Chalcogen bonding catalysis.

Catalysts play a major role in chemical synthesis, and catalysis is considered to be a green and economic process. Catalysis is dominated by covalent interactions between the catalyst and substrate. The design of non-covalent catalysts came into limelight only recently. Hydrogen bonding (HB) catalysts are well established among non-covalent catalysts, including asymmetric HB catalysts. Though halogen bonding (XB) catalysis and its asymmetric version are gaining admiration, non-covalent chalcogen bonding catalysis (ChB) is in the budding stage. This tutorial review will focus on the recently evolved chalcogen bonding catalysis and emphasis will be given to the chalcogen bonding of chiral molecules. Since successful enantioselective chalcogen bonding catalysis is yet to be reported, this review will focus on the basics of non-covalent bonding catalysis, chalcogen bonding catalysis, chiral chalcogenide synthesis, rigidification of transition states by ChB, stabilization of cations by chiral chalcogens, details of unsuccessful asymmetric chalcogen bonding catalysis, enantioseparation of racemic molecules using ChB, and the existence of ChB in chiral biomolecules.

Quaternary Carbon Editing Enabled by Sequential Palladium Migration.

Peripheral functionalization of a quaternary carbon via C(sp3)-H bond activation has made significant progress in recent years. However, direct editing of a quaternary carbon through Csp3-Csp3 bond cleavage and refunctionalization of nonstrained acyclic molecules remain underexploited. Herein we report a reaction in which a methyl group attached to a quaternary carbon is shifted to its neighboring secondary carbon with concurrent oxidation of the quaternary C-C single bond to the C═C double bond. Specifically, morpholinyl amide of 2,2-dimethyl alkanoic acids is converted to 2-methylene-3-methyl alkanoic acid derivatives in the presence of a catalytic amount of palladium acetate, Selectfluor and sodium carbonate. Control experiments suggest that the reaction proceeds via a sequence of selective C(sp3)-H activation of the methyl group, oxidation of the resulting C(sp3)-PdII to PdIV intermediate followed by unprecedented 1,3-PdIV migration, 1,2-methyl/PdIV dyotropic rearrangement and finally, ß-Hydride elimination. In this domino process, palladium migrates successively from the primary to the secondary and finally to the quaternary carbon, leading to the concurrent functionalization of a primary, a secondary, and a quaternary carbon.

Editing Tetrasubstituted Carbon: Dual C-O Bond Functionalization of Tertiary Alcohols Enabled by Palladium-Based Dyotropic Rearrangement.

Many elegant asymmetric syntheses of enantioenriched tertiary alcohols have been developed, and both the transition metal-catalyzed and the radical-based peripheral functionalization of tertiary alcohols have attracted intensive research interest in recent years. However, directly editing tetrasubstituted carbons remains challenging. Herein, we report a Pd-catalyzed migratory fluoroarylation reaction that converts tertiary alcohols to α-fluorinated tertiary alkyl ethers in good to excellent yields. An unprecedented 1,2-aryl/PdIV dyotropic rearrangement along the C-O bond, integrated in a PdII-catalyzed domino process, is key to the dual functionalization of both the hydroxyl group and the tetrasubstituted carbon. This reaction, which is compatible with a broad range of functional groups, generates a tertiary alkyl fluoride and an alkyl-aryl ether functional group with inversion of the absolute configuration at the tetrasubstituted stereocenter.

Arylative Ring Expansion of 3-Vinylazetidin-3-Ols and 3-Vinyloxetan-3-Ols to Dihydrofurans by Dual Palladium and Acid Catalysis.

In contrast to the well-studied 1-vinylcyclobutanols, the reactivity of 3-vinylazetidin-3-ols 1 and 3-vinyloxetan-3-ols 2 under transition metal catalysis remains largely unexplored. We report herein their unique reactivity under dual palladium and acid catalysis. In the presence of a catalytic amount of Pd(OAc)2(PPh3)2, AgTFA and triflic acid, the reaction of 1 or 2 with aryl iodides affords 2,3,4-trisubstituted dihydrofurans, which are valuable heterocycles in organic synthesis. Mechanistic studies reveal that this arylative ring-expansion reaction proceeds via a domino process involving Heck arylation of alkene, acid-catalyzed transposition of allylic alcohol and ring opening of the azetidine/oxetane by an internal hydroxyl group.

