Unnatural cyclic amino acids are important molecular precursors for biological studies and natural products synthesis.  Like the naturally occurring cyclic amino acid proline, their unique structures have been shown to greatly influence peptide folding and protein activity.  Typically their synthesis is limited to making small-ring unnatural cyclic amino acids, most commonly unnatural proline derivatives.  Little has been investigated into the biological applications of medium-sized ring unnatural cyclic amino acids due to the difficulties of their stereoselective syntheses.  We have successfully developed a stereoselective two-step, one pot approach to the more difficult medium-sized ring unnatural cyclic amino acids.  This process includes a tandem palladium catalyzed allylic amination/ [2,3]-Stevens rearrangement followed by a ruthenium catalyzed ring-closing metathesis.  These mild conditions allow for the inclusion of numerous aromatic and aliphatic side-chains, as well as functional groups that are well known cross-linking and photoaffinity probes.  By utilizing our previously developed palladium catalyzed tandem allylic amination/ [2,3]-Stevens rearrangement, we are able to access these amino acid derivatives diastereoselectively.  It is believed that the major isolated diastereomer is obtained via an exo transition state.  In addition, the use of Oppolzer's chiral auxiliary allows for the synthesis of enantiopure cyclic amino acid derivatives.

Synthesis of cyclic amino acids via tandem [2,3]-Stevens rearrangement/ring closing metathesis

247th National Meeting (2014)

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