Dynamic resolution of α-bromo-α-alkyl esters using N-methyl pseudoephedrine as a chiral auxiliary: Asymmetric syntheses of α-amino acid derivatives

Article abstract of DOI:10.1055/s-2002-25373

N-Methyl pseudoephedrine mediated dynamic resolution of α-bromo-α-alkyl esters in nucleophilic substitution reaction has been investigated. Best results are obtained when α-bromo-α-alkyl esters 1, 4 and 5 are allowed to equilibrate before the addition of nucleophile. This simple epimerization-substitution sequence provides a practical protocol for asymmetric syntheses of α-amino acid derivatives 2, 7 and 8 up to 98:2 enantiomeric ratio.

Full text of DOI:10.1055/s-2002-25373

790
LETTER
Dynamic Resolution of -Bromo- -Alkyl Esters Using N-Methyl Pseudo-
ephedrine as a Chiral Auxiliary: Asymmetric Syntheses of -Amino
Acid Derivatives
D
ynamic Reso
a
lution of
-
n
Bromo- -A
g
E
sters -kuk Lee, Jiyoun Nam, Yong Sun Park*
Department of Chemistry, Konkuk University, Seoul 143-701, Korea
Fax +82(2)34365382; E-mail: parkyong@kkucc.konkuk.ac.kr
Received 27 February 2002
-bromo ester ( RS)-1, the diastereomeric ratio (dr) of 1
obtained after flash chromatography was about 65:35 dr.
We found that two diastereomers were interconverting at
room temp. in various solvents, favoring S-epimer.4,5
Abstract: N-Methyl pseudoephedrine mediated dynamic resolu-
tion of -bromo- -alkyl esters in nucleophilic substitution reaction
has been investigated. Best results are obtained when -bromo- -
alkyl esters 1, 4 and 5 are allowed to equilibrate before the addition
of nucleophile. This simple epimerization-substitution sequence Treatment of ( RS)-1 ( S: R = 67:33) with benzylamine
provides a practical protocol for asymmetric syntheses of -amino
acid derivatives 2, 7 and 8 up to 98:2 enantiomeric ratio.
(1.2 equiv) as a nucleophile in CH3CN for 4 h (>96% con-
version) and subsequent removal of chiral auxiliary pro-
Key words: asymmetric synthesis, chiral auxiliaries, amino acids,
kinetic resolution, nucleophiles
vided the amino acid derivatives 2 in 80% yield with 92:8
enantiomeric ratio (er) and R-enantiomer as a major enan-
tiomer as shown in Table 1 (entry 1).5 In the presence of
Et3N (1.2 equiv), the substitution reaction provided, after
For asymmetric syntheses of -heteroatom substituted methanolysis, (R)-2 in 83% yield with an improved er of
carboxylic acids by nucleophilic substitution, dynamic 95:5 (entry 2).6 The observed ers and yields in entries 1
resolution of -halo esters or -halo amides having a and 2 suggest that -bromo stereogenic center is configu-
chiral auxiliary has been recently recognized as an effec- rationally labile with respect to the rate of substitution
tive synthetic method.1 For the effective dynamic resolu- with benzylamine and ( RS)-1 can be dynamically re-
tion, there must be a fast epimerization of the solved under the reaction conditions. When tetrabutylam-
diastereomers with respect to their rate of substitution monium bromide (TBAB, 0.2 equiv) was added to the
with the nucleophile. Two limiting pathways can be en- reaction, (R)-2 was obtained with 91:9 er (entry 3). In the
visaged for the asymmetric nucleophilic substitutions. In presence of both Et3N and TBAB, the reaction gave (R)-2
one pathway, -halo stereogenic center undergoes rapid in 82% yield with 93:7 er (entry 4).6 Based on the ob-
epimerization and one of the two diastereomers reacts served tendency of epimerization to favor ( S)-1 that is a
preferentially under the reaction condition. This is a case precursor of (R)-2, it seemed possible that the stereoselec-
of dynamic kinetic resolution, in which the stereoselectiv- tivity of the reaction would improve if sufficient time for
ity is determined by the difference in the diastereomeric epimerization was allowed. If the two diastereomers
transition state energies for the reaction with the nucleo- equilibrate to the thermodynamic ratio before the addition
philes. In a different pathway, the stereoselectivity of the of nucleophile, the higher asymmetric induction could
reaction is determined by the ratio of the diastereomers be obtained than in the substitution with 1 of lower drs.7
that is established before the substitution. This is termed Consistent with our hypotheses, the er of product 2 was
dynamic thermodynamic resolution2 because the ratio of increased to 98:2 when benzylamine was added after 1.5
diastereomer is thermodynamically controlled and the h epimerization in the presence of Et3N as shown in
stereoselectivity of the reaction is not determined by the Table 1 (entry 5).
