Synthesis of chiral 1,5-disubstituted pyrrolidinones via electrophile-induced cyclization of 2-(3-butenyl)oxazolines derived from (1R,2S)- and (1S,2R)-norephedrine

Article abstract of DOI:10.1016/j.tetasy.2006.11.006

Starting from (1R,2S)- and (1S,2R)-norephedrine, enantiomers of the corresponding 2-(3-butenyl)oxazolines were prepared in a two-step process. The cyclization of the intermediate alkenylamides with phenylselenyl bromide afforded cyclic imidates instead of the expected pyrrolidinones. The electrophile-induced cyclizations of 2-alkenyloxazolines with bromine or iodine produced diastereomeric mixtures of chiral 1,5-disubstituted pyrrolidinones. The ring closure of the all-cis (1R,2S,5R)-diastereomer 7 with NaH resulted in the tetrahydropyrrolo[2,1-b]oxazol-5-one derivative 18, which was alternatively prepared by the cyclocondensation of (1R,2S)-norephedrine with levulinic acid.

Full text of DOI:10.1016/j.tetasy.2006.11.006

Tetrahedron: Asymmetry 17 (2006) 2857–2863
Synthesis of chiral 1,5-disubstituted pyrrolidinones via
electrophile-induced cyclization of 2-(3-butenyl)oxazolines
derived from (1R,2S)- and (1S,2R)-norephedrine
a,c
Ivan Kanizsai, Zsolt Szakonyi,a Reijo Sillanpa¨a¨,b Matthias D’hooghe,c
´
Norbert De Kimpec,* and Ferenc Fulopa,*
¨ ¨
aInstitute of Pharmaceutical Chemistry, University of Szeged, PO Box 427, H-6701 Szeged, Hungary
bDepartment of Chemistry, University of Jyva¨skyla¨, PO Box 35, 40351 Jyva¨skyla¨, Finland
cDepartment of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
Received 24 July 2006; accepted 6 November 2006
Abstract—Starting from (1R,2S)- and (1S,2R)-norephedrine, enantiomers of the corresponding 2-(3-butenyl)oxazolines were prepared in
a two-step process. The cyclization of the intermediate alkenylamides with phenylselenyl bromide afforded cyclic imidates instead of the
expected pyrrolidinones. The electrophile-induced cyclizations of 2-alkenyloxazolines with bromine or iodine produced diastereomeric
mixtures of chiral 1,5-disubstituted pyrrolidinones. The ring closure of the all-cis (1R,2S,5R)-diastereomer 7 with NaH resulted in the
tetrahydropyrrolo[2,1-b]oxazol-5-one derivative 18, which was alternatively prepared by the cyclocondensation of (1R,2S)-norephedrine
with levulinic acid.
ꢀ 2006 Published by Elsevier Ltd.
1. Introduction
pharmacologically active compounds.9–11 c-Lactams allow
further transformations into various bicyclic lactams
possessing the nitrogen atom at the bridgehead. Similar
bicyclic compounds could also be synthesized with high
chemo- and diastereoselectivity by the condensation of
1,2-aminoalcohols with c-oxoacids.12–14
The electrophile-induced cyclization of alkenylamides and
2-alkenyloxazolidines is of great interest since it allows
access to functionalized lactones or lactams, which are
known to be interesting synthons for natural product syn-
theses.1–7 The cyclization process can proceed in different
ways. Depending on the experimental conditions, lactones
or lactams can be formed with electrophilic reagents, the
most frequently used being iodine, bromine and arylselenyl
bromide derivatives. During the ring-closing process, an
onium moiety is formed through electrophilic attack on
the double bond, after which the nitrogen or oxygen atom
of the amide can induce cyclization. After N-attack, lac-
tams are produced, while O-attack furnishes imidates, the
hydrolysis of which leads to the corresponding lactones.
c-Lactams, for example, chiral 2-methyl-4-pyrrolidinones,
are appropriate reagents for the determination of the enan-
tiomeric composition of alcohols,8 or they can serve as
precursors for the total synthesis of natural products or
(1R,2S)- and (1S,2R)-norephedrine have found widespread
use for asymmetric synthesis as catalysts or starting mate-
rials. For example, their derivatives are excellent catalysts
for the enantioselective Mukaiyama–Michael and Diels–
Alder reactions.15 N-Benzyl-substituted norephedrine
derivatives are efficient ligands for chiral Ru(III)-catalysed
hydrogenation transfer to functionalized ketones.16 This
protocol can also be utilized for the asymmetric reduction
of ketimines and N-alkylketimines.17 N-Alkylation of nor-
ephedrines allows the synthesis of substituted piperidine
derivatives.18 Oxazolidines derived from norephedrine can
be formed by ring closure, using dehydrating agents under
thermal conditions,19 or condensation reactions with ace-
tals20 or ketoacids.21
*
Corresponding authors. Tel.: +32 92 645951; fax: +32 92 646243
(N.D.K.); tel.: +36 62 545564; fax: +36 62 545705 (F.F.); e-mail
addresses: norbert.dekimpe@Ugent.be; fulop@pharm.u-szeged.hu
One aim of the present research was to investigate the
electrophile-induced cyclizations of 2-alkenyl oxazolines
0957-4166/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2006.11.006

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I. Kanizsai et al. / Tetrahedron: Asymmetry 17 (2006) 2857–2863
derived from either (+)- or (ꢀ)-norephedrines, focusing on
the regio- and diastereoselectivity of the cyclization pro-
cess. A further goal was to study the transformation of
the resulting chiral pyrrolidinone derivatives to N-bridged
bicyclic heterocycles, for example, pyrrolo[2,1-c][1,4]oxa-
zine or pyrrolo[2,1-b]oxazole derivatives.
