Design and synthesis of a new polymer-supported Evans-type oxazolidinone: An efficient chiral auxiliary in the solid-ph ase asymmetric alkylation reactions

Article abstract of DOI:10.1016/j.tet.2005.01.135

Wang resin-supported Evans' chiral auxiliary (23) was designed based on a novel polymer-anchoring strategy, which utilizes the 5-position of the oxazolidinone ring, and its new synthetic route applicable to multi-gram preparation in just a day was developed. Solid-phase Evans' asymmetric alkylation on 23-derived N-acylimide resin and following lithium hydroperoxide-mediated chemoselective hydrolysis afforded the corresponding α-branched carboxylic acids in desired high stereoselectivities (up to 97% ee) and moderate to good overall yield (up to 70%, for 3 steps), which were comparable to those of the conventional solution-phase methods. Furthermore, recovery and recycling of the polymer-supported chiral auxiliary were successfully achieved without decreasing the stereoselectivity of the product. Therefore, this is the first successful example that the solid-phase Evans' asymmetric enolate-alkylation was efficiently performed on the solid-support, and it is concluded that the connection to the solid-support via the 5-position of the oxazolidinone ring is an ideal strategy in the solid-phase Evans' chiral auxiliary.

Full text of DOI:10.1016/j.tet.2005.01.135

Tetrahedron 61 (2005) 3819–3833
Design and synthesis of a new polymer-supported Evans-type
oxazolidinone: an efficient chiral auxiliary in the solid-phase
asymmetric alkylation reactions
*
Tomoya Kotake, Yoshio Hayashi, S. Rajesh, Yoshie Mukai, Yuka Takiguchi, Tooru Kimura
*
and Yoshiaki Kiso
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, 21st Century COE Program,
Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan
Received 5 January 2005; accepted 28 January 2005
Abstract—Wang resin-supported Evans’ chiral auxiliary (23) was designed based on a novel polymer-anchoring strategy, which utilizes the
5-position of the oxazolidinone ring, and its new synthetic route applicable to multi-gram preparation in just a day was developed. Solid-
phase Evans’ asymmetric alkylation on 23-derived N-acylimide resin and following lithium hydroperoxide-mediated chemoselective
hydrolysis afforded the corresponding a-branched carboxylic acids in desired high stereoselectivities (up to 97% ee) and moderate to good
overall yield (up to 70%, for 3 steps), which were comparable to those of the conventional solution-phase methods. Furthermore, recovery
and recycling of the polymer-supported chiral auxiliary were successfully achieved without decreasing the stereoselectivity of the product.
Therefore, this is the first successful example that the solid-phase Evans’ asymmetric enolate-alkylation was efficiently performed on the
solid-support, and it is concluded that the connection to the solid-support via the 5-position of the oxazolidinone ring is an ideal strategy in
the solid-phase Evans’ chiral auxiliary.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
especially those used in chiral synthesis, in solution-phase
methods have been intensively and successfully applied to
the solid-phase methods so far.8 However, some solid-
supported chiral auxiliaries are problematic in achieving
high quality of stereoselective reactions.9 One of such well-
known examples is pseudoephedrine10 grafted onto the
Merrifield resin. This solid-supported auxiliary showed
lower stereoselectivity in asymmetric alkylation (approx.
85% ee) in comparison to the corresponding solution-phase
experiments.
Evans’ chiral oxazolidinone is one of the efficient
auxiliaries for preparing chiral building blocks necessary
to synthesize molecules possessing the accurate spatial
configuration of specific functional groups.1,2 Its generality
and reliability with high optical purity have already been
established in a variety of efficient asymmetric syntheses of
low molecular weight chiral compounds and complicated
natural products.3–5 Moreover, its potential is expanding in
the study of novel asymmetric reactions.6
Evans’ oxazolidinone has also been applied to the solid-
phase stereoselective reactions such as enolate-alkylation
reaction,11 aldol reaction,12 Diels–Alder cycloaddition13
and 1,3-dipolar cycloaddition.14 However, undesired results
similar to those observed in the solid-supported pseudo-
ephedrine case were reported, especially in the fundamental
solid-phase asymmetric enolate-alkylation reaction which
prepares optically active a-branched carboxylic acid
derivatives.11b Indeed, maximum stereoselectivity was
90% ee in asymmetric benzylation using the auxiliary
resin 1 (Fig. 1A).15 Moreover, a side reaction was reported
in the preparation of solid-supported L-serine derived chiral
oxazolidinone 2.16 Therefore, to improve the efficiency in
stereoselective reactions, we previously reported a
Solid-phase organic synthesis has been developed as a rapid
and diversified method in organic chemistry.7 As compared
to solution-phase, the solid-phase technology provides a
simple procedure ‘filtration’ for rapidly achieving the
isolation of desired compounds or recovering expensive
reagents or catalysts attached onto the solid-support for
recycling. Hence, many useful reagents or catalysts,
Keywords: Evans’ oxazolidinone; Polymer-supported chiral auxiliary;
Asymmetric synthesis; Solid-phase organic synthesis; Solid-phase asym-
metric alkylation; Recovery and recycling.
*
Corresponding authors. Tel.: C81 75 595 4635; fax: C81 75 591 9900;
e-mail: kiso@mb.kyoto-phu.ac.jp
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.135

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T. Kotake et al. / Tetrahedron 61 (2005) 3819–3833
phenylbutanoic acid 3 (allophenylnorstatine, Apns),18 can
afford a desired oxazolidinone derivative 4 with a benzyl
substituent at the 4-position as a chiral discriminating group
and a free carboxyl group at the 5-position which can
connect with the solid-support (Fig. 1B). In addition,
Burgess et al. pointed out that Wang resin had a better
enantiomeric excess than Merrifield resin in asymmetric
benzylation.11b Since Wang resin has an additional benzyl
moiety which has a space from the polystyrene backbone in
comparison to Merrifield resin, we planned to employ both
Wang resin and, as a further spacer, a piperidine-4-
carboxylic acid. Thus, in the designed solid-supported
auxiliary 5, this spacer is connected to the carboxyl group at
the 5-position of the oxazolidinone moiety by a tertiary-
amide bond and to Wang resin by an ester bond. This
tertiary-amide bond with no amide proton is stable under
both acidic and basic conditions. The ester bond between the
spacer and Wang resin can be formed by the standard
methods.
2.2. Evaluation of new oxazolidinone derivatives in
solution-phase model experiment
Figure 1. Reported polymer-supported Evans’ chiral auxiliaries anchored
at the 4-position of the oxazolidinone ring (A) and design of a new auxiliary
anchored at the 5-position (B).
To understand the efficacy of designed solid-support chiral
oxazolidinone 5 as a new chiral auxiliary, we first studied a
solution-phase experiment, using a model oxazolidinone
derivative 9 whose C-terminal is protected by a benzyl ester
to mimic Wang resin. As Scheme 1 shows, 9 was
synthesized by a three-step reaction. Namely, Boc-Apns-
OH 6 was coupled to benzyl piperidine-4-carboxylate 720 by
the EDC–HOBt (EDC: 1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide, HOBt: 1-hydroxybenzotriazole) method21 to
give dipeptide 8,22 followed by the removal of the Boc
group and CDI (1,10-carbonyldiimidazole) treatment19 to
afford the cis-configured oxazolidinone derivative 9 as a
single isomer. During the cyclization reaction, neither
aziridine nor 1,2-imidazoylamine byproduct formation
was observed.23 The cis-configuration of 9 was confirmed
by the coupling constant24 between H-4 and H-5, and NOE
experiments (Scheme 1 and Ref. 25). Synthesized 9 had
polymer-supported chiral Evans’ oxazolidinone with a
novel anchoring system onto the solid-support as a rapid
communication.17 In this article, we describe the detailed
design and synthesis of the polymer-supported chiral Evans’
oxazolidinone and its reusability in Evans’ asymmetric
alkylation.
2. Results and discussion
2.1. Design of a new polymer-supported chiral
oxazolidinone
One of the common features of polymer-supported Evans’
chiral auxiliary in all previous reports11–14 is that a chiral
4-substituted oxazolidin-2-one was connected to the solid-
support through the chiral discriminating moiety at the
4-position of the oxazolidinone ring (Fig. 1A). This made us
suspect that chiral control ability of Evans’ oxazolidinone is
influenced by the polystyrene backbone of the solid-support,
leading to the low stereoselectivity in the asymmetric
alkylation.11b Hence, we proposed an alternative anchoring
strategy, which leaves the crucial chiral discriminating
moiety unmodified, and utilizes the external 5-position for
connecting to the solid-support (Fig. 1B).
To prepare such a new oxazolidinone derivative, we focused
on a-hydroxy-b-amino acids, which are routinely used in
our laboratory as a core structure for the development of
effective aspartic protease inhibitors.18 The unique structure
of a-hydroxy-b-amino acids, in which three different
functional groups, i.e. amino, hydroxyl and carboxyl
groups, are located on two adjacent asymmetric carbon
atoms gave us the idea. Namely, the known oxazolidinone
formation19 at the 1,2-amino alcohol moiety of
a-hydroxy-b-amino acid, (2S,3S)-3-amino-2-hydroxy-4-
Scheme 1. Synthesis of a cis-configured oxazolidinone derivative 9 from
Boc-Apns-OH 6.

T. Kotake et al. / Tetrahedron 61 (2005) 3819–3833
3821
Scheme 2. Epimerization and deuterium incorporation to the cis-configured carboximide 9.
coupling constants of J4,5Z7.9, 8.1 Hz, which corresponded
to the representative value of the cis-configured
oxazolidinone.
This unexpected result prompted us to suggest that stable
trans-configured oxazolidinone 14 was suitable for the
auxiliary (Scheme 3). We synthesized 14 according to the
procedure shown in Scheme 1, starting from Boc-Pns-OH
13 (Pns: phenylnorstatine), a 2R isomer of 6, in 85% yield (3
steps). The relative stereochemistry of 14 was analyzed by
NMR. Coupling constants of J4,5 were 5.1 and 5.3 Hz,
which are well consistent with the known value in trans-
configuration24 and a strong NOE signal was observed
between H-5 and two protons at the benzylic position.25 In
addition, the most stable conformation of 14 obtained from
conformational analysis showed a dihedral angle of 136.48
between two methine hydrogens (H-4 and H-5). This value
and Karplus curve reasonably supported the observed
coupling constant. From these observations, the configur-
ation between H-4 and H-5 in 14 was confirmed as trans.
Furthermore, the absolute stereochemistry of 14 was
confirmed as 4S,5R by the X-ray crystal structural analysis
of (R)-phenylethylamide 1531 derived from 14 (Fig. 2). In
addition, it was found that the piperidine-4-carboxylic acid
spacer extended outside from the oxazolidinone core,
suggesting that this spacer does not interfere with the
asymmetric reaction.
Next, oxazolidinone 9 was N-acylated with 3-phenyl-
propionic acid by the mixed anhydride method to obtain
carboximide 10 (Scheme 2).26 Although there are three
a-protons in 10, the newly introduced carboximide a-proton
was expected to be most acidic. Since it was reported that
the imide-selective enolization of substrates with the both
carboximide and ester structures was accomplished by
careful base addition,27 and that after asymmetric reaction,
N-acyl fragments were selectively cleaved from the
auxiliary by the imide-specific lithium hydroperoxide-
mediated hydrolysis,28 we proposed 9 as a chiral auxiliary
that could be recovered and reused. However, its enolate
formation gave a new compound even with a careful
addition of LDA (1.2 equiv) to the cooled THF solution of
10 and a subsequent stirring for 0.5 h. This compound was
an epimerized trans-configured carboximide 11.29 This
result suggests that the a-proton of the carboxamide moiety
was predominantly deprotonated by LDA to diminish the
steric repulsion caused by cis-configuration.30 Indeed,
quenching lithium enolate generated in situ from 10 with
acetic acid-d (99at.% D) afforded the deuterized 12 in
85% yield. The deuterium was incorporated mainly at
the a-position of the carboxamide moiety (68% D)
along with the a-position of the N-acylimide moiety
(12% D).
Figure 2. X-ray crystal structure of (R)-phenylethylamide 15.
Next, we synthesized N-3-phenylpropionylated oxazolidi-
none 16 and subjected it to the deuterium labeling to
confirm the enolization position (Scheme 4) by the same
procedure described in Scheme 2. No particular change on
TLC was observed during the enolization and the recovered
product (88% yield) contained 76% of deuterized 17,
exclusively at the a-position of the desired carboximide
moiety with unmodified 16. This result suggests that the
Scheme 3. Synthesis of a trans-configured oxazolidinone derivative 14
from Boc-Pns-OH 13.

