Cyclization of interlocked fumaramides into β-lactams: experimental and computational mechanistic assessment of the key intercomponent proton transfer and the stereocontrolling active pocket

A detailed mechanistic study of the diastereoselective CsOH-promoted cyclization of interlocked fumaramides to give β-lactams is described. The mechanistic analysis comprises the experimental evaluation of the structure-reactivity relationship for a wide range of fumaramides [2]rotaxanes (Hammet-plots), KIE studies with deuterium-labelled interlocked fumaramides and computational analysis of two alternative mechanistic pathways for the cyclization process. The obtained results confirm that: (a) the rate-determining step is the deprotonation of the N-benzyl group of the thread by the amidate group of the macrocycle generated by the external base, (b) the polyamide macrocycle plays an important role not only as activating element but also as the stereodifferenciating factor responsible for the observed diastereoselection and (c) the higher flexibility of the adamantyl core speeds up the cyclization process in diadamantyl-derived rotaxanes.

A mechanistic study of the diastereoselective cyclization of interlocked fumaramides to give β-lactams unveils the key factors for successfully taming the process.     

Metastable doubly threaded [3]rotaxanes with a large macrocycle

Ring size is a critically important parameter in many interlocked molecules as it directly impacts many of the unique molecular motions that they exhibit. Reported herein are studies using one of the largest macrocycles reported to date to synthesize doubly threaded [3]rotaxanes. A large ditopic 46 atom macrocycle containing two 2,6-bis(N-alkyl-benzimidazolyl)pyridine ligands has been used to synthesize several metastable doubly threaded [3]rotaxanes in high yield (65–75% isolated) via metal templating. Macrocycle and linear thread components were synthesized and self-assembled upon addition of iron(ii) ions to form the doubly threaded pseudo[3]rotaxanes that could be subsequently stoppered using azide–alkyne cycloaddition chemistry. Following demetallation with base, these doubly threaded [3]rotaxanes were fully characterized utilizing a variety of NMR spectroscopy, mass spectrometry, size-exclusion chromatography, and all-atom simulation techniques. Critical to the success of accessing a metastable [3]rotaxane with such a large macrocycle was the nature of the stopper group employed. By varying the size of the stopper group it was possible to access metastable [3]rotaxanes with stabilities in deuterated chloroform ranging from a half-life of <1 minute to ca. 6 months at room temperature potentially opening the door to interlocked materials with controllable degradation rates.

Multiple metastable doubly threaded [3]rotaxanes using a large 46 atom ring were prepared and fully characterized. Varying the stopper group size gave a range of interlocked stabilities in CDCl₃ from a half-life of <1 minute to ca. 6 months.     

Rh(i)-catalyzed stereoselective desymmetrization of prochiral cyclohexadienones via highly exo-selective Huisgen-type [3 + 2] cycloaddition

A Rh(i)-catalyzed highly stereoselective desymmetrization of 2-alkynylbenzaldehyde-tethered cyclohexadienones triggered by intramolecular Huisgen-type [3 + 2] cycloaddition has been developed. This method enables convergent construction of complex epoxy-bridged polycyclic ring systems with five contiguous stereocenters with excellent exo-selectivity and broad substrate scope. The highly atom-economical process involves 6-endo-dig cyclization of carbonyl oxygen onto an activated alkyne resulting in a highly reactive metal–benzopyrylium intermediate, which readily undergoes intramolecular [3 + 2] annulation/hydration. Asymmetric induction is also achieved for the first time in Rh(i)-catalyzed 1,3-dipolar cycloaddition using an easily accessible chiral diene as the ligand.

A Rh(i)-catalyzed highly stereoselective desymmetrization of 2-alkynylbenzaldehyde-tethered cyclohexadienones triggered by intramolecular Huisgen-type [3 + 2] cycloaddition has been developed.     

