Asymmetric addition of Grignard reagents to ketones: culmination of the ligand-mediated methodology allows modular construction of chiral tertiary alcohols

A new class of biaryl chiral ligands derived from 1,2-diaminocyclohexane (1,2-DACH) has been designed to enable the asymmetric addition of aliphatic and, for the first time, aromatic Grignard reagents to ketones for the preparation of highly enantioenriched tertiary alcohols (up to 95% ee). The newly developed ligands L12 and L12′ together with the previously reported L0 and L0′ define a set of complementary chiral promoters, which provides access to the modular construction of a broad range of structurally diverse non-racemic tertiary alcohols, bearing challenging quaternary stereocenters. The present advancements bring to completion our asymmetric Grignard methodology by expanding the scope to aromatic organomagnesium reagents, while facilitating its implementation in organic synthesis thanks to improved synthetic routes for the straightforward access to the chiral ligands. The synthetic utility of the method has been demonstrated by the development of a novel and highly enantioselective formal synthesis of the antihistamine API clemastine via intermediate (R)-3a. Exploiting the power of the 3-disconnection approach offered by the Grignard synthesis, (R)-3a is obtained in 94% ee with ligand (R,R)-L12. The work described herein marks the finalization of our ongoing effort towards the establishment of an effective and broadly applicable methodology for the asymmetric Grignard synthesis of chiral tertiary alcohols.

Easily applied enantioselective addition of aliphatic and aromatic Grignard reagents to ketones provides modular and universal access to challenging chiral tertiary alcohols, enabling the straightforward preparation of natural products and APIs.     

Construction of a quaternary stereogenic center by asymmetric hydroformylation: a straightforward method to prepare chiral α-quaternary amino acids

The construction of chiral quaternary carbon stereocenters has been a long-standing challenge in organic chemistry. Particularly, α-quaternary amino acids that are of high importance in biochemistry still lack a straightforward synthetic method. We here reported a hydroformylation approach to access chiral quaternary stereogenic centers, which has been a long-standing challenge in transition metal catalysis. α,β-Unsaturated carboxylic acid derivatives undergo hydroformylation with a rhodium catalyst to generate an α-quaternary stereocenter under mild conditions. By using this method, a variety of chiral α-quaternary amino acids could be synthesized with satisfactory enantioselectivity. In-depth investigation revealed that the regioselectivity is dramatically influenced by the electronic properties of the substituents attached to the target C C bond. By applying NMR and DFT analyses, the chiral environment of a rhodium/Yanphos complex was depicted, based on which a substrate-catalyst interaction model was proposed.

A rhodium-catalyzed asymmetric hydroformylation reaction was reported to construct chiral α-quaternary amino acid derivatives. High chemo-, regio- and enantioselectivity were realized in one step.     

Enantioselective palladium-catalyzed C(sp2)–C(sp2) σ bond activation of cyclopropenones by merging desymmetrization and (3 + 2) spiroannulation with cyclic 1,3-diketones

Catalytic asymmetric variants for functional group transformations based on carbon–carbon bond activation still remain elusive. Herein we present an unprecedented palladium-catalyzed (3 + 2) spiro-annulation merging C(sp²)–C(sp²) σ bond activation and click desymmetrization to form synthetically versatile and value-added oxaspiro products. The operationally straightforward and enantioselective palladium-catalyzed atom-economic annulation process exploits a TADDOL-derived bulky P-ligand bearing a large cavity to control enantioselective spiro-annulation that converts cyclopropenones and cyclic 1,3-diketones into chiral oxaspiro cyclopentenone–lactone scaffolds with good diastereo- and enantio-selectivity. The click-like reaction is a successful methodology with a facile construction of two vicinal carbon quaternary stereocenters and can be used to deliver additional stereocenters during late-state functionalization for the synthesis of highly functionalized or more complex molecules.

An unprecedented palladium-catalyzed (3 + 2) spiro-annulation merging C–C bond activation and desymmetrization was developed for the enantioselective construction of synthetically versatile and value-added oxaspiro products with up to 95% ee.     