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T. Kotake et al. / Tetrahedron 61 (2005) 3819–3833
Evans’ chiral auxiliary system (Fig. 3).15,34 Interestingly,
this modeling also suggested that nucleophilic attack of the
hydroperoxide anion to the oxazolidinone carbonyl for the
endocyclic cleavage is effectively obstructed by the steric
effect of the benzyl and carboxamide moieties.35 From these
data, we selected the structure of 14 originating from Pns as
the candidate for solid-supported Evans’ auxiliary.
Scheme 4. Deuterium incorporation to trans-configured carboximide 16.
a-position of the imide N-acyl moiety in 16 has the most
acidic a-proton, which is predominantly deprotonated by
LDA. Self-condensation of 16 was not observed under this
reaction condition.
With these positive observations, we examined the Evans’
asymmetric allylation of the carboximide 16 as a model for
alkylation (Scheme 5).15 Briefly, to a solution of 16 in THF
was added LDA (1.2 equiv) dropwise at K78 8C. After
stirring for 0.5 h, the generated Z-O-enolate 1832 was treated
with allyl iodide (3.0 equiv), and the temperature of the
reaction mixture was gradually increased up to 0 8C over a
period of 3 h. Resultant 19 was hydrolyzed by LiOOH
without any purification.28 The desired a-allylated car-
boxylic acid 26c was obtained in good yield (2 steps 75%,
an average of 87% for each of the two steps in the reaction
sequence) and high stereoselectivity (96% ee),33 which
were comparable to the standard Evans’ asymmetric
allylation in solution-phase.15 Oxazolidinone 14 was
sufficiently recovered (94%) without epimerization, and
no byproduct produced by the endocyclic cleavage of the
oxazolidinone ring28 was observed. These results proved
that the trans-configured oxazolidinone 14 was effective as
a chiral auxiliary and that the spacer moiety did not interfere
with the asymmetric reaction.
Figure 3. Energy minimization study of enolate intermediate 18.
2.3. Solid-phase synthesis of Wang resin-supported
chiral oxazolidinone 23
In our previous communication,17 Wang resin-supported
chiral oxazolidinone 23 was obtained by the carbodiimide-
mediated coupling between Wang resin and the oxazolidi-
none-spacer unit prepared from 14 by hydrogenolysis. Since
four-step solution-phase synthesis of this unit and its excess
use (4 equiv) required for complete loading onto the resin
were inefficient, in the present study we developed a more
convenient synthetic route for 23 using Fmoc-based solid-
phase method as shown in Scheme 6.36 Namely, Fmoc-
piperidine-4-carboxylic acid 20 was first loaded to Wang
resin using the DIPCDI–DMAP (DIPCDI: 1,3-diisopropyl-
carbodiimide) method37 in CH2Cl2. After Fmoc-deprotec-
tion of 21 with 20% piperidine, Fmoc-Pns-OH was coupled
by the DIPCDI–HOBt method to give the dipeptide resin 22
followed by removal of the Fmoc group. The resultant 1,2-
amino alcohol moiety was converted to oxazolidinone with
CDI. Methanolysis of 23 with potassium carbonate in
anhydrous THF–MeOH yielded the corresponding methyl
ester 24 as a single isomer (95% for 6 steps). During this
synthesis, neither epimerization at the 5-position nor
byproduct formation such as aziridine and 1,2-aminoimi-
dazole was observed.23 It is noteworthy that all reactions in
Scheme 6 proceeded smoothly at room temperature within a
few hours, and multi-gram quantity of the oxazolidinone
resin 23 with high loading yield was efficiently synthesized
in just a day.
Scheme 5. Asymmetric allylation of the N-3-phenylpropionylated
carboximide 16.
2.4. Solid-phase Evans’ asymmetric alkylation with the
oxazolidinone resin 23
An energy minimization study of enolate intermediate 18
suggested that its conformation corresponds to that of the
original chelation-controlled model proposed for standard
At first, we investigated the solid-phase Evans’ asymmetric
allylation of the N-3-phenylpropionylated carboximide

T. Kotake et al. / Tetrahedron 61 (2005) 3819–3833
3823
Scheme 6. Solid-phase synthesis of Wang resin-supported oxazolidinone resin 23.
resin 25a, which was prepared from 23 by Mukaiyama
method (Scheme 7).38 It was found that the use of NaHMDS
(3 equiv) as a base and gradual increase of the temperature
of reaction mixture up to 0 8C over a period of 12 h in the
alkylation reaction were quite effective.39 After quenching
the reaction mixture with saturated NH4Cl aq, the allylated
carboximide resin was recovered, washed, then subjected to
the LiOOH-mediated hydrolysis. The desired chiral
a-allylated carboxylic acid 26c was obtained with high
stereoselectivity (96% ee), which was equal to the model
experiment in solution-phase (Table 1, entry 3). The
absolute configuration of acid 26c was determined in
comparison to the reported specific rotation,33 suggesting
that the asymmetric alkylation on resin 25a also proceeded
in the same chelation-controlled model as the solution-
phase method.15 During the hydrolytic cleavage, the ester
linkage and oxazolidinone core were stable.40 These
encouraging results urged us to understand the generality
of 23 in the Evans’ asymmetric alkylation reaction. Several
carboximide resins 25b–d were prepared and subjected to
the similar solid-phase alkylation reactions with a series of
electrophiles (R2X).41 The results are summarized in
Table 1. Favorably, not only highly reactive alkyl halides
such as MeI and BnBr but also less reactive EtI reacted
sufficiently under the same reaction conditions. Hydrolytic
cleavage of the resultant resin afforded the corresponding
chiral a-branched carboxylic acids 26a–k with satisfying
isolated yields (50–70%, for 3 steps) and enantiomeric
excesses (84–97% ee).42 Especially, in the asymmetric
benzylation of carboximide resin 25b, stereoselectivity was
found to be 97% ee (Table 1, entry 6), which was better than
the value reported by Burgess et al.,11b and was as high
enough as in the corresponding solution-phase asymmetric
alkylation utilizing the standard chiral 4-substituted oxazo-
lidin-2-one.15 The relatively lower yield was due to the fact
that the yield includes the three-step process from the
oxazolidinone resin 23 to the final alkylated product 26. We
consider that yield for two steps (alkylation and hydrolysis)
is similar to that of the solution-phase method, and average
yield calculated for each step was reasonably acceptable
(79–89%). We assume that these successful results are
attributed to our new polymer-anchoring strategy based on
the connection at the 5-position of the oxazolidinone ring.
This liberates the chiral differentiating benzyl group from
the polystyrene backbone of the resin, freeing the auxiliary
Scheme 7. Solid-phase asymmetric Evans’ alkylation.
Table 1. Results of the solid-phase asymmetric Evans’ alkylations
Entry
25
R1
R2X
26
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
25a
25a
25a
25a
25a
25b
25b
25b
25b
25c
25d
Bn-
Bn-
Bn-
Bn-
Bn-
Me-
Me-
Me-
MeI
EtI
Allyl-I
Propargyl-Br
BrCH2CO2Et
BnBr
4-BrBnBr
4-NO2BnBr
2,4-diClBnI
Allyl-I
26a
26b
26c
26d
26e
26f
26g
26h
26i
61(85)
50(79)
68(88)
62(85)
62(85)
70(89)
68(88)
55(82)
65(87)
50(79)
59(84)
85
88
96
96
92
97
97
97
97
96
84
9
10
11
Me-
PhO-
2,4-diClBn-
26j
26k
MeI
a Combined yield of 3 steps starting from oxazolidinone resin 23. Value in the parenthesis is the average yield for each step.
b Determined by chiral HPLC analysis after conversion to the corresponding (S)-a-methylbenzylamine-derived amides.

