Sébastien Comesse

Transfer hydrogenation (TH) offers a sustainable approach for the oxidation of poly-hydroxylated substrates without the need for protecting groups or strong oxidants.

A combined experimental and theoretical study on the iron-catalyzed oxidation of unprotected triols incorporating vicinal diols into hydroxylactones is presented using the Knölker catalyst. Focused on triols as mimics for complex polyols derived from sugars, this report rationalizes the difference in reactivity and selectivity observed between vicinal and nonvicinal primary alcohols in transfer hydrogenation. Moreover, DFT calculations performed on a model substrate allowed us to elucidate the key steps of the sequence, highlighting that the final oxidation step determines the selectivity of the whole process. Interestingly, the final product distribution was unexpectedly governed by an entropic contribution instead of electronics or steric effects.

Domino reactions are powerful tools for the straightforward synthesis of complex molecules with a particular emphasis on functionalized azacycles. We report a contribution in this field, implemented via a new thia–Michael/aldol sequence between readily accessible N-alkoxyacrylamides and α,β-unsaturated carbonyls, for access to polysubstituted δ-lactams with acceptable-to-good yields and good selectivity. This method, initially developed in a two-component approach and characterized by the mildness of its reaction conditions, was shown to be compatible with various thiophenol derivatives and to employ a simple pre-thiasilylation step in a one-pot process. This further extension to the monotype aza–Michael/thia–Michael/aldol sequence establishes a proof-of-concept that acrylamides can react as both 1,3-bis-nucleophiles and 1,4-electrophiles in a single flask operation.

Phosphorus chemistry occupies a pivotal position in contemporary organic chemistry but significant synthetic challenges still endure. In this report, a class of electrophilic phosphiranium salts, bearing fluorinated benzyl quaternizing groups, is introduced for the direct synthesis of diversely β-functionalized phosphines. We show that, in comparison with regular quaternary phosphiranium salts, these species display the sought balance of excellent stability and high electrophilic reactivity that allow the unlocking of the C-centered ring-opening reactions with different classes of weak nitrogen-, sulfur- and oxygen protic nucleophiles.

Knölker complexes have been recently used to perform the catalytic C1‐oxidation of unprotected sugars into sugar lactones. This oxidation method remained limited by the stability of the catalyst with the polyhydroxylated substrates. Our objective is now to overcome these limitations and extend this method to more challenging substrates such as disaccharides. We proposed in this paper two original designs of Knölker‐type complexes conceived to promote secondary H‐bond interactions with the OH groups of the substrates to stabilise the system and favour the transformation. In total, 8 novel pre‐catalysts were synthesised, fully characterised and applied in the anomeric oxidation of several sugar derivatives. Two of these new complexes proved to be more efficient than the Knölker complex for the oxidation of disaccharides. Moreover, a preliminary DFT study revealed the presence of H‐bonds interactions between the substrate and the oxygen atom on the ligand arm of the best complexes suggesting a beneficial role of this heteroatom on the catalytic efficiency.

The synthesis of polycyclic γ‐ and δ‐lactams bearing up to four contiguous fully controlled stereocenters is presented. For that purpose, we developed an original approach based on the use of 2,3‐epoxyamides in domino reactions by taking advantage of the nucleophilic nitrogen atom and electrophilic epoxide. In reaction with enol ethers bearing gem bis‐electrophiles on the double bond as Michael acceptors, four different reaction pathways were observed. They all started with a domino oxa‐Michael/aza‐Michael/epoxide opening sequence and depending on substrates engaged could be followed either by a lactonization or a hemiketalization/retro‐aldol cascade. Thus, four original fully‐substituted piperidine‐ or pyrrolidine‐2‐one scaffolds were selectively synthesized in good to high yields. Moreover, these polycyclic lactams were obtained in high stereo‐ and chemo‐selectively highlighting the efficiency and molecular diversity offered by this new methodology that should offer various synthetic opportunities in the future.

We herein describe a stereoselective organocatalyzed aza-Michael/Morita-Baylis-Hillman domino reaction between readily accessible acrylamides and alpha,beta-unsaturated carbonyls. This novel, PPh3-promoted atom economic one-pot process features medium to good yields and good stereoselectivity leading to variously substituted piperidin-2-ones bearing an exocyclic olefinic bond, which was shown to be an excellent anchor for further chemical diversification.

The main objective of the present work is to better delineate the positive impact of N ‐alkoxy versus N ‐alkyl moieties in domino reactions. The key role of the metallic counterion of the basic reagent via a templating effect has been established, giving an insight over the superiority of N ‐alkoxy α‐bromoacetamides compared to their N ‐alkyl analogues. The former demonstrated enhanced reactivity and efficiency, thus requiring milder conditions and leading to a wider scope of γ‐lactams in good to excellent yields ranging from 67 to 98%. Overall, this study contributes to the emerging point of view that N ‐alkoxy nitrogenated compounds are useful building blocks with powerful but still under‐developed synthetic potential, in particular in domino reactions.

An iron-catalysed transfer hydrogenation methodology has been developed to oxidise unprotected aldo-hexoses and -pentoses into sugar lactones using different acceptors.

Acrylamides are versatile building blocks that are easily obtained from readily available starting materials. During the last 20 years, these valuable substrates bearing a nucleophilic nitrogen atom and an electrophilic double bond have proven to be efficient domino partners, leading to a wide variety of complex aza-heterocycles of synthetic relevance. In this non-exhaustive review, metal-free and metal-triggered reactions followed by an annulation will be presented; these two approaches allow good modulation of the reactivity of the polyvalent acrylamides.1 Introduction2 Metal-Free Annulations2.1 Domino Reactions Triggered by a Michael Addition2.2 Domino Reactions Triggered by an Aza-Michael Addition2.3 Domino Processes Triggered by an Acylation Reaction2.4 Domino Reactions Triggered by a Baylis–Hillman Reaction2.5 Cycloadditions and Domino Reactions2.6 Miscellaneous Domino Reactions3 Metal-Triggered/Mediated Annulations3.1 Zinc-Promoted Transformations3.2 Rhodium-Catalyzed Functionalization/Annulation Cascades3.3 Cobalt-Catalyzed Functionalization/Annulation Cascades3.4 Ruthenium-Catalyzed Functionalization/Annulation Cascades3.5 Iron-Catalyzed Functionalization/Annulation Cascades3.6 Palladium-Catalyzed Functionalization/Annulation Cascades3.7 Copper-Catalyzed Transformations3.8 Transition Metals Acting in Tandem in Domino Processes4 Radical Cascade Reactions5 Conclusion