Catalytic asymmetric synthesis of 3,2′-pyrrolinyl spirooxindoles via conjugate addition/Schmidt-type rearrangement of vinyl azides and (E)-alkenyloxindoles

A catalytic asymmetric conjugate addition/Schmidt-type rearrangement of vinyl azides and (E)-alkenyloxindoles was realized. It afforded a variety of optically active 3,2′-pyrrolinyl spirooxindoles with high yields (up to 98%), and excellent diastereo- and enantioselectivities (up to 98% ee, >19 : 1 dr), even at the gram-scale in the presence of a chiral N,N′-dioxide–nickel(ii) complex. In addition, a possible catalytic cycle and transition state model were proposed to rationalize the stereoselectivity.

Lewis acid catalyzed asymmetric synthesis of 3,2′-pyrrolinyl spirooxindole skeletons via conjugate addition/Schmidt-type rearrangement of vinyl azides and (E)-alkenyloxindoles.     

Dynamic kinetic resolution of transient hemiketals: a strategy for the desymmetrisation of prochiral oxetanols

Identification of an electron poor trifluoroacetophenone allows the formation of uniquely stable hemiketals from prochiral oxetanols. When exposed to a cobalt(ii) catalyst, efficient ring-opening to densely functionalized dioxolanes is observed. Mechanistic studies suggest an unprecedented redox process between the cobalt(ii) catalyst and the hemiketal that initiates the oxetane-opening. Based on this observation, a dynamic kinetic resolution of the transient hemiketals is explored that uses a Katsuki-type ligand for stereoinduction (up to 99 : 1 dr and 96 : 4 er) and allows a variety of 1,3-dioxolanes to be accessed (20 examples up to 98% yield).

Desymmetrization of prochiral oxetanols via an electron-deficient hemiketal intermediate is achieved. Key to this process is the catalyst''s chiral recognition of one of the two hemiketal enantiomers enabling an efficient dynamic kinetic resolution.     

Asymmetric synthesis of dibenzo[b,d]azepines by Cu-catalyzed reductive or borylative cyclization

A copper-catalyzed asymmetric intramolecular reductive cyclization for the synthesis of dibenzo[b,d]azepines is described. Use of 2′-vinyl-biaryl-2-imines as substrates and in situ formed [Cu^I/(Ph-BPE)] as the catalyst enables the synthesis of 7-membered bridged biarylamines containing both central and axial stereogenic elements in high yields (up to 98%) and with excellent diastereo- and enantioselectivities (>20 : 1 d.r., up to 99% ee). Moreover, the same catalyst was found to facilitate a related borylative cyclization to afford versatile boronic ester derivatives. Both reactions proceed under mild conditions (rt) and are applicable to a variety of substituted aromatic and heterocyclic derivatives.

Dibenzo[b,d]azepines featuring axially chiral 7-member-bridged biaryls have been prepared by asymmetric reductive or borylative cyclizations using copper catalysis.     

Catalytic asymmetric transformations of racemic α-borylmethyl-(E)-crotylboronate via kinetic resolution or enantioconvergent reaction pathways

We report herein catalytic asymmetric transformations of racemic α-borylmethyl-(E)-crotylboronate. The Brønsted acid-catalyzed kinetic resolution–allylboration reaction sequence of the racemic reagent gave (Z)-δ-hydroxymethyl-anti-homoallylic alcohols with high Z-selectivities and enantioselectivities upon oxidative workup. In parallel, enantioconvergent pathways were utilized to synthesize chiral nonracemic 1,5-diols and α,β-unsaturated aldehydes with excellent optical purity.

We report herein catalytic asymmetric transformations of racemic α-borylmethyl-(E)-crotylboronate.     

Amplification of weak chiral inductions for excellent control over the helical orientation of discrete topologically chiral (M3L2)n polyhedra

Superb control over the helical chirality of discrete (M₃L₂)_n polyhedra (n = 2,4,8, M = Cu^I or Ag^I) created from the self-assembly of propeller-shaped ligands (L) equipped with chiral side chains is demonstrated here. Almost perfect chiral induction (>99 : 1) of the helical orientation of the framework was achieved for the largest (M₃L₂)₈ cube with 48 small chiral side chains (diameter: ∼5 nm), while no or moderate chiral induction was observed for smaller polyhedra (n = 2, 4). Thus, amplification of the weak chiral inductions of each ligand unit is an efficient way to control the chirality of large discrete nanostructures with high structural complexity.

