylborane (instead of 1.1
equiv as reported) gave routinely on the multigram scale
the corresponding (R)-homoallylic alcohol 1425 in 94%
yield after purification and with an ee of 94%. In these
conditions, 1 equiv of allylborane is engaged in the
formation of a complex with the nitrogen of the pyridine
and the free B-allyldiisopinocampheylborane reacts with
the aldehyde. When only 1 equiv of chiral allylborane is
added, the corresponding pyridine-allylborane complex
is formed to afford a less efficient chiral allyl reagent,
thus giving the alcohol 14 in only moderate yield and ee.
It should be noted that the rate of addition of the
aldehyde 13 (precooled to -65 °C)26 to the reaction
mixture at -100 °C is important, as well as the removal
of MgCl2 formed during the preparation of the B-
allyldiisopinocampheylborane. To save 1 equiv of chiral
allylborane,27 we attempted to eliminate the effect of the
pyridine nitrogen by adding first to the reaction mixture
1 equiv of triethylborane28 (at -78 °C for 1 h), the
reaction then being carried out as previously described
with 1.1 equiv of B-allyldiisopinocampheylborane. Under
these experimental conditions, however, chiral homo-
The retrosynthetic analysis of the piperidine ring con-
struction showed that RCM20 promised not only to effect
the ring formation but also to introduce directly the olefin
in the right position to afford in a straightforward
manner (S)-anatabine 3. The requisite N-allylamine 16
should then be available by N-allylation of the amine,
obtained from the corresponding chiral homoallylic azide
(S)-15, by chemoselective reduction. Finally from (S)-
anatabine 3, N-methylation or/and hydrogenation led to
the synthetic goals, furnishing (S)-anabasine 5, (S)-N-
methylanatabine 4, and (S)-N-methylanabasine 6.
Our first efforts focused on the preparation of the
common chiral homoallylic alcohol intermediate (R)-14,
which has already been obtained by Brown21 using an
asymmetric allylboration of commercial 3-pyridinecar-
boxaldehyde 13 with B-allyldiisopinocampheylborane
(prepared from (+)-B-chlorodiisopinocampheylborane22
(Ipc2BCl, DIP-Chloride) and allylmagnesium bromide)
(see Scheme 2). However, the first attempts to reproduce
this work met with limited success; alcohol 14 was
isolated in modest yields (40-50%) with low ee23 (70-
(20) For excellent reviews on the RCM with nitrogen-containing
compounds, see: (a) Phillips, A. J .; Abell, A. D. Aldrichimica Acta 1999,
32, 75-89. For a more general review, see: (b) Grubbs, R. H.; Chang,
S. Tetrahedron 1998, 54, 4413-4450. For recent examples, see: (a)
Fu¨rstner, A.; Thiel, O. R. J . Org. Chem. 2000, 65, 1738-1742. (b) Cook,
G. R.; Shanker, P. S.; Peterson, S. L. Org. Lett. 1999, 1, 615-617. (c)
Kigoshi, H.; Suzuki, Y.; Aoki, K.; Uemura, D. Tetrahedron Lett. 2000,
41, 3927-3930. (d) Wallace, D. J .; Cowden, C. J .; Kennedy, D. J .;
Ashwood, M. S.; Cottrell, I. F.; Dolling, U.-H. Tetrahedron Lett. 2000,
41, 2027-2029. (e) Grigg, R.; Sridharan, V.; York, M. Tetrahedron Lett.
1998, 39, 4139-4142. (f) Voigtmann, U.; Blechert, S. Org. Lett. 2000,
2, 3971-3974. (g) Maldaner, A. O.; Pilli R. A. Tetrahedron Lett. 2000,
41, 7843-7846.
(21) (a) Racherla, U. S.; Brown, H. C. J . Org. Chem. 1991, 56, 401-
404. (b) Racherla, U. S.; Liao, Y.; Brown, H. C. J . Org. Chem. 1992,
57, 6614-6617.
(22) For the preparation of B-allyldiisopinocampheylborane from
(+)-Ipc2BCl (purchased from Aldrich Chemical Co.), see: J adhav, P.
K.; Bhat, K. S.; Perumal, T.; Brown, H. C. J . Org. Chem. 1986, 51,
432-439. DIP-Chloride is the trademark of Aldrich Chemical Co.
(23) All enantiomeric excesses were determined by chiral HPLC
analysis on a Chiralcel OD-H column, 46 × 15 cm, flow rate 0.5 mL/
min.
(24) (a) Quallich, G. J .; Woodall, T. M. Tetrahedron Lett. 1993, 34,
785-788. (b) Masui, M.; Shioiri, T. Synlett 1997, 273-274.
(25) Analysis of the proton NMR spectrum of the (R)-O-acetyl-
mandelic ester derivative of this alcohol 14 confirmed the (R) absolute
configuration; see: Chataigner, I.; Lebreton, J .; Durand, D.; Guingant,
A.; Villie´ras, J . Tetrahedron Lett. 1998, 39, 1759-1762.
(26) Under -70 °C, the aldehyde crystallized.
(27) An enantioselective oxazaborolidine-catalyzed reduction of
2-benzoylpyridines was reported in which the nitrogen was protected
as N-allylpyridinium triflates; see: Corey, E. J .; Helal, C. J . Tetrahe-
dron Lett. 1996, 37, 5675-5678.
(28) Lutz, C.; Graf C.-D.; Knochel, P. Tetrahedron 1998, 54, 10317-
10328.

6308 J . Org. Chem., Vol. 66, No. 19, 2001
Felpin et al.
Sch em e 3
allylic alcohol was isolated in lower yields and enantio-
selectivies. One of the significant challenges associated
with the synthesis of pyridine derivatives concerns the
problem of the nitrogen reacting with reagents or cata-
lysts (vide supra).
In the meantime, an alternative synthesis of the chiral
alcohol 14 had been pursued using an enantioselective
reduction of the corresponding ketone, obtained by oxida-
tion of the racemic alcohol 14 with Dess-Martin perio-
dinane reagent.29 Unfortunately, this unstable ketone
spontaneously formed a completely conjugated R,â-
unsaturated ketone derivative. Surprisingly, the same
reaction sequence was carried out on a benzene ring
analogue of 14 and led cleanly to the corresponding â,γ-
unsaturated ketone, which was reduced at -20 °C with
(+)-Ipc2BCl to give the desired alcohol with high ee
(>99%).30
of the alcohol with mesyl chloride in the presence of Et3N.
