Ring-closing Step Research Articles

Mechanism of the Oxidative Ring-Closure Reaction during Gliotoxin Biosynthesis by Cytochrome P450 GliF.

During gliotoxin biosynthesis in fungi, the cytochrome P450 GliF enzyme catalyzes an unusual C-N ring-closure step while also an aromatic ring is hydroxylated in the same reaction cycle, which may have relevance to drug synthesis reactions in biotechnology. However, as the details of the reaction mechanism are still controversial, no applications have been developed yet. To resolve the mechanism of gliotoxin biosynthesis and gain insight into the steps leading to ring-closure, we ran a combination of molecular dynamics and density functional theory calculations on the structure and reactivity of P450 GliF and tested a range of possible reaction mechanisms, pathways and models. The calculations show that, rather than hydrogen atom transfer from the substrate to Compound I, an initial proton transfer transition state is followed by a fast electron transfer en route to the radical intermediate, and hence a non-synchronous hydrogen atom abstraction takes place. The radical intermediate then reacts by OH rebound to the aromatic ring to form a biradical in the substrate that, through ring-closure between the radical centers, gives gliotoxin products. Interestingly, the structure and energetics of the reaction mechanisms appear little affected by the addition of polar groups to the model and hence we predict that the reaction can be catalyzed by other P450 isozymes that also bind the same substrate. Alternative pathways, such as a pathway starting with an electrophilic attack on the arene to form an epoxide, are high in energy and are ruled out.

Insight into the Mechanism of CO2 Chemical Fixation into Epoxides by Windmill-Shaped Polyoxovanadate and n-Bu4NX (X = Br, I).

Carbon dioxide (CO2) coupled with epoxide to generate cyclic carbonate stands out in carbon neutrality due to its 100% atom utilization. In this work, the mechanism of CO2 cycloaddition with propylene oxide (PO) cocatalyzed by windmill-shaped polyoxovanadate, [(C2N2H8)4(CH3O)4VIV4VV4O16]·4CH3OH (V8-1), and n-Bu4NX (X = Br, I) was thoroughly investigated using density functional theory (DFT) calculations. The ring-opening, CO2-insertion, and ring-closing steps of the process were extensively studied. Our work emphasizes the synergistic effect between V8-1 and n-Bu4NX (X = Br, I). Through the analysis of an independent gradient model based on Hirshfeld partition (IGMH), it was found that the attack of n-Bu4NX (X = Br, I) on Cβ of PO triggers a distinct attractive interaction between the active fragment and the surrounding framework, serving as the primary driving force for the ring opening of PO. Furthermore, the effect of different cocatalysts was explored, with n-Bu4NI being more favorable than n-Bu4NBr. Moreover, the role of V8-1 in the CO2 cycloaddition reaction was clarified as not only acting as Lewis acid active sites but also serving as "electron sponges". This work is expected to advance the development of novel catalysts for organic carbonate formation.

Cyclic and Linear Tetrablock Copolymers Synthesized at Speed and Scale by Lewis Pair Polymerization of a One-Pot (Meth)acrylic Mixture and Characterized at Multiple Levels.

Cyclic block copolymers (cBCP) are fundamentally intriguing materials, but their synthetic challenges that demand precision in controlling both the monomer sequence and polymer topology limit access to AB and ABC block architectures. Here, we show that cyclic ABAB tetra-BCPs (cABAB) and their linear counterpart (lABAB) can be readily obtained at a speed and scale from one-pot (meth)acrylic monomer mixtures, through coupling the Lewis pair polymerization's unique compounded-sequence control with its precision in topology control. This approach achieves fast (<15 min) and quantitative (>99%) conversion to tetra-BCPs of predesignated linear or cyclic topology at scale (40 g) in a one-pot procedure, precluding the needs for repeated chain extensions, stoichiometric addition steps, dilute conditions, and postsynthetic modifications, and/or postsynthetic ring-closure steps. The resulting lABAB and cABAB have essentially identical molecular weights (Mn = 165-168 kg mol-1) and block degrees/symmetry, allowing for direct behavioral comparisons in solution (hydrodynamic volume, intrinsic viscosity, elution time, and refractive indices), bulk (thermal transitions), and film (thermomechanical and rheometric properties and X-ray scattering patterns) states. To further the morphological characterizations, allylic side-chain functionality is exploited via the thiol-ene click chemistry to install crystalline octadecane side chains and promote phase separation between the A and B blocks, allowing visualization of microdomain formation.

