Asymmetric synthesis of 5-substituted pyrrolidinones via a chiral N-acyliminium equivalent

Article abstract of DOI:10.1016/S0957-4166(01)00195-1

5-Substituted pyrrolidinones 5 were synthesized in good yields and with fair to good diastereoselectivities from the chiral non-racemic oxazolopyrrolidinone 4. Various nucleophiles including cuprates, silanes and phosphites were used. The chiral induction

Full text of DOI:10.1016/S0957-4166(01)00195-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1219–1224
Asymmetric synthesis of 5-substituted pyrrolidinones via a chiral
N-acyliminium equivalent
Isabelle Baussanne,a Ange`le Chiaronia and Jacques Royera,b,
*
aInstitut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, F-91198 Gif-sur-Yvette, France
bLaboratoire de Chimie The´rapeutique, UMR 8638 associe´e au CNRS et a` l’Universite´ Rene´ Descartes, Faculte´ de Pharmacie,
4 avenue de l’Observatoire, 75270 Paris cedex, France
Received 4 April 2001; accepted 27 April 2001
Abstract—5-Substituted pyrrolidinones 5 were synthesized in good yields and with fair to good diastereoselectivities from the
chiral non-racemic oxazolopyrrolidinone 4. Various nucleophiles including cuprates, silanes and phosphites were used. The chiral
induction is thought to arise from a chelated N-acyliminium species. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Since the methodology using silyloxypyrrole 3 is limited
to carbonyl compounds as the electrophile, we thought
it might be possible to increase the range of substituents
that could be introduced at C(5) by use of the ox-
azolopyrrolidinone 4, easily accessible from lactam 1
(vide infra). Compound 4 has been previously described
by Meyers et al.,10 who reported the nucleophilic addi-
tion of allylsilane to this compound as the unique
example of such an addition.10b We embarked on the
study of the reaction of various nucleophiles with 411
with the aim of extending the synthetic applications of
lactam 1.
The pyrrolidine ring system is a very important struc-
ture common to many naturally occurring and medici-
nally important compounds.1 It can also be used as a
chiral auxiliary,2 synthetic intermediate3 and as a com-
ponent of chiral ligands4 in synthesis. It thus seemed
pertinent to develop new asymmetric methods to con-
struct differently substituted pyrrolidines. In this
respect we have previously proposed the use of the
lactam 1 and its derivatives 2 and 3 as chiral precursors
for the asymmetric synthesis of various polysubstituted
pyrrolidines and pyrrolidinones (Fig. 1).6–9 Thus, 3-
alkylated pyrrolidinones have been obtained with excel-
lent diastereoselectivity by the alkylation of 15 or its
saturated homologue 2.6 Lactam 1 is also a precursor
of the chiral silyloxypyrrole 3 which permits substitu-
tion at C(5) through aldol-type condensation with achi-
ral aldehydes7 and imines.8 Furthermore, 1,4-addition
of cuprates to these aldol adducts afforded 4,5-disubsti-
Numerous examples of nucleophilic addition to chiral
N-acyliminium species derived from pyrrolidines have
been described. In most cases, the precursors used were
pyroglutamic acid12 or hydroxyproline,13 leading to the
formation of disubstituted pyrrolidines via endocyclic
chiral induction. On the other hand, examples of asym-
metric synthesis of mono-substituted pyrrolidines or
pyrrolidinones by nucleophilic attack on a chiral N-
acyliminium are rarer.10,14 It must be mentioned that,
tuted
pyrrolidinones
with
an
excellent
diastereoselectivity.9
Figure 1.
* Corresponding author. Fax: 33-(0)1 43291403; e-mail: jacques.royer@pharmacie.univ-paris5.fr
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00195-1

1220
I. Baussanne et al. / Tetrahedron: Asymmetry 12 (2001) 1219–1224
based on the examples found in the literature, the
diastereoselectivity of addition can be opposite depend-
ing on the use of p or s nucleophiles.12c
was required to establish the configuration of 6a.
Indeed 6a was found to be identical to the cyano-lac-
tam obtained by anodic oxidation of cyano-oxazolidine
11 (Scheme 2).15 The relative configuration of the latter
was deduced from NOE experiments.
2. Results and discussion
The bicyclic lactam 4 was synthesized by acidic treat-
ment of the chiral lactam 1 (prepared in one step from
(R)-(−)-phenylglycinol in 75% yield).5 Several proce-
dures were successfully applied (i.e. PTSA or HCl–
H2O–CH2Cl2), of which the best involved the treatment
of lactam 1 in CH2Cl2 solution with Amberlyst-15 at rt
Scheme 2.
for
3 h, affording 4 in quantitative yield. The
diastereoselectivity of the cyclization is total and the
newly formed stereogenic center has the same configu-
ration as that previously reported by Meyers et al.10a
(Scheme 1).