Formal oxo- and aza-[3 + 2] reactions of α-enaminones and quinones: a double divergent process and the roles of chiral phosphoric acid and molecular sieves

A double divergent process has been developed for the reaction of α-enaminones with quinones through facile manipulation of catalyst and additive, leading to structurally completely different products. The two divergent processes, which involve formal aza- and oxo-[3 + 2] cycloaddition reactions, are mediated by chiral phosphoric acid and molecular sieves, respectively. While inclusion of phosphoric acid in the reaction switched the reaction pathway to favor the efficient formation of a wide range of N-substituted indoles, addition of 4 Å molecular sieves to the reaction switched the reaction pathway again, leading to enantioselective synthesis of 2,3-dihydrobenzofurans in excellent yields and enantioselectivities under mild conditions. Studies in this work suggest that the chiral phosphoric acid acts to lower the transition state energy and promote the formation of amide intermediate for the formal aza-[3 + 2] cycloaddition and the molecular sieves serve to facilitate proton transfer for oxo-[3 + 2] cycloaddition. The reactivity of α-enaminones is also disclosed in this work.

A double divergent process for [3 + 2] cycloadditions of α-enaminones with quinones led to the formation of N-substituted indoles and 2,3-dihydrobenzofurans.     

Pre-regulation of the planar chirality of pillar[5]arenes for preparing discrete chiral nanotubes

Regulating the chirality of macrocyclic host molecules and supramolecular assemblies is crucial because chirality often plays a role in governing the properties of these systems. Herein, we describe pillar[5]arene-based chiral nanotube formation via pre-regulation of the building blocks'' chirality, which is different from frequently used post-regulation strategies. The planar chirality of rim-differentiated pillar[5]arenes is initially regulated by chiral awakening and further induction/inversion through stepwise achiral external stimuli. The pre-regulated chiral information is well stored in discrete nanotubes by interacting with a per-alkylamino-substituted pillar[5]arene. Such pre-regulation is more efficient than post-regulating the chirality of nanotubes.

Pillar[5]arene-based chiral nanotube formation via pre-regulation of the building blocks'' chirality is more efficient than post-regulating the chirality of nanotubes.     

Vibrational circular dichroism spectroscopy for probing the expression of chirality in mechanically planar chiral rotaxanes

Mechanically interlocked molecules can exhibit molecular chirality that arises due to the mechanical bond rather than covalent stereogenic units. Developing applications of such systems is made challenging by the absence of techniques for assigning the absolute configuration of products and methods to probe how the mechanical stereogenic unit influences the spatial arrangements of the functional groups in solution. Here we demonstrate for the first time that Vibrational Circular Dichroism (VCD) can be used to not only discriminate between mechanical stereoisomers but also provide detailed information on their (co)conformations. The latter is particularly important as these molecules are now under investigation in catalysis and sensing, both of which rely on the solution phase shape of the interlocked structure. Detailed analysis of the VCD spectra shows that, although many of the signals arise from coupled oscillators isolated in the covalent sub-components, intercomponent coupling between the macrocycle and axle gives rise to several VCD bands.

Through the looking glass: VCD spectroscopy provides unique insight into how a chiral mechanical bond imposes shape on rotaxanes in solution and allows their absolute configuration to be determined.     

Distinctive features and challenges in catenane chemistry

From being an aesthetic molecular object to a building block for the construction of molecular machines, catenanes and related mechanically interlocked molecules (MIMs) continue to attract immense interest in many research areas. Catenane chemistry is closely tied to that of rotaxanes and knots, and involves concepts like mechanical bonds, chemical topology and co-conformation that are unique to these molecules. Yet, because of their different topological structures and mechanical bond properties, there are some fundamental differences between the chemistry of catenanes and that of rotaxanes and knots although the boundary is sometimes blurred. Clearly distinguishing these differences, in aspects of bonding, structure, synthesis and properties, between catenanes and other MIMs is therefore of fundamental importance to understand their chemistry and explore the new opportunities from mechanical bonds.

Catenane chemistry is closely associated with that of rotaxane and knot, and this perspective highlights their similarities and differences in various aspects including synthesis, structure and properties.     

