The first enantioselective synthesis of (S)-5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine: A key intermediate for the preparation of SIB-1508Y

Article abstract of DOI:10.1016/S0957-4166(01)00204-X

The first enantioselective synthesis of (S)-5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine is described via intramolecular hydroboration-cycloalkylation of an azido-olefin intermediate. The chiral homoallylic alcohol was efficiently synthesized by enantioselective reduction of the corresponding ketone using (+)-diisopinocamphenylchloroborane as the key reaction. The total synthesis of (S)-SIB-1508Y was achieved with an enantiomeric excess (e.e.) of 94% in ten steps and in 18% overall yield from the commercially available 5-bromo-3-pyridinecarboxylic acid.

Full text of DOI:10.1016/S0957-4166(01)00204-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1121–1124
The first enantioselective synthesis of
(S)-5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine: a key
intermediate for the preparation of SIB-1508Y
Franc¸ois-Xavier Felpin, Giang Vo-Thanh, Jean Villie´ras and Jacques Lebreton*
Laboratoire de Synthe`se Organique, CNRS UMR 6513, Faculte´ des Sciences et des Techniques, 2 rue de la Houssinie`re,
BP 92208, 44322 Nantes Cedex 3, France
Received 13 April 2001; accepted 3 May 2001
Abstract—The first enantioselective synthesis of (S)-5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine is described via intramolecular
hydroboration–cycloalkylation of an azido-olefin intermediate. The chiral homoallylic alcohol was efficiently synthesized by
enantioselective reduction of the corresponding ketone using (+)-diisopinocamphenylchloroborane as the key reaction. The total
synthesis of (S)-SIB-1508Y was achieved with an enantiomeric excess (e.e.) of 94% in ten steps and in 18% overall yield from the
commercially available 5-bromo-3-pyridinecarboxylic acid. © 2001 Elsevier Science Ltd. All rights reserved.
The importance of nicotinic acetylcholine receptors
(nAChR) in several CNS disorders, including
Alzheimer’s disease (AD),1,2 Parkinson’s disease (PD)1
and Tourette’s syndrome1,2 is now well established.3,4
Several studies have demonstrated that the naturally
occurring alkaloid (S)-nicotine 1 and its analogues such
as (S)-ABT-418 3, display potent biological activity in
mammals by modulation of nAChR (Scheme 1).5
It should be pointed out that the synthesis of (S)-2 has
already been described in the literature7 by reduction of
the corresponding imine using the homochiral
(acyloxy)borohydride reagent derived from Cbz-D-pro-
line. However, the (S)-2 formed by the previously
reported process had low 30% e.e. After several unsuc-
cessful attempts at the preparation of the enantiomeri-
cally enriched amine 5, enantiopure (S)-SIB-1508Y 4
(>99% e.e.) was finally obtained by fractional crystal-
lization of a diastereomeric salt in an additional resolu-
tion process. As has already been observed by
Buchwald et al.,8 the asymmetric hydrogenation of
imines, for example the 2-phenyl-1-pyrroline, with
In connection with our studies on nAChR ligands and
our ongoing project on the asymmetric synthesis of
tobacco alkaloids, we have recently reported a new
enantioselective synthesis of these pyrrolidine and pipe-
ridine alkaloids.6 In this communication, we describe
the first enantioselective synthesis of (S)-(−)-5-bromo-3-
(1-methyl-2-pyrrolidinyl)pyridine 2, a key intermediate
for the preparation of (S)-SIB-1508Y 4, an important
nAChR agonist in clinical trials for the treatment of
Parkinson’s disease.
a
chiral titanocene catalyst proceeds to afford
corresponding amines with excellent enantioselec-
tivity (>99% e.e.). However, imines containing a pyri-
dine substituent, such as 3-pyridyl-2-pyrroline
(myosmine), were found not to react even under forcing
conditions.
Scheme 1.
* Corresponding author. E-mail: lebreton@chimie.univ-nantes.fr
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00204-X

