Oxyoxazolidinone as an auxiliary for heterocyclic synthesis. Enantioselective formation of N-unprotected 2-pyrrolidones from selenocarboxylate and allylamines via radical cyclization

Article abstract of DOI:10.1016/S0040-4020(03)01015-9

Optically active N-unprotected 2-pyrrolidones were prepared in a highly stereoselective manner through radical cyclization reaction of oxyoxazolidinone. Asymmetric induction from the oxyoxazolidinone ring system was generally high and oxazabicyclo[3.3.0]octanones were obtained in good yields. Treatment of the bicyclic compounds with TBAF resulted in the one-step cleavage of C-O and C-N bond, directly giving secondary 2-pyrrolidones in good yields along with recovery of chiral mandelic acid without loss of optical purity. The use of the present procedure gave optically active 4,5-disubstituted N-unprotected 2-pyrrolidone derivatives trans selectively.

Full text of DOI:10.1016/S0040-4020(03)01015-9

Tetrahedron 59 (2003) 6291–6299
Oxyoxazolidinone as an auxiliary for heterocyclic synthesis.
Enantioselective formation of N-unprotected 2-pyrrolidones from
selenocarboxylate and allylamines via radical cyclization
a
a
b
Akio Kamimura,a Yoji Omata, Keiichi Tanaka and Masashi Shirai
,
*
aDepartment of Applied Chemistry, Faculty of Engineering, Yamaguchi University, Ube 755-8611 Japan
bUbe Laboratory, Ube Industries Ltd., Ube 755-8633 Japan
Received 2 June 2003; accepted 23 June 2003
Abstract—Optically active N-unprotected 2-pyrrolidones were prepared in a highly stereoselective manner through radical cyclization
reaction of oxyoxazolidinone. Asymmetric induction from the oxyoxazolidinone ring system was generally high and oxazabicyclo[3.3.0]-
octanones were obtained in good yields. Treatment of the bicyclic compounds with TBAF resulted in the one-step cleavage of C–O and C–N
bond, directly giving secondary 2-pyrrolidones in good yields along with recovery of chiral mandelic acid without loss of optical purity. The
use of the present procedure gave optically active 4,5-disubstituted N-unprotected 2-pyrrolidone derivatives trans selectively.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
carves the desired secondary amides from the oxyoxa-
zolidinone unit in good yields. Additionally, chiral mandelic
acid is also recovered in good yields without loss of its
optical purity. In this paper, we will report full details of a
new type of synthesis of optically active N-unprotected
2-pyrrolidones via radical cyclization with chiral
oxyoxazolidinone rings.
The radical cyclization is frequently used as a key reaction
for the construction of carbo- or heterocyclic compounds.1
One of the merits of the reaction is that the cyclization
occurs under the neutral conditions as well as bringing high
regio- and/or stereoselectivity in the ring construction.
2-Pyrrolidone skeletons are often seen among natural
products and the efficient construction of the heterocyclic
compounds is sometimes of interest in organic synthesis.2
Due to the planar structural feature of amide group, simple
radical cyclization for secondary amides does not always
work successfully; simple radical reduction often competes
with the desired cyclization.3 To overcome this setback, one
solution is a strategy that introduces some substituent to
make the amide group take on a favorable conformation for
the cyclization. For example, existence of a temporary
substituent on the amide nitrogen atom allows successful
cyclization,4,5 although this method always requires its
removal step in later stage.6 Recently, we have developed a
ready preparation of a new type of chiral orthoester
equivalent, oxyoxazolidinones, which is expected to be a
potential chiral auxiliary for asymmetric synthesis.7 So far
we have examined 1,3-dipolar cycloaddition and the radical
cyclization under the chiral environment brought by this
novel heterocyclic structure and have achieved a good level
of asymmetric induction. The most useful feature of the
present strategy is that treatment with TBAF induces
simultaneous cleavage of C–N and C–O bonds, and thus
2. Results and discussion
The starting materials for the radical cyclization were
prepared from EDCI coupling reaction of commercially
available (S)-mandelic acid 1, allyl amine, and carboxylic
acid (Scheme 1). Obtained O-acyl-N-allylmandelamides 2
were used for the formation of oxyoxazolidinones 3. The
results are summarized in Table 1.
Treatment of 2a with TBSOTf resulted in the formation of
oxyoxazolidinone 3a in a quantitative yield. The ring
enclosure took 6 h for completion. The diastereoselectivity
of the cyclization depended on the a-substituent of the
O-acyl unit. Simple acetyl derivative, for example, gave
3aX as an almost single isomer (entry 1). The configuration
of 3 was determined by comparison with our previous
results.7 Bromoacetate 2b, on the other hand, gave a
diastereomeric mixture of 3b although it was formed
smoothly (entry 2). We examined phenylselenoacetate 2c
and the diastereoselectivity was improved to about a 6:1
level (entry 3). The major isomer 3cX was isolated in a
diastereomerically pure form by careful chromatographic
treatment.
Keywords: radical cyclization; orthoesters; stereoselection; pyrrolidines.
*
Corresponding author. Tel.: þ81-836-85-9231; fax: þ81-836-85-9201;
e-mail: ak10@yamaguchi-u.ac.jp
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01015-9

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A. Kamimura et al. / Tetrahedron 59 (2003) 6291–6299
yield (entry 1). No trace of simply reduced product 3aX was
observed in the reaction mixture. The product contained two
diastereomers 4aX and 4aY, whose ratio was revealed to be
79:21. To improve the stereoselectivity, various reaction
conditions were examined. The cyclization initiated by Et3B
at 08C took long time to finish the reaction, while the
diastereoselectivity was improved to 83:17 or 85:15 (entry 2
and 3). Thermal cyclization with 3cX took place smoothly
to give 4a in a 95% yield, but the diastereoselectivity
remained at a moderate level (entry 4). The photo-initiated
cyclization for 3cX at 08C improved the selectivity as well
as the yield of 4a up to 85:15 and 99%, respectively
(entry 5).
Removal of mandelic acid unit of 4a was achieved in one-
step by treatment with TBAF. Exposure of compound 4a,
inseparable 85:15 mixture of diastereomer 4aX and 4aY, to
TBAF resulted in the smooth disappearance of 4a and
N-unprotected 2-pyrrolidone 5a was formed in a spot-to-
spot manner. Purified 5a showed dextrorotatory, which
indicated that the absolute configuration at the C4 position
was R.8 It should be remarked that optically active mandelic
acid was recovered in 72% yield. The optical rotation of the
recovered mandelic acid was þ117.28, which showed that
no significant loss of optical purity at the chiral carbon in
mandelic acid unit had happened during the present series of
chemical transformation. Hence, this result opens a
possibility for recycled use of chiral mandelic acid.
Scheme 1. Reagents. (i) CH2vCHCH2NH2, EDCI; (ii) RCO2H, EDCI.
(iii) TBSOTf, 2,6-lutidine, DMAP, CH2Cl2, 08C.
Table 1. Preparation of optically active 2-oxy-1,3-oxazolidin-4-ones 3
c
Entry
R
2; yield
(%)a
[a]D
3; yield
(%)a
X/Yb
[a]D
1
2
3
Me
BrCH2
PhSeCH2
2a; 67
2b; 90
2c; 85
þ57.8
þ78.9
þ46.5
3a; 100
3b; 87
3c; 88
96/4
63/37
84/16
213.5
þ20.4
þ51.1
a
Isolated yield.
Determined by HPLC analyses (Chiral Pak-AD).
Specific rotations for major isomers.
b
c
The merits of the present strategy for the construction of
2-pyrrolidone derivatives 5 are summarized as follows: high
yields in each step, smooth radical cyclization without side
products, and one-step conversion to N-unprotected
secondary lactams. We next examined to use chiral amines
6, derived from commercially available optically active
amino acids, for the preparation of 4,5-disubstituted
2-pyrrolidones (Scheme 3).9 During the conversion, some
unavoidable racemization occurred and the optical purities
of 6 were indicated in Scheme 3. Mandelamide 2d, which
was prepared from 6d, underwent the formation of
oxyoxazolidinone 3d in 79% yield using the same
treatment. Unfortunately, 3d consisted of a mixture of
diastereomers, in which the major two isomers’ ratio is in
about 8:2. This result reflected that the stereoselectivity
during the formation of 3d was not as high as the formation
of 3a. Despite our extensive efforts, the present diaster-
eomeric mixture was inseparable so we used this mixture for
further conversion. Treatment of 3d with Bu3SnH gave
bicyclic lactam 4d in 90% yield. Again no simply reduced
product was observed. It should be mentioned that this
compound contained basically only two diastereomers; the
radical cyclization step was expected to proceed in a very
Scheme 2. Reagents. (i) Bu3SnH, AIBN, see Table 2; (ii) TBAF, THF.
