Asymmetric inverse electron-demand 1,3-dipolar cycloaddition of ynolates with a chiral nitrone derived from L-serine leading to β-amino acid derivatives

Article abstract of DOI:10.1016/j.tetasy.2005.07.023

Asymmetric 1,3-dipolar cycloaddition of lithium ynolates with a nitrone derived from Garner's aldehyde is described. The cycloadducts, 5-isoxazolidinones, were obtained in good yields with high diastereoselectivity. Alkylation of the intermediates, the 5-

Full text of DOI:10.1016/j.tetasy.2005.07.023

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2821–2831
Asymmetric inverse electron-demand 1,3-dipolar cycloaddition of
ynolates with a chiral nitrone derived from L-serine leading to
b-amino acid derivatives
Mitsuru Shindo,a,* Keiko Ohtsukib and Kozo Shishidob
aInstitute for Materials Chemistry and Engineering, Kyushu University, 6-1, Kasugakoen, Kasuga 816-8580, Japan
bInstitute of Health Biosciences, The University of Tokushima Graduate School, Sho-machi 1, Tokushima 770-8505, Japan
Received 29 June 2005; accepted 21 July 2005
Abstract—Asymmetric 1,3-dipolar cycloaddition of lithium ynolates with a nitrone derived from GarnerÕs aldehyde is described. The
cycloadducts, 5-isoxazolidinones, were obtained in good yields with high diastereoselectivity. Alkylation of the intermediates, the 5-
isoxazolidinone enolates, was also achieved with high selectivity, the products of which were converted into the enantiomerically
pure b-amino acids, b-lactams, and c-lactams. In our cycloaddition, lithium ynolates proved to be much better as nucleophiles than
lithium enolates.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
ucts can be easily converted into b-amino acids 4, we
were eager to extend the method to asymmetric reac-
tions. Recently, we reported the asymmetric 1,3-dipolar
cycloaddition of ynolates with the D-mannitol-derived
chiral nitrone 5 with an oxygen-based stereogenic
center.4
Ynolates 1 are a versatile reactive species with an elec-
tron-rich triple bond,1 however, asymmetric reactions
of ynolates still remain unexplored. If a wider selection
of asymmetric syntheses using these compounds could
be developed, ynolates would then become a more pow-
erful tool in the synthetic chemistÕs arsenal. Since our
development of a new synthetic method for ynolates,2
we have found that the anionic inverse electron-demand
1,3-dipolar cycloaddition of nitrones 2 with ynolates 1
gives 5-isoxazolidinones 3 [Scheme 1(a)].3 As the prod-
While good diastereoselectivity was achieved using this
nitrone, various kinds of asymmetric reactions of yno-
lates would have to be conducted to demonstrate the
potential usefulness of ynolates in asymmetric reactions.
Products which contain a nitrogen functionality would
Me
O
Me
R
CO2H
NH2
Pd-C/H2
Bn 0 °C
N+
O-
R
(a)
(b)
O
R
N
Bn
3
2
4
Me
O
O
OLi
O
O
O
1a
Bn
-78 °C MeI
N+
O-
N
Bn
O
5
95% (88% de)
Scheme 1.
*
Corresponding author. Tel.: +81 92 583 7803; fax: +81 92 583 7875; e-mail: shindo@cm.kyushu-u.ac.jp
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.07.023

2822
M. Shindo et al. / Tetrahedron: Asymmetry 16 (2005) 2821–2831
Boc
N
Boc
N
Boc
N
Nu
NuM
Bn
syn
(a)
Bn
N+
O-
N
OH
O
O
high de
O
O
7
8
Garner's aldehyde 6
RMgBr, R
RCH=CHZnEt,
Li
NuM:
, TMSCN
.
HP(O)(OEt)2 TBSOTf
CH2=C=C(OMe)Li
OAc
Boc
OAc
N
anti
O
(b)
N
O
40% de
Bn
9
Scheme 2.
be more valuable for the construction of bioactive
organic molecules. GarnerÕs aldehyde 6, readily pre-
pared from L-serine, is a valuable chiral building block
which is configurationally stable and has been used
extensively in asymmetric synthesis.5 Nitrone 7 derived
from GarnerÕs aldehyde 6 is also a good chiral building
block, particularly for construction of chiral diamines.
In fact, the addition of Grignard reagents,6 lithium acet-
ylides,7 vinylzinc,8 silyl cyanides,9 diethyl phosphite10
and allenyl lithium11 afforded the syn-adducts 8 with
excellent diastereoselectivity [Scheme 2(a)]. However,
successful additions of metal ester enolates have not
been reported.12 1,3-Dipolar cycloadditions of 7, the
most representative reaction of nitrones, have been re-
ported only once using vinyl acetate as a dipolarophile
to give the anti-adduct 9 with moderate diastereoselec-
tivity [Scheme 2(b)].12 Thus, the asymmetric cycloaddi-
tion of 7 with dipolarophiles still remains unexplored.
We herein report the asymmetric 1,3-dipolar cycloaddi-
tion of ynolates with the chiral nitrone 7 leading to
chiral building blocks bearing an amino substituent.
2. Results
2.1. Asymmetric cycloaddition
Lithium ynolate 1a, prepared from dibromo ester 10a13
with t-BuLi, reacted with the nitrone 7 at ꢀ78 ꢁC to
afford desired 5-isoxazolidinone 12a in 32% yield after
quenching with aqueous NaHCO3 solution, along with
68% recovery of 7 (Scheme 3: Table 1, entry 1). After
separation of the stereoisomers by silica gel column
chromatography, the diastereomeric ratio (12aA:12a-
B:12aC) was found to be 73:21:6. Due to broadening
1
in the H NMR spectrum, the relative configuration of
the major isomer 12aA could not be determined at this
stage, but it was shown to be (3S,4R) by the transforma-
tion to the b- and c-lactams, described later. The config-
uration of 12aB was determined to be (3S,4S) by X-ray
crystal structure analysis, however that of the minor iso-
mer 12aC has yet to be ascertained, but it is possibly
(3R,4S) rather than (3R,4R).14 Consequently, the dia-
stereofacial selectivity (3S vs 3R) of the addition to the
Me
CO2Et
Br Br
10a
Me
OLi
Boc
N
Boc
N
Me
sat. NaHCO3 aq
+
Bn
O
N+
O-
N
Bn
THF
OLi
O
O
1a
7
11a
O
O
O
4
Boc
N
Boc
N
Boc
N
3
O
O
O
N
Bn
N
Bn
N
Bn
O
O
O
(3S,4R)
(3S,4S)
(3R,4S)
12aA
12aB
12aC
Scheme 3.

M. Shindo et al. / Tetrahedron: Asymmetry 16 (2005) 2821–2831
2823
Table 1. Optimization of the reaction temperature for Scheme 3
Entry Temperature (ꢁC) Time (h) Yield (%) A:B:C
ratio of the isomers A, B, and C in 71% yield. Based
on these results, we then employed the conditions for
entry 4 (Table 1) in the following experiments.
dea
88
1
2
3
4
ꢀ78
ꢀ50
ꢀ20
0
2
1
1
1
32
76
66
95
73:21:6
57:28:15 70
72:23:5
71:24:5
We next examined the cycloadditions of several kinds of
ynolates with nitrone 7. As depicted in Table 2, cyclo-
adducts 12A were obtained in good yield with good to
excellent diastereoselectivity. In the cases of entries 1
and 3, since there was only a small amount of the minor
isomers, with no separation or isolation of the individual
isomers B and C required. The sterically hindered yno-
lates 1c and 1e afforded cycloadducts 12A without detec-
tion of minor isomers (entries 2 and 4). In the case of the
trimethylsilyl substituted ynolate 1e, the product was
isolated after desilylation by citric acid (entry 4).
90
90
a (A + B) versus C.
nitrone was 88% de. In order to improve the yield of the
cycloadducts, the reaction was carried out at higher tem-
perature. As shown in Table 1, the best yield of
the adducts was obtained at 0 ꢁC without the loss of
diastereoselectivity.
