Synthesis of a 2,5-Diazabicyclo[2.2.1]heptane-Derived α,β-Diamino Acid

Abstract

The synthesis of optically pure (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-1-carboxylic acid starting from easily available ‘chiral pool’ l-4-hydroxyproline is reported. A tandem Strecker reaction–intramolecular nucleophilic cyclization (STRINC) sequence was used as the key synthetic step for the first time to prepare a diamino acid. Careful examination of the side products obtained in the STRINC step allowed the suggestion of a mechanistic explanation for the observed facts and optimization the yield of the aminonitrile precursor. The reported scalable synthesis opens the way to use the diamino acid as a branch point in peptides and as a building block in drug discovery.

Key words

amino acids - molecular rigidity - Strecker reaction - nucleophilic cyclization - bicyclic compounds

• References

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