3824
T. Kotake et al. / Tetrahedron 61 (2005) 3819–3833
unit from the solid-support, which was not realized in the
previous system based on the 4-position anchoring.
8% in each cycle. After the fourth cycle, the resin was
cleaved by methanolysis to measure the amount of the
residual auxiliary. Methyl ester 24, which corresponds to the
chiral auxiliary on the resin, was obtained in 71% yield
along with the 22% of undesired N-allylated oxazolidinone
27.43 This indicated that the reduced yield obtained after
recycling was due to the formation of byproduct 27, in
which the substrate-loading site was completely blocked by
the allyl group (Fig. 4). It is thought that this unfavorable
side reaction was induced by the partial elimination of the
N-acyl moiety during enolate-alkylation steps. In fact, from
detailed analysis of our solution-phase model experiment,
6% of N-allylated byproduct formation was detected.
Therefore, the reaction conditions should be carefully
adjusted to minimize unfavorable N-alkylation of the
oxazolidinone resin.
2.5. Recycling of the Wang resin-supported auxiliary 23
The recycling of the expensive auxiliary is one of the key
points in the development of the polymer-supported chiral
auxiliary. However, the recycling of the polymer-supported
Evans’ oxazolidinone has been reported in only one case of
solid-phase 1,3-dipolar-cycloaddition,14b with a consider-
able reduction of regio- and stereo-selectivity depending on
the cycle number up to three, although the reason was
unclear.
Hence, the ability of recycling of the Wang resin-supported
chiral auxiliary 23 was studied in the solid-phase asym-
metric allylation, mentioned above, to obtain a-allylated
carboxylic acid 26c (Fig. 4). After the first cycle of
allylation, the recovered chiral auxiliary resin 23 was
washed and dried, then N-acylation with 3-phenylpropionic
acid gave the corresponding carboximide resin 25a again.
After the continuous second to fourth solid-phase asym-
metric allylation, the desired product 26c was obtained in
high enantioselectivity (96% ee each) (Table 2). Throughout
these cycles, the product’s stereoselectivity was maintained
successfully, although the yield gradually decreased about
3. Conclusion
In the development of an efficient tool to prepare versatile
chiral synthon, we designed and synthesized Wang resin-
supported Evans’ chiral oxazolidinone derivative based on
the novel polymer-anchoring strategy, which utilizes the
5-position of the oxazolidinone ring. Solid-phase asym-
metric Evans’ enolate-alkylation reaction on this auxiliary
resin proceeded successfully and a series of chiral
a-branched carboxylic acids was obtained in high stereo-
selectivities (up to 97% ee), which are parallel to those
obtained in the comparative classical solution-phase
experiments. Therefore, this is the first successful example
that Evans’ asymmetric alkylation reaction proceeded
efficiently on a solid-support. Furthermore, recycling of
this polymer-bound chiral auxiliary was achieved by
maintaining stereoselectivity of the product. This newly
developed solid-support auxiliary provides a variety of
chiral a-branched carboxylic acid derivatives, which would
be valuable synthetic building blocks in Medicinal
Chemistry.44 These results also suggest the significance of
the polymer-anchoring strategy of chiral auxiliary to
perform the satisfactory asymmetric induction in solid-
phase organic synthesis. Further application studies to other
solid-phase Evans’ asymmetric reactions are now in
progress.
4. Experimental
4.1. General
Figure 4. Recycling of the chiral auxiliary resin 23.
NMR spectra (1H and 13C) were recorded on a JEOL JNM-
AL300 (1H: 300 MHz; 13C:75.5 MHz) or a Varian UNITY
INOVA 400NB (1H: 400 MHz; 13C: 100 MHz) spec-
trometer and the chemical shift values were expressed in
parts per million downfield from tetramethylsilane (TMS)
as an internal standard. All coupling constants (J values)
were reported in Hertz (Hz). Infrared (IR) spectra were
recorded using a Shimadzu FT-IR-8300 Fourier Transform
Infrared Spectrophotometer. Melting points were taken on a
micro hot-stage apparatus (Yanagimoto) and were uncor-
rected. Mass spectra (MS) were obtained by electron impact
(EI) ionization methods on JEOL GCmate MS-BU20.
Elemental analyses were done on a Perkin–Elmer Series
Table 2. Recycling of the Wang resin-supported chiral oxazolidinone 23 in
Evans’ asymmetric allylation
Cycle
Yielda (%)
eeb (%)
1
2
3
4
68
59
49
42
96
96
96
96
a Combined yield of 3 steps starting from oxazolidinone resin 23.
b Determined by chiral HPLC analysis after conversion to the correspond-
ing (S)-a-phenylethylamides.

T. Kotake et al. / Tetrahedron 61 (2005) 3819–3833
3825
CHNS/O Analyzer 2400. Specific rotations were recorded
on a Horiba High-speed Accurate Polarimeter SEPA-300
with a sodium lamp and are reported as follows: [a]DT
(c g/100 mL, solvent). The enantiomeric excess was
determined by chiral HPLC analysis with JASCO HPLC
systems consisting of the following: pump, 880-PU;
detector, 875-UV, measured at 230 nm; column, Chiralcelw
OD normal phase column (4.6!250 mm; Daicel Chemical
Ind., Ltd, Tokyo, Japan); mobile phase, n-hexane/EtOH;
flow rate, 1.0 mL/min. Solvents used for HPLC analysis
were of HPLC grade. Organic extracts were dried over
sodium sulfate (Na2SO4), filtered, and concentrated using a
rotary evaporator at !40 8C bath temperature. Solids and
involatile oils were vacuum dried at !2 mmHg. Solution-
and solid-phase asymmetric alkylation reactions were
carried out under Ar atmosphere, using anhydrous THF in
flame-dried glassware. In the case of solid-phase asym-
metric alkylation reactions, immobilized substrates were
agitated by a slow stirring under Ar atmosphere.
brine. After the organic layer was dried over Na2SO4, the
solvent was removed under reduced pressure. The resulting
white powder 8 (5.5 g, 82%) was used for the next reaction
without any purification. RfZ0.44 (n-hexane/AcOEtZ1:1);
1
mp 37–39 8C; H NMR (400 MHz, CDCl3) d 7.41–7.14
(m, 10H), 5.16, 5.13 (2d, 0.5!2H, JZ12.3 Hz), 5.12 (s,
0.5!2H), 5.06 (br d, 0.5H, JZ8.4 Hz), 5.02 (br d, 0.5H,
JZ9.0 Hz), 4.58 (d, 0.5H, JZ2.2 Hz), 4.55 (d, 0.5H, JZ
2.2 Hz), 4.22–3.92 (m, 4H), 3.14, 3.06 (2ddd, 0.5!2H, JZ
13.7, 11.2, 3.1 Hz), 2.88, 2.54 (2ddd, 0.5!2H, JZ13.4,
11.2, 3.1 Hz, partially overlapping with the next signal),
2.71–2.51 (m, 3H), 2.08–1.21 (m, 4H), 1.38 (s, 0.5!9H),
1.37 (s, 0.5!9H); 13C NMR (75.5 MHz, CDCl3) d 173.5,
173.5, 169.9, 169.6, 155.6, 137.8, 135.7, 129.2, 129.1,
128.6, 128.4, 128.3, 128.2, 128.1, 126.5, 126.4, 79.6, 77.2,
69.9, 69.8, 66.5, 54.1, 53.4, 44.1, 42.0, 42.0, 40.7, 34.4,
34.2, 28.3, 27.6; [a]D26ZC16.3 (c 0.64, CHCl3); FT-IR
(CHCl3) nmax 3690, 3441, 3038, 1728, 1699, 1639, 1497,
1367, 1238, 1169, 698 cmK1; HRMS (EI): found MC
496.2576, C28H36N2O6 requires MC 496.2573. Anal. Calcd
for C28H36N2O6: C, 67.72; H, 7.31; N, 5.64; found: C,
67.69; H, 7.46; N, 5.58.
4.2. Materials
Commercially available chemicals were obtained from
Wako Pure Chemical Industries, Ltd (Osaka, Japan),
Nacalai Tesque, Inc. (Kyoto, Japan), Aldrich Chemical
Co., Inc. (Milwaukee, WI) and Tokyo Kasei Kogyo Co., Ltd
(Tokyo, Japan), and used without further purification.
Exceptionally, triethylamine was distilled from CaH2
under Ar atmosphere and stored over KOH (pellet).
Dehydrated MeOH and THF were purchased from Kanto
Chemical Co., Inc. (Tokyo, Japan) and stored over pre-
activated pellet-type molecular sieves 3A and 4A,
respectively. Wang resin (0.80 mmol/g, styrene–1%DVB,
200–400 mesh) was purchased from Watanabe Chem. Ind.,
Ltd (Hiroshima, Japan). Boc-Apns-OH and H-Pns-OH were
purchased from Nippon Kayaku (Tokyo, Japan). Boc- and
Fmoc-Pns-OH were prepared from H-Pns-OH by the
standard procedure. NaHMDS was used as supplied
(Aldrich) as a solution in THF (1.0 M). Column chroma-
tography was carried on Merck 107734 silica gel 60
(70–230 mesh). Analytical thin layer chromatography
(TLC) was performed using Merck 105715 silica gel 60
F254 precoated plates (0.25 mm thickness) and compounds
were visualized by UV illumination (254 nm) and by
heating after dipping in 10% ethanolic solution of
phosphomolybdic acid or after spraying ca. 0.7% ethanolic
solution of ninhydrin. Preparative TLC was done with
Merck 105717 silica gel 60 F254 plate (2.0 mm thickness).
4.3.2. Benzyl N-[(4S,5S)-4-benzyl-1,3-oxazolidin-2-one-
5-carbonyl]piperidine-4-carboxylate 9. Compound 8
(5.4 g, 10.9 mmol) was treated with 4 M HCl/dioxane
(45.0 mL) at 0 8C, and the reaction mixture was stirred at
room temperature for 2.5 h. After the solvent was removed
under reduced pressure, the obtained colorless oil was
dissolved in anhydrous THF (110 mL). To this solution was
added Et3N (2.3 mL, 16.4 mmol) dropwise at 0 8C, followed
by CDI (2.7 g, 16.4 mmol). The cloudy reaction mixture
was stirred overnight at room temperature, diluted with
AcOEt, and washed consecutively with 5% citric acid aq,
5% NaHCO3 aq, water and brine. After the organic layer
was dried over Na2SO4, the solvent was removed under
reduced pressure and the residue was applied to silica-gel
column chromatography (n-hexane/AcOEtZ1:10) to yield
9 as a white powder (4.0 g, 86% for 2 steps). RfZ0.27
(n-hexane/AcOEtZ1:10); mp 136–137 8C; 1H NMR
(400 MHz, CDCl3) d 7.40–7.14 (m, 10H), 5.41 (d, 0.5H,
JZ7.9 Hz), 5.39 (d, 0.5H, JZ8.1 Hz), 5.15 (s, 0.5!2H),
5.14 (s, 0.5!2H), 4.98 (br s, 0.5H), 4.92 (br s, 0.5H), 4.46,
4.23 (2dtd, 0.5!2H, JZ13.6, 4.0,1.5 Hz, partially over-
lapping with the next signal), 4.28–4.18 (m, 1H), 3.76 (m,
0.5!2H), 3.25, 3.11 (2ddd, 0.5!2H, JZ13.6,
10.3,3.3 Hz), 2.92–2.53 (m, 3H), 2.87–2.71 (m, 0.5!2H,
partially overlapping with the next signal), 2.05–1.93 (m,
2H), 1.80–1.62 (m, 2H); 13C NMR (75.5 MHz, CDCl3) d
173.4, 173.4, 163.8, 163.7, 157.4, 157.3, 135.8, 135.6,
129.2, 129.1, 129.1, 128.9, 128.6, 128.4, 128.1, 127.3,
127.2, 75.1, 74.9, 66.5, 55.5, 55.4, 44.1, 43.9, 41.5, 41.2,
40.8, 40.0, 37.4, 37.3, 28.1, 28.1, 27.6, 27.4; [a]2D5ZK58.4
(c 1.01, CHCl3); FT-IR (CHCl3) nmax 3030, 3020, 1774,
4.3. Synthesis of cis-configured oxazolidinone 9 and N-3-
phenylpropionylated carboximide 10
4.3.1. Benzyl N-{(2S,3S)-3-[(tert-butoxycarbonyl)-
amino]-2-hydroxy-4-phenylbutanoyl}piperidine-4-car-
boxylate 8. To a solution of Boc-Apns-OH 6 (4.0 g,
13.5 mmol), benzyl piperidine-4-carboxylate HCl 7 (4.1 g,
16.2 mmol) and HOBt$H2O (7.7 g, 16.2 mmol) in DMF
(68 mL) was added EDC$HCl (3.1 g, 16.2 mmol) in parts at
0 8C. After stirring for 0.5 h at the same temperature, Et3N
(7.0 mL, 16.2 mmol) was added dropwise, then the reaction
mixture was stirred overnight at room temperature. The
solution was diluted with AcOEt and washed consecutively
with 5% citric acid aq, 5% NaHCO3 aq, water (!2) and
1730, 1666, 1231, 1207, 800, 791, 768, 714, 675 cmK1
;
HRMS (EI): found MC 422.1843, C24H26N2O5 requires
MC 422.1841. Anal. Calcd for C24H26N2O5: C, 68.23; H,
6.20; N, 6.63; found: C, 68.14; H, 6.28; N, 6.49.
4.3.3. Benzyl N-[(4S,5S)-4-benzyl-(3-phenylpropionyl)-
1,3-oxazolidin-2-one-5-carbonyl]piperidine-4-carboxyl-
ate 10. To a solution of 3-phenylpropionic acid (1.8 g,
11.7 mmol) in anhydrous THF (30 mL) was added Et3N

