A formal synthesis of (-)-paroxetine by enantioselective ring enlargement of a trisubstituted prolinol

Article abstract of DOI:10.1002/1099-0690(200211)2002:21<3543::AID-EJOC3543>3.0.CO;2-0

A ring expansion and a radical dehalogenation have been used as the key steps in a formal total synthesis of (-)-paroxetine. The substituted piperidine ring precursor of (-)-paroxetine was generated by means of a stereoselective ring expansion of prolinol. ( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002).

Full text of DOI:10.1002/1099-0690(200211)2002:21<3543::AID-EJOC3543>3.0.CO;2-0

FULL PAPER
A Formal Synthesis of (؊)-Paroxetine by Enantioselective Ring Enlargement
of a Trisubstituted Prolinol
Janine Cossy,*[a] Olivier Mirguet,[a] Domingo Gomez Pardo,*[a] and Jean-Roger Desmurs[b]
Dedicated to Professor Marc Julia on the occasion of his 80th birthday
Keywords: Dehalogenation / Paroxetine / Piperidine / Prolinol / Ring expansion
A ring expansion and a radical dehalogenation have been
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
used as the key steps in a formal total synthesis of (−)-paroxet- 2002)
ine. The substituted piperidine ring precursor of (−)-paroxet-
ine was generated by means of a stereoselective ring expan-
sion of prolinol.
Introduction
Piperidine is the central structural feature of many biolo-
gically active compounds.[1Ϫ6] Substituted piperidines, more
particularly 4-arylpiperidines, are important structural ele-
ments in a number of these compounds, possibly due to
their similarity to the aryl alkylamine pharmacophore com-
mon in neurotransmitters such as serotonin [5-hydroxytryp-
tamine, (5-HT)], dopamine (DA), noradrenaline (NA), and
antagonists of opiate receptors. Drugs that modulate the
physiological and pathophysiological actions of 5-HT are
useful in the treatment of a variety of human diseases, in-
cluding depression, anxiety, alcoholism, chronic pain, em-
esis, and eating disorders such as obesity and bulimia.[7]
Such compounds are exemplified by the antipsychotic
5-HT-, and DA-antagonist haloperidol,[8] the analgesic
opioid agonist meperidine,[9] and the selective serotonin re-
uptake inhibitor (SSRI) paroxetine [Paxil, Deroxat]
(Figure 1).[10Ϫ11]
Paroxetine is an enantiomerically pure (Ϫ)-trans-3,4-di-
substituted piperidine. The drug is used in the treatment of
depression, obsessive compulsive disorder, and panic dis-
order.[12] Moreover, it has a reduced propensity to cause the
side-effects usually associated with tricyclic antidepress-
ants.[13] Because of its biological importance, several
enantiocontrolled syntheses have been reported.[14Ϫ32]
The stereochemical configurations at the C-3 and C-4 po-
sitions of the piperidine ring are critical for the activity of
Figure 1. Selected 4-arylpiperidines
this compound.[26] However, the synthetic methods usable
for the preparation of 3,4-disubstituted piperidine derivat-
ives are limited.[33Ϫ41]
In the context of our studies on ring expansion reac-
tions[42] of enantiomerically pure substituted prolinols to
give enantiomerically pure substituted 3-hydroxypiperid-
ines by use of trifluoroacetic anhydride,[43Ϫ45] or of substi-
tuted 3-chloropiperidines by use of mesyl chloride,[42,46]
we would like to report the synthesis of (Ϫ)-paroxet-
ine[47] (Scheme 1).
[a]
´
Laboratoire de Chimie Organique associe au CNRS, ESPCI,
10 rue Vauquelin, 75231 Paris Cedex 05, France
Fax: (internat.) ϩ 33Ϫ(0)140794660
E-mail: janine.cossy@espci.fr
[b]
Rhodia,
190 avenue Thiers, 69457 Lyon Cedex 06, France
Scheme 1. Ring expansion reactions
Eur. J. Org. Chem. 2002, 3543Ϫ3551  2002 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/02/1121Ϫ3543 $ 20.00ϩ.50/0
3543

J. Cossy, O. Mirguet, D. G. Pardo, J.-R. Desmurs
FULL PAPER
conjugate addition of lithium bis(4-fluorophenyl)cuprate to
(ϩ)-5 was achieved at Ϫ78 °C in THF to give compound
(ϩ)-6 in 70% yield and with a diastereomeric excess super-
ior to 98%[52] (Scheme 4). The relative trans stereochemistry
of the substituents at C-3 and C-4 was established by H
NMR from the coupling constant between 3-H and 4-H
Results and Discussion
Since secondary chlorides are selectively reduced in pref-
erence to primary chlorides by nBu3SnH in the presence of
AIBN,[48] the synthesis of (Ϫ)-paroxetine was envisaged as
proceeding from piperidine 10, the result in turn of a
chemoselective reduction of dichloride 8. This compound
would be produced from a ring expansion applied to proli-
nol 7, which would in turn be derived from the unsaturated
ester 5 by standard transformations. The last compound
would be synthesized from -pyroglutamic acid 1 via the
known bicyclic lactam (ϩ)-3[49] (Scheme 2).
1
(J ϭ 10.7 Hz).
Scheme 4
Different reducing agents were investigated for the trans-
formation of (ϩ)-6 into diol (Ϫ)-7. The best yield of (Ϫ)-7
(82%) was obtained when (ϩ)-6 was treated with BH3·THF
in refluxing THF.[53] The unexpected reactivity of
BH3·THF towards the ester functionality of (ϩ)-6 can be
explained by complexation of the oxygen atom of the lac-
tam ring by the boron atom of BH3·THF, which could pro-
duce the iminium ion a. Iminium ion a could be reduced to
the corresponding amine, and an intramolecular reduction
of the ester group could be achieved to produce aldehyde
b, which could subsequently be reduced to the bicyclic alco-
hol c. The complexation of the oxazolidine by BH3 could
give rise to the iminium d, which would be reduced to pro-
duce diol (Ϫ)-7 (Scheme 5). It is worth noting that the re-
duction of (ϩ)-6 to (Ϫ)-7 was a very fast reaction, which
probably means that the ester group was reduced first.
Scheme 2. Retrosynthetic analysis
Compound (ϩ)-3 was synthesized in three steps from -
pyroglutamic acid (1).[49] After treatment of -pyroglutamic
acid with thionyl chloride in methanol (88% yield), the cor-
responding methyl ester was reduced with NaBH4 (EtOH,
0 °C to room temp., yield ϭ 90%) and the amidoalcohol
(ϩ)-2[50] was protected with benzaldehyde in the presence
of a catalytic amount of p-toluenesulfonic acid (TsOH). The
optically pure bicyclic compound (ϩ)-3 was isolated in 69%
yield ([α]2D0 ϭ ϩ237, c ϭ 1.2, CHCl3) (Scheme 3).