enesulfonic acid (PTSA), affording oxazoline derivatives 5
and 6 in good yields. In an alternative method, chiral oxaz-
olines 5 and 6 were obtained directly in one step by the
reaction of norephedrine and 4-pentenoic acid in toluene
at reflux in the presence of a catalytic amount of PTSA.
However, the yields of 2-oxazolines 5 and 6 were much
lower than in the two-step procedure. Treatment of 2-oxaz-
olines 5 and 6 with bromine in dichloromethane and then
with aqueous K2CO3, or with iodine in acetonitrile
followed by aqueous K2CO3, resulted in pyrrolidinones
7–14 as a 50:50 (X = Br) or 57:43 (X = I) mixture of diaste-
reomers (Schemes 1 and 2).
2. Results and discussion
Chiral 3-(3-butenyl)-1,3-oxazolidines 5 and 6 were synthe-
sized by two methods. The starting materials, (1R,2S)- 1
and (1S,2R)-norephedrine 2, were acylated with 4-pente-
noyl chloride22 in dichloromethane in the presence of tri-
ethylamine, resulting in amides 3 and 4. The ring closure
of the hydroxyamides 3 and 4 was performed by refluxing
in toluene in the presence of a catalytic amount of p-tolu-
Thus, (1R,2S)-norephedrine 1 and (1S,2R)-norephedrine 2
were transformed into the corresponding lactams 7, 8, 11
and 12 (from 1) and 9, 10, 13 and 14 (from 2) according
to a three-step protocol.
(R)
Ph
OH
Ph
OH
i
O
Me
NH2
(S)
Me
N
H
3
1
iii
ii
Ph
(R)
(S)
Ph
Me
OH
N
Ph
OH
N
X
X
(R) O
(R
)
iv or v
+
Me
N
(S)
Me
O
O
5
7
8
12
X = Br
X = I
11
(R
) O
Ph
(R) O
Ph
H2O
N
(S)
Me
N
X
(S)
Me
X
Scheme 1. Reaction conditions: (i) 4-pentenoyl chloride (1 equiv), Et3N (1.1 equiv), CH2Cl2, 0 ꢁC, 3 h, N2, 90%; (ii) toluene, PTSA, 48 h reflux, 86%; (iii)
3-butenoic acid (1 equiv), toluene, PTSA, reflux, 3 days, 43%; (iv) Br2 (1.1 equiv), K2CO3, CH2Cl2/H2O, 0 ꢁC, 2.5 h, 56%, diastereomer ratio: 50:50 (7:8);
(v) I2 (3 equiv), MeCN, ꢀ20 ꢁC, 2 h, then Na2S2O5, K2CO3, 0 ꢁC, 0.5 h, 77%, diastereomer ratio: 57:43 (11:12).
(S)
(S)
Ph
OH
Ph
OH
i
O
Me (R
)
NH2
(R)
Me
N
H
2
4
iii
ii
(S
)
Ph
Me
OH
N
Ph
OH
N
X
X
Ph (S
)
O
N
6
iv or v
(S
)
+
(R)
Me
(R
)
Me
O
O
9
13
10
14
X = Br
X = I
Scheme 2. Reaction conditions: see in Scheme 1. (i) 57%; (ii) 83%; (iii) 45%; (iv) 53% diastereomer ratio: 50:50 (9:10); (v) 74%, diastereomer ratio: 57:43
(13:14).

I. Kanizsai et al. / Tetrahedron: Asymmetry 17 (2006) 2857–2863
2859
The electrophile-induced cyclization of 2-(3-butenyl)oxazo-
lines 5 and 6 was highly regioselective but less diastereo-
selective, and only the formation of the five-membered ring
product was observed. Diastereoisomeric c-lactams 7 and
8 were easily separated by column chromatography, result-
ing in one isomer in a crystalline form suitable for X-ray
diffraction analysis. Accordingly, this X-ray diffraction
analysis revealed that c-lactam 7 was (R)-5-bromomethyl-
1-[(1R,2S)-1-hydroxy-1-phenylpropan-2-yl]pyrrolidin-2-one
intramolecular hydrogen bond between the OH of the
alcohol group and the oxygen of the carbonyl group
(OHꢁ ꢁ ꢁO = 2.668(3) A).
˚
The cyclization of (4S,5R)-2-oxazoline
5 was also
attempted with phenylselenyl bromide in dichloromethane.