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T. Kotake et al. / Tetrahedron 61 (2005) 3819–3833
(3.1 mL, 22.5 mmol) and trimethylacetylchloride (1.3 mL,
10.8 mmol) dropwise at K18 8C. The reaction mixture was
stirred at the same temperature for 0.5 h, then anhydrous
LiCl (420 mg, 9.9 mmol) was added, followed by the slow
addition of a solution of oxazolidinone 9 (3.8 g, 9.0 mmol)
in anhydrous THF (20 mL). After the addition was
completed, the reaction mixture was stirred overnight at
room temperature. The solution was poured into ice-cold
satd NaHCO3 aq and the organic phase was extracted with
AcOEt, washed with water and brine, and dried over
Na2SO4. The solvent was removed under reduced pressure,
and the resulting oil was applied to silica-gel column
chromatography (n-hexane/AcOEtZ4:1) to yield the
desired compound 10 as a white solid (4.7 g, 95%). RfZ
0.48 (n-hexane/AcOEtZ1:1); mp 153–155 8C; 1H NMR
(400 MHz, CDCl3). Major isomer d 7.41–7.04 (m, 15H),
5.11–5.09 (m, 1H), 5.07 (s, 2H), 4.92–4.87 (m, 1H), 4.36–
4.33 (m, 1H), 3.36–3.26 (m, 2H), 3.11–2.93 (m, 6H), 2.22
(tt, 1H, JZ11.2, 3.7 Hz), 2.10 (td, 1H, JZ12.6, 3.1 Hz),
1.89–1.85 (m, 1H), 1.63–1.38 (m, 3H); minor isomer d
7.41–7.04 (m, 15H), 5.11–5.09 (m, 3H), 4.92–4.87 (m, 1H),
3.59 (ddd, 1H, JZ13.6, 6.4, 4.0 Hz), 3.36–3.20 (m, 2H),
3.11–2.93 (m, 4H), 3.14, 2.87 (2ddd, 2H, JZ13.4, 8.8,
3.7 Hz, partially overlapping with the next signal), 2.71–
2.64 (m, 1H), 2.47–2.41 (m, 1H), 1.77–1.70 (m, 1H), 1.63–
1.38 (m, 2H), 0.98–0.89 (m, 1H); 13C NMR (75.5 MHz,
CDCl3) d 173.2, 172.9, 171.9, 171.9, 162.0, 161.9, 151.7,
151.6, 140.2, 135.7, 135.6, 135.5, 129.6, 129.5, 128.7,
128.6, 128.6, 128.5, 128.4, 128.4, 128.1, 127.2, 127.1,
126.3, 73.3, 66.5, 66.4, 57.6, 57.5, 43.3, 43.1, 41.1, 40.8,
40.4, 39.0, 36.9, 34.2, 34.2, 30.1, 27.5, 27.2, 26.8, 26.1;
[a]2D5ZK25.2 (c 1.16, CHCl3); FT-IR (CHCl3) nmax 1790,
135.2, 129.6, 129.5, 129.3, 129.3, 128.6, 128.6, 128.5,
128.4, 128.4, 128.2, 128.1, 128.1, 127.7, 126.2, 71.8, 71.6,
71.5 (t, JZ24.1 Hz), 66.5, 66.5, 59.2, 59.1, 58.9, 58.8, 43.5,
43.3, 41.7, 41.6, 40.4, 40.3, 37.8, 37.7, 37.1, 37.0, 30.2,
28.2, 28.0, 27.4, 27.3; [a]2D6ZK15.1 (c 1.55, CHCl3);
FT-IR (CHCl3) nmax 1796, 1732, 1703, 1661, 1454, 1379,
1198, 1173, 772, 756, 727, 700, 679, 667 cmK1; HRMS
(EI): found MC 555.2478, C33H33DN2O6 requires MC
555.2479. Anal. Calcd for C33H33DN2O6: C, 71.33; HCD,
6.35; N, 5.04; found: C, 71.26; HCD, 6.06; N, 4.99.
4.4. Synthesis of trans-configured oxazolidinone 14 and
N-3-phenylpropionylated carboximide 16
4.4.1. Benzyl N-[(4S,5R)-4-benzyl-1,3-oxazolidin-2-one-
5-carbonyl]piperidine-4-carboxylate 14. To a solution of
Boc-Pns-OH 13 (12.4 g, 42.0 mmol), benzyl piperidine-4-
carboxylate$HCl 7 (12.9 g, 50.4 mmol) and HOBt$H2O
(7.7 g, 50.4 mmol) in DMF (210 mL) was added EDC$HCl
(9.7 g, 50.4 mmol) in parts at 0 8C. After stirring for 0.5 h at
the same temperature, Et3N (7.0 mL, 50.4 mmol) was added
dropwise, then the reaction mixture was stirred overnight at
room temperature. The solution was diluted with AcOEt and
washed consecutively with 5% citric acid aq, 5% NaHCO3
aq, water (!2) and brine. After the organic layer was dried
over Na2SO4, the solvent was removed under reduced
pressure. The resulting white powder (20.0 g, 96%) was
used for the next reaction without any purification. RfZ0.52
(n-hexane/AcOEtZ1:1); mp 34–36 8C; 1H NMR
(400 MHz, CDCl3) d 7.38–7.21 (m, 10H), 5.17, 5.12 (2d,
0.5!2H, JZ12.5 Hz), 5.10 (s, 0.5!2H), 4.87 (br d, 0.5H,
JZ10.8 Hz), 4.71 (br d, 0.5H, JZ10.3 Hz), 4.28–4.01 (m,
4H), 3.13–2.68 (m, 5H), 2.62–2.47 (m, 1H), 2.08–1.33 (m,
4H), 1.39 (s, 0.5!9H), 1.38 (s, 0.5!9H); 13C NMR
(75.5 MHz, CDCl3) d 173.6, 173.3, 170.3, 155.3, 155.2,
137.9, 137.7, 135.8, 135.6, 129.3, 128.6, 128.5, 128.2,
128.1, 128.0, 126.7, 79.4, 66.9, 66.6, 66.3, 53.8, 53.1, 43.7,
43.3, 42.1, 41.7, 41.0, 40.2, 38.8, 38.6, 28.2, 27.5, 27.2,
27.1, 26.7; [a]2D5ZK20.0 (c 0.47, CHCl3); FT-IR (CHCl3)
nmax 3439, 3005, 1717, 1701, 1639, 1499, 1454, 1393, 1367,
1240, 1169, 700 cmK1; HRMS (EI): found MC 496.2568,
C28H36N2O6 requires MC 496.2573. Anal. Calcd for
C28H36N2O6: C, 67.72; H, 7.31; N, 5.64; found: C, 67.65;
H, 7.31; N, 5.90.
1730, 1701, 1670, 1454, 1375, 1173, 718, 696 cmK1
;
HRMS (EI): found MC 554.2410, C33H34N2O6 requires
MC 554.2416. Anal. Calcd for C33H34N2O6: C, 71.46; H,
6.18; N, 5.05; found: C, 71.51; H, 6.40; N, 4.84.
4.3.4. Deuterium labeling study of the carboximide 10.
Under Ar atmosphere, the solution of the carboximide 10
(146.5 mg, 0.264 mmol) in anhydrous THF (2.6 mL) was
cooled to K78 8C (MeOH-dry ice bath), and LDA (1.8 M
solution in heptane/THF/ethylbenzene, 0.18 mL,
0.32 mmol) was added dropwise. After stirring for 0.5 h at
the same temperature, acetic acid-d (99at.% D) (0.31 mL,
5.28 mmol) was added slowly and the reaction mixture was
stirred for 1 h at room temperature. The solution was poured
into ice-cold satd NH4Cl aq and the organic phase was
extracted with AcOEt, washed with 5% NaHCO3 aq, water
and brine, and dried over Na2SO4. The solvent was removed
under reduced pressure, and the resulting oil was subjected
to preparative TLC (n-hexane/AcOEtZ3:2, 2 times
development) to yield the products as a white powder
(124.7 mg, 85%). The content of deuterium-incorporated 12
was detected by NMR. RfZ0.53 (n-hexane/AcOEtZ1:1);
Obtained dipeptide (20.0 g, 40.3 mmol) was treated with
4 M HCl/dioxane (140 mL) at 0 8C, and the reaction mixture
was stirred at room temperature for 2.5 h. After the solvent
was removed under reduced pressure, the colorless oil
obtained was dissolved in anhydrous THF (400 mL). To this
solution was added Et3N (8.4 mL, 60.5 mmol) dropwise at
0 8C, followed by the addition of CDI (9.8 g, 60.5 mmol).
The cloudy reaction mixture was stirred overnight at room
temperature, diluted with AcOEt, and washed consecutively
with 5% citric acid aq, 5% NaHCO3 aq, water and brine.
After the organic layer was dried over Na2SO4, the solvent
was removed under reduced pressure and the residue was
applied to silica-gel column chromatography (n-hexane/
AcOEtZ1:2) to yield 14 as a white powder (15.0 g, 88% for
2 steps). RfZ0.55 (n-hexane/AcOEtZ1:5); mp 91–93 8C;
1H NMR (400 MHz, CDCl3) d 7.40–7.20 (m, 10H), 5.28 (br
s, 0.5H,), 5.25 (br s, 0.5H), 5.14 (s, 0.5!2H), 5.12 (s, 0.5!
2H), 4.80 (d, 0.5H, JZ5.3 Hz), 4.79 (d, 0.5H, JZ5.1 Hz),
1
mp 40–41 8C; H NMR (400 MHz, CDCl3) d 7.42–7.18
(m, 15H), 5.14, 5.10 (2d, 0.5!2H, JZ12.3 Hz), 5.09 (s,
0.5!2H), 4.88 (d, 0.16H, JZ4.6 Hz), 4.87 (d, 0.16H, JZ
4.4 Hz), 4.71–4.64 (m, 1H), 4.19 (dt, 0.5H, JZ13.6,
4.2 Hz), 4.13 (dt, 0.5H, JZ13.4, 4.2 Hz), 3.45–3.18 (m,
2.88H), 3.08–2.94 (m, 2H), 2.87–2.32 (m, 5H), 1.91–1.86
(m, 1H), 1.65–1.38 (m, 2H and 0.5H), 1.18–1.10 (m, 0.5H);
13C NMR (100 MHz, CDCl3) d 173.3, 173.3, 172.1, 172.1,
164.8, 164.7, 152.5, 152.4, 140.3, 140.3, 135.7, 135.6,

