Title

An investigation of the reactivity of 2-methyleneoxetanes and 1,5-dioxaspiro(3.2)hexanes

Date of Completion

January 2001

Keywords

Chemistry, Organic

Degree

Ph.D.

Abstract

One scaffold that offers the potential for an efficient and selective construction of a wide range of molecular classes is 2-methyleneoxetanes, a largely unexplored class of strained heterocycles. 2-Methyleneoxetanes are readily prepared and have already exhibited interesting reactivity. Herein, we extend the utility of 2-methyleneoxetanes as synthetic intermediates by investigating their reactivity in three areas: (1) electrophile-mediated reactions, (2) reductive ring opening, and (3) studies toward the total synthesis of plakoside A. ^ 1. Electrophile mediated reactions. Studies on the reactivity of 2-methyleneoxetanes have demonstrated that the 2-methyleneoxetanes can be ring-opened at C4 by nucleophiles. However, when 2-methyleneoxetane 1 was treated with acetic acid, oxetane 2 was formed as a 4:1 mixture of diastereomers. On the other hand, when 1 was reacted with bromine, dibromoketone 3 was isolated in 87% yield. The divergence in outcome of using these two electrophiles is noteworthy and might be explained by steric hindrance in the bromonium ion leading to preferred attack at C4. ^ 2. Reductive ring opening of 2-methyleneoxetanes. In this part we focused on investigating a new methodology to prepare dianionic enolates by the reductive ring opening of 2-methyleneoxetanes. Subsequent trapping of the dianion with aldehydes, ketones, and alkyl halides provided functionalized ketones in a highly regioselective process. We also illustrated the effect of different substitutions on the oxetane on the pathway of reductive cleavage. ^ 3. Studies toward the total synthesis of plakoside A. In the third part we demonstrate that the ring opening of readily available 3-amino-1,5-dioxaspiro[3.2]hexane 16g with organocuprate reagents represents a novel approach to ceramides and sphingolipids. We have explored the ring-opening reactivity of the 4-amino-1,5-dioxaspiro[3.2]hexane, using organocuprate reagents, and probed the compatibility of the released functionality to a variety of reactions suitable for the expeditious synthesis of plakoside A and rationally designed analogs. To shed further light on the process by which ceramides interact with T-cells, we have synthesized a series of ceramides 106, 107, and 109. ^