Total Synthesis of Njaoamine C by Concurrent Macrocycle Formation.

In conceptual terms, the first total synthesis of the cytotoxic marine natural product njaoamine C differs from all known approaches toward related alkaloids of the manzamine superfamily in that both macrocyclic rings enveloping the diazatricyclic core are concomitantly formed; this goal was reached by double ring closing alkyne metathesis (dRCAM). The success of this maneuver does not merely reflect a favorable preorientation of the four alkyne chains that need to be concatenated in the proper pairwise manner but is also the outcome of dynamic covalent chemistry involving error correction by the chosen "canopy" molybdenum alkylidyne catalyst. The end game downstream of dRCAM capitalizes on the striking chemoselectivity of palladium-catalyzed hydrostannation, which selects for (hetero)arylalkynes even in the presence of sterically much more accessible dialkylalkynes or alkenes; for this preference, the method complements the classical repertoire of hydrometalation and semireduction reactions.

Strategies toward the Difunctionalizations of Enamide Derivatives for Synthesizing α,ß-Substituted Amines.

Enamide and enecarbamate derivatives containing a nucleophilic center at the ß-position from their nitrogen atom as well as a latent electrophilic site at their α-position are interesting motifs in organic chemistry. This dual reactivity─analogous that of the enamines─enables difunctionalization and increased structural complexity. Furthermore, an electron-withdrawing group on nitrogen drastically increases their stability. In that respect, enamides and enecarbamates are excellent partners for multicomponent transformations, and our research primarily focuses on these compounds in particular.Difunctionalization generally occurs through the nucleophilic addition of the enecarbamate on an electrophile to form iminium, which can subsequently react with a nucleophilic species. Although potent, such an approach is highly challenging due to the low stability of the intermediate iminium, leading to undesired hydrolysis or oligomerization. Epimerization, competitivity, and compatibility issues between the reaction partners are additional hindrances to developing these methodologies. To overcome these limitations, we described many complementary strategies.To control the enantioselectivity of these transformations, chiral phosphoric acids were found to be particularly well-suited to activate multiple reactants due to the formation of a hydrogen bonds network, allowing for an organized transition state in a chiral pocket. Interestingly, when deprotonated as phosphates, they can also play the role of ligands for Lewis acidic metals.To avoid iminium oligomerization, we successfully used stabilized α-arylated enamides. However, this approach was restricted to a simple nucleophilic addition at the ß-position. To achieve the difunctionalizations of α-unsubstituted derivatives, we explored reversibly linked nucleophile and electrophile to address their compatibility problem. Alternatively, we devised a sequential methodology for resolving the stability issue of the N-acyl iminium based on its intermediate trapping using a temporary nucleophile (alcohol or thiol). Interestingly, the trapping agent could further be displaced by the desired final α-substituent under Lewis acidic or photocatalytic activation. This led us to design new chiral and bifunctional phosphoric acid catalysts bearing chromophores to merge asymmetric organocatalysis and photochemistry.These photocatalysis studies incited us to focus on radical processes to manage original functionalizations that would not be feasible otherwise. ß-Alkylation and ß-trifluoromethylation of enecarbamates via visible-light-promoted atom transfer radical additions were successfully performed. As ß-allylations remained unattainable with the precedent methods, we eventually turned our attention to cerium(IV)-mediated oxidative single electron transfers. It allowed for singly occupied molecular orbital activation of these substrates to elicit their umpolung reactivity.Thus, the functionalization of enecarbamate derivatives appears as a valid synthetic strategy for obtaining important building blocks for agrochemical, pharmaceutical, and cosmetic industries, including diamines, haloamines, aminotryptamines, and less accessible trifluoromethylated or allylic compounds.

Decatungstate-Photocatalyzed Dearomative Hydroacylation of Indoles: Direct Synthesis of 2-Acylindolines.

We report herein a convenient and scalable dearomative hydroacylation reaction of indoles. Employing readily available aldehydes as the acyl source and TBADT as an inexpensive direct HAT photocatalyst, a variety of indoles derivatives were converted into synthetically interesting 2-acylindolines in good to excellent yields as well as great diastereoselectivity under mild conditions. An asymmetric version of the reaction was successfully developed and an experimental mechanistic investigation was carried out in order to gain further insights on the assumed reaction pathway.

Enantioselective and Diastereodivergent Synthesis of Spiroindolenines via Chiral Phosphoric Acid-Catalyzed Cycloaddition.

A diastereodivergent and enantioselective synthesis of chiral spirocyclohexyl-indolenines with four contiguous stereogenic centers is achieved by a chiral phosphoric acid-catalyzed cycloaddition of 2-susbtituted 3-indolylmethanols with 1,3-dienecarbamates. Modular access to two different diastereoisomers with high enantioselectivities was obtained by careful choice of reaction conditions. Their functional group manipulation provides an efficient access to enantioenriched spirocyclohexyl-indolines and -oxindoles. The origins of this stereocontrol have been identified using DFT calculations, which reveal an unexpected mechanism compared to our previous work dealing with enecarbamates.

Enamides and dienamides in phosphoric acid-catalysed enantioselective cycloadditions for the synthesis of chiral amines.

Chiral substituted cyclic amines are ubiquitous among biologically active molecules and natural products and are valuable intermediates in organic synthesis. Stable and easy to synthesize enamides and dienamides are versatile building blocks for the preparation of chiral amines. The exceptional synergy displayed between these synthetic synthons and chiral phosphoric acid catalysts has successfully been harnessed to develop straightforward formal cycloadditions exhibiting notably high enantiocontrol. This feature article showcases the remarkable versatility of these cycloadditions to access chiral cyclic amines with different ring sizes ranging from 5- to 7-membered rings, with an emphasis on biologically active natural products.

Enantioselective Redox-Divergent Chiral Phosphoric Acid Catalyzed Quinone Diels-Alder Reactions.

An efficient enantioselective construction of tetrahydronaphthalene-1,4-diones as well as dihydronaphthalene-1,4-diols by a chiral phosphoric acid catalyzed quinone Diels-Alder reaction with dienecarbamates is reported. The nature of the protecting group on the diene is key to the success of achieving high enantioselectivity. The divergent "redox" selectivity is controlled by using an adequate amount of quinones. Reversible redox switching without erosion of enantioselectivity was possible from individual redox isomers.

Catalyst-free cycloaddition of 1,3-diene-1-carbamates with azodicarboxylates: A rapid click reaction.

Novel click reactions are of continued interest in many scientific research areas and applications. Herein, we report a novel practical, catalyst-free, azo-Diels-Alder reaction between dienecarbamates and azodicarboxylates exhibiting a remarkable functional group tolerance. The availability of starting materials, mild reaction conditions, chemoselectivity and scalability make this cycloaddition a viable supplement to the other reactions in "click" chemistry.