However, only an inseparable mixture of compounds was
obtained. Under similar conditions, intermediate amide 3
underwent an electrophile-induced lactonization instead
of the expected lactamization.1 Iminolactone 15 obtained
decomposed during chromatographic purification on silica
gel. When 15 was stirred with SiO2 in dichloromethane, the
known23 racemic lactone 16 was obtained in 95% yield
(Scheme 3).
1
(Fig. 1). The diastereomeric ratio was determined by H
NMR, while the relative stereochemistry of product 8
was established by NOESY.
The attempted synthesis of pyrrolo[2,1-c][1,4]oxazines 17
(Scheme 5) from c-lactams 7 and 11 by cyclization with
bases, such as NaOMe or NaH, failed. The latter bicyclic
morpholines 17 could be suitable precursors of stereo-
defined 2,3,5-trisubstituted morpholines. Such compounds
have received considerable interest in recent years.24 How-
ever, c-lactams 7 and 11 underwent ring closure to yield
pyrrolo[2,1-b]oxazol-5-one 18 in a diastereoselective fash-
ion instead of the expected pyrrolo[2,1-c][1,4]oxazine 17
(Scheme 4).
Bicyclic compound 18 was prepared in 80% yield by an
alternative synthesis via tandem cyclization of (1R,2S)-nor-
ephedrine with levulinic acid (Scheme 4). This reaction is
highly stereoselective as only a single diastereomer was
detected in the crude reaction mixture. The stereochemical
outcome of this cyclization was also correlated with the
findings of Meyers and Burgess.25–27 The first step in the
cyclocondensation process is the reaction of norephedrine
Figure 1. X-ray diffraction structure of pyrrolidinone 7.
The X-ray crystallographic analysis showed, as depicted
in Figure 1, a (1S,2R,5R)-absolute configuration for 7.
The Flack’s parameter was 0.002(8) for this configura-
tion. The solid state conformation of 7 is stabilized by an
Ph
(R)
(R)
Ph
O
N
Me
OH
O
(S)
i
ii
O
N
O
(S)
Me
SePh
SePh
5
15
16
Scheme 3. Reaction conditions: (i) PhSeBr (1 equiv), CH2Cl2, 0 ꢁC, 0.5 h, 90%; (ii) SiO2, CH2Cl2, rt, 95%.
Ph
OH
N
Ph
OH
N
Ph
OH
N
X
H
X
H
NaH
-H
-X
Me
Me
Me
O
O
O
7,11
X = Br, I
H
Ph
O
N
Me
Ph
O
Me
N
Me
O
O
18
Scheme 4. Proposed reaction mechanism for ring closure of diastereomers 7 and 11 to bicyclic compound 18.

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(R) O Me
(R)
Ph
(R)
(S)
Ph
OH
N
Ph
O
N
X
(S)
i
ii
X
(R)
(R)
N
(S)
Me
Me (S)
Me
O
O
O
17
18
7,11
COOH
O
COOH
Ph (R) OH
Ph
Ph
Me
Ph
Me
OH
N
O
O
Me
Me
iii
Me
Me
N
H
(S)
Me
NH2
N
H
Me
COOH
1
19a
COOH
19b
19c
Scheme 5. Reaction conditions: (i) NaOMe or NaH (2–3 equiv), THF, rt to reflux; (ii) NaH (3 equiv), THF, 0 ꢁC to rt, 4 h, 76%; (iii) levulinic acid
(1 equiv), toluene, reflux, 32 h, 80%.
with the c-ketoacid, resulting in a three-component tauto-
meric mixture.28,29 From the tautomeric mixture, only
intermediate 19c is suitable as a participant in the second
cyclization step to result in (2R,3S,7aS)-3,7a-dimethyl-2-
phenylpyrrolo[2,1-b]oxazol-5(6H)-one 18 (Scheme 5).
for the direct separation was a Chirasil DEX CB column
(2500 · 0.25 mm I.D.) at 160 ꢁC and 80 kPa.
4.2. N-[(1S,2R)-2-Hydroxy-1-methyl-2-phenylethyl]-4-
pentenamide 3
To a stirred solution of 3.02 g (0.02 mol) of (1R,2S)-(ꢀ)-
norephedrine 1 and 2.22 g (0.22 mol) of triethylamine in
100 mL of dry CH2Cl2, a solution of 2.38 g (0.02 mol) of
4-pentenoyl chloride in 10 mL of dry CH2Cl2 was added
dropwise at 0 ꢁC under an N2 atmosphere. The mixture
was stirred for 3 h at 0 ꢁC, and then extracted with a 1 M
HCl solution (2 · 50 mL) and water (50 mL). The organic
phase was dried over MgSO4 and evaporated in vacuo,
and the crystalline product obtained was recrystallized
3. Conclusion
The electrophile-induced cyclization of chiral 2-(3-buten-
yl)oxazolines afforded new chiral 1,5-disubstituted
pyrrolidinones. The cyclocondensation of 5-halomethyl-c-
lactams resulted in bicyclic lactams with a tetrahydro-
pyrrolo[2,1-b]oxazole skeleton, which were alternatively
prepared in high yields via the condensation of norephe-
drine with levulinic acid.
