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Title: Towards the synthesis of alpha-cyclo peptide nucleic acid monomers
Author: Biyani, Manish Radheshyam
Awarding Body: Heriot-Watt University
Current Institution: Heriot-Watt University
Date of Award: 2012
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Peptide nucleic acids (PNAs) are potentially useful as mimics of DNA for gene therapy treatment of cancer and other genetic disorders. The original PNA molecule developed by Nielsen et al. lacks selectivity towards nucleic acid targets (DNA vs RNA) and the ability to incorporate new monomers for each alteration to be examined. Our design of L-α-PNA allows for the incorporation of different appropriate α-amino acid spacers into the oligomers during peptide synthesis. Selectivity towards nucleic acid targets is improved by freezing out conformation with incorporating cyclopentane ring in L-α-PNA. The aim of the research reported in this thesis was to develop viable synthetic routes to α-cycloPNA monomers, constrained analogues of PNA monomers. Our initial objective was to optimize an established synthetic pathway to a key cyclopentane α–amino acid intermediate suitably functionalized at the 3-position to enable subsequent preparation of pyrimidine and purine α-cycloPNA monomers. However, reproduction of the key cyclization step in our prototypical route to a key 3-alkoxy-1-aminocyclopentanecaboxylate precursor proved to be problematic and so alternative synthetic pathways were explored. All four diastereoisomers (203, 143, 204 and 144) of the required cyclopentane α–amino acid intermediate were prepared via hydroboration of ethyl N-Boc-1-aminocyclopent-3-ene-1-carboxylic acid in overall yields of 6.2% for the (1S/R, 3S/R)-alcohols (204 and 144) diastereoisomeric mixture and 13% for the (1R/S, 3S/R)-alcohol (203 and 143), also isolated as an inseparable diastereoisomeric mixture. Unfortunately, all attempts to resolve these mixtures failed. With both the (1S/R, 3S/R)-alcohols and (1R/S, 3S/R)-alcohols to hand, synthesis of a cytosine derivative of the α-cycloPNA monomer was investigated. The mixed (1R/S, 3S/R)-alcohol diastereoisomers were first converted into their respective camphorsulfonate derivatives (232 and 233) and treated with Cbz-protected cytosine. Unexpectedly, the corresponding O2-alkylated cytosine α-cycloPNA monomers (266 and 267) were afforded. Asymmetric hydroboration of the chiral cyclopentene intermediate bearing D-menthyl ester using either (+)- or (-)-IpcBH2.TMEDA were studied. This also gave unresolvable diastereoisomeric mixtures of (1R/S, 3S/R)-alcohols (299 and 300), in 82% yield, and (1R/S, 3S/R)-alcohols (299 and 300), in 69% yield. Finally, treatment of the (1R/S, 3S/R)-brosylate mixture derived from the (1R/S, 3S/R)-alcohols of D-menthyl esters with Cbz-protected cytosine again yielded the O2-alkylated cytosine α-cycloPNA monomers.
Supervisor: Howarth, Nicola Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available