Tandem [4 + 2]/[2 + 2] cycloaddition of o-carboryne with enynes: facile construction of carborane-fused tricyclics

o-Carboryne (1,2-dehydro-o-carborane) is a very useful synthon for the synthesis of a variety of carborane-functionalized molecules. With 1-Li-2-OTf-o-C₂B₁₀H₁₀ as the precursor, o-carboryne undergoes an efficient [4 + 2] cycloaddition with various conjugated enynes, followed by a subsequent [2 + 2] cycloaddition at room temperature, generating a series of carborane-fused tricyclo[6.4.0.0^2,7]dodeca-2,12-dienes in moderate to high isolated yields. This reaction is compatible with many functional groups and has a broad substrate scope. A reactive carborane-fused 1,2-cyclohexadiene intermediate is involved, which is supported by experimental results and DFT calculations. This protocol offers a convenient strategy for the construction of complex carborane-functionalized tricyclics.

An unprecedented tandem [4 + 2]/[2 + 2] cycloaddition of o-carboryne with enynes has been disclosed for the efficient synthesis of various carborane-fused tricyclics, in which a reactive carborane-fused 1,2-cyclohexadiene intermediate is involved.     

Molecularly pure miktoarm spherical nucleic acids: preparation and usage as a scaffold for abiotic intracellular catalysis

We present a fullerene-based strategy that allows the synthesis of molecularly pure miktoarm spherical nucleic acids (SNAs) with diverse structures, which, with post-functionalization, could serve as efficient scaffolds for intracellular catalysis. The SNA structure promotes cell permeability, nucleic acid stability, and catalytic efficiency, making the platform ideal for in cellulo reactions. Consequently, the tris(triazole)-bearing miktoarm SNA was able to effectively mediate intracellular copper-catalyzed alkyne–azide cycloaddition at nanomolar level of copper, and facilitate the same reaction in live zebrafish.

Biocompatible nano-constructs, with definite molecular structures and programmable subunits, can potentially be used as biocatalysts with modular functional moieties.     

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.     

Asymmetric synthesis,structures, and chiroptical properties of helical cycloparaphenylenes

Planar chiral carbon nanorings and nanobelts (CNRs and CNBs), the sidewall segment molecules of chiral-type carbon nanotubes (CNTs), have attracted attention owing to their characteristic chiroptical properties. From the appropriate CNTs, axially or planar chiral CNRs and CNBs have been designed and synthesized, but multiply helical sidewall segments were almost unexplored due to the difficulty in simultaneous control of multiple chiralities. In this article, we have succeeded in the perfectly diastereo- and enantiocontrolled catalytic synthesis of a cycloparaphenylene with four helical and two planar chiralities showing good chiroptical responses as chiral organic molecules. The perfectly stereocontrolled multiply helical structure was confirmed by a single-crystal X-ray diffraction analysis. The experimental and theoretical studies established the importance of the highly symmetric multiply helical structure in the cylindrical axis in obtaining good chiroptical responses.

The perfectly diastereo- and enantiocontrolled catalytic synthesis of a cycloparaphenylene with four helical and two planar chiralities showing good chiroptical responses was achieved by the rhodium-catalyzed alkyne cyclotrimerization.     

Anion Sensing by Solution‐ and Surface‐Assembled Osmium(II) Bipyridyl Rotaxanes

We report the preparation of [2]rotaxanes containing an electrochemically and optically active osmium(II) bipyridyl macrocyclic component mechanically bonded with cationic pyridinium axles. Such interlocked host systems are demonstrated to recognise and sense anionic guest species as shown by ¹H NMR, luminescence and electrochemical studies. The rotaxanes can be surface assembled on to gold electrodes through anion templation under click copper(I)‐catalysed Huisgen cycloaddition conditions to form rotaxane molecular films, which, after template removal, respond electrochemically and selectively to chloride.     

Access to substituted cyclobutenes by tandem [3,3]-sigmatropic rearrangement/[2 + 2] cycloaddition of dipropargylphosphonates under Ag/Co relay catalysis

We present herein an unconventional tandem [3,3]-sigmatropic rearrangement/[2 + 2] cycloaddition of simple dipropargylphosphonates to deliver a range of bicyclic polysubstituted cyclobutenes and cyclobutanes under Ag/Co relay catalysis. An interesting switch from allene–allene to allene–alkyne cycloaddition was observed based on the substitution of the substrates, which further diversified the range of compounds accessible from this practical method. Significantly, preliminary biological screening of these new compounds identified promising candidates as suppressors of cellular proliferation.