The enolates 11 of the 5-isoxazolidinones generated by
the cycloaddition were alkylated to furnish the 2,2-
disubstituted products 13 along with a small amount
of unalkylated products 12A (Table 3). In entry 1, the
minor stereoisomers were not detected, although the
C-3 minor isomer of enolate 11a should have been pres-
ent in ca. 5%. Unlike the protonation, since R is steri-
cally hindered, the stereoselectivity as well as the yield
Since the ratio of isomers 12aA and 12aB should be
dependent on the quenching conditions, tert-butanol
was added to the enolate solution at 0 ꢁC in place of
aqueous NaHCO3 solution to convert the cis-isomer
12aB into the thermodynamically more stable trans-iso-
mer 12aA. As expected, the isomer 12aB disappeared,
but the total yield of isomers A and C decreased to
73%. Quenching with acetic acid resulted in a 76:16:8
Table 2. Asymmetric cycloaddition of ynolates 1 with the nitrone 7
R
O
Boc
N
Boc
N
R
0 °C, 1 h
THF
sat. NaHCO3 aq
+
O
Bn
N+
O-
N
Bn
OLi
O
O
1
7
(3S,4R)
12A
major isomer
Entry
Ynolate (R)
Yield (%)
Major : minorsa
1
2
3
4
1b
Bu
i-Pr
Ph
12bA
12cA
12dA
12eA
85
93
89
92b
90:10
>99:1
94:6
1c
1d
1e
TMS
>99:1
a The sum of the minor isomers B and C, the ratio of which was not determined.
b After desilylation by citric acid (R = H in 12eA).
Table 3. Alkylation of 5-isoxazolidinone enolates
R
OLi
Boc
N
Boc
N
R
R'X, HMPA
+
Bn
O
N+
O-
N
Bn
OLi
O
O
1
7
11
R
R'
R
N
R'
O
R
O
R'
Boc
N
O
R
H
O
Boc
N
Boc
N
Boc
N
+
O
+
+
O
O
O
N
Bn
N
Bn
N
Bn
O
O
O
O
Bn
13C
12A
13A
13B
Entry
R
R0X
Yield of major isomer (%)
Major : minors
12A
1
2
3
4
Me
Bu
i-Pr
Me
MeI
MeI
MeI
13aA, 81
13bA, 75
13cA, 43
13aB, 84
>99:1
94:6
71:29
88:12
3
9
24
0
BnBr

2824
M. Shindo et al. / Tetrahedron: Asymmetry 16 (2005) 2821–2831
Table 4. Transformation to b-lactams
decreased (entry 3 vs Table 2, entry 2). The major iso-
mers were generated by the attack of iodomethane on
the a-face of the enolates (entries 2 and 3). However,
benzyl bromide attacked predominantly from the b-face,
in which case the benzyl bromide approached trans to
the oxazoline moiety (entry 4). The stereochemistry of
these compounds was determined by the transformation
to c-lactams (entry 3) or X-ray crystal structure analysis
(entry 4).
Entry
R1
R2
17 (%)
18 (%)
18a
1
2
3
4
5
6
Me
Bu
i-Pr
Ph
Bu
i-Pr
H
H
H
H
Me
Me
17a
92
53
99
83
67
58
98
58
61
76
60
76
17b
17c
17d
17e
17f
18b
18c
18d
18e
18f
Scheme 5. According to the reported method,15 the
b-amino acids were converted to the b-lactams 17 in
good yields (Table 4). The NOE experiments of 17 re-
vealed the cis-relationship between R1 and the C4–H.16
The b-lactams were N-benzylated with benzyl bromide
in good yields.17
2.2. Transformation to c-lactams
In order to determine the stereochemistry and demon-
strate the synthetic utility, we next tried to convert chiral
5-isoxazolidinones into c-lactams (Scheme 4). The major
isomers of the 5-isoxazolidinones 12 and 13 were re-
duced by Pd/C catalyzed hydrogenation to afford the
b-amino acids 14 almost quantitatively. Acetylation of
the amino group, followed by esterification, gave 15 in
75% yield. Removal of the acetonide and Boc group
was carried out with 2 equiv of acetyl chloride in meth-
anol to provide 16 quantitatively. However, attempts to
cyclize to c-lactam 160 under basic conditions resulted in
hydrolysis of the methyl ester or intramolecular transfer
of the acetyl group. Attempts to protect the amino
group of 14 with other N-protective groups such as
CbzCl, benzoyl chloride, or tosyl chloride were unsuc-
cessful, probably because of steric hindrance.
Finally, we attempted the transformation to the c-lac-
tams under acidic conditions. The b-lactam 18a was
treated with acetyl chloride (5 equiv) in MeOH for
4 h under reflux to give the deprotected b-lactam 19a
in 79% yield. In the presence of 10 equiv of acetyl chlo-
ride in MeOH, the reaction was allowed to run for 16 h
under reflux to afford 23% of the desired c-lactam 20a
along with 56% of 19a. To complete the conversion of
19a to 20a, it was found that the C3-epimerized c-lac-
tam 21a was generated under harsher conditions. Since
20a and 21a were inseparable by column chromatogra-
phy, we tried to completely convert 20a to 21a. Finally,
when the b-lactams were refluxed in 25% HCl–EtOH
for 6 h, cyclization, followed by epimerization, pro-
vided the c-lactam 21a, along with a small amount of
the unsaturated c-lactam 22a. On prolonged reaction,
22a was predominantly generated. In order to facilitate
the separation of 21a from 22a, the mixture was treated
with TBDPSCl to give the O-silylated c-lactam 23a in
26% overall yield and the nonsilylated 22a, which
were easily separated by column chromatography
(Scheme 6). The same transformation was applied to
18b,c, and 18d to furnish 23b,c, and 23d in moderate
yields.
2
R1
R
2
R1
O
R
Boc
N
Boc
N
CO2H
Pd/C, H2 (4 atm)
O
NH2
N
MeOH
quant.
O
O
Bn
14
12, 13
Boc
N
Boc
CO2H
CO2Me
NH
Ac
15
MeI, DBU
CH3CN
Ac2O, Et3N
CH2Cl2
N
NH2
O
O
14aA
75%
Investigation of the stereochemistry of 23a and 23b by
NOE difference spectroscopy revealed cis-relationships
between the Me, C4–H and the C5–H as shown in Fig-
ure 1. According to these results, epimerization of C3–H
during the acidic cyclization was also apparent. In 23c,
the NOE between C4–H and C5–H was not clear, due
to overlapping of signals, but NOE experiments on the
methylated c-lactam 20f, generated by the same proto-
col, disclosed the cis-relationship between C4–H and
C5–H (Scheme 7). In the case of 23d, although the C3
stereochemistry was ambiguous, the configuration of
O
Cl-
CO2Me
AcCl (2)
MeOH
H3N+
NH
AcHN
NH
Ac
HO
quant.
OH
16'
16
Scheme 4.
We then examined the transformation of b-amino acids
14 into c-lactams through b-lactams 17 as shown in
R2
R2
R1
O
R1
O
NOE
2
R1
R
BnBr
Boc
N
NH
Bu4NHSO4
MsCl, Bu4NHSO4, K2CO3
H2O, CHCl3
Boc
CO2H
NBn
H
N
N
Boc
NH2
30% NaOH aq
CH2Cl2
O
O
O
14
17
18
Scheme 5.

M. Shindo et al. / Tetrahedron: Asymmetry 16 (2005) 2821–2831
2825
O
R
O
R
O
R
25% HCl-EtOH
reflux, 6 h
NH
OH
Boc
NBn
NBn
H2N
HO
N
BnHN
O
20
18
19
O
O
R
TBDPSCl, imidazole
4-DMAP
R
NH
H
NH
OTBDPS
BnHN
CH2Cl2
BnHN
H
OH
21
23a (R=Me), 26%
23b (R=Bu), 28%
23c (R=i-Pr), 7%
23d (R=Ph), 8%
O
R
NH
OH
22
Scheme 6.
NOE
O
NH
O
NOE
R
O
Ph
H
NH
H
BnHN
NH
BnHN
H
H
OTBDPS
H
BnHN
OTBDPS
H
OTBDPS
NOE
NOE
R = Me, Bu
23a, 23b
23c
23d
Figure 1. NOE experiments.
O
i-Pr
O
O
Li
i-Pr
Me
Me
R
H
O-
25% HCl-EtOH
H
N
NH
Boc
O
NBn
N
BnHN
reflux, 6 h
32%
H
N
H
OH
NOE
O
Boc
NOE
18f
Figure 2.
