Catalytic Phosphorylation of Tyrosine via a Radical Arbuzov Reaction.

Synthetic protein/peptide modification is a powerful strategy for the development of new therapeutics and tools for chemical biology. Accordingly, the development of a synthetic variant of biological tyrosine phosphorylation, a cornerstone of the post-translational modification landscape, could find widespread application in the study of this fundamental biochemical signal. This work describes the development of a mechanistically novel, redox-neutral, photocatalytic tyrosine phosphorylation reaction via a radical Arbuzov-type mechanism.

Enantioselective Total Synthesis of (+)-Incargranine A Enabled by Bifunctional Iminophosphorane and Iridium Catalysis.

Herein we report the first enantioselective total synthesis of (+)-incargranine A, in nine steps. The total synthesis was enabled by an enantioselective intramolecular organocatalysed desymmetrising Michael addition of a malonamate ester to a linked dienone substrate that established pivotal stereocentres with excellent enantio- and complete diastereoselectivity. Furthermore, a key hemiaminal intermediate was accessed by developing an iridium-catalysed reductive cyclisation, and the scope of this transformation was explored to produce a range of bicyclic hemiaminal motifs.

1,2-Redox Transpositions of Tertiary Amides.

Reactions capable of transposing the oxidation levels of adjacent carbon atoms enable rapid and fundamental alteration of a molecule's reactivity. Herein, we report the 1,2-transposition of the carbon atom oxidation level in cyclic and acyclic tertiary amides, resulting in the one-pot synthesis of 1,2- and 1,3-oxygenated tertiary amines. This oxidation level transfer was facilitated by the careful orchestration of an iridium-catalyzed reduction with the functionalization of transiently formed enamine intermediates.

Bifunctional Iminophosphorane-Catalyzed Enantioselective Nitroalkane Addition to Unactivated α,β-Unsaturated Esters.

Herein we describe the enantioselective intermolecular conjugate addition of nitroalkanes to unactivated α,β-unsaturated esters, catalyzed by a bifunctional iminophosphorane (BIMP) superbase. The transformation provides the most direct access to pharmaceutically relevant enantioenriched γ-nitroesters, utilizing feedstock chemicals, with unprecedented selectivity. The methodology exhibits a broad substrate scope, including β-(fluoro)alkyl, aryl and heteroaryl substituted electrophiles, and was successfully applied on a gram scale with reduced catalyst loading, and, additionally, catalyst recovery was carried out.

Branching out: redox strategies towards the synthesis of acyclic α-tertiary ethers.

Acyclic α-tertiary ethers represent a highly prevalent functionality, common to high-value bioactive molecules, such as pharmaceuticals and natural products, and feature as crucial synthetic handles in their construction. As such their synthesis has become an ever-more important goal in synthetic chemistry as the drawbacks of traditional strong base- and acid-mediated etherifications have become more limiting. In recent years, the generation of highly reactive intermediates redox approaches has facilitated the synthesis of highly sterically-encumbered ethers and accordingly these strategies have been widely applied in α-tertiary ether synthesis.

A New Organocatalytic Desymmetrization Reaction Enables the Enantioselective Total Synthesis of Madangamine E.

The enantioselective total synthesis of madangamine E has been completed in 30 steps, enabled by a new catalytic and highly enantioselective desymmetrizing intramolecular Michael addition reaction of a prochiral ketone to a tethered -disubstituted nitroolefin. This key carbon-carbon bond forming reaction efficiently constructed a chiral bicyclic core in near-perfect enantio- and diastereo-selectivity, concurrently established three stereogenic centers, including a quaternary carbon, and proved highly scalable. Furthermore, the pathway and origins of enantioselectivity in this catalytic cyclization were probed using density functional theory (DFT) calculations, which revealed the crucial substrate/catalyst interactions in the enantio-determining step.

A modular and divergent approach to spirocyclic pyrrolidines.

An efficient three-step sequence to afford a valuable class of spirocyclic pyrrolidines is reported. A reductive cleavage/Horner-Wadsworth-Emmons cascade facilitates the spirocyclisation of a range of isoxazolines bearing a distal β-ketophosphonate. The spirocyclisation precursors are elaborated in a facile and modular fashion, a [3 + 2]-cycloaddition followed by the condensation of a phosphonate ester, introducing multiple points of divergence.

Installing the "magic methyl"- C-H methylation in synthesis.

The selective and efficient C-H methylation of sp and sp carbon centres has become a powerful transformation in the synthetic toolbox. Due to the potential for profound changes to physicochemical properties attributed to the installation of a "Magic Methyl" group at a strategic site in a lead compound, such techniques have become highly desirable in modern drug discovery and synthesis programmes. This review will cover the diverse techniques that have been employed to enable the selective installation of the C-Me bond in a wide range of chemical structures, from simple building blocks to complex drug-like architectures.