Superb control over the helical chirality of highly-entangled (M₃L₂)_n polyhedra (M = Cu(i), Ag(i); n = 2,4,8) was achieved via multiplication of weak chiral inductions by side chains accumulated on the huge polyhedral surfaces.     

Phosphite mediated asymmetric N to C migration for the synthesis of chiral heterocycles from primary amines

A phosphite mediated stereoretentive C–H alkylation of N-alkylpyridinium salts derived from chiral primary amines was achieved. The reaction proceeds through the activation of the N-alkylpyridinium salt substrate with a nucleophilic phosphite catalyst, followed by a base mediated [1,2] aza-Wittig rearrangement and subsequent catalyst dissociation for an overall N to C-2 alkyl migration. The scope and degree of stereoretention were studied, and both experimental and theoretical investigations were performed to support an unprecedented aza-Wittig rearrangement–rearomatization sequence. A catalytic enantioselective version starting with racemic starting material and chiral phosphite catalyst was also established following our understanding of the stereoretentive process. This method provides efficient access to tertiary and quaternary stereogenic centers in pyridine systems, which are prevalent in drugs, bioactive natural products, chiral ligands, and catalysts.

N-Alkylpyridinium salt of chiral amines undergoes phosphite mediated stereoretentive migrations to generate chiral alkylpyridines. The role of phosphite on reactivity and stereoselectivity were examined to achieve a catalytic asymmetric version.     

Asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters to functionalized chiral allylic alcohols via dynamic kinetic resolution

An iridium catalyzed asymmetric hydrogenation of racemic exocyclic γ,δ-unsaturated β-ketoesters via dynamic kinetic resolution to functionalized chiral allylic alcohols was developed. With the chiral spiro iridium catalysts Ir-SpiroPAP, a series of racemic exocyclic γ,δ-unsaturated β-ketoesters bearing a five-, six-, or seven-membered ring were hydrogenated to the corresponding functionalized chiral allylic alcohols in high yields with good to excellent enantioselectivities (87 to >99% ee) and cis-selectivities (93 : 7 to >99 : 1). The origin of the excellent stereoselectivity was also rationalized by density functional theory calculations. Furthermore, this protocol could be performed on gram scale and at a lower catalyst loading (0.002 mol%) without the loss of reactivity and enantioselectivity, and has been successfully applied in the enantioselective synthesis of chiral carbocyclic δ-amino esters and the β-galactosidase inhibitor isogalactofagomine.

An iridium catalyzed asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters via dynamic kinetic resolution was developed, providing efficient protocol for enantioselective synthesis of functionalized chiral allylic alcohols.     

Construction of polycyclic structures with vicinal all-carbon quaternary stereocenters via an enantioselective photoenolization/Diels–Alder reaction

All-carbon quaternary stereocenters are ubiquitous in natural products and significant in drug molecules. However, construction of all-carbon stereocenters is a challenging project due to their congested chemical environment. And, when vicinal all-carbon quaternary stereocenters are present in one molecule, they will dramatically increase its synthetic challenge. A chiral titanium promoted enantioselective photoenolization/Diels–Alder (PEDA) reaction allows largely stereohindered tetra-substituted dienophiles to interact with highly active photoenolized hydroxy-o-quinodimethanes, delivering fused or spiro polycyclic rings bearing vicinal all-carbon quaternary centers in excellent enantiomeric excess through one-step operation. This newly developed enantioselective PEDA reaction will inspire other advances in asymmetric excited-state reactions, and could be used in the total synthesis of structurally related complex natural products or drug-like molecules for drug discovery.

An enantioselective PEDA reaction was developed to enable stereohindered dienophiles to interact with transient photoenolized hydroxy-o-quinodimethanes, delivering fused or spiro polycyclic rings bearing 2–3 vicinal all-carbon quaternary centers in good yield and excellent ee.     