Radical cyclization for 3bX or 3cX was examined with the
use of Bu3SnH (Scheme 2). The results are summarized in
Table 2. Exposure of 3bX to Bu3SnH at 1108C resulted in the
clean formation of the desired bicyclic compound 4a in 85%
Table 2. Radical cyclization of 3X
Entry
3X
Z
Conditions
4a; yield (%)a
X/Yb
1
2
3
4
5
3bX
3bX
3bX
3cX
3cX
Br
Br
Br
SePh
SePh
Toluene, AIBN, Bu3SnH, reflux 1.5 h
Toluene, Et3B, Bu3SnH, 0 8C, 3 h then rt, 24 h
Toluene, Et3B, Bu3SnH, rt, 7 days
Toluene, AIBN, Bu3SnH, reflux 12 h
Toluene, AIBN, Bu3SnH, hn, 08C, 12 h
85
38
68
95
99
79/21
83/17
85/15
79/21
85/15
a
Isolated yield.
Determined by HPLC analyses (Chiral Pak-AD).
b

A. Kamimura et al. / Tetrahedron 59 (2003) 6291–6299
6293
Scheme 4. Reagents. (i) TBSOTf, 2,6-lutidine, DMAP, CH2Cl2, 08C;
(ii) Bu3SnH, AIBN, toluene, 1108C; (iii) TBAF, THF.
encouraged the radical cyclization occurred smoothly with-
out the formation of simple reduced products (Scheme 4).
The present method was applied to the construction of
trisubstituted 2-pyrrolidone. The starting material 2h was
readily prepared from mandelic acid, chiral allyl amine 6d,
and racemic 2-bromopropionic acid. The formation of
oxyoxazolidinone 3h was achieved smoothly in the same
procedure as mentioned above. Again an inseparable
diastereomeric mixture of 3h was obtained. This whole
diastereomeric mixture of 3h was treated with Bu3SnH
under the standard radical conditions and bicyclic com-
pound 4h was isolated in 87% yield. Treatment of 4h with
TBAF smoothly converted to trisubstituted 2-pyrrolidones
5h although they consisted in a pair of diastereomers whose
ratios were close to 6:4 (Scheme 5).
Scheme 3. Reagents. (i) (S)-mandelic acid, EDCI, Et3N; (ii) PhSeCH2-
CO2H, EDCI, DMAP, CH2Cl2, rt, 12 h; (iii) TBSOTf, 2,6-lutidine, DMAP,
CH2Cl2, 08C; (iv) Bu3SnH, AIBN, toluene, 1108C; (v) TBAF, THF (a)
enantiomeric excesses of amines 6 are in parentheses.
stereoselective manner. The diastereomeric mixture was
again inseparable using any methods. Exposure of 4d to
TBAF resulted in the smooth cleavage of C–N and C–O
bonds and 2-pyrrolidone 5d was isolated as a single
diastereomer. An NOE experiment for 5d clearly indicated
trans configuration between C4 and C5 since 2% of signal
enhancement at the C4 methyl group was observed on
irradiation at the H5 nuclei. The observed trans-selectivity
is easily rationalized by comparison with the previous
examples.1,4,5 HPLC analysis of 5d showed its enantiomeric
excess was 90%, which was the same value as the starting
amine 6 held. This suggests that 1,2-induction during the
radical cyclization step occurred in a highly stereoselective
manner regardless of the configuration at C2 position in 3.
From the synthetic point of view, the present method
provides a convenient strategy of enantioselective construc-
tion of 4,5-disubstituted 2-pyrrolidone. Starting from other
chiral amines 6 derived from natural or unnatural amino
acids, preparation of optically active 4,5-trans-disubstituted
2-pyrrolidones 5 was carried out successfully. In all cases,
ee values of 5 reflected the values of the ee for the starting
amines 6 so that the 1,2-induction in radical cyclization step
took place at almost the perfect level. Although mandelic
acid unit failed to give effective chiral bias for the radical
cyclization, it provides a suitable configuration that
Scheme 5. Reagents. (i) TBSOTf, 2,6-lutidine, DMAP, CH2Cl2, 08C;
(ii) Bu3SnH, AIBN, toluene, 1108C; (iii) TBAF, THF.
Preparation of N-unprotected 2H-isoquinolin-1-one was
examined with the present procedure. O-Acylmandelamide
2i, derived from o-iodobenzoic acid, was converted to
oxyoxazolidinone 3i, which then underwent radical cycliza-
tion to give bicyclic lactam 7 in 84% yield. Compound 7
consisted in four diastereomers in the ratio of 47:7:31:15.
No simply deharogenated products were observed in the
reaction mixture. Addition of TBAF to a solution of 7
induced smooth degradation of the oxyoxazolidinone unit to
give mandelic acid and 3,4-dihydro-2H-isoquinolin-1-one 8

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A. Kamimura et al. / Tetrahedron 59 (2003) 6291–6299
in 89% yield. The positive optical rotation of 8 indicated the
absolute configuration of 8 was S,10 although the extent of
enantiomeric excess of 8 was only 20%.
the same temperature for 6 h. 1 M HCl (20 mL) was added
to the reaction mixture and the resulting biphasic mixture
was extracted with CH2Cl2 (3£30 mL). The organic phase
was combined, washed with NaHCO3 and brine, and dried
over Na2SO4. Filtration and removal of solvent gave oil
residue, which was purified through flash chromatography
(silica gel/hexane–ethyl acetate 3:1 v/v) to give 2a in 67%
yield (0.3308 g, 1.4 mmol). Colorless oil. [a]D¼þ57.88
In conclusion, we have succeeded in developing a useful
method to prepare mono- and disubstituted N-unprotected
2-pyrrolidones in an optically active form. With the present
procedure, the oxyoxazolidinone ring system provides an
efficient asymmetric bias for chiral induction. Additionally,
one-step removal of mandelic acid from the cyclization
product achieves a ready formation of N-unprotected
2-pyrrolidone derivatives. All the steps involved in the
present sequence can be performed in good yields under
neutral and mild conditions. Recovered mandelic acid
maintained its optical purity. Thus, the present method
will open versatile applicability to the synthesis of
N-unprotected 2-pyrrolidone derivatives. Further investi-
gation and application for this strategy is now underway in
our laboratory.
1
(CHCl3). H NMR d 2.20 (s, 3H), 3.92 (t, 2H, J¼5.6 Hz),
5.14 (dd, 1H, J¼1.3, 11.2 Hz), 5.15 (dd, 1H, J¼1.5,
16.3 Hz), 5.83 (tdd, 1H, J¼5.7, 11.0, 16.5 Hz), 6.10 (s,
1H), 6.18 (br, 1H), 7.33–7.47 (m, 5H). 13C NMR d 20.4,
41.1, 75.1, 115.6, 127.0, 128.2, 128.4, 133.3, 135.2, 168.3,
169.3. IR (nmax, neat) 3300, 2960, 1720, 1650, 1240 cm21
.
HRMS (FAB) calcd for (MþH) C13H16NO3: 234.1130,
found 234.1128.
Other (S)-O-acyl-N-allylmandelamides 2 were prepared in a
similar manner.
3.1.2. (S)-(1)-O-Bromoacetyl-N-allylmandelamide (2b).
1
Colorless oil. [a]D¼þ78.98 (c 1.13, CHCl3). H NMR d
3. Experimental
3.1. General
3.85–4.00 (m, 4H), 5.17 (dd, 1H, J¼1.5, 17.2 Hz), 5.19 (dd,
1H, J¼1.3, 9.6 Hz), 5.83 (tdd, 1H, J¼5.5, 10.3, 17.2 Hz),
6.14 (s, 1H), 6.30 (br, 1H), 7.37–7.48 (m, 5H). 13C NMR d
25.4, 41.6, 76.5, 116.5, 127.3, 128.7, 129.1, 133.3, 134.5,
165.5, 167.6. IR (nmax, neat) 3200, 2960, 1720, 1650,
All 1H and 13C NMR spectra were recorded on a JEOL EX-
270 (270 MHz for 1H and 67.5 MHz for 13C) spectrometer.
Solvents were dried over the appropriate drying agents (K
for TH F, Na for ether, toluene, and benzene, CaH2 for
CH2Cl2) and distilled under nitrogen before use. Et3N was
purified by distillation. (S)-(2)-Mandelic acid, EDCI,
TBSOTf, 2,6-lutidine, Bu3SnH, AIBN and Et3B were
purchased from Aldrich and used without further purifi-
cation. Chiral amines 6d to 6g were prepared according to
the literature method.9 All the reactions presented here were
performed under nitrogen atmosphere unless mentioned.