Palladium-Based Dyotropic Rearrangement Enables A Triple Functionalization of Gem-Disubstituted Alkenes: An Unusual Fluorolactonization Reaction.

We report in this paper a Pd(II)-catalyzed migratory gem-fluorolactonization of ene-carboxylic acids. Reaction of 4-methylenealkanoic acid derivatives with Selectfluor in the presence of Pd(OAc)2 (1.0 mol %) at room temperature affords fluorolactones in good to excellent yields. 2-(2-Methylenecycloalkanyl)acetic acids are transformed to bridged fluorolactones under identical conditions. One C-C, one C-O and one tertiary C-F bond were generated along the gem-disubstituted carbon-carbon double bond in this operationally simple transformation. Trapping experiments indicates that the reaction is initiated by a 5-exo-trig oxypalladation followed by Pd oxidation, regioselective ring-enlarging 1,2-alkyl/Pd(IV) dyotropic rearrangement and C-F bond forming reductive elimination cascade. Post-transformations of these fluorolactones taking advantage of the electrophilicity of the 1-fluoroalkylcarboxylate function are also documented.

Design and Synthesis of C4-Symmetric Axially Chiral ß-Aryl Porphyrins and Application for Supporting Ir(III)-Catalyzed Enantioselective C-H Alkylation.

A hitherto unknown class of C4-symmetric Caryl-Cß (C3, C8, C13, C18) axially chiral porphyrins has been synthesized and the application of their iridium (Ir) complexes in catalytic asymmetric C(sp3)-H functionalization is documented. Cyclotetramerization of enantioenriched axially chiral 2-hydroxymethyl-3-naphthyl pyrroles under mild acidic conditions affords, after oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), the C4-symmetric α,α,α,α-atropenantiomer as an only isolable diastereomer. Both regioisomeric Ir(Por*)(CO)(Cl) complexes catalyze the carbene C-H insertion reaction affording the same enantiomer, albeit with slight difference in enantioselectivity. With the optimum Ir-complex 3 e, the 2-substituted arylacetic acid derivatives were generated from diazo compounds and cyclohexadiene in excellent yields and enantioselectivities.

Diverting the 5-exo-Trig Oxypalladation to Formally 6-endo-Trig Fluorocycloetherification Product through 1,2-O/Pd(IV) Dyotropic Rearrangement.

Pd-catalyzed cyclizative functionalization of γ-hydroxyalkenes affords tetrahydrofuran derivatives via a key 5-exo-trig oxypalladation step. Herein, we report a palladium(II)-catalyzed, Selectfluor-mediated formal 6-endo-trig fluorocycloetherification of γ-hydroxyalkenes for the synthesis of functionalized tetrahydropyrans. Mechanistically, an σ-alkyl-Pd(II) intermediate resulting from the 5-exo-trig oxypalladation process is isolated and characterized by X-ray crystallographic analysis. Its oxidation with Selectfluor to Pd(IV) triggers the chemoselective 1,2-O/Pd(IV) dyotropic rearrangement affording, after C-F bond-forming reductive elimination, the tetrahydropyrans with concurrent generation of a tertiary carbon-fluorine bond. The occurrence of this 1,2-positional interchange is further evidenced by trapping the rearranged quaternary C(sp3)-Pd bond by an internal nucleophile that is materialized by the development of a Pd(II)-catalyzed oxidative bis-heterocyclization of alkenes.

Enantioselective Total Synthesis of (+)-Stephadiamine.

An asymmetric synthesis of (+)-stephadiamine has been accomplished featuring (a) an enantioselective dearomatizative Michael addition to generate a quaternary stereocenter; (b) a domino sequence involving reductive generation of nitrone from γ-nitro ketone followed by a highly regio- and diastereo-selective intramolecular [3 + 2] cycloaddition to construct the aza[4,3,3]propellane core with concurrent generation of two quaternary stereocenters and two functional groups ready for subsequent transformations; (c) the Curtius rearrangement of the sensitive α,α-disubstituted malonic acid mono ester for the installation of α,α-disubstituted amino ester moiety; (d) a benzylic C-H oxidation under photoredox catalytic conditions; and (e) a highly diastereoselective ketone reduction affording δ-hydroxyester preorganized for lactonization.

