Isatogenols as Precursors for the Synthesis of Fully Substituted Indolines through Regio- and Stereoselective [3 + 2] Cycloaddition Using Various Olefins.

Here, we describe a unique reactivity of isatogen derivatives bearing a hydroxy group at the C3-position (isatogenol) and their synthetic application to highly regio- and stereoselective [3 + 2] cycloaddition reactions. This method provides facile access to polyfused and highly functionalized heterocycles including consecutive stereocenters. Furthermore, DFT calculations revealed that hydrogen bonding is a key to controlling the regio- and stereoselectivity in the cycloaddition using acrylates.

Direct S0 → Tn Transition under Visible Light Irradiation Enabling Synthesis of a Pseudoindoxyl Scaffold.

Pseudoindoxyl is a partial skeleton found in various natural products. Its light-absorption properties make it useful for the design of functional molecules. However, versatile synthesis methods have not yet been reported. In this report, we present a versatile synthetic method for pseudoindoxyls using the direct S0 → Tn transition under visible light irradiation. We also discuss the application of pseudoindoxyls as photocatalysts.

Nickel-catalysed regio- and stereoselective hydrocyanation of alkynoates and its mechanistic insights proposed by DFT calculations.

We have developed a nickel-catalysed regio- and stereoselective hydrocyanation of alkynoates that gives syn-ß-cyanoalkenes. DFT calculations suggest that a favored transition state promotes Cα-H bond formation for determining regio- and stereoselectivity of the products.

3-Oxidopyridinium Ions Are Versatile Bioorthogonal Dipoles for Use in Cycloadditions with Cyclooctynes.

3-oxidopyridinium ions are water stable and soluble heteroaromatic betaines that behave as latent dipoles and undergo a wide variety of cycloadditions. Research into the cycloaddition reactions of 3-oxidopyridiniums was spearheaded by Alan R. Katritzky and collaborators from the early 1970s until the late 1980s, but they have yet to be used for bioorthogonal applications. Herein we report that 3-oxidopyridiniums can readily react with 4-dibenzocyclooctynol (DIBO), a common bioorthogonal handle, in a [3+2] cycloaddition. The mechanism was investigated by altering the electronics of the reaction by changing the substituent on the 5 position of the pyridinium. Electron-donating 5-substituents have been shown to significantly increase the rate of the reaction, with bimolecular rate constants ranging from 3.3×10-4 s-1 with 5-trifluoromethyl-N-methyl-3-oxidopyridinium to 1.07 M-1 s-1 with 5-amino-N-methyl-3-oxidopyridinium. 3-oxidopyridiniums' appreciable cycloaddition rates and compatibility with bioorthogonally relevant environments give them the potential to be used in a variety of bioconjugation applications.

Mechanistic Analysis of Bioorthogonal Double Strain-Promoted Alkyne-Nitrone Cycloadditions Involving Dibenzocyclooctadiyne.

The reactions of nitrones with cyclooctadiynes were studied to establish the relative rates of sequential reactions and to determine the limits and scope of this bioorthogonal chemistry. We have established the second-order rate constants for the consecutive additions of a variety of nitrones onto diyne and studied the structure-activity relationships via Hammett plots. Results show that the addition of the second nitrone to the monointermediate occurs significantly faster than the first, with both reactions being faster than analogous reactions with azides. Computational chemistry supports these observations. The rate of second addition increases with electron-deficient nitrones, as demonstrated by a large rho value of 2.08, suggesting that the reaction rate can be controlled by nitrone selectivity. To further investigate the kinetic parameters of the reaction, dinitrone monomers containing cyclic and diaryl-nitrones were designed for use in oligomerization applications. Oligomerization was used as a probe to test the limits of the reactivity and attempt to isolate monocycloaddition products. The oligomer formed from a cyclic nitrone reacts faster, and detailed MALDI mass spectrometry analysis shows that monoaddition products exist only transiently and are not isolatable. These studies inform on the scope and limits of this chemistry in a variety of applications. We successfully demonstrated bacterial cell wall labeling using heterogeneous dual cycloadditions involving nitrone and azide dipoles, where the nitrone was the faster reacting partner on the bacterial cell surface.

