Synthesis of Five-Membered exo-Glycals from Six-Membered 2-Iodo-endo-glycals.

Five-membered exo-glycals were synthesized from six-membered 2-iodo-endo-glycals by a metal/halogen exchange/ring-opening sequence followed by a cyclization catalyzed by Ag2CO3.

Synthesis of 1,3-disubstituted bicyclo[1.1.1]pentanes by cross-coupling induced by transition metals - formation of C-C bonds.

The synthesis of 1,3-disubstituted bicyclo[1.1.1]pentanes (BCPs), by forming a C-C bond, can be achieved by cross-coupling reactions using transition metal catalysts. Two main strategies are described to access these 1,3-disubstituted BCPs, either from nucleophilic BCPs or electrophilic BCPs. Mechanisms are included where relevant.

Ni-Catalyzed Cross-Coupling of 2-Iodoglycals and 2-Iodoribals with Grignard Reagents: A Route to 2-C-Glycosides and 2'-C-Nucleosides.

The synthesis of 2-C-glycals and 2-C-ribals was achieved in good yields using a nickel-catalyzed cross-coupling between 2-iodoglycals and 2-iodoribal respectively and Grignard reagents. The prepared 2-C-glycals and ribals were then transformed into 2-C-2-deoxyglycosides, 2-C-diglycosides and 2'-C-2'-deoxynucleosides. The developed method was applied to the synthesis of a 2-chloroadenine 2'-deoxyribonucleoside - a structural analogue of cladribine (Mavenclad®, Leustatin®) and clofarabine (Clolar®, Evoltra®), two compounds used in the treatment of relapsing-remitting multiple sclerosis and hairy cell leukemia.

Incorporation of a cyclobutyl substituent in molecules by transition metal-catalyzed cross-coupling reactions.

In this review, the incorporation of a cyclobutyl substituent in molecules, by transition metal-catalyzed cross-coupling, is described by only considering the formation of C-C bonds. Three main strategies are used to introduce a cyclobutyl substituent in molecules by involving either electrophilic or nucleophilic cyclobutane derivatives.

Asymmetric desymmetrization of alkene-, alkyne- and allene-tethered cyclohexadienones using transition metal catalysis.

This review is covering the recent development of catalytic asymmetric domino reactions for the desymmetrization of alkene-, alkyne- and allene-tethered cyclohexadienones using transition metals and chiral ligands. This desymmetrization has emerged as an important strategy for the rapid construction of complex molecular skeletons, such as fused-polycycles or spirocyclic compounds in controlling multiple stereogenic centers.

Cobalt-Catalyzed Cross-Couplings between Alkyl Halides and Grignard Reagents.

Metal-catalyzed cross-couplings have emerged as essential tools for the construction of C-C bonds. The identification of efficient catalytic systems as well as large substrate scope made these cross-couplings key reactions to access valuable molecules ranging from materials, agrochemicals to active pharmaceutical ingredients. They have been increasingly integrated in retrosynthetic plans, allowing shorter and original route development. Palladium-catalyzed cross-couplings still largely rule the field, with the most popular reactions in industrial processes being the Suzuki and Sonogashira couplings. However, the extensive use of palladium complexes raises several problems such as limited resources, high cost, environmental impact, and frequent need for sophisticated ligands. As a consequence, the use of nonprecious and cheap metal catalysts has appeared as a new horizon in cross-coupling development. Over the last three decades, a growing interest has thus been devoted to Fe-, Co-, Cu-, or Ni-catalyzed cross-couplings. Their natural abundance makes them cost-effective, allowing the conception of more sustainable and less expensive chemical processes, especially for large-scale production of active molecules. In addition to these economical and environmental considerations, the 3d metal catalysts also exhibit complementary reactivity with palladium complexes, facilitating the use of alkyl halide partners due to the decrease of ß-elimination side reactions. In particular, by using cobalt catalysts, numerous cross-couplings between alkyl halides and organometallics have been described. However, cobalt catalysis still stays far behind palladium catalysis in terms of popularity and applications, and the expansion of the substrate scope as well as the development of simple and robust catalytic systems remains an important challenge.In 2012, our group entered the cobalt catalysis field by developing a cobalt-catalyzed cross-coupling between C-bromo glycosides and Grignard reagents. The generality of the coupling allowed the preparation of a range of valuable C-aryl and C-vinyl glycoside building blocks. We then focused on the functionalization of saturated N-heterocycles, and a variety of halo-azetidines, -pyrrolidines, and -piperidines were successfully reacted with aryl and alkenyl Grignard reagents under cobalt catalysis. With the objective of preparing valuable α-aryl amides, a cobalt-catalyzed cross-coupling applied to α-bromo amides was studied and then extended to α-bromo lactams. Recently, we also reported an efficient and general cross-coupling involving cyclopropyl- and cyclobutyl-magnesium bromides. This method allows the alkylation of functionalized small strained rings by a range of primary and secondary alkyl halides.

