Synthesis of 4-hydroxypiperidines containing a quaternary stereocenter by aza-Prins cyclization.

A straightforward and highly diastereoselective synthesis of -4-hydroxypiperidines is presented. This method allows access to C2 and C4 substituted piperidines, bearing a tetrasubstituted carbon stereocenter at C4. -Disubstituted homoallylic amines and ketoaldehydes as carbonyl partners have been rarely used in aza-Prins cyclizations, expanding the scope of this reaction.

Allylboration of Ketones Catalyzed by BINOL Derivatives: Which Species Are Involved Depending on Substrate Reactivity?

Allylboration reactions of ketones catalyzed by BINOL derivatives can exhibit highly variable stereochemical courses depending on the nature and reactivity of the ketone substrate. In this Article, we put into perspective the relationship between the nature of the starting material and the active species involved in the asymmetric allyboration catalyzed by BINOL derivatives. This work, aimed at comparing different plausible mechanisms by density functional theory (DFT) at the M06-2X/6-311+G(d,p) level involving different types of allylboronates in the presence of the organocatalyst, leads to the confirmation of the hitherto accepted hypothesis of a reaction promoted by the transient cyclic allyl-1,3,2-dioxaborolane derived from BINOLs in the case of unactivated or weakly activated ketones such as indanone.

Synthesis and Chemoinformatic Analysis of Fluorinated Piperidines as 3D Fragments for Fragment-Based Drug Discovery.

The concise synthesis of a small library of fluorinated piperidines from readily available dihydropyridinone derivatives has been described. The effect of the fluorination on different positions has then been evaluated by chemoinformatic tools. In particular, the compounds' p's have been calculated, revealing that the fluorine atoms notably lowered their basicity, which is correlated to the affinity for hERG channels resulting in cardiac toxicity.

Accessing spiropiperidines from dihydropyridones through tandem triflation-allylation and ring-closing metathesis (RCM).

A novel approach to build 2-spiropiperidine moieties starting from dihydropyridones was developed. The triflic anhydride-promoted conjugate addition of allyltributylstannane onto dihydropyridones allowed for the formation of bis-alkenyl intermediates that were converted to the corresponding spirocarbocycles with excellent yields ring closing metathesis. The vinyl triflate group generated on these 2-spiro-dihydropyridine intermediates could be successfully used as a chemical expansion vector for further transformations namely Pd-catalyzed cross-coupling reactions.

Catalytic Enantioselective Allylboration and Related Reactions of Isatins Promoted by Chiral BINOLs: Scope and Mechanistic Studies.

An improvement in the catalytic enantioselective allylboration of isatins with 2-allyl-1,3,2-dioxaborolane in the presence of chiral BINOL derivatives is reported, offering an efficient one-step access to enantioenriched -unprotected 3-allyl-3-hydroxy-2-oxindoles. This catalytic process is also effective for the crotylboration reaction with enantiomeric ratios (er) up to 97:3, as well as for the asymmetric synthesis of homopropargylic alcohols via an allenyl addition to indoline-2,3-diones. Origins of the high enantioselectivity in chiral BINOL-catalyzed allylboration of isatins were examined by DFT calculations.

Asymmetric Ruthenium Catalysis Enables Fluorophores with Point Chirality Displaying CPL Properties.

A novel enantiopure π-allylruthenium(IV) precatalyst allowed the enantioselective and stereospecific allylations of indoles and gave access to indolin-3-ones, containing vicinal stereogenic centers. Facile separation of diastereoisomers exhibiting opposite circularly polarized luminescence (CPL) activities in diverse solvents, including water, demonstrated the potential of these sustainable transformations and of the newly prepared molecules.

Circularly polarized luminescence of Eu(III) complexes with chiral 1,1'-bi-2-naphtol-derived bisphosphate ligands.

The interest for lanthanide circularly polarized luminescence (CPL) has been quickly growing for 10 years. However, very few of these studies have involved correlation between the dissymmetry factor (g ) and the chemical modifications in a series of chiral ligands. Four polymeric compounds of Eu(III) were prepared by using a series of binaphtyl derivatives for which the size of the π system as well as the number of stereogenic elements (i.