Anti-proliferating and apoptosis-inducing activity of chemical compound FTI-6D in association with p53 in human cancer cell lines.

Compounds with 3,4-fused tricyclic indole (FTI) frameworks are attractive scaffolds for drug discovery. We synthesized FTI-6D, a compound with this framework, which was cytotoxic in several human cancer cell lines. FTI-6D induced apoptosis via activation of the p53 downstream mitochondria-related apoptotic pathway, characterized by an increased ratio of pro-apoptotic Bcl-2 family members to anti-apoptotic members. This change was followed by caspase-9 and caspase-3 cleavage and activation in two cancer cell lines, RKO and AGS. The anti-proliferating effect of FTI-6D was remarkably detected in eight cancer cells with wild-type TP53 (TP53_wt), including RKO and AGS, but not in seven cancer cells with mutated TP53 (TP53_mut). Additionally, p53 protein levels increased after FTI-6D treatment in TP53_wt cancer cells, and the cytotoxic effect of FTI-6D was decreased by TP53 knockdown. Accordingly, the expression of p53 downstream genes involved in apoptotic signaling pathways, such as BBC3 and TP53INP1, and those involved in cell growth inhibition, such as CDKN1A, was upregulated in TP53_wt cancer cells. These results suggest that the anti-proliferative and apoptosis-inducing activities of FTI-6D rely on p53 and the corresponding signaling processes. This study demonstrated that FTI-6D shows anti-cancer activity against TP53_wt cancer cells. FTI-6D may have potential as a prototype compound for a new drug to utilize a functional p53 pathway in TP53_wt cancer cells.

Computation-Guided Total Synthesis of Vitisinol G.

Computational chemistry is useful in synthetic organic chemistry, as it can be used not only to analyze reaction mechanisms, but also to calculate biosynthetic pathways and to plan and evaluate strategies for total syntheses. Here we report the computation-guided total synthesis of vitisinol G, a resveratrol dimer.

A visible-light activated secondary phosphine oxide ligand enabling Pd-catalyzed radical cross-couplings.

Although transition metal-catalyzed reactions have evolved with ligand development, ligand design for palladium-catalyzed photoreactions remains less explored. Here, we report a secondary phosphine oxide ligand bearing a visible-light sensitization moiety and apply it to Pd-catalyzed radical cross-coupling reactions. The tautomeric phosphinous acid coordinates to palladium in situ, allowing for pseudo-intramolecular single-electron transfer between the ligand and palladium. Molecular design of the metal complexes aided by time-dependent density functional theory calculations enables the involvement of allyl radicals from π-allyl palladium(II) complexes, and alkyl and aryl radicals from the corresponding halides and palladium(0) complex. This complex enables radical cross-couplings by ligand-to-Pd(II) and Pd(0)-to-ligand single-electron transfer under visible-light irradiation.

Synthesis of Visible-Light-Activated Hypervalent Iodine and Photo-oxidation under Visible Light Irradiation via a Direct S0→Tn Transition.

Heavy atom-containing molecules cause a photoreaction by a direct S0 → Tn transition. Therefore, even in a hypervalent iodine compound with a benzene ring as the main skeleton, the photoreaction proceeds under 365-400 nm wavelength light, where UV-visible spectra are not observed by usual measurement method. Some studies, however, report hypervalent iodine compounds that strongly absorb visible light. Herein, we report the synthesis of two visible light-absorbing hypervalent iodines and their photooxidation properties under visible light irradiation. We also demonstrated that the S0 → Tn transition causes the photoreaction to proceed under wavelengths in the blue and green light region.

Computation-guided asymmetric total syntheses of resveratrol dimers.

