Asymmetric Hydrogenation of Trifluoromethyl Ketones: Application in the Synthesis of Odanacatib and LX-1031

Due to their stereoelectronic properties, trifluoromethyl (or perfluoroalkyl) ketones are challenging substrates in asymmetric (transfer) hydrogenation. We developed iridium catalysis bearing ferrocene-based tridentate ligands (f-amphol or f-ampha), offering a promising...

Advances in the catalyst- and reagent-controlled site-divergent intermolecular functionalization of C(sp3)–H bonds

Intermolecular C(sp3)–H bond functionalization reactions promise to revolutionize how we synthesize organic molecules by enabling the introduction of functionality at previously inert sites. However, one of the greatest challenges in this research field is site-selectivity, wherein chosen C(sp3)–H bonds must be selectively functionalized and other C(sp3)–H bonds with similar stereoelectronic properties must remain intact. To address this problem, chemists have developed methods that rely on targeting innately more reactive C(sp3)–H bonds or on using pre-installed functional groups to direct a catalyst or reagent to a particular C(sp3)–H bond. However, such approaches invariably have limited applicability because only a handful of innately reactive C(sp3)–H bonds or those nearby certain functional groups can be functionalized with good site-selectivity. To overcome these limitations, chemists also have developed catalysts and reagents that control the site of C(sp3)–H bond functionalization and have begun to unlock the potential of these reactions to achieve the site-divergent functionalization of C(sp3)–H bonds, wherein the site of functionalization is changed by modulating the stereoelectronic properties of the catalyst or reagent. This short review will provide a summary of selected examples of catalyst- and reagent-controlled site-divergent intermolecular functionalization of C(sp3)–H bonds, the factors responsible for modulating the site selectivity of these reactions, and will identify potential areas worthy of future research in this field.

Non-planar Boron Lewis Acids Taking the Next Step: Development of Tunable Lewis Acids, Lewis Superacids and Bifunctional Catalysts

Although boron Lewis acids commonly adopt a trigonal planar geometry, a number of compounds in which the trivalent boron atom is located in a pyramidal environment have been described. This review will highlight the recent developments of the chemistry and applications of non-planar boron Lewis acids, including a series of non-planar triarylboranes derived from the triptycene core. A thorough analysis of the properties and of the influence of the pyramidalization of boron Lewis acids on their stereoelectronic properties and reactivities is presented based on recent theoretical and experimental studies.1 Non-planar Trialkylboranes2 Non-planar Alkyl and Aryl-Boronates3 Non-planar Triarylboranes and Alkenylboranes3.1 Previous Investigations on Bora Barrelenes and Triptycenes3.2 Recent Work on Boratriptycenes from Our Research Group4 Applications of Non-planar Boranes4.1 Non-planar Alkyl Boranes and Boronates4.2 Non-planar Triarylboranes (Boratriptycenes)5 Other Non-planar Group 13 Lewis Acids6 Further Work and Perspectives

Thiol-ene "Click" Synthesis and Pharmacological Evaluation of C-Glycoside sp2-Iminosugar Glycolipids

The unique stereoelectronic properties of sp2-iminosugars enable their participation in glycosylation reactions, thereby behaving as true carbohydrate chemical mimics. Among sp2-iminosugar conjugates, the sp2-iminosugar glycolipids (sp2-IGLs) have shown a variety of interesting pharmacological properties ranging from glycosidase inhibition to antiproliferative, antiparasitic, and anti-inflammatory activities. Developing strategies compatible with molecular diversity-oriented strategies for structure–activity relationship studies was therefore highly wanted. Here we show that a reaction sequence consisting in stereoselective C-allylation followed by thiol-ene “click” coupling provides a very convenient access to α-C-glycoside sp2-IGLs. Both the glycone moiety and the aglycone tail can be modified by using sp2-iminosugar precursors with different configurational profiles (d-gluco or d-galacto in this work) and varied thiols, as well as by oxidation of the sulfide adducts (to the corresponding sulfones in this work). A series of derivatives was prepared in this manner and their glycosidase inhibitory, antiproliferative and antileishmanial activities were evaluated in different settings. The results confirm that the inhibition of glycosidases, particularly α-glucosidase, and the antitumor/leishmanicidal activities are unrelated. The data are also consistent with the two later activities arising from the ability of the sp2-IGLs to interfere in the immune system response in a cell line and cell context dependent manner.

