Unusual Transformations of Strain-Heightened Oxetanes

Abstract

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 CO 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.

Oxetanes in Drug Discovery Campaigns

“…This challenge has encouraged symbiotic efforts in academia and industry to enable their efficient inclusion into target compounds. Notable advances have been reported on the synthesis of oxetanes ,, and in the functionalization of the intact ring. − Together, these have further facilitated the investigation of oxetanes in drug discovery programs, which are beginning to bear fruit.…”

1,6-Dioxo-2-azaspiro[3.4]oct-2-enes and Related Spirocycles: Heterocycles from [3 + 2] Nitrile Oxide Cycloadditions with 2-Methyleneoxetanes, -Thietanes, and -Azetidines

“…2-Methyleneoxetanes 1 are readily accessible strained heterocycles, , remarkable because of their divergent reactivity as electrophiles and nucleophiles . While many of their reactions result in ring-opening, , there are outcomes where the oxetane remains intact. − These latter products are significant because of the known and emerging bioactivities of oxetane-containing molecules. − We have had particular interest in constructing spirocylic systems that take advantage of the electron-rich enol ether moiety of 2-methyleneoxetanes 1 .…”

Access to α,α-difluoro(arylthio)methyl oxetanes from α,α-difluoro(arylthio)methyl ketones and trimethylsulfoxonium halides: scope, mechanism and applications

“…Oxetanes are strained four-membered cyclic ethers. 1 The ring of oxetane adopts an essentially planar structure, which makes it a bioisostere of the gem -dimethyl group in medicinal chemistry. 2 Thus, oxetanes are stable motifs in many natural products and bioactive compounds (Fig.…”