Enantioselective [1,2]-Stevens rearrangement of thiosulfonates to construct dithio-substituted quaternary carbon centers

An enantioselective [1,2] Stevens rearrangement was realized by using chiral guanidine and copper(i) complexes. Bis-sulfuration of α-diazocarbonyl compounds was developed through using thiosulfonates as the sulfenylating agent. It was undoubtedly an atom-economic process providing an efficient route to access novel chiral dithioketal derivatives, affording the corresponding products in good yields (up to 90% yield) and enantioselectivities (up to 96 : 4 er). A novel catalytic cycle was proposed to rationalize the reaction process and enantiocontrol.

An asymmetric [1,2] Stevens rearrangement was realized via chiral guanidine and copper(i) complexes. A series of novel chiral dithioketal derivatives were obtained with good yields (up to 90% yield) and enantioselectivities (up to 96 : 4 er).     

Direct access to tetrasubstituted cyclopentenyl scaffolds through a diastereoselective isocyanide-based multicomponent reaction

An efficient strategy combining the stereocontrol of organocatalysis with the diversity-generating character of multicomponent reactions is described to produce structurally unique, tetrasubstituted cyclopentenyl frameworks. An asymmetric Michael addition–hemiacetalization between α-cyanoketones and α,β-unsaturated aliphatic aldehydes was performed for constructing cyclic hemiacetals, which were next employed as chiral bifunctional substrates in a new diastereoselective intramolecular isocyanide-based multicomponent reaction. This approach furnished a diversity of structurally complex compounds – including peptidomimetics and natural product hybrids in high stereoselectivity (up to >99% ee and up to >99 : 1 dr) and in moderate to high yields.

Simple and available reagents are combined in this new three-component isocyanide-based multicomponent reaction providing an interesting and straightforward way to prepare complex and highly functionalized cyclopentenyl rings.     

Dirhodium(ii)-catalysed cycloisomerization of azaenyne: rapid assembly of centrally and axially chiral isoindazole frameworks

Described herein is a dirhodium(ii)-catalyzed asymmetric cycloisomerization reaction of azaenyne through a cap-tether synergistic modulation strategy, which represents the first catalytic asymmetric cycloisomerization of azaenyne. This reaction is highly challenging because of its inherent strong background reaction leading to racemate formation and the high capability of coordination of the nitrogen atom resulting in catalyst deactivation. Varieties of centrally chiral isoindazole derivatives could be prepared in up to 99 : 1 d.r., 99 : 1 er and 99% yield and diverse enantiomerically enriched atropisomers bearing two five-membered heteroaryls have been accessed by using an oxidative central-to-axial chirality transfer strategy. The tethered nitrogen atom incorporated into the starting materials enabled easy late-modifications of the centrally and axially chiral products via C–H functionalizations, which further demonstrated the appealing synthetic utilities of this powerful asymmetric cyclization.

Rh(ii)-catalyzed asymmetric cycloisomerization of azaenyne through a cap-tether synergistic modulation strategy was described. Diverse centrally and axially chiral isoindazoles were prepared and directed C–H late-stage modifications were developed.