from EtOAc, resulting in 4.21 g (90%) of pure 3. Mp: 93–
20
94 ꢁC; ½aꢂD ¼ ꢀ111 (c 1.5, CH2Cl2); 1H NMR (CDCl3,
270 MHz): d 0.99 (d, 3H, J = 6.9 Hz, CH3), 2.23–2.42 (m,
4H, 2 · CH2), 3.87 (br s, 1H, NH), 4.27–4.34 (m, 1H,
CHN), 4.80–4.83 (m, 1H, CHOH), 4.99–5.09 (m, 2H,
CH@CH2), 5.73–5.86 (m, 1H, CH@CH2), 7.23–7.37 (m,
5H, CH, aromatic); 13C NMR (CDCl3, 67.9 MHz): d
14.2 (CH3), 29.5 (CH2CH@CH2), 35.6 (NCOCH2), 50.9
(CHNH), 76.1 (CHOH), 115.5 (CH@CH2), 126.2, 127.3,
128.0 (CH, aromatic), 136.7 (CH@CH2), 140.8 (Cq, aro-
matic), 173.0 (CO); IR (KBr, cmꢀ1) 3299, 1639, 1550,
702; LRMS (70 eV, m/z, %) 234 (M+1+, 4), 216 (2), 127
(100). Anal. Calcd for C14H19NO2 (233.31): C, 72.07; H,
8.21; N, 6.00. Found: C, 72.18; H, 8.27; N, 5.81.
4. Experimental
4.1. General experimental procedures
1H and 13C NMR, DEPT and COSY spectra were recorded
on a JEOL JNM-EX270 NMR spectrometer operating at
270 and 67.9 MHz. Optical rotations were measured with
an Optical Activity AA-10 polarimeter. IR spectra were
measured with a FT-IR spectrometer. Electron impact
(EI) mass spectra were obtained with a Varian MAT 112
mass spectrometer, operating at 70 eV. Melting points
The (1R,2S)-enantiomer 4 was prepared as described
were measured with a Buchi 535 melting point apparatus,
¨
and are uncorrected. Chromatographic separations were
performed on Merck Kieselgel 60 (230–400 mesh ASTM).
20
above; ½aꢂD ¼ þ111 (c 1.5, CH2Cl2); the spectroscopic data
and melting point were similar to those for compound 3.
Anal. Calcd for C14H19NO2 (233.31): C, 72.07; H, 8.21;
N, 6.00. Found: C, 72.35; H, 8.03; N, 6.17.
Reactions were monitored with Merck Kieselgel 60 F254
-
precoated TLC plates (0.25 mm thickness). Toluene was
redistilled over metal sodium; acetonitrile and dichloro-
methane were redistilled over calcium hydride; all other
chemicals and solvents were used as supplied. GC measure-
ments were made on a Crompack CP-9002 system, consist-
ing of a Flame Ionization Detector 901A and a Maestro II
Chromatography Data System (Chrompack International
B.V., Middelburg, The Netherlands). The column used
4.3. (4S,5R)-2-(3-Butenyl)-4-methyl-5-phenyl-4,5-dihydro-
1,3-oxazole 5
Method A: To a solution of 3.78 g (0.025 mol) of (1R,2S)-
(ꢀ)-norephedrine 1 in 80 mL of dry toluene, 2.50 g
(0.025 mol) of 4-pentenoic acid and a catalytic amount of

I. Kanizsai et al. / Tetrahedron: Asymmetry 17 (2006) 2857–2863
2861
PTSA were added and the mixture was refluxed with a
Dean–Stark trap; the water formed being collected for
48 h. The solution was then evaporated to dryness, and
the residue was dissolved in EtOAc (200 mL) and washed
with 5% NaHCO3 solution (2 · 50 mL). The organic phase
was dried over MgSO4 and evaporated in vacuo, and the
semisolid residue was purified by flash chromatography
on silica gel (hexane–EtOAc = 2:1), resulting in 2.3 g of
compound 5 (43%, Rf = 0.45).
5.82 (s, 1H, CHOH), 7.24–7.45 (m, 5H, CH, aromatic); 13C
NMR (CDCl3, 67.9 MHz): d 10.6 (CH3), 24.8, 31.5,
(CH2CH2), 36.5 (CH2Br), 59.9 (CHCH2Br), 61.0 (CHN),
76.8 (CHO), 127.0, 128.4, 129.3 (CH, aromatic), 143.4
(Cq, aromatic), 178.4 (C@O); IR (KBr, cmꢀ1) 3198, 1648,
1462, 1291, 753, 704; LRMS (70 eV, m/z, %) 311 (M+,
1), 294 (12), 204 (100), 163 (29), 126 (41), 120 (39). Anal.