Attempts to isolate this unstable mesylate 17 by chro-
matography proved problematic because of extensive
decomposition. This material was therefore used without
purification and was treated directly with sodium azide
in DMF at 60 °C to afford the (S)-azide 15 (94% ee) in
97% yield for the two steps. No epimerization was
observed at reaction temperatures below 65 °C. This
latter sequence could be readily run on a large scale in
high yields with inexpensive chemicals, and was there-
fore preferred to Thompson’s method.
The next step involved replacing the alcohol at the
benzylic position of 14 with an azide, resulting in
inversion of configuration. Transformation of an alcohol
into its corresponding azide has been widely reported
through various indirect and a few direct methods.
However, such reactions sometimes compete with an SN1
reaction process, with a resulting decrease in ee, par-
ticularly in those cases where the substitution reaction
occurred on the benzylic position.31 A more recent report
found that stereospecific substitution reactions on a (2-
pyridinyl)methyl carbon center are even more problem-
atic. Moreover, with such substrates, an additional
problem is caused by the homoallylic position of the
leaving group (activated alcohol function) which may, by
â-elimination, afford the fully conjugated system.
To test this critical step, we chose a recent procedure
reported by Thompson32 for the direct conversion of
electron-rich benzylic alcohols to azides with total inver-
sion of configuration. The chiral homoallylic alcohol 14
was treated with diphenyl phosphoroazidate (DPPA)33
and DBU in dry toluene; the corresponding phosphate
of 14 formed in situ was displaced by the azide anion to
afford, after purification by chromatography, the chiral
azide (S)-15 with a good yield. To our delight, a chiral
HPLC analysis revealed that this transformation pro-
ceeds exclusively with complete inversion of configura-
tion; no loss in ee was noted in the azide (S)-15 (ee 94%).
To probe this transformation in more detail, we tried
to use one of the most common methods for the prepara-
tion of primary and secondary aliphatic azides from the
corresponding alcohols by nucleophilic displacement of
the sulfonate intermediates by azide anion. To our
surprise, chiral azide (S)-15 could be prepared in two
steps in nearly quantitative yield, by nucleophilic dis-
placement of the corresponding mesylate (S)-17 by azide
anion, with complete inversion of configuration. The
mesylate (S)-17 was obtained by conventional treatment
Syn th esis of P yr r olid in e Alk a loid s. (S)-Nor n ico-
tin e 1 a n d (S)-Nicotin e 2. With the chiral azide 15 in
hand, our efforts were directed to the construction of the
pyrrolidine ring (see Scheme 3).34 For this purpose, we
used an intramolecular hydroboration-cycloalkylation of
the azido-olefin, which had already successfully been
used for the synthesis of pyrrolidinone and piperidine
derivatives.19 The chiral azide 15 was treated with an
excess of freshly prepared dicyclohexylborane to afford,
after hydrolysis with methanol, the first target tobacco
alkaloid: (S)-nornicotine 1 ([R]20 -35.2 (c 1, MeOH);
D
lit.14a [R]20 -35.6 (c 1.256, MeOH)) was isolated in 85%
D
yield as the sole product from the reaction mixture.
This one-pot sequence proceeds by hydroboration of the
double bond of 15 and subsequent formation of a boron-
nitrogen bond between the azide and the trialkylborane
to afford the cyclic azide borane complex intermediate
A. Finally, migration of the borane methylene group to
N-1 of A proceeds with a ring contraction and concomi-
tant loss of nitrogen.
The final transformation, the N-methylation of (S)-
nornicotine 135 to (S)-nicotine 2, was achieved using a
two-step procedure. The N-ethylcarbamate prepared from
1 was reduced by an excess of LiAlH4 to give (S)-nicotine
2 ([R]20D -145 (c 1, EtOH); lit.17a [R]20D -154 (c 4, EtOH))
in 92% overall yield for the two steps.
Spectral data (1H NMR, 13C NMR) for (S)-nornicotine18a
1 and (S)-nicotine17a 2 were in excellent agreement with
those recorded for the natural materials. Finally, the
stereochemical integrity of the conversion of the chiral
alcohol 14 (ee 94%) to (S)-nornicotine 1 and (S)-nicotine
2 was checked by an analysis on chiral HPLC, and no
decrease in the ee was noted.
(29) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155-
4156. (b) Meyer, S. D.; Schreiber, S. L. J . Org. Chem. 1994, 59, 7549-
7552.
(30) Singh, V. K. Synthesis 1992, 605-617 and references therein.
(31) (a) Allen, A. D.; Kanagasabapathy, V. M.; Tidwell, T. T. J . Am.
Chem. Soc. 1985, 107, 4513-4519. (b) Richard, J . P.; J encks, W. P. J .
Am. Chem. Soc. 1984, 106, 1383-1396. (c) Crossland, R. K.; Servis,
K. L. J . Org. Chem. 1970, 35, 3195-3196. (d) Uenishi, J .; Takagi, T.;
Ueno, T.; Hiraoka, T.; Yonemitsu, O.; Tsukube, H. Synlett 1999, 41-
44.
(32) Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M., Mathre,
D. J .; Grabowski, E. J . J . J . Org. Chem. 1993, 58, 5886-5888.
(33) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K. Tetrahe-
dron Lett. 1977, 1977-1980.
Syn th esis of P ip er id in e Alk a loid s. The amine (S)-
1836 was efficiently obtained in high yield by treatment
(34) An alternative synthesis of pyrrolidines using a reverse-Cope
cyclization on homoallylic hydroxylamines has been published recently;
see: Lee E.; Kim, S. K.; Kim, J . Y.; Lim, J . Tetrahedron Lett. 2000,
41, 5915-5918.
(35) Alternatively, (S)-nicotine 2 was obtained directly with a good
yield (78%) by treatment of (S)-nornicotine 1 with an excess of LiHMDS
followed by trapping with MeI.

Synthesis of Pyrrolidine and Piperidine Alkaloids
J . Org. Chem., Vol. 66, No. 19, 2001 6309
Sch em e 4
product in high yield. Unfortunately, under the same
conditions, all attempts using the protected N-allylamine
20 were unsuccessful; no metathesis was observed and
the starting material was recovered. The nearly quanti-
tative yield from RCM is in striking contrast with the
result obtained with 20.