Synthesis of Chroman-2,4-diones via Ring-Opening/Ring-Closing Reaction Involving Palladium-Catalyzed Intramolecular Aryloxycarbonylation.

Palladium-catalyzed aminocarbonylation of 3-iodochromone was studied in the presence of primary and secondary amines using atmospheric pressure of carbon monoxide as a carbonyl source. This procedure successfully provided a library of chromone-3-carboxamides and 3-substituted chroman-2,4-diones in 40 to 92% isolated yields. The reaction proceeded via highly chemoselective aminocarbonylation (up to 100%) in the presence of secondary amines by using monodentate or bidentate phosphine ligands. The tendency of 3-iodochromone substrate to undergo ANRORC rearrangement with N-nucleophiles was crucial to shift the reaction toward an unprecedented chemoselective carbonylative transformation, where a late-stage carbonyl insertion is favored concomitantly to the last ring-closure step. The proposed aza-Michael addition/ring-opening/intramolecular aryloxycarbonylation sequence showed compatibility, uniquely, to primary amines when XantPhos was used as a ligand. The solid-state structures of chromone-3-carboxamide (2a) and chroman-2,4-dione (3s) were undoubtedly established by single-crystal XRD analysis. A catalytic cycle was proposed to rationalize the formation of the two types of carbonylated compounds.

Investigating the Roles of Active Site Residues in Mycobacterium tuberculosis Indole-3-glycerol Phosphate Synthase, a Potential Target for Antitubercular Agents.

Mycobacterium tuberculosis drug resistance is emerging and new drug targets are needed. Tryptophan biosynthesis is necessary for M. tuberculosis replication and virulence. Indole-3-glycerol phosphate synthase (IGPS) catalyzes a step in M. tuberculosis tryptophan biosynthesis and has been suggested as a potential anti-infective target, but our understanding of this enzyme is limited. To aid in inhibitor design and gain a greater mechanistic picture of this enzyme, there is a need to understand the roles of active site amino acids in ligand binding and catalysis. In this work, we explored the roles of conserved active site amino acids Glu57, Lys59, Lys119, Glu168, and Glu219. Mutation of each to Ala results in loss of all detectable activity. The Glu57Gln, Lys59Arg, Lys119Arg, Glu168Gln, and Glu219Asp mutations result in large activity losses, while Glu219Gln has enhanced activity. Analysis of the enzymatic data yields the following main conclusions: (A) Lys119 is the likely catalytic acid in the CdRP ring closure step. (B) Glu168 stabilizes a charged reaction intermediate and may also be the catalytic base. (C) Glu57, Glu219, and Lys119 form a closely arranged triad in which Glu57 and Glu219 modulate the pKa of Lys119, and thus overall activity. This increased understanding of inter- and intramolecular interactions and demonstration of the highly coordinated nature of the M. tuberculosis IGPS active site provide new mechanistic information and guidance for future work with this potential new drug target.

Diverse Synthesis of 2H-Isoindole-Based Polycyclic Aromatic Compounds.

1,3-Disubstituted N-aryl-2H-isoindoles have been synthesized by a cascade reaction of divinyl ethers, which are derived from easily available 4-bromoisocoumarins, with substituted anilines in HFIP. This cascade reaction consists of a ring-opening step through addition-elimination mechanism and the following 5-exo-tet type ring-closing step via the intramolecular nucleophilic substitution reaction. Thus obtained 2H-isoindoles have been derivatized to high-order nitrogen-containing polycycles including less accessible benzo[a]ullazines.

In-depth DFT insights into the crucial role of hydrogen bonding network in CO2 fixation into propylene oxide promoted by Biomass-Derived deep eutectic solvents

The CO2 fixation into epoxide to produce cyclic carbonate is a promising route to realize the large-scale utilization of CO2. In this work, a detailed DFT investigation has been carried out to elucidate the mechanistic details of the CO2 conversion into propylene carbonate (PC) catalyzed by bio-mass derived deep eutectic solvents (bio-DESs), obtained by combining hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) molecules. Our calculations support the known beneficial effect of hydrogen bonds in activating the epoxide. On the other hand, DFT results also show that hydrogen bonds and transfers do also stabilize the negative charge of determining intermediates, with the consequent undesired effect of reducing the nucleophilicity of the oxygen atom involved in the final ring closure step. Moreover, hydrogen bonds are also established between the HBDs and the PC product, thus hampering its release.Our theoretical results offer an in-depth understanding of the CO2 fixation involving bio-DESs, which can guide towards the development of more efficient bio-catalysts.