Scheme 3
In order to introduce the aromatic group present in (Ϫ)-
paroxetine, compound (ϩ)-3 was transformed into the un-
saturated ester (ϩ)-5 in two steps, via the seleno derivatives
(Ϫ)-4 and (ϩ)-4Ј. The bicyclic compound (ϩ)-3 was depro-
tonated with an excess of LiHMDS (2.1 equiv.) and the
resulting anion was quenched at Ϫ78 °C with methyl chlo-
roformate (1 equiv., Ϫ78 °C, 1 h). The excess of base was
capable of achieving a second deprotonation, and the newly
formed anion was quenched with benzeneselenenyl chloride
(1 equiv., Ϫ78 °C, 1.5 h) to produce, in a one-pot operation,
the diastereomeric selenides (Ϫ)-4 and (ϩ)-4Ј in a ratio of
62:38. These two isomers were not separated or purified,
[51]
but were directly oxidized with H2O2
to afford the cor-
responding unsaturated ester (ϩ)-5 in nearly quantitative
yield (99% overall yield for the two-step sequence). The Scheme 5
3544
Eur. J. Org. Chem. 2002, 3543Ϫ3551

A Formal Synthesis of (Ϫ)-Paroxetine
FULL PAPER
Diol (Ϫ)-7 was then treated with MsCl at 0 °C for
40 min, and the reaction mixture was then heated under
reflux in the presence of Et3N for 30 hours to produce the
desired dichloropiperidine (Ϫ)-8 in 67% yield. Dichloropip-
eridine (Ϫ)-8 was treated, according to the literature pro-
cedure,[48] with nBu3SnH (1 equiv.) in the presence of AIBN
in refluxing toluene. Unfortunately, 3-methylpiperidine 9
was formed and could not be separated from the desired
product 10. These two compounds 9 and 10 were formed
in a 2:1 ratio (determined by GC/MS). It is noteworthy that
the use of tris(trimethylsilyl)silane [TTMSS] instead of
nBu3SnH also resulted in compounds 9 and 10 in a similar
ratio, but the conversion was not complete (70%)
(Scheme 6).
Scheme 7. Revised retrosynthetic analysis
amino alcohol (Ϫ)-14 could be isolated (Scheme 8). Since
oxazolidines can be opened by Et3SiH in the presence of
BF3·OEt2 to produce N-alkylamino alcohols,[55] lactam
(ϩ)-13 was treated with these reagents. In this case, amido
alcohol 14Ј was not formed, but the O-benzylated amido
alcohol (ϩ)-14ЈЈ was instead isolated in 95% yield
(Scheme 8).
This result can be explained by the Lewis acid coordinat-
ing the oxygen atom of the lactam (ϩ)-13 (path b) and not
the oxygen atom of the oxazolidine ring (path a) as previ-
ously observed for compound (ϩ)-6. The lone-pair elec-
trons of the oxygen atom of the oxazolidine ring participate
in the formation of the imine-oxonium ion f, and this inter-
mediate is then reduced with Et3SiH (path b) (Scheme 9).
Under conditions developed previously, the bicyclic lac-
Scheme 6
Because of this disappointing result, the synthesis of (Ϫ)- tam (ϩ)-13 was treated with BH3·THF. When compound
paroxetine from the bicyclic isobutyl ester 13 was examined. (ϩ)-13 was treated with 3 equivalents of BH3·THF at 0 °C
This compound would be transformed into prolinol 14, for 14 hours, the starting material was recovered unchanged
which, after treatment with MsCl, should undergo a ring (Table 1, entry 3). At room temperature, however, the ex-
expansion to produce piperidine 15, which should be trans- pected compound (Ϫ)-14 and the diol (Ϫ)-7 were isolated
formable into the precursor of (Ϫ)-paroxetine through (Ϫ)- in 27% and 54% yields, respectively (Table 1, entry 4). The
17. As previously, prolinol 14 was to be synthesized from - best conditions for obtaining amino alcohol (Ϫ)-14 were
pyroglutamic acid (1) via the bicyclic lactam 13 (Scheme 7). the use of 10 equivalents of BH3·THF for 1.5 hour at room
The synthesis of (ϩ)-13 from -pyroglutamic acid (1) was temperature. Under these conditions, (Ϫ)-14 was isolated in
similar to the synthesis of (ϩ)-6, except that methyl chloro- 44% yield and diol (Ϫ)-7 was isolated in 15% yield (Table 1,
formate was replaced by isobutyl chloroformate. The com- entry 5).
pound was obtained in 52% overall yield from -pyroglut-
The ring expansion reaction was then studied on amino
amic acid (1) (Scheme 4). The sterically hindered ester was alcohol (Ϫ)-14. Thus, when (Ϫ)-14 was treated with mesyl
chosen to avoid its reduction during the oxazolidine ring chloride (1.1 equiv.) at 0 °C in 1,2-dichloroethane for
opening of (ϩ)-13. In order to obtain (Ϫ)-14 from (ϩ)-13, 50 min and then heated under reflux for 36 hours in the
different reducing agents and conditions were examined. presence of triethylamine (3.1 equiv.), the expected trisubsti-
The results of these studies are summarized in Table 1.
tuted 5-chloropiperidine (Ϫ)-15 was isolated in 84% yield
When lactam (ϩ)-13 was reduced with LiBEt3H (Table 1, as a single diastereomer. The relative trans configuration of
entry 1), the intermediate hemiaminal 13Ј was formed, and the substituents at C-4 and C-5 was established by NMR
was treated immediately with triethylsilane in the presence analysis (δ 5-H ϭ 4.09 ppm, J5-Hax,4-Hax ϭ 10.7, J5-Hax,6-Hax
of BF3·OEt2 or TiCl4.[54] Under these conditions, a complex ϭ 10.7, J5-Hax,6-Heq ϭ 4.4 Hz,). The homoallylic cleav-
mixture resulted, from which neither lactam (ϩ)-13 nor age of the CϪCl bond with tris(trimethylsilyl)silane
Eur. J. Org. Chem. 2002, 3543Ϫ3551
3545

J. Cossy, O. Mirguet, D. G. Pardo, J.-R. Desmurs
FULL PAPER
Table 1. Reagents and conditions for the synthesis of (Ϫ)-14
Entry
1
Reducing agent
Equiv.
Conditions
Products (yield)
LiBEt3H then
Et3SiH, BF3·OEt2
Et3SiH, BF3·OEt2
BH3·THF
BH3·THF
BH3·THF
1
1
2
3
3
10
Ϫ78 °C
Degradation
(ϩ)-14ЈЈ (95%)
Starting material (ϩ)-13
(Ϫ)-14 (27%); (Ϫ)-7 (54%)
(Ϫ)-14 (44%); (Ϫ)-7 (15%)
2
3
4
5
Ϫ78 °C
14 h, 0 °C
60 h, 0 °C to room temp.
1.5 h, room temp.
(TTMSS) or n-tributyltin hydride (nBu3SnH) was exam-
ined. The best yield of (Ϫ)-16 (71%) was obtained when
(Ϫ)-15 was treated with nBu3SnH in the presence of AIBN
in refluxing toluene.[56] The use of TTMSS afforded (Ϫ)-16
in only 5% yield. The reduction of the ester group of (Ϫ)-
16 was achieved with LiAlH4 in THF, which furnished the
expected known piperidine (Ϫ)-17[17,23] [(Ϫ)-17·HCl:
[α]2D0 ϭ Ϫ10.6, c ϭ 1, MeOH; ref.[23] [α]2D0 ϭ Ϫ10.3, c ϭ 1,
MeOH] in quantitative yield (Scheme 10).
Scheme 8
Scheme 9
3546
Scheme 10. Formal total synthesis of (Ϫ)-paroxetine
Eur. J. Org. Chem. 2002, 3543Ϫ3551

A Formal Synthesis of (Ϫ)-Paroxetine
FULL PAPER
14.3, 7.4 Hz, 1 H) ppm. 13C NMR: δ ϭ 171.7 (s), 169.3 (s), 138.1
(d), 137.9 (s), 130 (d), 129.0 (d), 128.7 (d), 128.3 (d), 126.0 (d),
125.8 (s), 87.0 (d), 72.0 (t), 57.5 (s), 55.6 (d), 53.7 (q), 36.5 (t) ppm.
