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Asymmetric Synthesis using Chiral N-Acyliminium Ions

Nitrogen heterocycles can be found frequently in pharmaceuticals and natural products and are of great importance as synthetic building blocks.

The “asymmetric electrophilic α-amidoalkylation reaction” (AEαA) developed in our group gives convenient access to enantiomerically pure α-substituted nitrogen heterocyles. The method is based on N-acyliminium ion chemistry. As compared to iminium ions, N-acyliminium ions are significantly more reactive and of distinctly higher versatility thus giving rise to the respective addition products even when rather weak nucleophiles are employed.

“Asymmetric electrophilic α-amidoalkylation” (AEαA) is the extension of this concept to asymmetric synthesis. When N-acyliminium ions provided with a chiral N-acyl residue are employed, the addition reactions may proceed stereoselectively to provide the corresponding amides in diastereomerically enriched or even pure form. In our laboratories these addition products are used for natural product synthesis and for the preparation of enantiomerically pure test compounds.

The concept mentioned above is illustrated in the following scheme with piperidine as an example. Up to now, we have realized this method with various nitrogen containing heterocycles including pyridines, pyrrolidines, isoquinolines and β-carbolines.

The bicyclic carboxylic acid 5 developed by our group has proven to be a powerful chiral auxiliary for such “asymmetric electrophilic α-amidoalkylation” reactions. Current investigations are aimed at extending the scope of this chemistry to further applications.

Asymmetric Syntheses of α-Amino Acids

α-Disubstituted α-amino acids often display significantly different chemical, biochemical and pharmacological properties as compared to natural proteinogenic and non-proteinogenic amino acids. A monosubstituted (proteinogenic) amino acid, for example, being the substrate of an enzyme may be turned into an enzyme inhibitor by transformation into an α-disubstituted amino acid. In pharmaceutical research, α-disubstituted amino acids are also used as building blocks to replace single amino acids in natural peptides in order to increase the stability of these compounds or, possibly, improve their pharmacological profile. In this context and with a focus on the development of new ligands for the glycine binding site of the NMDA receptor, our group has established a new method for the asymmetric synthesis of α-quaternary α-amino acids.
The methodology is based on the chiral α-quaternary α-hydroxycarboxylic acid (S)-1, which can be efficiently converted into the oxazinone (S)-2 representing a powerful chiral glycine equivalent. High yields and stereoselectivities are observed for alkylation reactions of (S)-2. Electrophiles have been shown to enter the molecule preferentially from the sterically less hindered site of (S)-2. Thus, the configuration of the newly formed stereogenic center obtained by double alkylation depends on the order of the alkylation steps. Consequently, one may obtain either of the two stereoisomers by simply reversing the order of the alkylation reactions. Of course, also the conveniently accessible enantiomer of (S)-1 [(R)-1] may be employed to get access to both enantiomers of the final amino acid.

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