Revisiting photocyclization of the donor-acceptor stenhouse adduct: missing pieces in the mechanistic jigsaw discovered.

Donor-acceptor Stenhouse adducts (DASA) have recently emerged as a class of visible-light-induced photochromic molecular switches, but their photocyclization mechanism remains puzzling and incomplete. In this work, we carried out MS-CASPT2//SA-CASSCF calculations to reveal the complete mechanism of the dominant channels and possible side reactions. We found that a new thermal-then-photo isomerization channel, i.e., EEZ → EZZ → EZE, other than the commonly accepted EEZ → EEE → EZE channel, is dominant in the initial step. Besides, our calculations rationalized why the expected byproducts ZEZ and ZEE are unobserved and proposed a competitive stepwise channel for the final ring-closure step. The findings here redraw the mechanistic picture of the DASA reaction by better accounting for experimental observations, and more importantly, provide critical physical insight in understanding the interplay between thermal- and photo-induced processes widely present in photochemical synthesis and reactions.

Synthesis of a New β-Galactosidase Inhibitor Displaying Pharmacological Chaperone Properties for GM1 Gangliosidosis.

GM1 gangliosidosis is a rare lysosomal disease caused by the deficiency of the enzyme β-galactosidase (β-Gal; GLB1; E.C. 3.2.1.23), responsible for the hydrolysis of terminal β-galactosyl residues from GM1 ganglioside, glycoproteins, and glycosaminoglycans, such as keratan-sulfate. With the aim of identifying new pharmacological chaperones for GM1 gangliosidosis, the synthesis of five new trihydroxypiperidine iminosugars is reported in this work. The target compounds feature a pentyl alkyl chain in different positions of the piperidine ring and different absolute configurations of the alkyl chain at C-2 and the hydroxy group at C-3. The organometallic addition of a Grignard reagent onto a carbohydrate-derived nitrone in the presence or absence of a suitable Lewis Acid was exploited, providing structural diversity at C-2, followed by the ring-closure reductive amination step. An oxidation-reduction process allowed access to a different configuration at C-3. The N-pentyl trihydroxypiperidine iminosugar was also synthesized for the purpose of comparison. The biological evaluation of the newly synthesized compounds was performed on leucocyte extracts from healthy donors and identified two suitable β-Gal inhibitors, namely compounds 10 and 12. Among these, compound 12 showed chaperoning properties since it enhanced β-Gal activity by 40% when tested on GM1 patients bearing the p.Ile51Asn/p.Arg201His mutations.

Corey‐Сhaykovsky cyclopropanation of dehydroalanine in the Ni(II) coordination environment: Electrochemical vs. chemical activation

The Corey-Chaykovsky method was used for α,α-cyclopropanation of dehydroalanine in the form of chiral Ni(II) Schiff-base complexes. For generation of the Corey ylide, electrochemical and chemical deprotonation were tested. For sulphonium salts more easily reduced than the Michael acceptor, the direct electrochemical reduction of the salt in the presence of the dehydroalanine complex gives almost quantitative yield of the cyclopropanated amino acid derivative. For the salts reduced at more cathodic potentials than the Ni-Schiff-base complex and are not prone to rearrangements, electrochemical deprotonation followed by the addition of the complex gives significantly higher yield of the cyclopropanated complex then deprotonation with common bases. Notably, insertion of the substituent either in the sulphonium salt or at the double bond of the dehydroalanine complex yields formation of the cyclopropane derivatives with the opposite configurations of the β-stereocenter. The (R;R,cis)-isomer dominates in the former case whereas the (S;R,trans)-diastereomer is formed in the latter case. To shed light on the stereoselectivity observed, the activation free energies for four alternative ring-closure steps leading to four possible diastereomers were calculated using the DFT approach.

Conversion of CO2 to cyclic carbonates by metal-ethylenediamine complexes in ionic liquid: A DFT mechanistic study