T. Kotake et al. / Tetrahedron 61 (2005) 3819–3833
3827
4.69–4.64 (m, 1H), 4.40–4.37 (m, 0.5H), 4.19 (dt, 0.5H, JZ
13.6, 4.2 Hz), 3.89–3.86 (m, 0.5H), 3.74–3.71 (m, 0.5H),
3.23, 3.0 (2br t, 0.5!2H, JZ11.2 Hz, partially overlapping
with the next signal), 3.06–2.77 (m, 3H), 2.67–2.55 (m, 1H),
1.99–1.59 (m, 4H); 13C NMR (75.5 MHz, CDCl3) d 173.7,
173.4, 164.4, 164.3, 156.9, 135.8, 135.8, 135.7, 129.1,
129.0, 128.6, 128.3, 128.3, 128.1, 127.3, 76.8, 76.6, 66.5,
55.3, 44.8, 44.5, 42.0, 41.8, 41.0, 41.0, 40.9, 40.3, 28.4,
28.2, 27.5, 27.5; [a]D27ZK91.2 (c 1.28, CHCl3); FT-IR
(CHCl3) nmax 3452, 3036, 3007, 1771, 1730, 1653, 1456,
1387, 1313, 1271, 1238, 1209, 1173, 1038, 1011, 756, 737,
698, 667 cmK1; HRMS (EI): found MC 422.1845,
C24H26N2O5 requires MC 422.1842. Anal. Calcd for
C24H26N2O5: C, 68.23; H, 6.20; N, 6.63; found: C, 67.99;
H, 6.20; N, 6.55.
and a rotating anode generator. All calculations were
performed using the teXsan crystallographic software
package of Molecular Structure Corporation. Formula
C25H29N3O4, formula weightZ435.52, orthorhombic,
space group P212121 (#19), aZ17.986(2), bZ23.841(2),
3
cZ5.269(3) A, VZ2259(1) A , ZZ4, DcalcZ1.280 g/cm3,
F000Z928.00, m(Cu Ka)Z7.10 cmK1. Total of 1554
unique reflections (complete for 2q!1108) was used in
the solution and refinement of structure. The structure was
solved by direct methods using SAPI91,45 and expanded
using Fourier techniques with DIRDIF94 program.46 The
final refinement was done by the full-matrix least-squares
method with anisotropic thermal parameters for all non-
hydrogen atoms, and hydrogen atoms were included but not
refined. The final R value was 0.238 (RwZ0.087).
˚
˚
4.4.2. N-{N-[(4S,5R)-4-benzyl-1,3-oxazolidin-2-one-5-
carbonyl]piperidine-4-carboxyl}-(R)-1-phenethyl amide
15. To a solution of oxazolidinone 14 (141.1 mg,
0.334 mmol) in MeOH (3.0 mL) and water (0.35 mL) was
added 5% Pd-C (15.2 mg), and the reaction mixture was
stirred for 3 h under H2 atomosphere. The reaction mixture
was purged with Ar, then filtered through a pad of Celitew
with MeOH. After evaporation, the resulting oil was diluted
with AcOEt, and washed consecutively with water and
brine. After the organic layer was dried over Na2SO4, the
solvent was removed under reduced pressure. To a solution
of this carboxylic acid in DMF (4.0 mL) was added
HOBt$H2O (61.3 mg, 0.401 mmol) and EDC$HCl
(61.3 mg, 0.401 mmol) at 0 8C. After the mixture was
stirred for 0.5 h at the same temperature, (R)-a-methyl-
benzylamine (51.6 mL, 0.401 mmol) was added dropwise.
The reaction mixture was stirred for overnight at room
temperature, then diluted with AcOEt and washed with 5%
citric acid aq, 5% NaHCO3 aq, water and brine, and dried
over Na2SO4. The solvent was removed under reduced
pressure and the resulting crude product was purified by
preparative TLC (CHCl3/MeOHZ10:1, 2 times develop-
ment) to yield amide 15 as a white powder (133.7 mg, 92%
for 2 steps). Recrystalization of the obtained white
powder from CHCl3 afforded the white needles, which
was analyzed by X-ray crystallography. RfZ0.34 (CHCl3/
MeOHZ10:1); mp 190–191 8C; 1H NMR (400 MHz,
CDCl3) d 7.37–7.20 (m, 10H), 5.75 (br d, 0.5H, JZ
8.1 Hz), 5.72 (br d, 0.5H, JZ8.4 Hz), 5.13 (q, 0.5H, JZ
6.8 Hz), 5.11 (q, 0.5H, JZ7.0 Hz), 5.06 (s, 0.5H), 5.05 (s,
0.5H), 4.81 (d, 0.5H, JZ5.5 Hz), 4.79 (d, 0.5H, JZ5.7 Hz),
4.69–4.64 (m, 1H), 4.56–4.52 (m, 0.5H), 4.45–4.39 (m,
0.5H), 3.95–3.99 (m, 0.5H), 3.87–3.82 (m, 0.5H), 3.16, 2.87
(2ddd, 0.5!2H, JZ14.3, 11.5, 2.9 Hz, partially over-
lapping with the next signal), 3.01–2.67 (m, 3H), 2.39–
2.29 (m, 1H), 1.94–1.54 (m, 4H), 1.50 (d, 0.5!3H, JZ
7.0 Hz), 1.48 (d, 0.5!3H, JZ6.8 Hz); 13C NMR
(75.5 MHz, DMSO-d6) d 172.8, 165.6, 165.5, 157.4,
145.0, 144.8, 136.3, 136.2, 129.6, 129.5, 128.6, 128.3,
126.8, 126.6, 125.8, 74.3, 74.1, 55.8, 55.5, 47.6, 44.0, 41.4,
41.3, 28.9, 28.1, 27.7, 22.5; [a]2D5ZC9.4 (c 1.05, MeOH);
HRMS (EI): found MC 435.2157, C25H29N3O4 requires
MC 435.2158.
4.4.4. Benzyl N-[(4S,5R)-4-benzyl-(3-phenylpropionyl)-
1,3-oxazolidin-2-one-5-carbonyl]piperidine-4-carboxyl-
ate 16. To a solution of 3-phenylpropionic acid (6.8 g,
45.2 mmol) in anhydrous THF (100 mL) was added Et3N
(12.2 mL, 87.0 mmol) and trimethylacetylchloride (5.2 mL,
41.8 mmol) dropwise at -18 8C. The reaction mixture was
stirred at the same temperature for 0.5 h, then anhydrous
LiCl (1.6 g, 38.3 mmol) was added, followed by the slow
addition of a solution of oxazolidinone 14 (14.7 g,
34.8 mmol) in anhydrous THF (75 mL). After the addition
was completed, the reaction mixture was stirred overnight at
room temperature. The solution was poured into ice-cold
satd NaHCO3 aq and the organic phase was extracted with
AcOEt, washed with water and brine, and dried over
Na2SO4. The solvent was removed under reduced pressure,
and the resulting oil was applied to silica-gel column
chromatography (n-hexane/AcOEtZ4:1) to yield the
desired compound 16 as a white solid (18.5 g, 96%). RfZ
0.52 (n-hexane/AcOEtZ1:1); mp 39–41 8C; 1H NMR
(400 MHz, CDCl3) d 7.40–7.18 (m, 15H), 5.14, 5.10 (2d,
0.5!2H, JZ12.3 Hz), 5.09 (s, 0.5!2H), 4.88 (d, 0.5H, JZ
4.4 Hz), 4.87 (d, 0.5H, JZ4.4 Hz), 4.71–4.65 (m, 1H), 4.19
(dt, 0.5H, JZ13.7, 4.0 Hz), 4.13 (dt, 0.5H, JZ13.4, 4.2 Hz),
3.45–3.18 (m, 3H), 3.08–2.94 (m, 2H), 2.83–2.33 (m, 5H),
1.92–1.86 (m, 1H), 1.65–1.39 (m, 2H and 0.5H), 1.19–1.09
(m, 0.5H); 13C NMR (75.5 MHz, CDCl3) d 173.1, 171.9,
164.7, 164.5, 152.4, 152.3, 140.2, 135.6, 135.5, 135.0,
129.4, 129.3, 129.2, 129.1, 128.4, 128.3, 128.3, 128.2,
128.2, 127.9, 127.9, 127.5, 126.0, 71.7, 71.5, 66.3, 59.2,
58.8, 43.3, 43.1, 41.5, 41.4, 40.2, 40.1, 37.6, 37.5, 36.9,
36.9, 30.0, 28.0, 27.9, 27.2; [a]2D6ZK16.7 (c 2.09, CHCl3);
FT-IR (CHCl3) nmax 3040, 3007, 1794, 1728, 1701, 1659,
1497, 1454, 1379, 1310, 1292, 1263, 1244, 1171, 1103,
1078, 1030, 694 cmK1; HRMS (EI): found MC 554.2410,
C33H34N2O6 requires MC 554.2416. Anal. Calcd for
C33H34N2O6: C, 71.46; H, 6.18; N, 5.05; found: C, 71.28;
H, 5.99; N, 5.34.
4.4.5. Deuterium labeling study of the carboximide 16.
Under Ar atmosphere, the solution of the carboximide 16
(142.4 mg, 0.257 mmol) in anhydrous THF (2.6 mL) was
cooled to K78 8C (MeOH-dry ice bath), and LDA (1.8 M
solution in heptane / THF / ethylbenzene, 0.17 mL,
0.31 mmol) was added dropwise. After stirring for 0.5 h at
the same temperature, acetic acid-d (99at.% D) (0.30 mL,
5.14 mmol) was added slowly, then cooling bath was
removed and the reaction mixture was stirred for 1 h at room
4.4.3. Crystallography of amide 15. Diffraction data for 15
were collected on a Rigaku AFC7R diffractometer with
˚
graphite monochromated Cu Ka radiation (lZ1.54178 A)