Calcd for C14H18BrNO2 (312.21): C, 53.86; H, 5.81; N,
4.49. Found: C, 54.06; H, 5.87; N, 4.31.
Method B: 1.70 g (7.3 mmol) of amide 3 and a catalytic
amount of PTSA were dissolved in 100 mL of dry toluene
and the solution was refluxed with a Dean–Stark trap,
the water formed was collected for 48 h. The solution
was then evaporated to dryness, and the crude product
was purified by flash chromatography on silica gel (hexane–
The (1R,2S,5S) enantiomer 9 was prepared and isolated as
20
described above; ½aꢂD ¼ þ40 (c 1.0, CH2Cl2); the spectro-
scopic data and melting point were similar to those for
compound 7. Anal. Calcd for C14H18BrNO2 (312.21): C,
53.86; H, 5.81; N, 4.49. Found: C, 53.99; H, 5.65; N, 4.62.
20
EtOAc = 2:1), resulting in 1.35 g of compound 5 (86%,
Compound 8: ½aꢂD ¼ ꢀ38 (c 1.05, CH2Cl2); 1H NMR
20
Rf = 0.45). ½aꢂ ¼ ꢀ170 (c 0.1, MeOH); 1H NMR (CDCl3,
(CDCl3, 270 MHz): d 1.40 (d, 3H, J = 6.9 Hz, CH3),
2.93–2.63 (m, 4H, CH2CH2), 3.39–3.53 (m, 4H, CHCH2Br
and CHN, overlapping peaks), 4.50 (br s, 1H, CHOH),
5.13 (d, 1H, J = 4.0 Hz, CHOH), 7.23–7.43 (m, 5H, CH,
aromatic); 13C NMR (CDCl3, 67.9 MHz): d 12.4 (CH3),
24.4, 31.2 (CH2CH2), 36.4 (CH2Br), 59.2 (CHCH2Br),
61.3 (CHN), 76.0 (CHO), 126.7, 128.2, 128.9 (CH, aro-
matic), 143.0 (Cq, aromatic), 177.4 (C@O); IR (KBr,
cmꢀ1) 3333, 3054, 1667, 1266, 738; LRMS (70 eV, m/z,
%) 312 (M++1, 4), 311 (M+, 1), 295 (10), 294 (4), 284
(11), 205 (45), 204 (100), 126 (20). Anal. Calcd for
C14H18BrNO2 (312.21): C, 53.86; H, 5.81; N, 4.49. Found:
C, 53.65; H, 6.09; N, 4.55.
D
270 MHz): d 0.75 (d, 3H, J = 6.9 Hz, CH3), 2.43–2.53 (m,
4H, CH2CH2), 4.38–4.44 (m, 1H, CHN), 5.03–5.16 (m,
2H, CH@CH2), 5.56 (d, 1H, J = 9.6 Hz, CHO), 5.85–5.95
(m, 1H, CH@CH2), 7.18–7.38 (m, 5H, CH, aromatic);
13C NMR (CDCl3, 67.9 MHz): d 17.9 (CH3), 27.6, 30.0
(CH2CH2), 64.9 (CHN), 83.8 (CHO), 115.6 (CH@CH2),
127.8 (CH@CH2), 126.1, 128.2, 136.9 (CH, aromatic),
137.1 (Cq, aromatic), 166.3 (OC@N); IR (KBr,
cmꢀ1) 3066, 2976, 1671, 1455, 1171, 979, 700 ; LRMS
(70 eV, m/z, %) 215 (M+, 12), 214 (64), 107 (100), 67
(82). Anal. Calcd for C14H17NO (215.30): C, 78.10; H,
7.96; N, 6.51. Found: C, 78.27; H, 8.11; N, 6.41.
The (4R,5S) enantiomer 6 was prepared as described
The (1R,2S,5R)-enantiomer 10 was prepared and isolated
20
20
above; ½aꢂD ¼ þ180 (c 0.11, MeOH); the spectroscopic data
as described above; ½aꢂD ¼ þ39 (c 1.1, CH2Cl2); the spec-
were similar to those for compound 5. Anal. Calcd for
C14H17NO (215.30): C, 78.10; H, 7.96; N, 6.51. Found:
C, 78.32; H, 7.87; N, 6.65.
troscopic data were similar to those for compound 8. Anal.
Calcd for C14H18BrNO2 (312.21): C, 53.86; H, 5.81; N,
4.49. Found: C, 53.76; H, 5.93; N, 4.64.
4.4. (1S,2R,5R)-5-Bromomethyl-1-(2-hydroxy-1-methyl-2-
phenylethyl)-2-pyrrolidinone 7; (1S,2R,5S)-5-bromomethyl-
1-(2-hydroxy-1-methyl-2-phenylethyl)-2-pyrrolidinone 8
4.5. (1S,2R,5R)-5-Iodomethyl-1-(2-hydroxy-1-methyl-2-
phenylethyl)-2-pyrrolidinone 11; (1S,2R,5S)-5-iodomethyl-1-
(2-hydroxy-1-methyl-2-phenylethyl)-2-pyrrolidinone 12
To a stirred solution of 0.45 g (2.1 mmol) of 5 in 20 mL of
dry CH2Cl2 was added dropwise 0.37 g (2.3 mmol) of Br2,
dissolved in 7 mL of dry CH2Cl2, at 0 ꢁC under an N2
atmosphere. The mixture was stirred for 0.5 h at 0 ꢁC,
and 20 mL of 10% K2CO3 solution was then added to
the solution. After stirring for 2 h at 0 ꢁC the solution
was poured into a separatory funnel, the phases were sep-
arated and the aqueous phase was extracted once with
CH2Cl2 (30 mL). The combined organic phases were dried
over MgSO4 and evaporated in vacuo, and the crude prod-
uct obtained (diastereomer ratio: 50:50, based on NMR
measurement of the crude product) was purified by flash
chromatography on silica gel (CH2Cl2–EtOAc = 19:1),
resulting in 0.18 g (28%, Rf = 0.32) of compound 7 and
0.18 g (28%, Rf = 0.21) of compound 8.