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F.-X. Felpin et al. / Tetrahedron: Asymmetry 12 (2001) 1121–1124
a modest e.e. of 66%11 (instead of 94% in the case of
3-pyridinecarboxaldehyde). It is noteworthy that the
poor chiral induction achieved in the allylation of this
less reactive aldehyde was probably due to the presence
of the bromine at C(5) of the pyridine ring. So, we
decided to take another approach.
Our aim was therefore to obtain the chiral homoallylic
alcohol (R)-8, which can be prepared from the commer-
cially available corresponding carboxylic acid 9. The
formation of pyrrolidine ring is achieved by intramolec-
ular hydroboration–cycloalkylation tandem reactions
from the chiral azide (S)-6. A retrosynthetic analysis of
(S)-SIB-1508Y 4 is shown in Scheme 2.
An alternative route to prepare the chiral alcohol (R)-8
was investigated, involving an enantioselective reduc-
tion of the corresponding ketone, easily obtained by
oxidation of the racemic alcohol 11 with Dess–Martin
reagent. Starting from 5-bromo-3-pyridinecarboxalde-
hyde 10, the racemic alcohol 11 was prepared by allyla-
tion with allyl bromide in the presence of zinc in 97%
yield after purification by flash chromatography. Oxi-
dation of the alcohol 11, in mild conditions using the
Dess–Martin Periodinane (DMP) reagent,12 leading to
ketone 12 which was immediately used in the next step
without purification.
Our synthesis was initiated by the direct conversion of
5-bromo-3-pyridinecarboxylic acid 9 to the correspond-
ing aldehyde 10 in 63% yield using N,N-
dimethylchloromethyleneiminium chloride and lithium
tri-tert-butoxyalumium hydride according to the condi-
tions reported by Fujisawa et al.9 (Scheme 3).
Preparation of the chiral homoallylic alcohol (R)-8 was
a key step of our synthetic work. As already described
in the synthesis of pyrrolidine and piperidine alkaloids,6
we carried out the enantioselective allylation using B-
allyldiisopinocamphenylborane (prepared from (+)-
Ipc2BCl) on the aldehyde 10. However, the chiral
alcohol (R)-8 was obtained in 75% yield10 but with only
A similar reaction sequence carried out on the analogue
of homoallylic alcohol 11 without the bromine at C(5)
Scheme 2.
Scheme 3. Reagents and conditions: (a) (i) DMF, (ClCO)2, −20°C, 1.30 h; (ii) CuI (10 mol%), −78°C, LiAlH(Otert-Bu)3 (2 equiv.),
15 min; (b) (+)-Ipc2BCl (2.2 equiv.), Et2O, −100°C, 1 h; (c) Zn (2 equiv.), allyl bromide (2 equiv.), THF, rt, 1 h; (d) DMP (1.2
equiv.), CH2Cl2, rt, 15 min; (e) (+)-Ipc2BCl (2.2 equiv.), THF, −30°C, 20 h; (f) MsCl (1.5 equiv.), Et3N, CH2Cl2, 0°C, 5 min; (g)
NaN3 (1.5 equiv.), DMF, 60°C, 4 h; (h) B(C6H11)2H (2 equiv.), THF, rt for 1 h then reflux for 3 h.

