Oxetane Synthesis via Alcohol C-H Functionalization.

Oxetanes are strained heterocycles with unique properties that have triggered significant advances in medicinal chemistry. However, their synthesis still presents significant challenges that limit the use of this class of compounds in practical applications. In this Letter, we present a methodology that introduces a new synthetic disconnection to access oxetanes from native alcohol substrates. The generality of the approach is demonstrated by the application in late-stage functionalization chemistry, which is further exploited to develop a single-step synthesis of a known bioactive synthetic steroid derivative that previously required at least four synthetic steps from available precursors.

Polarity Transduction Enables the Formal Electronically Mismatched Radical Addition to Alkenes.

The formation of carbon-carbon bonds via the intermolecular addition of alkyl radicals to alkenes is a cornerstone of organic chemistry and plays a central role in synthesis. However, unless specific electrophilic radicals are involved, polarity matching requirements restrict the alkene component to be electron deficient. This limits the scope of a fundamentally important carbon-carbon bond forming process that could otherwise be more universally applied. Herein, we introduce a polarity transduction strategy that formally overcomes this electronic limitation. Vinyl sulfonium ions are demonstrated to react with carbon-centered radicals, giving adducts that undergo in situ or sequential nucleophilic displacement to provide products that would be inaccessible via traditional methods. The broad generality of this strategy is demonstrated through the derivatization of unmodified complex bioactive molecules.

Unusually Chemoselective Photocyclization of 2-(Hydroxyimino)aldehydes to Cyclobutanol Oximes: Synthetic, Stereochemical, and Mechanistic Aspects.

Photocyclization of carbonyl compounds (known as the Norrish-Yang reaction) to yield cyclobutanols is, in general, accompanied by fragmentation reactions. The latter are predominant in the case of aldehydes so that secondary cyclobutanols are not considered accessible via the straightforward Norrish-Yang reaction. A noteworthy exception has been reported in our laboratory, where cyclobutanols bearing a secondary alcohol function were observed upon UV light irradiation of 2-(hydroxyimino)aldehydes (HIAs). This reaction is here investigated in detail by combining synthesis, spectroscopic data, molecular dynamics, and DFT calculations. The synthetic methodology is generally applicable to a series of HIAs, affording the corresponding cyclobutanol oximes (CBOs) chemoselectively (i.e., without sizable fragmentation side-reactions), diastereoselectively (up to >99:1), and in good to excellent yields (up to 95%). CBO oxime ether derivatives can be purified and diastereomers isolated by standard column chromatography. The mechanistic and stereochemical picture of this photocyclization reaction, as well as of the postcyclization E/Z isomerization of the oxime double bond is completed.

Visible light-driven conjunctive olefination.

Carboxylic acids and aldehydes are ubiquitous in chemistry and are native functionalities in many bioactive molecules and natural products. As such, a general cross-coupling process that involves these partners would open new avenues to achieve molecular diversity. Here we report a visible-light-mediated and transition metal-free conjunctive olefination that uses an alkene 'linchpin' with a defined geometry to cross-couple complex molecular scaffolds that contain carboxylic acids and aldehydes. The chemistry merges two cornerstones of organic synthesis-namely, the Wittig reaction and photoredox catalysis-in a catalytic cycle that couples a radical addition process with the redox generation of a phosphonium ylide. The methodology allows the rapid structural diversification of bioactive molecules and natural products in a native form, with a high functional group tolerance, and also forges a new alkene functional group with a programmable E-Z stereochemistry.