Synthesis of thiourea and urea organocatalysts by opioids
Liu, Bo (2017) Synthesis of thiourea and urea organocatalysts by opioids. Master of Science thesis, Dublin City University.
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Organocatalysis is one of the fastest growing fields of research in organic chemistry. The many advantages of organocatalysts include their low costs, low toxicity, the ready availability of natural resources and in many cases, low reactivity with moisture and oxygen. These traits can be preferable to some classes of metal-based catalysts although a case-by-case comparison is required. When benefits over metal-based catalysts are realized, organocatalysts can make a contribution to green chemistry. One major advantage is that metal residues, which are difficult to remove from products when using metal-based catalysts, are avoided by an organocatalytic step which is of significance to the synthesis of pharmaceutical products, where metal content is strictly controlled.
Effective chiral organocatalysts can be derived from natural molecules from the chiral pool, which are a primary source of enantiomerically pure stereoisomers. Proline and the cinchona alkaloids are two key examples of organocatalyst precursors which have been widely studied. This work expands the scope of natural alkaloid precursors to include opiates.
Opiates, such as morphine and codeine, are abundant alkaloids readily available from the opium poppy and industrial plants and means by which to extract these compounds are well established. This is due to their ubiquitous use as analgesic drugs to relieve pain. The aim of this project was to prepare novel thiourea and urea organocatalysts from a series of opioid derivatives and study their performance in model asymmetric synthetic reactions suited to thiourea catalysts. The selected reaction was a Michael addition reaction between diethyl malonate and trans-β-nitrostyrene. One urea and one thiourea organocatalyst were prepared, both of the C2-symmetric group, and characterized by NMR, IR, melting point, optical rotation, MS and the compound structures were unambiguously assigned based on single crystal XRD results. The thiourea derivative catalyst gave high yields for the Michael addition reaction however, enantioinduction was poor, with less than 10% ee observed.
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