Synthesis and Suzuki-Miyaura Cross-Coupling of Alkyl Amine-Boranes. A Boryl Radical-Enabled Strategy.

Alkyl organoborons are powerful materials for the construction of C(sp3)-C(sp2) bonds, predominantly via Suzuki-Miyaura cross-coupling. These species are generally assembled using 2-electron processes that harness the ability of boron reagents to act as both electrophiles and nucleophiles. Herein, we demonstrate an alternative borylation strategy based on the reactivity of amine-ligated boryl radicals. This process features the use of a carboxylic acid containing amine-ligated borane that acts as boryl radical precursor for photoredox oxidation and decarboxylation. The resulting amine-ligated boryl radical undergoes facile addition to styrenes and imines through radical-polar crossover manifolds. This delivers a new class of sp3-organoborons that are stable solids and do not undergo protodeboronation. These novel materials include unprotected α-amino derivatives that are generally unstable. Crucially, these aliphatic organoboron species can be directly engaged in Suzuki-Miyaura cross-couplings with structurally complex aryl halides. Preliminary studies suggest that they enable slow-release of the corresponding and often difficult to handle alkyl boronic acids.

Phospholipid-Coated Boronic Oxide Nanoparticles as Boron Agents for Boron Neutron Capture Therapy.

Minimally invasive boron neutron capture therapy (BNCT) is an elegant approach for cancer treatment. The highly selective and efficient deliverability of boron agents to cancer cells is the key to maximizing the therapeutic benefits of BNCT. In addition, enhancement of the frequencies to achieve boron neutron capture reaction is also significant in improving therapeutic efficacy by providing a highly concentrated boron agent in each boron nanoparticle. As the density of the thermal neutron beam remains low, it is unable to induce high-efficiency cell destruction. Herein, we report phospholipid-coated boronic oxide nanoparticles as agents for BNCT that can provide a highly concentrated boron atom in each nanoparticle. The current system exhibited in vitro BNCT activity seven times higher than that of commercial boron agents. Furthermore, the system could penetrate cancer spheroids deeply, efficiently suppressing thermal neutron irradiation-induced growth.

Direct Regioselective Dehydrogenation of α-Substituted Cyclic Ketones.

We disclose a highly regioselective, catalytic one-step dehydrogenation of α-substituted cyclic ketones in the presence of 2,3-dichlorobenzo-5,6-dicyano-1,4-benzoquinone (DDQ). The high regioselectivity originates from a phosphoric acid-catalyzed enolization, selectively affording the thermodynamically preferred enol, followed by the subsequent oxidation event. Our method provides reliable access to several α-aryl and α-alkyl substituted α,ß-unsaturated ketones.

Palladium on Carbon-Catalyzed Benzylic Methoxylation for Synthesis of Mixed Acetals and Orthoesters.

The palladium on carbon (Pd/C)-catalyzed direct methoxylation of the benzylic positions of linear benzyl and cyclic ether substrates proceeded in the presence of i-Pr2 NEt under an oxygen atmosphere to give the corresponding mixed acetals. Cyclic acetal derivatives could also be converted into orthoesters. The present direct methoxylation via a carbon-hydrogen (C-H) functionalization can be accomplished using the easily-removed Pd/C and molecular oxygen as a green oxidant. The obtained mixed acetals were transformed into the corresponding ether products by chemoselective substitution of the methoxy group using a silyltriflate, 2,4,6-collidine, and a nucleophile. The orthoester derivative could also be transformed into the cyclic ketal under similar reaction conditions.

Disiloxane Synthesis Based on Silicon-Hydrogen Bond Activation using Gold and Platinum on Carbon in Water or Heavy Water.

Disiloxanes possessing a silicon-oxygen linkage are important as frameworks for functional materials and coupling partners for Hiyama-type cross coupling. We found that disiloxanes were effectively constructed of hydrosilanes catalyzed by gold on carbon in water as the solvent and oxidant in association with the emission of hydrogen gas at room temperature. The present oxidation could proceed via various reaction pathways, such as the hydration of hydrosilane into silanol, dehydrogenative coupling of hydrosilane into disilane, and the subsequent corresponding reactions to disiloxane. Additionally, the platinum on carbon catalyzed hydrogen-deuterium exchange reaction of arylhydrosilanes as substrates in heavy water proceeded on the aromatic nuclei at 80 °C with high deuterium efficiency and high regioselectivity at the only meta and para positions of the aromatic-silicon bond to give the deuterium-labeled disiloxanes.

