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The first diastereoselective synthesis of trisubstituted cubanes was achieved using a chiral auxiliary. To establish chirality within the cubane skeleton, at least three substituents must be introduced at the appropriate positions. Ready conversion of cubane carboxylic acid to a chiral amide followed by sequential

A novel rigid macrocyclic ligand based on the bis(pyridylimino)isoindole framework bearing the disulfide moiety was designed and synthesized to investigate the behavior of the disulfide in mononucl...

We herein describe the development of a mild and selective catalytic aerobic oxidation process of olefins. This catalytic aerobic oxidation reaction was designed based on experimental and spectrosc...

We have developed a nickel-catalyzed insertion reaction of an alkyne into a 2-(trifluoromethyl)-1,3-benzothiazole to give a seven-membered benzothiazepine that is converted into a 2-(trifluoromethyl)quinoline by thermal desulfidation. This process can be considered a formal substitution of a sulfur atom with an alkyne. The structure of the thianickelacycle intermediate formed through oxidative addition of a C–S bond in the benzothiazole to nickel(0) was confirmed by X-ray single-crystal structure analysis and in situ X-ray absorption fine-structure spectroscopy.

The enantioselective oxa-Diels–Alder reaction of nonactivated substrates by utilizing FeCl3 and a 1,1′-bi-2-naphthol (BINOL) derived chiral phosphoric acid as a multiple activation catalyst is reported. Various oxygen-containing six-membered heterocycles were obtained in high yields and in an enantioselective manner. Density functional theory (DFT) calculations elucidate that both Lewis acidic and Brønsted acidic moieties in the catalyst system synergistically activate two lone pairs of an aldehyde to facilitate enantioselective addition reaction of dienes.

Three-dimensional organic structures containing sp

Cubane, a hexahedral hydrocarbon, can be converted into an asymmetric molecule with a minimum of three substituents. The resulting chiral cubane can be used as a pharmacophore or a chiral ligand. Starting from the cubane carboxamide, the 1,2,3-substituted compound was synthesized by sequential ortho-metalation. The 1,3,5-substituted compound was synthesized by combining site-selective halogenation and halogen-metal exchange and the resulting racemate was subjected to enantiomeric resolution by HPLC.

The core technologies of fully automated organic synthesis include the management of large amounts of accumulated reaction examples, machine learning based on these experimental results, and subseq...

In the hexahedral hydrocarbon cubane, replacing hydrogen with other atoms at three positions within any one of the internal tetrahedrons can conceptually lead to the formation of a unique class of chiral molecules. In pursuit of this endeavor, we prepared 1,3-dibromo-4-deuteriocubane-N,N-diisopropylcarboxamide, which upon treatment with zincates affords 1,3,5-trisubstituted cubanes via simultaneous two-position substitution reactions. The proposed chiral attributes of this stereogeometric class were confirmed by enantiomeric resolution of a p-bromobenzyl derivative using chiral HPLC.

Copper(II) porphyrin-catalyzed coupling of alkyl tosylates and alkyl Grignard reagents afforded substituted alkanes. The role of the copper(II) porphyrin complex was examined using EPR and in-situ ...

Organohalogen compounds such as alkenyl bromides are versatile and essential building blocks in organic synthesis. Herein, we describe the nickel-catalyzed intermolecular carbobrominations of alkyn...

a bstract Carbonyl compounds employed as carbon nucleophiles have played a dominant role in synthetic organic chemistry; however, there is very limited use of these compounds as oxygen nucleophiles. In particular, there are only a few reports on the oxy-Michael addition of the enol forms of carbonyl nucleophiles. In this study, we present the asymmetric cycloetherification of enols, which are generated in situ from enone-bearing ketones, using chiral bifunctional organocatalysts bearing amino and squaramide groups. This transformation chemo- and enantioselectively afforded dihydropyran derivatives, which are the core structures of building blocks for synthesizing glycans.

We herein report a new synthetic method for the preparation of α-hydroxyketones by the dioxygenation of alkynes. The reaction proceeds at room temperature under the action of Fe porphyrin and pinacolborane under air as a green oxidant to produce α-hydroxyketones. The mild reaction conditions allow chemoselective oxidation with functional group tolerance. Terminal alkynes in addition to internal alkynes are applicable, affording unsymmetrical α-hydroxyketones that are difficult to obtain by any reported dioxygenation of unsaturated C-C bonds.

