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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. Once installed, the hemiaminal motif was used to initiate a biomimetic cascade to access the natural product directly in a single step., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

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. A novel 1,2-carbonyl transposition is described, and the breadth of this redox transposition strategy has been further explored by the development of aminoalcohol and enaminone syntheses. The diverse β-functionalized amine products were shown to be multifaceted and valuable synthetic intermediates, accessing challenging biologically relevant motifs.

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. The formal synthesis of a range of drug molecules, and an enantioselective synthesis of (S)-rolipram were achieved. Additionally, computational studies revealed key reaction intermediates and transition state structures, and provided rationale for high enantioselectivities, in good agreement with experimental results., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

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 via redox approaches has facilitated the synthesis of highly sterically-encumbered ethers and accordingly these strategies have been widely applied in α-tertiary ether synthesis. This review summarises and appraises the state-of-the-art in the application of redox strategies enabling acyclic α-tertiary ether synthesis.

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 β,β' -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. Following construction of the bicyclic core, the total synthesis of madangamine E could be completed, with key steps including a mild one-pot oxidative lactamization of an amino alcohol, a two-step Z -selective olefination of a sterically hindered ketone, and ring-closing metatheses to install the two macrocyclic rings.