(4R,5S)-1,5-Dimethyl-4-phenylimidazolidin-2-one as a chiral auxiliary for the diastereoselective alkylation of a new iminic glycine derivative: Practical asymmetric synthesis of α-amino acids

Article abstract of DOI:10.1016/S0957-4166(98)00113-X

The lithium enolate of enantiomerically pure N- [bis(methylthio)methylene] glycinate 11 derived from (4R,5S)-1,5-dimethyl-4- phenylimidazolidin-2-one reacts with alkyl halides giving the alkylated derivatives 12 with a high degree of control of the diastereoselectivity. These alkylated systems are easily hydrolyzed to the corresponding α-amino acids, the chiral auxiliary being recovered.

Full text of DOI:10.1016/S0957-4166(98)00113-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1125–1129
(4R,5S)-1,5-Dimethyl-4-phenylimidazolidin-2-one as a chiral
auxiliary for the diastereoselective alkylation of a new iminic
glycine derivative: practical asymmetric synthesis of α-amino
acids
Gabriela Guillena and Carmen Nájera ∗
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Received 24 February 1998; accepted 17 March 1998
Abstract
The lithium enolate of enantiomerically pure N-[bis(methylthio)methylene] glycinate 11 derived from (4R,5S)-
1,5-dimethyl-4-phenylimidazolidin-2-one reacts with alkyl halides giving the alkylated derivatives 12 with a high
degree of control of the diastereoselectivity. These alkylated systems are easily hydrolyzed to the corresponding
α-amino acids, the chiral auxiliary being recovered. © 1998 Elsevier Science Ltd. All rights reserved.
One of the most important strategies for the asymmetric synthesis of α-amino acids, based on
carbon–carbon bond forming reactions, is the α-alkylation of chiral glycine enolates.1 Imines derived
from glycine are very useful reagents because they are easily enolizable under different reaction
conditions, either with strong bases or under phase-transfer catalysis (PTC). In addition, the final
hydrolysis to the corresponding α-amino acids can be carried out under mild reaction conditions.
Several iminic glycine templates derived from different chiral auxiliaries have been reported.2–8 Some
representative examples are: (a) imino esters prepared from chiral carbonyl compounds such as 2-
hydroxypinan-3-one (12 and 23) and camphor (34 and 45); (b) chiral amides prepared from 2,5-
bis(methoxymethoxymethyl)pyrrolidine 56 and sultam derivatives 67; and (c) chiral esters 78 of 8-
phenylmenthol and also of menthol,8a binaphthol,8c and carbohydrates.8d
∗
Corresponding author. E-mail: cnajera@ua.es
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00113-X

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On the other hand, 1,5-dimethyl-4-phenylimidazolidin-2-ones, easily prepared from (+)- or (−)-
ephedrinium chloride and urea,9a have proved to be good chiral auxiliaries.9,10 Several N-allyl-9 and
N-acylimidazolidinones10 have been used as useful reagents for diastereoselective homoaldol reactions,9
alkylation of the corresponding enolates,9b,10a,g Michael additions,10b,c,d,e,h and Diels–Alder cycload-
dition reactions.10f In the present communication we describe the preparation of a new chiral iminic
glycine template derived from (4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-one and its application in
the asymmetric synthesis of α-amino acids by diastereoselective alkylation of its enolate.
The preparation of the iminic glycine derivative 11 was carried out by acylation of (4R,5S)-1,5-
dimethyl-4-phenylimidazolidin-2-one 89b with α-chloroacetyl chloride giving compound 911 in 77%
yield, which, after substitution with sodium azide12 and hydrogenation13 to the amine hydrochloride,
afforded product 10 in 85% yield. Final formation of the N-[bis(methylthio)methylene]glycinate 1114,15
(50% yield) was carried out following a two-step procedure,16 first by treatment with carbon disulfide
and methyl iodide and subsequent reaction with methyl iodide in the presence of potassium carbonate
(Scheme 1).
Scheme 1.
The alkylation process (Scheme 2) with allyl bromide was carried out in the presence of several bases,
additives and reaction conditions, which have been summarized in Table 1. Since hydrolysis of the N-
acyl group was mainly observed under solid–liquid PTC conditions (K2CO3 or KOH, CH3CN, TBAB, rt,
sonication), strong bases such as n-butyllithium, LDA, LHMDS and KOBut were used. The best chemical
yields and diastereoselectivities were obtained with LHMDS or KOBut in THF and in the presence of

G. Guillena, C. Nájera / Tetrahedron: Asymmetry 9 (1998) 1125–1129
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LiCl allowing the temperature to rise from −78 to −20 or 0°C in ca. 2.5 h (Table 1, entries 4 and 6).
These reaction conditions were used with other alkyl halides in order to prepare products 12 (Scheme 2
and Table 1). In the case of alkyl bromides it was neccessary to also add LiI in order to prepare in situ
the corresponding iodides. When the alkylating agent was not reactive enough we observed cleavage of
the acylimidazolidinone bond of starting reagent 11 under the basic reaction conditions.
Scheme 2.
The strong influence of LiCl on the chemical yields of the alkylation process is probably due to the
ability of lithium salts to change the degree of aggregation of the enolate, activation of electrophiles
by the Lewis acid, Li+, and also a general salt effect which changes the polarity of the solvent.17 The
Table 1
Diastereoselective alkylation of imidazolidinone glycine derivative 11

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increasing effect on the diastereoselectivity can be due to an intramolecular chelation in the intermediate
enolate, favouring the attack of the electrophile at the Si face (Scheme 2).
When representative alkylated imidazolidinones 12a (de: 88%) and 12b (de: 90%) were hydrolyzed
with LiOOH in THF/H2O,18 the chiral auxiliary was recovered in more than 90% yield. After deprotec-
tion of the imine with 1 N HCl and treatment of the resulting chlorhydrate with propylene oxide, (S)-
allylglycine (13a)19 and (S)-phenylalanine (13b) were obtained in 56 and 36% yield (based on compound
11) and in 88 and 90% ee,20 respectively.
We conclude that the iminic glycine derivative 11, easily prepared from the recoverable auxiliary
(4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-one, is an adequate starting chiral template for the asym-
metric synthesis of α-amino acids.
Acknowledgements
We are very grateful to the DGICYT, Spain (project no. PB94-1515) for financial support. G. G. thanks
Lilly S. A. for a predoctoral grant. We thank Prof. S. G. Davies for helpful suggestions.
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