Enantioselective Cross-couplings between Halide Derivatives and Organometallics by Using Iron and Cobalt Catalysts: Formation of C-C Bonds.

This review highlights the recent achievements of iron- and cobalt-catalyzed enantioselective cross-couplings of halide derivatives with organometallic reagents for the construction of C-C bonds. Synthetic applications of enantioselective cross-couplings to natural products and biologically active compounds are also covered showing the power of these cross-couplings in organic synthesis.

Synthesis of Azocanes from Piperidines via an Azetidinium Intermediate.

α-Trifluoromethyl azocanes are accessible from 2-(trifluoropropan-2-ol) piperidines by metal-free ring-expansion involving a bicyclic azetidinium intermediate. The opening of the azetidinium intermediate was achieved by various nucleophiles (amines, alcoholates, carboxylates, phosphonates, halides and pseudo-halides) with an excellent regio- diastereo- and enantioselectivity and in good yields. The relative configuration of the piperidines and azocanes were assigned and the deprotected azocanes offer opportunities for further derivatization.

Cobalt-Catalyzed 1,4-Aryl Migration/Desulfonylation Cascade: Synthesis of α-Aryl Amides.

A cobalt-catalyzed 1,4-aryl migration/disulfonylation cascade applied to α-bromo N-sulfonyl amides was developed. The reaction was highly chemoselective, allowing the preparation of α-aryl amides possessing a variety of functional groups. The method was used as the key step to synthesize an alkaloid, (±)-deoxyeseroline. Mechanistic investigations suggest a radical process.

Palladium-Catalyzed Regioselective Allylic Oxidation of Amorphadiene, a Precursor of Artemisinin.

A regioselective Pd-catalyzed allylic oxidation of amorphadiene, a key precursor to the antimalarial drug artemisinin, is described. Amorphadiene can be obtained in high yields by fermentation, but it is currently treated as a waste in the industrial semisynthetic artemisinin process. The catalytic step described here is a substitute for the P450 enzymes involved in the artemisinin biosynthesis and opens up new opportunities to supplement a critical step in the current semisynthetic route and increase the potential of the fermentation process.

Ring-opening of azetidiniums by nucleophiles. Synthesis of polysubstituted linear amines.

This microreview focuses on the nucleophilic ring-opening of azetidiniums presenting various substitution patterns at C2, C3, and C4. In most cases, the nucleophilic ring-opening occurred in a stereoselective and regioselective fashion producing functionalized linear amines. Experimental selectivities associated with Density Functional Theory (DFT) calculations have allowed a better understanding of the parameters governing the regioselectivities.

Cobalt-Catalyzed α-Arylation of Substituted α-Bromo α-Fluoro ß-Lactams with Diaryl Zinc Reagents: Generalization to Functionalized Bromo Derivatives.

A cobalt-catalyzed cross-coupling of α-bromo α-fluoro ß-lactams with diarylzinc or diallylzinc reagents is herein disclosed. The protocol proved to be general, chemoselective and operationally simple allowing the C4 functionalization of ß-lactams. The substrate scope was expanded to α-bromo lactams and amides, α-bromo lactones and esters as well as N- and O-containing heterocycles.

Chemo- and Diastereoselective Hydrosilylation of Amorphadiene toward the Synthesis of Artemisinin.

A formal synthesis of artemisinin starting from amorphadiene is described. This new route relies on the development of a catalytic chemo- and diastereoselective hydrosilylation. The practicability of this method is demonstrated by converting amorphadiene to dihydroartemisinic aldehyde using a one-pot hydrosilylation/oxidation sequence, minimizing the number of purifications and maximizing the productivity through a practical one-pot procedure. In addition, this approach can be coupled with a crystallization-induced diastereoselective transformation (CIDT) to enhance the optical purity of the key target intermediate, dihydroartemisinic aldehyde.