High resolution mass spectra (HRMS) were measured at
Advanced Instrumentation Centre, Ehime University,
Matsuyama, Japan.
1240 cm21
.
3.1.3. (S)-(1)-O-(Phenylseleno)acetyl-N-allylmandel-
amide (2c). White solid. Mp 49–508C. [a]D¼þ46.58 (c
1.06, CHCl3). 1H NMR d 3.60 (d, 2H, J¼5.3 Hz), 3.85 (m,
2H, J¼6.9 Hz), 5.11 (dd, 1H, J¼1.5, 17.3 Hz), 5.13 (dd, 1H,
J¼1.3, 10.2 Hz), 5.77 (tdd, 1H, J¼5.5, 10.4, 17.2 Hz), 6.10
(s, 1H), 6.33 (br, 1H), 7.26–7.55 (m, 10H). 13C NMR d
26.7, 41.4, 75.8, 116.3, 127.2, 127.9, 128.4, 128.7, 129.2,
132.7, 133.3, 135.0, 168.0, 168.8. IR (nmax) 3284, 1727,
1660, 1375, 1253, 1103 cm21. HRMS (FAB) calcd for
(MþH) C19H20NO738Se: 390.0608, found 390.0605.
3.1.4. (S)-(1)-O-(Phenylseleno)acetyl-N-(1-(S)-benzyl-
allyl)mandelamide (2d). Yellow oil [a]D¼þ38.88 (c
3.1.1. Preparation of (S)-(1)-O-acetyl-N-allylmandel-
amide (2a). General procedure. To a solution of allylamine
(1.178 g, 20.6 mmol), (S)-(þ)-mandelic acid (1.542 g,
10.1 mmol) and DMAP (0.1 g) in CH2Cl2 (10 mL) and
was added EDCI (3.8191 g, 20.0 mmol) at room tempera-
ture. The reaction mixture was allowed to stir for 12 h. 1 M
HCl (20 mL) was added to the solution and the resulting
mixture was extracted with CH2Cl2 (3£30 mL). The organic
phase was combined, washed successively with NaHCO3
and brine, and dried over Na2SO4. Filtration and removal of
solvent gave N-allylmandelamide in 83% yield (1.6048 g,
8.3 mmol). Colorless oil. [a]D¼þ70.48 (c 1.20, CHCl3). 1H
NMR d 3.77 (br, 1H), 3.87 (t, 2H, J¼5.6 Hz), 5.08 (dd, 1H,
J¼1.5, 18.3 Hz), 5.10 (dd, 1H, J¼1.3, 9.1 Hz), 5.78 (tdd,
1H, J¼5.5, 10.9, 16.5 Hz), 6.30 (br, 1H), 7.28–7.42 (m,
5H). 13C NMR d 41.5, 73.9, 116.3, 126.6, 128.3, 128.5,
133.5, 139.5, 172.4. Anal. Calcd for C11H13NO2: C, 69.09;
H, 6.85; N, 7.32%. Found: C, 68.94; H, 7.00; N, 7.19.
1
0.59, CHCl3). H NMR d 2.75 (dd, 1H, J¼7.9, 13.9 Hz),
2.94 (dd, 1H, J¼5.9, 13.9 Hz), 3.52–3.56 (m, 2H), 4.74–
4.82 (m, 1H), 5.06 (dd, 1H, J¼1.3, 10.2 Hz), 5.08 (dd, 1H,
J¼1.5, 17.3 Hz), 5.77 (ddd, 1H, J¼5.4, 10.3, 17.2 Hz), 6.06
(s, 1H), 6.38 (d, 1H, J¼8.6 Hz), 7.06–7.62 (m, 15H). 13C
NMR d 27.2, 40.6, 52.0, 75.8, 115.5, 126.6, 126.7, 127.6,
127.8, 128.3, 128.4, 128.5, 129.2, 129.3, 129.4, 133.1,
136.8, 136.9, 167.8, 168.7. IR (nmax, neat) 3368, 3029, 1658,
1531 cm21
.
HRMS (FAB) calcd
for (MþH)
C26H26NO738Se: 478.1086, found 478.1088.
3.1.5. (S)-(1)-O-(Phenylseleno)acetyl-N-(1-(R)-benzyl-
allyl)mandelamide (2e). White solid. [a]D¼þ46.88 (c
1
0.39, CHCl3). H NMR d 2.79 (dd, 1H, J¼7.3, 13.9 Hz),
2.85 (dd, 1H, J¼6.6, 13.6 Hz), 3.54 (d, 1H, J¼17.6 Hz),
3.56 (d, 1H, J¼17.0 Hz), 4.69–4.80 (m, 1H), 5.05 (dd, 1H,
J¼1.3, 17.2 Hz), 5.08 (dd, 1H, J¼1.3, 9.6 Hz), 5.79 (ddd,
1H, J¼5.6, 10.6, 17.2 Hz), 6.04 (s, 1H), 6.20 (d, 1H,
J¼8.3 Hz), 7.06–7.50 (m, 15H). 13C NMR d 26.7, 40.4,
51.8, 75.7, 115.2, 126.3, 127.1, 127.7, 128.1, 128.4, 128.6,
129.1, 132.5, 134.9, 136.7, 167.2, 168.6. IR (nmax) 1716,
To a solution of N-allylmandelamide (0.4019 g, 2.1 mmol),
Et3N (0.35 mL, 2.4 mmol) and DMAP (0.1 g) in CH2Cl2
(10 mL) was added acetyl chloride (0.15 mL, 2.7 mmol) at
08C over 15 min. The reaction mixture was allowed to stir at

A. Kamimura et al. / Tetrahedron 59 (2003) 6291–6299
6295
1409, 1251, 1114 cm21. HRMS (FAB) calcd for (MþH)
lutidine (0.15 mL, 1.3 mmol), DMAP (0.1 g), and TBSOTf
(0.30 mL, 1.3 mmol) in this order. The reaction mixture was
allowed to stir for 6 h. Pyridine (0.5 mL) was added to the
solution and the solvent was remove in vacuo. The residue
was subjected to through flash chromatography (silica gel/
hexane–ethyl acetate 10:1 v/v) to give 3a in 100% yield
(0.1804 g, 0.5 mmol). Colorless oil. [a]D¼213.58 (c 1.06,
CHCl3). 1H NMR d 0.16 (s, 3H), 0.21 (s, 3H), 0.90 (s, 9H),
1.78 (s, 3H), 3.82 (dd, 1H, J¼6.6, 15.8 Hz), 4.09 (dd, 1H,
J¼5.3, 15.8 Hz), 5.14 (dd, 1H, J¼1.3, 10.2 Hz), 5.21 (dd,
1H, J¼1.3, 17.2 Hz), 5.29 (s, 1H), 5.76–5.90 (m, 1H),
7.33–7.46 (m, 5H). 13C NMR d 23.6, 23.5, 17.9, 25.5,
28.6, 42.5, 76.5, 110.4, 117.3, 126.2, 128.4, 128.5, 133.2,
135.9, 169.8. IR (nmax, neat) 2950, 1720, 1400, 1210,
C26H26NO738Se: 478.1086, found 478.1093.
3.1.6. (S)-(1)-O-(Phenylseleno)acetyl-N-(1-(S)-iso-
propylallyl)mandelamide (2f). White solid. Mp 60–
1
618C. [a]D¼þ46.88 (c 0.39, CHCl3). H NMR d 0.87 (d,
3H, J¼6.9 Hz), 0.88 (d, 3H, J¼6.9 Hz), 1.73–1.86 (m, 1H),
3.58 (d, 1H, J¼17.2 Hz), 3.62 (d, 1H, J¼16.9 Hz), 4.29–
4.37 (m, 1H), 5.07 (dd, 1H, J¼1.3, 17.5 Hz), 5.08 (dd, 1H,
J¼1.3, 10.3 Hz), 5.68 (ddd, 1H, J¼5.9, 10.2, 17.2 Hz), 6.13
(s, 1H), 6.35 (d, 1H, J¼8.9 Hz), 7.26–7.53 (m, 10H). 13C
NMR d 18.5, 19.1, 27.4, 32.4, 57.0, 76.5, 116.5, 127.8,
128.4, 129.0, 129.3, 129.8, 133.1, 135.8, 136.4, 167.9,
169.1. IR (nmax) 3275, 3085, 1735, 1660, 1560, 1405, 1251,
1105 cm21
.
HRMS (FAB) calcd for (MþH)
1080 cm21
.
