Enantioselective reduction of heteroaromatic β,γ-unsaturated ketones as an alternative to allylboration of aldehydes. Application: Asymmetric synthesis of SIB-1508Y

Article abstract of DOI:10.1016/S0040-4020(02)00819-0

Enantioselective reduction of heteroaromatic β,γ-unsaturated ketones was found to be an efficient and convenient alternative to the allylboration of corresponding aldehydes. This new method was used for the formal asymmetric synthesis of SIB-1508Y 2.

Full text of DOI:10.1016/S0040-4020(02)00819-0

Tetrahedron 58 (2002) 7381–7389
Enantioselective reduction of heteroaromatic b,g-unsaturated
ketones as an alternative to allylboration of aldehydes.
Application: asymmetric synthesis of SIB-1508Y
*
Franc¸ois-Xavier Felpin, Marie-Jo Bertrand and Jacques Lebreton
` ´ `
Laboratoire de Synthese Organique, CNRS UMR 6513, Faculte des Sciences et des Techniques, 2 rue de la Houssiniere, BP 92208,
44322 Nantes Cedex 3, France
Received 25 April 2002; revised 26 June 2002; accepted 12 July 2002
Abstract—Enantioselective reduction of heteroaromatic b,g-unsaturated ketones was found to be an efficient and convenient alternative to
the allylboration of corresponding aldehydes. This new method was used for the formal asymmetric synthesis of SIB-1508Y 2. q 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
during the last decade.3 Moreover, several studies have
shown that the (S)-enantiomer of nicotine displays a higher
affinity for nicotinic receptors than the (R)-enantiomer; a
tendency also established for many analogues.4
The therapeutic potential of nicotine 1 for central nervous
system (CNS) disorders such as Alzheimer’s disease and
Parkinson’s disease is being recognized.1 However, nico-
tine’s cognitive-enhancing properties are severely limited
by side effects, particularly on the cardiovascular and
gastrointestinal systems.2 Interest in the discovery of new
agents, such as SIB-1508Y 2 or ABT-418 3 (Fig. 1), that
directly interact with nicotinic acetylcholine receptors
(nAChR) for the treatement of CNS disorders, has increased
This shows the importance of the control of chirality for
the synthesis of new nAChR agonists. In connection with
our efforts to investigate structure–activity relationships of
nAChR ligands, we have recently reported the enantio-
selective synthesis of nicotine 1,5 SIB-1508Y 2,6 and other
related piperidinic alkaloids.7 The preparation of chiral
homoallylic alcohols by enantioselective allylboration of
aldehydes was a key step in our synthesis (Scheme1).
However, we found that the allylboration of heteroaromatic
aldehydes with lIpc2Ball 9 gave, in some cases, homoallylic
alcohols with low enantioselectivities. Also, the use of this
moisture sensitive chiral allylborane reagent is not so
Figure 1.
Scheme 1.
Keywords: allylboration; enantioselective reduction; ketone; SIB-1508Y.
*
Corresponding author. Tel.: þ33-2-51-12-54-03; fax: þ33-2-51-12-54-12; e-mail: lebreton@chimie.univ-nantes.fr
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00819-0

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F.-X. Felpin et al. / Tetrahedron 58 (2002) 7381–7389
convenient mainly due to the difficulty of preparing and
handling it. Moreover, in some cases, the low reaction
temperature led to crystallization of the aldehyde substrate.
To our knowledge, only one report has described the
asymmetric allylation of heterocyclic aldehydes in which
allylboration of thiophenecarboxaldehyde derivatives with
Ipc2Ball was not totally enantioselective (75–80% ee).8
Thus, an alternative route to prepare chiral homoallylic
alcohols was investigated using an enantioselective
reduction of the corresponding b,g-unsaturated ketone
with (þ)-DIP-chloridee ((þ)-DIP-Cl) 10.9 To the best of
our knowledge, the enantioselective reduction of hetero-
aromatic b,g-unsaturated ketones has not yet been reported
in the literature (Fig. 2).
Scheme 3.
Table 1. Synthesis of homoallylic alcohols and ketones
Entry
Aldehyde
Alcohol, yield
(%)
Ketone, yield
(%)
1
8a, 98
8b, 97
12a, quant.
Figure 2.
2
12b, 60þ40 of a,b-isomer
Due to the importance of the chiral homoallylic alcohols in
the preparation of new nAChR agonists, we have carried out
a systematic comparison between allylboration of hetero-
aromatic aldehydes and reduction of b,g-unsaturated
ketones (Scheme 2).
3
8c, 98
8d, 66
8e, 87
8f, 97
8g, 98
8h, 90
8i, 85
8j, 86
12c, quant.
4
12d, quant.
Scheme 2.
The synthetic utility of this process is demonstrated by the
asymmetric synthesis of SIB-1508Y 2 that displays potent
activity against Parkinson’s disease.10
5
12e, quant.
2. Results and discusssion
2.1. Allylboration
6
12f, quant.
lIpc2Ball was initially prepared by the hydroboration–
methanolysis of (2)-a-pinene, followed by the reaction of
the borinate with allylmagnesium bromide.11 This chiral
allylborane, in the presence of aldehydes, furnishes homo-
allylic alcohols with low enantioselectivities. This failure
led us to check the quality of the Ipc2BOMe intermediate.
The 11B NMR spectrum of Ipc2BOMe showed a mixture
of Ipc2BOMe (53.1 ppm), IpcB(OMe)2 (31.8 ppm) and
B(OMe)3 (18.2 ppm) in respectively 77.5/19.8/2.7 ratio.
The use of this impure reagent in the preparation of lIpc2Ball
9 and subsequently in asymmetric allylboration led to
modest enantioselectivities. Thus, we decided to prepare
lIpc2Ball from the commercially available (þ)-DIP-Cl 10,
following the literature.12 As we have previously reported,
2.2 equiv. of allylborane is necessary for allylation of
heteroaromatic aldehydes such as 8b with basic nitrogen
in Et2O at 21008C. Only modest yields and low enantio-
selectivities were obtained with 1.1 equiv. It has been
shown that the basic pyridyl nitrogen atom complexes boron
7
12g, quant.
8
12h, quant.
9
12i, quant.