Known as one of the most significant and reliable access methods to chiral heterocycles, asymmetric cycloisomerization of conjugated enyne has caught extensive attention and interest for its wide applications in synthetic route design and mechanistic investigation.¹ Specifically, asymmetric cyclization of conjugated enynone (X = C, Z = O) has been successfully developed and applied to the rapid construction of various chiral furan-containing skeletons with high efficiency in an extremely operationally simple manner (Scheme 1a).² However, compared to the fruitful research with enynone, it is surprising that the analogous asymmetric version of azaenyne (Z = N–R) still remains underdeveloped.³ In fact, no successful example of catalytic asymmetric cyclization of azaenyne has been reported in the literature despite the apparent significance of nitrogen-containing five-membered heterocycles in the synthetic and pharmaceutical community.⁴ In 2004, Haley and Herges reported a detailed experimental and theoretical study of the cyclization reaction of (2-ethynylphenyl)-phenyldiazene, which is a unique azaenyne.⁵ According to the DFT calculations, very close and low activation barriers for 5-exo-dig and 6-endo-dig cyclization pathways under catalyst-free conditions were found, which shed light on the inherent challenges of the asymmetric reaction of azaenyne (Scheme 1b). For instance, there was usually a regioselectivity issue (5-exo and 6-endo) in the cyclization reaction of azaenyne because of their close reaction barriers where the competitive 6-endo-dig cyclization^3a,6 may lead to troublesome side-product formation. In addition, the low activation barrier deriving from the strong N-nucleophilicity of azaenyne may easily lead to self-cyclization which will cause severe background reactions to interfere with the asymmetric process. More troublingly, this transformation might suffer from catalyst deactivation arising from the high coordinating capability of the nitrogen atom in both starting materials and products, which might give more opportunities to the propagation of detrimental background reactions. In some cases, even a super-stoichiometric amount of transition metal has to be used to ensure effective conversion.^3a,7 Therefore, although many nonchiral approaches have been reported,^3,5 catalytic asymmetric cyclization of azaenyne still remains elusive due to the inherent obstacles aforementioned. With our continuous interest in alkyne chemistry,^2a,8 herein we designed a cap-tether synergistic modulation strategy to tackle these challenges, envisioning that modulation of the tethered atom and protecting cap of nitrogen in the azaenyne would intrinsically perturb and alter the reactivity of the starting material, and therefore the azaenyne motif could be effectively harnessed as a promising synthon for asymmetric transformations (Scheme 1c). It should be noted that the obtained centrally chiral product produced from intramolecular C–H insertion of donor-type metal carbene⁹ might be potentially converted into the axially chiral molecule via a central-to-axial chirality conversion strategy.Open in a separate windowScheme 1Development of the asymmetric cyclization reaction of conjugated azaenyne.With this design in mind, different types of azaenynes bearing typical tethering atoms and capping groups were chosen to test our hypothesis and representative results are shown in Scheme 2. First, tBu-capping imine (X = C, R = tBu) was selected as a substrate to test our hypothesis.^6a It was found that the imine exhibited low reactivity and the reaction temperature has to be elevated to 100 °C to initiate the transformation with or without catalyst. Unfortunately, the desired 5-exo-dig cyclization product was not detected, but isoquinoline from 6-endo-dig cyclization was obtained instead (Scheme 2a). To further regulate and control the regioselectivity and reactivity, triazene (X = N, R = N-piperidyl) was then investigated. Similarly, this substrate also showed low reactivity and it is still required to be heated at 100 °C for conversion. In the absence of a metal catalyst, an unexpected alkyne, deriving from the fragmentation of the triazene moiety, was produced in 41% yield. When 2 mol% Rh₂(OPiv)₄ was added as a catalyst, the side reaction could be efficiently suppressed and the reaction selectivity was apparently reversed. In this case, the target C–H insertion dihydrofuran was furnished as the major product in 30% yield but still accompanied by concomitant formation of 12% yield of undesired alkyne (Scheme 2b). The above investigations showed neither the imine nor triazene was an ideal substrate for the asymmetric reaction. Thus, we moved our attention to the diazene substrate (X = N, R = aryl). As demonstrated by Haley''s and Herges'' pioneering work, ortho-alkynyl diazene, compared with imine and triazene, was more unstable and tended to self-cyclization even at room temperature.^5a As shown in Scheme 2c, the ortho-alkynyl diazene degrades and 5-exo-dig cyclization products could be observed even in DCE solvent without any catalyst at room temperature. When the phenyl capping group was installed in the substrate, the reaction furnished 10% yield of isoindazole derivative. The uncatalyzed self-cyclization reaction was obviously accelerated when an electron-rich capping group (4-MeO–C₆H₄–) was introduced, affording the corresponding product in 20% yield. Inspired by these findings, we assumed that installation of an electron deficient group on the capping phenyl would reduce the nucleophilicity of the nitrogen atom and thus the troublesome self-cyclization reaction might be effectively inhibited. To our delight, when a bromo-substituent was introduced onto the phenyl cap, the undesired self-cyclization was almost suppressed. When Rh₂(OPiv)₄ was added as a catalyst, the desired carbene-involved C–H insertion product was furnished in 90% yield at room temperature. Worthy of note was the total absence of any cinnoline formation from 6-endo-dig cyclization.^3a,6b In short, the synthetic challenges associated with regioselectivity (5-exo-dig and 6-endo-dig), strong background reaction and catalyst deactivation could be successfully regulated and controlled via a tether-cap synergistic modulation strategy.Open in a separate windowScheme 2Typical substrate investigation.Encouraged by the above findings, ortho-alkynyl bromodiazene 1a was chosen as a model substrate and different types of chiral dirhodium catalysts¹⁰ were screened in DCE at room temperature for 48 h. As shown in