3828
T. Kotake et al. / Tetrahedron 61 (2005) 3819–3833
temperature. The solution was poured into ice-cold satd
NH4Cl aq and the organic phase was extracted with AcOEt,
washed with 5% NaHCO3 aq, water and brine, and dried
over Na2SO4. The solvent was removed under reduced
pressure, and the resulting oil was subjected to preparative
TLC (n-hexane/AcOEtZ1:1) to yield the products as a
white powder (125.7 mg, 88%). The content of deuterium-
incorporated 17 was detected by NMR. RfZ0.53 (n-hexane/
AcOEtZ1:1); mp 39–40 8C; 1H NMR (400 MHz, CDCl3) d
7.40–7.18 (m, 15H), 5.14, 5.10 (2d, 0.5!2H, JZ12.3 Hz),
5.09 (s, 0.5!2H), 4.88 (d, 0.5H, JZ4.6 Hz), 4.87 (d, 0.5H,
JZ4.6 Hz), 4.71–4.64 (m, 1H), 4.19 (dt, 0.5H, JZ13.6,
4.0 Hz), 4.13 (dt, 0.5H, JZ13.2, 4.0 Hz), 3.44–3.18 (m,
2.24H), 3.06–2.94 (m, 2H), 2.83–2.33 (m, 5H), 1.91–1.86
(m, 1H), 1.64–1.38 (m, 2H and 0.5H), 1.18–1.08 (m, 0.5H);
2H NMR (400 MHz, CHCl3) d 3.32 (s, 0.76D); 13C NMR
(75.5 MHz, CDCl3) d 173.3, 172.1, 164.8, 164.6, 152.5, 152.4,
140.3, 135.7, 135.6, 135.2, 129.5, 129.5, 129.3, 129.3, 128.6,
128.5, 128.4, 128.4, 128.1, 127.7, 126.2, 71.8, 71.6, 66.5, 59.2,
58.9, 43.5, 43.3, 41.7, 41.6, 40.3, 37.8, 37.7, 37.1, 37.0, 36.7 (t,
JZ19.9 Hz), 30.1, 30.1, 28.2, 28.0, 27.3; [a]2D7ZK14.8 (c
1.69, CHCl3); FT-IR (CHCl3) nmax 1792, 1732, 1703, 1661,
resin was positive (blue), whereas the oxazolidinone resin
23 was negative (colorless). The obtained resin was washed
with CHCl3 (20 mL) and MeOH (20 mL) (!5, sequen-
tially), then overnight drying in vacuo afforded the desired
pale yellowish oxazolidinone resin 23 (6.3 g) with loading
rate of 0.61 mmol/g.
4.5.1. O-Wang resin-supported N-[(9H-9-fluorenyl-
methoxy)carbonyl]piperidine-4-carboxylic acid 21.
FT-IR (KBr) nmax 1736, 1719 cmK1
.
4.5.2. O-Wang resin-supported N-((2R,3S)-3-{[(9H-9-
fluorenylmethoxy)carbonyl]amino}-2-hydroxy-4-
phenylbutanoyl)piperidine-4-carboxylic acid 22. FT-IR
(KBr) nmax 3398, 1733, 1718, 1638 cmK1
.
4.5.3. O-Wang resin-supported N-[(4S,5R)-4-benzyl-1,3-
oxazolidin-2-one-3-carbonyl]piperidine-4-carboxylic
acid 23. FT-IR (KBr) nmax 1763, 1740, 1655 cmK1
.
4.5.4. Methanolysis of the oxazolidinone resin 23 to
afford the methyl N-[(4S,5R)-4-benzyl-1,3-oxazolidin-2-
one-5-carbonyl]piperidine-4-carboxylate 24. Oxazolidi-
none-loaded resin 23 (129.9 mg, 0.083 mmol) was swollen
in anhydrous THF (0.85 mL) and anhydrous MeOH
(0.85 mL), then potassium carbonate (22.9 mg,
0.166 mmol) was added in one portion at 0 8C. The
heterogeneous reaction mixture was gently stirred for 2 h
at room temperature. The reaction was quenched by the
addition of satd NH4Cl aq, and the resultant resin was
removed by filtration. The filtrate was extracted with
AcOEt, and washed with water and brine, then dried over
Na2SO4. After solvent removal, the remaining crude oil was
purified by preparative TLC (n-hexane/AcOEtZ1:10) to
yield the oxazolidinone methyl ester 24 as a white solid
(27.4 mg, 95% in 6 steps from Wang resin). RfZ0.30
(n-hexane/AcOEtZ1:5); mp 39–40 8C; 1H NMR
(400 MHz, CDCl3) d 7.36–7.21 (m, 5H), 5.73 (br s, 1H),
4.82 (d, 0.5H, JZ5.5 Hz), 4.80 (d, 0.5H, JZ5.5 Hz), 4.67–
4.62 (m, 1H), 4.39–4.34 (m, 0.5H), 4.19 (dt, 0.5H, JZ13.6,
4.0 Hz), 3.83–3.79 (m, 0.5H), 3.70–3.65 (m, 0.5H, partially
overlapping with the next signal), 3.70 (s, 0.5!3H), 3.68 (s,
0.5!3H), 3.20, 3.00 (2ddd, 0.5!2H, JZ14.1, 10.6, 3.1 Hz,
partially overlapping with the next signal), 2.99–2.78 (m,
3H), 2.61–2.50 (m, 1H), 1.96–1.54 (m, 4H); 13C NMR
(75.5 MHz, CDCl3) d 174.3, 174.1, 164.5, 164.4, 157.1,
135.8, 135.7, 129.1, 128.8, 127.1, 76.4, 76.3, 55.4, 55.3,
51.8, 44.7, 44.4, 41.9, 41.7, 40.8, 40.7, 40.6, 40.1, 28.3,
28.1, 27.4; [a]2D5ZK104.4 (c 0.55, CHCl3); FT-IR (CHCl3)
nmax 3454, 3007, 2955, 1771, 1732, 1655, 1456, 1437, 1383,
1454,1371,1236, 1196, 1186, 1173, 797,725,700,673 cmK1
;
HRMS (EI): found MC 555.2482, C33H33DN2O6 requires
MC 555.2479. Anal. Calcd for C33H33DN2O6: C, 71.33;
HCD, 6.35; N, 5.04; found: C, 71.17; HCD, 6.29; N, 5.01.
4.5. Preparation of the Wang resin-supported
oxazolidinone 23 by Fmoc-based solid-phase synthesis
Wang resin (0.80 mmol/g resin) (5.0 g, 4.0 mmol) in a
cap-fitted reaction vessel was washed with CH2Cl2 (20 mL,
!5), then Fmoc-piperidine-4-carboxylic acid 20 (4.2 g,
12.0 mmol) and CH2Cl2 (30 mL) were charged. DIPCDI
(1.9 mL, 12.0 mmol) was added, followed by the addition of
DMAP (48.7 mg, 0.4 mmol). The heterogeneous reaction
mixture was vigorously shaken for 2 h at room temperature,
then filtered and washed with DMF (20 mL, !5). The
obtained white resin 21 was then washed with piperidine in
DMF (20%, v/v) (20 mL, !5) and treated with piperidine in
DMF (20%, v/v) (30 mL) for 0.5 h at room temperature. The
solvent and reagent were drained and the resin was washed
with DMF (20 mL), CHCl3 (20 mL), DMF (20 mL) (!5,
sequentially). Next, Fmoc-Pns-OH (5.0 g, 12.0 mmol),
HOBt$H2O (1.8 g, 12.0 mmol), DMF (30 mL) and DIPCDI
(1.9 mL, 12.0 mmol) were added, and the heterogenious
reaction mixture was vigorously shaken for 2 h at
room temperature, then filtered and washed with DMF
(20 mL, !5). The aliquot of the resultant resin 22 was
applied to the Kaiser-Test47 to check the reaction progress.
Starting secondary amine resin was positive (pale orange),
whereas the dipeptide-bound resin 22 was negative (color-
less). The obtained resin 22 was washed with piperidine in
DMF (20%, v/v) (20 mL, !5) and treated with piperidine in
DMF (20%, v/v) (30 mL) for 0.5 h at room temperature. The
solvent and reagent were drained and the resin was washed
with DMF (20 mL), CHCl3 (20 mL), DMF (20 mL) (!5,
sequentially). The obtained amino alcohol resin was washed
with THF (20 mL, !5), then CDI (1.9 g, 12.0 mmol) and
anhydrous THF (30 mL) were added. The heterogenious
reaction mixture was vigorously shaken for 3 h at
room temperature, then filtered and washed with THF
(20 mL, !5). Kaiser-Test of the starting primary amine
1317, 1269, 1240, 1194, 1177, 1040, 1015, 760, 745 cmK1
;
HRMS (EI): found MC 346.1526, C18H22N2O5 requires
MC 346.1528. Anal. Calcd for C18H22N2O5$0.25H2O: C,
61.61; H, 6.46; N, 7.98; found: C, 61.99; H, 6.26; N, 7.96.
4.6. General procedure for N-acylation of the Wang
resin-supported oxazolidinone resin 23, solid-phase
asymmetric alkylation, lithium hydroperoxide-mediated
hydrolysis, and the derivatization to the (S)-phenyl-
ethylamide for enantiomeric excess determination
Oxazolidinone-loaded resin 23 in a polystyrene reactor was
washed with CH2Cl2 (!5), then the corresponding