10
12j, quant.

F.-X. Felpin et al. / Tetrahedron 58 (2002) 7381–7389
7383
atoms easily.13 This resulting ate-complex is a less efficient
chiral reagent. A major difficulty in the synthesis of pyridine
derivatives concerns the coordination of catalysts or
reagents to the basic pyridine nitrogen. To save 1 equiv.
l
of Ipc2Ball 9, we attempted to complex the pyridine
nitrogen with BEt3 (2788C, 1 h).13c But the allylboration
Scheme 4.
l
conducted with 1.1 equiv. of Ipc2Ball under these experi-
mental conditions led to a homoallylic alcohol with low
yields and enantioselectivities.
Table 2. Synthesis of chiral homoallylic alcohols
Entry
Product
Allyoboration
ee (%) Yield (%)
Reduction
ee (%)
Yield (%)
2.2. Reduction
1
2
3
4
5
6
7
8
9
10
(R)-8a
(R)-8b
(R)-8c
(R)-8d
(R)-8e
(R)-8f
(R)-8g
(R)-8h
(R)-8i
(R)-8j
95
94
79
92
83
94
90
75
99
90
94
89
93
94
95
96
94
92
84
50
81
83
70
79
80
80
71
70
b,g-Unsaturated ketones were obtained by oxidation of
the corresponding racemic alcohol with Dess–Martin
periodinane (DMP).14 Starting from aldehyde, the racemic
alcohol was prepared by allylation with allylbromide in the
presence of Zn in nearly quantitative yields after flash
chromatography. Aldehydes 11i–j were prepared according
to the literature.15 The other aldehydes 11e–h were directly
obtained by reduction of the corresponding acid using
N,N-dimethylchloromethyleniminium and lithium tri-tert-
butoxyaluminium hydride according to the conditions
reported by Fujisawa et al.16
No reaction
66
85.5
90
91.5
88
75
74
73
75
78
reduction conducted on the mixture of a,b and b,g
unsaturated isomers of 12b, led to the alcohol (R)-8b with
modest yield (50%) but with good ee (90%).
Oxidation of racemic alcohols in very mild conditions using
the DMP, led to an unstable ketone in near quantitative
yields. In acidic or basic media, ketones were rapidly
isomerized to the more stable a,b-unsaturated derivatives.
However in neutral conditions, we did not detect isomeri-
zation of ketones except for compound 12b. Other oxidising
agent were checked such as Jones reagent or PCC, but under
these acidic conditions, ketones spontaneously isomerized
into a,b-unsaturated derivatives (Scheme 3 and Table 1).
Contrary to the reduction, the allylboration gave no constant
results in yields and ee. The asymmetric allylation of
11a–b, 11d and 11g–j afforded the corresponding hetero-
cyclic homoallylic alcohol with good to high enantiomeric
purities (86–95%). On the contrary, the allylation gave
modest ee with 11f and 11c and very poor with 11e. The
reason for these modest results is not clear.
It should be noted that all configurations of unknown chiral
homoallylic alcohols were confirmed by analysis of the
1H NMR spectrum of their (R )-O-acetyl-mandelic ester
derivatives.19
Reduction of homoallylic ketones was performed with
commercially available reagent (þ)-DIP-Cl 10. The choice
of this chiral reducing reagent was dictated by previous
results described in the literature on pyridine derivatives.13a,b
Asymmetric reduction of prochiral pyridinyl ketones by
Corey’s oxazaborolidine gave modest enantioselectivities
probably due to complexation between the nitrogen of
pyridine and the catalyst. To overcome this problem, an
excess of BH3·Me2S was used, but these conditions were
incompatible with double bonds.17
The synthetic utility of the reduction as an alternative to
allylboration is demonstrated by the formal asymmetric
synthesis of SIB-1508Y 2.
2.4. Formal synthesis of SIB-1508Y 2
Recently, SIBIA neurosciences laboratories reported the
synthesis of the new nAChR agonist SIB-1508Y 2.20 It
should be noted that, to our knowledge, researchers have
made several unsuccessful attempts at the asymmetric
preparation of (S )-15.21 The synthesis of enantiopure
SIB-1508Y 2 was finally accomplished using a combination
Brown described the reduction of 3-acetyl pyridine to the
corresponding alcohol with 92% ee with DIP-Cl 10. This
seems to be one of the best chiral reducing reagents of
prochiral ketones.18 One of the major points of DIP-Cl 10 is
its ease of use with reproducible results and more
convenient temperature conditions (2308C in THF). It
should be noted that 2.2 equiv. of the reagent was used for
the reduction. With only 1 equiv., no reduction was
observed. (see Section 2.1).
2.3. Results
Representative heterocyclic homoallylic alcohols were
obtained by allylboration or reduction. In many cases,
reduction was the best method to give heterocyclic
homoallylic alcohols with high ee (.90%) (Scheme 4 and
Table 2). The limitation of this method was the stability of
the homoallylic ketone as for 12b. However in this case, the
Scheme 5.

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F.-X. Felpin et al. / Tetrahedron 58 (2002) 7381–7389
(S )-5-bromonornicotine 15 to the SIB-1508Y 2 was
achieved according to the conditions previously reported
in the literature.
3. Conclusion
Our present study has shown that the enantioselective
reduction of heteroaromatic b,g-unsaturated ketone is an
easy and efficient alternative to the allylboration of
aldehydes for the preparation of optically active homoallylic
alcohols with high ee. The utility of this process was
demonstrated by the formal synthesis of nAChR agonist
SIB-1508Y. Use of this new method for the synthesis of
nicotinic analogues and studies of the structure–activity
relationships are in progress.
Scheme 6.
of enantioselective reduction, providing materials with 30%
ee, followed by resolution via crystallization of a diastereo-
meric salt with a tartric acid derivative (Scheme 5).
4. Experimental
4.1. General
Our synthesis started with the homoallylic alcohol (R )-8f
previously obtained with 94% ee in 48% yield over four
steps from commercially available 5-bromonicotinic acid
16 (Scheme 6).