The problems associated with pyridine nitrogen and
the compatibility of the olefin metathesis catalysts have
been reported many times, and we were not surprised
by this failure. a plausible explanation is that the
pyridine nitrogen interferes with the catalytic cycle by
coordinating to ruthenium.41
To circumvent this problem, our attention turned to a
pyridine derivative of 20 in which the nitrogen function-
ality is blocked and so cannot interfere with the ruthe-
nium. We chose protonation,42 which can be easily
achieved by bubbling dry hydrochloric acid gas into a
solution of 20, followed by removal of the solvent in a
vacuum. Treatment of the hydrochloride pyridium salt
of 20 with the Grubbs’ catalyst, followed by a basic
workup gave the desired piperideine 21 in good yield.43
Optimal yields were obtained when 5 mol % of the
catalyst was used followed by the addition of 2.5 mol %
after 4 h. The cyclization would not proceed to completion
with a single addition of 10 mol % of catalyst. Presum-
ably, the ruthenium catalyst decomposed in our acidic
conditions of refluxing dichloromethane.
of azide (S)-15 with an excess of hydrated tin chloride,37
without affecting the double bond (see Scheme 4).38
RCM methodologies have proved an elegant generic
synthetic approach for the total synthesis of cyclic natural
products and have been largely illustrated in recent
literature.20 In particular, the commercial availability of
Grubbs’ catalyst has enlarged the scope of this methodol-
ogy. We took advantage of the RCM reaction, which
offered the possibility of simultaneously forming the
piperidine skeleton and the double bond in the desired
position. At first, effort was focused on the preparation
of the chiral N-allylamine 18, precursor of the piperidine
ring. Our decision to proceed via N-allylation of the
N-benzyloxycarbonyl carbamate 19 was based on previ-
ous attempts39 to direct the N-monoallylation of amine
18. It was also anticipated that the N-benzyloxycarbonyl
group could serve as a masked methyl group at the final
stage (vide infra). Following a sequence already de-
scribed, amine 18 was protected as the benzyl carbamate
19, which was treated with an excess of sodium hydride
in the presence of allyl bromide, providing the protected
N-allylamine 20 in good yield.40
Having secured good access to this chiral building block
(S)-21, the completion of the synthesis of the four chiral
piperidine alkaloids 2-4 proved to be straightforward
and could be achieved using a single-, two-, or three-step
one-pot procedure, depending on the target piperdine
alkaloid (see Scheme 5). Thus, exposure of (S)-21 to an
atmosphere of hydrogen in the presence of Pd on carbon
as catalyst in EtOH caused simultaneous hydrogenation
of the double bond of (S)-21 and hydrogenolysis of the
benzyloxycarbonyl protecting group to give (S)-anabasine
5 ([R]20 -80.0 (c 0.91, MeOH); lit.44 [R]20 -79.2 (c 0.5,
D
D
MeOH)). (Scheme 5). The (S)-N-methylanatabine 4 was
easily obtained in good yield, by simple treatment of (S)-
21 with an excess of LiAH4, leading to the reduction of
the N-benzyloxycarbonyl protecting group to N-Me. For
the synthesis of (S)-anatabine 3 from the intermediate
(S)-21, catalytic hydrogenation was not suitable for the
cleavage of the N-benzyloxycarbonyl protecting group as
a result of the presence of the double bond in the
piperidine ring. To overcome this problem, the cleavage
of the protecting group of (S)-21 was achieved by reaction
with an excess of dimethyl sulfide in the presence of
etherate of boron trifluoride, according to a described
Before attempting the RCM on 20, we decided to
practice this cyclization on a racemic substrate, in which
the pyridine ring was switched to a phenyl ring. The
olefin metathesis reaction with 10 mol % of the Grubbs’
ruthenium benzylidene catalyst afforded the desired
(36) To prepare the chiral homoallylic amine 18, the Mitsunobu
inversion of alcohol (R)-14 with succinimide followed hydrazinolysis
was evaluated. On standard Mitsunobu reaction with diethyl azodi-
carboxylate (DEAD) and succinimide, the expected N-succinimide
derivative was obtained in low yield because of a difficult separation
of the product from residual reactants and byproducts. For a recent
procedure, see: Takahata, H.; Kubota, M.; Ikota, N. J . Org. Chem.
1999, 64, 8594-8601.
(37) (a) Bartra, M.; Romea, P.; Urpi, F.; Vilarrasa, J . Tetrahedron
1990, 46, 587-594. (b) Lebreton, J .; Waldner, A.; Leseuer, C.; De
Mesmaeker, A. Synlett 1994, 137-140.
(38) Examples of selective reduction of azides in the presence of
double bond using Lindlar catalytic hydrogenation have been reported
in the literature; see: Corey, E. J .; Nicolaou, K. C.; Balanson, R. D.;
Machida, Y. Synthesis 1975, 590-591.
(39) In our initial studies, attempts at N-allylation of the trifluoro-
acetamide derived from amine (S)-18 (TFAA/TEA/CH2Cl2) by sequen-
tial treatment with NaH and allylbromide failed. The desired N-alky-
lated product was obtained in poor yields (less than 20%) accompanied
with N-allyl-, N,N-diallyl derivatives. This N-allylation appeared to
be very sensitive to traces of moisture and/or to the quality of NaH
used.
method,45 leading to (S)-anatabine 3 in good yield ([R]20
D
-117.0 (c 0.94, MeOH); lit.46 [R]20D -98.15 (c unspecified,
(41) For similar problems of pyridine-metal coordination, see: (a)
Ling Ng, P.; Lambert, J . N. Synlett 1999, 1749-1750. (b) Raatz, D.;
Innertsberger, C.; Reiser, O. Synlett 1999, 1907-1910.
(42) (a) Fu, G. C.; Nguyen, S. B. T.; Grubbs, R. B. J . Am. Chem.
Soc. 1993, 115, 9856-9857. (b) Evans, P.; Grigg, R.; York, M.
Tetrahedron Lett 2000, 41, 3967-3970. (c) An example of successful
RCM on a more hindered and less basic 2-chloropyridine compound
was reported; see: Grigg, R.; Sridharan, V.; York, M. Tetrahedron Lett.
1998, 39, 4139-4142.
(43) Initially this sequence was run with an N-Boc carbamate as
protecting group; however, this choice turned out to be less efficient:
during the protonation of the pyridine ring with HCl gas, the N-Boc
was cleaved.
(40) (a) Falb, E.; Bechor, Y.; Nudelman, A.; Hassner, A.; Albeck, A.;
Gottlieb, H. E. J . Org. Chem. 1999, 64, 498-506. (b) Kise, N.; Oike,
H.; Okazaki, E.; Yoshimoto, M.; Shono, T. J . Org. Chem. 1995, 60,
3980-3992.
(44) Hattori, K.; Yamamoto, H. J . Org. Chem. 1982, 57, 3264-3265.
(45) (a) Haddad, M.; Imoga¨ı, H.; Larcheveˆque, M. J . Org. Chem.