C22H26NO830Se: 432.1078, found 432.1070.
Other optically active oxyoxazolidinones 3 were prepared in
a similar procedure. The diastereomers of 3bX, 3bY, and
3cX were separated by careful flash chromatography eluted
with hexane–ether 20:1 v/v.
3.1.7. (S)-(1)-O-(Phenylseleno)acetyl-N-(1-(R)-iso-
propylallyl)mandelamide
(2g).
1
White
solid.
[a]D¼þ25.78 (c 0.62, CHCl3). H NMR d 0.85 (d, 3H,
J¼6.9 Hz), 0.86 (d, 3H, J¼6.9 Hz), 1.71–1.83 (m, 1H,
J¼6.9 Hz), 3.58 (d, 1H, J¼14.8 Hz), 3.65 (d, 1H,
J¼13.8 Hz), 4.29–4.37 (m, 1H), 5.08 (dd, 1H, J¼1.3,
11.2 Hz), 5.08 (dd, 1H, J¼1.5, 17.2 Hz), 5.73 (ddd, 1H,
J¼6.0, 10.8, 16.9 Hz), 6.13 (s, 1H), 6.28 (d, 1H, J¼9.7 Hz),
7.26–7.62 (m, 10H). 13C NMR d 18.1, 18.6, 26.8, 31.9,
56.6, 75.9, 115.9, 127.3, 127.9, 128.6, 128.8, 129.1, 129.3,
132.5, 135.1, 136.0, 167.7, 168.9. IR (nmax) 3300, 2960,
1735, 1662, 1639, 1527, 1253, 1105 cm21. HRMS (FAB)
calcd for (MþH) C22H26NO738Se: 430.1086, found
430.1091.
3.1.11. (2S,5S)-N-Allyl-2-(tert-butyldimethylsilyl)oxy-2-
bromomethyl-5-phenyl-1,3-oxazolidin-4-one
(3bX).
1
Colorless oil. [a]D¼þ20.48 (c 0.96, CHCl3). H NMR d
0.18 (s, 3H), 0.25 (s, 3H), 0.92 (s, 9H), 3.57 (d, 1H,
J¼11.5 Hz), 3.71 (d, 1H, J¼11.9 Hz), 3.94 (dd, 1H, J¼6.9,
15.5 Hz), 4.06 (dd, 1H, J¼5.9, 15.5 Hz), 5.18 (dd, 1H,
J¼1.2, 10.1 Hz), 5.27 (dd, 1H, J¼1.3, 17.1 Hz), 5.37 (s,
1H), 5.85–5.98 (m, 1H), 7.31–7.62 (m, 5H). 13C NMR d
23.2, 22.9, 18.2, 26.0, 36.4, 43.5, 78.3, 109.7, 118.7,
127.0, 128.8, 129.0, 133.2, 135.0, 170.0. IR (nmax, neat)
2930, 1720, 1400, 1210, 1080 cm21
.
3.1.8. (S)-(1)-O-(2-Bromo)propionyl-N-(1-(S)-benzyl-
allyl)mandelamide (2h). Colorless oil. [a]D¼þ76.88 (c
0.56, CHCl3). 1H NMR d 1.68 (d, 3H, J¼6.9 Hz), 2.76–3.02
(m, 2H), 4.41–4.50 (m, 1H), 4.77–4.87 (m, 1H), 5.02–5.15
(m, 2H), 5.77–5.91 (m, 1H), 6.06 (s, 1H for minor isomer),
6.11 (s, 1H for major isomer), 6.15 (d, 1H, J¼7.6 Hz for
minor isomer), 6.30 (d, 1H, J¼7.9 Hz for major isomer),
7.01–7.51 (m, 10H). 13C NMR d 21.3, 21.5, 40.7, 40.8,
51.8, 52.0, 74.2, 115.2, 115.4, 126.7, 126.8, 127.3, 127.5,
127.6, 127.7, 128.4, 128.5, 128.6, 128.9, 129.2, 129.3,
129.4, 129.5, 134.5, 136.8, 136.9, 139.0, 167.2, 167.2,
171.8, 173.6. IR (nmax, neat) 3300, 3000, 1747, 1648, 1527,
3.1.12. (2R,5S)-N-Allyl-2-(tert-butyldimethylsilyl)oxy-2-
bromomethyl-5-phenyl-1,3-oxazolidin-4-one (3bY).
1
Colorless oil. [a]D¼þ22.78 (c 0.99, CHCl3). H NMR d
20.06 (s, 3H), 0.15 (s, 3H), 0.88 (s, 9H), 3.68 (d, 1H,
J¼11.2 Hz), 3.75 (d, 1H, J¼11.6 Hz), 3.96 (dd, 1H, J¼7.4,
15.3 Hz), 4.09 (dd, 1H, J¼5.6, 15.5 Hz), 5.22 (dd, 1H,
J¼1.2, 10.1 Hz), 5.31 (dd, 1H, J¼1.7, 17.2 Hz), 5.52 (s,
1H), 5.80–6.06 (m, 1H), 7.31–7.48 (m, 5H). 13C NMR d
23.6, 23.1, 17.7, 25.5, 37.7, 42.8, 80.9, 109.1, 118.4,
127.5, 128.4, 128.7, 132.6, 135.4, 169.3. IR (nmax, neat)
2950, 1720, 1400, 1210, 1080 cm21
.
1454, 1180 cm21. HRMS (FAB) calcd for (MþH)
79
23
C21H BrNO3: 416.0861, found 416.0865.
3.1.13. (2S,5S)-N-Allyl-2-(tert-butyldimethylsilyl)oxy-5-
phenyl-2-(phenylseleno)acetyl-1,3-oxazolidin-4-one
(3cX). Colorless oil. [a]D¼þ51.18 (c 1.15, CHCl3). 1H
NMR d 0.17 (s, 3H), 0.27 (s, 3H), 0.92 (s, 9H), 3.32 (d, 1H,
J¼12.9 Hz), 3.53 (d, 1H, J¼12.9 Hz), 3.83 (dd, 1H, J¼6.8,
15.7 Hz), 4.01 (dd, 1H, J¼5.6, 15.5 Hz), 5.13 (dd, 1H,
J¼1.3, 10.2 Hz), 5.20 (dd, 1H, J¼1.3, 17.1 Hz), 5.34 (s,
1H), 5.74–5.92 (m, 1H), 7.19–7.51 (m, 10H). 13C NMR d
23.7, 23.4, 17.7, 25.5, 38.1, 42.8, 78.0, 110.8, 117.9,
126.5, 127.0, 128.2, 128.3, 128.9, 129.1, 132.7, 132.8,
3.1.9. (S)-(1)-O-(2-Iodo)benzoyl-N-allylmandelamide
(2i). Colorless oil. [a]D¼þ77.78 (c 1.11, CHCl3). 1H
NMR d 3.96 (t, 2H, J¼5.8 Hz), 5.14 (dd, 1H, J¼1.3,
10.2 Hz), 5.18 (dd, 1H, J¼1.3, 17.2 Hz), 5.84 (tdd, 1H,
J¼5.4, 10.6, 17.2 Hz), 6.34 (s, 1H), 6.47 (br, 1H), 7.17–
8.03 (m, 9H). 13C NMR d 41.6, 76.7, 93.8, 116.5, 127.5,
128.0, 128.6, 128.9, 131.4, 133.0, 133.4, 134.1, 135.0,
141.2, 164.8, 167.8. IR (nmax, neat) 3300, 3000, 1731, 1662,
1567, 1247, 1135, 1103, 1018, 925 cm21. Anal.Calcd for
C18H16INO3: C, 51.32; H, 3.83; N, 3.33%. Found: C, 51.52;
H, 4.15; N, 3.24.
134.8, 169.5. IR (nmax, neat) 2910, 1720, 1400, 1240 cm21
.
Anal. Calcd for C25H33NO3SeSi: C, 59.75; H, 6.62; N,
2.79%. Found: C, 59.52; H, 6.67; N, 2.83.
3.1.10. Preparation of (2S,5S)-N-allyl-2-(tert-butyl-
dimethylsilyl)oxy-2-methyl-5-phenyl-1,3-oxazolidin-4-
one (3aX). General procedure. To a solution of 2a
(0.1169 g, 0.5 mmol) in CH2Cl2 at 08C was added 2,6-
3.1.14. (5S)-N-(1-(S)-Benzylallyl)-2-(tert-butyldimethyl-
silyl)oxy-5-phenyl-2-(phenylseleno)acetyl-1,3-oxazoli-
din-4-one (3d). Colorless oil. [a]D¼þ53.18 (c 1.18 CHCl3).
