Asymmetric Protonation of Enolate of α-Ammo Acid Derivatives Using Chiral Proton Sources

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Asymmetric protonation of prochiral metal enolates has become an efficient way of preparing nonracemic carbonyl compounds. Numerous chiral acids have been synthesized to date and have been utilized in enantioselective protonations. However, there are few reports on the protonation of enolates of α-amino acid derivatives giving high asymmetric induction.In this research, we examined the asymmetric protonation of enolates of α-amino acid derivatives with chiral alcohols possessing an asymmetric 2-oxazoline or chiral amides derived from α-amino acids. We have previously shown that (S,S)-imide and related imides possessing an asymmetric 2-oxazoline ring are efficient chiral proton sources for asymmetric protonation of lithium enolates derived from simple ketones such as 2-alkylcyclohexanones. We envisaged that if these chiral imides were applied to the protonation of enolates of α-amino acid derivatives, both L- and D-α-amino acids might be selectively obtained simply by changing the chira … More l proton source.Thus, we initially investigated the possibility of benzoic acid or benzyl alcohol derivatives bearing an asymmetric 2-oxazoline ring as chiral proton sources for the asymmetric protonation of lithium enolate of an alanine derivative and found that one diastereomer of a chiral benzylic secondary alcohol provided a moderate enantioselectivity. Chiral tertiary alcohols having a tetrahydrofuran (THF) ring in place of a benzene ring as a backbone were also synthesized and an increase in enantioselectivity was observed in the asymmetric protonation using these chiral alcohols. On the basis of the aforementioned results we further designed new chiral amides as chiral proton sources which can be synthesized from readily available α-amino acids. When the lithium enolate of alanine derivative was protonated with a chiral amide derived from L-tert-Leucine, biotin precursor, and cyclododecylamine, R-enriched product was obtained with 80% ee. These chiral amides were also found to act as effective asymmetric protonating agents for lithium enolates of other α-amino acid derivatives. Less