Although computational simulation-based natural product syntheses are in their initial stages of development, this concept can potentially become an indispensable resource in the field of organic synthesis. Herein we report the asymmetric total syntheses of several resveratrol dimers based on a comprehensive computational simulation of their biosynthetic pathways. Density functional theory (DFT) calculations suggested inconsistencies in the biosynthesis of vaticahainol A and B that predicted the requirement of structural corrections of these natural products. According to the computational predictions, total syntheses were examined and the correct structures of vaticahainol A and B were confirmed. The established synthetic route was applied to the asymmetric total synthesis of (-)-malibatol A, (-)-vaticahainol B, (+)-vaticahainol A, (+)-vaticahainol C, and (-)-albiraminol B, which provided new insight into the biosynthetic pathway of resveratrol dimers. This study demonstrated that computation-guided organic synthesis can be a powerful strategy to advance the chemical research of natural products.

Regio-divergent nickel catalysis: intramolecular [4+2] and [2+2] cycloaddition reactions between vinylallenes and alkynes.

Vinylallenes have been recognized as versatile C2 and C4 components for nickel-catalyzed intramolecular [4+2] and [2+2] cycloadditions. The former reaction was promoted by a Ni(0) complex (up to quantitative yield), and a Ni(II) salt was a key species for the latter reaction to give the corresponding regio- and stereocontrolled cycloadducts (up to 88% yield). DFT studies revealed that both reaction pathways involve a concerted mechanism through the activation of different C-C multiple bonds in the substrates.

Machine learning enabling prediction of the bond dissociation enthalpy of hypervalent iodine from SMILES.

Machine learning to create models on the basis of big data enables predictions from new input data. Many tasks formerly performed by humans can now be achieved by machine learning algorithms in various fields, including scientific areas. Hypervalent iodine compounds (HVIs) have long been applied as useful reactive molecules. The bond dissociation enthalpy (BDE) value is an important indicator of reactivity and stability. Experimentally measuring the BDE value of HVIs is difficult, however, and the value has been estimated by quantum calculations, especially density functional theory (DFT) calculations. Although DFT calculations can access the BDE value with high accuracy, the process is highly time-consuming. Thus, we aimed to reduce the time for predicting the BDE by applying machine learning. We calculated the BDE of more than 1000 HVIs using DFT calculations, and performed machine learning. Converting SMILES strings to Avalon fingerprints and learning using a traditional Elastic Net made it possible to predict the BDE value with high accuracy. Furthermore, an applicability domain search revealed that the learning model could accurately predict the BDE even for uncovered inputs that were not completely included in the training data.

Mechanistic Studies of the Pd- and Pt-Catalyzed Selective Cyclization of Propargyl/Allenyl Complexes.

Following the discovery of an unusual transition-metal-catalyzed reaction, the elucidation of the underlying mechanism is essential to understand the characteristic reactivity of the metal. We previously reported a synthetic method for tricyclic indoles using Pt-catalyzed Friedel-Crafts-type C-H coupling. In this reaction, the Pt catalyst selectively formed a seven-membered ring, but the Pd catalyst only afforded a six-membered ring. However, the reasons for the different selectivities caused by Pd and Pt were unclear. We performed density functional theory (DFT) calculations and experimental studies to reveal the origin of the different behaviors of the two metals. The calculations revealed that the formation of the six- and seven-membered rings proceeds via η1-allenyl and η3-propargyl/allenyl complexes, respectively. A molecular orbital analysis of the η3-propargyl/allenyl complex revealed that, for the platinum complex, the energy required to convert the unoccupied molecular orbital on the reactive carbon into the lowest unoccupied molecular orbital (LUMO) was lower than that for the palladium complex. In addition, DFT calculations revealed that the combination of platinum and bis[2-(diphenylphosphino)phenyl] ether (DPEphos) reduced the activation energy of the seven-membered cyclization in comparison with palladium or PPh3. Additional experimental studies, including NMR studies and stoichiometric reactions, support the aforementioned examination.

Py3-FITC: a new fluorescent probe for live cell imaging of collagen-rich tissues and ionocytes.

