Access to 12-Membered Cyclic ,-Diarylheptanoids: Total Synthesis of Actinidione via Isomyricanone.

We describe herein the first access to 12-membered cyclic[7,0],-diarylheptanoids. The key features of the synthesis include both a Suzuki-Miyaura coupling and a ring closing metathesis. Actinidione, a promising natural product, along with a bioactive tetracyclic derivative were obtained in 14 steps for the first time from cheap commercially available substrates with an overall yield of 18-21%.

Towards Atropoenantiopure N-C Axially Chiral Compounds Stereoselective C-N Bond Formation.

N-C axial chirality, although disregarded for decades, is an interesting type of chirality with appealing applications in medicinal chemistry and agrochemistry. However, atroposelective synthesis of optically pure compounds is extremely challenging and only a limited number of synthetic routes have been designed. In particular, asymmetric -arylation reactions allowing atroposelective N-C bond forming events remain scarce, although great advances have been achieved recently.

New synthesized polyoxygenated diarylheptanoids suppress lipopolysaccharide-induced neuroinflammation.

In neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease, Parkinson's disease and multiple sclerosis, neuroinflammation induced by the microglial activation plays a crucial role. In effort to develop effective anti-neuroinflammatory compounds, different new linear polyoxygenated diarylheptanoids were synthesized. In LPS-triggered BV-2 microglial cells their ability to reduce the concentration of IL-6 and TNF-α pro-inflammatory cytokines was evaluated.

The Affinity of Some Lewis Bases for Hexafluoroisopropanol as a Reference Lewis Acid: An ITC/DFT Study.

To figure out the possible role of 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) as well as to provide reference thermochemical data in solution, the formation of Lewis acid-base complexes between HFIP (Lewis acid) and a series of 8 different Lewis bases (3 sulfoxides, 3 Nsp pyridine derivatives, 1 aromatic amine, 1 cyclic aliphatic ether) was examined by isothermal titration calorimetry (ITC) experiments and static density functional theory augmented with Dispersion (DFT-D) calculations. Measured ITC association enthalpy values (ΔH ) lie between -9.3 and -14 kcal mol .

Enantioselective Synthesis of N-C Axially Chiral Compounds by Cu-Catalyzed Atroposelective Aryl Amination.

N-C axially chiral compounds have emerged recently as appealing motifs for drug design. However, the enantioselective synthesis of such molecules is still poorly developed and surprisingly no metal-catalyzed atroposelective N-arylations have been described. Herein, we disclose an unprecedented Cu-catalyzed atroposelective N-C coupling that proceeds at room temperature.

Access to the Enantiopure Axially Chiral Cyclophane Isoplagiochin D through Atropo-diastereoselective Heck Coupling.

Macrocyclization is typically the key step in the syntheses of cyclophane-type natural products. Considering cyclophanes with axially chiral biaryl moieties, the control of atroposelectivity is essential with biological activity and is synthetically challenging. We report an atroposelective approach involving Heck cyclization, which for the first time enables the total synthesis of an enantiopure macrocyclic bis(bibenzyl), namely isoplagiochin D.

Two Stereoinduction Events in One C-H Activation Step: A Route towards Terphenyl Ligands with Two Atropisomeric Axes.

Herein we disclose the synthesis of original chiral scaffolds-ortho-orientated terphenyls presenting two atropisomeric Ar-Ar axes. These unusual structures were built up by using the C-H activation approach, and remarkably, both chiral axes were controlled with excellent stereoselectivity in a single transformation. During the reaction, not only does atroposelective functionalization of a biaryl precursor occur to establish one stereogenic axis, but an unprecedented atropo-stereoselective C-H arylation also takes place to generate the second stereogenic element.

Increased Potency and Selectivity for Group III Metabotropic Glutamate Receptor Agonists Binding at Dual sites.

A group III metabotropic glutamate (mGlu) receptor agonist (PCEP) was identified by virtual HTS. This orthosteric ligand is composed by an l-AP4-derived fragment that mimics glutamate and a chain that binds into a neighboring pocket, offering possibilities to improve affinity and selectivity. Herein we describe a series of derivatives where the distal chain is replaced by an aromatic or heteroaromatic group.

Stereoselective Sulfinyl Aniline-Promoted Pd-Catalyzed C-H Arylation and Acetoxylation of Aliphatic Amides.

Stereoselective functionalization of aliphatic C-H bonds presents a great challenge. Following this target, we disclose herein an original strategy towards direct arylation of aliphatic chains at ß-methylene position based on a use of amide-sulfoxide bicoordinating directing group. Although moderate to high chiral induction (up to 9:1 d.

Enantiopure Sulfinyl Aniline as a Removable and Recyclable Chiral Auxiliary for Asymmetric C(sp )-H Bond Activation.

An original and recyclable chiral bidentate aniline-sulfoxide-based directing group has been developed. This auxiliary allows challenging stereoselective Pd-catalyzed direct functionalization of small cycloalkanes through C-aryl and C-alkyl bond formation. Although moderate diastereoselectivities are observed, both optically pure enantiomers of the highly functionalized products can be obtained separately by simple silica gel chromatography and cleavage of the chiral auxiliary.

1,1,1,3,3,3-Hexafluoroisopropanol as a Remarkable Medium for Atroposelective Sulfoxide-Directed Fujiwara-Moritani Reaction with Acrylates and Styrenes.

Axially chiral biaryls are ubiquitous structural motifs of biologically active molecules and privileged ligands for asymmetric catalysis. Their properties are due to their configurationally stable axis, and therefore, the control of their absolute configuration is essential. Efficient access to atropo-enantioenriched biaryl moieties through asymmetric direct C-H activation, by using enantiopure sulfoxide as both the directing group (DG) and chiral auxiliary, is reported.