difference in the rates of substitutions. Here we wish to
In an effort to understand how different reaction condi-
report nucleophilic substitution reactions of -halo esters
tions affect the stereoselectivity, we have monitored the
for asymmetric syntheses of -amino acid derivatives in
reaction by 1H NMR. When ( RS)-1 of 53:47 dr ( R: S)
was treated with Et3N in CH3CN at room temp., the mix-
ture equilibrated to a ratio of 3:97 ( R: S) within 1.5 h and
which two different pathways participate in reinforcing
the asymmetric induction.
Initial studies on dynamic resolution of -methyl- -bro- the ratio maintained during the course of reaction. After
mo ester were carried out with (S,S)-N-methyl pseu- benzylamine was added to the thermodynamically equili-
doephedrine as a chiral auxiliary.3 When (S,S)-N-methyl brated mixture, the substitution was completed within 4 h
pseudoephedrine and racemic -bromopropionic acid (>96% conversion) and provided ( R)-3 with 98:2 dr with
were treated with DCC and DMAP to prepare -methyl- inversion of configuration as anticipated for SN2 reaction.
The observed results indicate that the addition of Et3N ac-
celerated the epimerization of ( RS)-1, not much affecting
Synlett 2002, No. 5, 03 05 2002. Article Identifier:
the rate of substitution with benzylamine.4 Therefore, the
1437-2096,E;2002,0,05,0790,0792,ftx,en;Y02302ST.pdf.
enhanced er of 2 in entry 2 could be explained by the fast-
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Dynamic Resolution of -Bromo- -Alkyl Esters
791
Table 1 Effects of Base and X
This epimerization-substitution protocol is also practical
for the asymmetric syntheses of -butyl- -amino acid de-
rivative (R)-8 with 97:3 er from -butyl- -bromo ester 5
as shown in entry 4.8 On the other hand, the diastereomer-
ic ratio (65:35) of -iso-propyl- -bromo ester 6 remained
invariant upon treatment with Et3N for 24 h in CH3CN and
-iso-propyl substituent almost completely halted the sub-
stitution reaction, probably due to steric effect (entry 5).
Limited results indicate that the size and nature of the
alkyl group attached to the reacting center affect the rate
of both epimerization and substitution, which could also
alter the pathway of asymmetric induction. The dependen-
cy of product ratio on the dr of -bromo ester and the sig-
nificant enhancement of product ratio compared to
thermodynamic ratio of -bromo ester suggest that the
ers of (R)-7 and (R)-8 reflect not only the difference in
population of two diastereomers but the difference in rates
of substitution, induced by a dynamic thermodynamic and
kinetic resolution.7
Ph
O
1. BnNH2, Base, X-
2. TsOH, MeOH
MeO2C
NHBn
CH3
(R)-2
Me2N
Br
CH3
O
CH3
(αRS)-1
Entry
Base
–
X-
Yield (%)a Er (R:S)b
1
–
80
83
71
82
86
92:8
95:5
91:9
93:7
98:2
2
Et3N
–
–
3
TBAB
TBAB
–
4
Et3N
Et3N
5c
a All substitution reactions were carried out at rt for 4 h in CH3CN
with ( RS)-1 of 67:33 dr.
b The ers of 2 are determined by CSP-HPLC (Chiralcel-OD) with
hexane and 2-propanol as solvent.
c The nucleophile was added after 1.5 h epimerization in the
presence of Et3N.
