Michael Addition-Initiated Sequential Reactions from 1,3-Dicarbonyls for the Synthesis of Polycyclic Heterocycles

International audienceThis review aims to highlight the most significant recent developments on synthetic strategies involving consecutive, domino and multicomponent reactions featuring a Michael addition-initiating step for the synthesis of polycyclic heterocycles from 1,3-dicarbonyls. These original sequences constitute more efficient and eco-compatible alternatives to known synthetic approaches to heterocyclic compounds allowing for an even faster and highly desirable generation of molecular diversity and complexity

Activation of 1,2- and 1,3-Ketoamides with Thiourea Organocatalyst for the Enantioselective Domino Synthesis of Fuctionalized Cyclohexanes

International audienceSeveral reactive sites of 1,2- and 1,3-ketoamides were successively exploited in two complementary domino transformations for the synthesis of polysubstituted monocyclic or bridged bicyclic cyclohexanes, with the creation of up to six stereogenic centers. In both cases, a chiral bifunctional thiourea organocatalyst allowed efficient control of chirality in the final carbocycle

Benzoin and aza-benzoin

The benzoin condensation consists of the addition of an acyl anion equivalent to a carbonyl derivative to afford an α-hydroxyketone. When the electrophilic partner is replaced by an imine, the analogous aza-benzoin reaction results in the formation of an α-aminoketone. These processes require an inversion of polarity (umpolung) of an aldehyde, which can be achieved following three main strategies: (1) the multistep elaboration of stoichiometric acyl anion equivalents; (2) the catalysis by cyanide ions; and (3) the organocatalysis by N-heterocyclic carbenes (NHCs). Advantages and drawbacks of each method are discussed, especially in terms of chemo- and stereoselectivities. Recently developed alternative enantioselective catalytic approaches along with miscellaneous other methods are also presented

Vers la synthèse de l aglycone des landomycines

Les landomycines sont des substances naturelles d origine bactérienne isolées pour la première fois en 1990 à partir des fermentations de l actinobactérie Steptomyces cyanogenus. Elles se composent d un aglycone tétracyclique partiellement aromatique, nommé landomycinone, et d une chaîne polysaccharidique. Tous les membres de la famille y compris l aglycone, ont montré une forte activité antitumorale sur de nombreuses lignées cellulaires, notamment sur des lignées multirésistantes. Nous avons entrepris de mettre au point une synthèse efficace de la landomycinone. Le principal défi synthétique est la mise en place du cycle B, partiellement insaturé et porteur d une fonction alcool particulièrement fragile. Trois stratégies ont été étudiées. La première se base sur une réaction originale de formation du cycle B par domino Michael-aldolisation , qui a été menée avec succès. Toutefois, la construction du reste de la molécule, notamment via une réaction de Diels-Alder, n a pour l instant pas fonctionné .La deuxième rétrosynthèse prévoyait deux étapes clés : la construction de la fonction alcool par chlorovinylation initiée par le Cr(II), puis la fermeture du cycle B par métathèse cyclisante. De faibles rendements et des problèmes de reproductibilité nous ont conduits à l abandonner. La dernière approche a permis la construction de la structure tétracyclique de la landomycinone au moyen de deux réactions-clés métallocatalysées : une cyclotrimérisation d alcynes intramoléculaire et une métathèse cyclisante d alcènes. Un dernier aménagement fonctionnel (l oxydation du cycle C en quinone) reste à mettre au point pour terminer la synthèse.Landomycins are a class of natural products first isolated in 1990 from fermentation of actinobacteria Streptomyces cyanogenus. They consist in a partially aromatic fused tretracyclic aglycone, named landomycinone, and a glycosidic side chain. All members of the family, including the aglycone, exhibited a high antitumoral activity on a large number of cell lines, especially on multidrug resistant ones.We undertook the elaboration of an efficient synthesis of landomycinone. The main synthetic challenge is the construction of partially unsaturated cycle B, wich bears a very fragile alcohol functionality. Three distinct strategies have been studied. The first one relies on the closure of cycle B using an original domino Michael-aldolisation reaction, which has been efficiently performed. However, the construction of the rest of the molecule, notably via a Diels-alder reaction, is for the time not working. Two key-steps were planed within the second retrosynthesis : the construction of secondary alcohol by a Cr (II)-mediated chlorovinylation and then the construction of cycle B by ring-closing metathesis. Low yields and problems of reproducibility led us to give up this strategy. The last approach enabled the construction of the tretacyclic structure of landomycinone by the means of two metal-catalyzed key-steps : an intramolecular alkyne cyclomerisation and a ring-closure metathesis. A final functional transformation (conversion of cycle C into a quinone) is needed to complete the synthesis.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

L'éco-conception, un défi pour la recherche fondamentale

International audienceThe book chapter focus on the economies that could be done in synthesis to decrease at the same type costs, waste and energies

L'éco-conception, un défi pour la recherche fondamentale

International audienceThe book chapter focus on the economies that could be done in synthesis to decrease at the same type costs, waste and energies

N-Heterocyclic Carbene (NHC)-Catalyzed Intermolecular Hydroacylation of Cyclopropenes

International audienceWe report the first intermolecular NHC-catalyzed hydroacylation of electron-neutral olefins. Treatment of aromatic aldehydes with cyclopropenes under mild conditions affords valuable acylcyclopropanes in moderate to high yields with an excellent level of diastereocontrol. Preliminary mechanistic studies suggest that product formation occurs via a concerted syn hydroacylation pathway

Enantioselective Organocatalyzed Domino Synthesis of Six-Membered Carbocycles

International audiencePolysubstituted chiral cyclohexanes and cyclohexenes are important building blocks in organic synthesis. From historical and pioneering reports to the most recent accounts, this review focuses on domino enantioselective organocatalytic methodologies that have allowed the control of the relative and absolute configurations of up to six stereogenic centers in the construction of these versatile molecular architectures

Organocatalytic Enantioselective Construction of Polyaromatic Architectures

International audienceAromatics in 3D. Organocatalysis is now reaching beyond the control of stereogenic centers and opens new possibilities for the construction of complex polyaromatic structures with either helical or axial chirality

Organocatalytic Enantioselective Synthesis of Tetrahydropyridines

International audienceTetrahydropyridines are important heterocycles present in many molecules of natural and non‐natural origins that exhibit a wide array of biological activities. With several sp3‐hybridized carbon atoms in their structure, they often include one or several stereogenic centers, whose control represents a great synthetic challenge. For the past two decades, enantioselective organocatalysis has developed as a very powerful strategy to perform the synthesis of enantioenriched compounds, including heterocycles. In this Microreview, we wish to provide the readers with a general overview about the organocatalytic strategies that have been used to achieve the preparation of diversified families of tetrahydropyridines, thereby providing elements of reflection for further developments