To curtail the accumulation of CO2 concentration in the atmosphere, different strategies have been adopted at present. Among them, one of the possible methods of reducing CO2 level involves transforming it into useful organic compounds. In this line, converting CO2 to cyclic carbonates is a topic of interest as cyclic carbonates are commercially important chemicals. Recently, Honores and co-workers have experimentally prepared cyclic carbonates from cycloaddition of CO2 and ethylene oxide/propylene oxide/Epichlorohydrin catalyzed by Co-ethylenediamine (en) complexes using [BMIm][BF4] ionic liquid as solvent. This work explores the complete reaction mechanism of the cycloaddition reaction at B3LYP/LANL2DZ(6−31G*) level of density functional theory. Two mechanist routes were computed: first route deals with the reaction mechanism without the presence of ionic liquid and second route deals with the ionic liquid involved reaction mechanism. In both the routes, the ring closure step was calculated to be the rate-determining step with an activation barrier in the range of 47.87–52.23 kcal/mol in the absence of ionic liquid and 48.82 to 35.29 kcal/mol in the presence of ionic liquid. Interestingly, the involvement of ionic liquids in the reaction mechanism was found to remarkably reduce the activation free energy barriers by 2.12–19.31 kcal/mol in all the steps along the proposed mechanism. Geometrical analysis indicated that the ability of ionic liquids to form intermolecular hydrogen bonding interaction with the catalyst and substrate is the reason behind the decrease in the barriers. In order to quantify the strength of the hydrogen bonding interactions, NBO analysis was performed on key transition state geometries and nB-F → σ*H-N hydrogen bonding interactions between anionic part of IL and en ligand framework were found to possess significant second-order stabilization energies. Overall, this study sheds light on the mechanistic details of the cycloaddition reaction of CO2 and epoxide and also substantiates that the ionic liquids are efficient green solvents which can be employed in similar catalytic reactions to achieve more efficiency.

Screening of simple carbohydrates as a renewable organocatalyst for the efficient construction of 1,3-benzoxazine scaffold

A convenient protocol for the two component preparation of 1,3-benzoxazines by using several protected and unprotected carbohydrate molecules as organocatalysts have been developed which is broadly applicable to condensation reaction between variety of Mannich bases and paraformaldehyde. This study revealed that fructose have much higher catalytic activity than the other carbohydrates and can be an alternative to metal-containing catalysts as a green renewable organocatalyst for efficient and rapid construction of 1,3-benzoxazine skeleton. In this context, 21 benzoxazine compounds were successfully synthesized and spectral characterizations of these compounds were carried out by spectroscopic methods and elemental analysis. Furthermore, density functional theory (DFT) calculations have been performed to study the detailed mechanism of organocatalyst assisted synthesis of the benzoxazine monomers. The results obtained from these calculations showed that the more realistic reaction pathway involves formation of a phenolate based intermediate which loses a water molecule to form benzenaminium ion. Subsequently, this ion provides the formation of the corresponding benzoxazines with good yields through the intramolecular ring closure step.

Chirality-matched catalyst-controlled macrocyclization reactions.

Macrocycles, formally defined as compounds that contain a ring with 12 or more atoms, continue to attract great interest due to their important applications in physical, pharmacological, and environmental sciences. In syntheses of macrocyclic compounds, promoting intramolecular over intermolecular reactions in the ring-closing step is often a key challenge. Furthermore, syntheses of macrocycles with stereogenic elements confer an additional challenge, while access to such macrocycles are of great interest. Herein, we report the remarkable effect peptide-based catalysts can have in promoting efficient macrocyclization reactions. We show that the chirality of the catalyst is essential for promoting favorable, matched transition-state relationships that favor macrocyclization of substrates with preexisting stereogenic elements; curiously, the chirality of the catalyst is essential for successful reactions, even though no new static (i.e., not "dynamic") stereogenic elements are created. Control experiments involving either achiral variants of the catalyst or the enantiomeric form of the catalyst fail to deliver the macrocycles in significant quantity in head-to-head comparisons. The generality of the phenomenon, demonstrated here with a number of substrates, stimulates analogies to enzymatic catalysts that produce naturally occurring macrocycles, presumably through related, catalyst-defined peripheral interactions with their acyclic substrates.

Computational insight into biotransformation of halophenols by cytochrome P450: Mechanism and reactivity for epoxidation

