Abstract
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.
Key words
asymmetric synthesis - chiral auxiliaries - amino acids - kinetic resolution - nucleophiles
References
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Lee S.-k.
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Park YS.
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Caddick S.
Afonso CAM.
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Murtagh L.
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Durst T.
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Pelter A.
Goubet D.
Pritchard MC.
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<A NAME="RY02302ST-2">2 </A> This term was used by Prof. Peter Beak and coworkers for their mechanistic studies
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Gallagher DJ.
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Thayumanavan S.
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<A NAME="RY02302ST-3">3 </A>
(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.
<A NAME="RY02302ST-4">4 </A>
When a solution of 1 (αS :αR = 67:33) in CH3 CN was stirred for 1.5 h, spontaneous epimerization provided 1 with a ratio of 80:20 (αS :αR ).
<A NAME="RY02302ST-5">5 </A>
The absolute configurations of (αS )-1 was assigned by com-parison to the 1 H NMR of authentic diastereomer prepared from commercially available (S )-α-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.
<A NAME="RY02302ST-6">6 </A>
It has been proposed by several examples that the epimeri-zation of α-halo ester and
α-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
7a </A> For a quantitative analysis of the reactions of two interconverting diastereomeric
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7b </A> For cases in which the stereoselectivity of the product reflects the thermodynamic
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7c </A> Also see:
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8 </A>
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 .
<A NAME="RY02302ST-9">9 </A>
General procedure for the asymmetric synthesis of methyl-
N
-benzyl alaninate [(
R
)-2]: To a solution of (αRS )-1 (αS :αR = 60:40) in CH3 CN (ca. 0.1 M) at r.t. was added Et3 N (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. 1 H 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); 13 C 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 theS -enantiomer(minor) had a retention time of 5.4 min].