MS (EI): m/z (relative intensity) ϭ 417 (64) [Mϩ·], 415 (35) [Mϩ·],
311 (100), 309 (49), 260 (67), 231 (47), 228 (31), 183 (67), 182 (32),
181 (33), 157 (48), 155 (31), 105 (67), 91 (45), 78 (38), 77 (62).
C20H19NO4Se (416.33): calcd. C 57.70, H 4.60, N 3.36; found C
57.83, H 4.70, N 3.17.
Conclusion
Compound (Ϫ)-17, a known precursor in the synthesis
of (Ϫ)-paroxetine,[17] has been synthesized in ten steps from
-pyroglutamic acid (1), in an overall yield of 13.9% and
with two key steps: an enantioselective ring expansion of
prolinol induced by the mesyl chlorideϪEt3N process and
a homolytic cleavage of a CϪCl bond induced by nBu3SnH.
This transformation of the -pyroglutamic acid (1) into am-
ino alcohol (Ϫ)-17 constitutes a formal synthesis of (Ϫ)-pa-
roxetine.
Compound 4Ј: Rf ϭ 0.27 (EtOAc/petroleum ether, 80:20). [α]2D0
ϭ
ϩ221.8 (c ϭ 2.71, CHCl3). IR (neat): ν˜ ϭ 1729, 1710, 1435, 1374,
1255, 1226, 748, 693 cmϪ1. 1H NMR: δ ϭ 7.68 (m, 2 H), 7.47Ϫ7.21
(8 H), 6.24 (s, 1 H), 4.15Ϫ3.99 (2 H), 3.71 (s, 3 H), 3.07 (m, 1 H),
3.05 (dd, J ϭ 14.0, 7.0 Hz, 1 H), 2.15 (dd, J ϭ 14.0, 5.9 Hz, 1 H)
ppm. 13C NMR: δ ϭ 170.8 (s), 169.3 (s), 137.6 (s), 137.4 (d), 129.7
(d), 129.0 (d), 128.5 (d), 128.2 (d), 126.0 (s), 125.8 (d), 87.3 (d),
71.3 (t), 58.4 (s), 55.9 (d), 53.3 (q), 36.0 (t) ppm. MS (EI): m/z
(relative intensity) ϭ 417 (64) [Mϩ·], 415 (35) [Mϩ·], 311 (100), 309
(49), 260 (65), 231 (49), 228 (32), 183 (70), 182 (31), 181 (34), 157
(45), 155 (31), 105 (66), 91 (45), 78 (35), 77 (58).
Experimental Section
General Remarks: Unless otherwise specified, materials were pur-
chased from commercial suppliers and used without further puri-
fication. THF and Et2O were distilled from Na benzophenone-ke-
tyl immediately prior to use. Amines and solvents were distilled
from CaH2 prior to use. Moisture-sensitive reactions were con-
ducted in oven-dried glassware and under an argon atmosphere.
Analytical thin-layer chromatography was performed on Merck
precoated silica gel (60F254) plates and flash column chromato-
graphy on Merck Kieselgel 60 (230Ϫ400 mesh). Melting points are
uncorrected. IR: PerkinϪElmer 298 or PerkinϪElmer 1600. Op-
tical rotations: PerkinϪElmer 343 polarimeter. Elemental analyses:
Methyl (3S,7aR)-5-Oxo-3-phenyl-5,7a-dihydro-1H,3H-pyrrolo[1,2-c]-
oxazole-6-carboxylate [(؉)-5]: An aqueous H2O2 solution (30%,
12.5 mL, 123.7 mmol, 10 equiv.) was added dropwise at 0 °C to a
solution of the crude diastereoisomeric mixture of (Ϫ)-4 and (ϩ)-
4Ј (5.1 g, 12.30 mmol) in CH2Cl2 (60 mL). The mixture was stirred
at 0 °C for 45 min before being quenched with an aqueous HCl
solution (1.2 , 30 mL). The aqueous layer was extracted with
CH2Cl2 (4 ϫ 30 mL) and the combined organic layers were washed
with a saturated aqueous NaHCO3 solution (2 ϫ 40 mL) and brine
(40 mL), dried over MgSO4, filtered, and then concentrated under
reduced pressure. Compound (ϩ)-5 (3.2 g, 12.3 mmol, 100% yield
over two steps) was obtained as a yellow solid: m.p. 137 °C; Rf ϭ
0.19 (EtOAc/petroleum ether, 40:60). [α]2D0 ϭ ϩ195.7 (c ϭ 1.11,
CHCl3). IR (KBr): ν˜ ϭ 1748, 1723, 1434, 1344, 1220, 1161, 1102,
702 cmϪ1. 1H NMR: δ ϭ 8.00 (d, J ϭ 1.8 Hz, 1 H), 7.53 (m, 2 H),
7.47Ϫ7.28 (3 H), 6.26 (s, 1 H), 4.62 (m, 1 H), 4.31 (dd, J ϭ 7.7,
7.7 Hz, 1 H), 3.88 (s, 3 H), 3.49 (m, 1 H) ppm. 13C NMR: δ ϭ
171.3 (s), 161.1 (s), 154.7 (d), 137.9 (s), 131.9 (s), 128.6 (d), 128.3
(d), 125.9 (d), 87.6 (d), 67.3 (t), 62.1 (d), 52.2 (q) ppm. MS (CIϩ,
CH4): m/z (relative intensity) ϭ 260 (100) [M ϩ Hϩ], 259 (6), 228
(25), 200 (11), 198 (3), 184 (9), 182 (6), 156 (26), 123 (3), 107 (13).
HRMS (CIϩ, CH4) calcd. for C14H14NO4 [[M ϩ H]ϩ] 260.0923,
found 260.0921.
´
´
Service Regional de Microanalyse de lЈUniversite P. et M. Curie.
´
HRMS: Centre de Spectrochimie de lЈEcole Normale Superieure.
NMR: Bruker AC 300 spectrometer (300 MHz and 75 MHz for 1H
and 13C, respectively). Spectra were recorded in CDCl3 as solvent,
and chemical shifts (δ) were expressed in ppm relative to residual
1
CHCl3 at δ ϭ 7.27 ppm for H and to CDCl3 at δ ϭ 77.0 ppm for
13C. MS: Mass spectra were obtained by GC/MS with electron im-
pact ionization on a 5971 Hewlett Packard instrument at 70 eV;
only selected ions are reported.
Methyl
(3S,6R,7aR)-5-Oxo-3-phenyl-6-(phenylseleno)tetrahydro-
1H,3H-pyrrolo[1,2-c]oxazole-6-carboxylate [(؊)-4] and Methyl
(3S,6S,7aR)-5-Oxo-3-phenyl-6-(phenylseleno)tetrahydro-1H,3H-
pyrrolo[1,2-c]oxazole-6-carboxylate [(؉)-4Ј]: A solution of (ϩ)-3[49]
(2.50 g, 12.3 mmol) in THF (50 mL) was added at Ϫ78 °C to a
solution of LiHMDS (26.0 mL, 1  in THF, 26.0 mmol, 2.1 equiv.)
in THF (100 mL). The mixture was stirred at Ϫ78 °C for 30 min,
and methyl chloroformate (0.95 mL, 12.0 mmol, 1 equiv.) was ad-
ded dropwise. The solution was stirred for 1 h at Ϫ78 °C, and a
solution of benzeneselenenyl chloride (2.5 g, 13.0 mmol, 1 equiv.)