Determination of the absolute configuration of phosphinic analogues of glutamate.

A series of phosphinic glutamate derivatives (e.g.LSP1-2111) have been proven to be potent agonists of metabotropic glutamate (mGlu) receptors and shown promising in vivo activity.

Synthesis of axially chiral biaryls through sulfoxide-directed asymmetric mild C-H activation and dynamic kinetic resolution.

A mild and robust direct C-H functionalization strategy has been applied to the synthesis of axially chiral biaryls. Such an efficient and stereoselective transformation occurs through an original dynamic kinetic resolution pathway enabling the conversion of diastereomeric mixtures of non-prefunctionalized substrates into atropisomerically pure, highly substituted biaryl scaffolds. The main feature of this transformation is the use of an enantiopure sulfoxide as both chiral auxiliary and traceless directing group.

Isolation, structural determination and synthetic approaches toward amphidinol 3.

This review highlights the isolation and the structural determination of amphidinol 3 (AM3), as well as the synthetic efforts to its preparation. The mechanism of action of AM3 will not be developed herein.

Diastereoselective synthesis of the C14–C29 fragment of amphidinol.

An efficient stereoselective synthesis of the C14–C29 fragment highlighting a coupling reaction between a 1,3-dithiane derivative and an α-branched aldehyde was realized. This highly convergent synthesis involved two chiral pools, L-malic acid and (+)-camphorsulfonic acid, which are the starting compounds to control the six stereogenic centers present in the C14–C29 fragment of amphidinol 3.

Asymmetric C(sp(2) )-H activation.

A "niche" topic in the past decade, the asymmetric C-H bond activation has been attracting growing interest over the last few years. Particularly significant advances have been achieved in the field of direct, stereoselective transformations of C(sp(2) )-H bonds. This Concept article intends to showcase different types of asymmetric C(sp(2) )-H bond activation reactions, emphasising both the nature of the stereo-discriminating step and the variability of valuable scaffolds that could be rapidly constructed by means of such strategies.

Palladium-catalyzed intramolecular direct arylation of 2-bromo-diaryl sulfoxides via C-H bond activation.

Efficient access to dibenzothiophene-S-oxides from differently substituted 2-bromo-diarylsulfinyl moieties using ligandless Pd(OAc)2 as the catalyst and KOAc as the base in dimethylacetamide at 130 °C is reported. Various dibenzothiophene-S-oxides were obtained in excellent yields.

Recent advances in the diastereoselective Reformatsky-type reaction.

The classical Reformatsky reaction introduced for the first time in 1887 has been recognized as one among the most useful methods for C-C bond formation. Diastereoselective versions based on the use of chiral auxiliaries as well as enantioselective protocols using chiral ligands have been successfully developed during the last few years. This tutorial review highlights the main recent achievements (since 2004) in the diastereoselective Reformatsky reaction; diastereochemical control has been efficiently achieved using a large variety of chiral auxiliaries to perform the synthesis of specific cyclic and acyclic chiral moieties.

Diastereoselective synthesis of the C17-C30 fragment of amphidinol 3.

The diastereoselective synthesis of the C17-C30 fragment of amphidinol 3 (AM3) 1 was achieved from the enantio-enriched aldehyde 20, Weinreb amide 14 and 2-bromo-3-(trimethylsilyl)propene, which was used as a bifunctional conjunctive reagent. The absolute configuration of the stereogenic centers, in both aldehyde 20 and Weinreb amide 14, were efficiently controlled by using (+)-(R)-methyl-p-tolylsulfoxide as the unique source of chirality.

Transition-metal-free atropo-selective synthesis of biaryl compounds based on arynes.

A modular way towards biaryls: Highly enantioenriched biphenyls can be prepared based on a transition-metal-free aryl-aryl coupling followed by efficient desymmetrization or deracemization and chemoselective functionalization (see scheme).

Stereoselective synthesis of P-chirogenic dibenzophosphole-boranes via aryne intermediates.

A new aryne-mediated tandem cross-coupling/P-cyclization sequence starting from tertiary phosphine-boranes and 1,2-dibromobenzenes is reported. P-chirogenic dibenzophospholes become accessible in a regio-, chemo-, and diastereoselective way.

Stereoselective synthesis of o-bromo (or iodo)aryl P-chirogenic phosphines based on aryne chemistry.

The efficient synthesis of chiral or achiral tertiary phosphines bearing an o-bromo (or iodo)aryl substituent is described. The key step of this synthesis is based on the reaction of a secondary phosphine borane with the 1,2-dibromo (or diiodo)arene, owing to the formation in situ of an aryne species in the presence of n-butyllithium. When P-chirogenic secondary phosphine boranes were used, the corresponding o-halogeno-arylphosphine boranes were obtained without racemization in moderate to good yields and with ee up to 99%.

Construction of the biaryl-part of vancomycin aglycon via atropo-diastereoselective Suzuki-Miyaura coupling.

An atropo-diastereoselective synthesis with dr up to 98/2 towards the biaryl subunit of vancomycin based on the use of enantiopure β-hydroxysulfoxide derivatives as novel chiral auxiliary is reported.

Bromine-lithium exchange: An efficient tool in the modular construction of biaryl ligands.

Regioselective bromine-lithium exchange reactions on polybrominated biaryls enable the modular synthesis of various polysubstituted biphenyls such as bis(dialkylphosphino)-, bis(diarylphosphino)- and dialkyl(diaryl)phosphinobiphenyls. All permutations of substituents at the ortho positions of the biphenyls are possible. In a similar manner, one can gain access to monophosphine analogues.