Synthesis of unusually strained spiroheterocyclic ring systems and their exploits in synthesis

Abstract

Small ring compounds have continually captivated physical and synthetic organic chemists because of their remarkable structures and the reactions that are feasible due to the inherent ring strain of these systems. Isolable, small, strained carbocyclic and heterocyclic rings have been known for over a century, but recently there have been a number of new spiroheterocycles described. Specifically, the utility of oxa- and dioxaspiropentanes as well as oxa- and dioxaspirohexanes has been demonstrated in the synthesis of natural and unnatural products. The ring systems investigated to date have shown interesting and varied reactivity patterns due to the unique physical properties of these small rings. The aim of this review is to provide an overview of the synthesis and reactivity of small strained spiroheterocycles and to illustrate their applications in synthetic endeavors. This review will be restricted to spiro heterocyclic pentane and hexane systems, as other types of strained systems have been recently reviewed.1 An initial, general overview of reactivity patterns for these systems identified by various researchers will hopefully enable the reader to put the following discussion of reactions and applications in perspective. Oxaspiro[2.2]pentanes and 1,4-dioxaspiro[2.2]pentanes I exhibit similar reactivity patterns.2 The C-O bond of the epoxide is cleaved upon either acid-mediated rearrangement or nucleophile addition. 1-Oxaspiro[2.3]hexanes II, 1,4-dioxaspiro[2.3]hexanes III, and 4-oxaspiro[2.3]hexanes IV offer two primary modes of reactivity. The predominant Lewis acid promoted rearrangement through a stabilized carbocation provides cyclopentanone products, yet nucleophilic addition favors the more hindered epoxide C-O bond. However, dioxaspirohexanes III tend to undergo nucleophilic substitution primarily at either of the epoxide C-O bonds. Of the four possible reactive centers in 1,4-dioxaspiro[2.3]hexan-5-ones IV only substitution at the less hindered epoxide C-O bond or the C=O bond has been observed under various reaction conditions.