20f
Scheme 7.
electronegative group (NBoc) is perpendicular to the
C@N bond while the proton (CH@N) occupies the inner
position. The ynolate would attack the nitrone anti to
the C–N(Boc) bond.
C4 and C5 was found to be the same as that of the oth-
ers by NOE experiments.
Since metal enolates of methyl acetate are much less
reactive than ynolates,12 we decided to add the lithium
enolate of ethyl propionate to nitrone 7. We obtained
the 5-isoxazolidinone 12a in 33% yield with a diastereo-
meric ratio of 62:38 (12aA:12aC). This is actually a
worse yield than this for the ynolates, which are more
compact nucleophiles, and hence allow for greater effi-
ciency. This remarkable contrast demonstrates the high
potential of ynolates in asymmetric reactions.
3. Discussion
Ynolates have been shown to have high diastereofacial
selectivity as well as high reactivity with the nitrone 7,
derived from GarnerÕs aldehyde. According to several
reports18,7b on the addition of organometallic reagents
to nitrone 7, the stereochemical outcome would be as
shown in Figure 2. In this transition state model, the

2826
M. Shindo et al. / Tetrahedron: Asymmetry 16 (2005) 2821–2831
The C4 stereochemistry was determined in the proton-
ation or alkylation of 5-isoxazolidinone enolates. Under
either kinetic or thermodynamic protonation conditions,
cis-protonation or alkylation predominated to give the
trans-products, which would be thermodynamically
more stable than the cis-products (Table 2, entries 1–3;
Table 3, entries 1–3). Since the reaction center would
be sp3-like rather than sp2 in the transition state, which
would be relatively very product-like, the trans-products
should be generated. Furthermore, the N-benzyl group,
which may occupy the face opposite to the N-Boc-oxazo-
lidine, would assist in the a-attack of the electrophiles
(Fig. 3). In the benzylation (Table 3, entry 4) however,
the larger electrophile group would avoid steric interfer-
ence with the N-Boc-oxazolidine, and thus the opposite
stereoselectivity would be achieved.
Merck. Optical rotation: JASCO P-1010. Melting point:
Buchi 535. All reactions were performed under an Ar
¨
atmosphere, unless otherwise noted. The nitrone 7 was
prepared by the procedure of Merino.6 a,a-Dibromo es-
ters were prepared using our procedure.13
5.2. Asymmetric cycloaddition
5.2.1. Representative procedure: (3S,4R)-3-((R)-3-tert-
butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)-2-benzyl-4-
methylisoxazolidin-5-one 12aA. To a solution of ethyl
2,2-dibromopropanoate (312 mg, 1.2 mmol) in anhy-
drous THF (6 mL), cooled to ꢀ78 ꢁC, was added drop-
wise a solution of t-BuLi (3.4 mL, 4.8 mmol, 1.44 M in
pentane). The yellow solution was stirred for 3 h at
ꢀ78 ꢁC and allowed to warm to 0 ꢁC. After 30 min, a
solution of nitrone 7 (334 mg, 1.0 mmol) in THF
(2 mL) was added to the colorless reaction mixture.
After 1 h at 0 ꢁC, a satd NaHCO3 solution (20 mL)
was added, and the mixture was stirred vigorously at
rt. The resulting mixture was extracted with EtOAc
(3 · 20 mL). The combined organic phase was washed
with brine (20 mL) and dried over MgSO4. Removal
of the solvent under reduced pressure and purification
of the residue by column chromatography (SiO2;
EtOAc–hexane, 1:9) afforded a mixture of the isomers
(372 mg, 71:24:5, 95%) as a colorless oil. The major iso-
mer 12aA was separated from the mixture by HPLC. 1H
NMR (400 MHz, DMSO, 70 ꢁC): d = 1.21 (d,
J = 6.8 Hz, 3H), 1.41 (s, 3H), 1.44 (s, 9H), 1.53 (s,
3H), 2.99 (dq, J = 6.8, 11.2 Hz, 1H), 3.67 (dd, J = 6.8,
11.2 Hz, 1H), 4.03 (ddd, J = 6.8, 6.8, 9.6 Hz, 1H), 4.04
(d, J = 14.4 Hz, 1H), 4.09 (br s, 1H), 4.23 (dd, J = 1.6,
9.6 Hz, 1H), 4.29 (d, J = 14.4 Hz, 1H), 7.28–7.34 (m,
5H); 13C NMR (75 MHz, CDCl3): d = 15.7, 16.2, 22.0,
23.5, 25.7, 26.5, 28.2, 28.4 , 37.8, 56.3, 56.7, 63.3, 63.4,
63.7, 70.8, 72.2, 80.7, 81.0, 94.4, 95.1, 127.8, 128.1,
128.4, 128.5, 128.9, 129.0, 134.9, 135.2, 151.8, 152.8,
176.2; IR (neat): 1778, 1696 cmꢀ1; MS (EI): m/z = 390
E
R
OLi
OLi
O
H
O
H
R
Ph
N
Ph
N
E
O
NBoc
O
NBoc
cis-protonation or alkylation
leading to trans-product
trans-protonation or alkylation
leading to cis-product
Figure 3. cis-protonation or alkylation leading to trans-product trans-
protonation or alkylation leading to cis-product.
4. Conclusion
We have reported the highly stereoselective 1,3-dipolar
cycloaddition of ynolates with GarnerÕs aldehyde-de-
rived nitrone to furnish the 3,4-disubstituted and 3,4,4-
trisubstituted 5-isoxazolidinones. These adducts can
then be taken onto the enantiomerically pure b-amino
acids and c-lactams, which are useful as chiral building
blocks. Expanding on our previous report, we have also
found that ynolates, and not enolates, demonstrated a
greater possibility for high stereodifferentiation.
(M+), 57 (100%); HRMS (EI): m/z calcd for
23
C21H30N2O5, 390.2155. Found: 390.2168. ½aꢁD ¼ ꢀ93.9
(c 1.16, CHCl3).
5.2.2. (3S,4S)-2-Benzyl-3-((R)-3-tert-butoxycarbonyl-2,2-
dimethyloxazolidin-4-yl)-4-methylisoxazolidin-5-one 12aB.
Colorless prisms, mp 139–140 ꢁC (ether/hexane); 1H
NMR (400 MHz, CDCl3): d = 1.28 (d, J = 7.1 Hz, 3H),
1.50 (s, 9H), 1.56 (s, 3H), 1.62 (s, 3H), 2.72 (br, 1H),
3.59 (br, 1H), 3.94 (br s, 1H), 4.03 (dd, J = 7.1, 9 Hz,
1H), 4.26 (br, 1H), 4.28 (dd, J = 1.7, 9 Hz, 1H), 4.42
(d, J = 14 Hz, 1H), 7.27–7.42 (m, 5H), IR (CHCl3):
1773, 1688 cmꢀ1. Anal. Calcd for C21H30N2O5, C,
5. Experimental
5.1. General
64.59; H, 7.74; N, 7.17. Found: C, 64.29; H, 7.58; N,
25
THF was distilled from Na–benzophenone ketyl. 1H
NMR (JNM AL-400, 400 MHz) and 13C NMR (JNM
AL-300, 75 MHz and AL-400, 100 MHz) spectra were
recorded in CDCl3, unless otherwise noted, while chem-
ical shifts (d) are given in ppm relative to TMS (0.0 ppm).
IR spectra: JASCO FTIR-410. Mass spectra: JEOL
JMS-SX102A, JMS-DX303, JMS-AMSUN200, Waters
LCT-premier. Column chromatography: Kanto silica
gel. Preparative HPLC was performed using Mightysil
Si60, Kanto. Analytical TLC: Silica gel 60 F254 plates,
7.11; ½aꢁD ¼ ꢀ90.2 (c 1.05, CHCl3). Crystallographic
data for this structure have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary
publication numbers CCDC-273643. This data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html.
5.2.3. (3S,4R)-2-Benzyl-3-((R)-3-tert-butoxycarbonyl-2,2-
dimethyloxazolidin-4-yl)-4-butylisoxazolidin-5-one 12bA.