1998, 63, 5680-5683. (b) Sanchez, I. H.; Lopez, F. J .; Soria, J . J .;
Larraza, M. I.; Flores, H. J . J . Am. Chem. Soc. 1983, 105, 7640-7643.

6310 J . Org. Chem., Vol. 66, No. 19, 2001
Felpin et al.
Sch em e 5
MeOH)). Finally, (S)-N-methylanabasine 6 was synthe-
sized from (S)-21 by taking advantage of the Eschweiler-
Clarke47 reductive amination procedure. Following this
procedure, intermediate (S)-21 was stirred in a mixture
of MeOH with aqueous formaldehyde at room tempera-
ture under an atmosphere of hydrogen in the presence
of Pd on carbon. This led to the concomitant hydrogena-
tion of the double bond and removal of the N-benzyloxy-
carbonyl protecting group, affording (S)-anabasine 6 in
situ, which was N-methylated via the reduction of the
iminium.
The spectroscopic data (1H NMR, 13C NMR) of (S)-
anatabine 3 and (S)-anabasine 5 were identical with
those previously reported for the racemic materials.48 The
spectroscopic data (1H NMR, 13C NMR) for (S)-N-methyl-
anatabine 4 and (S)-N-methylanabasine 6 are in good
agreement with those partially reported in the literature
for the racemic materials.49
Synthesis of such analogues and studies of the structure-
activity relationships are in progress.
Exp er im en ta l Section
Gen er a l Meth od s. 1H and 13C NMR spectra were recorded
at 200 and 50 MHz using CDCl3 as internal standard (7.26
and 77.16 ppm, respectively). Flash column chromatography
was performed on Merck silica gel (60 Å, 230-400 mesh).
HMRS were recorded at the Centre Re´gional de Mesures
Physique de l’Ouest. Chiral HPLC was performed with a
CHIRACEL OD-H column, 46 × 15 cm, flow rate 0.5 mL/min.
Grubbs’ catalyst was purchased from Strem. (+)-DIPCl was
purchased from Aldrich. All reactions were performed under
N2 in a flame-dried flask using anhydrous solvents. Grignard
reagents were titrated by Watson and Eastham’s method.52
P r ep a r a tion of Allylbor a n e Rea gen t F r ee fr om Ma g-
n esiu m Sa lts. A solution of commercial allylmagnesium
bromide in ether (48 mL, 1 M, 48 mmol) was added to a
solution of (+)-B-chlorodiisopinocampheylborane ((+)-DIPCl)
(16.0 g, 49.9 mmol) in ether (50 mL) at 0 °C. The resulting
mixture was stirred for 1 h at room temperature and then
concentrated in vacuo. The residue was extracted with anhy-
drous pentane (3×). Stirring was stopped to permit the
magnesium salts to settle, and the supernatant pentane
extract was filtered through a pad of Celite. The pentane was
evaporated under reduced pressure to give (+)-B-allyldiisopi-
nocampheylborane ((+)-Ipc2Ball) (15.6 g, 96%) as a colorless
oil.
The enantiomeric excess in (S)-anabasine 3, (S)-N-
methylanatabine 4, (S)-anabasine 5, and (S)-anatabine
6 was determined by chiral HPLC; a slight drop of ee
was noted (less than 1-2% for all products).50
The optical rotation of our synthetic (S)-N-methylana-
tabine 4 ([R]20D -157.5 (c 0.8, MeOH)) and (S)-N-methyl-
anabasine 6 ([R]20D -132.3 (c 0.8, MeOH)) matched those
reported by Spath51 for the natural products, [R]20
D
-171.4 (c 0.5, MeOH) and [R]20 -143.8 (c 0.4, MeOH)
(R)-1-P yr id in -3-yl-bu t-3-en -1-ol (14). To a solution of (+)-
B-allyldiisopinocampheylborane (15.6 g, 47.8 mmol) in ether
(50 mL) at -100 °C was slowly added, via a cannula, a solution
of 3-pyridinecarboxaldehyde 13 (2.0 mL, 21.2 mmol) in ether
(40 mL) maintained at -65 °C. After stirring at -100 °C for
1 h, the reaction mixture was quenched with methanol (1 mL).
The resulting mixture was then allowed to warm to room
temperature and extracted with 1 N aqueous HCl. The
combined aqueous layers were treated with 30% aqueous
NaOH solution until pH 12-13 and then extracted with CH2-
Cl2 (4×). The combined extracts were dried over anhydrous
MgSO4, filtered, and concentrated in vacuo. Purification by
flash chromatography (5% MeOH-CH2Cl2) gave the alcohol
14 (3.16 g, 94%) as a pale yellow oil; 94% ee, determined by
chiral HPLC (hexane/i-PrOH ) 95/5, 23.3 min for (S)-alcohol
and 24.6 min for (R)). [R]20D ) 28 (c 1, EtOH); IR (KBr) ν 1585,
D
for (S)-N-methylanatabine 4 and (S)-N-methylanabasine
6 respectively.
Con clu sion
We have accomplished a highly efficient enantioselec-
tive synthesis of tobacco alkaloids. From a common chiral
intermediate, two different strategies have been used to
construct the piperidine and pyrrolidine rings. Access to
unnatural (R)-enantiomers of these alkaloids could be
obtained by replacing (+)-Ipc2BCl with (-)-Ipc2BCl. The
present approach provides a facile route to these natural
alkaloids and could be applicable to the preparation of a
wide range of chiral structural analogues of piperidine
and pyrrolidine heterocyclic compounds, providing a
better understanding of their pharmacological activities.
1
1642, 2979, 3077, 3444 cm-1; H NMR δ (ppm) 2.47 (m, 2H),
3.51 (s, 1H), 4.87 (t, 1H, J ) 6.6 Hz), 5.01-5.10 (m, 2H), 5.63-
5.83 (m, 1H), 7.53 (dd, 1H, J ) 7.9 Hz and J ) 4.1 Hz), 7.98
(d, 1H, J ) 7.9 Hz), 8.60 (d, 1H, J ) 4.1 Hz), 8.68 (s, 1H); 13
C
NMR δ (ppm) 43.1, 70.0, 119.2, 125.2, 132.8, 137.9, 141.8,
(46) Wada, E.; Kisaki, T.; Ihida, M. Arch. Biochem. Biophys. 1959,
80, 258-267.
146.3, 147.1; MS (CI/NH3) m/z 150 (MH+, 100), 167.
(47) Vazquez-Tato, M. P.; Seijas, J . A.; Fleet, G. W. J .; Mathews, C.