For the phosphonate 7a, the configuration of the newly
created stereogenic center was established by X-ray
crystallographic analysis (Fig. 3).
Scheme 1.
We first reproduced the reported10b addition of allylsi-
lane to 4 in the presence of titanium tetrachloride in
dichloromethane at room temperature. Using the same
conditions, trimethylsilylcyanide and trimethylphos-
phite were found to add to oxazolidine 4 to give
a-cyano and a-phosphono pyrrolidinones 6 and 7 with
good diastereoselectivity and yield (Table 1).
Table 1. Addition of nucleophiles to 4 in CH2Cl2 and in
the presence of 1 equiv. of TiCl4
Nucleophile
Product
Yield (%)
dea
Allylsilane
TMSCN
P(OMe)3
5
6
7
83
89
86
74b
80
62
Figure 3.
Alkyl chains may be introduced onto acyliminium
derivatives through lower order cuprates complexed
with BF3·OEt2 (Scheme 3).12c In our case, the best
results were obtained in THF with cuprates generated
from CuBr·Me2S, at rt. Simple alkyl groups (Me, Bu)
were easily introduced in good yield and selectivity
(Table 2) through cuprate addition in THF at −78°C
followed by stirring at rt for 12 h. The phenyl group
a Determined by 1H NMR analysis of the crude reaction mixture.
b The same experiment was reported with 92% yield and 80% de.10b
In each case the mixtures could be easily separated by
simple flash chromatography. The relative configura-
tion of the major isomer of these new pyrrolidinone
derivatives corresponds to that depicted in Fig. 2. Lac-
tam 5a10b is a known compound. Chemical correlation
Figure 2.

I. Baussanne et al. / Tetrahedron: Asymmetry 12 (2001) 1219–1224
1221
Scheme 3.
Table 2. Addition of organocuprates to 4 in the presence
of BF3·OEt2
Nucleophile
Solvent
Product
Yield (%)
dea
MeCu
nBuCu
nBuCu
PhCu
THF
THF
Et2O
THF
8
9
9
85
95
38
32
76
74
–
10
75
Figure 4.
a Determined by 1H NMR analysis of the crude reaction mixture.
was added with good stereoselectivity but in poor yield
using this method (Table 2).
3. Experimental
All starting materials were commercially available and
purified following standard techniques. THF was
freshly distilled from sodium benzophenone ketyl,
methanol from magnesium iodine and dichloromethane
from P2O5. Product purification was performed by flash
chromatography on silica gel (Merck art. 9305). Spe-
cific rotations were measured at room temperature on a
Perkin–Elmer 241 polarimeter. NMR spectra were
recorded on Bruker AC-300, AC-250 or AC-200 instru-
ments using Me4Si as internal standard. Mass spectra
were recorded on AEI MS-9 (CI; isobutane) or AEI
MS-50 (EI) instruments. Elemental analyses were per-
formed by the microanalysis laboratory at the Institut
de Chimie des Substances Naturelles (Gif-sur-Yvette).
The use of higher order cuprates formed from CuCN
and complexed to BF3·OEt2 dramatically decreased the
yield of the reaction and no reaction occurred when
CuI was used to form the organometallic species. Fur-
thermore, slightly lower yields and/or selectivities were
observed at 0°C or if ether was used instead of THF as
solvent. The variations in diastereoselectivity as a func-
tion of experimental conditions have not yet been thor-
oughly studied.
It was important to determine the configuration of the
new stereogenic center obtained using this type of
nucleophile. This was done by chemical transformation
of the butyl pyrrolidinone 9a. The comparison of spec-
troscopic data for pyrrolidine 12 obtained by LiAlH4
reduction of pyrrolidinone 9a (Scheme 4) with those of
the known compound16 obtained from (R)-(−)-phenyl-
glycinol permitted assignment of the configuration of
the newly formed stereocenter of 9a as (5R).
3.1. (3R,7aS)-3-Phenyl-2,3,5,6,7,7a-hexahydro-
pyrrolo[2,1-b]oxazol-5-one 4
The a,b-unsaturated lactam 1 (720 mg, 3.54 mmol) was
dissolved in CH2Cl2 (20 mL) and Amberlyst-15 (1–2 g)
was added. The solution was stirred at rt for 3 h. The
pH was maintained below 6 during the course of the
reaction by addition of Amberlyst-15. The solution was
filtered and the solvent was evaporated. The oxazolopy-
rrolidin-2-one 4 was obtained without further purifica-
tion as a white solid (720 mg, 100%) identical in all
aspects (except specific rotation) with its enantiomer
described by Meyers. Compound 4: [h]D=−179 (c=1.3,
ethanol) (lit.:10a [h]D=+154 (c=1.29, ethanol)). Anal.
calcd for C12H13NO2: C, 70.92; H, 6.45; N, 6.89.
