PTC and organic bases-LiCl assisted alkylation of imidazolidinone- glycine iminic derivatives for the asymmetric synthesis of α-amino acids

Article abstract of DOI:10.1016/S0957-4166(98)00402-9

Iminic derivatives of (4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-one and glycine 4 have been highly diastereoselectively alkylated with activated alkyl halides or electrophilic olefins either under PTC conditions or in the presence of the strong organic bases DBU or BEMP at -20°C in the presence of LiCl. Hydrolysis of the alkylated imino imides gave (S)-α-amino acids with recovery of the imidazolidinone chiral auxiliary.

Full text of DOI:10.1016/S0957-4166(98)00402-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3935–3938
PTC and organic bases–LiCl assisted alkylation of
imidazolidinone–glycine iminic derivatives for the asymmetric
synthesis of α-amino acids
Gabriela Guillena and Carmen Nájera ∗
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
Received 22 September 1998; accepted 30 September 1998
Abstract
Iminic derivatives of (4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-one and glycine 4 have been highly dia-
stereoselectively alkylated with activated alkyl halides or electrophilic olefins either under PTC conditions or in
the presence of the strong organic bases DBU or BEMP at −20°C in the presence of LiCl. Hydrolysis of the
alkylated imino imides gave (S)-α-amino acids with recovery of the imidazolidinone chiral auxiliary. © 1998
Elsevier Science Ltd. All rights reserved.
The diasteroselective alkylation of chiral glycine enolates is generally carried out with strong an-
hydrous bases such as BunLi, LDA or LHMDS and at very low temperatures.1 Phase transfer ca-
talysis (PTC) is the mildest reaction condition because K2CO3 or alkaline metal hydroxides can
be used as bases.2 However, this methodology requires the use of activated alkyl halides and imi-
nic derivatives. PTC asymmetric alkylation can be carried out (a) with chiral acyclic benzophenone
glycinate 13 or cyclic 24 and 35 derivatives or (b) with achiral iminic glycinates and chiral ca-
talyst such as cinchoninium and cinchonidinium salts6 or TADDOL.7 Recently, strong organic bases
such as Schwesinger’s8 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine
(BEMP)9 and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) have been used for the first time in the highly
diastereoselective alkylation of alanine derived oxazine 2 with unactivated alkyl halides at room tem-
perature in the presence of LiI affording, after hydrolysis, highly enantiomerically enriched α-methyl
α-amino acids.10
∗
Corresponding author. Fax: +34-96-5903549; e-mail: cnajera@ua.es
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00402-9

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In connection with our project on the preparation of synthetically useful chiral glycine and alanine
templates for the asymmetric synthesis of α-amino acids, we have found that (4R,5S)-1,5-dimethyl-4-
phenylimidazolidin-2-one11 is a good auxiliary12 for the diastereoselective alkylation of the correspon-
ding iminic glycine derivative 4a.13 In this case, LHMDS or KOBut in the presence of LiCl at −78°C
have to be used in the alkylation process, and the use of solid–liquid PTC conditions (K2CO3 or KOH,
CH3CN, tetrabutylammonium bromide) at room temperature promoted the cleavage of the N-acyl group.
In this communication, we describe the diastereoselective alkylation and Michael addition reactions of
imidazolidinone–glycine iminic reagents 4 under PTC and strongly basic conditions.
The studies on the alkylation of compounds 4a13 and 4b14,15 with allyl iodide (Scheme 1) under
different reaction conditions have been summarized in Table 1 (entries 1–8). Both reagents behave in
a similar fashion under the different conditions assayed. In the case of the benzophenone derivative 4b,
yields for compound 7a are lower than for 6a due to partial deprotection observed during the purification
step. For this reason, after the alkylation process the crude product 7a was transformed into amine 8a by
extractive work-up with 0.5 N HCl and K2CO3 in order to deprotect the amino group. The solid–liquid
PTC as well as the organic base-promoted alkylations with allyl iodide were carried out at −20°C in
CH3CN as solvent, thus avoiding hydrolysis of the N-acyl group.
Scheme 1.
The use of an excess of LiCl was found to be crucial in all cases for achieving high diastereoselection.
For instance, a ca. 1:1 mixture of diastereomers was obtained when using BEMP as base in the absence
of LiCl (Table 1, entry 6). We presume again13 that the presence of the lithium ion plays an important role
in the structure of the enolate chelating both oxygen atoms and the nitrogen of the imine, thus blocking
the conformational motion. LiOH was an adequate inorganic base for PTC conditions (Table 1, entries
1 and 2), again the reaction with K2CO3 failed (Table 1, entry 3). BEMP or DBU were used in a small
excess (1.5 equiv.)16 and gave similar yields and diastereoselectivities but the reaction is faster with the
later and is also more convenient from an economical point of view.
Reagent 4b seems to be slightly superior to 4a and avoids the use of the unpleasant carbon disulphide
during the preparation. For these reasons, the reactions with other alkyl halides and the Michael addition
with electrophilic olefins were carried out with 4b (Table 1, entries 9–17). In general, better yields and
diastereomeric excesses have been obtained with DBU–LiCl than with PTC conditions, whereas Michael
addition with acrylates (Table 1, entries 16 and 17) afforded better diastereoselectivities with tert-butyl
than with ethyl ester but with lower yield.
Hydrolysis17 of products 8a (de: 98%) and 8b (de: 96%) were carried out with LiOH in THF/H2O
affording the recovered chiral auxiliary imidazolidinones in 83 and 73% yield, respectively. The corres-

G. Guillena, C. Nájera / Tetrahedron: Asymmetry 9 (1998) 3935–3938
3937
Table 1
Reaction conditions for the diastereoselective alkylation of imidazolidinone–glycine derivative 4
ponding α-amino acids 9a and 9b were obtained after ion exchange chromatography (Dowex) in 50 and
69% yield (based on starting iminic derivative 4b, Scheme 1) and with 94 and 87% of ee,18 respectively.19
We conclude that PTC conditions or strong organic bases, especially DBU in the presence of LiCl,
are very convenient conditions for the diastereoselective alkylation of iminic imidazolidinone–glycine
reagents for the asymmetric synthesis of α-amino acids.
Acknowledgements
We thank the Dirección General de Investigación Científica y Técnica (DGICYT) of the Spanish
Ministerio de Educación y Cultura (MEC) (PB94-1515) for financial support. G.G. thanks Lilly S.A.
for a predoctoral grant.

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14. The new iminic reagent 4b was prepared in 45% yield by reaction of hydrochloride 515 with benzophenone imine in
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15. Prepared from (4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-one in 65% yield.13
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17. Hydrolysis of 6a (de: 88%) and 6b (de: 90%) has been carried out with LiOOH providing α-amino acids 9a and 9b in
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yields.13
18. Ees were analysed by HPLC using a Crownpak CR (+) column.
19. Slight partial racemization was observed during the hydrolysis.