in THF (25 mL) was added. The mixture was stirred for 1.5 h at
this temperature before addition of an aqueous HCl solution (1.2
, 30 mL). The mixture was allowed to warm to room temp. and
was extracted with Et2O (3 ϫ 30 mL). The combined organic layers
were washed with brine (20 mL), dried over MgSO4, filtered, and
concentrated in vacuo. Although the 62:38 mixture of diastereo-
Methyl (3S,6S,7R,7aR)-7-(4-Fluorophenyl)-3-phenyl-5-oxo-tetrahy-
dro-1H,3H-pyrrolo[1,2-c]oxazole-6-carboxylate [(؉)-6]: n-Butylli-
thium (9.72 mL, 2.5  in hexanes, 24.30 mmol, 10 equiv.) was ad-
ded dropwise at Ϫ78 °C to a solution of 4-bromofluorobenzene
(2.67 mL, 24.26 mmol, 10 equiv.) in THF (62 mL). The solution
was stirred at Ϫ78 °C for 30 min and was then added dropwise by
cannula to a suspension of copper iodide (2.31 g, 12.13 mmol, 5.0
equiv.) in THF (38 mL) at Ϫ78 °C. The resulting mixture was
warmed slowly to Ϫ30 °C and stirred for 40 min at this temperature
to give a clear orange solution. After the mixture had again been
cooled to Ϫ78 °C, a solution of (ϩ)-5 (0.63 g, 2.43 mmol) in THF
(38 mL) was added dropwise and the reaction mixture was stirred
for 30 min before addition of a saturated aqueous NH4Cl/NH4OH
(32%): 2:1 solution (75 mL). After 1 h of stirring, the deep blue
aqueous layer was extracted with Et2O (2 ϫ 75 mL) and CH2Cl2 (2
ϫ 50 mL). The combined organic layers were washed with aqueous
1
mers (Ϫ)-4 and (ϩ)-4Ј (determined by H NMR analysis) was car-
ried on without purification, the following analytical data were ob-
tained from a small-scale run with purification by flash column
chromatography on silica gel (EtOAc/petroleum ether, 10:90).
Compound 4: M.p. 87 °C; Rf ϭ 0.41 (EtOAc/petroleum ether,
20:80). [α]2D0 ϭ Ϫ33.3 (c ϭ 1.17, CHCl3). IR (KBr): ν˜ ϭ 1730, 1705,
1434, 1256, 1213, 745, 694 cmϪ1. 1H NMR: δ ϭ 7.60 (dd, J ϭ 8.1, NaOH (1 , 2 ϫ 50 mL) and brine (75 mL), dried over MgSO4,
1.1 Hz, 2 H), 7.43Ϫ7.24 (6 H), 7.10 (m, 2 H), 6.24 (s, 1 H), 4.11
filtered, and concentrated under reduced pressure. Purification by
(dd, J ϭ 8.1, 6.2 Hz, 1 H), 3.86 (s, 3 H), 3.47 (dd, J ϭ 8.5, 8.1 Hz, flash column chromatography on silica gel (petroleum ether/
1 H), 3.18 (m, 1 H), 2.93 (dd, J ϭ 14.3, 5.9 Hz, 1 H), 2.60 (dd, J ϭ
Eur. J. Org. Chem. 2002, 3543Ϫ3551
EtOAc, 95:5, then 80:20) afforded (ϩ)-6 (0.61 g, 1.72 mmol, 70%
3547

J. Cossy, O. Mirguet, D. G. Pardo, J.-R. Desmurs
FULL PAPER
yield) as a pale yellow oil: Rf ϭ 0.34 (EtOAc/petroleum ether,
20:80). [α]2D0 ϭ ϩ62.8 (c ϭ 1.09, CHCl3). IR (neat): ν˜ ϭ 1745, 1716,
160 (11), 92 (12), 91 (100). HRMS (CIϩ, CH4) calcd. for
C19H2135Cl2FN [M ϩ H]ϩ] 352.1035, found 352.1025 and calcd.
1513, 1349, 1273, 1225, 1165, 701 cmϪ1. 1H NMR: δ ϭ 7.53Ϫ7.43 for C19H2135Cl37ClFN [M ϩ H]ϩ 354.1009, found 354.1003.
(2 H), 7.42Ϫ7.29 (3 H), 7.25 (m, 2 H), 7.05 (m, 2 H), 6.43 (s, 1 H),
Isobutyl (3S,6R,7aR)-5-Oxo-3-phenyl-6-(phenylseleno)tetrahydro-
4.27Ϫ4.12 (2 H), 4.03 (d, J ϭ 10.7 Hz, 1 H), 3.94 (m, 1 H), 3.89
1H,3H-pyrrolo[1,2-c]oxazole-6-carboxylate [(؊)-11] and Isobutyl
(3S,6S,7aR)-5-Oxo-3-phenyl-6-(phenylseleno)tetrahydro-1H,3H-
(dd, J ϭ 8.1, 5.9 Hz, 1 H), 3.77 (s, 3 H) ppm. 13C NMR: δ ϭ 170.6
(s), 168.2 (s), 162.1 (d, J ϭ 247.2 Hz), 137.5 (s), 133.6 (d, J ϭ
3.7 Hz), 128.7 (dd, J ϭ 7.9 Hz), 128.6 (d), 128.3 (d), 125.8 (d),
115.9 (dd, J ϭ 21.3 Hz), 87.3 (d), 70.6 (t), 63.6 (d), 59.0 (d), 52.6
(q), 49.1 (d) ppm. MS (EI): m/z (relative intensity) ϭ 355 (0.03)
[Mϩ·], 297 (36), 296 (81), 267 (8), 149 (10), 148 (21), 123 (10), 122
(100), 121 (11), 117 (10), 109 (10), 105 (18), 91 (10), 90 (9), 77 (9).
pyrrolo[1,2-c]oxazole-6-carboxylate
[(؉)-11Ј]:
n-Butyllithium
(20.66 mL, 2.5  in hexanes, 51.65 mmol, 2.1 equiv.) was added
dropwise at Ϫ78 °C to a solution of HMDS (10.9 mL, 51.66 mmol,
2.1 equiv.) in THF (200 mL). After the mixture had been kept for
40 min at Ϫ78 °C, a solution of (ϩ)-3[49] (5.00 g, 24.58 mmol) in
THF (100 mL) was added dropwise. The mixture was stirred at
Ϫ78 °C for 45 min, and isobutyl chloroformate (3.26 mL,
24.67 mmol, 1 equiv.) was added dropwise. The solution was stirred
for 30 min at Ϫ78 °C and a solution of benzeneselenenyl chloride
(4.79 g, 24.51 mmol, 1 equiv.) in THF (50 mL) was added. The re-
action was stirred for 1.5 h at this temperature before addition of
aqueous HCl (1.2 , 100 mL). The mixture was allowed to warm to
room temp. and extracted with Et2O (3 ϫ 100 mL).The combined
organic layers were washed with brine (75 mL), dried over MgSO4,
filtered, and concentrated in vacuo. Although the 62:38 mixture of
diastereomers (Ϫ)-11 and (ϩ)-11Ј (determined by 1H NMR ana-
lysis) was carried on without purification, the following analytical
data were obtained from a small-scale run purified by flash column
chromatography on silica gel (toluene/Et2O, 99:1).
(2S,3R,4S)-1-Benzyl-3-(4-fluorophenyl)pyrrolidine-2,4-bismethanol
[(؊)-7]: BoraneϪtetrahydrofuran complex (5.50 mL, 1  in THF,
5.50 mmol, 5.2 equiv.) was added at room temp. to a solution of
(ϩ)-6 (375 mg, 1.05 mmol) in THF (20 mL), and the mixture was
heated at reflux for 19 h. The reaction mixture was cautiously
quenched at 0 °C by addition of methanol until gas evolution
stopped, and the solvents were evaporated. The residue was dis-
solved in methanol (20 mL) and heated at reflux for 1 h. The solu-
tion was concentrated in vacuo, methanol (20 mL) was added, and
the solvents were evaporated. This procedure was repeated twice.
