Dynamic kinetic resolution of α-chloro esters in asymmetric nucleophilic substitution using diacetone-D-glucose as a chiral auxiliary

Article abstract of DOI:10.1016/j.tetlet.2005.04.003

Diacetone-D-glucose mediated dynamic kinetic resolution of α-chloro-α-aryl esters in nucleophilic substitution reactions has been investigated. Reactions of various amine nucleophiles in the presence of TBAI and DIEA can provide the substitution products 2-10 up to 97% yield and 97:3 dr. This simple procedure with easy removal of the chiral auxiliary provides a practical protocol for asymmetric syntheses of α-amino acid derivatives up to 97:3 er.

Full text of DOI:10.1016/j.tetlet.2005.04.003

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4115–4117
Dynamic kinetic resolution of a-chloro esters in asymmetric
nucleophilic substitution using diacetone-D-glucose as
a chiral auxiliary
Hyun Jung Kim, Eun-kyoung Shin, Ji-yeon Chang, Yongtae Kim and Yong Sun Park*
Department of Chemistry, Konkuk University, Seoul 143-701, Republicof Korea
Received 17 March 2005; revised 30 March 2005; accepted 1 April 2005
Available online 22 April 2005
Abstract—Diacetone-D-glucose mediated dynamic kinetic resolution of a-chloro-a-aryl esters in nucleophilic substitution reactions
has been investigated. Reactions of various amine nucleophiles in the presence of TBAI and DIEA can provide the substitution
products 2–10 up to 97% yield and 97:3 dr. This simple procedure with easy removal of the chiral auxiliary provides a practical
protocol for asymmetric syntheses of a-amino acid derivatives up to 97:3 er.
Ó 2005 Elsevier Ltd. All rights reserved.
Chiral auxiliary mediated dynamic resolution of a-halo
esters or a-halo amides has been recently recognized as
an effective synthetic method for asymmetric syntheses
of a-heteroatom substituted carboxylic acid deriva-
were treated with benzylamine (BnNH , 1.5 equiv),
2
tetrabutylammonium iodide (TBAI, 1.0 equiv), and
diisopropylethylamine (DIEA, 1.0 equiv) in CH Cl at
room temperature for 12h, the amino acid derivative
2
2
1
,2
tives. Although many existing chiral auxiliaries can
achieve a useful level of diastereoselection in the dy-
namic resolution process, it is still desirable to find effec-
tive chiral auxiliaries for achieving practical asymmetric
nucleophilic substitution. Carbohydrates are readily
available inexpensive natural products in which numer-
ous functional groups and stereogenic centers are pres-
ent in a molecule. A number of carbohydrate based
templates have been used as chiral auxiliaries for various
2 was produced in 86% yield with 96:4 diastereomeric
5
ratio (dr, aS:aR) as shown in Table 1 (entry 1). The
observed dr and yield suggest that a-chloro stereogenic
center is configurationally labile with respect to the rate
of substitution with benzylamine and (aRS)-1 can be
dynamically resolved under the reaction condition.
Most of the solvents explored gave similar selectivities.
As shown in entries 2–5, the substitution product 2
was obtained with 97:3 dr in CHCl , 97:3 dr in ether,
3
3
stereoselective reactions. Herein, we report first success-
ful example of carbohydrate mediated dynamic resolu-
96:4 dr in THF and 96:4 dr in hexane. However, the
selectivity was reduced in CH CN (entry 6) and the reac-
3
tion of a-halo esters in nucleophilic substitution for
asymmetric syntheses of a-amino acid derivatives.
tion was very slow in toluene. The faster reaction at
50 °C gave the product with slightly lower stereoselectiv-
ity (93:7 dr) compared to the reaction at rt. Similar
stereoselectivity was observed in the substitution at
0 °C (entries 7 and 8). In the absence of TBAI, the reac-
tion of a-chloro ester 1 gave the substitution product 2
with almost the same stereoselectivity (entry 9). How-
ever, the rate of the substitution is substantially
decreased compared to the reactions with TBAI and
require longer reaction time (70 h) to obtain moderate
yield (54% yield). In addition, in the absence of both
TBAI and DIEA, the reaction did not produce product
4
Initial studies on dynamic resolution of a-phenyl-a-
chloro ester were carried out with diacetone-D-glucose
as a chiral auxiliary. Treatment of diacetone-D-glucose
with racemic a-chloro-a-phenylacetyl chloride in the
presence of Et N provided a-chloro-a-phenyl ester
3
(
(
aRS)-1 in 80% yield with 55:45 diastereomeric ratio
dr). When the two diastereomeric mixtures of (aRS)-1
2
, and most of the starting material was recovered (entry
0). The results in entries 9 and 10 pointed to the impor-
Keywords: Dynamic kinetic resolution; Asymmetric syntheses; Nucleo-
philic substitution; Carbohydrate; Chiral auxiliary.
1
tance of the presence of iodide ion and base for sufficient
rate acceleration. When 1 with 88:12dr was treated with
*
Corresponding author. Tel.: +82 2450 3377; fax: +82 23436 5382;
e-mail: parkyong@konkuk.ac.kr
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.003