Found: C, 71.11; H, 6.59; N, 7.04%.
Scheme 4.
In summary, we have shown a new reactivity of lactam
1, which through oxazolidine 4, permits diastereoselec-
tive substitution at C(5) of the pyrrolidin-2-one ring. It
is noteworthy that both s and p nucleophiles under
different experimental conditions underwent nucleo-
philic approach on the same face of the pyrrolidine.
The mechanism of the reaction may involve
acyliminium intermediate I (Fig. 4) arising from 4
under Lewis acid conditions or an SN2-like reaction
through partial opening of the oxazolidine ring.10c
3.2. General procedure for nucleophilic addition to the
oxazolopyrrolidin-2-one 4
Method A: The bicyclic lactam 4 was dissolved in dry
CH2Cl2 (0.10 mmol/mL) under an argon atmosphere
and the solution was cooled to −78°C. The nucleophile
(3 equiv.) was added to the solution via a syringe,

1222
I. Baussanne et al. / Tetrahedron: Asymmetry 12 (2001) 1219–1224
followed by TiCl4 (1.5 equiv.). The solution was
warmed to rt and, after completion of the reaction
(TLC), was treated with saturated aqueous NaHCO3
and then extracted twice with CH2Cl2. The organic
layers were dried over Na2SO4 then the solvent was
evaporated in vacuo. The crude product was purified by
flash chromatography on silica gel.
trimethylsilylcyanide (0.39 mL; 2.92 mmol) as nucleo-
phile. The reaction time was 2.5 h. Flash chromatog-
raphy (AcOEt–heptane: 9/1) of the crude reaction mix-
ture afforded the major diastereomer 6a (179 mg, 80%)
as a white amorphous solid and the minor diastereomer
6b (20 mg, 9%).
1
Major diastereomer 6a: [h]D=−46 (c=2.4, CH2Cl2); H
NMR (300 MHz, CDCl3): l (ppm)=7.35 (5H, m), 4.86
(1H, dd, 3.9, 8.1 Hz), 4.34 (1H, dd, 3.9, 8.0 Hz), 4.24
(1H, dd, 8.1, 12.4 Hz), 4.05 (1H, dd, 4.0, 12.4 Hz), 3.8
(1H, sl), 2.73 (1H, td, 9.2, 16.9 Hz), 2.54 (1H, ddd, 4.7,
8.6, 17.0 Hz), 2.38 (2H, m); 13C NMR (62.5 MHz,
CDCl3): l (ppm)=175.4, 135.6, 128.9, 128.6, 127.6,
117.5, 62.2, 60.5, 47.8, 30.0, 24.5; MS (IC; isobutane):
m/z=231 (MH+), 204 (MH+−HCN), 111 (MH+−
PhCHꢀCHOH). Anal. calcd for C13H14N2O2: C, 67.81;
H, 6.13; N, 12.16. Found: C, 67.82; H, 6.32; N, 11.99%.
Method B: The cuprate was prepared by stirring the
organolithium reagent (3 equiv.) and CuBr·Me2S (3
equiv.) for 20 min in dry THF under an argon atmo-
sphere at −40°C. The solution was cooled to −78°C,
then 3 equiv. of BF3·OEt2 and a solution of 4 (1 equiv.)
in dry THF (0.3 mmol/mL) were added and the temper-
ature was allowed to rise to rt. After completion of the
reaction, the mixture was treated with a saturated
solution of NH4Cl and a concentrated solution of
ammonia (2/1). After stirring for 15 min the mixture
was extracted with CH2Cl2 (3×). The combined organic
layers were dried over MgSO4 and the solvent was
removed in vacuo. The crude product was purified by
flash chromatography on silica gel.
Minor diastereomer 6b: 1H NMR (200 MHz, CDCl3): l
(ppm)=7.4 (5H, m), 5.35 (1H, dd, 4.1, 8.2 Hz), 4.40
(1H, m), 4.25 (1H, m), 4.15 (1H, dd, 3.8, 8.2 Hz), 2.8
(1H, td, 9.0, 16.9 Hz), 2.60 (1H, ddd, 4.6, 8.6, 17.0 Hz),
2.35 (3H, m); 13C NMR (50 MHz, CDCl3): l (ppm)=
175.0, 135.1, 129.4, 128.9, 128.1, 118.1, 61.8, 58.5, 46.6,
29.7, 25.1.
3.3. (5S)-Allyl-1-(2-hydroxy-(1%R)-phenylethyl)-pyrrol-
idin-2-one 5a
Method A was applied to 4 (222 mg, 1.09 mmol) with
allyltrimethylsilane (0.52 mL, 3.3 mmol) as nucleophile.
The reaction time was 2.5 h. Flash chromatography
(AcOEt–heptane: 4/1) of the crude reaction mixture
afforded the major diastereomer 5a (195 mg, 73%) as
an amorphous solid and the minor diastereomer 5b (27
mg, 10.3%).
3.5. [1-(2-Hydroxy-(1%R)-phenylethyl)-5-oxo-pyrrolidin-
(2R)-yl]-phosphonic acid dimethyl ester 7a
Method A was applied to 4 (1.03 g, 5.07 mmol) with
trimethylphosphite (1.79 mL, 5.21 mmol) as nucleo-
phile. The reaction time was 2 h. Flash chromatogra-
phy (CH2Cl2–MeOH: 97/3) of the crude reaction mix-
ture afforded the major diastereomer 7a as an
amorphous solid (1.11 g, 70%) and the minor
diastereomer 7b (253 mg, 16%).
Major diastereoisomer 5a: [h]D=+26 (c=1.1, CH2Cl2);
1H NMR (250 MHz, CDCl3): l (ppm)=7.3 (5H, m),
5.64 (1H, tdd, 7.2, 11.2, 16.0 Hz), 5.07 (2H, 2d, 10.9,
17.0 Hz), 4.87 (1H, dd, 6.3, 7.3 Hz), 4.64 (1H, dd, 4.0,
8.0 Hz), 4.26 (1H, ddd, 7.1, 8.0, 11.0 Hz), 4.01 (1H,
ddd, 4.0, 6.0, 11.0 Hz), 3.55 (1H, ddd, 3.7, 7.7, 11.6
Hz), 2.52 (1H, td, 8.9, 17.3 Hz), 2.37 (1H, ddd, 5.0, 9.6,
17.1 Hz), 1.95–2.25 (3H, m), 1.8 (1H, ddd, 4.7, 9.2, 17.8
Hz); 13C NMR (62.5 MHz, CDCl3): l (ppm)=176.7,
137.5, 132.5, 128.4, 127.5, 127.1, 118.5, 63.1, 60.8, 58.0,
37.0, 30.7, 23.4; MS (IC; isobutane): m/z=246 (MH+),
204 (MH+−CH2ꢀCHCH2), 126 (MH+−PhCHꢀCHOH).
Anal. calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71.
Found: C, 73.16; H, 7.89; N, 5.61%.
1
Major diastereomer 7a: [h]D=−40 (c=1, CHCl3); H
NMR (250 MHz, CDCl3): l (ppm)=7.3 (5H, m), 4.85
(1H, dd, 3.3, 7.9 Hz), 4.57 (1H, dd, 6.6, 7.8 Hz), 4.32
(1H, ddd, 7.7, 8.0, 12.5 Hz), 4.00 (1H, ddd, 3.4, 6.2,
12.4 Hz), 3.83+3.79 (2×3H, 2d, 10.5 Hz), 2.75 (1H, td,
10.5, 17.4 Hz), 2.45 (1H, m), 2.3 (2H, m); 13C NMR
(75.3 MHz, CDCl3): l (ppm)=177.0, 137.2, 128.9,
128.1, 127.3, 64.9, 64.1, 56.0 (d, 160 Hz), 53.8+52.9 (2d,
8 Hz), 31.3, 21.4; MS (IC; isobutane): m/z=314 (MH+),
282 (MH+−CH2OH), 203 (MH+−PO(OMe)2), 194
(MH+−PhCHꢀCHOH). Anal. calcd for C14H20NO5P:
C, 53.67; H, 6.43; N, 4.47. Found: C, 53.44; H, 6.33; N,
4.41%.
Minor diastereomer 5b: 1H NMR (250 MHz, CDCl3): l
(ppm)=7.3 (5H, m), 5.55 (1H, tdd, 7.0, 10.3, 17.0 Hz),
5.0 (2H, 2d, 10.3, 17.0 Hz), 4.76 (1H, dd, 4.4, 7.8 Hz),
4.25 (1H, m), 4.08 (1H, m), 3.9 (1H, m), 3.58 (1H, ddd,
3.7, 8.1, 12.1 Hz), 2.57 (1H, ddd, 8.3, 9.3, 17.2 Hz), 2.42
(1H, ddd, 5.2, 9.7, 17.1 Hz), 2.25 (1H, m), 1.95–2.17
(2H, m), 1.8 (1H, m); 13C NMR (62.5 MHz, CDCl3): l
(ppm)=177.3, 137.7, 133.0, 128.7, 127.9, 118.7, 64.6,
61.9, 60.9, 39.2, 30.8, 24.0.
Crystallographic data: Colorless crystal of 0.30×0.30×
0.35 mm. C14H20NO5P, Mw=313.28. Monoclinic sys-
tem, space group P21, Z=2, a=6.374(4), b=8.026(6),
3
,
,
c=15.115(8) A, i=95.05 (2)°, V=770.2 A , dc=1.351
−3
,
g cm , F(000)=332, u (Mo Kh)=0.71073 A, v=0.20
mm−1; 10585 data measured (−55h55, −95k59,
−175l517) with a Nonius Kappa-CCD area-detector
diffractometer, of which 1912 reflections were unique
and 1766 observed having I]2|(I).
3.4. 1-(2-Hydroxy-(1%R)-phenylethyl)-5-oxo-pyrrolidin-
(2S)-carbonitrile 6a
The structure was solved with SHELXS8617 and
refined with SHELXL93.17 H atoms riding. Refinement
Method A was applied to 4 (198 mg, 0.975 mmol) with

I. Baussanne et al. / Tetrahedron: Asymmetry 12 (2001) 1219–1224
1223
converged to R1(F)=0.0376 for the 1766 observed
reflections and wR2(F2)=0.0949 for all the 1912 data,
phous solid (1.188 g, 84%); the minor diastereomer 9b
(172 mg, 12%) was also obtained.
goodness-of-fit S=1.067. Residual electron density
between −0.25 and 0.15 e A . In the crystal, the
−3
1
,
Major diastereomer 9a: [h]D=+32 (c=2, CH2Cl2); H
molecules are linked in chains along the a axis direction
through hydrogen bonds established between the
hydroxyl groups O(8)-H and the oxygen atoms O(17)
NMR (300 MHz, CDCl3): l (ppm)=7.3 (5H, m), 4.75
(1H, sl), 4.5 (1H, dd, 3.5, 7.9 Hz), 4.25 (1H, dd, 7.9,
12.2 Hz), 3.98 (1H, dd, 3.6, 12.2 Hz), 3.4 (1H, m), 2.54
(1H, td, 8.5, 17.1 Hz), 2.43 (1H, ddd, 5.6, 9.6, 17.1 Hz),
2.09 (1H, m), 1.75 (1H, m), 1.6 (1H, m), 1.1–1.4 (5H,
m), 0.9 (3H, t, 6.6 Hz); 13C NMR (75.3 MHz, CDCl3):
l (ppm)=176.9, 137.6, 128.7, 128.5, 66.0, 61.7, 59.2,
32.2, 31.2, 26.6, 24.1, 22.2, 13.9; MS (IC; isobutane):
m/z=262 (MH+), 142 (MH+−PhCHꢀCHOH). Anal.
calcd for C16H23NO2: C, 73.53; H, 8.87; N, 5.36.
Found: C, 73.21; H, 8.87; N, 5.11%.
,
(distances O(8)···O(17)=2.744, HO(8)···O(17)=1.83 A,
angle OꢁHꢁO=167.7°). Full crystallographic results
have been deposited as supplementary material (CIF
file) at the Cambridge Crystallographic Data Centre,
UK.
Minor diastereomer 7b: 1H NMR (250 MHz, CDCl3): l
(ppm)=7.35 (5H, m), 5.25 (1H, dd, 4.6, 9.0 Hz), 4.38
(1H, dd, 9.1, 11.9 Hz), 4.20 (1H, dd, 4.6, 11.9 Hz), 3.78
(1H, dd, 10.5, 15.7 Hz), 3.64+3.72 (2×3H, 2d, 10.6 Hz),
2.65 (1H, ddd, 1.4, 11.7, 16.7 Hz), 2.0–2.4 (3H, m); 13C
NMR (75.3 MHz, CDCl3): l (ppm)=178.2, 136.5,
128.6, 128.1, 127.9, 62.5, 60.4, 54.3 (d, 162 Hz), 53.8+
52.8 (2d, 8 Hz), 30.4, 22.6.
