Solid phase asymmetric alkylation reactions using 2-imidazolidinone chiral auxiliary

Article abstract of DOI:10.1016/j.tetlet.2009.01.127

A novel solid supported 2-imidazolidinone chiral auxiliary was prepared from O-benzyl-l-tyrosine and Wang resin. Asymmetric alkylation reactions in the solid phase proceeded with excellent stereoselectivities, which were even higher than those observed in the conventional solution phase method.

Full text of DOI:10.1016/j.tetlet.2009.01.127

Tetrahedron Letters 50 (2009) 4015–4018
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Tetrahedron Letters
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Solid phase asymmetric alkylation reactions using 2-imidazolidinone
chiral auxiliary
Quynh Pham Bao Nguyen a, Jae Nyoung Kim b, Taek Hyeon Kim a,
*
a Department of Applied Chemistry and Center for Functional Nano Fine Chemicals, Chonnam National University, Gwangju 500-757, Republic of Korea
b Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju, 500-757, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel solid supported 2-imidazolidinone chiral auxiliary was prepared from O-benzyl-L-tyrosine and
Received 2 January 2009
Revised 22 January 2009
Accepted 26 January 2009
Available online 29 January 2009
Wang resin. Asymmetric alkylation reactions in the solid phase proceeded with excellent stereoselectiv-
ities, which were even higher than those observed in the conventional solution phase method.
Ó 2009 Elsevier Ltd. All rights reserved.
Polymer bound chiral auxiliaries, which enable the asymmet-
ric synthesis of libraries of homochiral compounds, have re-
ceived increasing interest within the last few years.1 Such
solid supported chiral auxiliaries offer some advantages as com-
pared to their application in the solution phase, including a
simple filtration procedure for the isolation of the desired com-
pounds or the recovery of the expensive chiral auxiliaries, and
their possible extension to a continuous flow system. In addi-
tion, the microenvironment of the polymeric backbone could
lead to an improvement in the stereoselectivity for a given
transformation.2 Oxazolidinones remain the most extensively
explored solid supported auxiliaries. Their utility in solid phase
asymmetric alkylation,3 aldol condensation,4 Diels–Alder,5 and
1,3-dipolar cycloadditions6 has been reported. However, solid
phase asymmetric alkylation using oxazolidinone chiral auxilia-
ries has not been accomplished in a highly stereoselective man-
ner (max 90% ee) due to unfavorable steric effect from resin at
4-position of the oxazolidinone ring, and the key issue of poly-
mer recyclability has not been addressed.3a Therefore, an
improvement in stereoselectivity of solid supported oxazolidi-
none was then reported (max 97% ee) by using other anchoring
system, in which the connection of the oxazolidinone chiral
auxiliary to resin was performed from the 5-position of oxazo-
lidinone ring instead of 4-position. The recycling of this solid
supported oxazolidinone was also achieved by maintaining the
stereoselectivity, but the yield was somewhat reduced due to
the side reaction and it was only reused in the same reaction,
viz. asymmetric allylation. In addition, the synthesis of this so-
lid supported chiral auxiliary was started with uneasily avail-
able starting material.3b
report the preparation of a novel solid-supported chiral auxiliary
based on 2-imidazolidinone and the preliminary results of our
investigations concerning the asymmetric alkylation reactions on
solid supports and the potential for recycling of the solid supported
2-imidazolidinone chiral auxiliaries.
Chiral 2-imidazolidinone 5 was prepared from commercially
available O-benzyl-L-tyrosine in four steps (Scheme 1). The reduc-
tion of tyrosine to the corresponding alcohol 2 was easily accom-
plished with the previously reported procedure using LiAlH4.4a
Chiral 2-imidazolidinone 4 was prepared in moderate yield in
two simple steps: the addition of phenyl isocyanate to 2 and cycli-
zation using t-BuOK and TsCl.8 Finally, the chiral auxiliary 5 was
formed after removing the O-protecting benzyl group. One of the
attractive features of the chiral auxiliary 5 is that it serves a dual
purpose: it has a phenolic hydroxy group that allows for its attach-
ment to resins and the chiral 2-imidazolidinone itself can serve as a
chiral auxiliary to carry out asymmetric reactions.
The solid supported 2-imidazolidinone chiral auxiliary 6 was
formed by immobilizing 2-imidazolidinone on Wang resin under
Mitsunobu conditions using triphenyl phosphine and diisopropyl
azodicarboxylate (DIAD) (Scheme 2). The loading capacity of the
resin was difficult to determine accurately. It was determined by
the evaluation of the mass increase of the resin after the attach-
ment step,2 and was confirmed by elemental analysis (%N).4a
According to these methods, the loading yield of resin 6 was up
to 80%. In the case of oxazolidinone chiral auxiliaries, the loading
yields when N-propionylated oxazolidinone is directly coupled to
various resins were only 30–60%.3a From our experiments, the
loading yield of the N-propionylated imidazolidinone chiral auxil-
iary to Wang resin was lower (60–70%) than that of the imidazolid-
inone chiral auxiliary 5 to Wang resin (up to 80%). Acylation on the
solid phase proceeded smoothly to yield resin 7 in quantitative
yield. Obviously, the monitoring of the reaction progress on a solid
support cannot be accomplished as easily as that in the case of
solution chemistry, where thin layer chromatography (TLC) is used.
However, chromatographic monitoring was possible after the
2-Imidazolidinone has been reported to be a versatile auxiliary
for asymmetric syntheses, exhibiting excellent levels of stereocon-
trol, greater stability, and recyclability.7 In this Letter, we wish to
* Corresponding author. Tel.: +82 62 530 1891; fax: +82 62 530 1889.
E-mail address: thkim@chonnam.ac.kr (T.H. Kim).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.127

4016
Q. P. B. Nguyen et al. / Tetrahedron Letters 50 (2009) 4015–4018
OH
OH
HOOC
NH2
NHCNHPh
O
NH2
PhNCO
LiAlH4
THF, rt, 6 h
THF, rt, 30 min
BnO
BnO
BnO
1
2, 77%
3, 98%
O
O
PhN
NH
PhN
NH
H2, Pd/C
CH3COOH, rt, 20 h
t-BuOK, TsCl
THF, OoC, 20 min
OH
OBn
5
, 90%
4, 49%
Scheme 1. Synthesis of 2-imidazolidinone chiral auxiliary in solution phase.
O
O
O
O
O
O
R
R
NH
PhN
PhN
NH
PhN
N
PhN
N
Ph3P, DI A D
CH2Cl2-THF, rt, 2 days
t-BuOK
TFA
CH2Cl2, rt, 5 min
HO
+
RCH2COCl
0oC, THF, 30 min
OH
O
O
OH
Wang resin
7a,
5
6
R = CH3
7b, R = CH2Ph
7a'
7b'
Scheme 2. Synthesis of solid supported N-acylated 2-imidazolidinone chiral auxiliary.
cleavage of the acylated resin 7 with trifluoroacetic acid (TFA) for
5 min at room temperature.
NH4Cl. The resultant resin was separated from the reaction mix-
ture by the filtration, followed by washing with THF/H2O (1:1 v/
v), THF, DMF, CH2Cl2, and MeOH sequentially and then dried in
vacuo. Treatment of the alkylated resin 8 with TFA allowed the
determination of yield as well as de value of the alkylation prod-
ucts by analysis of compound 9 (Scheme 3). The diastereomeric
excess was easily obtained by 1H NMR, which showed different
chemical shifts for the two diastereoisomers (e.g., 9a and 9c).9
For the solid phase asymmetric alkylation reaction, resin 7
(loading capacity 1 mmol/g) was swollen in THF and cooled to
ꢀ78 °C, followed by the dropwise addition of 1 M NaHMDS
(3 equiv). After continuously stirring for 3 h at the same temper-
ature, the alkyl halide (10 equiv) was added and reacted for 16 h.
Then, the reaction mixture was quenched by adding saturated
O
O
O
O
O
O
R
R
R
PhN
N
PhN
N
N
PhN
R'
R'
NaHMDS
TFA
R'X, -78oC, 16h
CH2Cl2, rt, 2h
O
O
OH
7
8
9
Scheme 3. Solid phase asymmetric alkylation reactions.