Table 2 Effect of Alkyl Groups
Ph
O
MeO2C
NHBn
1. Et3N
Me2N
Br
O
2. BnNH2
3. TsOH, MeOH
er equilibrium to the thermodynamic ratio of ( S)-1 than
in entry 1 (Table 1). We have also made the qualitative
observation that the diastereomeric ratio of ( R)-3 in Fig-
ure reflects the diastereomeric ratio of equilibrated ( S)-1.
These preliminary results implied that the primary path-
way of the asymmetric induction is a dynamic thermody-
namic resolution in which the product ratio is determined
by the thermodynamic ratio between ( S)-1 and ( R)-1 di-
astereomers, but a contribution from a dynamic kinetic
resolution cannot be discounted.7
R
CH3
R
7 (R=CH2CH3)
4 (R=CH2CH3)
8 (R=CH2CH2CH2CH3)
9 (R=CH(CH3)2)
5 (R=CH2CH2CH2CH3)
6 (R=CH(CH3)2)
Entry
R
Epimerizationa
Yield (%)b
Er (R:S)c
78:22
98:2
1
2
3
4
5
ethyl
0 h, 60:40
24 h, 88:12
2 h, 61:39
24 h, 85:15
24 h, 65:35
84
85
85
86
–
ethyl
n-butyl
n-butyl
iso-propyl
76:24
97:3
R*O2C
NHBn
CH3
R*O2C
Br
R*O2C
Br
CH3
(αS)-1
αR:αS=3:97
R* = (S,S)-N-methyl pseudoephedrine
CH3
(aRS)-1
αR:αS=53:47
Et3N
Epimerization
H2NBn
Substitution
–
(αR)-3
a Time for epimerization with Et3N and dr ( S: R) before the addition
of nucleophile are shown.
αR:αS=98:2
b All reactions were carried out at r.t. in CH3CN.
c The ers of 7 and 8 are determined by CSP-HPLC (Chiralcel-OD)
with hexane and 2-propanol as solvents.
Figure
The scope of this methodology was investigated with
three different -bromo esters 4–6 as shown in Table 2.
When -ethyl- -bromo ester 4 (60:40 dr) was treated with
benzylamine and Et3N for 18 h, subsequent methanolysis
provided the corresponding amino acid derivatives (R)-7
in 84% yield with 78:22 er (entry 1).8 Encouraged by the
high asymmetric induction using the epimerization-sub-
stitution protocol in the reaction of -methyl- -bromo es-
ter 1, we treated 4 (60:40 dr) with Et3N in CH3CN for 24
h for an epimerization, which provided the equilibrated
mixture 4 with a thermodynamic ratio of 88:12. Even with
the slower rate of epimerization and the lower thermody-
namic ratio of 4, the substitution with benzylamine for 24
h provided, after methanolysis, the highly enantioen-
riched amino acid derivative (R)-7 with a 98:2 er (entry 2).
In summary, we have developed an efficient chiral auxil-
iary mediated method for the asymmetric syntheses of -
amino acid derivatives via dynamic resolution of -bromo
esters. The simple epimerization-substitution protocol9 in
obtaining highly enantioenriched amino acid derivatives
that are suitably protected for further synthetic elaboration
suggests further development of this methodology. Cur-
rent work is aimed at understanding mechanistic details of
these processes and applying this methodology to other
nucleophiles.
Acknowledgement
This work was supported by Korea Research Foudation Grant.
(KRF 2000-015-DP0263)
Synlett 2002, No. 5, 790–792 ISSN 0936-5214 © Thieme Stuttgart · New York

792
S.-k. Lee et al.