Minor diastereomer 9b: 1H NMR (300 MHz, CDCl3): l
(ppm)=7.45 (5H, m), 4.87 (1H, m), 4.38 (1H, m), 4.22
(2H, m), 3.63 (1H, m), 2.68 (1H, ddd, 7.6, 9.4, 17.1 Hz),
2.56 (1H, ddd, 5.8, 9.7, 17.0 Hz), 2.27 (1H, m), 1.86
(1H, m), 1.65 (1H, m), 1.05–1.45 (5H, m), 0.9 (3H, t,
6.6 Hz); 13C NMR (62.5 MHz, CDCl3): l (ppm)=
176.8, 137.8, 128.4, 127.7, 127.5, 63.4, 61.4, 61.2, 34.2,
30.9, 26.6, 24.1, 22.3, 13.8.
3.6. 1-(2-Hydroxy-(1%R)-phenylethyl)-(5R)-methyl-
pyrrolidin-2-one 8a
3.8. 1-(2-Hydroxy-(1%R)-phenylethyl)-(5R)-phenyl-pyrrol-
Method B was applied to 4 (215 mg, 1.06 mmol) with
methylcuprate (from 3.18 mL of 1 M MeLi in THF and
654 mg of CuBr·Me2S). The reaction time was 12 h.
After purification (CH2Cl2–MeOH: 97/3), the major
diastereomer 8a was obtained pure as an oil (174 mg,
75% yield) and the minor diastereomer 8b (22.5 mg,
9.7%) was also isolated.
idin-2-one 10a
Method B was applied to 4 (223 mg, 1.1 mmol) with
phenylcuprate (from 1.65 mL of 2 M PhLi and 678 mg
of CuBr·Me2S). The reaction time was 12 h. After
purification (AcOEt–heptane: 4/1), the major
diastereomer 10a (87 mg, 28%) was obtained pure as a
yellow oil. The minor diastereomer 10b (11 mg, 3.7%)
was also isolated.
1
Major diastereomer 8a: [h]D=+86 (c=1.4, CH2Cl2); H
NMR (200 MHz, CDCl3): l (ppm)=7.3 (5H, m), 4.9
(1H, dd, 6.5, 7.4 Hz), 4.57 (1H, dd, 3.7, 7.7 Hz), 4.23
(1H, ddd, 7.3, 7.7, 11.9 Hz), 4.01 (1H, ddd, 4.0, 6.0,
12.0 Hz), 3.55 (1H, qd, 6.2, 12.6 Hz), 2.48 (2H, m), 2.16
(1H, m), 1.62 (1H, m), 1.12 (3H, d, 6.3 Hz); 13C NMR
(62.5 MHz, CDCl3): l (ppm)=176.4, 137.5, 128.4,
127.5, 127.1, 63.4, 60.8, 54.5, 30.6, 26.7, 19.5; MS (IC;
isobutane): m/z=220 (MH+), 202 (MH+−H2O), 100
(MH+−PhCHꢀCHOH). Anal. calcd for C13H17NO2: C,
71.21; H, 7.81; N, 6.39. Found: C, 71.01; H, 8.02; N,
5.87%.
Major diastereomer 10a: [h]D=+11 (c=0.7, CH2Cl2);
1H NMR (250 MHz, CDCl3): l (ppm)=7.05–7.4 (10H,
m), 4.87 (1H, dd, 6.1, 7.9 Hz), 4.4 (1H, dd, 5.5, 8.1 Hz),
4.18 (1H, ddd, 7.8, 8.1, 11.9 Hz), 4.07 (1H, dd, 1.9, 9.2
Hz), 3.93 (1H, ddd, 5.2, 6.3, 12.0 Hz), 2.68 (1H, dd, 7.1,
9.5 Hz), 2.59 (1H, dd, 6.4, 9.4 Hz), 2.42 (1H, m), 1.97
(1H, m); 13C NMR (62.5 MHz, CDCl3): l (ppm)=
177.4, 140.6, 137.3, 129.1, 128.2, 128.1, 127.8, 127.4,
126.6, 64.2, 63.9, 62.9, 31.3, 28.8; MS (IC; isobutane):
m/z=282 (MH+), 162 (MH+−PhCHꢀCHOH). Anal.
calcd for C18H19NO2: C, 76.84; H, 6.81; N, 4.98.
Found: C, 76.25; H, 7.11; N, 4.62%.
Minor diastereomer 8b: 1H NMR (200 MHz, CDCl3): l
(ppm)=7.3 (5H, m), 4.77 (1H, dd, 4.5, 7.1 Hz), 4.12
(3H, m), 3.64 (1H, qd, 6.4, 12.8 Hz), 2.55 (1H, dd, 7.6,
9.2 Hz), 2.48 (1H, dd, 6.3, 9.2 Hz), 2.20 (1H, m), 1.62
(1H, m), 1.07 (3H, d, 6.3 Hz); 13C NMR (75.3 MHz,
CDCl3): l (ppm)=176.9, 137.9, 128.6, 127.8, 127.3,
64.4, 61.4, 56.9, 30.8, 27.6, 21.7.