Halophenols (XPs) have aroused great interests due to their high toxicity and low biodegradability. Previous experimental studies have shown that XPs can be catalytically transformed into epoxides and haloquinones by cytochrome P450 enzymes (CYPs). However, these metabolites have never been detected directly. Moreover, the effects of the reaction site and the type and number of halogen substituents on the biotransformation reactivity of halophenols still remain unknown. In this work, we performed density functional theory (DFT) calculations to simulate the CYP-mediated biotransformation of 36 XPs with mono-, di-, and tri-halogen (F, Cl, and Br) substitutions to unravel the mechanism and relevant kinetics of XPs epoxidation. The whole epoxidation process consists of initial rate-determining O-addition and subsequent ring-closure steps. The simulation results show that the epoxidation in low-spin (LS) state is kinetically preferred over that in high-spin (HS) state, and the formation of epoxide metabolite is strongly exothermic. For all XPs, the epoxidation reactivity follows the order of ortho/para O-addition > meta O-addition. Moreover, the O-addition with higher energy barriers roughly corresponds to chlorophenols and fluorophenols with more halogen atoms. Compared with dichlorophenols, the additional ortho-Cl substitution on trichlorophenols can slightly increase the energy barriers of meta O-addition. By contrast, the additional inclusion of an ortho-Cl to monochlorophenols enhances the meta O-addition reactivity of dichlorophenols. Overall, the present work clarifies the biotransformation routes of XPs to produce epoxides, and identifies the key factors affecting the epoxidation reactivity, which are beneficial in understanding comprehensively the metabolic fate and toxicity of XPs.

On-Demand Continuous Manufacturing of Ciprofloxacin in Portable Plug-and-Play Factories: Development of a Highly Efficient Synthesis for Ciprofloxacin

The experimental approach taken and challenges overcome in developing a high-purity production (>100 g) scale process for the telescoped synthesis of the antibiotic ciprofloxacin is outlined. The process was first optimized for each step sequentially with regard to purity and yield, with necessary process changes identified and implemented before scaling for longer runs. These changes included implementing a continuous liquid–liquid extraction (CLLE) step and eliminating and replacing the base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) initially used in the ring-closure step due to DBU plausibly forming a decomposition side product that negatively impacted the final product purity. Process conditions were scaled 1.5–2-fold in order to enable the ultimate project goal of producing enough crude ciprofloxacin within 24 h to manufacture 1000 250 mg tablets. Working toward this goal, several production-scale runs were carried out to assess the reproducibility and robustness of the finalized process conditions, with the first three steps being run continuously up to 22 h and the last two steps being run continuously up to 10 h. The end result is a process with a throughput of ∼29 g/h (∼700 g/24 h) with a crude product stream profile of 94 ± 2% and 34 ± 3 mg/mL after five chemical transformations across four reactors and one continuous CLLE unit operation with each intermediate step maintaining a purity >95% by HPLC.

1-Alkoxyvinyl Ester as an Excellent Acyl Donor: Efficient Macrolactone Synthesis.

Ketene acetal derivatives, such as 1-alkoxyvinyl esters and O-silyl ketene acetals, belong to the category of O-substituted enols of esters, which easily react with various types of nucleophiles, Nu-H, under neutral conditions to give the corresponding acylated and silylated products in excellent yields only by evaporation of the generated volatile esters. Silyl ketene acetals can be easily synthesized by various simple procedures, whereas 1-alkoxyvinyl esters require an equimolar or catalytic amount of a mercury salt to synthesize them. This drawback prevented the advancement of the chemistry of 1-alkoxyvinyl esters. In 1993, we developed a useful synthetic method of 1-alkoxyvinyl esters using a small amount (0.5-1 mol %) of a ruthenium catalyst. Encouraged by this discovery, we subsequently developed various reactions and applied them to the synthesis of natural products. It is noteworthy that the stereoselective total synthesis of fredericamycin A was achieved by the combined use of these reactions. Macrocyclization was variously utilized for the synthesis of natural macrolides by two types of approaches: direct macrolactonization of α,ω-hydroxy acids or intermolecular esterification between an acid and alcohol followed by a ring-closure step. Additionally, several new reactions using 1-alkoxyvinyl esters or their analogs as key intermediates on the basis of our methods were recently reported. In this paper, we introduce our efforts from the synthesis of 1-alkoxyvinyl esters to the application such as natural product syntheses and recent advancements.

DFT insight into Hashmi phenol synthesis catalyzed by Au single-walled nanotubes: mechanism and charge effect