J .; Hemmings, P. R.; Brown, D. Tetrahedron 1995, 51, 959-974.
(48) Yang, C.-M.; Tanner, D. D. Can. J . Chem. 1997, 75, 616-620.
(49) (a) Quan, P. M.; Karns, T. K. B.; Quin, L. D. J . Org. Chem.
1965, 30, 2769-2772. (b) Alberici, G. F.; Andrieux, J .; Adam, G.; Plat,
M. M. Tetrahedron Lett. 1983, 24, 1937-1940.
(50) For (S)-anatabine 3, all attempts to separate the enantiomers
failed and the ee was measured on the hydrogenated product, (S)-
anabasine 5.
(R)-Meth a n esu lfon ic Acid 1-P yr id in -3-yl-bu t-3-en yl Es-
ter (17). To a solution of alcohol 14 (6.0 g, 40.3 mmol) and
Et3N (11.2 mL, 80.6 mmol) in CH2Cl2 (200 mL) at 0 °C was
slowly added methanesulfonyl chloride (4.7 mL, 60.5 mmol).
After stirring for 10 min, the mixture was diluted with water
and the layers were separated. The organic layer was washed
(51) Spath, E.; Kesztler, F. Ber. Dtsch. Chem. Ges. 1937, 70, 2450-
2454.
(52) Watson, S. C.; Eastham, J . F. J . Organomet. Chem. 1967, 165-
168.

Synthesis of Pyrrolidine and Piperidine Alkaloids
J . Org. Chem., Vol. 66, No. 19, 2001 6311
with water (100 mL) and brine (2×), dried over anhydrous
MgSO4, filtered, and concentrated at room temperature under
reduced pressure to afford the crude mesylate 17 (9.1 g, 100%)
as a yellow oil. The product was immediately used in the next
step, without purification, because of extensive decomposition.
7.30 (m, 6H), 7.55-7.59 (m, 1H), 8.47-8.50 (m, 1H), 8.55 (s,
1H); 13C NMR δ (ppm) 40.5, 52.5, 66.8, 119.0, 123.3, 128.0,
128.0, 128.4, 132.9, 133.9, 136.1, 137.5, 148.0, 148.5, 155.6;
HRMS (EI) calcd for C17H18N2O2 (M+) 282.1368, found 282.1373.
(S)-Allyl-(1-pyr idin -3-yl-bu t-3-en yl)-car bam ic Acid Ben -
zyl Ester (20). To a stirred solution of 19 (1.4 g, 5 mmol) in
dry DMF freshly distilled (50 mL) at 0 °C was added NaH
(60%, 1.19 g, 29.8 mmol). After the evolution of H2 ceased, allyl
bromide (1.3 mL, 14.9 mmol) was added. After stirring for 30
min at room temperature, the mixture was quenched with
water (20 mL). The aqueous layer was extracted with ether
(3×). The combined extracts were washed with brine (3×) and
dried over anhydrous MgSO4. Removal of the solvent left an
oil that was purified by flash chromatography (40% ethyl
[R]20 65.5 (c 1.16, MeOH); 1H NMR δ (ppm) 2.60-2.91 (m,
D
2H), 2.85 (s, 3H), 5.10-5.20 (m, 2H,), 5.62 (t, 1H, J ) 6.7 Hz),
5.66-5.82 (m, 1H), 7.35 (dd, 1H, J ) 7.9 Hz, J ) 7.8 Hz), 7.72
(m, 1H), 8.62 (m, 2H); 13C NMR δ (ppm) 38.9, 41.0, 80.6, 119.8,
123.5, 131.1, 133.6, 134.1, 148.0, 150.2.
(S)-3-(1-Azid o-bu t-3-en yl)-p yr id in e (15). Meth od A. To
a solution of mesylate 17 (9 g, 39.6 mmol) in freshly distilled
DMF (120 mL) was added, in one portion, NaN3 (3.87 g, 59.5
mmol). The resulting mixture was stirred at 60 °C for 4 h and
then diluted with water. The layers were separated and the
aqueous layer was extracted with ether (3×). The combined
extracts were washed with brine (2×), dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure.
Purification by flash chromatography (40% ethyl acetate-
hexane) gave azide 15 (6.72 g, 97%) as a colorless oil; 94% ee,
determined by chiral HPLC (hexane/i-PrOH ) 95/5, 13.1 min
acetate/hexane), affording amine 20 (1.21 g, 76%). [R]20 -52
D
1
(c 1, MeOH); IR (KBr) ν 1642, 1694, 3033 cm-1; H δ (ppm)
2.77 (t, 2H, J ) 7.5 Hz), 3.60-3.79 (m, 2H), 4.90-5.08 (m, 4H),
5.15 (s, 2H), 5.33 (sl, 1H), 5.57-5.84 (m, 2H), 7.18-7.26 (m,
1H), 7.31 (s broad, 5H) 7.60 (s broad, 1H), 8.49 (d, 1H, J ) 4.6
Hz), 8.57 (s, 1H); 13C NMR δ (ppm) 35.2, 46.9, 57.1, 67.4, 116.7,
118.1, 123.2, 127.9, 128.0, 128.4, 134.1, 134.7, 135.3, 135.6,
136.4, 148.8, 149.5, 156.2; HRMS (EI) calcd for C20H22N2O2
(M+) 322.1681, found 322.1679.
for (S)-azide and 14.8 min for (R)). [R]20 -96.9 (c 1, CHCl3);
D
IR (KBr) ν 1591, 1642, 2096, 3081 cm-1
;
1H NMR δ (ppm)
2.46-2.70 (m, 2H), 4.56 (t, 1H, J ) 6.9 Hz) 5.07-5.17 (m, 2H),
5.63-5.83 (m, 1H), 7.28-7.35 (m, 1H), 7.62-7.68 (m, 1H),
8.56-8.60 (m, 2H); 13C NMR δ (ppm) 40.2, 63.1, 118.9, 123.4,
132.6, 134.1, 134.7, 148.4, 149.5; HRMS (EI) calcd for C6H5N4
(M - C3H5) 133.0514, found 133.0512.
Meth od B. To a solution of alcohol 14 (0.2 g, 1.34 mmol) in
dry toluene (2 mL), was added diphenylphosphoryl azide (0.38
g, 1.38 mmol). The resulting mixture was cooled to 0 °C, and
DBU (0.21 mL, 1.38 mmol) was added. The reaction was
stirred for 3 days at room temperature and was quenched with
water (5 mL). The white precipitate was filtered through a
pad of Celite, and the aqueous layer was extracted with ether
(3×). The combined extracts were washed with brine (2×),
dried over anhydrous MgSO4, filtered, and concentrated in
vacuo. The residue was purified by flash chromatography (20%
ethyl acetate/hexane) to give 15 (0.2 g, 88%) as a pale yellow
oil.