Enantioselective Total Synthesis of (-)-Artatrovirenol A.

We report herein an enantioselective total synthesis of (-)-artatrovirenol A, a structurally unprecedented cage-like sesquiterpenoid. The synthesis features the following key steps: (a) cationic chiral oxazaborolidinium-catalyzed Diels-Alder reaction between isoprene and ethyl (E)-5-((tert-butyldimethylsilyl)oxy)-4-oxopent-2-enoate for the rapid synthesis of an enantioenriched 10-carbon bicyclic lactone; (b) union of two enantioenriched fragments by a diastereoselective Mukaiyama-Michael addition for the convergent assembly of an intermediate with all 15 carbons of the natural product; (c) intramolecular de Mayo [2 + 2] cycloaddition/retro-aldol sequence transforming a bicyclic compound to a tetracyclic one with concomitant generation of a five- and a seven-membered ring; (d) Lewis acid-triggered intramolecular ring opening of epoxide generating the norbornane substructure; and (e) Chugaev elimination converting the norbornane to the more strained norbornene.

Divergent Asymmetric Total Synthesis of (-)-Voacafricines A and B.

A divergent asymmetric total synthesis of voacafricines A and B, hexacyclic monoterpene indole alkaloids, has been accomplished featuring the following key steps: a) a catalyst-controlled asymmetric Pictet-Spengler reaction of 6-methoxytryptamine with a chiral α-ketoester affording a 1,1-disubstituted tetrahydro-ß-carboline in excellent yield and diastereoselectivity; b) oxidative cleavage of a 3,5-disubstituted cyclopentene furnishing a dialdehyde intermediate, which was effectively differentiated through spontaneous cyclization with the neighboring hydroxy and secondary amine functions; c) intramolecular nucleophilic addition of a tertiary amino nitrogen atom to the in situ generated oxonium species generating stereoselectively an unprecedented 8-alkyl octahydro-2H-5,8-methanofuro[2,3-b]azepin-8-ium motif bearing five contiguous stereocenters. The synthesis confirmed the absolute configuration of these two natural products.

Terminal Alkynes as One-Carbon Donors in [5+1] Heteroannulation: Synthesis of Pyridines via Ynimine Intermediates and Application in the Total Synthesis of Anibamine B.

Transition-metal-catalyzed [4+2] heteroannulation of α,ß-unsaturated oximes and their derivatives with alkynes has been developed into a powerful strategy for the synthesis of pyridines. It nevertheless lacks regioselectivity when unsymmetrically substituted alkynes are used. We report herein the unprecedented synthesis of polysubstituted pyridines by a formal [5+1] heteroannulation of two readily accessible building blocks. A copper-catalyzed aza-Sonogashira cross-coupling between ß,γ-unsaturated oxime esters and terminal alkynes affords ynimines, which, without isolation, undergo an acid-catalyzed domino reaction involving ketenimine formation, 6π-electrocyclization and aromatization to afford pyridines. Terminal alkynes served as a one-carbon donor to the pyridine core in this transformation. Di- through pentasubstituted pyridines are accessible with complete regioselectivity and excellent functional-group compatibility. The first total synthesis of anibamine B, an indolizinium alkaloid with potent antiplasmodial activity, was accomplished featuring this reaction as a key step.

Organocatalytic Enantioselective Diels-Alder Reaction of 2-Trifluoroacetamido-1,3-dienes with α,ß-Unsaturated Ketones.

