Synthesis of unusual, strained heterocycles: Versatile templates for organic synthesis

Date of Completion

January 2003


Chemistry, Organic




2-Methyleneoxetanes, 2-methyleneazetidines and 3-alkylidene-2-methylene-oxetanes are unusual, novel, strained heterocycles, which contain unique functionalities. This dissertation presents new syntheses for these classes of heterocycles and delineates investigations of their utility as synthetic intermediates and/or biologically active molecules. ^ Studies to optimize the methylenation of β-lactones with dimethyltitanocene as a strategy for the preparation of 2-methyleneoxetanes are described. To demonstrate the utility of 2-methyleneoxetanes as molecular scaffolds, a synthetic approach towards laureatin, a potent mosquito larvicide, using a 2-methyleneoxetane as a key intermediate, is presented. ^ The development of a new synthetic protocol for the preparation of 2-methyleneazetidines is described. This protocol entails the reaction of N-activated-β-lactams with dimethyltitanocene. It appears that methyl transfer from dimethyltitanocene represents an alternative pathway of the reaction that predominates in cases where the Lewis basicity of the lactam nitrogen is not sufficiently dampened. Access to 2-methyleneazetidines gave us the opportunity to study some aspects of their reactivity and examine their potential as inhibitors of β-lactamases. ^ Finally, the development of a methodology for the first general synthesis of 3-alkylidene-2-methyleneoxetanes is described. This method entails the methylenation of α-alkylidene-β-lactones with dimethyltitanocene. In addition, two new strategies for the preparation of α-alkylidene-β-lactones from Morita-Baylis-Hillman adducts are delineated. ^