(S)-Allyl-(1-pyr idin -3-yl-bu t-3-en yl)-car bam ic Acid Ben -
zyl Ester Hyd r och lor id e. Protonation of the pyridine was
achieved by bubbling dry HCl gas into a solution of diethylenic
amine 20 (1.21 g, 3.8 mmol) in CH2Cl2 (30 mL). Removal of
the solvent gave the hydrochloride pyridinium salt (1.35 g,
100%) as a oil. 1H NMR δ (ppm) 2.85-2.95 (m, 2H), 3.79-
4.05 (m, 2H), 5.09-5.18 (m, 7H), 5.61-5.81 (m, 2H), 7.31-
7.33 (m, 5H), 7.90 (sl, 1H), 8.44 (sl, 1H), 8.79-8.81 (m, 2H);
13C NMR δ (ppm) 34.3, 48.7, 56.8, 67.2, 117.7, 118.9, 126.4,
127.4, 127.7, 128.0, 132.3, 133.4, 135.4 139.5, 139.8, 140.5,
145.0, 155.1.
(S)-3,6-Dih yd r o-2H-[2,3′]bip yr id in yl-1-ca r boxylic Acid
Ben zyl Ester (21). To a solution of the amine hydrochloride
of 20 (1.43 g, 3.98 mmol) in anhydrous degassed CH2Cl2 (50
mL) was added a solution of bis(tricyclohexylphosphine)-
benzylidene ruthenium dichloride (160 mg, 0.2 mmol) in CH2-
Cl2 (20 mL). The resulting mixture was stirred at reflux under
argon. After 4 h, an additional portion of catalyst (80 mg, 0.1
mmol) was added, and the reaction was found to be complete
after a total of 8 h. After the mixture cooled to room temper-
ature, saturated aqueous NaHCO3 was added. The solution
was extracted with CH2Cl2 (3×) and concentrated in vacuo.
The residue was purified by flash chromatography (40% ethyl
acetate/hexane) to give 21 (0.92 g, 79%) as a yellow oil; 92%
ee, determined by chiral HPLC (hexane/i-PrOH ) 98/2, 28.2
min for (S)-carbamate and 34.1 min for (R)). [R]20D -83 (c 0.99,
(S)-1-P yr id in -3-yl-bu t-3-en yla m in e (18). To a solution of
azide 15 (6.5 g, 37.3 mmol) in MeOH (120 mL) at 0 °C was
added a solution of hydrated tin chloride (SnCl2‚2H2O) in
MeOH (50 mL) over 30 min. After 3 h of stirring at room
temperature, the solvent was removed under reduced pressure.
To the residue was added successively CH2Cl2 (20 mL) and
water (20 mL). The solution was treated with KOH in pellets
until the emulsion disappeared (pH ) 13). The aqueous layer
was extracted with CH2Cl2 (4×). The combined extracts were
washed with brine (2×) and dried over anhydrous MgSO4.
Removal of solvent left an oil that was purifed by flash
chromatography (10% MeOH/CH2Cl2), affording the amine 18
1
MeOH); IR (KBr) ν 1660, 1700, 2953, 3036 cm-1; H NMR δ
(ppm) syst AB, 2.48-2.57 (A, dm, 1H, J ) 17.8 Hz), 2.72-
2.81 (B, dm, 1H, J ) 17.8 Hz), syst AB 3.35-3.47 (A, dm, 1H,
J ) 19 Hz), 4.28-4.39 (dm, 1H, J ) 19 Hz), 5.20 (s, 2H), 5.64-
5.70 (m, 2H), 5.87-5.96 (m, 1H), 7.17-7.27 (m, 1H), 7.32-
7.38 (m, 5H), 7.58-7.62 (m, 1H), 8.48 (d, 1H, J ) 4,4 Hz), 8.57
(s, 1H); 13C NMR δ (ppm) 27.4, 40.4, 49.2, 67.4, 122.9, 123.2,
124.2, 127.9, 128.1, 128.5, 134.5, 136.0, 136.4, 148.5, 148.6,
155.4; HRMS (EI) calcd for C18H18N2O2 (M+) 294.1368, found
294.1376.
(5.42 g, 98%) as a colorless oil. [R]20 -30.5 (c 0.92, MeOH);
D
IR (KBr) ν 1577, 1640, 3076, 3270, 3364 cm-1; 1H NMR δ (ppm)
1.75 (s, 2H), 2.28-2.52 (m, 2H), 4.04 (dd, 1H, J ) 7.6 Hz, J )
5.6 Hz), 5.06-5.16 (m, 2H), 5.63-5.84 (m, 1H), 7.22 (dd, 1H,
J ) 4.7 Hz, J ) 7.6 Hz), 7.69 (dt, 1H, J ) 1.7 Hz, J ) 7.6 Hz),
8.47 (dd, 1H, J ) 1.7 Hz, J ) 4.7 Hz), 8.57 (d, 1H, J ) 1.7 Hz);
13C NMR δ (ppm) 43.6, 52.6, 117.9, 123.0, 133.6, 134.3, 140.5
148.1, 148.2; HRMS (EI) calcd for C6H7N2 (M - C3H5)
107.0609, found 107.0612.