The compound (Ϫ)-7 (270 mg, 0.86 mmol, 82% yield) was obtained
as a yellowish oil and was carried on without further purification:
Rf ϭ 0.50 (CH2Cl2/MeOH, 97:3). [α]2D0 ϭ Ϫ53.3 (c ϭ 1.05, CHCl3).
1
IR (neat): ν˜ ϭ 3377, 2926, 1604, 1511, 1225, 1160, 1047 cmϪ1. H
Compound 11: M.p. 88 °C; Rf ϭ 0.60 (toluene/diethyl ether, 80:20).
[α]2D0 ϭ Ϫ12.1 (c ϭ 1.00, CHCl3). IR (KBr): ν˜ ϭ 1732, 1696, 1401,
1256, 1220, 742, 691 cmϪ1. 1H NMR: δ ϭ 7.57 (m, 2 H), 7.41Ϫ7.22
(6 H), 7.05 (m, 2 H), 6.21 (s, 1 H), 4.08 (dd, J ϭ 8.1, 6.3 Hz, 1 H),
4.02 (d, J ϭ 6.6 Hz, 1 H), 4.01 (d, J ϭ 6.6 Hz, 1 H), 3.43 (dd, J ϭ
8.5, 8.1 Hz, 1 H), 3.07 (m, 1 H), 2.92 (dd, J ϭ 14.7, 5.9 Hz, 1 H),
2.56 (dd, J ϭ 14.7, 7.4 Hz, 1 H), 2.02 (m, 1 H), 0.96 (d, J ϭ 6.6 Hz,
3 H), 0.96 (d, J ϭ 7.0 Hz, 3 H) ppm. 13C NMR: δ ϭ 171.9 (s),
168.8 (s), 138.1 (d), 138.0 (s), 129.8 (d), 129.0 (d), 128.6 (d), 128.3
(d), 126.0 (d), 125.9 (s), 87.0 (d), 72.8 (t), 72.1 (t), 57.9 (s), 55.6 (d),
36.4 (t), 27.7 (d), 19.0 (q) ppm. MS (EI): m/z (relative intensity) ϭ
459 (60) [Mϩ·], 457 (30) [Mϩ·], 353 (37), 351 (19), 302 (61), 297
(100), 295 (50), 188 (58), 183 (49), 157 (48), 105 (85), 91 (53), 78
(50), 77 (61), 57 (56). C23H25NO4Se (459.09): calcd. C 60.25, H
5.50, N 3.05; found C 60.15, H 5.42, N 3.06.
NMR: δ ϭ 7.39Ϫ7.17 (7 H), 7.01 (m, 2 H), 4.07 (d, J ϭ 13.2 Hz,
1 H), 3.73 (dd, J ϭ 11.6, 3.1 Hz, 1 H), 3.61 (dd, J ϭ 10.5, 5.0 Hz,
1 H), 3.53 (dd, J ϭ 10.5, 6.8 Hz, 1 H), 3.44 (dd, J ϭ 11.6, 1.5 Hz,
1 H), 3.36 (d, J ϭ 13.2 Hz, 1 H), 3.10 (dd, J ϭ 9.2, 7.3 Hz, 1 H),
3.05 (dd, J ϭ 9.9, 3.7 Hz, 1 H), 2.81 (dd, J ϭ 10.3, 8.5 Hz, 1 H),
2.70 (ddd, J ϭ 9.2, 2.9, 1.5 Hz, 1 H), 2.48Ϫ2.29 (3 H) ppm. 13C
NMR: δ ϭ 161.8 (d, J ϭ 245.0 Hz), 138.3 (d, J ϭ 3.3 Hz), 138.2
(s), 129.5 (dd, J ϭ 7.9 Hz), 128.6 (d), 128.5 (d), 127.3 (d), 115.5
(dd, J ϭ 21.2 Hz), 73.8 (d), 65.4 (t), 58.2 (t), 57.9 (t), 56.8 (t), 48.2
(d), 46.6 (d) ppm. MS (EI): m/z (relative intensity) ϭ 284 (73) [Mϩ·
Ϫ CH2OH·], 266 (5), 162 (9), 135 (4), 133 (3), 109 (4), 92 (8), 91
(100), 65 (5). HRMS (CIϩ, CH4) calcd. for C19H23FNO2 [M ϩ H]ϩ
316.1713, found 316.1713.
(3S,4R,5S)-1-Benzyl-3-chloro-5-(chloromethyl)-4-(4-fluorophenyl)-
piperidine [(؊)-8]: Methanesulfonyl chloride (0.14 mL, 1.81 mmol,
2.10 equiv.) was added dropwise at 0 °C to a solution of (Ϫ)-7
(270 mg, 0.86 mmol) in 1,2-dichloroethane (5.5 mL). The mixture
was stirred for 40 min, and Et3N (0.48 mL, 3.45 mmol, 4.0 equiv.)
was added. The resulting solution was heated under reflux for 30 h
and quenched with an aqueous NaOH solution (1 , 2.5 mL). The
aqueous layer was extracted with CH2Cl2 (3 ϫ 10 mL) and the
combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. Puri-
fication by flash column chromatography on silica gel (petroleum
ether/CH2Cl2, 60:40) afforded (Ϫ)-8 (203 mg, 0.58 mmol, 55% yield
over two steps) as a yellow oil: Rf ϭ 0.50 (petroleum ether/CH2Cl2,
63:47). [α]2D0 ϭ Ϫ15.0 (c ϭ 2.36, CHCl3). IR (neat): ν˜ ϭ 1512, 1454,
Compound 11Ј: Rf ϭ 0.67 (toluene/diethyl ether, 80:20) [α]2D0
ϩ147.7 (c ϭ 1.64, CHCl3). IR (neat): ν˜ ϭ 1716, 1252, 1225 cmϪ1
ϭ
.
1H NMR: δ ϭ 7.68 (m, 2 H), 7.47Ϫ7.21 (8 H), 6.25 (s, 1 H), 4.07
(m, 2 H), 3.99Ϫ3.84 (2 H), 3.13Ϫ2.95 (2 H), 2.12 (dd, J ϭ 13.8,
6.1 Hz, 1 H), 1.93 (m, 1 H), 0.88 (d, J ϭ 6.6 Hz, 6 H) ppm. 13C
NMR: δ ϭ 170.8 (s), 169.0 (s), 137.8 (s), 137.5 (d), 129.7 (d), 129.1
(d), 128.6 (d), 128.3 (d), 126.3 (s), 125.8 (d), 87.2 (d), 72.3 (t), 71.5
(t), 59.2 (s), 56.1 (d), 36.5 (t), 27.6 (d), 18.8 (q), 18.7 (q) ppm. MS
(CIϩ, CH4): m/z (relative intensity) ϭ 460 (100) [M ϩ Hϩ], 458
(57) [M ϩ Hϩ], 382 (9), 380 (5), 354 (30), 352 (17), 304 (24). HRMS
(CIϩ, CH4) calcd. for C23H26NO480Se [M ϩ H]ϩ 460.1028, found
460.1031 and calcd. for C23H26NO478Se [M ϩ H]ϩ 458.1041,
found 458.1030.
