The preparation and reactivity of 2-methyleneoxetanes

Date of Completion

January 1999


Chemistry, Organic




The first general and reliable route to 2-methyleneoxetanes (1) has been developed via the methylenation of β-lactones (33) with dimethyltitanocene (36). A study of conditions for the optimization of the synthesis and the isolation of 2-methyleneoxetanes is described. ^ It has been shown that under Brønsted acidic conditions, 2-methyleneoxetanes hydrolyze to from β-hydroxyketones (45-46). Under basic conditions two types of reactivity have been observed. First, a 2-methyleneoxetane has been shown to form a C-4 benzyl substituted ketone (55) after nucleophilic addition of benzyllithium. Under such conditions the enolate intermediate can be captured by electrophiles. Second, 2-methyleneoxetanes have been shown to rearrange to form homopropargylic alcohols (48-54 ). Optimized conditions have been found to effect this transformation, and the results of that study are presented here. A variety of homopropargylic alcohols are accessible from 2-methyleneoxetanes, and it has been shown that the stereochemical integrity of a 2-methyleneoxetane is maintained during the course of the reaction. ^ The utility of 2-methyleneoxetanes as structural isosteres to biologically significant β-lactones has been shown. The synthesis of the 2-methyleneoxetane analog of Orlistat (1k) was accomplished via our method of the methylenation of β-lactones. In an assay versus porcine pancreatic lipase using tributyrin as the substrate an IC50 value of 1.7 μg/ml was found for 1k, compared to 0.4 μg/ml for Orlistat ( 33k). ^ In addition, a brief description of a study of the ring-closing metathesis of 2-methyleneoxetanes containing a pendent olefin is described in an appendix. ^