(S)-1,2,3,4,5,6-H exa h yd r o-[2,3′]b ip yr id in yl, (S)-An a -
ba sin e (5). A solution of 21 (0.40 g, 1.37 mmol) in ethanol (15
mL) containing palladium on carbon (0.14 g, 10% mol) was
hydrogenated at room temperature for 14 h. The catalyst was
removed by filtration, and the residue was purified by flash
chromatography (5% MeOH/CH2Cl2) to give (S)-anabasine 5
(0.18 g, 82%) as a colorless oil; 92% ee, determined by chiral
HPLC (hexane/i-PrOH ) 98/2, 32.2 min for (R)-anabasine and
(S)-(1-P yr id in -3-yl-bu t-3-en yl)-ca r ba m ic Acid Ben zyl
Ester (19). To a solution of amine 18 (2.0 g, 13.5 mmol) in
dry CH2Cl2 (100 mL) at 0 °C was added successively potassium
carbonate (1.86 g, 13.5 mmol) and benzyl chloroformate (2.3
mL, 16.2 mmol). After stirring for 30 min at room temperature,
the mixture was hydrolyzed with saturated aqueous NaHCO3
(50 mL). The layers were separated, and the aqueous layer
was extracted with CH2Cl2 (3×). The combined extracts were
dried over anhydrous MgSO4 and concentrated under reduced
pressure. Purification by flash chromatography (40% ethyl
acetate/hexane) gave the carbamate 19 (2.89 g, 76%) as a
colorless oil. [R]20D -25 (c 0.97, MeOH); IR (KBr) ν 1532, 1641,
35.7 min for (S)). [R]20 -80 (c 0.91, MeOH); IR (KBr) ν 1318,
D
1424, 1577, 2933, 3031 cm-1; 1H NMR δ (ppm) 1.46-1.92 (m,
6H), 2.00 (s, 1H), 2.75-2.85 (m, 1H), 3.22 (dm, 1H, J ) 11
Hz), 3.64 (dd, 1H, J ) 11 Hz, J ) 2.2 Hz), 7.25 (dd, 1H, J )
7.9 Hz J ) 4.7 Hz), 7.73 (dm, 1H, J ) 7.9 Hz), 8.49 (dt, 1H, J
) 4.7 Hz, J ) 1.7 Hz), 8.59 (s, 1H); 13C NMR δ (ppm) 24.5,
24.9, 34.0, 46.9, 59.1, 122.9, 133.7, 139.7, 148.0, 148.1; MS (CI/
NH3) m/z 163 (MH+, 100).
1
1716, 3033 cm-1; H NMR δ (ppm) 2.51 (t, 2H, J ) 7.0 Hz),
4.81 (m, 1H), 5.06-5.13 (m, 4H), 5.55-5.76 (m, 2H), 7.19-

6312 J . Org. Chem., Vol. 66, No. 19, 2001
Felpin et al.
(S)-1,2,3,6-Tetr a h yd r o-[2,3′]bip yr id in yl. (S)-An a ta bin e
(3). A solution of 21 (0.33 g, 1.13 mmol) in dry CH2Cl2 (16 mL)
was treated with dimethyl sulfide (2.23 mL, 30.5 mmol) and
boron trifluoride etherate (1.43 mL, 11.3 mmol). The mixture
was stirred for 2 h, and then an additional amount of dimethyl
sulfide (1.15 mL, 16.9 mmol) was added. The reaction mixture
was stirred for another 4 h and poured into 10% aqueous
NaOH. The aqueous layer was extracted with CH2Cl2 (3×).
The combined extracts were washed with brine (2×), dried over
anhydrous MgSO4, and concentrated in vacuo. The crude
product was purified by flash chromatography (5% MeOH/CH2-
Cl2) to furnish (S)-anatabine 3 (120 mg, 67%) as a colorless
oil. All attempts to separate the enantiomers on the chiral
HPLC column failed, and the ee was determined to be 92% on
reaction was quenched with MeOH and diluted with ether,
and the organic layer was extracted with 1 N aqueous HCl
(6×). The combined aqueous layers were treated with 30%
aqueous NaOH solution until pH 13-14 and then extracted
with CH2Cl2 (3×). The combined extracts were dried over
anhydrous MgSO4. Removal of the solvent left an oil that was
purified by flash chromatography (5% EtOH/CH2Cl2) yielding
(S)-nornicotine 1 (0.33 g, 85%); 94% ee, determined by chiral
HPLC (hexane/i-PrOH ) 95/5, 28.0 min for (R)-nornicotine and
1
30.0 min for (S)). [R]20 -35.2 (c 1, MeOH); H NMR δ (ppm)
D
1.66 (1H, m), 1.9 (2H, m), 2.1 (1H), 2.2 (1H, m), 3.1 (2H, m),
4.14 (1H, J ) 7.3 Hz, J ) 2 Hz), 7.22 (1H, dd, J ) 7.9 Hz, J )
4.9 Hz), 7.70 (pseudo dt, 1H, J ) 7.9 Hz, J ) 2.1 Hz), 8.45
(dd, 1H, J ) 4.9 Hz, J ) 1.7 Hz), 8.6 (d, 1H, J ) 1.8 Hz); 13C
NMR δ (ppm) 25.3, 34.1, 46.7, 59.8, 123.2, 134.0, 140.0, 148.0,
148.4; MS (EI) m/z 147 (M+ - 1).
the hydrogenated product. [R]20 -117 (c 0.94, MeOH); IR
D
1
(KBr) ν 1311, 1425, 1577, 1656, 2915, 3030 cm-1; H NMR δ
(ppm) 2.09 (s, 1H), 2.16-2.21 (m, 2H), 3.41 (dm, 1H, J ) 17
Hz), 3.54 (dm, 1H, J ) 17 Hz), 3.83 (t, 1H, J ) 7.2 Hz), 5.68-
5.85 (m, 2H), 7.20 (dd, 1H, J ) 4.9 Hz, J ) 7.9 Hz), 7.66 (ddd,
1H, J ) 7.9 Hz, J ) 1.7 Hz, J ) 2.1 Hz), 8.43 (dd, 1H, J ) 4.9
Hz, J ) 1.7 Hz), 8.54 (d, 1H, J ) 2.1 Hz); 13C NMR δ (ppm)
33.7, 45.9, 55.2, 123.5, 125.0, 126.1, 134.1, 139.7, 148.6, 148.7;
MS (CI/NH3) m/z 161 (MH+, 100), 178.
(S)-2-P yr id in -3yl-p yr r olid in e-1-ca r boxylic Acid Eth yl
Ester (17). To a solution of (S)-nornicotine 1 (0.16 g, 1.1 mmol)
in dry CH2Cl2 (10 mL) at 0 °C were added successively
potassium carbonate (0.15 g, 1.1 mmol) and methyl chlorofor-
mate (0.1 mL, 1.3 mmol). After stirring for 1 h at room
temperature, the mixture was hydrolyzed with saturated
aqueous NaHCO3 (50 mL). The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3×). The combined
extracts were dried over anhydrous MgSO4 and concentrated
under reduced pressure. Purification by flash chromatography
(50% ethyl acetate/hexane) gave the carbamate 17 (0.21 g,
(S)-1-Meth yl-1,2,3,4,5,6-h exah ydr o-[2,3′]bipyr idin yl. (S)-
N-Meth yla n a ba sin e (6). To a solution of 21 (0.40 g, 1.38
mmol) in distilled methanol (15 mL) was added aqueous
formaldehyde (37% solution, 0.32 mL, 4.14 mmol). The reaction
mixture was stirred at room temperature under an atmosphere
of hydrogen in the presence of a catalytic amount of palladium
on carbon (140 mg, 10% mol) for 24 h. The catalyst was
removed by filtration through a pad of Celite, and the solvent
was removed under reduced pressure. Purification by flash
chromatography (5% MeOH/CH2Cl2) gave (S)-N-methylana-
basine 6 (0.21 g, 88%) as a colorless oil; 92% ee, determined
by chiral HPLC (hexane/i-PrOH ) 98/2, 7.3 min for (S)-N-
95%) as a yellow oil. [R]20 -105.6 (c 1.33, MeOH); 1H NMR δ
D
(ppm) 1.75-1.86 (m, 3H), 2.24-2.39 (m, 1H), 3.48-3.62 (m,
5H), 4.89 (m, 1H), 7.18 (dd, 1H, J ) 4.7 Hz and J ) 7.8 Hz),
7.42 (sl, 1H), 8.41 (m, 2H); 13C NMR δ (ppm) 22.8, 23.7, 34.5,
35.5, 47.1, 47.5, 52.4, 58.8, 59.2, 123.3, 132.9, 133.2, 147.6,
148.2, 155.5; MS (EI) m/z 206 (M+), 191 (M+ - Me), 147 (M+
- COOMe).
