Dynamic Kinetic Resolution Utilizing A Chiral Auxiliary by Stereoselective SN2 Alkylation With Malonic Ester Enolate

Tetrahedron Letters, Vol. 36, No. 35, pp.
6251-6252, 1995
Pergamon Elsevier Science Ltd
Printed in Great Britain
0040-4039/95 $9.50+0.00
0040-4039(95)01236-2
Dynamic Kinetic Resolution Utilizing a Chiral Auxiliary by

Stereoselective SN2 Alkylation with Malonic Ester Enolate
Akira Kubo, Masami Takahashi, Hitoshi Kubota, and Ken-ichi Nunami*
Research Laboratory of Applied Biochemistry, Tanabe Seiyaku Co., Ltd.,

16-89. Kashima-3-chorae, ¥odogawa-ku, Osaka 532 Japan
Abstract: Dynamickinetic resolutionby highly stereoselectivecarbon-carbonbond formation

utilizing2-oxoimidazolidine-4-carboxylateas a chiralauxiliarywas exploited. The reactionof tert-
butyl (4S)-l-methyl-3-(2-bromopropionyl)-2-oxoimidazolidine-4-carboxylate (1) with sodium
dimethylmalonatein HMPAat roomtemperaturepredominantlyaffordedtert-butyl (4S)-l-methyl-3-
((2R)-2-methy•-3•3-bis(meth•xy•arb•ny•)pr•pi•ny•)-2-•x•imidaz••idine-4-carb•xy•ate ((S,R)-2a) in
a good yield.
In recent years, dynamic kinetic resolution has been noticed as one of the efficient methods for
asymmetric synthesis. 1 As a part of our studies on exploiting a new category of stereoselective
transformation process using 2-oxoimidazolidine-4-carboxylateas a chiral auxiliary, we reported the kinetic
resolution and the dynamic kinetic resolution of tert-butyl (4S)-l-methyl-3-(2-bromopropionyl)-2-
oxoimidazolidine-4-carboxylate(1) with benzylamine, which led to the synthesis of optically active cx-amino
acid. 2 In order to extend this methodology to the synthesis of a wide variety of chiral compounds, the
reaction employing other types of nucleophiles should be investigated. We wish to report here the dynamic
kinetic resolution of 1 with a carbon nucleophile.
Malonic ester enolates were selected as carbon nucleophiles based on their soft nucleophilicityenough
to make alkylation easily and on their appropriate basicity to cause rapid epimerization at the asymmetric
carbon attached to the bromo substituent of 1,2b which is essential to achieve the dynamic kinetic resolution,
but not to racemize the asymmetric carbon of 2-oxoimidazolidine ring of 1. Besides, their alkylated products
were expected to be converted to chiral 0t-alkylsuccinic acid derivatives which have been noticed as key
building blocks for the synthesis of a variety of biologically active compounds.
First, the reaction of I with sodium dimethyl malonate was examined in several kinds of polar solvents
which accelerated epimerization of I in the presence of a base (Table 1, entry 1--3). 2b All reactions afforded
(S,R)-2a predominantly 3 as expected but the selectivity was much affected by a solvent. The best result was
observed by using HMPA (entry 3). The selectivity was greatly reflected by the epimerization speed of 1,
which was higher in HMPA than in DMSO or DMF. 2b Besides, when the isolated product 2a was treated
again with sodium dimethyl malonate at room temperature for 3h in HMPA, 2a was recovered without any
epimerization. These results apparently indicated that (S,R)-2a was predominantly afforded by the dynamic
kinetic resolution of I with sodium dimethyl malonate. Next, the effect of ester moiety of malonic esters on
stereoselectivity was examined. The bulkiness of the ester moieties of malonate scarcely influenced the
6251
6252
selectivity of the reaction (entry 4--6). On the other hand, sodium dibenzyl malonate increased the
stereoselectivity affording 88% de of (S,R)-2e in 82% yield (entry 7).
In summary, highly stereoselective dynamic kinetic resolution of 1, which was composed of the chiral
auxiliary and an acyl moiety having a racemic leaving group in the c~-position, with malonic ester enolates
would be a new entry to the synthesis of a variety of chiral ct-alkylsuccinic acid derivatives. It is noteworthy
that the selectivity of the reaction was in striking contrast to that of the reaction of benzylamine with 1.2b The
mechanistic study and further expansion of the utility of this methodology are now under investigation in this
laboratory.
T a b l e 1. D y n a m i c Kinetic Resolution of Bromo Derivatives 1
(scNMek.,, NaCH(COOR)2 tBuOOC(S)l

