Conspectus
Oxetanes are important motifs for drug discovery
and are valuable
templates in organic synthesis. Much of their use as synthetic intermediates
exploits their inherent strain, often resulting in chain extensions
at the expense of the heterocycle. Modifications on the carbon alpha
to the oxygen of oxetanes, such as the CO of β-lactones,
extend the modes of reactivity. Nevertheless, the outcomes are still
largely predictable. On the other hand, other alpha modifications,
such as a CH2, a spiro-oxiranyl moiety, or a spiro-cyclopropyl
group, increase strain and open pathways not available to simple oxetanes
or β-lactones. Methods in generating 2-methyleneoxetanes, 1,5-dioxaspiro[3.2]hexanes,
and 4-oxaspiro[2.3]hexanes have been developed by us and others. To
date, reactions of these systems have sometimes been predictable,
but often the outcomes have been unexpected. This has provided fertile
ground for thinking about what controls reactivity and what other
reaction pathways might be accessible to these strain-heightened oxetanes.
This Account summarizes the published literature on the most straightforward
approaches to 2-methyleneoxetanes, dioxaspirohexanes, and oxaspirohexanes
and on their reactivity. In contrast to simple oxetanes, reactions
of 2-methyleneoxetanes with nucleophiles at C4 release an enolate
rather than an alkoxide. Also, 2-methyleneoxetanes can be converted
to homopropargyl alcohols or undergo a silicon accelerated isomerization/electrocyclic
ring opening, processes accessible only because of the exocyclic double
bond. In addition, oxetane oxocarbenium ions, derived from protonation
of the enol ether, can react with nucleophiles to provide 2,2-disubstituted
oxetanes. Oxaspirohexanes are readily prepared by Simmons–Smith
cyclopropanation of 2-methyleneoxetanes. These unusual systems undergo
a variety of substituent dependent rearrangements in the presence
of the Lewis acid BF3·Et2O. In addition,
upon treatment with Zeise’s dimer, oxaspirohexanes are transformed
to synthetically useful 3-methylenetetrahydrofurans. Dioxaspirohexanes
are easily accessed by dimethyldioxirane oxidation of 2-methyleneoxetanes.
Predictably, dioxaspirohexanes react with many nucleophiles to give
α-functionalized-β′-hydroxy ketones. Unexpectedly,
2,2-disubstituted oxetanes can also be selectively produced. This
latter pathway has led to further unusual transformations, illuminating
computational studies, and novel routes to biologically relevant molecules.