The nickel-catalyzed formal [5+2] cycloaddition of five-membered benzothiophenes and alkynes giving seven-membered benzothiepines via unprecedented dearomatization is reported. The reaction involves the carbothiolation of alkynes with sulfur-containing aromatic heterocycles affording sulfur-containing heterocyclic compounds via ring expansion. As a result, this method facilitates divergent access to thermally metastable benzothiepines. The structure of the thianickelacycle intermediate, which is formed via oxidative addition of the C-S bond in benzothiophenes to nickel(0), was confirmed by in situ X-ray absorption fine structure spectroscopy and density functional theory calculation.

An efficient iron porphyrin Lewis acid-catalyzed cycloaddition of aziridines with aldehydes has been developed to provide oxazolidines with high regio- and diastereoselectivity. The cycloaddition proceeds in toluene with 1 mol % of the iron catalyst at 25 °C. A theoretical study and synchrotron-based X-ray absorption fine structure measurements provided fundamental insights into the aziridine-iron porphyrin complex, which is the key intermediate for the generation of the 1,3-dipole synthon.

An organocatalytic method for the asymmetric synthesis of syn-1,3-dioxanes as protected 1,3-diols via dynamic kinetic resolution of in situ generated chiral cyanohydrins has been developed. This method involves a reversible cyanohydrin formation/hemiacetalization/intramolecular oxy-Michael addition reaction cascade, affording a chiral syn-1,3-diol structure with simultaneous construction of two stereogenic centers. The use of trifluoromethyl ketones is crucial for the efficient three-component cascade reaction, and a chiral bifunctional organocatalyst imparts high enantio- and diastereoselectivities in the formation of the chiral syn-1,3-diol motifs.

The organocatalytic enantio- and diastereoselective cycloetherification of in situ generated cyanohydrins through the concomitant construction of three chiral carbon centers is reported. This protocol facilitates the concise synthesis of optically active tetrahydropyran derivatives, which are ubiquitous scaffolds found in various bioactive compounds, through the simultaneous construction of multiple bonds and stereogenic centers, including tetrasubstituted chiral carbons. The resulting products also contain multiple synthetically important functional groups, which expand their possible usefulness as chiral building blocks.

The first desymmetrization of gem-diols forming chiral hemiketal carbons was accomplished via organocatalytic enantio- and diastereoselective cycloetherification, which afforded optically active tetrahydropyrans containing a chiral hemiketal carbon and tetrasubstituted stereocenters bearing synthetically versatile fluorinated groups. The desymmetrization of silanediols was also demonstrated as an asymmetric route to chiral silicon centers.

The aza-Diels-Alder reaction of nonactivated dienes and imines was realized through the action of the ion-paired Lewis acid catalyst [FeCl2]+[FeCl4]- generated by the in situ disproportionation of FeCl3. The uniquely high reactivity of [FeCl2]+[FeCl4]- was attributed to both the highly Lewis acidic FeCl2+ and thermodynamically stable FeCl4- acting as an ion-paired catalyst. Synchrotron-based X-ray absorption fine structure measurements provided fundamental insights into the disproportionation and structure of the resulting ion-paired iron complex. A theoretical study was performed to analyze the catalytic reaction and better understand the "ion-pairing effect" which transforms simple FeCl3 into a high turnover frequency Lewis acid catalyst in the aza-Diels-Alder reaction of nonactivated dienes and imines.

Attempts to obtain enantiomerically enriched tetrahydrofuran derivatives via an intramolecular oxy-Michael addition reaction of ε-hydroxyenone is discussed. Despite previous difficulties associated with the asymmetric induction of this reaction, which can proceed even without a catalyst, a highly efficient asymmetric induction was realized using a bifunctional organocatalyst derived from a cinchona alkaloid. The reaction could be extended to ζ-hydroxyenone to yield an optically active tetrahydropyran derivative with a high ee. In these reactions, it is important for the gentle acidic and basic sites in the bifunctional organocatalyst to be arranged properly within the molecular skeleton of the catalyst. The high performance asymmetric induction relied on the affinity of the catalyst for the substrate, which played an important role. A disubstituted tetrahydropyran synthesis could be effectively performed via kinetic resolution using ζ-hydroxyenone containing a secondary alcohol moiety using a chiral phosphoric acid catalyst.

The 1,5-benzothiazepine framework is well-known as a versatile pharmacophore, and its derivatives have numerous biological activities. Therefore, various synthetic routes to these important compounds have already been investigated. However, in light of the increase in optically active pharmaceuticals, it is of significance to also develop enantioselective synthetic methods. Among various strategies, methods based on enantioselective catalysis are generally efficient in both academia and industry with respect to different factors such as atom or step economy, economic reasons, and diversity-oriented synthesis. While various methodologies had already been investigated until the 1990s, soon after the discovery of marketed pharmaceuticals such as diltiazem, a blockbuster drug containing a 1,5-benzothiazepine unit, additional catalytic strategies also appeared. Thus, this Perspective provides an account of the progress on enantioselective catalysis for the asymmetric synthesis of 1,5-benzothiazepine derivatives.