(S)-3-(1-Meth yl-p yr r olid in -2-yl)-p yr id in e, (S)-Nicotin e
(2). To a suspension of LiAlH4 (44.2 mg, 1.16 mmol) in
anhydrous THF (10 mL) at 0 °C was added dropwise a solution
of 17 (0.2 g, 0.97 mmol) in THF (5 mL). After 8 h of stirring at
room temperature, the reaction was quenched with 10%
aqueous NaOH (10 mL). The aqueous layer was extracted with
CH2Cl2 (3×), dried over anhydrous MgSO4, and concentrated
under reduced pressure. The residue was purified by flash
chromatography (5% EtOH/CH2Cl2) to give (S)-nicotine 2 (0.15
g, 95%) as a colorless oil; 94% ee, determined by chiral HPLC,
methylanabasine and 8.9 min for (R)). [R]20 -132.3 (c 0.8,
D
MeOH); IR (KBr) ν 1321, 1426, 1575, 2981, 3027 cm-1
;
1H
NMR δ (ppm) 1.31-1.87 (m, 6H), 1.99 (s, 3H), 2.06-2.20 (m,
1H), 2.79-2.85 (m, 1H), 2.99-3.06 (m, 1H), 7.21-7.31 (m, 1H),
7.66-7.72 (m, 1H), 8.47-8.53 (m, 2H); 13C NMR δ (ppm) 24.7,
25.9, 35.9, 44.4, 57.3, 68.2, 123.5, 134.8, 140.1, 148.5, 149.2;
HRMS (EI) calcd for C11H16N2 (M+) 176.1313, found 176.1311.
(S)-1-Meth yl-1,2,3,6-tetr a h yd r o-[2,3′]bip yr id in yl. (S)-N-
Meth yla n a ta bin e (4). To a suspension of LiAlH4 (0.23 g, 6.2
mmol) in THF (20 mL) at 0 °C under nitrogen was added
dropwise a solution of 21 (0.40 g, 1.37 mmol) in THF (20 mL).
The mixture was stirred at room temperature for 6 h. The
reaction was quenched with 10% aqueous NaOH (30 mL). The
aqueous layer was extracted with CH2Cl2 (3×). The combined
extracts were washed with brine (2×), dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (5%
MeOH/CH2Cl2) to yield (S)-N-methylanatabine 4 (0.17 g, 71%)
as a colorless oil; 92% ee, determined by chiral HPLC (hexane/
i-PrOH ) 98/2, 15.2 min for (S)-N-methylanatabine and 18.7
(hexane/i-PrOH ) 98/2), 10.9 min for (S)-nicotine and 12.9 min
1
for (R)). [R]20 -145 (c 1, EtOH); H NMR δ (ppm) 1.62-2.10
D
(m, 3H), 2.14 (s, 3H), 2.17-2.36 (m, 2H), 3.07 (t, 1H, J ) 8.3
Hz), 3.23 (t, 1H, J ) 8.2 Hz), 7.24 (dd, 1H, J ) 8 Hz, J ) 4.9
Hz), 7.71 (app dt, 1H, J ) 8 Hz, J ) 2 Hz), 8.47 (dd, 1H, J )
2 Hz, J ) 4.9 Hz), 8.51 (t, 1H, J ) 2 Hz); 13C NMR δ (ppm)
22.7, 35.2, 40.4, 57.1, 69.0, 123.7, 135.0, 138.7, 148.7, 149.6;
MS (EI) m/z 162 (M+).
Ack n ow led gm en t. This program is supported in
part by the MRT (grant for F.-X.F) and in part by the
Regional Council of the Pays-de-la-Loire (grant for S.G.).
We are indebted to Drs. Bertrand Carboni and Franc¸ois
Carreaux (Universite´ de Rennes, UMR-CNRS 6510) for
helpful discussions and reprints and to Marie-J o Ber-
trand for skilled technical assistance in HPLC. Thanks
are also due to Mr. G. Nourisson for recording of the
mass spectra and Dr. Andre´ Guingant for fruitful
discussions.
min for (R)). [R]20 -157.5 (c 0.4, MeOH); IR (KBr) ν 1321,
D
1426, 1576, 1667, 2984, 3033 cm-1; H NMR δ (ppm) 2.07 (s,
1
3H), 2.29-2.38 (m, 2H), 2.89-3.01 (m, 1H), 3.28-3.40 (m, 2H),
5.74-5.88 (m, 2H), 7.25-7.32 (m, 1H), 7.67-7.72 (m, 1H),
8.51-8.56 (m, 2H); 13C NMR δ (ppm) 35.0, 43.3, 55.0, 62.8,
123.6, 124.6, 125.3, 135.2, 138.3, 148.8, 149.6; HRMS (EI) calcd
for C11H14N2 (M+) 174.1157, found 174.1156.
(S)-3-P yr r olid in -2-yl-p yr id in e, (S)-Nor n icotin e (1). To
a stirred solution of freshly distilled cyclohexene (1.58 mL, 15.6
mmol) in 10 mL of THF at 0 °C was added dropwise 2.0 M
BH3-Me2S complex in THF (3.94 mL, 7.9 mmol). The resulting
white suspension of dicyclohexylborane was stirred for 1 h at
0 °C and then cooled to -15 °C prior to the addition of azide
15 (450 mg, 2.59 mmol) in 5 mL of THF. The resulting mixture
was allowed to warm to room temperature. After 12 h, the
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O010386B