Colorless oil; purified by preparative HPLC (EtOAc–

M. Shindo et al. / Tetrahedron: Asymmetry 16 (2005) 2821–2831
2827
hexane, 1:9); 1H NMR (400 MHz, DMSO, 80 ꢁC):
d = 0.86 (t, J = 6.8 Hz, 3H), 1.25 (m, 2H), 1.41 (s,
3H), 1.43 (s, 9H), 1.52 (s, 3H), 1.41–1.61 (m, 4H), 2.93
(dt, J = 6.0, 8.4 Hz, 1H), 3.78 (br s, 1H), 4.03–4.12 (m,
3H), 4.08 (d, J = 14 Hz, 1H), 4.27 (d, J = 14 Hz, 1H),
7.28–7.35 (m, 5H); 13C NMR (75 MHz, DMSO):
d = 13.7, 21.8, 22.20, 22.25, 23.4, 25.6, 26.4, 27.6, 27.8,
29.2, 29.6, 41.7, 56.2, 56.5, 62.5, 63.0, 63.4, 66.3, 67.5,
79.1, 79.8, 93.7, 93.9, 127.5, 127.6, 128.20, 128.28,
129.0, 129.1, 135.9, 151.5, 152.1, 176.00, 176.09; IR
(neat): 1774, 1694 cmꢀ1; MS (EI): m/z = 432 (M+), 91
50 ꢁC): d = 1.45 (s, 3H), 1.48 (s, 9H), 1.51 (s, 3H), 2.65
(dd, J = 5.2, 17.2 Hz, 1H), 2.95 (dd, J = 5.6, 14.4 Hz,
1H), 3.85–4.19 (m, 6H), 7.29–7.34 (m, 5H); IR (neat):
23
1783, 1697 cmꢀ1; ½aꢁD ¼ ꢀ133.0 (c 1.16, CHCl3).
5.3. Asymmetric cycloaddition, followed by alkylation
5.3.1. Representative procedure for the synthesis of 13:
(3S)-2-benzyl-3-((R)-3-tert-butoxycarbonyl-2,2-dimethyl-
oxazolidin-4-yl)-4,4-dimethylisoxazolidin-5-one 13aA. To
a solution of ethyl-2,2-dibromopropanoate (312 mg,
1.2 mmol) in anhydrous THF (6 mL), cooled to ꢀ78 ꢁC,
was added dropwise a solution of t-BuLi (3.3 mL,
4.8 mmol, 1.47 M in pentane). The yellow solution was
stirred for 3 h at ꢀ78 ꢁC and allowed to warm to 0 ꢁC.
After 30 min, a solution of nitrone 7 (334 mg, 1.0 mmol)
in THF (2 mL) was added to the colorless reaction mix-
ture. After the reaction was stirred for 1 h at 0 ꢁC, HMPA
(0.52 mL, 3.0 mmol) and MeI (0.31 mL, 5 mmol) were
added. The mixture was stirred for 2 h at 0 ꢁC, and a satd
NaHCO3 solution (15 mL) was then added. The resulting
mixture was extracted with EtOAc (3 · 20 mL). The com-
bined organic phase was washed with H2O and brine
(20 mL), and dried over MgSO4. Removal of the solvent
under reduced pressure and purification of the residue by
column chromatography (SiO2; EtOAc–hexane, 1:9)
afforded a colorless oil (328 mg, 81%): 1H NMR
(400 MHz, DMSO, 70 ꢁC): d = 1.28 (s, 3H), 1.29 (s,
3H), 1.38 (s, 9H), 1.44 (s, 3H), 1.58 (s, 3H), 3.50 (d,
J = 8.0 Hz, 1H), 3.94 (d, J = 14.8 Hz, 1H), 3.98 (dd,
J = 7.2, 10 Hz, 1H), 4.06 (dd, J = 1.6, 10 Hz, 1H), 4.37
(d, J = 14.8 Hz, 1H), 4.42 (m, 1H), 7.31 (m, 5H); 13C
NMR (100 MHz, CDCl3, 50 ꢁC): d = 18.8, 24.2, 26.9,
28.3, 28.5, 45.1, 56.2, 63.7, 74.1, 81.0, 94.8, 127.6, 128.2,
(100%); HRMS (EI): m/z calcd for C24H36N2O5,
24
432.2626. Found: 432.2644. ½aꢁD ¼ ꢀ119.1 (c 1.16,
CHCl3).
5.2.4. (3S,4R)-2-Benzyl-3-((R)-3-tert-butoxycarbonyl-2,2-
dimethyloxazolidin-4-yl)-4-isopropylisoxazolidin-5-one
12cA. Colorless oil; purified by preparative HPLC
(EtOAc–hexane, 1:9); 1H NMR (400 MHz, CDCl3):
d = 0.98, 1.07 (d, J = 6.0 Hz, 3H · 2), 1.12, 1.18 (d,
J = 6.0 Hz, 3H · 2), 1.42, 1.44 (s, 3H · 2), 1.48 (s, 9H),
1.58, 1.61(s, 3H · 2), 1.89 (br s, 1H), 2.98 (m, 1H),
3.79 (br s, 1H), 4.02–4.25 (m, 5H), 7.33 (br s, 5H); 13C
NMR (75 MHz, CDCl3): d = 17.9, 18.0, 20.3, 20.5,
22.0, 23.4, 25.9, 26.7, 28.2, 28.4, 29.8, 47.7, 57.6, 58.1,
63.7, 64.1, 65.4, 66.8, 80.5, 80.9, 94.4, 95.0, 127.8,
128.1, 128.4, 128.6, 128.8, 129.2, 135.2, 152.8, 175.2,
175.6; IR (neat): 1771, 1702 cmꢀ1; MS (EI): m/z = 416
(M+), 57 (100%); HRMS (EI): m/z calcd for
23
C23H34N2O5, 418.2468. Found: 418.2451. ½aꢁD
¼
ꢀ125.2 (c 0.95, CHCl3).
5.2.5. (3S,4R)-2-Benzyl-3-((R)-3-tert-butoxycarbonyl-2,2-
dimethyloxazolidin-4-yl)-4-phenylisoxazolidin-5-one 12dA.
Colorless oil; purified by preparative HPLC (EtOAc–
hexane, 1:9); 1H NMR (400 MHz, DMSO, 80 ꢁC):
d = 1.01 (s, 3H), 1.31 (s, 3H), 1.34 (s, 9H), 4.04 (dd,
J = 7.0, 10.0 Hz, 1H), 4.20 (d, J = 14.4 Hz, 1H; m,
1H), 4.31 (t, J = 10.0 Hz, 1H; m, 1H), 4.42 (d,
J = 14.4 Hz, 1H; m, 1H), 7.28–7.40 (m, 10H); 13C
NMR (100 MHz, CDCl3): d = 23.4, 25.6, 28.2, 48.8,
56.8, 63.0, 63.1, 68.4, 80.7, 94.3, 127.8, 128.2, 128.3,
128.6, 128.8, 129.0, 134.4, 135.1, 152.4, 173.4; IR (neat):
1778, 1689 cmꢀ1; MS (EI): m/z = 452 (M+), 91 (100%);
128.8, 135.8, 153.0, 178.2; IR (neat): 1772, 1698 cmꢀ1
;
MS (FAB): m/z = 405 (M++H), 91 (100%); HRMS
(FAB): m/z calcd for C22H33N2O5 (M++H), 405.2389.
25
Found: 405.2368. ½aꢁD ¼ ꢀ111.2 (c 0.93, CHCl3).
5.3.2. (3S,4R)-2-Benzyl-3-((R)-3-tert-butoxycarbonyl-2,2-
dimethyloxazolidin-4-yl)-4-butyl-4-methylisoxazolidin-5-
one 13bA. Colorless oil; purified by preparative HPLC
(EtOAc–hexane, 1:9); 1H NMR (400 MHz, DMSO
80 ꢁC, a mixture of rotomer): d = 0.87 (m, 3H · 2),
1.27, 1.30 (s, 3H · 2), 1.37, 1.39 (2s, 9H · 2), 1.45, 1.47
(s, 3H · 2), 1.58, 1.59 (s, 3H · 2), 1.27–1.82 (m,
6H · 2), 3.47, 3.58 (d, J = 8.0 Hz, 1H · 2), 3.84–4.05
(m, 3H · 2), 4.37 (m, 1H · 2), 4.43, 4.54 (br, 1H · 2),
7.25–7.36 (m, 5H · 2); 13C NMR (100 MHz, CDCl3,
50 ꢁC): d = 13.6, 18.9, 22.8, 26.5, 26.9, 28.1, 36.9, 48.6,
56.4, 63.8, 64.0, 69.4, 80.7, 94.4, 127.2, 127.9, 128.7,
135.7, 153.0, 177.5; IR (neat): 1770, 1697 cmꢀ1; MS
(EI): m/z = 446 (M+), 246 (100%); HRMS (EI): m/z
HRMS (EI): m/z calcd for C26H32N2O5, 452.2311.