T. Kotake et al. / Tetrahedron 61 (2005) 3819–3833
3829
carboxylic acid (3.0 equiv), 2-chloro-1-methylpyridinium
iodide (3.0 equiv) and anhydrous CH2Cl2 (0.08 mmol resin/
mL) were added. The mixture was shaken for 10 min,
followed by the addition of Et3N (5.0 equiv) and DMAP
(0.3 equiv). The reaction mixture was shaken for 2 h at
room temperature and filtered, then the resultant resin was
washed with CH2Cl2 (!5). The reaction was repeated once
again, and the obtained resin was washed with DMF, CHCl3
and MeOH (!5, sequentially), then overnight drying in
vacuo afforded the desired carboximide resin 25. Under Ar
atmosphere, carboximide resin 25 in a glass reaction vessel
was swollen in THF (20 mL/mmol resin) for 10 min at room
temperature, and the heterogeneous mixture was cooled to
K78 8C (MeOH-dry ice bath), followed by the dropwise
addition of 1.0 M THF solution of NaHMDS (3.0 equiv).
After continuously stirring for 1 h at the same temperature,
the corresponding alkyl halide (10.0 equiv) was added. The
temperature of the reaction mixture was gradually increased
up to 0 8C over 12 h with gentle stirring, then quenched by
the addition of satd NH4Cl aq, and tri-phase reaction
mixture was stirred for additional 15 min. at 0 8C. The
resultant resin was separated from the reaction mixture by
filtration, followed by washing with THF-H2O (1:1), THF
and MeOH (!5, sequentially). Then, the resin was dried
well in the desiccator under reduced pressure for 3 h. THF-
H2O (3:1, v/v) (0.05 mmol resin/mL) was added to the
a-alkylated carboximide resin, and the resin was swollen for
10 min. at 0 8C. Next, 30% aqueous H2O2 (6.0 equiv) and
LiOH$H2O (3.0 equiv) were added. After gentle stirring for
2 h at the same temperature, the reaction was quenched by
the addition of 1.5 N NaHSO3 aq, and the deacylated resin
was filtered off. The filtrate was acidified to pH 2 with 1 N
HCl aq, and extracted with AcOEt. The extract was washed
with brine, and dried over Na2SO4. After removal of the
solvent under reduced pressure, the residue was purified by
preparative TLC to yield the desired a-alkylated carboxylic
acids 26. The recovered oxazolidinone resin 23 was washed
with THF, CHCl3 and MeOH (!5, sequentially), then dried
in the desiccator under reduced pressure. Determination of
the enantiomeric excess of the obtained carboxylic acids 26
was carried out by derivatization to the corresponding (S)-
phenylethyl amides and chiral HPLC analysis. To a 0.05 M
solution of the acids 26 in DMF was added HOBt$H2O
(1.2 equiv) and EDC$HCl (1.2 equiv) at 0 8C. The mixture
was stirred for 0.5 h at the same temperature, and (S)-
phenylethylamine (1.2 equiv) was added dropwise. The
reaction mixture was stirred overnight at room temperature,
then diluted with AcOEt and washed with 5% citric acid aq,
5% NaHCO3 aq, water and brine, and dried over Na2SO4.
The solvent was removed under reduced pressure, and the
resulting amide was subjected to the HPLC analysis without
any purification. Enantiomeric excess was calculated from
the peak areas of the corresponding two diastereomers.
(75.5 MHz, CDCl3) d 181.7, 139.0, 129.0, 128.4, 126.4,
41.1, 39.3, 16.5; [a]2D8ZC20.6 (c 0.87, CHCl3): lit.,48
[a]DZC25.5 (c 1.00, CHCl3); FT-IR (CHCl3) nmax 3038,
2980, 1709, 1454, 1238, 719, 698, 675 cmK1; HRMS (EI):
found MC 164.0838, C10H12O2 requires MC 164.0837.
Anal. Calcd for C10H12O2: C, 73.15; H, 7.37; found: C,
73.25; H, 7.47. Enantiomeric excess was 85% ee determined
by chiral HPLC analysis of the corresponding (S)-a-
methylbenzylamine-derived amide with Chiralcelw OD
normal phase column (n-hexane/EtOHZ30/1, 1.0 mL/
min, 230 nm), major isomerZ13.1 min, minor isomerZ
16.8 min.
4.6.2. (S)-2-Benzylbutanoic acid 26b. The title compound
26b was obtained according to the general procedure using
the oxazolidinone resin 23 (193.8 mg, 0.118 mmol). Puri-
fication by preparative TLC (CHCl3/MeOHZ10:1) gave
26b as a colorless oil (10.6 mg, 50% yield in 3 steps from
oxazolidinone resin 23). RfZ0.53 (CHCl3/MeOHZ10:1);
1H NMR (300 MHz, CDCl3) d 7.30–7.16 (m, 5H), 2.98 (dd,
1H, JZ13.6, 7.7 Hz), 2.75 (dd, 1H, JZ13.6, 6.8 Hz), 2.66–
2.57 (m, 1H), 1.72–1.54 (m, 2H), 0.96 (t, 3H, JZ7.3 Hz);
13C NMR (75.5 MHz, CDCl3) d 181.3, 139.1, 128.9, 128.4,
126.4, 48.8, 37.7, 24.7, 11.6; [a]2D6ZC30.7 (c 0.86,
benzene): lit.,49 [a]D24ZC34.7 (c 8.45, benzene); FT-IR
(CHCl3) nmax 1707, 1462, 1383, 1096, 899, 696, 652 cmK1
;
HRMS (EI): found MC 178.0999, C11H14O2 requires MC
178.0994. Anal. Calcd for C11H14O2: C, 74.13; H, 7.92;
found: C, 73.99; H, 7.99. Enantiomeric excess was 88% ee
determined by chiral HPLC analysis of the corresponding
(S)-a-methylbenzylamine-derived amide with Chiralcelw
OD normal phase column (n-hexane/EtOHZ30/1, 1.0 mL/
min, 230 nm), major isomerZ11.3 min, minor isomerZ
16.1 min.
4.6.3. (S)-2-Benzyl-4-pentenoic acid 26c. The title com-
pound 26c was obtained according to the general procedure
using the oxazolidinone resin 23 (302.1 mg, 0.184 mmol).
Purification by preparative TLC (CHCl3/MeOHZ10:1)
gave 26c as a colorless oil (23.8 mg, 68% yield in 3 steps
from oxazolidinone resin 23). RfZ0.50 (CHCl3/MeOHZ
1
10:1); H NMR (300 MHz, CDCl3) d 7.31–7.16 (m, 5H),
5.78 (ddt, 1H, JZ17.1, 10.3,7.0 Hz), 5.12–5.05 (m, 2H),
3.03–2.94 (m, 1H), 2.82–2.72 (m, 2H), 2.44–2.25 (m, 2H);
13C NMR (75.5 MHz, CDCl3) d 180.7, 138.8, 134.7, 128.9,
128.5, 126.5, 117.5, 46.9, 37.3, 35.6; [a]2D6ZC24.0 (c 1.27,
CHCl3): lit.,33 [a]D25ZC19.2 (c 12.2, CHCl3); FT-IR
(CHCl3) nmax 3084, 3067, 3038, 1709, 922, 802, 775, 764,
746, 739, 729, 721, 700, 675, 667 cmK1; HRMS (EI): found
MC 190.0989, C12H14O2 requires MC 190.0994. Anal.
Calcd for C12H14O2: C, 75.76; H, 7.42; found: C, 75.50; H,
7.50. Enantiomeric excess was 96% ee determined by chiral
HPLC analysis of the corresponding (S)-a-methylbenzyl-
amine-derived amide with Chiralcelw OD normal phase
column (n-hexane/EtOHZ30/1, 1.0 mL/min, 230 nm),
major isomerZ11.6 min, minor isomerZ15.2 min.
4.6.1. (S)-2-Benzylpropanoic acid 26a. The title com-
pound 26a was obtained according to the general procedure
using the oxazolidinone resin 23 (277.5 mg, 0.169 mmol).
Purification by preparative TLC (n-hexane/AcOEtZ1:1)
gave 26a as a colorless oil (16.8 mg, 61% yield in 3 steps
from oxazolidinone resin 23). RfZ0.63 (n-hexane/AcOEtZ
1:1); 1H NMR (300 MHz, CDCl3) d 7.32–7.17 (m, 5H), 3.08
(dd, 1H, JZ13.0, 6.1 Hz), 2.83–2.71 (m, 1H), 2.67 (dd, 1H,
JZ13.0, 7.9 Hz), 1.18 (d, 3H, JZ6.8 Hz); 13C NMR
4.6.4. (S)-2-Benzyl-4-pentynoic acid 26d. The title com-
pound 26d was obtained according to the general procedure
using the oxazolidinone resin 23 (206.9 mg, 0.126 mmol).
Purification by preparative TLC (CHCl3/MeOHZ10:1) gave
26d as a colorless oil (14.7 mg, 62% yield in 3 steps from
oxazolidinone resin 23). RfZ0.44 (CHCl3/MeOHZ10:1); 1H

3830
T. Kotake et al. / Tetrahedron 61 (2005) 3819–3833
NMR (300 MHz, CDCl3) d 7.31–7.20 (m, 5H), 3.09 (dd, 1H,
JZ13.4, 6.6 Hz), 2.99–2.85 (m, 2H), 2.44 (dd, 2H, JZ6.4,
2.6 Hz), 2.06 (t, 1H, JZ2.6 Hz); 13C NMR (75.5 MHz,
CDCl3) d 179.5, 138.1, 129.0, 128.5, 126.7, 80.9, 70.6, 45.9,
36.3, 20.0; [a]2D6ZK10.9 (c 1.24, CHCl3); FT-IR (CHCl3)
nmax 3308, 1719, 1217, 1200, 770, 700, 671 cmK1; HRMS
(EI): found MC 188.0835, C12H12O2 requires MC 188.0837.
Anal. Calcd for C12H12O2$0.25H2O: C, 74.78; H, 6.54; found:
C, 75.14; H, 6.57. Enantiomeric excess was 96% ee
determined by chiral HPLC analysis of the corresponding
(S)-a-methylbenzylamine-derived amide with Chiralcelw OD
normal phase column (n-hexane/EtOHZ30/1, 1.0 mL/min,
230 nm), major isomerZ16.4 min, minor isomerZ18.6 min.
(CHCl3/MeOHZ10:1) gave 26g as a white powder
(18.6 mg, 68% yield in 3 steps from oxazolidinone resin
23). RfZ0.55 (CHCl3/MeOHZ10:1); mp 60–62 8C; 1H
NMR (300 MHz, CDCl3) d 7.41 (d, 2H, JZ8.4 Hz), 7.06 (d,
2H, JZ8.4 Hz), 3.01 (dd, 1H, JZ13.0, 6.4 Hz), 2.77–2.68
(m, 1H), 2.64 (dd, 1H, JZ13.0, 7.5 Hz), 1.18 (d, 3H, JZ
6.8 Hz); 13C NMR (75.5 MHz, CDCl3) d 181.1, 138.0,
131.5, 130.7, 120.3, 40.9, 38.7, 16.6; [a]2D6ZK26.4 (c 1.02,
CHCl3); FT-IR (CHCl3) nmax 3030, 1711, 1466, 1381, 1231,
1215, 1097, 893, 800, 787, 750, 733, 725, 696, 677,
654 cmK1; HRMS (EI): found MC 241.9949, C10H11BrO2
requires MC 241.9942. Anal. Calcd for C10H11BrO2: C,
49.41; H, 4.56; found: C, 49.56; H, 4.66. Enantiomeric
excess was 97% ee determined by chiral HPLC analysis of
the corresponding (S)-a-methylbenzylamine-derived amide
with Chiralcelw OD normal phase column (n-hexane/
EtOHZ50/1, 1.0 mL/min, 230 nm), major isomerZ
30.8 min, minor isomerZ27.5 min.
4.6.5. (R)-2-Benzyl-4-ethoxy-4-oxobutanoic acid 26e. The
title compound 26e was obtained according to the general
procedure using the oxazolidinone resin 23 (259.8 mg,
0.158 mmol). Purification by preparative TLC (CHCl3/
MeOHZ10:1) gave 26e as a colorless oil (23.1 mg, 62%
yield in 3 steps from oxazolidinone resin 23). RfZ0.41
(CHCl3/MeOHZ10:1); 1H NMR (300 MHz, CDCl3) d
7.32–7.17 (m, 5H), 4.11 (q, 2H, JZ7.2 Hz), 3.21–3.10 (m,
2H), 2.83–2.74 (m, 1H), 2.64 (dd, 1H, JZ17.0, 8.9 Hz),
2.41 (dd, 1H, JZ17.0, 4.6 Hz), 1.22 (t, 3H, JZ7.2 Hz); 13C
NMR (75.5 MHz, CDCl3) d 179.5, 171.7, 137.9, 129.1,
128.6, 126.8, 60.8, 42.8, 37.4, 34.8, 14.1; [a]2D6ZC10.6 (c
1.15, CHCl3): lit.,50 [a]D28ZC10.0 (c 2.9, CHCl3); FT-IR
(CHCl3) nmax 1732, 1717, 910, 777, 754, 739, 721, 700, 679,
652 cmK1; HRMS (EI): found MC 236.1051, C13H16O4
requires MC 236.1048. Anal. Calcd for C13H16O4: C, 66.09;
H, 6.83; found: C, 65.93; H, 6.81. Enantiomeric excess was
92% ee determined by chiral HPLC analysis of the
corresponding (S)-a-methylbenzylamine-derived amide
with Chiralcelw OD normal phase column (n-hexane/
EtOHZ30/1, 1.0 mL/min, 230 nm), major isomerZ
15.7 min, minor isomerZ16.6 min.
4.6.8. (R)-3-(4-Nitrophenyl)-2-methylpropanoic acid
26h. The title compound 26h was obtained according to
the general procedure using the oxazolidinone resin 23
(256.2 mg, 0.156 mmol). Purification by preparative TLC
(CHCl3/MeOHZ10:1) gave 26h as a pale yellowish powder
(21.2 mg, 65% yield in 3 steps from oxazolidinone resin 23).
RfZ0.44 (CHCl3/MeOHZ10:1); mp 101–103 8C; 1H NMR
(300 MHz, CDCl3) d 8.16 (d, 2H, JZ8.8 Hz), 7.36 (d, 2H,
JZ8.8 Hz), 3.15 (dd, 1H, JZ16.5, 9.9 Hz), 2.86–2.77 (m,
2H), 1.23 (d, 3H, JZ6.6 Hz); 13C NMR (75.5 MHz, CDCl3)
d 181.0, 146.9, 146.7, 129.8, 123.7, 40.8, 39.0, 16.8;
[a]2D5ZK36.9 (c 1.14, CHCl3); FT-IR (CHCl3) nmax 1713,
1607, 1522, 1464, 1381, 1348, 1231, 1097, 895, 733, 694,
648 cmK1; HRMS (EI): found MC 209.0683, C10H11NO4
requires MC for 209.0688. Anal. Calcd for C10H11NO4: C,
57.41; H, 5.30; N, 6.70; found: C, 57.58; H, 5.39; N, 6.72.
Enantiomeric excess was 97% ee determined by chiral
HPLC analysis of the corresponding (S)-a-methylbenzyl-
amine-derived amide with Chiralcelw OD normal phase
column (n-hexane/EtOHZ20/1, 1.0 mL/min, 230 nm),
major isomerZ33.2 min, minor isomerZ37.5 min.
4.6.6. (R)-2-Benzylpropanoic acid 26f. The title compound
26f was obtained according to the general procedure using
the oxazolidinone resin 23 (236.5 mg, 0.144 mmol). Puri-
fication by preparative TLC (n-hexane/AcOEtZ1:1) gave
26f as a colorless oil (16.6 mg, 70% yield in 3 steps from
oxazolidinone resin 23). RfZ0.63 (n-hexane/AcOEtZ1:1);
1H NMR (300 MHz, CDCl3) d 7.31–7.17 (m, 5H), 3.08 (dd,
1H, JZ13.0, 6.1 Hz), 2.80–2.70 (m, 1H), 2.67 (dd. 1H, JZ
13.0, 7.9 Hz), 1.18 (d, 3H, JZ6.8 Hz); 13C NMR
(75.5 MHz, CDCl3) d 182.3, 139.0, 129.0, 128.4, 126.4,
41.2, 39.3, 16.5; [a]2D8ZK30.7 (c 1.04, CHCl3): lit.,51
[a]2D2ZK30.1 (c 1.00, CHCl3); FT-IR (CHCl3) nmax 1707,
1464, 1381, 1231, 893, 800, 694, 648 cmK1; HRMS (EI):
found MC 164.0830, C10H12O2 requires MC 164.0837.
Anal. Calcd for C10H12O2: C, 73.15; H, 7.37; found: C,
72.94; H, 7.31. Enantiomeric excess was 97% ee determined
by chiral HPLC analysis of the corresponding (S)-a-
methylbenzylamine-derived amide with Chiralcelw OD
normal phase column (n-hexane/EtOHZ30/1, 1.0 mL/
min, 230 nm), major isomerZ16.8 min, minor isomerZ
13.1 min.
4.6.9. (R)-3-(2,4-Dichlorophenyl)-2-methylpropanoic
acid 26i. The title compound 26i was obtained according
to the general procedure using the oxazolidinone resin 23
(251.2 mg, 0.153 mmol). Purification by preparative TLC
(CHCl3/MeOHZ10:1) gave 26i as a pale yellowish oil
(25.3 mg, 71% yield in 3 steps from oxazolidinone resin 23).
RfZ0.56 (CHCl3/MeOHZ10:1); 1H NMR (300 MHz,
CDCl3) d 7.37 (m, 1H), 7.16–7.15 (m, 2H), 3.12 (dd, 1H,
JZ12.8, 6.6 Hz), 2.90–2.82 (m, 1H), 2.79 (dd, 1H, JZ12.8,
7.2 Hz), 1.22 (d, 3H, JZ6.8 Hz); 13C NMR (75.5 MHz,
CDCl3) d 181.9, 135.4, 134.9, 133.0, 132.0, 129.4, 127.0,
39.3, 36.3, 16.8; [a]D27ZK44.9 (c 1.00, CHCl3); FT-IR
(CHCl3) nmax 1709, 1474, 1383, 1103, 901, 870, 802, 725,
712, 677, 652 cmK1; HRMS (EI): found MC 232.0055,
C10H10Cl2O2 requires MC 232.0058. Anal. Calcd for
C10H10Cl2O2: C, 51.53; H, 4.32; found: C, 51.68; H, 4.44.
Enantiomeric excess was 97% ee determined by chiral
HPLC analysis of the corresponding (S)-a-methylbenzyl-
amine-derived amide with Chiralcelw OD normal phase
column (n-hexane/EtOHZ70/1, 1.0 mL/min, 230 nm),
major isomerZ24.2 min, minor isomerZ21.7 min.
4.6.7. (R)-3-(4-Bromophenyl)-2-methylpropanoic acid
26g. The title compound 26g was obtained according to
the general procedure using the oxazolidinone resin 23
(185.5 mg, 0.113 mmol). Purification by preparative TLC

