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Title: Extending applications of magnesium amide bases in asymmetric synthesis and a mild and selective N-debenzylation method
Author: Monks, Natalie R.
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2013
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Expansion of the application of readily available chiral magnesium-bisamides was the overall focus of the majority of this study. Comparing a structurally simple C2-symmetric magnesium bisamide and a chelating magnesium bisamide, a range of cyclobutanone substrates have been desymmetrised. Early studies employed the chlorotriethylsilane electrophile, however, efficiency of the processes with the chosen base system with cyclobutanone substrates was low. When the alternative electrophile, diphenylphosphoryl chloride, was utilised, however, a drastic improvement in both reactivity and selectivity was achieved. Optimisation of the reaction conditions with both a C2-symmetric magnesium bisamide and a chelating magnesium bisamide revealed selectivities of up to 99:1 er for the enantioenriched enol phosphate products. Furthermore, it was found that no additives are required within this novel base system and the deprotonation can be performed at a more elevated temperature of -40 °Cwhilst maintaining high selectivity. This efficient desymmetrisation was applied to a range of cyclobutanone substrates and seven novel enol phosphate products were formed in enantioselectivities between 76:24 and 99:1er, with the majority producing ratios greater than 89:11 er. Further application of a C2-symmetric magnesium bisamide was also sought by employing this base reagent within the synthetic route towards the natural product (+)-(S)-Sporochnol A. To this end, a scalable pathway towards a novel 4,4-disubstituted cyclohexanone was devised. The asymmetric deprotonation of this intermediate, utilising a C2-symmetric magnesium bisamide, subsequently embedded the all carbon quaternary stereocentre required within the natural product. Trapping the resulting chiral enolate with diphenylphosphoryl chloride furnished the desired enol phosphate in 88:12 er, which is an excellent level of enantioselectivity for a substrate of this type at a reaction temperature of -78 °C. Furthermore, the utility of the enol phosphate product was highlighted through a palladium-catalysed cross-coupling reaction with a Grignard reagent. Although completion of the synthesis of (+)-(S)-Sporochnol A was not achieved, the key asymmetric deprotonation and subsequent cross-coupling step were successful and high yielding. An additional study was the development of an improved method for the oxidation of secondary N-benzylamines. The application of DIAD as a means to oxidise secondary N-benzylamines, followed by a subsequent hydrolysis step has been employed to afford debenzylated free amines. This oxidation methodology has thus been applied to a range of amine substrates as an improved, mild, and selective method for benzyl deprotection. High yields of the free amines were obtained and the reaction proved to be tolerant of other functional groups and heteroatoms. Moreover, when an enantiopure secondary N-benzylamine was deprotected, the free primary amine remained optically pure, proving that these mild conditions do not interfere with other functionality within the molecule.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available