Solid-State Near-Infrared Circularly Polarized Luminescence from Chiral Yb -Single-Molecule Magnet.

A field-induced chiral Yb Single-Molecule Magnet (SMM) displayed an unprecedented near-infrared circularly polarized luminescence (NIR-CPL) in the solid-state. The bridging bis(1,10-phenantro[5,6b])tetrathiafulvalene triad (L) allowed an efficient sensitization of the NIR F → F emission while the NIR-CPL is associated to the f-f transitions of the Yb ion bearing chiral β-diketonate derived-camphorate ancillary ligands.

Inhibitory Effects of Secondary Metabolites from the Lichen Stereocaulon evolutum on Protein Tyrosine Phosphatase 1B.

Protein tyrosine phosphatase 1B plays a significant role in type 2 diabetes mellitus and other diseases and is therefore considered a new drug target. Within this study, an acetone extract from the lichen was identified to possess strong protein tyrosine phosphatase 1B inhibition in a cell-free assay (IC of 11.8 µg/mL).

BINOL derivatives-catalysed enantioselective allylboration of isatins: application to the synthesis of (R)-chimonamidine.

The asymmetric synthesis of the 3-allyl-3-hydroxyoxindole skeleton was accomplished in yields up to 99% via a metal-free and enantioselective allylation of isatins (90-96% ee) using BINOL derivatives as catalysts and an optimized allylboronate. This methodology was applied at a gram-scale to the synthesis of the natural product (R)-chimonamidine.

Enantioselective Brønsted Acid Catalysis as a Tool for the Synthesis of Natural Products and Pharmaceuticals.

Synthesis of biologically active molecules (whether at laboratory or industrial scale) remains a highly appealing area of modern organic chemistry. Nowadays, the need to access original bioactive scaffolds goes together with the desire to improve synthetic efficiency, while reducing the environmental footprint of chemical activities. Long neglected in the field of total synthesis, enantioselective organocatalysis has recently emerged as an environmentally friendly and indispensable tool for the construction of relevant bioactive molecules.

Synergistic Effect of the TiCl4/p-TsOH Promoter System on the Aza-Prins Cyclization.

A novel aza-Prins cyclization promoted by a synergistic combination between a Lewis acid and a Brønsted acid to efficiently afford piperidines is described. Contrary to what has been previously reported in the literature, the generality of the reaction employing N-alkyl, N-aryl, and nonprotected homoallylamines has been demonstrated. The reaction is highly diastereoselective depending on the homoallylic amine used, N-PMP homoallyl amine leading preferentially to the trans diastereomer, and free homoallylamine affording the deprotected piperidine as single cis diastereomer.

Depsides: lichen metabolites active against hepatitis C virus.

A thorough phytochemical study of Stereocaulon evolutum was conducted, for the isolation of structurally related atranorin derivatives. Indeed, pilot experiments suggested that atranorin (1), the main metabolite of this lichen, would interfere with the lifecycle of hepatitis C virus (HCV). Eight compounds, including one reported for the first time (2), were isolated and characterized.

Catalytic, highly enantioselective, direct amination of enecarbamates.

Amination of enecarbamates with dibenzylazodicarboxylate and oxygenated nucleophiles in the presence of a catalytic amount of chiral phosphoric acid afforded optically active stable precursors of α-hydrazinoimines, which were reduced or oxidized, respectively, to vicinal diamines or α-amino acid precursors with excellent yield and enantioselectivity.

Chiral calcium-BINOL phosphate catalyzed diastereo- and enantioselective synthesis of syn-1,2-disubstituted 1,2-diamines: scope and mechanistic studies.

A highly enantioselective, chiral, Lewis acid calcium-bis(phosphate) complex, Ca[3 a]n, which catalyzes the electrophilic amination of enamides with azodicarboxylate derivatives 2 to provide versatile chiral 1,2-hydrazinoimines 4 is disclosed. The reaction gives an easy entry to optically active syn-1,2-disubstituted 1,2-diamines 6 in high yields with excellent enantioselectivities, after a one-pot reduction of the intermediate 1,2-hydrazinoimines 4. The geometry and nature of the N-substituent of the enamide affect dramatically both the reactivity and the enantioselectivity.