1
1226, 1160, 832, 700 cmϪ1. H NMR: δ ϭ 7.44Ϫ7.25 (5 H), 7.21
(m, 2 H), 7.03 (m, 2 H), 4.07 (ddd, J ϭ 11.0, 11.0, 4.4 Hz, 1 H),
Isobutyl (3S,7aR)-5-Oxo-3-phenyl-5,7a-dihydro-1H,3H-pyrrolo[1,2-c]-
3.65 (d, J ϭ 13.2 Hz, 1 H), 3.58 (d, J ϭ 13.2 Hz, 1 H), 3.39Ϫ3.23 oxazole-6-carboxylate [(؉)-12]: Aqueous H2O2 (30%, 12.5 mL,
(2 H), 3.17Ϫ3.02 (2 H), 2.64 (m, 1 H), 2.35Ϫ2.13 (3 H) ppm. 13C
NMR: δ ϭ 162.0 (d, J ϭ 246.0 Hz), 137.4 (s), 135.1 (d, J ϭ 3.0 Hz),
123.37 mmol, 5 equiv.) was added dropwise at 0 °C to a solution of
the crude diastereoisomeric mixture of (Ϫ)-11 and (ϩ)-11Ј (11.22 g,
129.0 (d), 128.4 (d), 128.3 (dd, J ϭ 6.7 Hz), 127.4 (d), 115.6 (dd, 24.47 mmol) in CH2Cl2 (100 mL). The mixture was stirred at 0 °C
J ϭ 21.4 Hz), 62.4 (t), 61.2 (t), 60.7 (d), 56.3 (t), 53.1 (d), 45.9 (t), for 30 min before being quenched by addition of an aqueous HCl
44.0 (d) ppm. MS (EI): m/z (relative intensity) ϭ 355 (2) [Mϩ·], 353
solution (1.2 , 50 mL). The aqueous layer was extracted with
(10) [Mϩ·], 351 (15) [Mϩ·], 318 (24), 317 (15), 316 (69), 302 (17), CH2Cl2 (4 ϫ 50 mL) and the combined organic layers were washed
3548
Eur. J. Org. Chem. 2002, 3543Ϫ3551

A Formal Synthesis of (Ϫ)-Paroxetine
with a saturated aqueous NaHCO3 (2 ϫ 75 mL) and brine (50 mL), was then obtained as a yellowish solid, and compound (Ϫ)-7 (6 mg,
FULL PAPER
dried over MgSO4, filtered, and then concentrated under reduced
pressure. Compound (ϩ)-12 (7.34 g, 24.36 mmol, 99% yield over 2
steps) was obtained as a yellow solid: m.p. 104 °C (EtOH); Rf ϭ
0.41 (toluene/diethyl ether, 80:20). [α]2D0 ϭ ϩ193.2 (c ϭ 1.03,
CHCl3). IR (KBr): ν˜ ϭ 1740, 1347, 1225, 1166, 1112, 1018, 754
0.02 mmol, 15% yield) as a yellowish oil.
Compound 14: M.p. 71 °C; Rf ϭ 0.35 (petroleum ether/EtOAc,
80:20). [α]2D0 ϭ Ϫ54.6 (c ϭ 1.91, CHCl3). IR (KBr): ν˜ ϭ 3448, 1730,
1511, 1226, 1175, 1160 cmϪ1. 1H NMR: δ ϭ 7.40Ϫ7.17 (7 H), 7.01
(m, 2 H), 4.07 (d, J ϭ 13.2 Hz, 1 H), 3.81 (dd, J ϭ 10.7, 7.0 Hz, 1
H), 3.78 (dd, J ϭ 10.7, 6.6 Hz, 1 H), 3.75Ϫ3.63 (2 H), 3.48Ϫ3.36
(2 H), 3.41(d, J ϭ 13.2 Hz, 1 H), 3.06 (ddd, J ϭ 9.2, 8.1, 4.8 Hz,
1 H), 2.89 (dd, J ϭ 9.9, 9.2 Hz, 1 H), 2.77 (dd, J ϭ 9.2, 1.5 Hz, 1
H), 2.44 (br. s, 1 H), 1.80 (m, 1 H), 0.79 (d, J ϭ 6.6 Hz, 3 H), 0.78
(d, J ϭ 6.6 Hz, 3 H) ppm. 13C NMR: δ ϭ 173.6 (s), 161.8 (d, J ϭ
245.4 Hz), 138.1 (s), 136.9 (d, J ϭ 3.7 Hz), 129.5 (dd, J ϭ 7.9 Hz),
128.5 (d), 128.4 (d), 127.3 (d), 115.5 (dd, J ϭ 21.4 Hz), 73.0 (d),
70.9 (t), 57.9 (t), 57.6 (t), 56.0 (t), 49.3 (d), 48.8 (d), 27.6 (d), 18.9
1
cmϪ1. H NMR: δ ϭ 7.96 (d, J ϭ 1.8 Hz, 1 H), 7.57Ϫ7.48 (2 H),
7.44Ϫ7.30 (3 H), 6.27 (s, 1 H), 4.63 (m, 1 H), 4.32 (dd, J ϭ 8.1,
7.3 Hz, 1 H), 4.07 (d, J ϭ 6.6 Hz, 2 H), 3.51 (dd, J ϭ 8.5, 8.1 Hz,
1 H), 2.05 (m, 1 H), 1.00 (d, J ϭ 6.6 Hz, 6 H) ppm. 13C NMR:
δ ϭ 171.4 (s), 161.0 (s), 153.9 (d), 138.1 (s), 132.7 (s), 128.7 (d),
128.5 (d), 126.1 (d), 87.8 (d), 71.4 (t), 67.5 (t), 62.2 (d), 27.7 (d),
19.0 (q) ppm. MS (CIϩ, CH4): m/z (relative intensity) ؍ 302 (100)
[M ϩ Hϩ], 246 (25), 228 (38), 224 (13), 196 (20), 140 (18), 107 (16).
HRMS (CIϩ, CH4) calcd. for C17H20NO4 [M ϩ H]ϩ 302.1392,
found 302.1387.
(q) ppm. MS (EI): m/z (relative intensity) ϭ 354 (95) [Mϩ·
Ϫ
CH2OH·], 340 (11), 311 (10), 253 (12), 252 (36), 162 (34), 91 (100).
HRMS (CIϩ, CH4) calcd. for C23H29FNO3 [M ϩ H]ϩ 386.2131,
found 386.2130.
Isobutyl (3S,6S,7R,7aR)-7-(4-Fluorophenyl)-5-oxo-3-phenyl-tetrahy-
dro-1H,3H-pyrrolo[1,2-c]oxazole-6-carboxylate [(؉)-13]: n-Butylli-
thium (14.60 mL, 2.5  in hexanes, 36.50 mmol, 11 equiv.) was ad-
ded dropwise at Ϫ78 °C to a solution of 4-bromofluorobenzene
(4.02 mL, 36.52 mmol, 11 equiv.) in THF (60 mL). The solution
was stirred at Ϫ78 °C for 30 min and was then added dropwise
by cannula at Ϫ78 °C to a suspension of copper iodide (3.47 g,
18.22 mmol, 5.70 equiv.) in THF (30 mL). The resulting mixture
was warmed slowly to Ϫ25 °C and stirred for 30 min at this temper-
ature to give a clear orange solution. After the mixture had again
been cooled to Ϫ78 °C, a solution of (ϩ)-12 (1.00 g, 3.32 mmol) in
THF (36 mL) was added dropwise and the mixture was stirred for
2 h before being quenched with saturated aqueous NH4Cl/NH4OH
(32%): 2:1 solution (100 mL). After 1 h of stirring, the deep blue
aqueous layer was extracted with Et2O (2 ϫ 75 mL) and CH2Cl2
(50 mL). The combined organic layers were washed with an aque-
ous NaOH solution (1 , 2 ϫ 75 mL) and brine (75 mL), dried
over MgSO4, filtered, and concentrated under reduced pressure.