1H NMR, 13C NMR spectra were recorded at 200 and
50 MHz using residual CDCl3 (7.26 ppm) and CDCl3
(77.16 ppm) as internal standard, respectively. Flash
column chromatography was performed on Merck silica
The next step involved the conversion of alcohol (R )-8f to
the corresponding azide 18 by nucleophilic substitution of
the chiral mesylate 17 (Scheme 7). No decrease in optical
purity was observed during the transformation. Indeed, on a
benzylic position this reaction sometimes competes with an
SN1 reaction process, with a resulting decrease in optical
purity.22 The conversion of alcohol (R )-8f to the azide 18
via the displacement of the corresponding mesylate 17 in
83% over two steps was found to be better that Mitsunobu
conditions23 (DPPA, DEAD, P(Ph)3) which led to a
complex mixture and low yields. Formation of the
pyrrolidine ring was achieved by an original procedure
which involved an intramolecular hydroboration–cyclo-
alkylation sequence developed by Carboni and Vaultier.24
When treated with an excess of dicyclohexylborane in THF,
azide 18 was transformed into the (S )-5-bromo-3-(1-H-2-
pyrrolidinyl)pyridine 15 with total retention of configu-
ration in 62% yield. Enantiomeric excess and absolute
stereochemistry were determined by hydrogenation of 15
to afford a compound which was identical in all respects
to (S)-nornicotine with 94% ee. Finally, conversion of the
˚
gel (60 A, 230–400 mesh). All ee were determined by
Chiral HPLC with a CHIRACEL OD-H column, 46£15 cm,
flow rate 0.5 mL/min. (þ)-DIP-chloridee is a trademark of
the Aldrich Chemical Company. All reactions were
performed under N2 in a flame-dried flask using anhydrous
solvents.
4.2. Reduction of acids to aldehydes: general procedure
To a solution of DMF (38.8 mL, 0.50 mol) in anhydrous
CH2Cl2 (80 mL) at 2208C, oxalyl chloride (13 mL,
0.15 mol) was added. After 90 min, the mixture was
concentrated under reduced pressure. Then dry acetonitrile
(70 mL) and THF (160 mL) were added at 2308C and a
solution of acid (50 mmol) in THF (70 mL) and pyridine
(4.1 mL, 50 mmol) was added dropwise. The resulting
mixture was stirred for 90 min at 2308C, cooled to 2788C
and a solution of copper iodide (10% mol) and tri-tert-
butoxyaluminium hydride (25.4 g, 0.1 mol) in THF (90 mL)
was added. After stirring for 15 min, the reaction was
quenched with 7% aqueous HBr solution. The resulting
mixture was allowed to warm up to room temperature and
basified with 30% aqueous NaOH solution. The aqueous
layer was extracted with ether. The combined extracts were
washed with saturated aqueous NaHCO3, saturated aqueous
NaCl, dried over MgSO4 and concentrated under reduced
pressure. The product was purified by flash chromatography
to give the corresponding aldehyde.
4.2.1. Quinoline-6-carboxyaldehyde (11e). Purification by
flash chromatography (60% ethyl acetate–hexane) gave
aldehyde 11e (2.59 g, 33%) as a pale yellow solid. Mp 75–
768C (lit.25 mp 75–768C); IR (KBr) 1431, 1693,
1
2859 cm21. H NMR d 7.48 (dd, 1H, J¼4.3, 8.4 Hz), 8.16
(s broad, 2H), 9.00–9.03 (m, 1H), 10.16 (s, 1H); 13C NMR d
122.3, 126.8, 127.8, 130.9, 133.7, 134.4, 137.5, 151.0,
1503.2, 191.5. MS (EI) m/z 157 (Mþ).
Scheme 7.

F.-X. Felpin et al. / Tetrahedron 58 (2002) 7381–7389
7385
l
4.2.2. 5-Bromo-pyridine-3-carboxyaldehyde (11f). Purifi-
cation by flash chromatography (50% ethyl acetate–
hexane) gave aldehyde 11f (5.86 g, 63%) as a white solid.
Mp 958C (lit.26 mp 95–968C); IR (KBr) 1580, 1711, 2720,
Allylboration of aldehydes. To a solution of Ipc2Ball
(7.18 g, 22 mmol) in ether (25 mL) at 21008C was slowly
added via a cannula a solution of aldehyde (10 mmol) in
ether (20 mL). After 1 h of stirring at 21008C, the reaction
mixture was quenched with methanol (1 mL) and 1N
aqueous HCl (10 mL). The mixture was basified with 30%
aqueous NaOH solution until pH 12–13, and then extracted
with CH2Cl2 (4£100 mL). The combined extracts were
dried over anhydrous MgSO4, filtered and concentrated in
vacuo. Purification by flash chromatography gave the chiral
alcohol.
1
2827 cm21. H NMR d 8.26–8.29 (m, 1H), 8.88 (d, 1H,
J¼1.8 Hz), 8.96 (d, 1H, J¼1.8 Hz), 10.06 (s, 1H); 13C NMR
d 121.8, 132.6, 138.1, 150.0, 155.9, 189.4. MS (EI) m/z 188
(Mþ, 81Br), 186 (Mþ, 79Br).
4.2.3. 6-Chloro-pyridine-3-carboxyaldehyde (11g). Purifi-
cation by flash chromatography (30% ethyl acetate–
hexane) gave aldehyde 11g (3.75 g, 53%) as a white solid.
Mp 798C (lit.27 mp 808C); IR (KBr) 1561, 1589, 1701, 2876,
3064, 3096 cm21. 1H NMR d 7.46–7.50 (m, 1H), 8.11 (dd,
1H, J¼2.4, 8.4 Hz), 8.82 (d, 1H, J¼2.4 Hz), 10.06 (s, 1H);
13C NMR d 125.2, 130.4, 138.1, 152.4, 157.0, 189.3. MS
(EI) m/z 141 (Mþ, 35Cl), 143 (Mþ, 37Cl), 140 (M2Hþ,
35Cl), 142 (M2Hþ, 37Cl).
4.5. Reduction of carbonyl compounds: general
procedure—method C
To a solution of (þ)-DIP-Cl (3.53 g, 11 mmol) in THF
(5 mL) cooled at 2308C was added a solution of ketone
(5 mmol) in THF (2 mL). The resulting mixture was stirred
overnight. After completion, acetaldehyde (1.68 mL,
30 mmol) was added to consume the excess (þ)-DIP-Cl.
