Garbi, Amel (2005) Stereocontrolled synthesis of highly functionalised tetrahydrofurans,. Doctoral thesis, Durham University.
Polysubstituted tetrahydrofurans appear in a large variety of bioactive structures of both natural and unnatural origin. The stereochemistry of the substituents has a profound effect on function; therefore, the development of new methodology for the stereoselective construction of tetrahydrofuran rings is very attractive. A tandem methodology for the stereoselective synthesis of 2,3,5-trisubstitutedtetrahydrofurans is reported here. This involves a catalytic C-H insertion of diazocarbonyl acetal templates followed by the stereoselective reductive cleavage of the resultant bicyclic acetals. A key area of this project is the formation and reaction of diazoketones. The diazoketones were prepared in good yields (70-85%) by acylation of diazomethane with a mixed anhydride, which involves the initial activation of the acid group of the corresponding acid acetal precursors. Alternatives to the use of diazomethane have been examined but proved to be less efficient. Two routes towards the synthesis of the acid acetals have been examined. A one-pot process involving the treatment of 1,3- and 2,2-disubstitutedpropane- 1,3-diols with pyruvic acid gave poor yields (30-38%). A two-step procedure involving the initial synthesis of pyruvate ester acetals, by ketalisation of 2-substitutedpropane- 1,3-diols followed by their hydrolysis, led to the formation of acid acetals in good yield (~ 75% after 2 steps). Rhodium (II) acetate is an efficient catalyst for the decomposition of diazoketones leading to transition metal-carbenoids (or metallocarbenes), reactive intermediates susceptible to insertion into a C-H bond. Determination of the optimum conditions for the C-H insertion process has been achieved and electronic effects of the substituents on the C-H insertion process have been examined. The reaction was regioselective, occurring at the C-H bond a to the oxygen, and a variety of bicyclic ketones were prepared in moderate but reproducible yields. The bicyclic core intermediate, present in naturally occurring bioactive molecules, is also a target for synthesis. An attempt to synthesize sordidin, an aggregation pheromone released by male banana weevils, is reported. Finally, the reductive cleavage of these bicyclic ketones, upon Et3SiH/Lewis Acid treatment, has been examined. In all cases, the reactions were stereoselective leading to 2,3-anti-3,5-cis-trisubstituted tetrahydrofurans. The stereoselectivity increased with the size of the OR group at C-3.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||09 Sep 2011 09:51|