Q. P. B. Nguyen et al. / Tetrahedron Letters 50 (2009) 4015–4018
4017
Table 1
values of the chiral acids were determined by HPLC (chiralcel
ODH column) after their conversion to the corresponding chiral
esters with diazomethane (CH2N2).11 As expected, no racemiza-
tion occurred during the hydrolysis of the alkylated resin 8 in
NaOH.
Diastereoselective alkylations of solid supported chiral auxiliaries 7 and cleavage of 8
Entry
Substrate
R
R0X
Product
Yielda (%)
deb (%)
1
2
3
4
7a
7b
7b
7b
CH3
Bn
Bn
PhCH2Br
CH2@CHCH2Br
CH3I
8a, 9a
8b, 9b
8c, 9c
8d, 9d
40
35
30
37
>99
>99
>99
>99
The recycling of the expensive auxiliary is the key issue in
the development of solid supported chiral auxiliaries. However,
there have been few extensive studies on the issue of efficient
recycling. The recycling of the solid supported Evans’ oxazolid-
inone was achieved by maintaining the stereoselectivity of the
product, but the yield was somewhat reduced due to the side
reaction and it was only reused in the same reaction, viz.
asymmetric allylation.3b Procter reported the recycling of the
same resin with different reactions.12 However, in some cases,
the final pure product could not be obtained, due to the
incomplete cleavage in the previous cycle. After treatment
the recovered resin 6 with TFA (Scheme 4), the clean genera-
tion of the chiral auxiliary 5 was obtained with purity >80%
by HPLC analysis of crude product. That encouraged us to
study the recycling of our chiral auxiliary. As expected, our so-
lid supported chiral auxiliary 6, which was very stable under
NaOH cleavage conditions, could be reused three times
with no significant drop in the enantiomeric excess or yield
(Table 3).
Bn
CH„CCH2Br
a
Yields of 9 after four steps based on original loading of Wang resin.
b
Determined by 1H NMR and HPLC (chiracel ODH column).
The validity of using this observation for determining the de va-
lue was also confirmed by HPLC analysis (see Supplementary
data for details). As shown in Table 1, benzyl bromide, allyl bro-
mide, methyl iodide, and propagyl bromide reacted very well to
give the alkylated products with moderate to good yield and
excellent de values (up to 99% de). The most striking feature
of the solid supported chiral auxiliary 7 is that the sterically
undemanding methylation, which is often difficult to control,
proceeded with remarkable diastereoselectivity, which was even
higher than that obtained from the same model in the solution
phase reaction. Prasad reported that the methylation reaction
of the 3-dihydrocinnamoyl-2-imidazolidinone in solution affor-
ded a de of 89%,10 but, in our case, viz. the alkylation reaction
on the solid support, the methylated product was obtained with
a de of up to 99%. This can be explained by considering that the
microenvironment of the polymeric backbone of the solid sup-
ported chiral auxiliary could lead to an improvement in the dia-
stereoselectivity for a given transformation.2
In conclusion, we developed a new solid supported 2-imi-
dazolidinone chiral auxiliary. Asymmetric alkylation reactions
in the solid phase proceeded with good yield and excellent ste-
reoselectivity, which were even higher than those obtained in
the conventional solution phase methods. This solid supported
chiral auxiliary was easily recovered by hydrolysis with sodium
Resin 8 can be cleaved to the acid with LiOH without H2O2 to
suppress the endocyclic cleavage of the chiral auxiliary or, more
rapidly, by refluxing in 2 M NaOH/dioxane (1:1 v/v) for 4 h. The
chiral acids 10a–d were obtained in moderate yields, high purity,
and excellent enantiomeric excess (ee >99%) (Table 2). The ee
hydroxide to afford the chiral
a-substituted carboxylic acid in
excellent enantiomeric excess and high purity. In addition, our
solid supported chiral auxiliary could be reused three times
with no significant drop in the stereoselectivity or yield
(Scheme 5).
Table 2
Transformation of alkylated resin 8 to acids
Table 3
Entry
Substrate
Condition
Product
Yielda (%)
Purityb (%)
ee (%)
Recyling of the solid supported chiral auxiliary 6
d
1
2
3
4
5
8a
8a
8b
8c
8d
LiOH
10a
10a
10b
10c
10d
24
30
21
24
20
—
—
Run
R
R0X
Product
Yielda (%)
Purityb (%)
ee (%)
NaOH/dioxane
NaOH/dioxane
NaOH/dioxane
NaOH/dioxane
90
90
>99
>99
>99
>99
1st
Me
Bn
Bn
Bn
BnBr
CH2@CHCH2Br
MeI
10a
10b
10c
10d
30
22
23
20
90
75
>99
>99
>99
>99
89
2nd
3rd
4th
95 (>99)c
80
CH„CCH2Br
>99c
a
Yield in four steps based on original loading of Wang resin.
b
c
a
b
c
Determined by HPLC (chiracel ODH column) of crude product in n-hexane.
Value in parentheses is purity after column chromatography.
Not determined.
Yields in four steps from the resin 6 based on original loading of Wang resin.
Determined by HPLC (chiracel ODH column) of crude product in n-hexane.
After column chromatography.
d
O
O
O
O
R
N
PhN
NH
PhN
NH
OH
PhN
R'
O
LiOH
R
TFA
CH2Cl2, rt, 5 min
+
HO
or NaOH/dioxane
R'
O
O
10
8
6
5
Scheme 4. Hydrolysis and recovery of solid supported chiral auxiliary.