In situ generation of allenes through [3,3]-sigmatropic rearrangement of propargylphosphonates. Divergent allene–allene or allene–alkyne cycloaddition by Ag/Co relay catalysis. Products as promising suppressors of cellular proliferation.     

Asymmetric synthesis of dihydro-1,3-dioxepines by Rh(ii)/Sm(iii) relay catalytic three-component tandem [4 + 3]-cycloaddition

Heterocycles have been widely used in organic synthesis, agrochemical, pharmaceutical and materials science industries. Catalytic three-component ylide formation/cycloaddition enables the assembly of complex heterocycles from simple starting materials in a highly efficient manner. However, asymmetric versions remain a yet-unsolved task. Here, we present a new bimetallic catalytic system for tackling this challenge. A combined system of Rh(ii) salt and chiral N,N′-dioxide–Sm(iii) complex was established for promoting the unprecedented tandem carbonyl ylide formation/asymmetric [4 + 3]-cycloaddition of aldehydes and α-diazoacetates with β,γ-unsaturated α-ketoesters smoothly, affording various chiral 4,5-dihydro-1,3-dioxepines in up to 97% yield, with 99% ee. The utility of the current method was demonstrated by conversion of products to optically active multi-substituted tetrahydrofuran derivatives. A possible reaction mechanism was provided to elucidate the origin of chiral induction based on experimental studies and X-ray structures of catalysts and products.

Catalytic asymmetric tandem carbonyl ylide formation/[4 + 3]-cycloaddition of β,γ-unsaturated α-ketoesters, aldehydes and α-diazoacetates was achieved by using a bimetallic rhodium(ii)/chiral N,N′-dioxide–Sm(iii) complex catalyst.     

Enantioselective transition metal catalysis directed by chiral cations

Enantioselective transition metal catalysis directed by chiral cations is the amalgamation of chiral cation catalysis and organometallic catalysis. Thus far, three strategies have been revealed: ligand scaffolds incorporated on chiral cations, chiral cations paired with transition metal ‘ate’-type complexes, and ligand scaffolds incorporated on achiral anions. Chiral cation ion-pair catalysis has been successfully applied to alkylation, cycloaddition, dihydroxylation, oxohydroxylation, sulfoxidation, epoxidation and C–H borylation. This development represents an effective approach to promote the cooperation between chiral cations and transition metals, increasing the versatility and capability of both these forms of catalysts. In this review, we present current examples of the three strategies and suggest possible inclusions for the future.

Enantioselective transition metal catalysis directed by chiral cations is the amalgamation of chiral cation catalysis and organometallic catalysis.     

Discovery of an all-donor aromatic [2]catenane

We report herein the first all-donor aromatic [2]catenane formed through dynamic combinatorial chemistry, using single component libraries. The building block is a benzo[1,2-b:4,5-b′]dithiophene derivative, a π-donor molecule, with cysteine appendages that allow for disulfide exchange. The hydrophobic effect plays an essential role in the formation of the all-donor [2]catenane. The design of the building block allows the formation of a quasi-fused pentacyclic core, which enhances the stacking interactions between the cores. The [2]catenane has chiro-optical and fluorescent properties, being also the first known DCC-disulphide-based interlocked molecule to be fluorescent.

An all-donor [2]catenane has been synthesised via dynamic combinatorial chemistry. It features stacked benzodithiophenes which are quasi-pentacyclic through hydrogen bonding.     

Meeting key synthetic challenges in amanitin synthesis with a new cytotoxic analog: 5′-hydroxy-6′-deoxy-amanitin

Appreciating the need to access synthetic analogs of amanitin, here we report the synthesis of 5′-hydroxy-6′-deoxy-amanitin, a novel, rationally-designed bioactive analog and constitutional isomer of α-amanitin, that is anticipated to be used as a payload for antibody drug conjugates. In completing this synthesis, we meet the challenge of diastereoselective sulfoxidation by presenting two high-yielding and diastereoselective sulfoxidation approaches to afford the more toxic (R)-sulfoxide.