23
Found: 452.2311. ½aꢁD ¼ ꢀ86.4 (c 1.34, CHCl3).
5.2.6. (3S)-2-Benzyl-3-((R)-3-tert-butoxycarbonyl-2,2-di-
methyloxazolidin-4-yl)-isoxazolidin-5-one 12eA0. To a
solution of the crude mixture of (3-((R)-3-tert-butoxy-
carbonyl-2,2-dimethyloxazolidin-4-yl)-2-benzyl-4-trimeth-
ylsilylisoxazolidin-5-one) in THF (4.5 mL) and H2O
(1.5 mL) was added citric acid (768 mg, 4 mmol) and
the mixture stirred for 1 d at rt. A satd NaHCO3 solu-
tion was added and the mixture was extracted with
EtOAc (3 · 20 mL). The combined organic phase was
washed with brine (20 mL) and dried over MgSO4.
Removal of the solvent under reduced pressure and
purification of the residue by column chromatography
(SiO2; EtOAc–hexane, 1:1) afforded a colorless oil
(346 mg, 92%). The analytical data were consistent with
the literature data:12 1H NMR (400 MHz, CDCl3,
calcd for C25H38N2O5, 446.2781. Found: 446.2789.
23
½aꢁD ¼ ꢀ130.1 (c 0.96, CHCl3).
5.3.3. (3S,4R)-2-Benzyl-3-((R)-3-tert-butoxycarbonyl-2,2-
dimethyloxazolidin-4-yl)-4-isopropyl-4-methylisoxazolidin-
5-one 13cA. Colorless oil; purified by preparative
HPLC (EtOAc–hexane, 1:9); 1H NMR (400 MHz,
DMSO, 80 ꢁC): d = 0.97 (d, J = 6.8 Hz, 3H), 1.03 (d,
J = 6.8 Hz, 3H), 1.26 (s, 3H), 1.38 (s, 9H), 1.44 (s,

2828
M. Shindo et al. / Tetrahedron: Asymmetry 16 (2005) 2821–2831
3H), 1.55 (s, 3H), 1.98 (m, 1H), 3.60 (d, J = 6.8 Hz, 1H),
3.90 (d, J = 9.6 Hz, 1H), 3.99–4.08 (m, 2H), 4.29–4.35
(m, 2H), 7.24–7.37 (m, 5H); 13C NMR (100 MHz,
CDCl3, 50 ꢁC): d = 17.5, 17.9, 27.1, 28.3, 34.2, 51.3,
56.8, 64.7, 69.3, 80.7, 94.7, 127.5, 128.2, 129.0, 136.0,
153.2, 178.0; IR (neat): 1765, 1697 cmꢀ1; MS (EI):
5.4.2. (3R,4S)-4-((R)-3-tert-Butoxycarbonyl-2,2-dimeth-
yloxazolidin-4-yl)-3-butylazetidin-2-one 17b. Colorless
oil; purified by column chromatography (EtOAc–hex-
ane, 1:1); 1H NMR (400 MHz, CDCl3): d = 0.90 (t,
J = 6.8 Hz, 3H), 1.48 (s, 9H), 1.57 (s, 3H), 1.63 (s,
3H), 1.75 (m, 1H), 1.30–1.63 (m, 5H), 2.93 (br, 1H),
3.52 (br, 1H), 3.81 (br, 1H), 4.00 (m, 2H), 6.15 (br,
1H); 13C NMR (75 MHz, CDCl3): d = 13.8, 22.6, 24.2,
27.1, 28.3 (·4), 29.3, 53.6, 56.6, 59.5, 64.4, 80.9, 94.4,
153.2, 170.4; IR (neat): 1757, 1695 cmꢀ1; MS (FAB):
m/z = 327 (M++H), 154 (100%); HRMS (FAB): m/z
m/z = 432 (M+), 92 (100%); HRMS (EI): m/z calcd
24
for C24H36N2O5, 432.2624. Found: 432.2609. ½aꢁD
¼
ꢀ122.0 (c 1.06, CHCl3).
5.3.4. (3S,4R)-2,4-Dibenzyl-3-((R)-3-tert-butoxycarbonyl-
2,2-dimethyloxazolidin-4-yl)-4-methylisoxazolidin-5-one
13aB. Colorless needles; mp 131.9–132.2 ꢁC (Et2O–
calcd for C17H31N2O4 (M++H), 327.2284. Found:
27
327.2290. ½aꢁD ¼ ꢀ22.3 (c 1.10, CHCl3).
1
hexane); H NMR (400 MHz, DMSO, 70 ꢁC): d = 1.32
(s, 12H), 1.47 (s, 3H), 1.48 (s, 3H), 2.90 (d,
J = 14.0 Hz, 1H), 3.13 (d, J = 14.0 Hz, 1H), 3.36 (br s,
1H), 3.38 (d, J = 9.2 Hz, 1H), 3.81 (br s, 1H), 3.95 (m,
1H), 4.03 (d, J = 14.4 Hz, 1H), 4.42 (br s, 1H), 7.21–
7.37 (m, 10H); 13C NMR (100 MHz, CDCl3): d = 20.5,
24.8, 27.6, 28.2, 44.3, 50.6, 57.8, 64.3, 65.0, 68.3, 80.9,
94.4, 126.6, 127.3, 127.9, 128.4, 130.5, 135.6, 135.9,
153.1, 177.6, 177.7; IR (CHCl3): 1762, 1691 cmꢀ1; MS
(EI): m/z = 480 (M+), 57 (100%). Anal. Calcd for
5.4.3. (3R,4S)-4-((R)-3-tert-Butoxycarbonyl-2,2-dimeth-
yloxazolidin-4-yl)-3-isopropylazetidin-2-one 17c. Color-
less oil; purified by column chromatography (EtOAc–
hexane, 1:1); 1H NMR (400 MHz, CDCl3): d = 1.02
(d, J = 6.4 Hz, 3H), 1.08 (d, J = 7.2 Hz, 3H), 1.48 (s,
12H), 1.58 (s, 3H), 1.98 (m, 1H), 2.76 (br, 1H), 3.59
(m, 1H), 3.86 (dd, J = 9.6, 8.4 Hz, 1H), 3.99 (dd,
J = 9.6, 6.4 Hz, 1H), 4.06 (m, 1H), 5.90–6.20 (br, 1H);
13C NMR (100 MHz, CDCl3): d = 20.0, 20.8, 24.3,
27.2, 27.8, 28.4, 54.3, 59.6, 60.0, 64.3, 80.8, 94.3, 153.0,
169.7; IR (neat): 1757, 1697 cmꢀ1; MS (EI): m/z = 312
C28H36N2O5: C, 69.98; H, 7.55; N, 5.83. Found: C,
24
69.74; H, 7.56; N, 5.80. ½aꢁD ¼ ꢀ212.0 (c 1.13, CHCl3).
Crystallographic data for this structure have been
deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC-
273642. This data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html.
(M+), 113 (100%); HRMS (EI): m/z calcd for
27
C16H28N2O4, 312.2049. Found: 312.2029. ½aꢁD ¼ ꢀ28.3
(c 1.17, CHCl3).