4116
H. J. Kim et al. / Tetrahedron Letters 46 (2005) 4115–4117
Table 1. Dynamic kinetic resolution of a-chloro ester 1 in nucleophilic
substitution
Table 2. Reactions with various amine nucleophiles
O
O
O
O
O
1
2
O
R R NH
R1
O
O
O
O
(
αR)-1
DIEA
TBAI
CH Cl
12 h
O
O
Cl
2 N
O
O
R
O
O
Cl
O
O
O
Ph
O
2
2
Ph
O
Ph
O
O
1
3-10
BnNH2
O
O
1
R R NH
2
a
Yield (%)
b
Entry
1
Dr (aS:aR)
DIEA
TBAI
BnHN
O
O
Ph
62( 3)
97:3
O
r.t.
Ph
O
Ph
NH2
2
O
(
αS)-1
O
O
2
75 (4)
95:5
NH2
Cl
O
O
3
4
NH2
48 (5)
97 (6)
95:5
97:3
Ph
O
a
Yield (%)
b
Entry
1
Dr of S.M.
Condition
Dr (aS:aR)
MeO
NH2
55:45
CHCl
55:45
55:45
55:45
55:45
55:45
55:45
55:45
55:45
CH Cl
2
2
86
53
96:4
97:3
97:3
Ph
Ph
N
H
Ph
2
3
4
5
6
7
8
9
1
55:45
3
5
6
7
61 (7)
82( 8)
73 (9)
94:6
96:4
93:7
Ether
THF
51
7296:4
70
N
H
n-Hexane,
CH CN
96:4
90:10
93:7
3
96
NH
c
c
c
50 °C
0 °C
No TBAI
No TBAI,
No DIEA
76
9297:3
54
N.R.
95:5
—
8
96 (10)
97:3
c
NH
0
a
d
Isolated yields.
1
The drs are determined by H NMR of reaction mixture.
1
1
1
230:70
88:12
CH
CH
2
Cl
Cl
2
2
83
85
96:4
95:5
b
d
2
a
b
c
Isolated yields.
The drs are determined by H NMR of reaction mixture.
1
As an extension of the above DKR, same sequences
were applied to two different a-chloro-a-aryl esters as
shown in Scheme 1. Treatment of a-p-methylphenyl a-
chloro acetate 11 with benzylamine, TBAI, and DIEA
gave the substitution product 13 in 88% yield with
2 2
The reactions were carried out in CH Cl .
d
The mixtures are prepared by column chromatography with frac-
tional collection.
benzylamine in the presence of TBAI and DIEA, the
reaction gave product 2 with 96:4 dr as shown in entry
O
1
1. Also, almost the same dr of 2 was observed in the
O
reaction of 1 with reversed diastereomeric enrichment
of 30:70 dr (entry 12). Thus, the dr of product 2 is not
dependent on the starting ratio of two epimers of 1.
These preliminary results indicate that the epimerization
promoted by TBAI and DIEA is sufficiently fast with
respect to the rate of substitution and the primary
pathway of the asymmetric induction is a dynamic
kinetic resolution.
RNH2
DIEA
TBAI
O
O
O
O
O
O
RHN
Cl
O
O
O
O
Ar
O
Ar
O
1
1
3 (R=PhCH , Ar=p-CH -Ph)
2
3
11 (Ar = p-CH3-Ph)
12 (Ar = p-Ph-Ph)
(Ar = Ph)
8
8% yield, 96:4 dr
4 (R=PhCH , Ar=p-Ph-Ph)
2
1
6
6% yield, 94:6 dr
3 (R= Ph2CH, Ar=Ph)
2% yield, 97:3 dr
(R=p-MeO-Ph, Ar=Ph)
With the identification of diacetone-D-glucose as an
appropriate stereocontrolling element for dynamic
kinetic resolution of a-chloro-a-phenyl acetate, we set
out to examine the scope of this methodology with eight
different amine nucleophiles as shown in Table 2. We
were pleased to observe that this methodology is efficient
for a variety of primary amine, secondary amine, and
cyclic amine nucleophiles, affording amino acid deriva-
tives 3–10 in 97–48% isolated yields with high stereo-
selectivities as shown in entries 1–8. Limited results
indicate that the size and nucleophilicity of amines
may have relatively little effect on stereoselectivity, but
that it significantly affected the yield.
6
6
9
7% yield, 97:3 dr
MeOH
Et N
1
1
1
5 (R=PhCH , Ar=p-CH -Ph)
3
2
3
5
7% yield, 96:4 er
6 (R=Ph CH, Ar=Ph)
2
RHN
CO Me
2
8
0% yield, 97:3 er
7 (R=p-MeO-Ph, Ar=Ph)
7% yield, 96:4 er
Ar
9
Scheme 1.