The mixture was allowed to warm to room temperature and
stirred for 1 h. The solvent was removed under reduced
pressure and (2)-a-pinene formed during the reaction was
collected by bulb to bulb distillation (508C, 10 mm Hg, 1 h).
The residue was dissolved in ether (30 mL) and quenched
with 4N aqueous HCl (25 mL). The mixture was basified
with solid KOH until pH 11–12 and extracted with ether
(3£30 mL). The combined organic extracts were dried over
anhydrous MgSO4 and filtered. Removal of the solvent left
an oil which was purified by flash chromatography to afford
the chiral alcohol.
4.2.4. 5,6-Dichloro-pyridine-3-carboxyaldehyde (11h).
Purification by flash chromatography (30% ethyl acetate–
hexane) gave aldehyde 11h (2.73 g, 31%) as a pale yellow
solid. Mp 42–438C (lit.28 mp 438C). IR (KBr) 1578, 1716,
2857 cm21. 1H NMR d 8.22 (d, 1H, J¼2.0 Hz), 8.75 (d, 1H,
J¼2.0 Hz), 10.07 (s, 1H); 13C NMR d 131.3, 132.0, 137.6,
149.0, 160.2, 188.2. MS (EI) m/z 175 (Mþ, 35Cl), 179 (Mþ,
37Cl).
4.3. Synthesis of homoallylic alcohols. Racemic allylation
of aldehydes: general procedure—method A
A flask fitted with a dropping funnel and a condenser was
charged with Zn (1.05 g, 16 mmol) and was covered with
THF (1 mL). A solution of allylbromide (1.38 mL,
16 mmol) in THF (10 mL) was slowly added to maintain
the temperature at 25–308C. After the addition, the mixture
was stirred for 1 h at room temperature. Then, a solution of
aldehyde (8 mmol) in THF (10 mL) was slowly added, and
the resulting mixture was stirred for an additional hour
(except for aldehyde 8d which was stirred for 12 h at reflux).
After completion of the reaction, the resulting mixture
was hydrolyzed with saturated aqueous NH4Cl (10 mL).
The aqueous phase was extracted with CH2Cl2 (3£20 mL).
The combined organic extracts were washed with brine
(2£), dried over anhydrous MgSO4 and concentrated in
vacuo. The residue was purifed by flash chromatography
affording the homoallylic alcohol.
4.5.1. (R)-1-Phenyl-but-3-en-1-ol (8a). Purification by
flash chromatography (10% ethyl acetate–hexane) gave
8a as a pale yellow oil. IR (KBr) 1641, 2079, 3030, 3076,
1
3383 cm21. H NMR d 2.04 (s broad, 1H), 2.49–2.57 (m,
2H), 4.75 (dd, 1H, J¼5.9, 7.2 Hz), 5.13 (s, 1H), 5.18–5.23
(m, 1H), 5.73–5.94 (m, 1H), 7.27–7.39 (m, 5H); 13C d
NMR 43.4, 73.2, 117.7, 125.7, 127.2, 128.1, 134.3, 143.8.
MS (CI/NH3) m/z 148 (Mþ), 166 (MþNHþ4 ). HPLC (hexane/
i-PrOH¼99/1, 25.0 min for (R)-alcohol and 31.7 min for
(S)).
Method A: 1.16 g; 98%.
Method B: 1.23 g; 83%; 95% ee; [a ]2D0¼þ44 (c 1.1, ben-
zene), lit.11a [a ]D20¼244.92 (c 7.38, benzene).
4.4. Allylboration of aldehydes: general procedure—
method B
Method C: 0.56 g; 76%; 99% ee; [a ]2D0¼þ45.9 (c 1.3,
benzene).
Preparation of allylborane reagent free of Mg2þ salts. A
solution of commercial allylmagnesium bromide in ether
(48 mL, 1 M, 48 mmol) was added to a solution of (þ)-B-
chlorodiisopinocampheylborane ((þ)-DIP-Cl) (16.0 g,
49.9 mmol) in ether (50 mL) at 08C. The resulting mixture
was stirred for 1 h at room temperature and then con-
centrated in vacuo. The residue was extracted with
anhydrous pentane (3£30 mL): stirring was discontinued
to permit the Mg2þ salts to settle and the supernatant pentane
extract was filtered over a pad of celite. Pentane was
evaporated under reduced pressure to give B-allyldiisopino-
campheylborane (lIpc2Ball) (15.6 g, 96%) as a colourless oil.
4.5.2. (R )-1-Pyridin-3-yl-but-3-en-1-ol (8b). Purification
by flash chromatography (5% EtOH–CH2Cl2) gave 8b as a
pale yellow oil. IR (KBr) 1585, 1642, 2907, 2979, 3077,
3444 cm21
.
1H NMR d 2.47 (m, 2H), 4.87 (t, 1H, J¼
6.6 Hz), 5.01–5.10 (m, 2H), 5.63–5.83 (m, 1H), 7.53 (dd,
1H, J¼7.9 Hz, 4.1 Hz), 7.98 (d, 1H, J¼7.9 Hz), 8.60 (d, 1H,
J¼4.1 Hz), 8.68 (s, 1H); 13C NMR d 43.1, 70.0, 119.2,
125.2, 132.8, 137.9, 141.8, 146.3, 147.1. MS (CI/ NH3) m/z
150 (MþHþ), 167 (MþNHþ4 ). HPLC (Hexane/i-PrOH¼
95/5, 23.3 min for (S )-alcohol and 24.6 min for (R )).
Method A: 1.16 g; 97%.

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F.-X. Felpin et al. / Tetrahedron 58 (2002) 7381–7389
Method B: 1.40 g; 94%; 94% ee; [a ]2D0¼þ28 (c 1, EtOH),
Method C: 0.70 g; 70%; 93% ee; [a ]2D0¼þ18.4 (c 0.74,
lit.8 [a ]2D0¼228 (c 1.03, EtOH).
EtOH).
Method C: 0.37 g; 50%; 90% ee; [a ]2D0¼þ27.2 (c 1.1,
4.5.6. (R)-1-(5-Bromo-pyridin-3-yl)-but-3-en-1-ol (8f).
Purification by flash chromatography (30% ethyl acetate–
hexane) gave 8f as a pale yellow oil. IR (KBr) 1642, 2979,
EtOH).
1
4.5.3. (R)-1-Thiophen-3-yl-but-3-en-1-ol (8c). Purifi-
cation by flash chromatography (10% ethyl acetate–
hexane) gave 8c as a yellow oil. IR (KBr) 1641, 2978,
3076, 3258 cm21. H NMR d 2.37–2.57 (m, 2H), 3.43 (s
broad, 1H), 4.76 (t, 1H, J¼6.7 Hz), 5.10–5.20 (m, 2H),
5.67–5.88 (m, 1H), 7.89 (app t, 1H, J¼2.3 Hz), 8.40 (d, 1H,
J¼2.3 Hz), 8.50 (d, 1H, J¼2.3 Hz); 13C NMR d 43.8, 70.3,
119.5, 121.0, 133.2, 136.7, 141.5, 145.7, 149.6. MS
(CI/NH3) m/z 228 (MþHþ, 79Br), 230 (MþHþ, 81Br).
HRMS (EI) calcd for C9H11N1O1Br1 (MþHþ) 228.0024,
found: 228.0019. HPLC (hexane/i-PrOH¼98/2, 25.4 min
for (S)-alcohol and 26.8 min for (R ).
1
3076, 3375 cm21. H NMR d 2.12 (s, 1H), 2.43–2.68 (m,
2H), 4.82 (t, 1H, J¼6.9 Hz), 5.12–5.22 (m, 2H), 5.71–5.92
(m, 1H), 7.08 (dd, 1H, J¼1.4, 5.0 Hz), 7.18–7.21 (m, 1H),
7.28 (dd, 1H, J¼3.0, 5.0 Hz); 13C d NMR 43.1, 69.7, 118.6,
120.9, 125.7, 126.2, 134.3, 145.5. HRMS (EI) calcd
for C8H10O1S1 (Mþ) 154.0452, found: 154.0445. HPLC
(hexane/i-PrOH¼99/1, 26.0 min for (R)-alcohol and
29.2 min for (S )).
Method A: 1.77 g; 97%.
Method A: 1.21 g; 98%.
Method B: 1.71 g; 75%; 66% ee; [a ]2D0¼þ11 (c 1.23,
MeOH).
Method B: 1.39 g; 90%; 79% ee; [a]2D0¼þ11.3 (c 1.22,
EtOH), lit.8 [a]D20¼þ14.4 (c 1.61, EtOH).
Method C: 0.90 g; 79%; 94% ee; [a ]2D0¼þ16.2 (c 1.47,
MeOH).
Method C: 0.62 g; 81%; 94% ee; [a ]2D0¼þ13.8 (c 1.1,
EtOH).
4.5.7. (R )-1-(6-Chloro-pyridin-3-yl)-but-3-en-1-ol (8g).
Purification by flash chromatography (20% ethyl acetate–
hexane) gave 8g as a colourless oil. IR (KBr) 1589, 1598,
4.5.4. (R )-1-Quinolin-3-yl-but-3-en-1-ol (8d). Purification
by flash chromatography (40% ethyl acetate–hexane) gave
8d as a yellow solid. Mp 47–488C; IR (KBr) 1636, 2943,
3138 cm21. 1H NMR d 2.56 (t, 2H, J¼6.6 Hz), 4.91 (t, 1H,
J¼6.6 Hz), 5.05–5.16 (m, 2H), 5.69–5.89 (m, 1H), 7.44–
7.75 (m, 3H), 7.98–8.08 (m, 2H), 8.72 (d, 1H, J¼2.1 Hz);
13C NMR d 43.8, 71.2, 119.0, 126.9, 127.9, 128.9, 129.4,
132.9, 133.8, 137.0, 147.4, 149.4. HRMS (EI) calcd for
C10H14N1O1 (MþHþ) 200.1075, found: 200.1076. HPLC
(hexane/i-PrOH¼95/5, 27.5 min for (S)-alcohol and
37.9 min for (R ).
1
1642, 2980, 3078, 3363 cm21. H NMR d 2.45 (t, 2H, J¼
6.3 Hz), 3.37 (d, 1H, J¼3.2 Hz), 4.75 (dt, 1H, J¼3.2,
6.3 Hz), 5.04–5.13 (m, 2H), 5.63–5.83 (m, 1H), 7.25 (d,
1H, J¼8.2 HZ), 7.64 (dd, 1H, J¼2.4, 8.2 Hz), 8.23 (d, 1H,
J¼2.4 Hz); 13C NMR d 43.7, 70.3, 119.3, 124.1, 133.3,
136.8, 138.5, 147.6, 150.2. MS (CI/NH3) m/z (35Cl), (37Cl).
HRMS (EI) calcd for C9H11N1O1Cl1 (MþHþ) 184.0529,
found: 184.0526. HPLC (hexane/i-PrOH¼95/5, 16.0 min
for (R)-alcohol and 19.1 min for (S )).
Method A: 1.44 g; 98%.
Method A: 1.05 g; 66%.
Method B: 1.17 g; 74%; 85.5% ee; [a ]2D0¼þ64.2 (c 1.12,
Method B: 1.49 g; 75%; 92% ee; [a ]2D0¼þ27 (c 1.1, EtOH).
EtOH).
Method C: 0.83 g; 83%; 89% ee; [a ]2D0¼þ26.1 (c 0.91,
Method C: 0.74 g; 80%; 95% ee; [a ]2D0¼þ72 (c 1.48,
EtOH).
EtOH).
4.5.5. (R )-1-Quinolin-6-yl-but-3-en-1-ol (8e). Purification
by flash chromatography (5% EtOH–CH2Cl2) gave 8e as a
yellow solid. Mp 69–708C; IR (KBr) 1577, 1642, 2976,
4.5.8. (R )-1-(5,6-Dichloro-pyridin-3-yl)-but-3-en-1-ol
(8h). Purification by flash chromatography (20% ethyl
acetate–hexane) gave 8h (1.57 g, 90%) as a colourless oil.