1
Minor diastereomer 10b: H NMR (250 MHz, CDCl3):
l (ppm)=7.05–7.4 (10H, m), 5.10 (1H, m), 4.4 (1H, dd,
5.4, 14.0 Hz), 3.82 (1H, m), 3.75 (1H, m), 2.8 (1H, m),
2.55 (1H, m), 2.40 (1H, m), 1.90 (1H, m); 13C NMR
(75.3 MHz, CDCl3): l (ppm)=175.7, 142.5, 135.7,
128.7, 128.5, 127.9, 127.5, 126.8, 126.6, 63.2, 60.0, 30.1,
29.2.
3.7. (5R)-Butyl-1-(2-hydroxy-(1%R)-phenylethyl)-pyrrol-
idin-2-one 9a
Method B was applied to 4 (1.10 g, 5.42 mmol) with
butylcuprate (from 10.2 mL of 1.6 M BuLi in hexanes
and 654 mg of CuBr·Me2S). The reaction time was 12
h. After purification (CH2Cl2–MeOH: 97.5/2.5), the
major diastereomer 9a was obtained pure as an amor-
3.9. ((2S)-Butyl-pyrrolidin-1-yl)-(1%R)-phenyl-ethan-2-ol
12
The lactam 9a (288 mg, 1.10 mmol) was dissolved in
dry THF (5 mL) under an argon atmosphere; LiAlH4
(125 mg; 3.31 mmol) was slowly added to the solution

1224
I. Baussanne et al. / Tetrahedron: Asymmetry 12 (2001) 1219–1224
which was stirred at rt for 18 h. The mixture was cooled
to 0°C then aqueous HCl (1N, 10 mL) was added
dropwise and the solution was stirred for a further 30
min. After extraction with CH2Cl2, the organic layer
was washed with aqueous NaOH (1N) and further
washed with brine and then concentrated in vacuo. The
crude product was purified by flash chromatography
(CH2Cl2–MeOH: 95/5). The pyrrolidine 12 was
obtained as a colorless oil in 80% yield. Analytical data
are identical with those reported in the literature,16
indicating the same relative stereochemistry and thus
the same absolute configuration, since both products
were prepared from (R)-(−)-phenylglycinol. Neverthe-
less, a difference was observed in the specific rotation:
[h]D=−129 (c=2.5, CH2Cl2) (lit.15 [h]D=−123.3 (c=2,
CH2Cl2)). Anal. calcd for C16H25NO: C, 77.68; H,
10.19; N, 5.66. Found: C, 76.75; H, 10.19; N, 5.46%.
Pichon, M.; Figade`re, B.; Cave´, A. Tetrahedron Lett.
1997, 38, 2259–2262.
8. (a) Dudot, B.; Royer, J.; Sevrin, M.; George, P. Tetra-
hedron Lett. 2000, 41, 4367–4371; (b) Dudot, B.; Chia-
roni, A.; Royer, J. Tetrahedron Lett. 2000, 41, 6355–6358.
9. Baussanne, I.; Royer, J. Tetrahedron Lett. 1998, 39, 845–
848.
10. In the following publications, the (+)-enantiomer of 4 was
described and used: (a) Meyers, A. I.; Lefker, B. A.;
Sowin, T. L.; Westrum, L. J. J. Org. Chem. 1989, 54,
4243–4246; (b) Meyers, A. I.; Burgess, L. E. J. Org.
Chem. 1991, 56, 2294–2296; (c) Burgess, L. E.; Meyers,
A. I. J. Am. Chem. Soc. 1991, 113, 9858–9859; (d)
Westrum, L. J.; Meyers, A. I. Tetrahedron Lett. 1994, 35,
973–976; (e) Meyers, A. I.; Brengel, G. P. Chem. Com-
mun. 1997, 1–8.
11. Piperidine homologue of 4 has been reported and studied:
(a) Royer, J.; Husson, H.-P. Heterocycles 1993, 36, 1493–
1496; (b) Micouin, L.; Quirion, J.-C.; Husson, H.-P.
Synth. Commun. 1996, 26, 1605–1611; (c) Amat, M.; Lior,
N.; Bosch, J.; Solans, X. Tetrahedron 1997, 53, 719–730.
