Studies towards the synthesis of useful proline derivatives

The role of conformational restraints, such as β-turn mimetics, in peptides for use in medicinal chemistry is discussed. Synthesis of proposed β-turn mimetics are briefly reviewed and an improved synthesis of [2R,5S,8S]-1-Aza-8-amino-9-oxo-4-thiabicyclo-[4.3.0] nonane-2-carboxylate (bicyclic turn dipeptide or Btd) is proposed. The synthesis of Fmoc-Btd-OH, for use in SPPS was accomplished in 20% yield from Z-L-glutamic acid. The key step involved stereo-controlled, tandem cyclisation of L-cysteine methyl ester onto 3-Z-4-(3-oxo-propyl)-5-oxo-oxazolidine. Fmoc-Btd-OH was demonstrated to be suitable for use in SPPS by the synthesis of H-Asp-Btd-Tyr-OH in 61% yield. As a general route to ring-substituted proline derivatives, a novel, ion-accelerated 1,3-dipolar cycloaddition of a nitrone anion to an alkene was proposed. In the course of the investigation is was found that N-benzyl-α-phenyl nitrone could be metallated with NaNHDS and alkylated with methyl iodide. N-hydroxypyrrolidines were formed in good yields when the metallated species was generated in the presence of a range of unsaturated esters and sulphones. The study showed that the expected [3+ 2] cycloaddition mechanism was extremely unlikely, and the observed results indicated that a two-step conjugate addition mechanism was most likely. Formation of a dipolar intermediate could arise from nucleophilic attack of the metallated nitrone on a polarised double or triple carbon-carbon bond, followed by cyclisation. Lack of time prevented the extension of the chemistry to form the desired proline derivatives.