A new polymer-supported Evans-type chiral auxiliary derived from α-hydroxy-β-amino acid, phenylnorstatine: Synthesis and application in solid-phase asymmetric alkylation reactions

Article abstract of DOI:10.1016/j.tetlet.2004.03.043

Based on a new anchoring strategy, a polymer-supported chiral oxazolidinone was prepared starting from (2R,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid (phenylnorstatine, Pns) and Wang resin. Solid-phase asymmetric alkylation on this resin proceeded in high diastereoselectivity comparable to that of conventional solution-phase model experiments. This study suggests that anchoring through the 5-position of oxazolidinone is highly suited to achieving diastereoselective alkylation reactions on solid-support.

Full text of DOI:10.1016/j.tetlet.2004.03.043

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3651–3654
A new polymer-supported Evans-type chiral auxiliary derived
from a-hydroxy-b-amino acid, phenylnorstatine: synthesis and
application in solid-phase asymmetric alkylation reactions
Tomoya Kotake, S. Rajesh, Yoshio Hayashi, Yoshie Mukai, Mitsuhiro Ueda,
Tooru Kimura and Yoshiaki Kiso*
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University,
Yamashina-ku, Kyoto 607-8412, Japan
Received 6 February 2004; revised 2 March 2004; accepted 5 March 2004
Abstract—Based on a new anchoring strategy, a polymer-supported chiral oxazolidinone was prepared starting from (2R,3S)-3-
amino-2-hydroxy-4-phenylbutanoic acid (phenylnorstatine, Pns) and Wang resin. Solid-phase asymmetric alkylation on this resin
proceeded in high diastereoselectivity comparable to that of conventional solution-phase model experiments. This study suggests
that anchoring through the 5-position of oxazolidinone is highly suited to achieving diastereoselective alkylation reactions on solid-
support.
Ó 2004 Elsevier Ltd. All rights reserved.
Recently, solid-phase organic synthesis has become a
popular methodology for the preparation of organic
molecules,1 especially the preparation of compound
libraries in the process of drug discovery.2 It allows for
a facile isolation of the desired compounds with easy
elimination of by-products and excess reagents using a
full- or semi-automatic process. Polymer-supported
chiral auxiliaries are especially advantageous because
they can be recovered by simple filtration and poten-
tially recycled. Evans’ oxazolidinone is one of the most
versatile chiral auxiliaries for asymmetric acyl group-
based transformation.3 The attachment of Evans’ oxa-
zolidinone to solid-supports and its utility in asymmetric
alkylation,4 aldol condensation,5 and Diels–Alder,6 and
1,3-dipolar7 cycloadditions have been reported using 1
(Fig. 1A). However, the application of 1 is limited,
probably due to the difficulty of monitoring and opti-
mizing the solid-phase reaction more than the corre-
sponding solution-phase reactions. In addition, the
solid-phase asymmetric alkylation on the resin 1 has not
been accomplished in a high stereoselective manner
(max 90% ee) and a marked undesired effect of the solid-
O
A
B
HN
O
4
O
= Merrifield resin etc.
O
1
HN
O
O
OH
H2N
OH
O
OH
α-hydroxy-β-amino acid
O
HN
O
5
Linker
O
= Wang resin
Figure 1. Polymer-supported Evans-type chiral auxiliaries. (A) Chiral
auxiliary anchored at the 4-position.4–7 (B) The new auxiliary derived
from a-hydroxy-b-amino acid anchored at the 5-position.
Keywords: Evans’ oxazolidinone; Chiral auxiliary; Phenylnorstatine;
Asymmetric alkylation; Solid-phase; Polymer-supported.
* Corresponding author. Tel.: +81-75-595-4635; fax: +81-75-591-9900;
e-mail: kiso@mb.kyoto-phu.ac.jp
supports on the yield and ee was reported.4 One reason
for these undesired results could be that the critical
chiral discriminating unit, that is, the benzyl group at
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.043