F.-X. Felpin et al. / Tetrahedron: Asymmetry 12 (2001) 1121–1124
1123
Scheme 4. Reagents and conditions: (a) HCHO (37% aqueous), HCO2H, 80°C, 3 h; (b) 2-methyl-3-butyn-2-ol (2.5 equiv), CuI
(cat.), 10% Pd/C (cat.), Ph3P, K2CO3, DME, rt then reflux for 16 h; (c) NaH (10% mol), toluene, reflux, 2 h.
tion. As reported in the literature,7 no drop in e.e. was
of the pyridine ring yielded an unstable ketone, which
detected for the last two steps (Scheme 4).
isomerized spontaneously into the conjugated a,b-
unsaturated derivative.
In summary, we have described a new and efficient
enantioselective synthesis of (S)-SIB-1508Y 4,
a
One of the major points of our synthetic work that has
received considerable attention is the reduction of the
prochiral ketone to give an enantiopure alcohol. Thus,
the formation of the alcohol (R)-8 was carried out by
enantioselective reduction of the ketone 12 using (+)-
diisopinocamphenylchloroborane according to the con-
ditions reported by Brown et al.13 We obtained the
alcohol (R)-8 as the sole product from the reaction in
79% purified yield14 with an e.e. of 94%.11
nAChR agonist in clinical trials for the treatment of
Parkinson’s disease. Using the synthesis presented
above, 4 was synthesized in ten steps from 5-bromo-3-
pyridinecarboxylic acid in 18% overall yield and with
an e.e. of 94%. In this fashion, a preparatively useful
multigram scale process for the synthesis of (S)-SIB-
1508Y was obtained. The described synthesis should
enable the design and synthesis of various other ana-
logues of tobacco alkaloids. Further work in this area is
in progress.
The next step in the synthesis involved transformation
of the alcohol 8 to the azide 6 which was effected by
nucleophilic displacement of the corresponding mesy-
late by azide ion. The chiral alcohol (R)-8 was esterified
by the action of methanesulfonyl chloride in the pres-
ence of triethylamine, affording the unstable mesylate
(R)-7,15 which was directly treated with sodium azide in
DMF at 60°C to afford the azide (S)-6 in 83% yield
from the two steps.16 Displacement of the mesylate at
the benzylic position of 7 occurred with complete inver-
sion of configuration as established by chiral HPLC
analysis (e.e.=94%).17 Under certain conditions an SN1
reaction process sometimes competed with the desired
reaction, with an accompanying decrease in the e.e. of
the product.18
Acknowledgements
This work was supported by the ‘Conseil Ge´ne´ral de la
Loire Atlantique’, the ‘Centre National de la Recherche
Scientifique’ and the ‘Ministe`re de l’Education
Nationale de la Recherche et de la Technologie’ with a
doctoral fellowship for F.-X.F. We thank Gilbert
Nourrisson for recording the mass spectra and Marie-
Jo Bertrand for skilled experimental assistance in
HPLC. Finally, we thank Dr. Richard J. Robins for
friendly and fruitful discussions.
As already described,6b formation of the pyrrolidine
ring was achieved by intramolecular hydroboration–
cycloalkylation tandem reactions of azido-olefin. Thus,
hydroboration–cycloalkylation of the azide (S)-6 with
an excess of dicyclohexylborane proceeded as expected,
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furnished
the
(S)-5-bromo-3-(1-H-2-pyrro-
lidinyl)pyridine 519 with an e.e.20 of 94% in 62% yield.
Finally, conversion of the (S)-5-bromonornicotine 5 to
the (S)-SIB-1508Y 4 essentially followed the known
sequence, reported in the literature.7 Reductive amina-
tion of (S)-5 using an Eschweiler–Clark procedure gave
the (S)-5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine 2
in 94% yield without epimerization of the stereogenic
center.21 Cross-coupling of (S)-2 with mebynol (2-
methyl-3-butyn-2-ol) in the presence of catalytic quan-
tity of 10% Pd/C, triphenylphosphine, copper iodide
and potassium carbonate afforded 13 in high yield.
Deprotection was accomplished by simple heating of 13
in toluene in the presence of a catalytic amount of
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7.89 (t, 1H, J=2.3 Hz), 8.40 (d, 1H, J=2.3 Hz), 8.50 (d,
1H, J=2.3 Hz); 13C NMR (50 MHz, CDCl3): l 43.8,
70.3, 119.5, 121.0, 133.2, 136.7, 141.5, 145.7, 149.6; MS
(CI/NH3) m/z 228 (M−H+, 79Br), 230 (M−H+, 81Br).
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10. All yields cited herein are of isolated, purified materials,
which gave satisfactory 1H, 13C NMR and IR spectra,
and either MS or elemental analysis in agreement with
the assigned structures and literature data for known
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11. All e.e. values were determined by HPLC with a chiral
column (Chiracel OD-H 0.46×15 cm). For the homoal-
lylic alcohol (R)-8, separation conditions: elution with a
mixture of hexane/iso-PrOH 98/2; flow rate: 0.5 mL/min:
retention time 26.8 min for alcohol (R)-8 and 25.4 min
for (S).
16. Demaison, C.; Hourioux, C.; Roingeard, P.; Agrofoglio,
L. A. Tetrahedron Lett. 1998, 39, 9175–9178.
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18. (a) Allen, A. D.; Kanagasabapathy, V. M.; Tidwell, T. T.
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19. Data for compound 5: [h]2D0=−26 (c 1.06, MeOH) 1H
NMR (200 MHz, CDCl3): l 1.44–1.61 (m, 1H), 1.67–1.9
(m, 2H), 2.06 (s, 1H), 2.06–2.21 (m, 1H), 2.89–3.12 (m,
2H), 4.07 (t, 1H, J=7.6 Hz), 7.80–7.81 (m, 1H), 8.38 (d,
1H, J=1.8 Hz), 8.42 (d, 1H, J=2.3 Hz); 13C NMR (50
MHz, CDCl3): l 25.5, 34.5, 46.9, 59.1, 120.8, 136.7,
142.7, 146.6, 149.0. MS (EI) m/z 228 (M+, 81Br), 226,
(M+, 79Br).
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bromine by hydrogenolysis of 5. For the (S)-nornicotine
separation conditions: elution with a mixture of hexane/
iso-PrOH 95/5; flow rate: 0.5 mL/min: retention time 30.0
min for (S)-nornicotine and 28.0 min for the (R)-
enantiomer.
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4156–4158; (b) Meyer, S. D.; Schreiber, S. L. J. Org.
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14. Representative procedure for the alcohol (R)-8: To a
solution of (+)-DIPCl (6.25 g, 19.5 mmol) in THF (5 mL)
at −30°C was added a solution of the ketone 12 (2 g, 8.85
mmol) in THF (5mL). After stirring for 20 h at −30°C,
the reaction was quenched with MeOH (1 mL) and
aqueous HCl (1N, 5 mL). The mixture was basified with
KOH pellets until the pH was 11–12. The mixture was
extracted with CH2Cl2 (3×10 mL). The organic phases
were washed with saturated NaCl solution (2×15 mL),
dried over anhydrous MgSO4, and concentrated under
reduced pressure. Purification by flash chromatography
on silica gel gave the alcohol 7 as a pale yellow oil (1.59
g, 79%). [h]2D0=+16.2 (c 1.47, MeOH). 1H NMR (200
MHz, CDCl3): l 2.37–2.57 (m, 2H), 3.4 (sl, 1H), 4.76 (t,
1H, J=6.7 Hz), 5.10–5.20 (m, 2H), 5.67–5.88 (m, 1H),
21. The e.e. value was determined by chiral HPLC analysis of
the (S)-nicotine, obtained directly by removal of the
bromine by hydrogenolysis of 2. For the (S)-nicotine
separation conditions: elution with a mixture of hexane/
iso-PrOH 49/1; flow rate: 0.5 mL/min: retention time 10.9
min for (S)-nornicotine and 12.9 min for the (R)-enan-
tiomer.
.