T. Kotake et al. / Tetrahedron 61 (2005) 3819–3833
3831
4.6.10. (R)-2-Phenoxy-4-pentenoic acid 26j. The title
compound 26j was obtained according to the general
procedure using the oxazolidinone resin 23 (284.0 mg,
0.173 mmol). Purification by preparative TLC (CHCl3/
MeOHZ10:1) gave 26j as a white solid (16.7 mg, 50%
yield in 3 steps from oxazolidinone resin 23). RfZ0.48
(CHCl3/MeOHZ10:1); mp 30–31 8C; 1H NMR (400 MHz,
CDCl3) d 9.19 (br s, 1H), 7.31–7.25 (m, 2H), 7.02–6.98 (m,
1H), 6.90 (dd, 2H, JZ8.8, 1.1 Hz), 5.91 (ddt, 1H, JZ17.0,
10.3, 7.0 Hz), 5.21 (dd, 1H, JZ17.0, 1.6 Hz), 5.16 (dd, 1H,
JZ10.3, 1.6 Hz), 4.72 (t, 1H, JZ6.2 Hz), 2.72–2.76 (m,
2H); 13C NMR (75.5 MHz, CDCl3)? d 176.5, 157.4, 131.9,
129.6, 122.1, 119.0, 115.3, 75.9, 36.8; [a]2D8ZC7.9 (c 1.96,
CHCl3); FT-IR (CHCl3) nmax 1732, 1599, 1495, 1238, 771,
750, 735, 691 cmK1; HRMS (EI): found MC 192.0782,
C11H12O3 requires MC 192.0786. Anal. Calcd for
C11H12O3: C, 68.74; H, 6.29; found: C, 68.49; H, 6.34.
Enantiomeric excess was 96% ee determined by chiral
HPLC analysis of the corresponding (S)-a-methylbenzyl-
amine-derived amide with Chiralcelw OD normal phase
column (n-hexane/EtOHZ50/1, 1.0 mL/min, 230 nm),
major isomerZ8.3 min, minor isomerZ9.8 min.
0.47 (n-hexane/AcOEtZ1:5); 1H NMR (400 MHz, CDCl3)
d 7.35–7.17 (m, 5H), 5.78 (dddd, 1H, JZ17.2, 10.3, 7.3,
4.8 Hz), 5.26–5.19 (m, 2H), 4.70 (d, 0.5H, JZ4.4 Hz), 4.69
(d, 0.5H, JZ4.6 Hz), 4.66–4.60 (m, 1H), 4.30 (dtd, 0.5H,
JZ3.4, 4.0, 1.5 Hz), 4.24–4.21 (m, 0.5H), 4.20–4.17 (m,
0.5H), 4.15–4.10 (m, 0.5H), 3.68–3.51 (m, 2H), 3.69 (s,
0.5!3H), 3.67 (s, 0.5!3H, partially overlapping with the
next signal), 3.15–2.71 (m, 4H), 2.56–2.45 (m, 1H), 1.91–
1.38 (m, 4H); 13C NMR (75.5 MHz, CDCl3) d 174.3, 174.0,
164.5, 164.4, 156.0, 155.9, 135.3, 135.2, 131.6, 129.2,
128.9, 128.9, 127.3, 127.2, 118.9, 118.8, 73.5, 73.3, 57.0,
56.9, 51.8, 45.2, 44.7, 44.4, 41.9, 41.7, 40.7, 40.2, 38.1,
37.9, 28.4, 28.1, 27.5, 27.4; [a]2D6ZK85.9 (c 1.19, CHCl3);
FT-IR (CHCl3) nmax 1753, 1746, 1655, 1456, 1437, 1175,
895, 648 cmK1; HRMS (EI): found MC 386.1846,
C21H26N2O5 requires MC 386.1841. Anal. Calcd for
C21H26N2O5: C, 65.27; H, 6.78; N, 7.25; found: C, 64.99;
H, 6.49; N, 7.47.
Acknowledgements
The authors would like to express our sincere gratitude to
Dr. S. Ogawa (Kyoto Pharmaceutical University) for X-ray
crystallographic analysis and in the NMR spectroscopy
measurement. We also thank Dr. V. K. Sharma for the
manuscript preparation. This research was supported in part
by the 21st Century COE Program ‘Development of Drug
Discovery Frontier Integrated from Tradition to Proteome’,
the Frontier Research Program and grants from the Ministry
of Education, Culture, Sports, Science and Technology
(MEXT) of Japan. On a final note, T. Kotake is grateful for
Research Fellowships of JSPS for Young Scientists.
4.6.11. (S)-3-(2,4-Dichlorophenyl)-2-methylpropanoic
acid 26k. The title compound 26k was obtained according
to the general procedure using the oxazolidinone resin 23
(208.5 mg, 0.127 mmol). Purification by preparative TLC
(CHCl3/MeOHZ10:1) gave 26k as a colorless oil (17.4 mg,
59% yield in 3 steps from oxazolidinone resin 23). RfZ0.52
(CHCl3/MeOHZ10:1); 1H NMR (300 MHz, CDCl3) d 7.37
(m, 1H), 7.17–7.16 (m, 2H), 3.12 (dd, 1H, JZ12.8, 6.6 Hz),
2.90–2.80 (m, 1H), 2.79 (dd, 1H, JZ12.8, 7.3 Hz), 1.22 (d,
3H, JZ6.8 Hz); 13C NMR (75.5 MHz, CDCl3) d 181.8,
135.4, 134.9, 133.0, 132.1, 129.4, 127.0, 39.2, 36.3, 16.8;
[a]2D7ZC34.7 (c 0.95, CHCl3); FT-IR (CHCl3) nmax 1711,
1474, 901, 733, 698, 675, 667, 652 cmK1; HRMS (EI):
found MC 232.0054, C10H10Cl2O2 requires MC 232.0058.
Anal. Calcd for C10H10Cl2O2: C, 51.53; H, 4.32; found: C,
51.93; H, 4.62. Enantiomeric excess was 85% ee determined
by chiral HPLC analysis of the corresponding (S)-a-
methylbenzylamine-derived amide with Chiralcelw OD
normal phase column (n-hexane/EtOHZ70/1, 1.0 mL/
min, 230 nm), major isomerZ21.7 min, minor isomerZ
24.2 min.
References and notes
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