3652
T. Kotake et al. / Tetrahedron Letters 45 (2004) 3651–3654
the 4-position of the oxazolidinone ring in 1, was used to
anchor the solid-support.
The synthesis of oxazolidinone derivative 4 is outlined
below (Scheme 1). BocAPnsAOH10 2 was coupled to
benzyl piperidine-4-carboxylateÆHCl by the EDC–HOBt
method11 to give 3. Removal of the N-Boc group of 3
and subsequent reaction with 1,10-carbonyldiimidazole
(CDI)12 gave the desired oxazolidinone 4 in good
yields.13 During this cyclization reaction, no epimeriz-
ation at the 5-position, and no aziridine by-product
formation14 were observed. Oxazolidinone 4 was then
N-3-phenylpropionylated and the resultant carboximide
5a was subjected to a model alkylation study in the
solution-phase.15 As Table 1 shows, the new oxazolidi-
none derivative 4 could function as an efficient chiral
auxiliary with suitable reactivity in terms of yield and
stereoselectivity. In addition, no disruption of both the
oxazolidinone ring and the benzyl ester was observed
during the cleavage with LiOOH.16 Similar results were
also obtained in the use of other imides 5b and 5c with
N-phenoxyacetyl and N-propionyl groups, respectively
(Table 1).
Hence, to create a new anchor liberating the benzyl
group, we focused on the chiral a-hydroxy-b-amino
acids, phenylnorstatine [Pns, (2R,3S)-3-amino-2-hydr-
oxy-4-phenylbutanoic acid] and its (2S,3S)-stereoiso-
mer, allophenylnorstatine (Apns), which are well-known
units with the hydroxymethylcarbonyl (HMC) isostere
necessary for inhibiting aspartyl proteases.8 As shown in
Figure 1B, these a-hydroxy-b-amino acids can be con-
verted to the corresponding oxazolidinones with a carb-
oxyl group at the 5-position of the ring for anchoring to
the solid-support. Here, we describe the synthesis of a
new polymer-supported Evans’ chiral auxiliary derived
from Pns and demonstrate that solid-phase asymmetric
alkylation proceeds with high stereoselectivity parallel
to that obtained with the model substrate under classical
solution conditions.
In the design of new polymer-supported oxazolidinone,
piperidine-4-carboxylic acid was used as a linker, which
can connect the chiral auxiliary through a base-insensi-
tive tertiary-amide bond. Wang resin9 was used as the
solid-support, since the ester bond between the linker
and resin can be easily formed by standard condensation
methods and cleaved by mild acids like TFA or meth-
anolysis to monitor the reaction.
In the case of N-acyloxazolidinone derived from
BocAApnsAOH, epimerization at the 5-position was
observed during the base treatment, suggesting that the 5-
position as well as the desired a-position of the acyl group
were deprotonated by LDA, while deprotonation in the
Pns-derived N-acyloxazolidinone was specific to the a-
position. This was probably due to increased acidity at
O
Ph
Ph
O
O
b, c
a
d
HN
Bn
O
O
BocHN
OH
BocHN
N
COOBn
N
96%
88%
(2 steps)
96%
COOBn
OH
OH
2
3
4
O
O
O
O
O
e
f
Ph
N
O
O
Ph
N
O
Ph
OH
R
N
N
Bn
Bn
R
COOBn
COOBn
60-66%
(2 steps)
O
5a
6a
7a
Scheme 1. Reagents and conditions: (a) benzyl piperidine-4-carboxylateÆHCl, HOBtÆH2O, EDCÆHCl, Et3N, DMF, 0 °C to rt; (b) 4 M HCl/1,4-
dioxane, 0 °C to rt; (c) Et3N, CDI, THF, 0 °C to rt; (d) 3-phenylpropionic acid, tBuCOCl, Et3N, LiCl, THF, )18 °C to rt; (e) LDA, RX, THF, )78 to
0 °C; (f) LiOH, 30% H2O2, THF–H2O (3:1), 0 °C.
Table 1. Results of asymmetric alkylation
Entry
Imide
R2X
MeI
Solid-phase
Ee (%)b
Solution-phase
Ee (%)b
Yield (%)a
Yield (%)c
1
2
10/5a
10/5a
48
54
85
96
62
66
86
96
I
Br
3
10/5a
51
94
64
95
4
5
6
10/5a
11/5b
12/5c
47
38
40
92
96
97
60
48
57
90
96
98
Br
CO2Et
I
BnBr
a Yield in four steps based on original loading of Wang resin (see Scheme 2).
b Determined by HPLC analysis after conversion to the corresponding (S)-phenylethyl amide derivatives.
c Yield in two steps starting from 5 (see Scheme 1).