H. J. Kim et al. / Tetrahedron Letters 46 (2005) 4115–4117
4117
9
6:4 dr. Also, the reactions of a-p-phenylphenyl a-
Desroses, M.; Tatibou e¨ t, A.; Lucchi, O. D.; Rollin, P.
Tetrahedron 2003, 59, 4563; (f) Yu, H.; Ballard, C. E.;
Boyle, P. D.; Wang, B. Tetrahedron 2002, 58, 7663; (g)
Enholm, E. J.; Cottone, J. S.; Allais, F. Org. Lett. 2001, 3,
chloro acetate 12 took place with high stereoselectivity,
affording 14 in 66% yield with 94:6 dr. The removal of
the diacetone-D-glucose chiral auxiliary was readily
achieved by the treatment of esters 3, 6, and 13 in meth-
anol with Et N at room temperature for 2–3 days. The
3
basic methanolysis furnished arylglycine methyl esters
1
45; (h) Totani, K.; Nagatsuka, T.; Yamaguchi, S.; Takao,
K. J. Org. Chem. 2001, 66, 5965; (i) Bach, T.; H o¨ fer, F.
J. Org. Chem. 2001, 66, 3427; (j) Khiar, N.; Alcudia, F.;
Espartero, J.-L.; Rodriguez, L.; Fern a´ ndez, I. J. Am. Chem.
Soc. 2000, 122, 7598; (k) Huang, G.; Hollingsworth, R. I.
Tetrahedron Lett. 1999, 40, 581; (l) Yoshida, T.; Chika, J.;
Takei, H. Tetrahedron Lett. 1998, 39, 4305; (m) Hultin, P.;
Earle, M. A.; Sudharshan, M. Tetrahedron 1997, 53, 14823;
1
within experimental error.
5, 16, and 17 in 98–57% yields without racemization
6
We have presented a novel and practical approach for
the asymmetric syntheses of unnatural a-amino acid
derivatives via dynamic kinetic resolution of a-chloro es-
ters using carbohydrate as a chiral auxiliary. The simple
protocol with mild conditions and the easy removal of
chiral auxiliary suggests further development of this
methodology. Further applications of this methodology
to various a-alkyl substituents and nucleophiles are
currently under investigation.
(
n) Chiappe, C.; Moro, G. L.; Munforte, P. Tetrahedron:
Asymmetry 1997, 8, 2311; (o) Angibaud, P.; Chaumette, J.
L.; Desmurs, J. R.; Duhamel, L.; Pl e´ , G.; Valnot, J. Y.;
Duhamel, P. Tetrahedron: Asymmetry 1995, 6, 1919.
. In Ref. 1e, Ben and Durst previously reported that
D-glucose diacetonide mediated nucleophilic substitution
of a-ethyl-a-bromo acetate in the presence of tetrahexyl-
4
3
ammonium iodide and Et N gave a substitution product
with low diastereoselectivity (2:1).
5
. The absolute configurations of (aS)-2 and (aS)-6 were
determined after the removal of chiral auxiliary by
comparison of the CSP-HPLC retention time with authen-
tic products prepared from L-phenylglycine.
Acknowledgements
This work was supported by Korea Research Found-
ation Grant (KRF 2003-041-C00191).
6. Experimental procedure for the asymmetric preparation of
N-p-methoxyphenyl (S)-phenylglycine methyl ester (17): To
2 2
a solution of (aRS)-1 in CH Cl (ca. 0.1 M) at room
temperature was added DIEA (1.0 equiv), TBAI (1.0 equiv),
and a nucleophile (p-anisidine, 1.5 equiv). After the resulting
reaction mixture was stirred at room temperature for 12h,
the solvent was evaporated and the crude material was
purified by column chromatography to give 6 in 97% yield
References and notes
1
. For reviews on dynamic resolution of a-halo esters, see: (a)
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1
2
004, 45, 2545; (b) Nam, J.; Lee, S.-k.; Park, Y. S.
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1
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(CDCl , 400 MHz) 7.49–7.32(m, 5H), 6.73 (d, J = 7.0 Hz,
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(d, J = 2.9 Hz, 1H), 5.08 (s, 1H), 4.22–3.88 (m, 5H), 3.70 (s,
3
1
3
2
. For reviews on dynamic resolution of a-halo amides, see:
3H), 1.46 (s, 3H), 1.41 (s, 3H), 1.32(s, 3H), 1.18 (s, 3H);
NMR (CDCl , 100 MHz) 171.3, 153.2, 140.5, 137.6, 129.4,
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72.8, 67.8, 62.4, 56.1, 27.3, 27.1, 26.5, 25.6. For removal of
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3
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1
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3
2
2
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7
ously. The enantiomeric ratio of 17 was determined to be
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racemic material as a standard (Chiralcel OD column; 10%
2-propanol in hexane; 0.5 mL/min; The S-enantiomer
(major) had a retention time of 18.6 min, and the R-
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3
005, 70, 529; (b) Knauer, S.; Kunz, H. Tetrahedron: