Inherently chiral nor-heteracalixarenes: design and synthesis via enantioselective intramolecular Suzuki-Miyaura reaction.

There has been a recent upsurge in research aimed at synthesizing inherently chiral molecules devoid of point, axial, planar and helical chiralities. We present herein our design and enantioselective synthesis of a series of inherently chiral macrocycles. These compounds, termed nor-heteracalixaromatics, feature a biaryl bond that replaces one of the aryl-heteroatom-aryl linkages found in classic heteracalix[4]aromatics. Macrocyclization of linear achiral substrates via an intramolecular Suzuki-Miyaura cross-coupling reaction affords the 15-membered cyclophane without any chiral elements in high yields and enantioselectivities. Notably, the formation of the aryl-aryl bond does not induce axial chirality at the biaryl linkage. Instead, it restricts the free rotation of an aromatic ring located four bonds away, leading to the inherent chirality of the macrocycle. The intriguing chiroptical properties of these compounds made them promising platform for the development of CPL emitters.

[4+1] Heteroannulation to Form 1-Pyrrolines through Alder-Ene Reaction of in situ Generated Ynimines: Development and Application in Total Synthesis of Borrecapine.

We report in this paper a novel Cu-catalyzed synthesis of polysubstituted 1-pyrrolines. The reaction of ß,γ-unsaturated oxime esters 4 with terminal alkynes 5 in the presence of a catalytic amount of Cu(OAc)2 and 2,2'-biquinoline affords the corresponding 1,6-enynimines, which undergo a highly stereoselective Alder-ene reaction to afford 1-pyrrolines with concomitant generation of a quaternary carbon and a 2-azadiene motif. It represents an unusual [4+1] heteroannulation reaction wherein terminal alkynes act as a one carbon donor and are 1,1-difunctionalized. Mechanistic studies suggest that the allylic hydrogen trans to the oxime ester main chain is selectively transferred to the electron-rich alkyne during the pericyclic reaction. The resulting 1-pyrrolines undergo facile acid-catalyzed regioselective Wagner-Meerwein rearrangement to provide 2H-pyrroles in excellent yields. The 2H-pyrroles are also accessible from 4 and 5 in a one-pot manner without isolation of the 1-pyrrolines. Leveraging this heteroannulation reaction as a key step, the first total synthesis of borrecapine, a 2,3,3,5-tetrasubstituted pyrrolidine, is accomplished.

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.

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.

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.

A time segment adaptive optimization method based on separability criterion and correlation analysis for motor imagery BCIs.

Motor imagery (MI) plays a crucial role in brain-computer interface (BCI), and the classification of MI tasks using electroencephalogram (EEG) is currently under extensive investigation. During MI classification, individual differences among subjects in terms of response and time latency need to be considered. Optimizing the time segment for different subjects can enhance subsequent classification performance. In view of the individual differences of subjects in motor imagery tasks, this article proposes a Time Segment Adaptive Optimization method based on Separability criterion and Correlation analysis (TSAOSC). The fundamental principle of this method involves applying the separability criterion to various sizes of time windows within the training data, identifying the optimal raw reference signal, and adaptively adjusting the time segment position for each trial's data by analyzing its relationship with the optimal reference signal. We evaluated our method on three BCI competition datasets, respectively. The utilization of the TSAOSC method in the experiments resulted in an enhancement of 4.90% in average classification accuracy compared to its absence. Additionally, building upon the TSAOSC approach, this study proposes a Nonlinear-TSAOSC method (N-TSAOSC) for analyzing EEG signals with nonlinearity, which shows improvements in the classification accuracy of certain subjects. The results of the experiments demonstrate that the proposed method is an effective time segment optimization method, and it can be integrated into other algorithms to further improve their accuracy.

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.

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.

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.

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.

Asymmetric Synthesis of Enantioenriched Zigzag-Type Molecular Belts by Kinetic Resolution and Subsequent Transformations.

Asymmetric synthesis of enantioenriched zigzag-type molecular belts featuring copper/H8-binaphthol-catalyzed kinetic resolution of a resorcinarene derivative and subsequent transformations was developed. The acquired rigid and C4-symmetric belt exhibited remarkably enhanced photophysical and chiroptical properties in comparison to its conformationally fluxional macrocyclic precursor.

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.

Oxidative rearrangement of 1,1-disubstituted alkenes to ketones.

The Wacker process, which is widely used to convert monosubstituted alkenes into the corresponding methyl ketones, is thought to proceed through a PdII/Pd0 catalytic cycle involving a ß-hydride elimination step. This mechanistic scenario is inapplicable to the synthesis of ketones from the 1,1-disubstituted alkenes. Current approaches based on semi-pinacol rearrangement of PdII intermediates are limited to the ring expansion of highly strained methylene cyclobutane derivatives. Herein, we report a solution to this synthetic challenge by designing a PdII/PdIV catalytic cycle incorporating a 1,2-alkyl/PdIV dyotropic rearrangement as a key step. This reaction, compatible with a broad range of functional groups, is applicable to both linear olefins and methylene cycloalkanes, including macrocycles. Regioselectivity favors the migration of the more substituted carbon, and a strong directing effect of the ß-carboxyl group was also observed.

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.

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.

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.

Inherently chiral calixarenes by a catalytic enantioselective desymmetrizing cross-dehydrogenative coupling.

Under the catalysis of PdBr2 and a chiral phosphoramidite ligand, the upper-rim mono (2-bromoaroyl)-substituted calix[4]arene derivatives underwent a facile enantioselective desymmetrization reaction to afford 9H-fluorene-embedded inherently chiral calixarenes in good yields with excellent enantioselectivities. The transannular dehydrogenative arene-arene coupling reaction proceeded most probably through an oxidative addition of the Caryl-Br bond to a ligated palladium catalyst followed by a sequence of an enantioselective 1,5-palladium migration and an intramolecular C-H arylation sequence. This new family of inherently chiral calixarenes possesses unique chiroptical properties thanks to their highly rigid structure induced by the 9H-fluorene segment.

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.

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.