5.4.4. (3R,4S)-4-((R)-3-tert-Butoxycarbonyl-2,2-dimeth-
yloxazolidin-4-yl)-3-phenylazetidin-2-one 17d. Color-
less oil; purified by column chromatography (EtOAc–
5.4. Conversion into b-lactams
1
hexane, 1:1); H NMR (400 MHz, CDCl3): d = 1.49 (s,
5.4.1. Representative procedure for the synthesis of 17:
(3R,4S)-4-((R)-3-tert-butoxycarbonyl-2,2-dimethyloxazoli-
din-4-yl)-3-methylazetidin-2-one 17a. The isoxazolidi-
none 12aA (128 mg, 0.33 mmol) was added to a
suspension of 10% Pd/C (25 mg, 20% w/w) in methanol
under H2 at 4.0 atm, and the mixture stirred at room
temperature for 2 h. The solution was filtered, and the
solvents removed in vacuo to afford the b-amino acid
14a (100 mg, >99%). To a solution of b-amino acid
14a (100 mg, 0.33 mmol) in CHCl3 (1.5 mL) and H2O
(0.3 mL), were added Bu4NHSO4 (16.8 mg, 0.04 mmol)
and KHCO3 (132.4 mg, 1.32 mmol). MsCl (0.05 mL,
0.66 mmol) was added, and the mixture stirred vigor-
ously at room temperature for 0.5 h. The resulting mix-
ture was extracted with EtOAc (3 · 10 mL) and the
combined organic phase washed with brine (10 mL)
and dried over Na2SO4. Removal of the solvent under
reduced pressure and purification of the residue by col-
umn chromatography (SiO2; EtOAc–hexane, 1:1) affor-
ded 17a (86.6 mg, 92%): Colorless prisms; mp 102.2–
102.7 ꢁC (EtOAc–hexane); 1H NMR (400 MHz,
CDCl3): d = 1.32 (d, J = 7.6 Hz, 3H), 1.48 (s, 9H),
1.54 (s, 6H), 2.98 (br, 1H), 3.44 (br, 1H), 3.79 (br,
1H), 4.04 (br, 2H), 6.13 (br, 1H); 13C NMR (75 MHz,
CDCl3): d = 13.1, 24.4, 27.2, 28.3, 48.3, 58.5, 59.5,
64.4, 80.9, 94.3, 153.1, 170.6; IR (CHCl3): 1759,
1683 cmꢀ1; MS (EI): m/z = 284 (M+), 170 (100%). Anal.
12H), 1.53 (s, 3H), 3.87–4.40 (m, 5H), 6.47 (br, 1H),
7.26–7.35 (m, 5H); 13C NMR (100 MHz, CDCl3):
d = 24.5, 27.2, 28.4, 58.5, 58.9, 59.6, 64.5, 81.0, 94.5,
127.3, 127.4, 128.7, 134.3, 153.0, 167.7; IR (neat):
1763, 1689 cmꢀ1; MS (FAB): m/z = 347 (M++H), 369
(100%, M++Na); HRMS (FAB): m/z calcd for
C19H26N2O4Na (M++Na), 369.1790. Found: 369.1766.
26
½aꢁD ¼ ꢀ24.7 (c 1.60, CHCl3).
5.4.5. (3R,4S)-4-((R)-3-tert-Butoxycarbonyl-2,2-dimethyl-
oxazolidin-4-yl)-3-butyl-3-methylazetidin-2-one 17e. Col-
orless oil; purified by column chromatography (EtOAc–
1
hexane, 1:1); H NMR (400 MHz, CDCl3): d = 0.85 (t,
J = 6.4 Hz, 3H), 1.18 (s, 3H), 1.25–1.63 (m, 21H), 3.42
(d, J = 9.6 Hz, 1H), 3.65 (br d, J = 8.8 Hz, 1H), 4.07
(m, 2H), 6.38 (br, 1H); 13C NMR (100 MHz, CDCl3):
d = 14.0, 15.8, 23.1, 24.5, 26.7, 27.7, 28.4, 36.0, 57.8,
59.2, 61.3, 65.3, 80.9, 94.0, 153.3, 172.8; IR (neat): 1762,
1698 cmꢀ1; MS (APCI+): m/z = 341 (M++H); HRMS
(APCI+): m/z calcd for C18H33N2O4(M++H), 341.2440.
26
Found: 341.2426. ½aꢁD ¼ ꢀ20.2 (c 1.22, CHCl3).
5.4.6. (3R,4S)-4-((R)-3-tert-Butoxycarbonyl-2,2-dimeth-
yloxazolidin-4-yl)-3-isopropyl-3-methylazetidin-2-one 17f.
Colorless oil; purified by column chromatography
(EtOAc–hexane, 1:1) 1H NMR (400 MHz, CDCl3):
d = 0.99 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H),
1.15 (s, 3H), 1.48 (s, 15H), 1.89 (m, 1H), 3.41 (d, J =
8.8 Hz, 1H), 3.57 (d, J = 8.8 Hz, 1H), 4.00 (m, 1H),
4.10 (m, 1H), 6.42 (br, 1H); 13C NMR (100 MHz,
Calcd for C14H24N2O4: C, 59.13; H, 8.51; N, 9.85.
25
Found: C, 58.89; H, 8.35; N, 9.84. ½aꢁD ¼ ꢀ18.2 (c
1.02, CHCl3).

M. Shindo et al. / Tetrahedron: Asymmetry 16 (2005) 2821–2831
2829
CDCl3): d = 12.5, 17.7, 18.3, 24.4, 27.8, 28.5, 32.5, 59.3,
59.5, 61.7, 65.4, 81.0, 94.0, 153.3, 172.8; IR (neat): 1762,
1698 cmꢀ1; MS (APCI+): m/z = 327 (M+H); HRMS
1H · 2), 2.88, 2.98 (br d, J = 7.3 Hz, 1H · 2), 3.49 (m,
1H · 2), 3.61–3.85 (m, 2H · 2, 1H · 2, 1H), 4.03 (br s,
1H), 4.05 (d, J = 15.3 Hz, 1H), 4.35 (s, 2H), 4.57 (d,
J = 15.3 Hz, 1H), 7.26–7.34 (m, 5H · 2); 13C NMR
(100 MHz, CDCl3): d = 20.0, 20.2, 20.9, 21.1, 22.4,
23.8, 26.5, 27.2, 28.2, 28.4, 44.8, 45.1, 54.8, 56.9, 55.92,
55.99, 57.7, 58.1, 62.1, 62.4, 80.2, 80.7, 94.9, 94.8,
127.5, 127.7, 128.2, 128.4, 128.6, 128.7, 135.6, 136.4,
(APCI+): m/z calcd for C17H31N2O4 (M++H),
26
327.2284. Found: 327.2278. ½aꢁD ¼ ꢀ21.0 (c 0.91,
CHCl3).
5.5. Conversion to N-benzyl-b-lactams
151.6, 152.7, 169.9, 170.1; IR (neat): 1747, 1695 cmꢀ1
;
5.5.1. Representative procedure for the synthesis of 18:
(3R,4S)-1-benzyl-4-((R)-3-tert-butoxycarbonyl-2,2-dimeth-
MS (EI): m/z = 402 (M+), 174 (100%); HRMS (EI):
m/z calcd for C23H34N2O4, 402.2519. Found: 402.2539.
27
yloxazolidin-4-yl)-3-methylazetidin-2-one 18a. To
a
½aꢁD ¼ ꢀ12.1 (c 0.84, CHCl3).
solution of b-lactam 17a (25 mg, 0.08 mmol) in CH2Cl2
(1.5 mL) and 30% aq NaOH (1.5 mL), was added
Bu4NHSO4 (16.8 mg, 0.04 mmol). Benzyl bromide
(0.01 mL, 0.13 mmol) was added and the mixture stirred
vigorously at room temperature for 2 h. H2O was added
to the resulting mixture, which was extracted with
CH2Cl2 (3 · 10 mL). The combined organic phase was
washed with brine (10 mL) and dried over Na2SO4. Re-
moval of the solvent under reduced pressure and purifi-
cation of the residue by column chromatography (SiO2;
EtOAc–hexane, 3:7) afforded 18a (32.4 mg, 98%): Color-
5.5.4.
(3R,4S)-1-Benzyl-4-((R)-3-tert-butoxycarbonyl-
2,2-dimethyloxazolidin-4-yl)-3-phenylazetidin-2-one 18d.