Polypyrrole-based polyamides are used as sequence-specific DNA probes. However, their cellular uptake and distribution are affected by several factors and have not been extensively studied in vivo. Here, we generated a series of fluorescence-conjugated polypyrrole compounds and examined their cellular distribution using live zebrafish and cultured human cells. Among the evaluated compounds, Py3-FITC was able to visualize collagen-rich tissues, such as the jaw cartilage, opercle and bulbus arteriosus, in early-stage living zebrafish embryos. Then, we stained cultured human cells with Py3-FITC and found that the staining became more intense as the amount of collagen was increased. In addition, Py3-FITC-stained HR cells, which represent a type of ionocyte on the body surface of living zebrafish embryos. Py3-FITC has low toxicity, and collagen-rich tissues and ionocytes can be visualized when soaked in Py3-FITC solution. Therefore, Py3-FITC may be a useful live imaging tool for detecting changes in collagen-rich tissue and ionocytes, including their mammalian analogues, during both normal development and disease progression.

Visible Light-Induced Direct S0 → Tn Transition of Benzophenone Promotes C(sp3)-H Alkynylation of Ethers and Amides.

Benzophenone has an S0 → S1 absorption band at 365 nm. However, the rarely reported S0 → Tn transition occurs upon irradiation at longer wavelengths. Herein, we employed benzophenone as a catalyst and exploited its S0 → Tn transition in C(sp3)-H alkynylations with hypervalent iodine reagents. The selective benzophenone excitation prevented alkynylating reagent decomposition, enabling the reaction to proceed under mild conditions. The reaction mechanism was investigated by spectroscopic and computational studies.

Visible-Light-Induced Metal-/Photocatalyst-Free C-H Bond Imidation of Arenes.

In this study, a visible-light-induced intermolecular C-H bond imidation of arenes was achieved at ambient condition. By using simple phthalimide with (diacetoxyiodo)benzene and molecular iodine, direct metal-/photocatalyst-free C-N bond formation was achieved. The imidation protocol was designed by using time-dependent density functional theory calculations and experimentally demonstrated for 28 substrates with as high as 96% yield. Mechanistic studies indicated that radical-mediated aromatic substitution occurred via photolysis of N-iodophthalimide under visible-light irradiation.

A Direct S0 →Tn Transition in the Photoreaction of Heavy-Atom-Containing Molecules.

According to the Grotthuss-Draper law, light must be absorbed by a substrate to initiate a photoreaction. There have been several reports, however, on the promotion of photoreactions using hypervalent iodine during irradiation with light from a non-absorbing region. This contradiction gave rise to a mystery regarding photoreactions involving hypervalent iodine. We demonstrated that the photoactivation of hypervalent iodine with light from the apparently non-absorbing region proceeds via a direct S0 →Tn transition, which has been considered a forbidden process. Spectroscopic, computational, and synthetic experimental results support this conclusion. Moreover, the photoactivation mode could be extended to monovalent iodine and bromine, as well as bismuth(III)-containing molecules, providing new possibilities for studying photoreactions that involve heavy-atom-containing molecules.

Predicting reactivity for bioorthogonal cycloadditions involving nitrones.

Nitrones are useful dipoles in both synthesis and in bioorthogonal transformations to report on biological phenomena. In bioorthogonal reactions, nitrones are both small and relatively easy to incorporate into biomolecules, while providing versatility in their ability to harbor different substituents that tune their reactivity. Herein, we examine the reactivities of some common and useful nitrone cycloadditions using density functional theory (DFT) and the distortion/interaction (D/I) model. The data show that relative reactivities can be predicted using these approaches, and useful insights gained further enchancing reactivities of both nitrones and their dipolarophile reaction partners. We find that D/I is a useful guide to understanding and predicting reactivities of cycloadditions involving nitrones.

Total Synthesis of Lundurine and Related Alkaloids: Synthetic Approaches and Strategies.

This review focuses on the total synthesis of lundurines A-C. Their main structural feature is a unique cyclopropa[b]indole core that has been found only in these alkaloids. In addition to this characteristic structure, the biological activity makes them as attractive synthetic targets. However, almost two decades passed from their isolation and structural determination in 1995 to their first total synthesis. The first part of this review summarizes the synthetic approaches to the tri- and tetracyclic ring systems of lundurine as well as an inter- and intramolecular cyclopropanation strategy that gives the cyclopropa[b]indole core. The second part presents a detailed description of four total syntheses that were reported from 2014 to 2016. In addition, the asymmetric total synthesis of the related alkaloids grandilodine C and lapidilectine B is described.