An efficient σ-Lewis acidic Ag(I) complex has been obtained by complexation with an electron-donating π-conjugated molecule as a side-on π ligand. The σ-Lewis acidity is possibly derived from the controlled linear coordination around Ag(I) due to the π ligand. A combination of UV-Vis absorption spectroscopy and X-ray absorption near-edge structure analyses clearly revealed that the complex is formed by π ligand-to-Ag(I) charge-transfer interaction. The σ-Lewis acidity was evaluated by IR spectroscopy using 2,6-dimethyl-γ-pyrone as the σ-Lewis basic molecule.

The stereoselectivity for the addition of an organometallic reagent to an aldehyde or ketone possessing a Lewis basic atom at the α-position can be predicted according to the well-known Chelation Model. Herein we discuss stereoselective reactions of bis(iodozincio)methane, which can coordinate to a heteroatom containing substrate with two zinc atoms in the reagent. Zinc atom coordination in a face-to-face manner to the substrates containing two heteroatoms enables specific molecular recognition, realizing novel molecular transformations.

In this study, the isothiourea-catalyzed enantioselective formal [4+3] cycloaddition of various α,β-unsaturated carboxylic acid derivatives with 2-aminothiophenols was developed. Mechanistic studies suggested that the reaction proceeds via a reversible sulfa-Michael addition to α,β-unsaturated acylammonium intermediates, followed by the enantioselective formation of a seven-membered ring, enabling the facile and divergent synthesis of optically active 2- and 3-substituted 1,5-benzothiazepines. This process was demonstrated to be highly versatile, affording the corresponding products in excellent regioselectivities and high enantioselectivities. Furthermore, this method enabled the synthesis of chiral 2,3-disubstituted 1,5-benzothiazepines in high regio-, enantio-, and diastereoselectivities. Hence, this protocol can be applied for the construction of a library of useful pharmaceutical candidates.

Bifunctional organocatalysts bearing amino and urea functional groups in a chiral molecular skeleton were applied to the enantioselective synthesis of axially chiral benzamides via aromatic electrophilic bromination. The results demonstrate the versatility of bifunctional organocatalysts for the enantioselective construction of axially chiral compounds. Moderate to good enantioselectivities were afforded with a range of benzamide substrates. Mechanistic investigations were also carried out.

The enantioselective syntheses of axially chiral heterobiaryls were accomplished through the aromatic electrophilic halogenation of 3-(quinolin-8-yl)phenols with bifunctional organocatalysts that control the molecular conformations during successive halogenations. Axially chiral quinoline derivatives, which have rarely been synthesized in an enantioselective catalytic manner, were afforded in moderate-to-good enantioselectivities through bromination, and an analogous protocol also enabled enantioselective iodination. In addition, this catalytic reaction, which allows enantioselective control through the use of mono-ortho-substituted substrates, allowed the asymmetric synthesis of 8-arylquinoline derivatives bearing two different halogen groups in high enantioselectivities.

Enantioselective bromination of axially chiral cyanoarenes bearing high intrinsic rotational barriers via dynamic kinetic resolution using bifunctional organocatalysts is reported. Sequential addition of a brominating reagent in several portions at an optimized temperature was effective in accomplishing high enantioselectivities.

Cationic cobalt porphyrin-catalyzed allylation of aldehydes with allyltrimethylsilanes is developed. The formation of the aldehyde-cobalt porphyrin complex, the key intermediate for the addition of allylsilanes, is confirmed by theoretical studies and synchrotron-based X-ray absorption fine-structure measurements. Facile dissociation of the product by allylation from the cobalt complex regenerates the active complex with the aldehyde. The readily obtainable [Co(TPP)]SbF6 complex serves as an efficient catalyst for this allylation.

The iodine–metal exchange reaction on cubane was examined using various lithium organozincates. Among these, the dianionic zincate, n-Bu4ZnLi2, gave optimum results. The resulting cubyl metal species could be converted into various cubane derivatives via addition reactions with electrophiles, such as an organohalide or aldehyde. The potential functional group tolerance of organozincates lends this protocol to the synthesis of polyfunctionalized cubane derivatives.

In this study, novel asymmetric cycloetherification via the kinetic resolution of secondary or tertiary alcohols using chiral phosphoric acid catalysts was developed, affording tetrahydropyrans (THPs) with two stereogenic centers. The cyclization of the recovered optically active alcohols afforded other stereoisomers of THPs. These protocols offer efficient synthetic routes to various optically active THP derivatives, which are important structures found in a range of biologically active agents.