Purification by flash column chromatography on silica gel (petro-
leum ether/EtOAc, 95:5 then 80:20) afforded (ϩ)-13 (1.28 g,
3.22 mmol, 97% yield) as a white solid: m.p. 112 °C; Rf ϭ 0.33
(petroleum ether/EtOAc, 90:10). [α]2D0 ϭ ϩ48.8 (c ϭ 1.01, CHCl3),
IR (KBr): ν˜ ϭ 1740, 1716, 1513, 1350, 1225, 1162 cmϪ1. 1H NMR:
δ ϭ 7.53Ϫ7.29 (5 H), 7.25 (m, 2 H), 7.04 (m, 2 H), 6.44 (s, 1 H),
4.30Ϫ4.12 (2 H), 4.11Ϫ3.99 (2 H), 3.98Ϫ3.81 (3 H), 1.95 (m, 1 H),
0.91 (d, J ϭ 6.6 Hz, 3 H), 0.90 (d, J ϭ 6.6 Hz, 3 H) ppm. 13C
NMR: δ ϭ 170.8 (s), 167.9 (s), 162.3 (d, J ϭ 247.2 Hz), 137.7 (s),
133.8 (d, J ϭ 3.7 Hz), 128.8 (dd, J ϭ 7.9 Hz), 128.8 (d), 128.5 (d),
126.0 (d), 116.9 (dd, J ϭ 22.0 Hz), 87.4 (d), 71.9 (t), 70.8 (t), 63.7
(d), 59.4 (d), 49.2 (d), 27.7 (d), 18.7 (q) ppm. MS (EI): m/z (relative
intensity) ϭ 397 (46) [Mϩ·], 396 (44), 367 (15), 340 (16), 296 (27),
291 (25), 190 (29), 166 (100), 149 (81), 148 (34), 121 (29), 105 (43).
C23H24FNO4 (397.44): calcd. C 69.51, H 6.09, N 3.52; found C
69.39, H 6.13, N 3.39.
Isobutyl (3R,4R,5S)-5-[(Benzyloxy)methyl]-4-(4-fluorophenyl)-2-oxo-
pyrrolidine-3-carboxylate [(؉)-14ЈЈ]: BF3·Et2O (18 µL, 0.14 mmol,
1.1 equiv.) was added dropwise at Ϫ78 °C to a solution of (ϩ)-13
(50 mg, 0.13 mmol) and triethylsilane hydride (22 µL, 0.14 mmol,
1.1 equiv.) in CH2Cl2 (0.7 mL). The reaction mixture was stirred
for 30 min at this temperature before further addition of Et3SiH
(22 µL, 0.14 mmol, 1.1 equiv.) and BF3·Et2O (18 µL, 0.14 mmol,
1.1 equiv.). The reaction mixture was stirred for 2 h at Ϫ78 °C and
quenched with a saturated aqueous NaHCO3 (1 mL). The aqueous
layer was extracted with CH2Cl2 (3 ϫ 2 mL), dried over MgSO4,
filtered, and concentrated in vacuo. Purification by flash column
chromatography on silica gel (petroleum ether/EtOAc, 70:30) gave
compound (ϩ)-14ЈЈ (48 mg, 0.12 mmol, 95% yield) as a colourless
oil: Rf ϭ 0.53 (EtOAc/petroleum ether, 40:60). [α]2D0 ϭ ϩ6.1 (c ϭ
2.10, CHCl3). IR (neat): ν˜ ϭ 3228, 1736, 1709, 1513, 1227, 1162
1
cmϪ1. H NMR: δ ϭ 7.43Ϫ7.25 (5 H), 7.22 (m, 2 H), 7.04 (m, 2
H), 6.72 (br. s, 1 H), 4.53 (d, J ϭ 11.8 Hz, 1 H), 4.48 (d, J ϭ
11.8 Hz, 1 H), 4.10Ϫ3.76 (3 H), 3.74Ϫ3.36 (4 H), 1.93 (m, 1 H),
0.88 (d, J ϭ 6.6 Hz, 3 H), 0.87 (d, J ϭ 6.6 Hz, 3 H) ppm. 13C
NMR: δ ϭ 170.5 (s), 168.7 (s), 162.1 (d, J ϭ 246.6 Hz), 137.3 (s),
134.7 (d, J ϭ 3.0 Hz), 129.1 (dd, J ϭ 7.9 Hz), 128.5 (d), 127.9 (d),
127.7 (d), 116.0 (dd, J ϭ 21.4 Hz), 73.5 (t), 72.1 (t), 71.7 (t), 59.3
(d), 56.4 (d), 46.3 (d), 27.6 (d), 18.9 (q) ppm. MS (CIϩ, CH4): m/z
(relative intensity) ؍ 400 (100) [M ϩ Hϩ], 398 (20), 344 (6), 343
(4), 326 (12), 312 (5), 293 (3), 154 (2). HRMS (CIϩ, CH4) calcd.
for C23H27FNO4 [M ϩ H]ϩ 400.1924, found 400.1921.
Isobutyl (3S,4R,5S)-1-Benzyl-5-chloro-4-(4-fluorophenyl)piperidine-
3-carboxylate [(؊)-15]: Methanesulfonyl chloride (24 µL,
0.31 mmol, 1.1 equiv.) was added dropwise at 0 °C to a solution of
(Ϫ)-14 (110 mg, 0.28 mmol) in 1,2-dichloroethane (1.8 mL). The
mixture was stirred for 50 min, and Et3N (0.12 mL, 0.86 mmol, 3.1
equiv.) was added. The resulting solution was heated under reflux
for 36 h and quenched with an aqueous NaOH solution (1 ,
Isobutyl (3S,4R,5S)-1-Benzyl-4-(4-fluorophenyl)-5-(hydroxymethyl)-
pyrrolidine-3-carboxylate [(؊)-14]: BoraneϪtetrahydrofuran com- 0.5 mL). The aqueous layer was extracted with CH2Cl2 (3 ϫ 5 mL)
plex (1.3 mL, 1  in THF, 1.30 mmol, 10 equiv.) was added to a
solution of (ϩ)-13 (51 mg, 0.13 mmol) in THF (1 mL) at room
temp. The mixture was stirred for 1.5 h and then cooled to 0 °C
before being quenched with MeOH (3 mL). The solution was con-
and the combined organic layers were washed with brine, dried
over MgSO4, filtered, and concentrated under reduced pressure.
Purification by flash column chromatography on silica gel (petro-
leum ether/EtOAc, 95:5) afforded (Ϫ)-15 (95 mg, 0.23 mmol, 84%
centrated under reduced pressure and the residue was dissolved in yield) as a white solid: M.p. 77 °C; Rf ϭ 0.35 (petroleum ether/
methanol (5 mL) before being heated under reflux for 1 h. The re-
action mixture was concentrated under reduced pressure and this
procedure was repeated twice. The crude material was purified by
EtOAc, 95:5). [α]2D0 ϭ Ϫ5.2 (c ϭ 1.06, CHCl3). IR (KBr): ν˜ ϭ 1728,
1513, 1229, 1186, 1150, 750 cmϪ1. 1H NMR: δ ϭ 7.44Ϫ7.28 (5 H),
7.23 (m, 2 H), 7.03 (m, 2 H), 4.09 (ddd, J ϭ 10.7, 10.7, 4.4 Hz, 1
flash column chromatography on silica gel (petroleum ether/ H), 3.67 (dd, J ϭ 10.7, 6.6 Hz, 1 H), 3.66 (s, 2 H), 3.57 (dd, J ϭ
EtOAc, 90:10). Compound (Ϫ)-14 (22 mg, 0.06 mmol, 44% yield)
10.7, 6.6 Hz, 1 H), 3.37 (ddd, J ϭ 11.4, 4.4, 1.5 Hz, 1 H), 3.15 (ddd,
Eur. J. Org. Chem. 2002, 3543Ϫ3551
3549

J. Cossy, O. Mirguet, D. G. Pardo, J.-R. Desmurs
FULL PAPER
J ϭ 11.0, 3.3, 1.5 Hz, 1 H), 3.07Ϫ2.85 (2 H), 2.48Ϫ2.31 (2 H), 1.64
(m, 1 H), 0.71 (d, J ϭ 6.6 Hz, 3 H), 0.70 (d, J ϭ 6.6 Hz, 3 H) ppm.