Enantioselective synthesis of α-amino ketones through palladium-catalyzed asymmetric arylation of α-keto imines

Chiral α-amino ketones are common structural motifs in natural products and pharmaceuticals, as well as important synthons in organic synthesis. Thus, establishing efficient methods for preparing compounds with these privileged scaffolds is an important endeavor in synthetic chemistry. Herein we disclose a new catalytic asymmetric approach for the synthesis of chiral α-amino ketones through a chiral palladium-catalyzed arylation reaction of in situ generated challenging α-keto imines from previously unreported C-acyl N-sulfonyl-N,O-aminals, with arylboronic acids. The current reaction offers a straightforward approach to the asymmetric synthesis of acyclic α-amino ketones in a practical and highly stereocontrolled manner. Meanwhile, the multiple roles of the chiral Pd(ii) complex catalyst in the reaction were also reported.

Chiral α-amino ketones are common structural motifs in natural products and pharmaceuticals, as well as important synthons in organic synthesis.     

Characterization of the T4 gp32–ssDNA complex by native,cross-linking,and ultraviolet photodissociation mass spectrometry

Protein–DNA interactions play crucial roles in DNA replication across all living organisms. Here, we apply a suite of mass spectrometry (MS) tools to characterize a protein-ssDNA complex, T4 gp32·ssDNA, with results that both support previous studies and simultaneously uncover novel insight into this non-covalent biological complex. Native mass spectrometry of the protein reveals the co-occurrence of Zn-bound monomers and homodimers, while addition of differing lengths of ssDNA generates a variety of protein:ssDNA complex stoichiometries (1 : 1, 2 : 1, 3 : 1), indicating sequential association of gp32 monomers with ssDNA. Ultraviolet photodissociation (UVPD) mass spectrometry allows characterization of the binding site of the ssDNA within the protein monomer via analysis of holo ions, i.e. ssDNA-containing protein fragments, enabling interrogation of disordered regions of the protein which are inaccessible via traditional crystallographic techniques. Finally, two complementary cross-linking (XL) approaches, bottom-up analysis of the crosslinked complexes as well as MS1 analysis of the intact complexes, are used to showcase the absence of ssDNA binding with the intact cross-linked homodimer and to generate two homodimer gp32 model structures which highlight that the homodimer interface overlaps with the monomer ssDNA-binding site. These models suggest that the homodimer may function in a regulatory capacity by controlling the extent of ssDNA binding of the protein monomer. In sum, this work underscores the utility of a multi-faceted mass spectrometry approach for detailed investigation of non-covalent protein-DNA complexes.

Ultraviolet photodissociation and native mass spectrometry allow characterization of the formation and binding interactions of protein-ssDNA complexes.     

A BINOL-phosphoric acid and metalloporphyrin derived chiral covalent organic framework for enantioselective α-benzylation of aldehydes

The catalytic asymmetric α-benzylation of aldehydes represents a highly valuable reaction for organic synthesis. For example, the generated α-heteroarylmethyl aldehydes, such as (R)-2-methyl-3-(pyridin-4-yl)propanal ((R)-MPP), are an important class of synthons to access bioactive drugs and natural products. We report herein a new and facile synthetic approach for the asymmetric intermolecular α-benzylation of aldehydes with less sterically hindered alkyl halides using a multifunctional chiral covalent framework (CCOF) catalyst in a heterogeneous way. The integration of chiral BINOL-phosphoric acid and Cu(ii)-porphyrin modules into a single COF framework endows the obtained (R)-CuTAPBP-COF with concomitant Brønsted and Lewis acidic sites, robust chiral confinement space, and visible-light induced photothermal conversion. These features allow it to highly promote the intermolecular asymmetric α-benzylation of aldehydes via visible-light induced photothermal conversion. Notably, this light-induced thermally driven reaction can effectively proceed under natural sunlight irradiation. In addition, this reaction can be easily extended to a gram-scale level, and its generality is ascertained by asymmetric α-benzylation reactions on various substituted aldehydes and alkyl bromides.