Colorless oil; purified by column chromatography
(EtOAc–hexane, 3:7); 1H NMR (400 MHz, CDCl3):
d = 1.30 (s, 3H · 2), 1.41–1.51 (m, 12H · 2), 3.57, 3.72
(m, 1H · 2), 3.72, 4.01 (br, 1H · 2), 3.92 (br d,
J = 10.0Hz, 1H · 2), 4.13 (br d, J = 7.6 Hz, 1H · 2),
4.26 (d, J = 14.8 Hz, 1H), 4.34–4.49 (m, 1H · 2), 4.42
(d, J = 15.6 Hz, 1H), 4.48 (d, J = 15.6 Hz, 1H), 4.56
(d, J = 14.8 Hz, 1H), 7.23–7.41 (m, 10H · 2); 13C
NMR (100 MHz, CDCl3): d = 22.6, 24.0, 26.7, 27.4,
28.4, 45.4, 45.5, 55.9, 56.0, 56.3, 57.0, 58.9, 59.5, 62.2,
62.5, 80.4, 80.8, 94.3, 94.8, 127.0, 127.1, 127.2, 127.7,
127.9, 128.1, 128.2, 128.4, 128.50, 128.57, 128.7, 128.8,
134.6, 135.4, 136.2, 151.3, 152.5, 168.4; IR (neat):
1756, 1698 cmꢀ1; MS (FAB): m/z = 437 (M+H), 91
1
less oil; H NMR (400 MHz, CDCl3): d = 1.25, 1.26 (s,
3H · 2), 1.36, 1.49 (s, 9H · 2), 1.41, 1.42 (s, 3H · 2),
1.45, 1.52 (s, 3H · 2), 3.13, 3.23 (m, 1H · 2), 3.41, 3.52
(br s, 1H · 2), 3.55–3.76 (m, 2H · 2), 3.83, 4.02 (br s,
1H · 2), 4.18 (d, J = 14.8 Hz, 1H), 4.37 (s, 2H), 4.50
(d, J = 14.8 Hz, 1H), 7.23–7.53 (m, 5H · 2); 13C NMR
(100 MHz, CDCl3): d = 13.0, 22.5, 24.0, 26.6, 27.3,
28.3, 45.1, 45.2, 46.3, 46.5, 55.9, 56.9, 59.4, 60.0, 62.3,
62.7, 80.2, 80.7, 94.0, 94.4, 127.6, 127.8, 128.1, 128.3,
128.7, 128.8, 135.8, 136.4, 151.4, 152.5, 171.1; IR (neat):
1753, 1698 cmꢀ1; MS (FAB): m/z = 375 (M+H), 57
(100%); HRMS (FAB): m/z calcd for C26H33N2O4
27
(M++H), 437.2440. Found: 437.2458. ½aꢁD ¼ þ38.1 (c
0.96, CHCl3).
5.5.5.
(3R,4S)-1-Benzyl-4-((R)-3-tert-butoxycarbonyl-
(100%); HRMS (FAB): m/z calcd for C21H31N2O4
26
(M++H), 375.2284. Found: 375.2271. ½aꢁD ¼ þ8.7 (c
2,2-dimethyloxazolidin-4-yl)-3-butyl-3-methylazetidin-2-
one 18e. Colorless oil; purified by column chromato-
graphy (EtOAc–hexane, 3:7); 1H NMR (400 MHz,
CDCl3): d = 0.85 (t, J = 6.4 Hz, 3H), 1.18–1.28 (m,
12H), 1.50–1.64 (m, 12H), 3.20 and 3.22 (br, 1H), 3.49
and 3.52 (br, 1H), 3.67 (d, J = 14.2 Hz, 1H), 3.91 (m,
1H), 4.23 and 4.33 (br, 1H), 4.97 (d, J = 14.2 Hz, 1H),
7.21–7.30 (m, 5H); 13C NMR (100 MHz, CDCl3):
d = 13.9, 15.7, 23.2, 24.7, 26.8, 27.8, 28.6, 36.1, 44.5,
56.1, 58.1, 61.1, 65.5, 80.9, 94.3, 127.4, 128.3, 128.6,
136.1, 153.1, 173.3; IR (CHCl3): 1750, 1696 cmꢀ1; MS
(APCI+): m/z = 431 (M++H); HRMS (APCI+):
1.39, CHCl3).
5.5.2. (3R,4S)-1-Benzyl-3-butyl-4-((R)-3-tert-butoxycar-
bonyl-2,2-dimethyloxazolidin-4-yl)-azetidin-2-one
18b.
Colorless oil; purified by column chromatography
(EtOAc–hexane, 3:7); 1H NMR (400 MHz, CDCl3):
d = 0.87 (t, J = 6.8 Hz, 3H · 2), 1.25–1.71 (m,
21H · 2), 3.06, 3.15 (m, 1H · 2), 3.51 (br s, 1H · 2),
3.66 (m, 1H · 2, 1H), 3.79 (br s, 1H), 3.81, 4.01 (br s,
1H · 2), 4.12 (d, J = 15.2 Hz, 1H), 4.33 (d, J = 16 Hz,
1H), 4.38 (d, J = 16 Hz, 1H), 4.52 (d, J = 15.2 Hz,
1H), 7.25–7.37 (m, 5H · 2); 13C NMR (100 MHz,
CDCl3): d = 13.8, 23.8, 22.3, 22.7, 26.4, 27.1, 28.3,
28.4, 29.5, 45.0, 45.1, 51.5, 51.7, 55.9, 56.9, 57.2, 58.2,
62.2, 62.5, 80.2, 80.7, 94.3, 94.7, 127.6, 127.9, 128.3,
128.4, 128.8, 128.9, 135.8, 136.5, 151.6, 152.8, 170.9.
IR (neat): 1751, 1698 cmꢀ1; MS (EI): m/z = 416 (M+),
m/z calcd for C25H39N2O4 (M++H), 431.2910. Found:
28
431.2896. ½aꢁD ¼ þ0.2 (c 0.92, CHCl3).
5.5.6.
(3R,4S)-1-Benzyl-4-((R)-3-tert-butoxycarbonyl-
2,2-dimethyloxazolidin-4-yl)-3-methyl-3-isopropylazetidin-
2-one 18f. Colorless prisms; mp 109–110 ꢁC (EtOAc–
hexane); 1H NMR (400 MHz, CDCl3): d = 0.84 (d,
J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H), 1.14 (s, 3H),
1.30 (br, 3H), 1.51 (s, 3H), 1.57 (s, 9H), 1.80 (m, 1H),
3.24, 3.26 (br s, 1H), 3.59, 3.62 (br s, 1H), 3.85 (m,
2H), 4.34 (br s, 1H), 4.95 (d, J = 14.8 Hz, 1H), 7.22–
7.31 (m, 5H); 13C NMR (100 MHz, CDCl3): d = 11.9,
17.9, 18.6, 24.8, 27.9, 28.6, 33.0, 44.4, 58.2, 59.9, 64.9,
65.5, 80.9, 94.3, 127.4, 128.3, 128.7, 136.2, 153.2,
173.1; IR (CHCl3): 1734, 1687 cmꢀ1; MS (APCI+):
m/z = 417 (M++H); HRMS (APCI+): m/z calcd for
188 (100%); HRMS (EI): m/z calcd for C24H36N2O4,
27
416.2675. Found: 416.2682. ½aꢁD ¼ þ1.8 (c 0.92,
CHCl3).
5.5.3.
(3R,4S)-1-Benzyl-4-((R)-3-tert-butoxycarbonyl-
2,2-dimethyloxazolidin-4-yl)-3-isopropylazetidin-2-one 18c.
Colorless oil; purified by column chromatography
(EtOAc–hexane, 3:7); 1H NMR (400 MHz, CDCl3):
d = 0.93 (d, J = 6.6 Hz, 3H · 2), 1.04 (d, J = 6.6 Hz,
3H · 2), 1.33–1.56 (m, 15H · 2), 1.76, 1.90 (m,

2830
M. Shindo et al. / Tetrahedron: Asymmetry 16 (2005) 2821–2831
C24H37N2O4 (M++H), 417.2753. Found: 417.2764.
½aꢁD ¼ ꢀ14.3 (c 0.54, CHCl3).