12. (a) Ce´limene, C.; Dhimane, H.; Le Bail, M.; Lhommet,
G. Tetrahedron Lett. 1994, 35, 6105–6106; (b) Skrinjar,
M.; Wistrand, L.-G. Tetrahedron Lett. 1990, 31, 1775–
1778; (c) Wistrand, L.-G.; Skrinjar, M. Tetrahedron 1991,
47, 573–582.
13. (a) Renaud, P.; Seebach, D. Helv. Chim. Acta 1986, 69,
1704–1710; (b) Thaning, M.; Wistrand, L.-G. J. Org.
Chem. 1990, 55, 1406–1408; (c) Thaning, M.; Wistrand,
L.-G. Acta Chem. Scand. 1989, 43, 290–295; (d) Thaning,
M.; Wistrand, L.-G. Acta Chem. Scand. 1992, 46, 194–
199.
References
1. (a) Martin, S.F. In The Alkaloids; Brossi, A., Ed.; Aca-
demic Press: Orlando, 1987; Vol. 30, Chapter 3; (b)
Elbein, A.; Molyneux, R. I. In Alkaloids, Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New
York, 1990; Vol. 5, pp. 1–54; (c) Numata, A.; Ibuka, T.
In: The Alkaloids; Brossi, A., Ed.; Academic Press: NY,
1987; Vol. 31, Chapter 6; (d) Ohfune, Y.; Tomita, M. J.
Am. Chem. Soc. 1982, 104, 3511–3513; (e) Johnson, R.
L.; Koerner, J. F. J. Med. Chem. 1988, 31, 2057–2066; (f)
Pu¨schl, A.; Boesen, T.; Zuccarello, G.; Dahl, O.; Pitsch,
S.; Nielsen, P. E. J. Org. Chem. 2001, 66, 707–712.
2. (a) Huryn, D. M. In Comprehensive Organic Synthesis;
Trost, B. M.; Fleming, I., Eds.; Oxford: Pergamon, 1991;
Vol. 1, p. 64; (b) Whitesell, J. K. Chem. Rev. 1989, 89,
1581–1590.
14. (a) Kim, M. Y.; Starrett, J. E.; Weinreb, S. M. J. Org.
Chem. 1981, 46, 5383–5389; (b) Suzuki, H.; Aoyagi, S.;
Kibayashi, C. Tetrahedron Lett. 1994, 35, 6119–6121; (c)
Polniaszek, R. P.; Belmont, S. E.; Alvarez, R. J. Org.
Chem. 1990, 55, 215–223; (d) Sato, K.; Koga, T.;
Masuya, K.; Tanino, K.; Kuwajima, I. Synlett 1996,
751–752; (e) Allin, S. M.; Northfield, C. J.; Page, M. I.;
Slawin, A. M. Z. J. Chem. Soc., Perkin Trans. 1 2000,
1715–1721.
3. (a) Arseniyadis, S.; Huang, P. Q.; Piveteau, D.; Husson,
H.-P. Tetrahedron 1988, 44, 2457–2470; (b) Yoda, K.;
Kitayama, H.; Katagiri, T.; Takabe, K. Tetrahedron
1992, 48, 3313–3322; (c) Hamada, Y.; Hara, O.; Kawai,
A.; Kohno, Y.; Shioiri, T. Tetrahedron 1991, 47, 8635–
8652.
15. Billon-Souquet, F.; Martens, T.; Royer, J. Tetrahedron
1996, 52, 15127–15136 (in this paper, the relative configu-
ration of the starting cyano oxazolidine 11 was unknown
and in fact corresponded to that of epimeric material).
16. Burgess, L. E.; Meyers, A. I. J. Org. Chem. 1992, 57,
1656–1662.
17. (a) Sheldrick, G. M. SHELXS86, Acta Crystallogr. A
1990, 46, 467–473; (b) Sheldrick, G. M. SHELXL93,
Program for the Refinement of Crystal Structures; Univer-
sity of Go¨ttingen: Germany, 1993.
4. (a) Rigo, B.; Lespagnol, C.; Pauly, M. J. Heterocyclic
Chem. 1988, 25, 49–57; (b) Corey, E. J.; Yuen, P.-W.;
Hannon, F. J.; Wierda, D. A. J. Org. Chem. 1990, 55,
784–786.
5. Baussanne, I.; Chiaroni, A.; Husson, H.-P.; Riche, C.;
Royer, J. Tetrahedron Lett. 1994, 35, 3931–3934.
6. Baussanne, I.; Travers, C.; Royer, J. Tetrahedron: Asym-
metry 1998, 9, 797–804.
7. (a) Baussanne, I.; Royer, J. Tetrahedron Lett. 1996, 37,
1213–1316; (b) Baussanne, I.; Schwardt, O.; Royer, J.;
.