Enantioselective Prins cyclization: BINOL-derived phosphoric acid and CuCl synergistic catalysis.

The first catalytic enantioselective Prins cyclization is disclosed. The reaction is catalyzed by the combination of a chiral BINOL-derived bis-phosphoric acid and CuCl. The process consists of a tandem Prins/Friedel-Crafts cyclization that affords the hexahydro-1H-benzo[f]isochromenes products with three new contiguous stereogenic centers in high yields, and good enantio- and excellent diastereoselectivities.

Catalytic enantioselective [4 + 2]-cycloaddition: a strategy to access aza-hexacycles.

The aza-Diels Alder reaction has become one of the most widely used synthetic tools for the preparation of N-containing 6-membered heterocycles. Numerous important developments have been reported to render this reaction catalytic and enantioselective. This tutorial review highlights strategies and recent advances to achieve high efficiency and selectivity through the use of organocatalysts and transition metal complexes, allowing also the extension of this transformation substrate scope.

D-proline-based peptidomimetic inhibitors of anthrax lethal factor.

In this work we reported the generation of d-proline-derived hydroxamic acids as inhibitors of anthrax lethal factor (LF), taking advantage of a pyrrolidine ring as the central scaffold and a hydroxamate group as the Zn(2+) chelating agent. The introduction of two hydrophobic groups addressing the S1' subsite and a long substrate-binding groove was conceived by overlapping the bioactive conformations of two reported LF inhibitors. Micromolar affinity of compound 38 suggested cis-3-substituted-1-sulfonamido-d-proline hydroxamic acids as a promising class of peptidomimetic inhibitors for developing novel LF inhibitors.

Highly enantioselective electrophilic α-bromination of enecarbamates: chiral phosphoric acid and calcium phosphate salt catalysts.

Metal-free chiral phosphoric acids and chiral calcium phosphates both catalyze highly enantio- and diastereoselective electrophilic α-bromination of enecarbamates to provide an atom-economical synthesis of enantioenriched vicinal haloamines. Either enantiomer can be formed in good yield with excellent diastereo- and enantioselectivity simply by switching the catalyst from a phosphoric acid to its calcium salt.

One-pot sequential Ti-/Cu-catalysis for tandem amidation/Ullmann-type cyclization: synthesis of model benzodiazepine(di)ones promoted by microwave irradiation.

The application of sequential Ti-/Cu-catalysis in the model one-pot synthesis of benzodiazepine(di)ones promoted by microwave irradiation demonstrates the expediency of dual catalysis in coupling-cyclization methods useful for diversity-oriented synthesis.

Exploiting the divergent reactivity of α-isocyanoacetate: multicomponent synthesis of 5-alkoxyoxazoles and related heterocycles.

A novel multicomponent synthesis of 5-alkoxyoxazoles, based on a new reactivity profile of α-isocyanoacetates, is described. Thus, simply heating a solution of amine, aldehyde, and α-(EWG-phenyl)-α-isocyanoacetate or α-(4-pyridyl)-α-isocyanoacetate (EWG=electron-withdrawing group) in toluene provided 5-alkoxyoxazoles in good to excellent yields. Reaction of the 5-alkoxyoxazoles with various α,β-unsaturated acyl chlorides led to the formation of epoxytetrahydropyrrolo[3,4-b]pyridin-5-ones by a domino N-acylation/Diels-Alder cycloaddition sequence.

Chiral calcium organophosphate-catalyzed enantioselective electrophilic amination of enamides.

Highly enantioselective direct amination of enamides catalyzed by chiral nonracemic calcium bis(phosphate) complex 3g afforded optically active 1,2-hydrazinoimines 4. Following a subsequent in situ hydrolysis or reduction, 2-hydrazinoketones 5 or syn-1,2-disubstituted 1,2-diamines 6 were obtained in high yields and excellent enantiomeric excess.