Amino acids enantioselective alkylation

Synthetic utility of stereoselective alkylations in natural product chemistry is exemplified by the preparation of optically active 2-arylglycine esters (38). Chirally specific a-amino acids with methoxyaryl groups attached to the a-carbon were prepared by reaction of the dimethyl ether of a chiral bis-lactam derivative with methoxy arenes. Using SnCl as the Lewis acid, enantioselectivities ranging from 65 to 95% were obtained. 

Early examples of enantioselective extractions are the resolution of a-aminoalco-hol salts, such as norephedrine, with lipophilic anions (hexafluorophosphate ion) [184-186] by partition between aqueous and lipophilic phases containing esters of tartaric acid [184-188]. Alkyl derivatives of proline and hydroxyproline with cupric ions showed chiral discrimination abilities for the resolution of neutral amino acid enantiomers in n-butanol/water systems [121, 178, 189-192]. On the other hand, chiral crown ethers are classical selectors utilized for enantioseparations, due to their interesting recognition abilities [171, 178]. However, the large number of steps often required for their synthesis [182] and, consequently, their cost as well as their limited loadability makes them not very suitable for preparative purposes. Examples of ligand-exchange [193] or anion-exchange selectors [183] able to discriminate amino acid derivatives have also been described. 

Several alkyl aryl sulfides were electrochemically oxidized into the corresponding chiral sulfoxides using poly(amino acid)-coated electrodes . Although the levels of enan-tioselection were quite variable, the best result involved t-butyl phenyl sulfoxide which was formed in 93% e.e. on a platinum electrode doubly coated with polypyrrole and poly(L-valine). Cyclodextrin-mediated m-chloroperbenzoic acid oxidation of sulfides proceeds with modest enantioselectivity . 

The reaction of lithiated 2-alkyl-2-oxazolines with nitrones enables stereoselective and enantioselective syntheses of 5-isoxazolidinones, which are used as precursors of 3-amino acids. Highly enantiomerically enriched 5-izoxazolido-nones and 3-amino acids of inverse configuration can be generated by simply changing the chirality of the initial 2- . sopropyl-2-oxazoline (600). 

Alkyl aryl sulfides were anodically oxidized to the corresponding chiral sulfoxides by using poly(amino acid[-coated electrodes. Partially very high enantioselec-tivities (93% ee) were reported [374, 375] however, the reproducibility depended strongly on the lot of the poly(amino acid) used [376]. Earlier, with a similar approach, by using an edge surface graphite anode that was chemically modified with (.S )-phenylalanine, an enantioselectivity of 0.5 to 2.5% was found in the oxidation of methylp-tolyl sulfide to the sulfoxide [377]. 

Furthermore, a highly efficient route to A-tert-butoxycarbonyl (Boc)-protected p-amino acids via the enantioselective addition of silyl ketene acetals to Al-Boc-aldimines catalyzed by thiourea catalyst 4 has been reported (Scheme 12.2)." From a steric and electronic standpoint, the A-Boc imine substrates used in this reaction are fundamentally different from the A-alkyl derivatives used in the Strecker reaction. 

The enantioselective synthesis of a-amino acids is an important goal in preparative organic chemistry89. The use of l,3-oxazolidin-5-ones for this purpose has already been shown. A number of examples utilizing six-membered heterocycles exist whereby the basic idea remains the same i.e., the nonracemic enolate is attacked preferentially from the less hindered side because of a built-in auxiliary bias which can be removed in the alkylation step in order to liberate the nonracemic a-amino acid90. 

This process was developed in order to synthesize unnatural a-amino acids. Naturally occurring, enantiomerically pure amino acids, as well as achiral glycine, have been used as starting materials in order to enantioselectively introduce a-substituents1 14. The resulting cyclic esters and amides have been alkylated and subjected to aldol reactions1-14. 

Enantioselective a-alkylation of the enolates of synthetic equivalents for glycine (R3 = H) and several other a-amino acids (R3 4= H) equivalents can be accomplished via 4-imidazolidinone derivatives of type 11,4,<5,7,8,1°-12. Both of the pure enantiomers of the glycine equivalent are readily available. Alkylation of these ultimately furnishes enantiomerically pure a-amino adds with a a-hydrogen11,12, whereas if R3 =t= H in the starting 4-imidazolidinones 1 then a-alkyl-a-amino acids 2 are obtained4,7 8,10-12. 

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