LETTER
(7) (a) For a quantitative analysis of the reactions of two
References
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products by a Curtin–Hammett–Winstein–Holness prin-
ciple, see: Seeman, J. I. Chem. Rev. 1983, 83, 83. (b) For
cases in which the stereoselectivity of the product reflects
the thermodynamic ratios of diastereomeric intermediates,
see: Gately, D. A.; Norton, J. R. J. Am. Chem. Soc. 1996,
118, 3479. (c) Also see: Basu, A.; Gallagher, D. J.; Beak, P.
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(1) (a) Lee, S.-k.; Lee, S. Y.; Park, Y. S. Synlett 2001, 1941.
(b) Caddick, S.; Afonso, C. A. M.; Candeias, S. X.;
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Pelter, A.; Goubet, D.; Pritchard, M. C. Tetrahedron:
Asymmetry 1995, 6, 93.
(2) This term was used by Prof. Peter Beak and coworkers for
their mechanistic studies of electrophilic asymmetric
substitution reaction: Beak, P.; Basu, A.; Gallagher, D. J.;
Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29,
552.
(3) (S,S)-N-Methyl pseudoephedrine is commercially available
and can also be easily prepared by N-methylation of (S,S)-
pseudoephedrine with MeI and NaH.
(4) When a solution of 1 ( S: R = 67:33) in CH3CN was stirred
for 1.5 h, spontaneous epimerization provided 1 with a ratio
of 80:20 ( S: R).
(5) The absolute configurations of ( S)-1 was assigned by com-
parison to the 1H NMR of authentic diastereomer prepared
from commercially available (S)- -bromo-propionic acid.
The absolute configuration of (R)-2 was assigned by com-
parison of CSP-HPLC retention time with authentic material
prepared from (R)-alanine.
(6) It has been proposed by several examples that the epimeri-
zation of -halo ester and -halo amide can be promoted by
a base via keto-enol tautomerism and/or by a halide source
via nucleophilic displacement of the bromide ion.1
(8) The absolute configuration of (R)-7 was assigned by
comparison of CSP-HPLC retention time with authentic
material prepared from commercially available (R)-2-
aminobutyric acid. The absolute configuration of (R)-8 was
assigned by analogy to the formation of (R)-2 and (R)-7.
(9) General procedure for the asymmetric synthesis of
methyl-N-benzyl alaninate [(R)-2]: To a solution of ( RS)-
1 ( S: R = 60:40) in CH3CN (ca. 0.1 M) at r.t. was added
Et3N (1.2 equiv). The resulting reaction mixture was stirred
at r.t. for 1.5 h, and then benzylamine (1.2 equiv) was added.
After 4 h, the mixture was filtered and the solvent eva-
porated. The crude mixture and p-toluenesulfonic acid (0.1
equiv) in methanol were refluxed for 24 h. The solvent was
evaporated and the crude material was purified by column
chromatography to give methyl-N-benzyl alaninate [(R)-2].
From 100 mg of 1, 53 mg (86% isolated yield) of 2 was
obtained as a colorless oil. 1H NMR (CDCl3, 400 MHz)
7.32–7.23 (m, 5 H), 3.80 (d, J = 12.8 Hz, 1 H), 3.72 (s, 3 H),
3.67 (d, J = 12.8 Hz, 1 H), 3.39 (q, J = 7.0 Hz, 1 H), 1.85 (br,
1 H), 1.32 (d, J = 7.0 Hz, 3 H); 13C NMR (CDCl3, 100 MHz)
176.6, 140.1, 128.8, 128.6, 127.5, 56.3, 52.4, 52.2, 19.5. The
enantiomeric ratio of 2 was determined to be 98:2 in favor of
the R enantiomer by chiral HPLC using racemic material as
a standard and the absolute configuration was assigned by
comparison of CSP-HPLC retention time with authentic
material prepared from (R)-alanine. [Chiralcel OD column;
10% 2-propanol in hexane; 0.9 mL/min; the R-enantio-
mer(major) had a retention time of 6.0 min, and the
S-enantiomer(minor) had a retention time of 5.4 min].
Synlett 2002, No. 5, 790–792 ISSN 0936-5214 © Thieme Stuttgart · New York