To a stirred solution of 0.22 g (1.0 mmol) of oxazoline 5 in
10 mL of dry acetonitrile, 0.75 g (3 mmol) of iodine was
added in one portion at ꢀ20 ꢁC. After stirring for 2 h at
this temperature, the reaction mixture was treated with sat-
urated sodium metabisulfite solution at 0 ꢁC, the solution
was basified with 10% K2CO3 solution and stirring was
continued for a further 30 min at 0 ꢁC. The mixture was
poured into a separatory funnel and extracted with CH2Cl2
(3 · 80 mL). The organic phase was dried (MgSO4) and
evaporated in vacuo, and the crude product obtained (dia-
stereomer ratio: 57:43, based on NMR measurement of the
crude product) was purified by flash chromatography on
silica gel (CH2Cl2–EtOAc = 19:1), resulting in 0.16 g
(44%, Rf = 0.34) of compound 11 and 0.12 g (33%,
Rf = 0.22) of compound 12.
20
20
Compound 7: mp: 108–111 ꢁC; ½aꢂD ¼ ꢀ42 (c 1.0, CH2Cl2);
Compound 11: mp: 114–116 ꢁC; ½aꢂD ¼ ꢀ74 (c 1.0,
1H NMR (CDCl3, 270 MHz): d 1.22 (d, 3H, J = 6.9 Hz,
CH3), 2.02–2.66 (m, 4H, CH2CH2), 3.36 (ddd, 1H,
J = 1.7, 7.3, 13.3 Hz, CHCH2Br), 3.48–3.59 (m, 2H,
CH2Br), 3.88–3.92 (m, 1H, CHN), 5.21 (br s, 1H, CHOH),
CH2Cl2); 1H NMR (CDCl3, 270 MHz): d 1.19 (d, 3H,
J = 6.9 Hz, CH3), 1.83–2.68 (m, 4H, CH2CH2), 3.26–3.40
(m, 3H, CHCH2I, overlapping peaks), 3.54–3.62 (m, 1H,
CHN), 5.25 (s, 1H, CHOH), 5.93 (s, 1H, CHOH), 7.23–

2862
I. Kanizsai et al. / Tetrahedron: Asymmetry 17 (2006) 2857–2863
7.45 (m, 5H, CH, aromatic); 13C NMR (CDCl3,
67.9 MHz): d 9.3 (CH3), 11.3, 25.3 (CH2CH2), 30.2
(CH2I), 58.7 (CHCH2I), 59.6 (CHN), 76.5 (CHO), 125.9,
127.3, 128.2 (CH, aromatic), 142.3 (Cq, aromatic), 177.2
(C@O); IR (KBr, cmꢀ1) 3200, 2936, 1647, 1460, 753, 704;
LRMS (70 eV, m/z, %) 359 (M+, 1), 341 (1), 252 (100),
126 (20), 112 (10), 97 (8). Anal. Calcd for C14H18INO2
(359.21): C, 46.81; H, 5.05; N, 3.90. Found: C, 46.96; H,
5.01; N, 4.11.
132.97 (CH, aromatic), 132.40, 136.50 (Cq, aromatic),
167.37, 167.42 (C@O); IR (NaBr, liquid film, cmꢀ1) 2932,
1667, 1438, 909, 733; LRMS (70 eV, m/z, %) 388
(M+H+, 2), 389 (M+, 1), 371 (7), 214 (100), 157 (7), 134
(94). Anal. Calcd for C20H23NO2Se (388.37): C, 61.85; H,
5.97; N, 3.61. Found: C, 61.72; H, 6.23; N, 3.39.
4.7. 5R*-5-(Phenylselenylmethyl)dihydro-2(3H)-furanone
1623
The (1R,2S,5S)-enantiomer 13 was prepared and isolated
A mixture of 0.79 g (2 mmol) of cyclic imidate 15 and
2.00 g of silica gel in CH2Cl2 (30 mL) was stirred for 4 h
at room temperature. The silica gel was filtered off and
washed with CH2Cl2 several times. After evaporation of
the solvent, the resulting crude product was identified as
lactone 16. All the analytical and spectroscopic data on
compound 16 were similar to those mentioned in the
literature.23
20
as described above; ½aꢂD ¼ þ73 (c 1.0, CH2Cl2); the spec-
troscopic data and melting point were similar to those for
compound 11. Anal. Calcd for C14H18INO2 (359.21): C,
46.81; H, 5.05; N, 3.90. Found: C, 47.12; H, 5.27; N, 4.02.