We report a new synthetic approach for the intermolecular α-alkylation of aldehydes with alkyl halides based on a BINOL-phosphate and Cu(ii)-porphyrin derived multifunctional CCOF catalyst via visible-light induced photothermal conversion.     

Regiodivergent sulfonylarylation of 1,3-enynes via nickel/photoredox dual catalysis

Catalytic difunctionalization of 1,3-enynes represents an efficient and versatile approach to rapidly assemble multifunctional propargylic compounds, allenes and 1,3-dienes. Controlling selectivity in such addition reactions has been a long-standing challenging task due to multiple reactive centers resulting from the conjugated structure of 1,3-enynes. Herein, we present a straightforward method for regiodivergent sulfonylarylation of 1,3-enynes via dual nickel and photoredox catalysis. Hinging on the nature of 1,3-enynes, diverse reaction pathways are feasible: synthesis of α-allenyl sulfones via 1,4-sulfonylarylation, or preparation of (E)-1,3-dienyl sulfones with high chemo-, regio- and stereoselectivity through 3,4-sulfonylarylation. Notably, this is the first example that nickel and photoredox catalysis are merged to achieve efficient and versatile difunctionalization of 1,3-enynes.

A mild reaction protocol for regiodivergent sulfonylarylation of 1,3-enynes via dual nickel and photoredox catalysis has been developed, which led to efficient synthesis of α-allenyl sulfones or 1,3-dienyl sulfones.     

Dynamic supramolecular self-assembly of platinum(ii) complexes perturbs an autophagy–lysosomal system and triggers cancer cell death

Self-assembly of platinum(ii) complexes to form supramolecular structures/nanostructures due to intermolecular ligand π–π stacking and metal–ligand dispersive interactions is widely used to develop functional molecular materials, but the application of such non-covalent molecular interactions has scarcely been explored in medical science. Herein is described the unprecedented biological properties of platinum(ii) complexes relevant to induction of cancer cell death via manifesting such intermolecular interactions. With conjugation of a glucose moiety to the planar platinum(ii) terpyridyl scaffold, the water-soluble complex [Pt(tpy)(C CArOGlu)](CF₃SO₃) (1a, tpy = 2,2′:6′,2′′-terpyridine, Glu = glucose) is able to self-assemble into about 100 nm nanoparticles in physiological medium, be taken up by lung cancer cells via energy-dependent endocytosis, and eventually transform into other superstructures distributed in endosomal/lysosomal and mitochondrial compartments apparently following cleavage of the glycosidic linkage. Accompanying the formation of platinum-containing superstructures are increased autophagic vacuole formation, lysosomal membrane permeabilization, and mitochondrial membrane depolarization, as well as anti-tumor activity of 1a in a mouse xenograft model. These findings highlight the dynamic, multi-stage extracellular and intracellular supramolecular self-assembly of planar platinum(ii) complexes driven by modular intermolecular interactions with potential anti-cancer application.

Self-assembly of platinum(ii) glycosylated arylacetylide gave transformable superstructures upon enzymatic action in cellulo, leading to perturbation of an autophagy-lysosomal system and cancer cell death.     

A chiral cobalt(ii) complex catalyzed enantioselective aza-Piancatelli rearrangement/Diels–Alder cascade reaction

A chiral N,N′-dioxide/cobalt(ii) complex catalyzed highly diastereoselective and enantioselective tandem aza-Piancatelli rearrangement/intramolecular Diels–Alder reaction has been disclosed. Various valuable hexahydro-2a,5-epoxycyclopenta[cd]isoindoles bearing six contiguous stereocenters have been obtained in good yields with excellent diastereo- and enantio-selectivities from a wide range of both readily available 2-furylcarbinols and N-(furan-2-ylmethyl)anilines.

An asymmetric aza-Piancatelli rearrangement/Diels–Alder cascade reaction between 2-furylcarbinols and N-(furan-2-ylmethyl)anilines was realized by using a chiral N,N′-dioxide/cobalt(ii) complex catalyst.