The mechanism and charge effect of cycloisomerization of ω-alkynylfuran (Hashmi phenol synthesis) catalyzed by single-walled helical gold nanotubes (Au SWNTs) have been systematically investigated via density functional theory. Cycloisomerization of ω-alkynylfuran occurs by the 5-exo Friedel–Crafts-type (FCT) mechanism, namely 5-exo cyclization, furan ring opening, and ring closing of the dienone carbene–gold intermediate. The reactions with Au(6,0), Au(6,1), Au(6,2) and Au(6,3) SWNTs show low energy barriers along the 5-exo FCT path in acetonitrile solvent, but have different the rate-determining steps. From an energy perspective, the reaction rate-determining step catalyzed by Au(6,0) and Au(6,3) is the ring-closing of dienone carbine-gold intermediate, but that of Au(6,1) and Au(6,2) is the IM5 dissociation from the Au SWNTs, which can be attributed to the diversity of the d-band centers of the Au(6,m) SWNTs. The effect of the charge of the Au SWNTs on the catalytic activity was also investigated. Theoretical analysis shows a prominent charge effect, where the cationic Au(6,0), Au(6,3) SWNTs and anionic Au(6,1), Au(6,2) SWNTs are more favorable for the Hashmi phenol synthesis reaction. This results can be attributed to the Au(6,0) and Au(6,3) SWNTs with positive charge can reduce the adsorption energy of the substrate on the catalyst surface and decrease the energy barrier of the cyclization process and ring-closing step. Besides, the Au(6,1) and Au(6,2) with an anion could obviously decrease the dissociation energy of IM5 which is help for the Hashmi phenol reaction. Theoretical analysis shows that the structure and charge effects could influence the catalytic activity of Au(6,m) SWNTs toward Hashmi phenol synthesis. This work will provide insight into cycloisomerization of ω-alkynylfuran and valuable information for application of Au SWNTs in catalysis.

Macrocyclic sulfone derivatives: Synthesis, characterization, in vitro biological evaluation and molecular docking.

An artificial series of macrocycles based on 4,4'-sulfonyldiphenol intermediate was synthesized using a multistep procedure involving oxidation of bisphenol sulfide, etherification of phenolic hydroxyl groups, and final ring closure with different diamines. Different chemical species having aromatic, heteroaromatic, and aliphatic characters were incorporated into macrocyclic frameworks in the final step of ring closure. This simple and easily executable synthetic strategy was applied to synthesize 15 macrocycles (5a-o) in excellent yields. Characterization of the synthesized products was achieved through well-known modern spectroscopic techniques such as IR, NMR, and Mass. Macrocycles 5m and 5n were found to show significant AChE inhibition with IC50 values of 76.9 ± 0.24 and 71.2 ± 0.77 μM, respectively. Macrocycle 5n was also found to be an active inhibitor of butyrylcholinesterase (BChE) with IC50 score of 55.3 ± 0.54 μM. Among others, macrocycle 5l cyclized with o-phenylenediamine demonstrated moderate inhibition with IC50 value of 81.1 ± 0.54 μM. Increasing interest in studying interactions of macrocycles with different enzymatic targets compelled us to design and synthesize sulfone-based macrocycles that might prove as highly potent class of biologically active compounds.

Ring-Closing Metathesis Approaches towards the Total Synthesis of Rhizoxins.

Efforts are described towards the total synthesis of the bacterial macrolide rhizoxin F, which is a potent tubulin assembly and cancer cell growth inhibitor. A significant amount of work was expanded on the construction of the rhizoxin core macrocycle by ring-closing olefin metathesis (RCM) between C(9) and C(10), either directly or by using relay substrates, but in no case was ring-closure achieved. Macrocycle formation was possible by ring-closing alkyne metathesis (RCAM) at the C(9)/C(10) site. The requisite diyne was obtained from advanced intermediates that had been prepared as part of the synthesis of the RCM substrates. While the direct conversion of the triple bond formed in the ring-closing step into the C(9)-C(10) E double bond of the rhizoxin macrocycle proved to be elusive, the corresponding Z isomer was accessible with high selectivity by reductive decomplexation of the biscobalt hexacarbonyl complex of the triple bond with ethylpiperidinium hypophosphite. Radical-induced double bond isomerization, full elaboration of the C(15) side chain, and directed epoxidation of the C(11)-C(12) double bond completed the total synthesis of rhizoxin F.

Synthesis and circularly polarized luminescence properties of BINOL-derived bisbenzofuro[2,3-b:3’,2’-e]pyridines (BBZFPys)

A series of optically active bisbenzofuro[2,3-b:3’,2’-e]pyridine (BBZFPy) derivatives was synthesized starting with the readily available (S)- and (R)-1,1’-bi-2-naphthols through a palladium-catalyzed multiple intramolecular C–H/C–H coupling as the key ring-closure step. The effect of terminal tert-butyl substituents on the BBZFPy skeleton was systematically investigated to uncover a unique aggregation-induced enhancement of CPL characteristics in the solid state. The crystal structures of the coupling products were also evaluated by single crystal X-ray analysis and the well-ordered intermolecular stacking arrangements appeared to be responsible for the enhanced CPL.