(d, J = 13.2 Hz, 1H), 3.64 (m, 1H), 3.75 (m, 2H), 5.71
(br s, 1H), 7.13–7.15 (m, 2H), 7.22–7.47 (m, 9H), 7.60–
7.65 (m, 4H); 13C NMR (100 MHz, CDCl3): d = 19.2,
19.3, 20.0, 26.9, 27.5, 52.5, 52.8, 56.4, 57.0, 64.2, 127.0,
127.7, 127.9, 128.2, 129.7, 129.8, 132.6, 132.7, 135.3,
135.4, 139.4, 176.9; IR (neat): 1698 cmꢀ1; MS (APCI+):
m/z = 501 (M++H); HRMS (APCI+): m/z calcd
28
5.6. Conversion into c-lactams
5.6.1. Representative procedure for the synthesis of 23:
(3S,4S,5R)-4-benzylamino-5-(tert-butyldiphenylsiloxymeth-
yl)-3-methylpyrrolidin-2-one 23a. A solution of the b-
lactam 18a (20 mg, 0.05 mmol) in 25% HCl–EtOH
(2 mL) was refluxed for 6 h. After removal of the solvent
under reduced pressure, the residue was diluted with
H2O and EtOAc. The solution was cooled to 0 ꢁC,
and Et3N was added until pH 9. The resulting mixture
was saturated with NaCl and extracted with EtOAc
(3 · 10 mL). The combined organic phase was dried
over Na2SO4, and the solvent was removed under re-
duced pressure. The residue was diluted with CH2Cl2,
and imidazole (5 mg, 0.07 mmol) and a catalytic amount
of 4-DMAP added. TBDPSCl (0.01 mL, 0.06 mmol)
was added to the resulting mixture, which was stirred
at room temperature for 4 h. Water was added, and
the mixture extracted with CH2Cl2 (3 · 10 mL). The
combined organic phase was washed with brine and
dried over Na2SO4. Removal of the solvent under re-
duced pressure and purification of the residue by column
chromatography (SiO2; EtOAc–hexane, 1:1) afforded
for C31H41N2O2Si (M+H), 501.2937. Found: 501.2943.
28
½aꢁD ¼ ꢀ45.2 (c 0.28, CHCl3).
5.6.4. (3S,4S,5R)-4-(Benzylamino)-5-(tert-butyldiphenyl-
siloxymethyl)-3-phenylpyrrolidin-2-one 23d. Orange oil:
purified by column chromatography (EtOAc–hexane,
1:1); 1H NMR (400 MHz, C6D6): d = 0.85 (s, 9H),
2.86 (br, 1H), 3.00 (d, J = 12.8 Hz, 1H), 3.06 (d,
J = 12.8 Hz, 1H), 3.16 (dd, J = 7.6, 10.4 Hz, 1H), 3.28
(dd, J = 2.8, 10.8 Hz, 1H), 3.40 (d, J = 10.4 Hz, 1H),
3.49 (dd, J = 4.8, 10.8 Hz, 1H), 5.78 (br s, 1H), 6.64–
6.66 (m, 2H), 6.74–6.99 (m, 9H), 7.46–7.50 (m, 4H);
13C NMR (100 MHz, CDCl3): d = 19.2, 27.0, 52.2,
54.6, 56.3, 63.6, 63.8, 126.9, 127.2, 127.73, 127.77,
128.2, 128.5, 128.7, 129.7, 129.8, 132.5, 132.6, 135.4,
135.5, 137.5, 139.2, 175.7; IR (neat): 1701 cmꢀ1
;
MS (APCI+): m/z = 535 (M+H); HRMS (APCI+): m/
z calcd for C34H39N2O2Si (M+H), 535.2781. Found:
27
535.2808. ½aꢁD ¼ ꢀ55.7 (c 0.19, CHCl3).
1
23a (6.5 mg, 26%); Colorless oil; H NMR (400 MHz,
CDCl3): d = 0.96 (s, 9H), 1.16 (d, J = 7.2 Hz, 3H),
1.60 (br, 1H), 2.31 (dq, J = 7.2, 10.0 Hz, 1H), 3.13
(dd, J = 7.6, 10.0 Hz, 1H), 3.56 (m, 1H), 3.63 (d,
J = 12.8 Hz, 1H), 3.67 (d, J = 12.8 Hz, 1H), 3.61–3.73
(m, 2H), 5.65 (br, 1H), 7.11–7.37 (m, 10H), 7.53–7.64
(m, 5H); 13C NMR (100 MHz, CDCl3): d = 14.6, 19.2,
26.9, 42.2, 52.6, 56.1, 63.2, 63.7, 127.0, 127.7, 127.8,
128.3, 129.7, 129.8, 132.4, 132.6, 135.3, 135.4, 139.6,
177.9; IR (neat): 1698 cmꢀ1; MS (EI): m/z = 472 (M+),
5.6.5. (3R,4S,5R)-4-(Benzylamino)-5-(hydoxymethyl)-3-
isopropyl-3-methylpyrrolidin-2-one 20f. Colorless oil:
purified by column chromatography (EtOAc–hexane,
1:1); 1H NMR (400 MHz, CDCl3): d = 1.03 (d,
J = 6.8 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H), 1.20 (s,
3H), 1.64 (br, 2H), 2.03 (m, 1H), 3.36 (d, J = 6.4 Hz,
1H), 3.76 (ddd, J = 6.4, 6.4, 7.2 Hz, 1H), 3.83 (d,
J = 12.8 Hz, 1H), 3.84 (dd, J = 6.4, 11.6 Hz, 1H), 3.90
(d, J = 12.8 Hz, 1H), 3.91 (dd, J = 7.2, 11.6 Hz, 1H),
5.82 (br, 1H), 7.29–7.36 (m, 5H); 13C NMR
(100 MHz, CDCl3): d = 19.00, 19.07, 19.8, 29.2, 49.1,
54.7, 54.9, 62.7, 67.6, 127.5, 128.0, 128.6, 138.6, 180.0;
IR (neat): 3329, 1679 cmꢀ1; MS (APCI+): m/z = 277
415 (100%); HRMS (EI): m/z calcd for C29H36N2O2Si,
27
472.2546. Found: 472.2524. ½aꢁD ¼ ꢀ48.5 (c 0.83,
CHCl3).
(M++H); HRMS (APCI+): m/z calcd for C16H25N2O2
5.6.2. (3S,4S,5R)-4-(Benzylamino)-3-butyl-5-(tert-butyl-
diphenylsiloxymethyl)pyrrolidin-2-one 23b. Pale yellow
oil: purified by column chromatography (EtOAc–hex-
ane, 1:1); 1H NMR (400 MHz, CDCl3): d = 0.88 (t,
J = 6.8 Hz, 3H), 1.03 (s, 9H), 1.25–1.71 (m, 6H), 2.33
(m, 1H), 3.29 (m, 1H), 3.64–3.81 (m, 5H), 5.71 (br s,
1H), 7.16–7.44 (m, 6H), 7.61–7.71 (m, 4H); 13C NMR
(100 MHz, CDCl3): d = 14.1, 19.2, 23.0, 26.9, 29.0,
29.1, 46.9, 52.5, 56.1, 60.4, 63.9, 127.0, 127.5,
127.7, 127.8, 128.3, 129.4, 129.7, 129.8, 132.5, 132.6,
134.6, 135.3, 135.4, 177.6; IR (neat): 1698 cmꢀ1; MS
(APCI+): m/z = 515 (M+H); HRMS (APCI+):
26
(M++H), 277.1916. Found: 277.1940. ½aꢁD ¼ ꢀ59.9 (c
0.23, CHCl3).
Acknowledgements
We thank Professor S. Kanemasa (Kyushu University)
for valuable discussions. Support has been provided in
part by a Grant-in-Aid for Scientific Research, the Min-
istry of Education, Culture, Sports, Science, and Tech-
nology, Japan.
m/z calcd for C32H43N2O2Si (M++H), 515.3094. Found:
27
515.3113. ½aꢁD ¼ ꢀ45.2 (c 0.53, CHCl3).
References
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siloxymethyl)-3-isopropylpyrrolidin-2-one 23c. Yellow
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2.17 (m, 1H), 2.27 (dd, J = 3.8, 8.5 Hz, 1H), 3.37 (dd,
J = 7.8, 8.5 Hz, 1H), 3.59 (d, J = 13.2 Hz, 1H), 3.64
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