We report herein the first examples of chiral phosphoric acid-catalyzed enantioselective Diels-Alder reactions between 2-trifluoroacetamido-1,3-dienes 1 and α,ß-unsaturated carbonyl compounds 2. Polysubstituted 1-acetamido cyclohexenes 3 were formed in high yields with excellent diastereo- and enantioselectivities. The reaction proceeds through a stepwise process as shown by deuterium labelling experiments. A catalytic enantioselective three-component reaction of 1, 2 and ortho-hydroxybenzhydryl alcohols 4 was subsequently developed furnishing the densely functionalized hexahydroxanthenes 5 in a highly stereoselective manner. This multicomponent reaction generates four chemical bonds with concurrent creation of five contiguous stereocenters.

Organocatalytic Enantioselective Pictet-Spengler Reaction of α-Ketoesters: Development and Application to the Total Synthesis of (+)-Alstratine A.

We report herein an asymmetric Pictet-Spengler reaction of α-ketoesters. In the presence of a catalytic amount of simple alanine-derived squaramide and p-nitrobenzoic acid, reaction of tryptamines with methyl 2-oxoalkanoates afforded the corresponding 1-alkyl-1-methoxycarbonyl tetrahydro-ß-carbolines (THBCs) in high yields and ee values. A primary kinetic isotope effect (KIE=4.5) using C2-deteurium-labelled tryptamine indicates that rearomatization through deprotonation of the pentahydro-ß-carbolinium ion could be the rate- and enantioselectivity-determining step. A concise enantioselective total synthesis of (+)-alstratine A, a hexacyclic cagelike monoterpene indole alkaloid, featuring this reaction as a key step, was subsequently accomplished. Remeasurement of the [a]D value of the natural product indicates that natural alstratine A is dextrorotatory rather than levorotatory as it was initially reported in the isolation paper.

Asymmetric Construction of α,α-Disubstituted Piperazinones Enabled by Benzilic Amide Rearrangement.

An unprecedent asymmetric catalytic benzilic amide rearrangement for the synthesis of α,α-disubstituted piperazinones is reported. The reaction proceeds via a domino [4+1] imidazolidination/formal 1,2-nitrogen shift/1,2-aryl or alkyl migration sequence, employing readily available vicinal tricarbonyl compounds and 1,2-diamines as starting materials. This approach provides an efficient access to chiral C3-disubsituted piperazin-2-ones with high enantiocontrol, which are exceedingly difficult to access from the existing synthetic methodologies. The observed enantioselectivity was proposed to be controlled by dynamic kinetic resolution in the 1,2-aryl/alkyl migration step. The resulting densely functionalized products are versatile building blocks to bioactive natural products, drug molecules and their analogues.

Highly Strained Oxygen-Doped Chiral Molecular Belts of the Zigzag-Type with Strong Circularly Polarized Luminescence.

Herein we report a two-directional cyclization strategy for the synthesis of highly strained depth-expanded oxygen-doped chiral molecular belts of the zigzag-type. From the easily accessible resorcin[4]arenes, an unprecedented cyclization cascade generating fused 2,3-dihydro-1H-phenalenes has been developed to access expanded molecular belts. Stitching up the fjords through intramolecular nucleophilic aromatic substitution and ring-closing olefin metathesis reactions furnished a highly strained O-doped C2 -symmetric belt. The enantiomers of the acquired compounds exhibited excellent chiroptical properties. The calculated parallelly aligned electric (µ) and magnetic (m) transition dipole moments are translated to the high dissymmetry factor (|glum | up to 0.022). This study provides not only an appealing and useful strategy for the synthesis of strained molecular belts but also a new paradigm for the fabrication of belt-derived chiroptical materials with high CPL activities.

Modular Synthesis of Benzocyclobutenes via Pd(II)-Catalyzed Oxidative [2+2] Annulation of Arylboronic Acids with Alkenes.

Benzocyclobutenes (BCBs) are highly valuable compounds in organic synthesis, medicinal chemistry, and materials science. However, catalytic modular synthesis of functionalized BCBs from easily accessible starting materials remains limited. We report herein an efficient synthesis of diversely functionalized BCBs by a Pd(II)-catalyzed formal [2+2] annulation between arylboronic acids and alkenes in the presence of N-fluorobenzenesulfonimide (NFSI). An intermolecular carbopalladation followed by palladium oxidation, intramolecular C(sp2)-H activation by a transient C(sp3)-Pd(IV) species, and selective carbon-carbon (C-C) bond-forming reductive elimination from a high-valent five-membered palladacycle is proposed to account for the reaction outcome. Kinetically competent oxidation of alkylPd(II) to alkylPd(IV) species is important to avoid the formation of a Heck adduct. The reaction forges two C-C bonds of the cyclobutene core and is compatible with a wide range of functional groups. No chelating bidentate directing group in the alkene part is needed for this transformation.