20
Compound 12: an oil; ½aꢂD ¼ ꢀ49 (c 1.1, CH2Cl2); 1H
NMR (CDCl3, 270 MHz): d 1.42 (d, 3H, J = 7.3 Hz,
CH3), 1.76–2.06 (m, 2H, O@CCH2CH2), 2.16–2.64 (m,
2H, O@CCH2CH2), 3.15–3.44 (m, 4H, CHCH2I and
CHN, overlapping peaks), 4.46 (br s, 1H, CHOH), 5.12
(d, 1H, J = 4.3 Hz, CHOH), 7.24–7.41 (m, 5H, CH, aro-
matic); 13C NMR (CDCl3, 67.9 MHz): d 11.8 (CH2), 13.2
(CH3), 26.3, 31.3 (CH2I), 59.5 (CHCH2I), 61.8 (CHN),
76.3 (CHO), 127.0, 128.5, 129.2 (CH, aromatic), 143.3
(Cq, aromatic), 177.6 (C@O); IR (KBr, cmꢀ1) 3343, 2938,
1666, 1457, 907, 733, 651; LRMS (70 eV, m/z, %) 360
(M+H+, 1), 359 (M+, 1), 342 (5), 341 (12), 252 (100), 126
(22), 112 (6), 97 (10). Anal. Calcd for C14H18INO2
(359.21): C, 46.81; H, 5.05; N, 3.90. Found: C, 46.64; H,
5.17; N, 3.72.
A pale-yellow crystalline compound: mp: 42–45 ꢁC (lit.23
1
mp: 44–46 ꢁC); H NMR (CDCl3, 270 MHz): d 1.88–2.02
(m, 2H), 2.35–2.64 (m, 3H), 3.01 (dd, 1H, J = 7.9,
12.8 Hz), 3.30 (dd, 1H, J = 4.6, 12.8 Hz), 4.61–4.71 (m,
1H), 7.28–7.31 (m, 3H), 7.53–7.57 (m, 2H); 13C NMR
(CDCl3, 67.9 MHz): d 27.17, 28.34, 31.50, 78.85, 127.06,
128.82, 128.97, 132.42, 176.28; IR (KBr, cmꢀ1) 2932,
1667, 1438, 909, 733; LRMS (70 eV, m/z, %) 257
(M+H+, 100), 256 (M+, 1), 172 (32), 100 (23), 85 (80), 77
(28). Anal. Calcd for C11H12O2Se (255.17): C, 51.78; H,
4.74. Found: C, 51.59; H, 4.86.
4.8. (2R,3S,7aS)-3,7a-Dimethyl-2-phenylpyrrolo[2,1-b]-
oxazol-5(6H)-one 18
The (1R,2S,5R)-enantiomer 14 was prepared and isolated
20
as described above; ½aꢂD ¼ þ48 (c 1.0, CH2Cl2); the spec-
troscopic data and melting point were similar to those for
compound 12. Anal. Calcd for C14H18INO2 (359.21):
C, 46.81; H, 5.05; N, 3.90. Found: C, 46.71; H, 4.93; N,
3.65.
Method A: To a suspension of NaH (53 mg, 1.2 mmol, 60%
dispersion in oil) in 5 mL of dry THF, pyrrolidinone deriv-
ative 7 (100 mg, 0.32 mmol) was added in small portions.
The reaction mixture was allowed to warm up to room
temperature and then stirred for 4 h. Afterwards, the excess
of NaH was decomposed by means of MeOH (5 mL). The
mixture was poured into water (15 mL), the organic phase
was separated using CHCl3 (25 mL). The organic phase
was dried over Na2SO4 and evaporated in vacuo. The
crude product was purified by means of flash chromatogra-
phy with n-hexane–EtOAc (3:2) on Al2O3 (Rf = 0.5), result-
ing in the pure compound 18 (60 mg, 76%). Iodomethyl
derivative 11 was reacted under the same reaction condi-
tions to furnish bicyclic lactam 18 in 67% yield.
4.6. (1R,2S)-1-Phenyl-2-[((2Z)-5-(phenylselenylmethyl)-
dihydro-2(3H)-furanylidene)amino]-1-propanol 15
To a stirred solution of 0.20 g (0.86 mmol) of carboxamide
3 in 25 mL of dry CH2Cl2, 0.20 g (0.86 mmol) of phenyl-
selenyl bromide was added in one portion at 0 ꢁC under
N2. After stirring for 0.5 h at 0 ꢁC, CH2Cl2 was added to
the solution (20 mL) and the mixture was washed with
10% NaOH solution (15 mL). The organic phase was dried
over MgSO4 and evaporated in vacuo, resulting in a
mixture of two diastereomers (oily product, 0.30 g, 90%).
The attempted separation of the isomers by chromatogra-
phy was not successful because of the partial decomposi-
tion of the cyclic imidate 15 to lactone 16.
Method B: A mixture of 0.30 g (2 mmol) of (1R,2S)-nor-
ephedrine and 0.23 g (2 mmol) of levulinic acid in 25 mL
of toluene was refluxed with a Dean–Stark trap; the water
formed was collected for 32 h. The solution was then evap-
orated in vacuo to dryness, and the residue was purified by
flash chromatography on neutral Al2O3 (hexane–EtOAc =
2:1), resulting in 0.37 g of compound 18 (80%, Rf = 0.45).