Understanding Factors that Control the Structural (Dis)Assembly of Sulphur-Bridged Bimetallic Sites

Bimetallic structures of the general type [M2(µ-S)2] are omnipresent in nature, for biological function [M2(µ-S)2] sites interconvert between electronically distinct, but isostructural, forms. Different from structure-function relationships, the current understanding of the mechanism of formation and persistence of [M2(µ-S)2] sites is poorly developed. This work reports on bimetallic model compounds of nickel that interconvert between functional structures [Ni2(µ-S)2]+/2+ and isomeric congeners [2{κ-S–Ni}]2+/+, S = Aryl-S−, in which the nickel ions are geometrically independent. Interconversion of the two sets of structures was studied quantitatively by UV–VIS absorption spectroscopy and cyclic voltammetry. Assembly of the [Ni2(µ-S)2]+ core from [2{κ-S–Ni}]+ is thermodynamically and kinetically highly preferred over the disassembly of [Ni2(µ-S)2]2+ into [2{κ-S–Ni}]2+. Labile Ni-η2/3-bonding to aromatic π-systems of the primary thiophenol ligand is critical for modeling (dis)assembly processes. A phosphine coligand mimics the role of anionic donors present in natural sites that saturate metal coordination. Three parameters have been identified as critical for structure formation and persistence. These are, first, the stereoelectronic properties of the metals ions, second, the steric demand of the coligand, and, third, the properties of the dative bond between nickel and coligand. The energies of transition states connecting functional and precursor forms have been found to depend on these parameters.

Towards Understanding the Phenytoin-like Antiepileptic Effect of Cannabidiol and Related Phytocannabinoid Metabolites: Insights from Molecular Modeling

<div> Cannabidiol (CBD), a nonpsychotropic constituent of <i>Cannabis sativa</i>, has recently been approved by the US FDA for the treatment of certain forms of pediatric epilepsy. The mechanism by which CBD exerts its antiepileptic effects, however, is not known. Herein we describe the results of molecular modeling studies comparing the stereoelectronic properties of phenytoin (PHT) with those of CBD and its carboxylic acid metabolite, as well as of 7-hydroxycannabidivarin. Also, the cyclohexenecarboxylic acid core of 7-COOH-CBD perfectly mimics the unsaturated bioactive metabolite of the commonly used antiepileptic valproic acid was also noted. We propose that C–7 oxidized phytocannabinoid metabolites are involved in the phenytoin-like anticonvulsant effects of the parent phytocannabinoid drugs.</div>

Towards Understanding the Phenytoin-like Antiepileptic Effect of Cannabidiol and Related Phytocannabinoid Metabolites: Insights from Molecular Modeling

<div> Cannabidiol (CBD), a nonpsychotropic constituent of <i>Cannabis sativa</i>, has recently been approved by the US FDA for the treatment of certain forms of pediatric epilepsy. The mechanism by which CBD exerts its antiepileptic effects, however, is not known. Herein we describe the results of molecular modeling studies comparing the stereoelectronic properties of phenytoin (PHT) with those of CBD and its carboxylic acid metabolite, as well as of 7-hydroxycannabidivarin. Also, the cyclohexenecarboxylic acid core of 7-COOH-CBD perfectly mimics the unsaturated bioactive metabolite of the commonly used antiepileptic valproic acid was also noted. We propose that C–7 oxidized phytocannabinoid metabolites are involved in the phenytoin-like anticonvulsant effects of the parent phytocannabinoid drugs.</div>