α‐Alkylation of Amino Acids without Racemization. Preparation of Either (S)‐ or (R)‐α‐Methyldopa from (S)‐Alanine

Abstract

Enantiomerically pure cis-and trans-5-alkyl-l-benzoyl-2-(tert-butyl)-~~-methylimidazolidin-4-ones (1, 2, 11, 15, 16) and trans-2-(terf-butyl)-3-methyl-5-phenylimidazolidin-4-one (20). readily available from (S)-alanine, (S)-valine, (S)-methionine, and (R)-phenylglycine are deprotonated to chiral enolates (cf. 3, 4, 12, 21). Diastereoselective alkylation of these enolates to 5,5-dialkyl-or 5-alkyl-5-arylimidazolidinones (5, 6, 9, 10, 13a-d, 17, 18, 22) and hydrolysis give a-alkyl-a-amino acids such as (R)and (S)-a-methyldopa (7 and 8a, resp.), (S)-amethylvaline (14) and (R)-a-methyl-methionine (19). The configuration of the products is proved by chemical correlation and by NOE 'H-NMR measurements (see 23, 24). In the overall process, a simple, enantiomerically pure a-amino acid can be a-alkylated with retention or with inversion of configuration through pivalaldehyde acetal derivatives. Since no chiral auxiliary is required, the process is coined 'self-reproduction of a center of chirality'. The method is compared with other a-alkylations of amino acids occurring without racemization. The importance of enantiomerically pure, a-branched a-amino acids as synthetic intermediates and for the preparation of bio~ogicdl~y active compounds is discussed.In [l], we have shown that simple amino acids such as (S)-alanine, (S)-valine, (R)-phenylglycine, (S)-phenylalanine, and (S)-methionine can be converted selectively to imidazolidinones such as 1 and 2 of either cis-or trans-configuration. We now show that these imidazolidinones are deprotonated to synthetically useful chiral enolates.A) Reactions of the Chiral Imidazolidinone Enolates with Electrophiles. -As a first example, the preparation of ( R ) -or (S)-a -methyldopa ( =I 2-amino-2-methyl-3-(3,4-di-hydroxypheny1)propionic acid) from (S)-alanine is described (Scheme I). Solutions of the imidazolidinones (1 or 2) in THF were treated at dry-ice temperature with a slight excess of lithium diisopropylamide (LDA). Bright orange-red-colored solutions of the enantiomeric enolates (3, 4) were formed, which were combined with 3,4-dimethoxybenzyl bromide. Rapid decolorization indicated the progress of the alkylation step furnishing the enantiomeric 5,5-disubstituted imidazolidinones (5, 6, ca. 60 YO). We did not detect more than one diastereoisomer by HPLC of the crude products. Within experimental error, the two isomers 5 and 6 had identical physical properties such as melting points, IR, and NMR spectra, but an opposite sense of specific rotation.The heterocyclic ring and the phenolic methyl-ether groups of the enantiomer 6 were cleaved by heating for 4 hours in 6~ HC1 at 180" in a sealed tube. Isolation of the a-methyldopa thus produced caused considerable problems due to the known [2a] sen-') 2,Part of the projected Ph. D. theses of J.

Lithium Diisopropylamide-Mediated Reactions of Imines, Unsaturated Esters, Epoxides, and Aryl Carbamates: Influence of Hexamethylphosphoramide and Ethereal Cosolvents on Reaction Mechanisms

“…41 Quenching with D 2 O failed to afford significant levels of deuterated 34, which is not particularly surprising in light of Seebach's studies of D 2 O quenches when i-Pr 2 NH is present. 42 In the absence of HMPA, little or no metalated epoxide is observed (although some minor 6 Li resonances are noted. )…”

Biomimetic Synthesis of (.+-.)-Galanthamine and Asymmetric Synthesis of (-)-Galanthamine Using Remote Asymmetric Induction

“…Originally, synthesis of chiral 1,3-imidazolidin-5-one and its application to chiral induction was reported by Seebach, who proposed the concept as Self Regeneration of Stereocenters (SRS). [62][63][64] Among naturally abundant amino acids, phenylalanine and valine were chosen as the chiral auxiliary to form the fused imidazolidinone because the bulky isopropyl and benzyl groups on amino acid residues would provide promising stereoselectivities. In the beginning, we simply expected that the spontaneous Michael addition after deprotection of R 1 in B would progress diastereoselectively to afford cyclic ether (C) with the desired configuration.…”

“…The configuration of the major isomers was also supported by the experimental data in the synthesis of imidazolidinone derivatives, which was reported by Seebach. [62][63][64] The amino group of 29a was next protected with a trifluoroacetyl group to prepare 30a, a substrate of the phenol coupling. The imidazolidinone derivatives 30b and 30c were also prepared from 29b and 29c in order to compare the coupling reactions.…”

Asymmetric propionate aldol reactions of a chiral lithium enolate accessible from direct enolization with n-butyllithium

“…The organic layer was separated and the aqueous layer was extracted with CH 2 Cl 2 (2 x 100 mL). The combined organic layers were washed with brine, dried over MgSO 4 14.53 mmol) in dry THF (28 ml) was cooled to -78 °C under a nitrogen atmosphere and n-butyllithium (2.5 M in hexane, 5.8 ml, 14.53 mmol) was added dropwise. After 30 minutes of stirring at the same temperature, a solution of methyl ketone 4 (3.0 g, 11.18 mmol) in dry THF (28 ml) was added dropwise and stirring was continued at -78 °C for 2 h. Then methyl iodide (2.21 mL, 14.53 mmol) was added at the same temperature and the mixture was stirred at -30°C for 1.5 h. The reaction was quenched at -30 °C with 60 mL of 1N HCl, and the mixture was allowed to reach room temperature.…”