'''\`
~_
~-NMer~
"~0
(s)
t-NMe
tBuOOC"'~N/~'O
tBuOOC.... N,-~O
o~Br r.t. " O ~ cH(COOR)2 + O'~=.-) CH(COOR)2
Me Me Me
1 (S,R)-2 (S,S)-2
Entrya R Solvent Time (h) Yield(%)b Product (S,R)-2 : (S,S)-2 b
1 Me DMF 24 77 2a 68 : 32
2 Me DMSO 3 97 2a 69 : 31
3 Me HMPAc 3 92 2a 88 : 12
4 Et HMPA 12 86 2b 91 : 9
5 ipr HMPA 12 93 2c 90 : 10
6 tBu HMPA 12 73 2d 89 : 11
7 CH2Ph HMPA 12 82 2e 94 : 6
a) The reactionwas carriedout with 1.0 mmolof I and sodiumdialkylmalonate,whichwas freshlyprepared from
malonicesterand Nail in 8 ml of solvent, b) Determinedby HPLCanalysis, c) Hexamethylphosphoramide.
References and Notes

1. a) Kagan, H. B.; Fiaud, J. C. Topics in Stereochemistry, eds. Eliel, E. L. and Wilen, S. H., 1988,
vol. 18, p.249, b) Hayashi, M.; Miwata, H.; Oguni, N. J. Chem. Soc., Perkin Trans. 1 1991,
1167. c) VanNieuwenhze, M. S.; Sharpless, K. B. J. Am. Chem. Soc. 1993, 115, 7864. d)
Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.; Akutagawa, S.;
Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H. J. Am. Chem. Soc. 1989, 111, 9134. e)
Sttirmer, R. Angew. Chem., Int. Ed. Engl. 1990, 29, 59. f) Koh, K.; Ben, R. N.; Durst, T.
Tetrahedron Lett. 1993, 34, 4473. g) Koh, K.; Durst, T. J. Org. Chem. 1994, 59, 4683.
2. a) Kubota, H.; Kubo, A.; Nunami, K. Tetrahedron Lett. 1994, 35, 3107. b) Nunami, K.; Kubota,
H.; Kubo, A. Tetrahedron Lett. 1994, 35, 8639.
3. In order to confirm the stereochemistry of the product, (S,R)-2e was converted to dimethyl 2-
methylsuccinate and its optical rotation value was compared to that in the literature.4
4. Rossi, R.; Diversi, P.; Ingrosso, G. Gazz. Chim. Ital. 1968, 98, 1391.
(Received in Japan 6 May 1995; revised 26 June 1995; accepted 28 June 1995)

Dynamic Kinetic Resolution Utilizing A Chiral Auxiliary by Stereoselective SN2 Alkylation With Malonic Ester Enolate

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Tetrahedron Letters, Vol. 36, No. 35, pp.

Dynamic Kinetic Resolution Utilizing a Chiral Auxiliary by

Akira Kubo, Masami Takahashi, Hitoshi Kubota, and Ken-ichi Nunami*

Research Laboratory of Applied Biochemistry, Tanabe Seiyaku Co., Ltd.,

Abstract: Dynamickinetic resolutionby highly stereoselectivecarbon-carbonbond formation

T a b l e 1. D y n a m i c Kinetic Resolution of Bromo Derivatives 1

(scNMek.,, NaCH(COOR)2 tBuOOC(S)l

Entrya R Solvent Time (h) Yield(%)b Product (S,R)-2 : (S,S)-2 b

References and Notes

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