Asymmetric Transfer Hydrogenation of gem-Difluorocyclopropenyl Esters: Access to Enantioenriched gem-Difluorocyclopropanes.

Catalytic enantioselective access to disubstituted functionalized gem-difluorocyclopropanes, which are emerging fluorinated motifs of interest in medicinal chemistry, was achieved through asymmetric transfer hydrogenation of gem-difluorocyclopropenyl esters, catalyzed by a Noyori-Ikariya (p-cymene)-ruthenium(II) complex, with (N-tosyl-1,2-diphenylethylenediamine) as the chiral ligand and isopropanol as the hydrogen donor. The resulting cis-gem-difluorocyclopropyl esters were obtained with moderate to high enantioselectivity (ee=66-99 %), and post-functionalization reactions enable access to valuable building blocks incorporating a cis- or trans-gem-difluorocyclopropyl motif.

2nd PSL Chemical Biology Symposium (2019): At the Crossroads of Chemistry and Biology.

Chemical Biology is the science of designing chemical tools to dissect and manipulate biology at different scales. It provides the fertile ground from which to address important problems of our society, such as human health and environment.

Assembly of the Entire Carbon Backbone of a Stereoisomer of the Antitumor Marine Natural Product Hemicalide.

A strategy for the assembly of the entire carbon backbone of a stereoisomer of the antitumor marine natural product hemicalide has been investigated. The devised convergent approach relies on Horner-Wadsworth-Emmons and Julia-Kocienski olefination reactions for the construction of the C6=C7 and C34=C35 double bonds, respectively, an aldol reaction to create the C27-C28 bond, and a Suzuki-Miyaura cross-coupling as the endgame to form the C15-C16 bond.

Synthesis of amorpha-4,11-diene from dihydroartemisinic acid.

Amorphadiene is a natural product involved in the biosynthesis of the antimalarial drug artemisinin. A convenient four-step synthesis of amorphadiene, starting from commercially available dihydroartemisinic acid, is reported. The targeted molecule is isolated with an overall yield of 85% on a multi-gram scale in four steps with only one chromatography.

Effects of Asparagopsis taxiformis metabolites on the feeding behaviour of post-larval Acanthurus triostegus.

Our study highlights the effect of the macroalgae Asparagopsis taxiformis on the feeding behaviour of the tropical surgeonfish Acanthurus triostegus. The presence of A. taxiformis chemical cues reduced A. triostegus feeding, suggesting that the presence of this algae could affect not only the survival of fish in the post-larval stage, but also alter the grazing pressure on coral reefs.

Sigmatropic rearrangements of cyclopropenylcarbinol derivatives. Access to diversely substituted alkylidenecyclopropanes.

Cyclopropenes constitute useful precursors of other classes of compounds incorporating a three-membered ring. Although the transformation of substituted cyclopropenes into alkylidenecyclopropanes can be accomplished through different strategies, this review is focusing specifically on the use of [2,3]- and [3,3]-sigmatropic rearrangements involving cyclopropenylcarbinol derivatives as substrates. These sigmatropic rearrangements, which have been developed in recent years, allow a remarkably efficient and stereoselective access to a wide variety of heterosubstituted and/or functionalized alkylidenecyclopropanes which would not be readily accessible by other strategies. The different [2,3]- and [3,3]-sigmatropic rearrangements of cyclopropenylcarbinol derivatives disclosed to date, as well as the analysis of their substrate scope and some applications of the products arising from those reactions, are presented in this review.

Highly Enantioselective, Base-Free Synthesis of α-Quaternary Succinimides through Catalytic Asymmetric Allylic Alkylation.

The synthesis of diversely substituted five-membered ring succinimide derivatives is reported featuring a direct, base-free, palladium-catalyzed asymmetric allylic alkylation. The method allows a straightforward access to the desired heterocyclic scaffold bearing an all-carbon α-quaternary stereogenic center in high yields and good to excellent enantioselectivities. To further demonstrate the synthetic utility of the method, the allylated products were further converted to various versatile chiral building blocks, including a chiral pyrrolidine and a spirocyclic derivative, using selective transformations.