T. Kotake et al. / Tetrahedron Letters 45 (2004) 3651–3654
3653
O
O
O
O
R1
a
c
b
HN
Bn
O
HN
Bn
O
N
O
O
4
N
N
N
Bn
99%
COOH
COO
COO
O
O
10 (R1 = PhCH2)
11 (R1 = PhO)
12 (R1 = CH3)
8
9
O
O
O
R1
HO
e
d
R1
N
O
O
=
OH
O
R2
R2
N
Bn
COO
38-54%
(4 steps)
P
Wang resin
7a-c
13
Scheme 2. Reagents and conditions: (a) H2, Pd/C, MeOH–H2O (9:1), rt, overnight; (b) Wang resin, DIC, DMAP, DMF, rt, 3 h; (c) R1CH2CO2H,
2-chloro-1-methylpyridinium iodide, Et3N, DMAP, CH2Cl2, rt, 2 h; (d) LDA, R2X, THF, 0 °C, 3.5 h; (e) LiOH, 30% H2O2, THF–H2O (3:1), 0 °C,
1 h.
the 5-position of the Apns-derived oxazolidinone caused
by steric repulsion between the benzyl and carboxamide
groups in a cis-configuration.
high stereoselectivity (85–97% ee) comparable to the
solution-phase model experiments was obtained in this
solid-phase system with a total yield of 38–54% (in four
steps), calculated from the original loading of Wang
resin. These results suggest that anchoring to the resin at
the 5-position of the oxazolidinone ring is highly suit-
able for realizing reasonable enantiomeric ratios, prob-
ably achieving greater freedom from the polystyrene
scaffold than the previous auxiliary involving the 4-
position. It also suggests that the asymmetric alkylation
reaction proceeded through the same chelation con-
trolled model as reported in standard Evans-type oxa-
zolidinone chemistry.3a These findings would resolve the
concern raised by Burgess and Lim4 in the solid-phase
asymmetric alkylation using the polymer-supported
Evans’ chiral auxiliary, and our new polymer-supported
oxazolidinone is applicable in the synthesis of a variety
of chiral a-alkylated carboxylic acids.
Hence, for the solid-phase synthesis, Pns-derived oxa-
zolidinone 4 was selected and its benzyl ester was
removed by hydrogenolysis, and the resultant carboxylic
acid 8 was attached to the Wang resin by the established
method with 1,3-diisopropylcarbodiimide (DIC)17 in the
presence of a catalytic amount of DMAP (Scheme 2).
Analysis of the loading rate by methanolysis of the resin
9 gave a complete recovery of the corresponding methyl
ester, indicating that quantitative loading was achieved.
It is pertinent to note that the previous reported auxiliary
1 on Wang resin having only 56% of loading might have
potential side reactions by the residual free-
hydroxyl group.4 On the contrary, we were able to
efficiently synthesize a new Wang resin-supported Evans-
type chiral auxiliary 9 with a quantitative loading.
In conclusion, we have developed a new polymer-sup-
ported Evans-type chiral auxiliary, anchored to the
Wang resin through a carboxyl group at the 5-position
of the oxazolidinone ring and a piperidine-4-carboxyl
linker, and found it to be a useful tool for solid-phase
asymmetric alkylation with no reduction in stereoselec-
tivity. This convenient polymer-supported chiral auxil-
iary is applicable in the preparation of a library of chiral
a-branched carboxylic acids such as 3-phenylpropionic
acid derivatives having inhibitory activity against serine
proteases.21 Further studies of well-known asymmetric
reactions in the use of the Evans’ auxiliary, such as aldol
condensation and cycloadditions, and the recycling of
the resin are under investigation.
For the solid-phase asymmetric alkylation, to a well-
swollen carboximide resin 10–12 in THF, derived from 9
by the mixed anhydride-LiCl N-acylation18 or Mukai-
yama reagent,19 was added LDA (2 equiv) at 0 °C, fol-
lowed by the addition of alkyl halide (10 equiv). After
stirring for 3 h at the same temperature, the solid-phase
reaction was quenched by adding saturated aqueous
NH4Cl. The resin was recovered by filtration and was
subsequently washed with THF and MeOH to give 13.
LiOOH-mediated chemoselective hydrolysis of 13 gave
the desired chiral a-alkylated carboxylic acids 7a–c.20
Since no disruption of the ester bond between the linker
and resin was observed during these steps and methan-
olysis of recovered resin afforded the corresponding
oxazolidinone methyl ester in high yield (94% yield
Table 1, entry 2), it indicated that the polymer-sup-
ported auxiliary was stable to LiOOH treatment.
Therefore, it is considered that the recovered resin 9 has
a potential for reuse. Enantiomeric excess of the
obtained acids was determined by HPLC analysis after
derivatization to the corresponding (S)-phenylethyl
amides by the EDC–HOBt method. As Table 1 shows,
Acknowledgements
This research was supported in part by grants and the
Frontier Research Program of the Ministry of Educa-
tion, Science and Culture of Japan.

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T. Kotake et al. / Tetrahedron Letters 45 (2004) 3651–3654
4.20 (m, 0.5H), 3.80–3.84 (m, 0.5H), 3.65–3.70 (m, 0.5H),
References and notes
3.14–3.24 (m, 0.5H), 2.93–3.02 (m, 2H), 2.76–2.88 (m,
1.5H), 2.54–2.65 (m, 1H), 1.55–1.98 (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,
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one-5-carbonyl]piperidine-4-carboxylate (4): mp 91–93 °C;
Rf 0.55 (n-hexane:AcOEt ¼ 1:5); 1H NMR (300 MHz,
CDCl3) d 7.20–7.40 (m, 10H), 5.25 (br s, 1H), 5.14 (s, 1H),
5.12 (s, 1H), 4.79 (d, 0.5H, J ¼ 5:5 Hz), 4.78 (d, 0.5H,
J ¼ 5:5 Hz), 4.63–4.69 (m, 1H), 4.33–4.38 (m, 0.5H), 4.16–