Elucidating a highly diastereoselective sulfoxidation of S-deoxy-amanitin to afford α-amanitin and a more synthetically accessible analog of near-native toxicity.     

Organocatalytic cycloaddition–elimination cascade for atroposelective construction of heterobiaryls

The first chiral phosphoric acid (CPA) catalyzed cycloaddition–elimination cascade reaction of 2-naphthol- and phenol-derived enecarbamates with azonaphthalenes has been established, providing a highly atroposelective route to an array of axially chiral aryl-C3-benzoindoles in excellent yields with excellent enantioselectivities. The success of this strategy derives from the stepwise process involving CPA-catalyzed asymmetric formal [3 + 2] cycloaddition and subsequent central-to-axial chirality conversion by elimination of a carbamate. In addition, the practicality of this reaction had been verified by varieties of transformations towards functionalized atropisomers.

An organocatalytic asymmetric cycloaddition–elimination cascade reaction of aryl enecarbamates with azonaphthalenes has been developed to access axially chiral heterobiaryls in excellent yields and enantioselectivities.     

Molecular engineering enabling reversible transformation between helical and planar conformations by cyclization of alkynes

Molecular engineering enabling reversible transformation between helical and planar conformations is described herein. Starting from easily available 2-(pyridin-2-yl)anilines and alkynes, a one-pot strategy is set up for the synthesis of aza[4]helicenes via two successive rhodium-catalyzed C–H activation/cyclizations. Helical pyrrolophenanthridiziniums can be transformed into planar conformations through the cleavage of acidic pyrrole N–H, leading to turn-off fluorescence. NMR spectra, single crystal X-ray diffraction and DFT calculations demonstrate that the formation of an intramolecular C–H⋯N hydrogen bond is beneficial to stabilize the pyrrole nitrogen anion of the planar molecule and provide increased planarity. The reversible conformation transformations can be finely adjusted by the electron-donating and -withdrawing groups on the π⁺-fused pyrrole skeleton in the physiological pH range, thus affording an opportunity for pH-controlled intracellular selective fluorescence imaging. Pyrrolophenanthridiziniums show turn-on fluorescence in lysosomes owing to the acidic environment of lysosomes and turn-off fluorescence out of lysosomes, indicating the occurrence of the deprotonation reaction outside lysosomes and the corresponding transformation from helical to planar conformations.

One-pot synthesis of aza[4]helicenes is accomplished through two successive C–H activation/cyclizations, which exhibit on/off fluorescence switching through reversible transformation between helical and planar conformations.     

Catalytic "active-metal" template synthesis of [2]rotaxanes, [3]rotaxanes, and molecular shuttles, and some observations on the mechanism of the cu(i)-catalyzed azide-alkyne 1,3-cycloaddition

A synthetic approach to rotaxane architectures is described in which metal atoms catalyze covalent bond formation while simultaneously acting as the template for the assembly of the mechanically interlocked structure. This "active-metal" template strategy is exemplified using the Huisgen-Meldal-Fokin Cu(I)-catalyzed 1,3-cycloaddition of azides with terminal alkynes (the CuAAC "click" reaction). Coordination of Cu(I) to an endotopic pyridine-containing macrocycle allows the alkyne and azide to bind to metal atoms in such a way that the metal-mediated bond-forming reaction takes place through the cavity of the macrocycle--or macrocycles--forming a rotaxane. A variety of mono- and bidentate macrocyclic ligands are demonstrated to form [2]rotaxanes in this way, and by adding pyridine, the metal can turn over during the reaction, giving a catalytic active-metal template assembly process. Both the stoichiometric and catalytic versions of the reaction were also used to synthesize more complex two-station molecular shuttles. The dynamics of the translocation of the macrocycle by ligand exchange in these two-station shuttles could be controlled by coordination to different metal ions (rapid shuttling is observed with Cu(I), slow shuttling with Pd(II)). Under active-metal template reaction conditions that feature a high macrocycle:copper ratio, [3]rotaxanes (two macrocycles on a thread containing a single triazole ring) are also produced during the reaction. The latter observation shows that under these conditions the mechanism of the Cu(I)-catalyzed terminal alkyne-azide cycloaddition involves a reactive intermediate that features at least two metal ions.