1
1
3060, 3164 cm21. H NMR d 2.47–2.66 (m, 2H), 3.38 (s,
IR (KBr) 1641, 2981, 3078, 3376 cm21. H NMR d 2.42–
1H), 4.92 (t, 1H, J¼6.7 Hz), 5.09–5.20 (m, 2H), 5.71–5.92
(m, 1H), 7.31–7.37 (dd, 1H, J¼4.3, 8.2 Hz), 7.64–7.69 (dd,
1H, J¼1.8, 8.2 Hz), 7.75 (s broad, 1H), 8.01 (d, 1H, J¼
8.9 Hz), 8.08 (d, 1H, J¼8.9 Hz), 8.77–8.80 (dd, 1H, J¼4.3,
1.8 Hz); 13C NMR d 43.9, 73.0, 118.7, 121.3, 124.3, 127.9,
128.1, 129.4, 134.3, 136.3, 142.6, 147.8, 150.2. HRMS
(CI/NH3) calcd for C10H14N1O1 (MþHþ) 200.1075, found:
200.1067. HRMS (EI) calcd for C10H12N1O1 (M2Hþ)
198.0919, found: 198.0923. HPLC (hexane/i-PrOH¼96/4,
87.9 min for (R )-alcohol and 95.9 min for (S)).
2.50 (m, 2H), 3.26 (d, 1H, J¼3.3 Hz), 4.72–7.80 (m, 1H),
5.06–5.16 (m, 2H), 5.63–5.84 (m, 1H), 7.79 (d, 1H,
J¼2.1 Hz), 8.15 (d, 1H, J¼2.1 Hz); 13C NMR d 43.6, 69.7,
119.8, 130.5, 132.8, 136.7, 140.2, 145.0, 147.8. HRMS (EI)
calcd for C9H10N1O1Cl2 (MþHþ) 218.0139, found:
218.0139. HPLC (hexane/i-PrOH¼99/1, 48.5 min for
(R )-alcohol and 52.5 min for (S )).
Method A: 1.57 g; 90%.
Method B: 1.58 g; 73%; 90% ee; [a]2D0¼þ18.2 (c 1.1, EtOH).
Method A: 1.39 g; 87%.
Method B: no reaction.
Method C: 0.87 g; 80%; 96% ee; [a ]2D0¼þ19.8 (c 1.1,
EtOH).

F.-X. Felpin et al. / Tetrahedron 58 (2002) 7381–7389
7387
1
4.5.9. (R )-1-(5-Methoxy-pyridin-3-yl)-but-3-en-1-ol (8i).
Purification by flash chromatography (2% EtOH–CH2Cl2)
gave 8i as a colourless oil. IR (KBr) 1588, 1641, 2935, 3076,
3228 cm21. 1H NMR d 2.52 (t, 2H, J¼6.9 Hz), 3.22 (s, 1H),
3.86 (s, 3H), 4.78 (t, 1H, J¼6.6 Hz), 5.11–5.20 (m, 2H),
5.70–5.91 (m, 1H), 7.27–7.29 (m, 1H), 8.09 (s broad, 1H),
8.13 (s broad, 1H); 13C NMR d 43.7, 55.6, 70.7, 118.4,
133.9, 135.9, 139.5, 141.0, 155.9. HRMS (CI/NH3) calcd
for C10H14N1O2 (MþHþ) 180.1025, found: 180.1031.
HPLC (hexane/i-PrOH¼95/5, 20.7 min for (S)-alcohol
and 22.7 min for (R )).
yellow oil. The H NMR spectrum of the crude product
showed a partial isomerization of the double bond (40%).
b,g-Unsaturated ketone (60%) 1H NMR d 3.75 (d, 2H,
J¼7.2 Hz), 5.20–5.27 (m, 2H), 5.97–6.15 (m, 1H), 7.41–
7.47 (m, 1H), 8.21–8.25 (m, 1H), 8.75–8.77 (m, 1H), 9.15
1
(s broad, 1H). a,b-unsaturated ketone (40%) H NMR d
2.05 (d, 3H, J¼7.9 Hz), 7.05–7.60 (m, 2H), 7.75–8.00 (m,
2H), 8.50–8.66 (m, 2H).
4.6.3. 1-Thiophen-3-yl-but-3-en-1-one (12c). After the
usual work-up, the homoallylic ketone 12c (0.92 g, quant.)
was quickly used in the next step without purification. H
1
Method A: 1.22 g; 85%.
NMR d 3.66 (dt, 2H, J¼6.7, 1.4 Hz), 5.16–5.26 (m, 2H),
5.96–6.16 (m, 1H), 7.32 (dd, 1H, J¼2.9, 5.0 Hz), 7.55 (dd,
1H, J¼1.2, 5.0 Hz), 8.07 (dd, 1H, J¼2.9, 1.2 Hz); 13C NMR
d 43.9, 119.9, 129.7, 133.0, 138.2, 147.7, 154.7, 195.6. MS
(EI) m/z 152 (Mþ), 137 (M2CH3).
Method B: 1.34 g; 75%; 91.5% ee; [a ]2D0¼þ20.3 (c 1.2,
MeOH).
Method C: 0.63 g; 71%; 94% ee; [a]2D0¼þ21.1 (c 1.1,
MeOH).
4.6.4. 1-Quinolin-3-yl-but-3-en-1-one (12d). After the
usual work-up, the homoallylic ketone 12d (1.19 g,
quant.) was obtained as a pale yellow solid without
purification, and was quickly used in the next step. 1H
NMR d 3.89 (dt, 2H, J¼6.7, 1.4 Hz), 5.24–5.33 (m, 2H),
6.03–6.23 (m, 1H), 7.59–7.67 (m, 1H), 7.80–7.88 (m, 1H),
7.94 (d, 1H, J¼8.1 Hz), 8.15 (d, 1H, J¼8.3 Hz), 8.73 (d, 1H,
J¼2.1 Hz), 9.43 (s broad, 1H); 13C NMR d 43.9, 119.6,
127.0, 127.7, 128.9, 129.5, 129.6, 130.4, 132.2, 137.5,
149.3, 150.0, 196.9. MS (EI) m/z 197 (Mþ), 182 (M2CH3).
4.5.10. (R)-1-(6-Methoxy-pyridin-3-yl)-but-3-en-1-ol (8j).
