Abstract
D.Phil.
The topic of this thesis centres around the construction of carbocycles from carbohydrates
involving the use of SmI2 as reagent. Carbocycles, in particular functionalised cyclopentanes, form important substructures in a plethora of natural compounds, many of which are biologically active. The conversion of carbohydrates into stereodefined cyclopentanoids represents an attractive means of generating this type of compounds.
The SmI2-mediated cyclisation of hex-5-enals, derived from suitably substituted carbohydrate precursors via a zinc-mediated Grob-fragmentation reaction, was found to be a facile reaction generating stereodefined cyclopentanols in moderate yields. The effect of varying stereochemistry and substitution pattern on the outcome of the cyclisation was also investigated. In order to achieve a more efficient route to the cyclic products, a Grobfragmentation based on SmI2 was investigated. The substituent at the anomeric position of the carbohydrate was found to be crucial to the success of the fragmentation. This protocol gave rise to conditions under which fragmentation and cyclisation could be effected in a tandem fashion mediated by SmI2. Various attempts at intermolecular trapping of the organosamarium species generated after cyclisation proved fruitless. In order to circumvent these obstacles a tandem radical bicyclisation reaction was investigated for the construction of highly functionalised bicyclic ring systems. This approach proved to be a successful alternative for incorporating functionality at the exocyclic carbon atom which is otherwise difficult to achieve. The second part of this work is directed at the synthesis of stereodefined alkoxyaminocyclopentanes from carbohydrates promoted by SmI2. The intramolecular trapping of a radical by an oxime ether represents an attractive means of generating these compounds. The preparation of the iodo oxime ether starting materials from suitably substituted carbohydrates is discussed. The radical cyclisation under the action of SmI2 was found to be a facile process providing a rapid route to aminocyclopentanes which are used as key intermediates for the preparation of carbocyclic glycosidase inhibitors and analogues.
In the third part of this work, the construction of functionalised cyclobutanols from
carbohydrate precursors is discussed. The 4-exo-trig cyclisation holds promise as a general route for the stereoselective synthesis of highly functionalised cyclobutanols. Initial attempts at the 4-exo-trig cyclisation proved fruitless. It was subsequently established that the radical acceptor plays a crucial role in the success of the transformation. This led to the isolation of the first carbohydrate derived cyclobutanol.
The final part of this thesis involves the development of a new approach for the conversion of suitably functionalised pentose derivatives into chiral cyclopentanols. Cyclisation of a ribose derived hemiacetal via its in situ formed hex-5-ynal is discussed. This approach opens new possibilities for the construction of complex carbocycles from readily available carbohydrate starting materials.