4018
Q. P. B. Nguyen et al. / Tetrahedron Letters 50 (2009) 4015–4018
O
NH
PhN
O
R
HO
R'
NaOH
RCH2COCl
O
6
O
O
O
O
R
R
N
PhN
N
PhN
R'
O
O
R'X
Scheme 5. Recycling of the solid supported chiral auxiliary 6.
2. Gaertner, P.; Schuster, C.; Knollmueller, M. Lett. Org. Chem. 2004, 1, 249–
253.
Acknowledgments
3. (a) Burgess, K.; Lim, D. Chem. Commun. 1997, 785–786; (b) Kotake, T.; Hayashi,
Y.; Rajesh, S.; Mukai, Y.; Takiguchi, Y.; Kimuara, T.; Kiso, Y. Tetrahedron 2005,
61, 3819–3833.
4. (a) Purandare, A. V.; Natarajan, S. Tetrahedron Lett. 1997, 38, 8777–8780; (b)
Phoon, C. W.; Abell, C. Tetrahedron Lett. 1998, 39, 2655–2658.
5. Winker, J. D.; McCoull, W. Tetrahedron Lett. 1998, 39, 4935–4936.
6. Faita, G.; Paio, A.; Quadrelli, P.; Rancati, F.; Seneci, P. Tetrahedron 2001, 57,
8313–8322.
This work was supported by the Regional Technology Innova-
tion Program of the Ministry of Commerce, Industry and Energy
(Grant No. RTI04-03-03). The spectroscopic data were obtained
from the Korea Basic Science Institute, Gwangju branch.
Supplementary data
7. Roos, G. H. P. S. Afr. J. Chem. 1997, 51, 7–18.
8. (a) Kim, T. H.; Lee, G. J. J. Org. Chem. 1999, 64, 2941–2943; (b) Kim, T. H.; Lee, G.
J.; Cha, M. H. Synth. Commun. 1999, 29, 2753–2758.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.01.127.
9. Compound 9a: 1H NMR (CDCl3) d 6.68–7.36 (14H, m), 4.77 (1H, s), 4.63 (1H, m),
4.30 (1H, dd, J = 7.4, 14.3 Hz), 3.83 (1H, t, J = 9.2 Hz), 3.46 (1H, dd, J = 7.4,
9.5 Hz), 3.25 (1H, dd, J = 7.3, 13.2 Hz), 3.00 (1H, dd, J = 3, 13.5 Hz), 2.68 (1H, dd,
J = 7.6, 13.2 Hz), 2.59 (1H, dd, J = 8.6, 13.5 Hz), 1.18 (1H, d, J = 8.7 Hz).
Compound 9c: 1H NMR (CDCl3) d 6.71–7.61 (14H, m), 4.73 (1H, s), 4.50 (1H,
m), 4.27 (1H, dd, J = 7.4, 13.4 Hz), 3.64 (1H, t, J = 9.2 Hz), 3.42 (1H, dd, J = 1.8,
9.4 Hz), 3.15 (1H, dd, J = 3.2, 13.4 Hz), 3.05 (1H, dd, J = 7.6, 13.3 Hz), 2.73 (2H,
m), 1.28 (1H, dd, J = 7 Hz).
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