Purification by flash chromatography (2% EtOH–CH2Cl2)
gave 8j (1.24 g, 86%) as a yellow oil. IR (KBr) 1574, 1609,
.
1641, 2946, 3077, 3373 cm21 1H NMR d 2.46 (t, 2H,
J¼7.0 Hz), 2.63 (s, 1H), 3.89 (s, 3H), 4.66 (t, 1H, J¼6.4 Hz),
5.07–5.16 (m, 2H), 5.65–5.85 (m, 1H), 6.70 (d, 1H, J¼
8.5 Hz), 7.55–7.60 (dd, 1H, J¼8.5, 2.1 Hz), 8.02 (s broad,
1H); 13C NMR d 43.6, 53.6, 70.9, 110.9, 118.8, 132.1, 134.0,
136.8, 144.7, 163.9. HRMS (CI/NH3) calcd for C10H14N1O2
(MþHþ) 180.1025, found: 180.1016. HPLC (hexane/
i-PrOH¼95/5, 14.8 min for (R)-alcohol and 16.2 min for
(S)).
4.6.5. 1-Quinolin-6-yl-but-3-en-1-one (6e). After the usual
work-up, the homoallylic ketone 6e (1.19 g, quant.) was
quickly used in the next step without purification. 1H NMR
d 3.89 (dt, 2H, J¼6.6, 1.4 Hz), 5.21–5.30 (m, 2H), 6.03–
6.24 (m, 1H), 7.48 (dd, 1H, J¼4.3, 8.2 Hz), 8.16 (d, 1H,
J¼9 Hz), 8.24–8.31 (m, 2H), 8.46 (d, 1H, J¼2 Hz), 9.02
(dd, 1H, J¼1.7, 4.3 Hz); 13C NMR d 43.7, 119.2, 122.1,
127.6, 127.9, 129.8, 130.2, 130.9, 134.5, 137.8, 150.2,
152.8, 197.5. MS (EI) m/z 197 (Mþ), 182 (M2CH3).
Method A: 1.24 g; 86%.
Method B: 1.40 g; 78%; 88% ee; [a ]2D0¼þ26 (c 1.2,
MeOH).
Method C: 0.63 g; 70%; 92% ee; [a]2D0¼þ27.3 (c 1.6,
MeOH).
4.6.6. 1-(5-Bromo-pyridin-3-yl)-but-3-en-1-one (6f).
After the usual work-up, the homoallylic ketone 6f
(1.36 g, quant.) was quickly used in the next step without
purification. 1H NMR d 3.75 (d, 2H, J¼6.6 Hz), 5.19–5.31
(m, 2H), 5.94–6.14 (m, 1H), 8.35–8.37 (dd, 1H, J¼2.1,
1.8 Hz), 8.84 (d, 1H, J¼2.1 Hz), 9.06 (d, 1H, J¼1.8 Hz);
13C NMR d 43.9, 119.9, 121.4, 129.7, 133.0, 138.2, 147.7,
154.7, 195.6. MS (EI) m/z 227 (Mþ, 81Br), 225 (Mþ, 79Br);
212 (M2CH3, 81Br), 210 (M2CH3, 79Br).
4.6. Oxidation of alcohols: general procedure
To a solution of DMP (4.58 g, 10.8 mmol) in CH2Cl2
(15 mL) at room temperature was added a solution of
alcohol (6 mmol) in CH2Cl2 (10 mL). After 30 min of
stirring, the mixture was diluted with ether (40 mL) and
washed with 1: 1–10% Na2S2O3: saturated aqueous
NaHCO3 solution (1£50 mL), followed by brine (2£
50 mL). The combined extracts were dried over anhydrous
MgSO4, and concentrated under reduced pressure.
4.6.7. 1-(6-Chloro-pyridin-3-yl)-but-3-en-1-one (12g).
After the usual work-up, the homoallylic ketone 12g
(1.09 g, quant.) was quickly used in the next step without
purification. 1H NMR d 3.72 (dt, 2H, J¼6.7, 1.4 Hz), 5.16–
5.29 (m, 2H), 5.92–6.12 (m, 1H), 7.42 (dd, 1H, J¼0.8,
8.4 Hz), 8.18 (dd, 1H, J¼2.6, 8.4 Hz), 9.92 (dd, 1H, J¼0.8,
2.6 Hz); 13C NMR d 43.8, 119.8, 124.7, 129.9, 130.7, 138.3,
150.1, 155.8, 195.6. MS (EI) m/z 181 (Mþ, 35Cl), 183 (Mþ,
37Cl).
4.6.1. 1-Phenyl-but-3-en-1-one (12a). After the usual
work-up, the homoallylic ketone 12a (0.88 g, quant.) was
quickly used in the next step without purification. IR (KBr)
1598, 1644, 1685, 2882, 3081 cm21. H NMR d 3.75 (dt,
2H, J¼6.5, 1.4 Hz), 5.16–5.26 (m, 2H), 5.99–6.19 (m, 1H),
7.41–7.61 (m, 3H), 7.94–8.00 (m, 2H); 13C NMR 43.5,
118.8, 128.4, 128.7, 131.2, 133.3, 136.7, 198.1. MS
(CI/NH3) m/z 164 (MþNHþ4 ), 147 (MþHþ).
1
4.6.8. 1-(5,6-Dichloro-pyridin-3-yl)-but-3-en-1-one
(12h). After the usual work-up, the homoallylic ketone
12h (1.30 g, quant.) was quickly used in the next step
without purification. 1H NMR d 3.73 (dt, 2H, J¼6.6,
4.6.2. 1-Pyridin-3-yl-but-3-en-1-one (12b). After the usual
work-up, the homoallylic ketone 12b was obtained as a pale

7388
F.-X. Felpin et al. / Tetrahedron 58 (2002) 7381–7389
1.4 Hz), 5.18–5.32 (m, 2H), 5.92–6.12 (m, 1H), 8.28
(d, 1H, J¼2 Hz), 8.81 (d, 1H, J¼2 Hz); 13C NMR d 43.9,
120.1, 129.5, 131.5, 131.7, 138.1, 147.1, 153.4, 194.7. MS
(EI) m/z 215 (Mþ, 35Cl), 217 (Mþ, 37Cl); 200 (M2CH3,
35Cl), 202 (M2CH3, 37Cl).