Migrative Carbofluorination of Saturated Amides Enabled by Pd-Based Dyotropic Rearrangement.

Directly editing an all-carbon quaternary carbon itself of nonstrained acyclic molecules remains underexploited despite the recent advances in the fields of both C-H and C-C bond activation. Herein, we report a palladium-catalyzed migrative carbofluorination of saturated amides enabled by the activation of both the C(sp3)-H and the Cquaternary-Cσ bonds. In this transformation, the α-quaternary carbon of Weinreb amides is converted to α-tertiary fluoride with concurrent migration of an aryl or an amido group from the α- to ß-carbon. DFT calculations indicate that the dyotropic rearrangement proceeds through an unusual anti-selective [2.1.0] bicyclic transition state. The reaction, compatible with a broad range of functional groups, is stereospecific and is applicable to the synthesis of enantioenriched products.

Thiazole Boron Difluoride Dyes with Large Stokes Shift, Solid State Emission and Room-Temperature Phosphorescence.

The small Stokes shift and weak emission in the solid state are two main shortcomings associated with the boron-dipyrromethene (BODIPY) family of dyes. This study presents the design, synthesis and luminescent properties of boron difluoro complexes of 2-aryl-5-alkylamino-4-alkylaminocarbonylthiazoles. These dyes display Stokes shifts (Δλ, 77-101 nm) with quantum yields (ϕFL ) up to 64.9 and 34.7 % in toluene solution and in solid state, respectively. Some of these compounds exhibit dual fluorescence and room-temperature phosphorescence (RTP) emission properties with modulable phosphorescence quantum yields (ϕPL ) and lifetime (τp up to 251 µs). The presence of intramolecular H-bonds and negligible π-π stacking revealed by X-ray crystal structure might account for the observed large Stokes shift and significant solid-state emission of these fluorophores, while the enhanced spin-orbit coupling (SOC) of iodine and the self-assembly driven by halogen bonding, π-π and C-H… π interactions could be responsible for the observed RTP of iodine containing phosphors.

Visible light photoredox-catalysed remote C-H functionalisation enabled by 1,5-hydrogen atom transfer (1,5-HAT).

The generation of heteroatom-centred radicals (X˙), followed by intramolecular 1,5-hydrogen atom transfer (1,5-HAT) and the functionalisation of the translocated carbon-centred radicals, is the basic mechanism of the classic Hofmann-Löffler-Freytag (HLF) reaction and the Barton reaction. The chemoselectivity of the 1,5-HAT process is different from that of the transition metal-catalysed counterpart, providing, therefore, a complementary tool for remote C(sp3)-H bond functionalisation. There is a recent resurgence in this research field due to the emergence of visible light photocatalysis. This tutorial review summarises the recent progress in the remote functionalisation of C-H bonds featuring a key 1,5-HAT step with particular focus on photoredox-catalyzed remote C-H functionalisation.

Catalytic Enantioselective Pictet-Spengler Reaction of α-Ketoamides Catalyzed by a Single H-Bond Donor Organocatalyst.

The asymmetric Pictet-Spengler reaction (PSR) with aldehydes is well known. However, PSR involving ketones as electrophilic partners is far-less developed. We report herein the first examples of catalytic enantioselective PSR of tryptamines with α-ketoamides. A new class of easily accessible prolyl-urea organocatalysts bearing a single H-bond donor function catalyzes the title reaction to afford 1,1-disubstituted tetrahydro-ß-carbolines in excellent yields and enantioselectivities. The kinetic isotope effect using C2-deuterium-labelled tryptamine indicates that the rearomatization of the pentahydro-ß-carbolinium ion intermediate might be the rate- and the enantioselectivity-determining step.