Standard approaches

Diethyl-acetamidomalonate Route:

The probably most widely used first approach to unnatural amino acids goes via alkylation of diethyl acetamidomalonate. This process is daily routine in our laboratories and is an easy access to a large number of analogues in gram scale. This route yields in a racemic mixture of both enantiomers, which can be separated by enzymatic methods or other separation technologies. This route is preferred, if both stereoisomers are required in comparable quantities.
The limitations of this process are, if

• the alkylating reagent is not available;
• only one of the two enantiomers is required;
• available enzymes are not able to separate both isomers.

Typical compounds, which are accessible through this process are phenylalanine derivatives and amino acids with certain aliphatic residues carrying additional functional groups.

Asymmetric Strecker Synthesis:

The Strecker synthesis converts aldehydes into amino acids bearing one carbon more than the starting aldehyde. In case a chiral amine is used in the place of ammonium chloride chiral induction will yield in a preferred enantiomer. This route is favored, if the corresponding aldehyde is accessible and if its residue R can successfully turned into one conformal direction. In such cases this route can easily be up-scaled.