1H NMR d 20.03 (s, 3H for minor isomer), 0.01 (s, 3H for

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A. Kamimura et al. / Tetrahedron 59 (2003) 6291–6299
minor isomer), 0.10 (s, 3H for major isomer), 0.24 (s, 3H for
major isomer), 0.88 (s, 9H for minor isomer), 1.02 (s, 9H,
for major isomer), 3.17–3.63 (m, 4H), 4.02–4.13 (m, 1H),
4.02–4.13 (m, 1H), 4.76 (d, 1H, J¼17.5 Hz for major
isomer), 4.96 (d, 1H, J¼10.2 Hz for major isomer), 5.05 (d,
1H, J¼12.2 Hz for minor isomer), 5.10 (d, 1H, J¼10.2 Hz
for minor isomer), 5.20 (s, 1H for minor isomer), 5.38 (s, 1H
for major isomer), 6.04–6.18 (m, 1H), 7.18–7.57 (m, 15H).
13C NMR d 23.6, 23.5, 23.3, 23.0, 14.0, 17.5, 22.5, 25.6,
25.7, 38.2, 38.3, 58.5, 58.9, 76.5, 79.7, 111.8, 111.4, 117.8,
126.4, 126.6, 126.9, 127.1, 127.5, 127.5, 127.7, 128.3,
128.4, 128.5, 128.7, 128.9, 129.0, 129.1, 129.4, 129.5,
130.8, 132.4, 132.8, 133.2, 133.9, 134.6, 134.9, 135.5,
137.9, 138.2, 169.1, 169.3. IR (nmax, neat) 3000, 1720, 1672,
1251, 1105 cm21. HRMS (FAB) calcd for (MþH) C32H40-
NO3Si80Se: 592.1950, found 592.1953.
3H for minor isomer), 0.23 (s, 3H for major isomer), 0.31 (s,
3H for minor isomer), 0.88–0.96 (m, 6H), 0.91 (s, 9H for
major isomer), 0.94 (s, 9H for minor isomer), 2.42–2.55 (m,
1H for minor isomer), 2.64–2.78 (m, 1H for major isomer),
3.14–3.59 (m, 3H), 5.08–5.26 (m, 2H), 5.26 (s, 1H for
minor isomer), 5.31 (s, 1H for major isomer), 6.26–6.39 (m,
1H), 7.18–7.62 (m, 10H). 13C NMR d (ppm) 23.3, 23.0,
22.8, 14.0, 17.9, 18.0, 20.0, 20.2, 20.6, 22.6, 25.4, 25.6,
25.7, 25.9, 27.5, 29.2, 31.5, 38.8, 39.0, 64.8, 65.3, 77.9,
80.9, 111.2, 111.3, 118.1, 118.5, 126.3, 126.8, 127.0, 127.3,
128.3, 128.4, 129.0, 130.7, 131.2, 131.7, 132.8, 132.8,
134.2, 135.4, 136.3, 168.9, 169.4. IR (nmax, neat) 3000,
1718, 1253, 1230, 1108 cm21. HRMS (FAB) calcd for
(MþH) C28H40NO3Si80Se: 546.1942, found 546.1935.
3.1.18. (5S)-N-(1-(S)-Benzylallyl)-2-(tert-butyldimethyl-
silyl)oxy-2-(1-bromo)propionyl-5-phenyl-1,3-oxazolidin-
4-one (3h). Colorless oil. [a]D¼þ37.48 (c 0.37 CHCl3). 1H
NMR d 20.20 (s, 3H for isomer A), 0.10 (s, 3H for isomer
B), 0.16 (s, 3H for isomer C), 0.26 (s, 3H for isomer B), 0.27
(s, 3H for isomer D), 0.33 (s, 3H for isomer C), 0.35 (s, 3H
for isomer A), 0.36 (s, 3H for isomer D), 0.84 (s, 9H for
isomer C), 0.88 (s, 9H for isomer A), 1.02 (s, 9H for isomer
B), 1.04 (s, 9H for isomer D), 1.41 (d, 3H, J¼6.9 Hz for
isomer D), 1.63 (d, 3H, J¼6.6 Hz for isomer C), 1.69 (d, 3H,
J¼6.9 Hz for isomer B), 1.73 (d, 3H, J¼6.6 Hz for isomer
A), 3.09 (m, 1H), 3.66–3.75 (m, 1H), 4.11–4.22 (m, 2H),
4.72–4.96 (m, 2H), 5.46 (s, 1H), 6.10–6.27 (m, 1H), 7.17–
7.64 (m, 10H). 13C NMR d 23.8, 23.6, 23.4, 23.3, 23.2,
22.9, 22.8, 22.7, 14.1, 14.2, 18.0, 18.1, 19.2, 20.1, 20.3,
20.5, 22.6, 25.4, 25.6, 25.7, 25.8, 25.9, 31.5, 38.2, 38.5,
39.8, 59.1, 59.3, 59.5, 60.3, 60.8, 61.2, 76.2, 76.8, 77.3,
77.6, 79.9, 110.9, 111.4, 111.9, 118.4, 118.5, 118.7, 126.1,
126.2, 126.4, 126.5, 126.6, 127.0, 127.4, 127.8, 127.9,
128.0, 128.2, 128.2, 128.3, 128.4, 128.6, 128.8, 128.8,
129.4, 129.6, 133.4, 133.6, 134.5, 134.8, 135.0, 137.7,
137.9, 138.4, 169.0, 169.1. IR (nmax, neat) 3000, 1735, 1666,
1527, 1450, 1227, 1178, 1074 cm21. HRMS (FAB) calcd
for (MþH) C27H37BrNO3Si: 530.1726, found 530.1719.
3.1.15. (5S)-N-(1-(R)-Benzylallyl)-2-(tert-butyldimethyl-
silyl)oxy-5-phenyl-2-(phenylseleno)acetyl-1,3-oxazoli-
din-4-one (3e). Colorless oil. [a]D¼þ3.68 (c 0.55 CHCl3).
1H NMR d 20.09 (s, 3H for major isomer), 0.14 (s, 3H for
minor isomer), 0.18 (s, 3H for major isomer), 0.29 (s, 3H for
minor isomer), 0.88 (s, 9H for minor isomer), 0.92 (s, 9H for
major isomer), 2.88–2.99 (m, 1H), 3.36–3.51 (m, 3H),
3.91–4.02 (m, 1H), 4.96 (d, 1H, J¼17.2 Hz), 5.10 (d, 1H,
J¼10.1 Hz for major isomer), 5.16 (d, 1H, J¼5.9 Hz for
minor isomer), 5.21 (s, 1H for minor isomer), 5.28 (s, 1H for
major isomer), 6.29–6.44 (m, 1H), 6.89–7.60 (m, 15H). 13C
NMR d 23.6, 23.3, 23.2, 22.9, 13.9, 17.7, 22.4, 25.6,
25.7, 31.4, 37.6, 37.8, 38.4, 38.7, 59.1, 59.4, 77.7, 80.6,
110.9, 111.0, 117.1, 117.8, 125.5, 126.2, 126.3, 126.4,
126.5, 126.7, 126.7, 127.5, 127.9, 128.1, 128.4, 128.7,
128.9, 129.5, 131.5, 132.7, 135.2, 135.2, 135.3, 135.9,
137.6, 137.8, 169.0, 169.2. IR (nmax, neat) 3000, 1716, 1409,
1251, 1072 cm21. HRMS (FAB) calcd for (MþH) C32H40-
NO3Si78Se: 592.1950, found 592.1950.
