No description available.

No description available.

Doctor of Philosophy (PhD), Science / A concise stereo-selective synthesis of a protected form of APTO 1, an unusual amino acid component of microsclerodermin C 2, was undertaken. Sequential Sharpless Asymmetric Aminohydroxylation (AA) and Asymmetric Dihydroxylation (AD) reactions were used to introduce the chiral amino and hydroxyl groups. Specific directing groups were chosen to ensure high regio- and enantio-selectivity in these reactions. The target compound was reached in a linear reaction sequence of fourteen steps. The strategy was designed to generate common intermediates which could be used to access analogous amino acid fragments in other microsclerodermins. A protected form of AETD 3, from microsclerodermin E, was synthesised via a late-stage common intermediate. Initial studies into the modification of the sequence to allow access to AMPTD 4 and 10-methyl AMPTD 5 were made.

Doctor of Philosophy (PhD), Science / A concise stereo-selective synthesis of a protected form of APTO 1, an unusual amino acid component of microsclerodermin C 2, was undertaken. Sequential Sharpless Asymmetric Aminohydroxylation (AA) and Asymmetric Dihydroxylation (AD) reactions were used to introduce the chiral amino and hydroxyl groups. Specific directing groups were chosen to ensure high regio- and enantio-selectivity in these reactions. The target compound was reached in a linear reaction sequence of fourteen steps. The strategy was designed to generate common intermediates which could be used to access analogous amino acid fragments in other microsclerodermins. A protected form of AETD 3, from microsclerodermin E, was synthesised via a late-stage common intermediate. Initial studies into the modification of the sequence to allow access to AMPTD 4 and 10-methyl AMPTD 5 were made.

A novel method for asymmetric synthesis of α-hydroxy ketone with excellent regio- and stereoselectivity has been established by the systematic investigation of asymmetric dihydroxylation of allenes. The efficiency of kinetic resolution of racemic allenes was also investigated by using the AD reaction on both 1,3-disubstituted and trisubstituted allenes. Steric effects, electronic effects and allene substitution are also discussed. Aziridines were formed by copper-catalyzed intramolecular nitrene addition to alkenes. The carbamate group was used as the tether between the alkene and the nitrene. Subsequent nucleophilic attack of the aziridine was accomplished using RSH, R2NH, N3-,or ROH as the nucleophile. This addition was found to be regio- and stereoselective. This methodology has provided a new strategy for the stereoselective construction of three adjacent functional groups, in particular the 1,2 diamino-3-hydroxy unit. The rhodium-catalyzed intramolecular aziridination of allenic N-sulfonyloxy carbamates has been established. Efficient ring opening of these bicyclic compounds may provide synthetic utility in organic chemistry. The intramolecular aziridination of allenic sulfamate esters was tested on a single example to afford in situ a ring opened product.

Pyranonaphthoquinone lactones have been recently found to be selective inhibitors of the serine-threonine kinase AKT/PKB. AKT/PKB plays a major role in tumorigenesis, hence these compounds have a great potential to act as anti-cancer agents. They act by a novel bioreductive alkylation mechanism of inhibition of AKT/PKB. In this work, 7-deoxykalafungin, a pyranonaphthoquinone lactone and its deconstruction analogs were synthesized. The structural features of the compounds necessary to inhibit AKT1 potently and selectively were determined. It was observed that compounds with a pyran ring were more potent in inhibiting AKT1. Conversely, flexible compounds were found to be weak inhibitors of AKT1. Also, presence of a lactone ring was found to be favorable in inhibiting AKT1. Of the compounds tested, 7-deoxykalafungin was the most potent inhibitor of AKT1 (IC50 = 0.28 µM against AKT1) and compound 4-61 was the most potent inhibitor of PKA (IC50 = 0.43 µM against PKA).