Following notable cases of remarkable potency increases in methylated analogues of lead compounds, this review documents the state-of-the-art in C–H methylation technology.
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...
The synthesis of α-tertiary ethers has traditionally presented a major challenge; however, contemporary redox chemistry has led to development of a plethora of powerful new approaches.
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.
Reactions capable of transposing the oxidation levels of adjacent carbon atoms in organic molecules enable rapid and fundamental alteration of a molecule’s reactivity. Herein, we report the 1,2-transposition of 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. Remarkably, a novel 1,2-carbonyl transposition was observed when the commercial oxidant mCPBA was selected as the coupling partner. The scope of this transformation and the breadth of this redox transposition strategy has been explored and the diverse β-functionalized amine products were shown to be multi-faceted and valuable synthetic intermediates, accessing challenging biologically-relevant motifs.
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 stereocenter, and proved highly scalable. Furthermore, the pathway and origins of enantioselectivity in this catalytic cyclisation 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 oxidation-lactamisation, a two-step Z-selective olefination of a sterically hindered ketone, and ring-closing metatheses to install the two macrocyclic rings.
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.
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.
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