3.1.16. (5S)-2-(tert-Butyldimethylsilyl)oxy-5-N-(1-(S)-
isopropylallyl)-phenyl-2-(phenylseleno)acetyl-1,3-oxa-
zolidin-4-one (3f). Colorless oil. [a]D¼þ65.08 (c 1.13
CHCl3). 1H NMR d 0.00 (s, 3H for minor isomer), 0.10 (s,
3H for minor isomer), 0.21 (s, 3H for major isomer), 0.31 (s,
3H for major isomer), 0.90 (s, 9H for minor isomer), 0.93 (d,
6H, J¼6.6 Hz for major isomer), 0.94 (s, 9H for major
isomer), 1.00 (d, 6H, J¼6.6 Hz for minor isomer), 2.36–
2.44 (m, 1H for minor isomer), 2.66–2.79 (m, 1H for major
isomer), 3.32 (t, 1H, J¼9.7 Hz for major isomer), 3.42–3.48
(m, 2H), 3.84 (t, 1H, J¼9.1 Hz for minor isomer), 5.06–
5.21 (m, 2H), 5.25 (s, 1H for minor isomer), 5.36 (s, 1H for
major isomer), 6.00–6.18 (m, 1H), 7.14–7.62 (m, 10H). 13C
NMR d 23.6, 23.1, 22.8, 22.7, 18.0, 20.0, 20.5, 20.6,
20.7, 25.6, 25.7, 26.0, 28.1, 30.5, 38.2, 40.4, 63.1, 65.2,
77.7, 80.5, 111.3, 111.7, 118.0, 119.7, 126.7, 127.1, 127.6,
128.3, 128.5, 128.9, 129.1, 131.1, 131.3, 131.6, 132.0,
3.1.19. (2S)-N-Allyl-2-(tert-butyldimethylsilyl)oxy-2-
(iodo)phenyl-5-phenyl-1,3-oxazolidin-4-one (3i). Color-
less oil. [a]D¼þ12.98 (c 1.57, CHCl3). 1H NMR d 20.58 (s,
3H for major isomer), 20.23 (s, 3H for major isomer), 0.22
(s, 3H for minor isomer), 0.27 (s, 3H for minor isomer), 0.91
(s, 9H for minor isomer), 1.04 (s, 9H for major isomer), 3.47
(dd, 1H, J¼6.6 Hz, 15.5 Hz for minor isomer), 3.68 (dd, 1H,
J¼6.4, 15.3 Hz for major isomer), 3.95 (dd, 1H, J¼6.3,
15.5 Hz for major isomer), 3.97 (dd, 1H, J¼5.9, 14.7 Hz for
minor isomer),4.91–5.02 (m, 2H), 5.62 (s, 1H for minor
isomer), 5.66–5.82 (m, 1H), 5.99 (s, 1H for major isomer),
7.00–8.02 (m, 9H). 13C NMR d 23.7, 23.0, 22.8,22.6,
14.0, 14.1, 18.4, 22.6, 25.6, 26.0, 26.1, 31.5, 42.9, 43.4,
75.9, 80.8, 93.0, 94.8, 110.2, 110.9, 117.8, 118.0, 126.3,
127.1, 127.3, 127.6, 127.9, 128.5, 128.9, 129.0, 130.5,
130.7, 130.9, 131.1, 132.0, 133.5, 135.5, 138.8, 140.1,
142.9, 169.4, 170.1. IR (nmax, neat) 2900, 1710, 1420, 1240,
1200 cm21. MS (FAB) m/z 536 [(MþH)þ, 11%].
132.9, 134.4, 134.8, 135.6, 136.2, 168.8, 169.8. IR (nmax
neat) 3050, 2920, 1720, 1560, 1450, 1400, 1240 cm21
,
.
HRMS (FAB) calcd for (MþH) C28H40NO3Si80Se:
546.1942, found 546.1935.
3.1.17. (5S)-2-(tert-Butyldimethylsilyl)oxy-5-N-(1-(R)-
isopropylallyl)-phenyl-2-(phenylseleno)acetyl-1,3-oxa-
zolidin-4-one (3g). Colorless oil. [a]D¼230.68 (c 1.21
3.1.20. Preparation of (2S)-7a-(tert-butyldimethylsilyl)-
oxy-6-methyl-2-phenyltetrahydropyrrolo[2,1-b]oxazol-
3-one (4a) through radical cyclization. General pro-
cedure. To a solution of 3c (1.1473 g, 2.28 mmol) in
1
CHCl3). H NMR d 0.06 (s, 3H for major isomer), 0.15 (s,

A. Kamimura et al. / Tetrahedron 59 (2003) 6291–6299
6297
toluene (34 mL) at 0 8C was added a solution of Bu3SnH
(1.25 mL, 4.50 mmol) and AIBN (0.052 g, 0.32 mmol) in
toluene (80 mL) over 12 h under UV irradiation conditions.
The solvent was removed in vacuo and the residue was
subjected to flash chromatography to give 4a in 76% yield
(0.6017 g, 1.73 mmol). The diastereomer ratio was 85:15
which was determined by HPLC analysis (Chiral Pak-AD).
Colorless oil. 1H NMR d 0.18 (s, 3H for minor isomer), 0.20
(s, 3H for major isomer), 0.22 (s, 3H for minor isomer), 0.23
(s, 3H for major isomer), 0.92 (s, 9H for minor isomer), 0.94
(s, 9H for major isomer), 1.12 (d, 1H, J¼6.6 Hz for minor
isomer), 1.17 (d, 1H, J¼6.6 Hz for major isomer), 1.82–
1.92 (m, 1H), 2.42–2.51 (m, 2H), 2.80 (dd, 1H, J¼6.9,
11.6 Hz for major isomer), 3.10 (dd, 1H, J¼8.1, 11.4 Hz for
minor isomer), 3.43 (dd, 1H, J¼8.1, 11.4 Hz for minor
isomer), 3.91 (dd, 1H, J¼7.8, 12.0 Hz for major isomer),
5.57 (s, 1H for major isomer), 5.67 (s, 1H for minor isomer),
7.33–7.41 (m, 5H). 13C NMR d 23.7, 23.5, 23.4, 23.3,
17.6, 19.3, 25.4, 25.6, 33.9, 33.2, 45.5, 45.7, 48.7, 49.3,
81.5, 82.8, 117.7, 118.1, 126.4, 126.5, 128.5, 135.6, 172.2.
major isomer), 0.95 (s, 9H for major isomer), 1.64–1.80 (m,
1H), 2.26–2.29 (m, 1H), 2.46–2.52 (m, 1H), 2.75–2.88 (m,
1H), 3.19–3.62 (m, 1H), 4.11–4.20 (m, 1H), 5.38 (s, 1H for
major isomer), 5.64 (s, 1H for minor isomer), 7.17–7.51 (m,
10H). 13C NMR d 23.8, 23.6, 23.2, 14.0, 17.5, 18.7, 20.2,
22.5, 25.6, 25.8, 31.4, 35.4, 39.4, 39.8, 41.4, 44.2, 47.3,
62.2, 64.9, 82.3, 83.6, 116.5, 118.1, 126.2, 128.0, 128.1,
128.2, 129.0, 129.2, 137.3, 138.4, 169.3, 170.6. IR (nmax
,
neat) 3000, 1687, 1257, 1228 cm21. HRMS (FAB) calcd for
(MþH) C26H36NO3Si: 438.2464, found 438.2467.
3.1.23. (2S,5S)-7a-(tert-Butyldimethylsilyl)oxy-5-iso-
propyl-6-methyl-2-phenyltetrahydropyrrolo[2,1-b]oxa-
zol-3-one (4f). Colorless oil. 1H NMR d 20.14, 0.10 (s, 3H
for minor isomer), 0.12 (s, 3H for minor isomer), 0.21 (s, 6H
for major isomer), 0.68 (d, 3H, J¼6.9 Hz for major isomer),
0.84 (d, 3H, J¼6.6 Hz for minor isomer), 0.86 (s, 9H for
minor isomer), 0.92 (d, 3H, J¼7.3 Hz for major isomer),
0.94 (s, 9H for major isomer), 1.03 (d, 3H, J¼6.6 Hz for
minor isomer), 1.18 (d, 3H, J¼6.6 Hz for minor isomer),
1.26 (d, 3H, J¼7.3 Hz for major isomer), 2.24–2.32 (m,
1H), 2.35–2.51 (m, 1H), 2.89–3.00 (m, 1H), 3.22 (t, 1H,
J¼7.1 Hz for minor isomer), 3.35 (t, 1H, J¼3.3 Hz for
major isomer), 5.34 (s, 1H for minor isomer), 5.56 (s, 1H for
major isomer), 7.31–7.49 (m, 5H). 13C NMR d 24.8, 23.8,
23.6, 15.7, 16.5, 17.9, 18.6, 18.9, 19.5, 20.4, 22.6, 25.2,
25.5, 25.6, 26.0, 29.3, 33.8, 38.2, 38.7, 40.7, 68.1, 69.2,
82.3, 83.6, 117.3, 126.3, 127.6, 127.9, 128.3, 128.4, 128.5,
130.0, 130.1, 175.1. IR (nmax, neat) 3000, 11733, 1375,
1247, 1047 cm21. HRMS (FAB) calcd for (MþH)
C22H36NO3Si: 390.2465, found 390.2462.
IR (nmax, neat) 3000, 1750, 1650, 1300, 1250 cm21
.
Anal.Calcd for C19H29NO3Si: C, 65.67; H, 8.41; N,
4.03%. Found: C, 65.78; H, 8.67; N, 3.92.