13C NMR: δ ϭ 171.5 (s), 162.0 (d, J ϭ 245.4 Hz), 137.1 (s), 135.2
(d, J ϭ 3.0 Hz), 129.6 (dd, J ϭ 7.9 Hz), 128.9 (d), 128.4 (d), 127.4
(d), 115.2 (dd, J ϭ 31.4 Hz), 70.6 (t), 62.0 (t), 61.0 (t), 59.6 (d),
55.4 (t), 52.8 (d), 50.0 (d), 27.4 (d), 18.7 (q) ppm. MS (EI): m/z
(relative intensity) ϭ 405 (1) [Mϩ·], 403 (3) [Mϩ·], 369 (14), 368
(56), 354 (39), 314 (11), 312 (31), 276 (25), 91 (100). HRMS (CIϩ,
CH4) calcd. for C23H2835ClFNO2 [M ϩ H]ϩ 404.1793, found
404.1788 and calcd. for C23H2837ClFNO2 [M ϩ H]ϩ 406.1773,
found 406.1765.
Acknowledgments
ˆ
The authors would like to thank RhoneϪPoulenc-Rhodia for fin-
ancial support and Dr. Marvin S. Yu (SmithKline Beecham)[17] for
1
providing us with the H NMR spectra of compound (Ϫ)-17. One
of us, O. M., thanks the MRET for a grant.
[1]
P. S. Watson, B. Jiang, B. Scott, Org. Lett. 2000, 2, 3679Ϫ3681.
M. J. Schneider, Alkaloids: Chemical and Biological Perspectives
[2]
(Ed.: S. W. Pelletier), Pergamon: Oxford, 1996, vol. 10, p.
155Ϫ299.
[3]
H. Takahata, T. Momose, The Alkaloids (Ed.: G. A. Cordell),
Academic Press: San Diego, 1993, vol. 44, p. 189Ϫ256.
[4]
Isobutyl
(3S,4R)-1-Benzyl-4-(4-fluorophenyl)piperidine-3-carb-
A. D. Elbein, R. J. Molyneux, Alkaloids: Chemical and Biolo-
gical Perspectives, (Ed.: S. W. Pelletier), Wiley: New York, 1987,
vol. 5, p. 1Ϫ54.
G. B. Fodor, B. Colasanti, Alkaloids: Chemical and Biological
Perspectives, (Ed.: S. W. Pelletier, Wiley: New York, 1985, vol.
3, p. 1Ϫ90.
T. H. Jones, M. S. Blum, Alkaloids: Chemical and Biological
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AIBN (3 mg, 0.02 mmol, 0.05 equiv.) were added to a solution of
(Ϫ)-15 (161 mg, 0.40 mmol) in toluene (2.10 mL). The resulting so-
lution was heated under reflux for 1.75 h and the toluene was evap-
orated. The crude product was then dissolved in CH2Cl2 (5 mL)
and washed with a saturated aqueous KF solution (3 ϫ 5 mL).
The resulting organic layer was dried over MgSO4, filtered, and
concentrated in vacuo. Purification by flash column chromato-
graphy on silica gel (pentane, then pentane/CH2Cl2, 96:4, then
pentane/Et2O, 80:20) afforded compound (Ϫ)-16 (105 mg,
0.28 mmol, 71% yield) as a colourless oil: Rf ϭ 0.48 (pentane/
diethyl ether, 80:20). [α]2D0 ϭ Ϫ5.6 (c ϭ 1.05, CHCl3). IR (neat):
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6.6 Hz, 1 H), 3.61 (s, 2 H), 3.59 (dd, J ϭ 10.7, 6.6 Hz, 1 H), 3.17
(ddd, J ϭ 11.0, 3.5, 1.5 Hz, 1 H), 3.02 (m, 1 H), 2.96Ϫ2.74 (2 H),
2.28 (dd, J ϭ 11.0, 10.7 Hz, 1 H,), 2.17 (m, 1 H), 1.85 (m, 2 H),
1.65 (m, 1 H), 0.71 (d, J ϭ 6.6 Hz, 6 H) ppm. 13C NMR: δ ϭ 173.2
(s), 161.6 (d, J ϭ 244.1 Hz), 139.2 (d, J ϭ 3.0 Hz), 138.0 (s), 129.0
(d), 128.7 (dd, J ϭ 7.3 Hz), 128.2 (d), 127.1 (d), 115.1 (dd, J ϭ
21.4 Hz), 70.3 (t), 62.9 (t), 56.1 (t), 53.5 (t), 49.5 (d), 44.7 (d), 33.3
(t), 27.4 (d), 18.7 (q) ppm. MS (EI): m/z (relative intensity) ϭ 369
(13) [Mϩ·], 296 (13), 279 (14), 278 (16), 268 (20), 232 (13), 146
(14), 132 (17), 120 (20), 119 (18), 91 (100). HRMS (EI) calcd. for
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2 equiv.) in THF (0.15 mL). The mixture was allowed to warm at
room temp. and stirred for 50 min before successive additions of
water (3 µL), aqueous NaOH (3.75 , 37 µL), and water (238 µL).
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under reduced pressure. Purification of the crude material by flash
column chromatography on silica gel (CHCl3/MeOH, 97:3) af-
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[20]
[21]
[22]
[23]
MeOH)]. IR (neat): ν˜ ϭ 3377, 1509, 1223, 833, 700 cmϪ1 1H
.
NMR: δ ϭ 7.41Ϫ7.23 (5 H), 7.17 (m, 2 H), 6.98 (m, 2 H), 3.63 (d,
J ϭ 13.2 Hz, 1 H), 3.56 (d, J ϭ 13.2 Hz, 1 H), 3.36 (dd, J ϭ 11.0,
2.2 Hz, 1 H), 3.28Ϫ3.11 (2 H), 2.98 (m, 1 H), 2.34 (m, 1 H),
2.12Ϫ1.92 (3 H), 1.91Ϫ1.69 (3 H) ppm. 13C NMR: δ ϭ 161.4 (d,
J ϭ 244.1 Hz), 140.1 (d, J ϭ 3.0 Hz), 137.9 (s), 129.3 (d), 128.8
(dd, J ϭ 7.9 Hz), 128.2 (d), 127.1 (d), 115.3 (dd, J ϭ 21.4 Hz), 63.9
(t), 63.4 (t), 57.2 (t), 53.8 (t), 44.2 (d), 44.1 (d), 34.4 (t) ppm. MS
(EI): m/z (relative intensity) ϭ 299 (27) [Mϩ·], 298 (24), 268 (19),
208 (19), 176 (20), 120 (39), 91 (100); CI (CH4): m/z (relative intens-
ity) ϭ 300 (100) [M ϩ Hϩ], 283 (5), 282 (28), 281 (4), 280 (15), 222
(3), 204 (3), 154 (3).
´
´
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J. Kreidl, L. Czibula, J. Deutschne, E. Werkne Papp, J. Nagyne
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