4.7.3. (S )-3-Bromo-5-pyrrolidin-2-yl-pyridine (15). To a
stirred solution of freshly distilled cyclohexene (5.49 mL,
54.2 mmol) in THF (35 mL) at 08C was added dropwise
2.0 M BH3-Me2S complex in THF (53.8 mL, 0.108 mol).
The resulting white suspension of dicyclohexylborane was
stirred for 1 h at 08C and then cooled to 2158C prior to the
addition of azide 18 (4.5 g, 17.8 mmol) in THF (10 mL).
The resulting mixture was allowed to warm up to room
temperature. After 12 h, the reaction was quenched with
MeOH, diluted with ether (100 mL) and the organic layer
was extracted with 1N aqueous HCl (6£70 mL). The
combined aqueous layers were treated with 30% aqueous
NaOH solution until pH 13–14 and then extracted with
CH2Cl2. The combined extracts were dried over anhydrous
MgSO4. Removal of the solvent left a residue which was
purified by flash chromatography (5% EtOH–CH2Cl2)
yielding 15 (2.5 g, 62%) as a colourless oil. The enantio-
meric excess value (94% ee) was determined by chiral
HPLC analysis of the (S)-nornicotine, obtained directly
by removal of the bromine by hydrogenolysis of 15. For
the (S)-nornicotine separation conditions: elution with a
mixture of hexane/i-PrOH 95/5; flow rate: 0.5 ml/min:
retention time 28.0 min for (R)-nornicotine and 30.0 min
4.6.9. 1-(5-Methoxy-pyridin-3-yl)-but-3-en-1-one (12i).
After the usual work-up, the homoallylic ketone 12i
(1.07 g, quant.) was quickly used in the next step without
1
purification. H NMR d 3.75 (dt, 2H, J¼6.7, 1.4 Hz), 3.88,
(s, 3H), 5.16–5.27 (m, 2H), 5.94–6.14 (m, 1H), 7.65–7.73
(m, 1H), 8.46 (d, 1H, J¼2.6 Hz), 8.77 (s broad, 1H); 13C
NMR d 43.9, 55.7, 117.9, 119.3, 130.2, 132.4, 142.0, 142.8,
155.9, 196.7. MS (EI) m/z 177 (Mþ), 162 (M2CH3).
4.6.10. 1-(6-Methoxy-pyridin-3-yl)-but-3-en-1-one (12j).
After the usual work-up, the homoallylic ketone 12j (1.07 g,
quant.) was quickly used in the next step without
1
purification. H NMR d 3.66–3.70 (m, 2H), 3.98 (s, 3H),
5.16–5.25 (m, 2H), 5.94–6.15 (m, 1H), 6.77 (d, 1H, J¼
8.7 Hz), 8.12 (dd, 1H, J¼2.4, 8.7 Hz), 8.78 (d, 1H,
J¼2.4 Hz); 13C NMR d 43.3, 54.0, 111.2, 118.9, 126.2,
130.8, 138.3, 149.2, 166.7, 195.6. MS (EI) m/z 177 (Mþ),
162 (M2CH3).
1
for (S). [a ]2D0¼226 (c 1.06, MeOH). H NMR d (ppm)
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, J¼7.6 Hz),
7.80–7.81 (m, 1H), 8.38 (d, 1H, J¼1.8 Hz), 8.42 (d, 1H,
J¼2.3 Hz). 13C NMR d (ppm) 25.5, 34.5, 46.9, 59.1, 120.8,
136.7, 142.7, 146.6, 149.0. MS (EI) m/z 228 (Mþ, 81Br),
226, (Mþ, 79Br).
4.7. Synthesis of SIB-1508Y
4.7.1. (R )-Methanesulfonic acid 1-(5-bromo-pyridin-3-
yl)-but-3-enyl ester (17). To a solution of alcohol (R )-8f
(5.2 g, 22.8 mmol) and Et3N (6.35 mL, 45.6 mmol) in
CH2Cl2 (110 mL) at 08C, was slowly added methane-
sulfonyl chloride (2.65 mL, 34.2 mmol). After stirring for
10 min, the mixture was diluted with water and the layers
were separated. The organic layer was washed with water,
brine (2£70 mL), dried over anhydrous MgSO4, filtered and
concentrated at room temperature under reduced pressure to
afford the crude mesylate 17 (6.25 g, 100%) as a yellow oil.
The product was immediately used in the next step, without
purification, due to extensive decomposition. [a]2D0¼þ50
(c 1.2, MeOH). 1H NMR d (ppm) 2.58–2.88 (m, 2H), 2.93
(s, 3H), 5.12–5.22 (m, 2H), 5.56–5.78 (m, 2H), 7.87 (t, 1H,
J¼2 Hz), 8.54 (d, 1H, J¼1.8 Hz), 8.68 (d, 1H, J¼2.1 Hz);
13C NMR d (ppm) 38.9, 41.0, 79.1, 120.4, 130.8, 136.1,
137.4, 145.5, 150.5.
Acknowledgments
´ ´
This work was supported by the ‘Conseil General de la
Loire Atlantique’, the ‘Centre National de la Recherche
`
Scientifique’ and the ‘Ministere 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. Drs Richard J. Robins, Giang
´
Vo-Thanh and Andre Guingant are gratefully acknowledged
for friendly and fruitful discussions.
4.7.2. (S)-3-(1-Azido-but-3-enyl)-5-bromo-pyridine (18).
To a solution of mesylate 11 (6.1 g, 22.3 mmol) in freshly
distilled DMF (70 mL), was added, in one portion, NaN3
(2.17 g, 33.4 mmol). The resulting mixture was stirred at
608C for 4 h and then diluted with ether (150 mL) and water
(70 mL). The layers were separated and the aqueous layer
was extracted with ether (3£100 mL). The combined
extracts were washed with brine (2£100 mL), dried over
anhydrous MgSO4, filtered and concentrated under reduced
pressure. Purification by flash chromatography (20% ethyl
acetate–hexane) gave azide 18 (4.67 g, 83%) as a colourless
oil. [a]2D0¼281.8 (c 1.29, MeOH). IR (KBr) n¼1643, 2100,
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