3.1.21. Preparation of (2S,5S)-5-benzyl-7a-(tert-butyl-
dimethylsilyl)oxy-6-methyl-2-phenyltetrahydropyr-
rolo[2,1-b]oxazol-3-one (4d). General procedure. A
solution of 3d (0.9777 g, 1.65 mmol), Bu3SnH (0.55 mL,
2.05 mmol) and AIBN (0.0491 g, 0.30 mmol) in toluene
(17 mL), purged by nitrogen, was heated at refluxing
temperature for 4 h. The solvent was removed in vacuo
and the residue was subjected through flash chromatography
(silica gel/hexane–ether 20:1 then 5:1 v/v) to give 4d in
90% yield (0.6497 g, 1.48 mmol). Colorless oil. The
diastereomer ratio was determined by HPLC analyses
(Chiral Pak-AD). The ratio was¼70:29:1:.0. [a]D¼
þ47.88 (c 0.34, CHCl3). 1H NMR d 20.14 (s, 3H for
minor isomer), 0.10 (s, 3H for major isomer), 0.13 (s, 3H for
minor isomer), 0.19 (s, 3H for major isomer), 0.74 (d, 3H,
J¼6.9 Hz for major isomer), 0.82 (d, 3H, J¼6.9 Hz for
minor isomer), 0.90 (s, 9H for minor isomer), 0.92 (s, 9H for
major isomer), 1.27–1.36 (m, 1H), 1.79 (m, 1H), 2.22–2.38
(m, 1H), 2.64 (dd, 1H, J¼9.2, 13.8 Hz for major isomer),
2.84 (dd, 1H, J¼8.2, 13.2 Hz for minor isomer), 3.58–3.61
(m, 1H), 3.75–3.87 (m, 1H), 5.32 (s, 1H for minor isomer),
5.55 (s, 1H for major isomer), 7.21–7.47 (m, 10H). 13C
NMR d 23.7, 23.6, 23.5, 23.4, 13.5, 14.0, 17.6, 19.1,
20.7, 22.6, 23.3, 25.6, 25.7, 27.7, 29.0, 31.5, 35.7, 38.2,
39.0, 39.8, 42.0, 43.8, 46.8, 62.6, 63.3, 83.5, 83.6, 117.2,
117.9, 126.3, 126.5, 128.3, 128.4, 129.3, 129.4, 135.8,
137.7, 169.1, 171.6. IR (nmax, neat) 3000, 1743, 1687, 1290,
1257, 1214, 1186 cm21. HRMS (EI) calcd for (Mþ)
C26H35NO3Si: 437.2386, found 437.2390.
3.1.24. (2S,5R)-7a-(tert-Butyldimethylsilyl)oxy-5-iso-
propyl-6-methyl-2-phenyltetrahydropyrrolo[2,1-b]oxa-
1
zol-3-one (4g). Colorless oil. H NMR d 20.34 (s, 3H for
minor isomer), 0.07 (s, 3H for minor isomer), 0.19 (s, 3H for
major isomer), 0.22 (s, 3H for major isomer), 0.82 (s, 9H
for minor isomer), 0.90 (d, 3H, J¼6.9 Hz for minor isomer),
0.91 (d, 3H, J¼6.9 Hz for minor isomer), 0.92 (s, 3H for
major isomer), 1.01 (d, 3H, J¼6.9 Hz for major isomer),
1.02 (d, 3H, J¼6.9 Hz for major isomer), 1.12 (d, 3H,
J¼7.3 Hz for minor isomer), 1.23 (d, 3H, J¼7.3 Hz for
major isomer), 1.65–1.88 (m, 2H), 2.11 (dd, 1H, J¼10.4,
12.3 Hz for minor isomer), 2.31 (dd, 1H, J¼6.9, 11.9 Hz for
major isomer), 2.43–2.54 (m, 1H), 2.87–3.30 (m, 1H), 5.43
(s, 1H for major isomer), 5.66 (s, 1H for minor isomer),
7.25–7.50 (m, 5H). 13C NMR d 23.8, 23.5, 23.4, 22.8,
16.5, 17.7, 17.8, 19.7, 19.8, 20.1, 20.3, 22.5, 23.4, 25.3, 25.6,
25.8, 25.9, 33.2, 34.0, 37.8, 44.0, 47.9, 68.1, 68.9, 82.3, 84.7,
117.0, 118.8, 126.4, 128.3, 128.4, 128.5, 128.6, 128.7, 135.8,
135.9, 168.5, 171.4. IR (nmax, neat) 2960, 1741, 1689, 1463,
1375, 1288, 1255, 1216, 1184 cm21. HRMS (FAB) calcd for
(MþH) C22H36NO3Si: 390.2465, found 390.2462.
Other bicyclic lactams 4e to 4h were prepared in a similar
procedure.
3.1.25. (2S,5S)-5-Benzyl-7a-(tert-butyldimethylsilyl)oxy-
6,7-dimethyl-2-phenyltetrahydropyrrolo[2,1-b]oxazol-3-
1
one (4h). Colorless oil. [a]D¼þ39.28 (c 0.72 CHCl3). H
3.1.22. (2S,5R)-5-Benzyl-7a-(tert-butyldimethylsilyl)oxy-
6-methyl-2-phenyltetrahydropyrrolo[2,1-b]oxazol-3-one
NMR d 20.15 (s, 3H for one isomer), 20.10 (s, 3H for one
isomer), 0.09 (s, 3H for one isomer), 0.11 (s, 3H for
one isomer), 0.18 (s, 3H for one isomer), 0.19 (s, 3H for one
isomer), 0.21 (s, 3H for one isomer), 0.22 (s, 3H for one
isomer), 0.89 (s, 9H for one isomer), 0.92 (s, 9H for
one isomer), 0.93 (s, 9H for one isomer), 0.94 (s, 9H for one
1
(4e). Colorless oil. H NMR d 20.27 (s, 3H for minor
isomer), 20.14 (s, 3H for minor isomer), 0.22 (s, 6H for
major isomer), 0.80 (d, 3H, J¼7.2 Hz for minor isomer),
0.82 (s, 9H for minor isomer), 0.89 (d, 3H, J¼6.3 Hz for

6298
A. Kamimura et al. / Tetrahedron 59 (2003) 6291–6299
isomer), 0.74–1.03 (m, 6H), 2.05–2.32 (m, 1H), 2.49–3.00
(m, 1H), 3.12–3.19 (m, 1H), 3.52–3.67 (m, 1H), 3.99–4.04
(m, 1H), 5.27 (s, 1H for one isomer), 5.35 (s, 1H for one
isomer), 5.47 (s, 1H for one isomer), 5.64 (s, 1H for one
isomer), 7.13–7.49 (m, 10H). 13C NMR d 24.0, 23.8,
23.7, 23.5, 23.4, 23.2, 23.1, 8.5, 9.0, 13.9, 14.1, 15.1, 15.9,
17.2, 17.6, 17.9, 19.8, 22.4, 23.1, 25.4, 25.6, 25.7, 25.8, 31.4,
35.9, 36.7, 39.0, 41.2, 41.8, 43.8, 45.4, 47.4, 60.0, 62.9, 64.5,
74.0, 83.5, 84.8, 118.1, 118.5, 119.1, 126.0, 126.1, 126.2,
126.2, 126.3, 126.4, 126.5, 126.6, 126.7, 127.5, 127.6, 127.9,
128.2, 128.2, 128.3, 128.4, 128.6, 128.6, 128.8, 129.1, 129.3,
129.3, 129.5, 129.8, 130.0, 134.2, 135.3, 135.9, 136.3, 136.4,
137.6, 137.6, 168.4, 171.2, 174.7, 178.0. IR (nmax, neat) 3000,
1730, 1253, 1186 cm21. HRMS (FAB) calcd for (MþH)
C27H38NO3Si: 452.2621, found 452.2616.
3.1.29. 5-(S)-Benzyl-3,4-dimethylpyrrolidin-2-one (5h).
The diastereomeric ratio of 5h was determined by HPLC
analysis for its N-Boc derivative (Chiral Pak AD, hexane/
2-PrOH 99:1 v/v; flow rate, 0.5 mL/min; major-N-Boc-5h;
tR¼20.4 min, minor-N-Boc-5h; tR¼18.6 min) to be 59:41.