1H NMR (CDCl3, 270 MHz): d 0.71 (d, 3H, J = 7.3 Hz,
CH3), 1.86–2.10 (m, 2H, CH2CH2), 2.50–2.59 (m, 2H),
3.00–3.46 (m, 2H), 3.82–3.86 (m, 1H, CHCH2Se), 4.32–
4.40 (m, 1H, CHN), 5.52 (dd, 1H, J = 4.5, 9.8 Hz, CHOH),
7.13–7.53 (m, 10H, CH, aromatic); 13C NMR (CDCl3,
67.9 MHz): d 17.57 (CH3), 24.95, 32.04, 32.10, 35.83
(CH2), 64.24, 64.31 (NCHCH2), 69.60, 69.67 (CH3CHN),
83.83 (CHOH), 125.79, 126.72, 127.64, 128.03, 128.90,
20
1
A pale-yellow oil; ½aꢂD ¼ ꢀ25 (c 0.25, MeOH); H NMR
(CDCl3, 270 MHz): d 0.84 (d, 3H, J = 7.1 Hz), 1.69 (s,
3H), 2.16 (dt, 1H, J = 9.1, 12.6 Hz), 2.29 (dd, 1H,
J = 8.1, 12.6 Hz), 2.46 (dd, 1H, J = 8.3, 16.3 Hz), 2.67–
2.77 (m, 1H), 4.41–4.47 (m, 1H), 4.99 (d, 1H,

I. Kanizsai et al. / Tetrahedron: Asymmetry 17 (2006) 2857–2863
2863
J = 5.45 Hz, CHN), 7.27–7.38 (m, 5H, CH, aromatic); 13C
NMR (CDCl3, 67.9 MHz) 15.9 (CH3), 28.3 (CH3), 33.9
(CH2), 37.8 (CH2), 55.6 (CH), 82.8 (CH2), 99.5 (Cq),
126.8, 128.5, 129.0 (CH, aromatic), 137.1 (Cq, aromatic),
178.4 (C@O); IR (KBr, cmꢀ1) 2979, 1709, 1552, 1089,
702; Anal. Calcd for C14H17NO2: C, 72.70; H, 7.41; N,
6.06. Found: C, 72.93; H, 7.21; N, 6.19.
4. Ziegler, F. E.; Fang, J. M.; Tam, C. C. J. Am. Chem. Soc.
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4.9. X-ray crystallographic study
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Crystallographic data were collected at 173 K with a Non-
ius-Kappa CCD area detector diffractometer using graph-
ite-monochromatized Mo-Ka radiation (k = 0.71073 A).
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data.
˚
´
´
12. Amat, M.; Canto, M.; Llor, N.; Ponzo, V.; Perez, M.; Bosch,
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Crystal data for 7 C14H17BrN2, Mr = 312.20, orthorhombic,
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space group P212121 (no. 19), a = 9.1003(3), b = 9.1587(3),
3
˚
˚
c = 16.6475(5) A, a, b, c = 90ꢁ, V = 1387.52(8) A , T = 173 K,
Z = 4, l(MoKa) = 0.282 mmꢀ1, 2536 unique reflections
(Rint = 0.0209), which were used in calculations. The final
wR(F2) was 0.0544 (all data) and the Flack’s parameter
was ꢀ0.002(8).
The structure was solved by direct methods by use of the
SIR97 program32 and full-matrix, least-squares refinements
on F2 were performed by use of the SHELXL-97 program.33
The CH hydrogen atoms were included at the fixed dis-
tances with the fixed displacement parameters from their
host atoms. The OH hydrogen atom was refined isotropi-
cally. The figure was drawn with ORTEP-3 for Windows.34
The deposition number CCDC 615696 contains the supple-
mentary crystallographic data for this paper. These data
can be obtained free of charge at www.ccdc.cam.ac.uk/
conts/retrieving.html [or from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: (internat.) +44-1223-336-033; e-mail:
deposit@ccdc.cam.ac.uk].
´
20. Garcıa-Valverde, M.; Pedrosa, R.; Vicente, M. Tetrahedron
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21. Ragan, J. A.; Claffey, M. C. Heterocycles 1995, 41, 57–70.
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27. Meyers, A. I.; Burgess, L. E. J. Org. Chem. 1992, 57, 1656–
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´ ´
28. Lazar, L.; Fulo¨p, F. Eur. J. Org. Chem. 2003, 3025–3042.
¨
Acknowledgements
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29. Fulo¨p, F.; Bernath, G.; Mattinen, J.; Pihlaja, K. Tetrahedron
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1989, 45, 4317–4324.
The authors are indebted to the Bilateral Scientific and
Technological Research Cooperation between Flanders
and Hungary for a research Grant (B-11/04).
30. Otwinowski, Z.; Minor, W. In Macromolecular Crystallogra-
phy, Part A; Carter, C. W., Jr., Sweet, R. M., Eds.; Methods
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