Mina, John G. (2005) Stereocontrolled Synthesis Of Highly Functionalized Heterocycles. Masters thesis, Durham University.
Polysubstituted heterocycles appear in various natural compounds that have potential biological activity. Consequently, synthetic routes towards such compounds have become a major interest for organic chemists taking into consideration the importance of the stereochemical control during the course of synthesis. This report presents a tandem C֊H insertion - L. Α. promoted acetal cleavage sequence for a stereocontrolled synthesis of 2,3,5-trisubstituted THF derivatives and 2,3,5,6-tetrasubstituted oxepane derivatives via the use of an intermediate bicyclic template. This initial step involves ketalization of substituted 1,3-propanediols with methyl pyruvate to yield the 1,3-dioxane ring. Hydrolysis to the acid acetal and acylation of diazomethane using the mixed anhydride procedure yielded the diazocarbonyl precursor for the insertion reaction. The decomposition of the diazocarbonyl compound was catalysed by Rh(_2)(OAc)(_4) to yield an acceptor metallocarbene which inserted regioselectively into the C-H bond α to the oxygen atom in the dioxane ring to form a five membered ring yielding the bicyclic ketone template in a moderate yield. Reduction of the ketone was stereoselective and led to one epimer. Direct treatment of the resultant alcohol or the protected derivative with Et(SiH/L.A. led to the formation of the 2,3,5- trisubstituted THF derivative indicating that the diastereoselectivity was a function of the bulkiness of the alcohol protecting group. Subsequent inversion of the 7-OH stereochemistry directed the acetal cleavage reaction towards the formation of the oxepane ring which proved the crucial role of the hydroxyl or the alkoxy group at C(7) as a controller of the regioselectivity of the acetal cleavage reaction.
|Item Type:||Thesis (Masters)|
|Award:||Master of Arts|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||09 Sep 2011 09:56|