1
Yellow oil [a]D¼223.98 (c 0.61 CHCl3). H NMR d 1.03
(d, 3H, J¼6.9 Hz for major isomer), 1.09 (d, 3H, J¼7.6 Hz
for major isomer), 1.14 (d, 3H, J¼6.6 Hz for minor isomer),
1.18 (d, 3H, J¼7.3 Hz for minor isomer), 1.62–1.76 (m, 1H
for minor isomer), 2.00–2.19 (m, 1H for major isomer),
2.22–2.35 (m, 1H), 2.47–2.64 (m, 1H), 2.92–3.06 (m, 1H),
3.31–3.47 (m, 1H), 5.44 (br, 1H), 7.16–7.35 (m, 5H). 13C
NMR d 10.3, 13.7, 13.8, 16.2, 38.0, 39.2, 40.9, 41.1, 44.5,
44.6, 60.9, 61.0, 126.5, 126.6, 128.5, 128.6, 128.8, 128.9,
137.5, 137.6, 179.0, 180.0. IR (nmax, neat) 3245, 1700, 1658,
1454, 1268 cm21. HRMS (FAB) calcd for (MþH)
C13H18NO: 204.1388, found 204.1386.
3.1.26. Preparation of (R)-(1)-4-methylpyrrolidin-2-one
(5a).8 General procedure. To a solution of 4a (0.6017 g,
1.73 mmol) in THF (2 mL) was added TBAF (2 mL, 1.0 M
in THF solution) at room temperature. The reaction mixture
was allowd to stir for 30 min. The solvent was removed in
vacuo and the residue was subjected to flash chromato-
graphy (silica gel/hexane–ethyl acetate 3:1 then ethyl
acetate–acetone 3:1, 1:1, ethyl acetate–AcOH 9:1 v/v) to
give 5a in 84% yield (0.1441 g, 1.45 mmol). [a]D¼þ30.08
3.1.30. Preparation of 10b-(tert-Butyldimethylsilyl)oxy-
6-methyl-2-(S)-phenyl-6,10b-dihydro-5H-oxazolo[2,3-
a]isoquinolin-3-one (7). This compound was prepared in a
similar procedure to the preparation of 4. The diastereo-
meric ratio of 7 was determined by HPLC analysis (Chiral
Pak AD, hexane/2-PrOH 95:5 v/v; flow rate, 0.5 mL/min;
retention times for 4 diastereomers were; 23.4, 26.9, 27.7,
and 32.6 min) to be 46:7:31:15. Colorless oil. [a]D¼þ64.58
(c 1.18 CHCl3). 1H NMR d 20.20 (s, 3H for major isomer),
0.07 (s, 3H for major isomer), 0.19 (s, 3H for minor isomer),
0.20 (s, 3H for minor isomer), 0.84 (s, 9H for major isomer),
0.89 (s, 9H for minor isomer), 1.34 (d, 3H, J¼6.6 Hz for
minor isomer), 1.38 (d, 3H, J¼6.6 Hz for major isomer),
3.02–3.31 (m, 2H), 4.21 (dd, 1H, J¼5.3, 11.9 Hz for minor
isomer), 4.31 (dd, 1H, J¼6.1, 12.4 Hz for major isomer),
5.17 (s, 1H for major isomer), 5.53 (s, 1H for minor isomer),
7.03–7.67 (m, 9H). 13C NMR d 23.8, 23.7, 23.4, 23.3,
14.1, 17.8, 18.0, 18.1, 18.8, 22.6, 23.4, 25.5, 25.6, 30.9,
31.5, 42.5, 42.8, 79.9, 80.1, 106.1, 124.8, 126.2, 126.3,
126.4, 126.5, 126.7, 127.0, 127.1, 127.2, 127.3, 128.3,
128.4, 128.8, 129.1, 135.7, 136.1, 136.8, 136.9, 137.7,
137.8, 168.4. IR (nmax, neat) 3050, 2950, 1730, 1450,
1
(c 1.08, CHCl3). H NMR d 1.15 (d, 3H, J¼6.6 Hz), 1.95
(dd, 1H, J¼7.1, 15.3 Hz), 2.43 (d, 1H, J¼8.3 Hz), 2.48–
2.64 (m, 2H), 2.97 (dd, 1H, J¼5.9, 9.2 Hz), 3.51 (t, 1H,
J¼8.4 Hz), 5.64 (br, 1H). 13C NMR d 19.9, 29.7, 38.8, 50.0,
179.2. IR (nmax, neat) 3287, 1679, 1274 cm21. (S)-(þ)-
Mandelic acid 1 was also recovered in 72% yield (0.1895 g,
1.2 mmol). [a]D¼þ117.28 (CHCl3).
Other mandelic-acid free pyrrolidones 5 were prepared in a
similar manner.
3.1.27. (4R,5S)-5-Benzyl-4-methylpyrrolidin-2-one (5d).
The enantiomeric ratio of 5d or e was determined by HPLC
analysis (Chiral Cel OJ, hexane/2-PrOH 95:5 v/v; flow rate,
0.5 mL/min; 4R, 5S-5d; tR¼31.8 min, 4S, 5R-5e;
tR¼39.1 min) to be 95:5. Yellow oil. [a]D¼246.18 (c
0.71, CHCl3). 1H NMR d 1.13 (d, 3H, J¼6.6 Hz), 2.00 (dd,
1H, J¼7.8, 16.7 Hz), 2.14–2.17 (m, 1H), 2.52 (dd, 1H,
J¼8.4, 16.7 Hz), 2.59 (dd, 1H, J¼9.2, 13.5 Hz), 2.96 (dd,
1H, J¼4.3, 13.5 Hz), 3.38–3.45 (m, 1H), 5.44 (br, 1H),
7.16–7.36 (m, 5H). 13C NMR d 18.9, 35.3, 38.6, 41.7, 63.0,
126.8, 128.7, 128.9, 137.5, 177.0. IR (nmax, neat) 3200,
1685, 1456 cm21. HRMS (EI) calcd for (Mþ) C12H15NO:
189.1154, found 189.1183.
1240 cm21
.
3.1.31. Preparation of 4-methyl-3,4-dihydro-2H-iso-
quinolin-1-one (8).10 This compound was prepared in a
similar procedure to the preparation of 5. The enantiomeric
ratio of 8 was determined by HPLC analysis (Chiral Pak
AD, hexane/2-PrOH 97:3 v/v; flow rate, 0.5 mL/min; S-8;
tR¼45.1 min, R-8; tR¼46.9 min) to be 60:40. Colorless oil.
1
[a]D¼þ20.38 (c 1.10, CHCl3). H NMR d 1.36 (d, 3H,
J¼6.9 Hz), 3.07–3.19 (m, 1H), 3.29 (ddd, 1H, J¼3.4, 6.3,
8.6 Hz), 3.65 (ddd, 1H, J¼2.6, 4.8, 8.4 Hz), 6.02 (br, 1H),
7.26 (d, 1H, J¼7.6 Hz), 7.37 (dt, 1H, J¼1.0, 7.5 Hz), 7.47
(dt, 1H, J¼1.3, 7.6 Hz), 8.08 (dd, 1H, J¼1.7, 7.9 Hz). 13C
NMR d 17.9, 31.7, 45.8, 125.4, 126.4, 127.4, 127.7, 131.9,
3.1.28. (4R,5S)-5-Isopropyl-4-methylpyrrolidin-2-one
(5f). The enantiomeric ratio of 5f or 5g was determined
by HPLC analysis for its N-Boc derivative (chiral Pak AD,
hexane/2-PrOH 99:1 v/v; flow rate, 0.5 mL/min; 4R, 5S-N-
Boc-5f; tR¼21.9 min, 4S, 5R-N-Boc-5g; tR¼20.4 min) to be
143.6, 166.3. IR (nmax, neat) 3300, 2950, 1720, 1580 cm21
.
1
89:11. Yellow oil [a]D¼þ5.08 (c 0.42 CHCl3). H NMR d
HRMS (FAB) calcd for (MþH) C10H12NO: 162.0919,
0.91 (d, 3H, J¼6.9 Hz), 0.94 (d, 3H, J¼6.6 Hz), 1.14 (d, 3H,
J¼6.9 Hz), 1.57–1.76 (m, 1H), 1.94 (dd, 1H, J¼5.6,
17.2 Hz), 2.18–2.27 (m, 1H), 2.55 (dd, 1H, J¼8.9,
17.2 Hz), 2.97 (t, 1H, J¼5.1 Hz), 5.97 (br, 1H). 13C NMR
found 162.0923.
Acknowledgements
d 18.1, 19.2, 21.4, 31.9, 32.6, 39.2, 68.4, 178.4. IR (nmax
,
neat) 3220, 1693, 1465, 1388, 1280 cm21. HRMS (EI) calcd
Financial support from Sasakawa Scientific Research Grant
(to Y. O.) is appreciated.
for (Mþ) C17H23NO3: 289.1678, found 289.1673.

A. Kamimura et al. / Tetrahedron 59 (2003) 6291–6299
6299
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