Studies towards the synthesis of useful proline derivatives
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.
University of Southampton
1992
Norris, Simon Richard
(1992)
Studies towards the synthesis of useful proline derivatives.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
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.
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Published date: 1992
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Local EPrints ID: 461868
URI: http://eprints.soton.ac.uk/id/eprint/461868
PURE UUID: b186b306-8393-4f0d-ba00-995c91220008
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Date deposited: 04 Jul 2022 18:57
Last modified: 04 Jul 2022 18:57
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Author:
Simon Richard Norris
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