(Bio)isosteres of - and -substituted benzenes.

Saturated bioisosteres of substituted benzenes offer opportunities to fine-tune the properties of drug candidates in development. Bioisosteres of -benzenes, such as those based on bicyclo[1.1.

Synthesis of polysubstituted bicyclo[2.1.1]hexanes enabling access to new chemical space.

Saturated bridged-bicyclic compounds are currently under intense investigation as building blocks for pharmaceutical drug design. However, the most common methods for their preparation only provide access to bridgehead-substituted structures. The synthesis of bridge-functionalised species is highly challenging but would open up many new opportunities for molecular design.

Bicyclobutanes as unusual building blocks for complexity generation in organic synthesis.

Bicyclobutanes are among the most highly strained isolable organic compounds and their associated low activation barriers to reactivity make them intriguing building-blocks in organic chemistry. In recent years, numerous creative synthetic strategies exploiting their heightened reactivity have been presented and these discoveries have often gone hand-in-hand with the development of more practical routes for their synthesis. Their proclivity as strain-release reagents through their weak central C-C bond has been harnessed in a variety of addition, rearrangement and insertion reactions, providing rapid access to a rich tapestry of complex molecular scaffolds.

Organophotocatalytic [2+2] Cycloaddition of Electron-Deficient Styrenes.

A visible-light organophotocatalytic [2+2] cycloaddition of electron-deficient styrenes is described. Photocatalytic [2+2] cycloadditions are typically performed with electron-rich styrene derivatives or α,β-unsaturated carbonyl compounds, and with transition-metal-based catalysts. We have discovered that an organic cyanoarene photocatalyst is able to deliver high-value cyclobutane products bearing electron-deficient aryl substituents in good yields.

Lewis Acid Catalyzed Transfer Hydromethallylation for the Construction of Quaternary Carbon Centers.

The design and gram-scale synthesis of a cyclohexa-1,4-diene-based surrogate of isobutene gas is reported. Using the highly electron-deficient Lewis acid B(C F ) , application of this surrogate in the hydromethallylation of electron-rich styrene derivatives provided sterically congested quaternary carbon centers. The reaction proceeds by C(sp )-C(sp ) bond formation at a tertiary carbenium ion that is generated by alkene protonation.

Photochemical Alkene Isomerization for the Synthesis of Polysubstituted Furans and Pyrroles under Neutral Conditions.

A photochemical approach to polysubstituted heterocycles using UV-induced alkene isomerization is described. The method allows for the synthesis of disubstituted furans and pyrroles under mild and neutral conditions and also provides access to a class of trisubstituted furans pertinent to natural-product synthesis. The method has broad functional-group tolerance and many richly decorated heterocycles have been prepared incorporating functional groups that are unstable under Brønsted and Lewis acidic conditions.

Metal-Free Transfer Hydroiodination of C-C Multiple Bonds.

The design and a gram-scale synthesis of a bench-stable cyclohexa-1,4-diene-based surrogate of gaseous hydrogen iodide are described. By initiation with a moderately strong Brønsted acid, hydrogen iodide is transferred from the surrogate onto C-C multiple bonds such as alkynes and allenes without the involvement of free hydrogen iodide. The surrogate fragments into toluene and ethylene, easy-to-remove volatile waste.

Regioselective Transfer Hydrodeuteration of Alkenes with a Hydrogen Deuteride Surrogate Using B(CF) Catalysis.

A regioselective hydrodeuteration of alkenes using monodeuterated cyclohexa-1,4-dienes as surrogates for hydrogen deuteride (HD) gas is reported. The metal-free process proceeds under B(CF) catalysis presumably by deuteride abstraction to form borodeuteride [DB(CF)] and highly Brønsted-acidic Wheland intermediates. Low catalyst loadings (2.

Asymmetric Total Synthesis of (-)-(3 R)-Inthomycin C.

A short (10 step) and efficient (15% overall yield) synthesis of the natural product (-)-(3 R)-inthomycin C is reported. The key steps comprise three C-C bond-forming reactions: (i) a vinylogous Mukaiyama aldol, (ii) an olefin cross-metathesis reaction, and (iii) an asymmetric Mukaiyama-Kiyooka aldol. This route is notable for its brevity and has the advantage of lacking stoichiometric tin-promoted cross-coupling reactions present in previous approaches.