Additional Nucleophile-Free FeCl3-Catalyzed Green Deprotection of 2,4-Dimethoxyphenylmethyl-Protected Alcohols and Carboxylic Acids.

The deprotection of the methoxyphenylmethyl (MPM) ether and ester derivatives can be generally achieved by the combinatorial use of a catalytic Lewis acid and stoichiometric nucleophile. The deprotections of 2,4-dimethoxyphenylmethyl (DMPM)-protected alcohols and carboxylic acids were found to be effectively catalyzed by iron(III) chloride without any additional nucleophile to form the deprotected mother alcohols and carboxylic acids in excellent yields. Since the present deprotection proceeds via the self-assembling mechanism of the 2,4-DMPM protective group itself to give the hardly-soluble resorcinarene derivative as a precipitate, the rigorous purification process by silica-gel column chromatography was unnecessary and the sufficiently-pure alcohols and carboxylic acids were easily obtained in satisfactory yields after simple filtration.

Biarylmethane and Fused Heterocyclic Arene Synthesis via in Situ Generated o- and/or p-Naphthoquinone Methides.

o- and/or p-naphthoquinone methides (NQMs) can be selectively prepared by the ring opening of 1-(siloxymethyl)-1,4-epoxy-1,4-dihydronaphthalene derivatives based on a substituent effect at the 4 position of the substrates. The 4-alkyl- or silyl-substituted 1-(siloxymethyl)-1,4-epoxy-1,4-dihydronaphthalene was transformed to o-NQM (1-naphthoquinone-2-methide), which underwent Friedel-Crafts 1,4-addition of the α,ß-unsaturated carbonyl moiety to provide the 2-benzyl-1-naphthol as the biarylmethane and [4 + 2]-cycloaddition with a dienophile to give the fused heterocyclic arene. Meanwhile, the 4-unsubstituted 1-(siloxymethyl)-1,4-epoxy-1,4-dihydronaphthalene could be converted to the corresponding 4-benzyl-1-naphthol by the Friedel-Crafts 1,6-addition of p-NQM (1-naphthoquinone-4-methide) generated by the site-selective ring opening of the 1,4-epoxy moiety. Furthermore, the 4-(siloxymethyl)-(1,4-bis(siloxymethyl))-1,4-epoxy-1,4-dihydronaphthalene was transformed into a 2,4-bisbenzyl-1-naphthol or pentacyclic derivative via both the o- and p-NQM intermediates.

Extracellular Vesicles Comprising Carborane Prepared by a Host Exchanging Reaction as a Boron Carrier for Boron Neutron Capture Therapy.

With their low immunogenicity and excellent deliverability, extracellular vesicles (EVs) are promising platforms for drug delivery systems. In this study, hydrophobic molecule loading techniques were developed via an exchange reaction based on supramolecular chemistry without using organic solvents that can induce EV disruption and harmful side effects. To demonstrate the availability of an exchanging reaction to prepare drug-loading EVs, hydrophobic boron cluster carborane (CB) was introduced to EVs (CB@EVs), which is expected as a boron agent for boron neutron capture therapy (BNCT). The exchange reaction enabled the encapsulation of CB to EVs without disrupting their structure and forming aggregates. Single-particle analysis revealed that an exchanging reaction can uniformly introduce cargo molecules to EVs, which is advantageous in formulating pharmaceuticals. The performance of CB@EVs as boron agents for BNCT was demonstrated in vitro and in vivo. Compared to L-BPA, a clinically available boron agent, and CB delivered with liposomes, CB@EV systems exhibited the highest BNCT activity in vitro due to their excellent deliverability of cargo molecules via an endocytosis-independent pathway. The system can deeply penetrate 3D cultured spheroids even in the presence of extracellular matrices. The EV-based system could efficiently accumulate in tumor tissues in tumor xenograft model mice with high selectivity, mainly via the enhanced permeation and retention effect, and the deliverability of cargo molecules to tumor tissues in vivo enhanced the therapeutic benefits of BNCT compared to the L-BPA/fructose complex. All of the features of EVs are also advantageous in establishing anticancer agent delivery platforms.

Isolation and characterization of a marine cyclohexylacetate-degrading bacterium Lutimaribacter litoralis sp. nov., and reclassification of Oceanicola pacificus as Lutimaribacter pacificus comb. nov.

A novel aerobic, Gram-negative, non-motile, pleomorphic, and rod-shaped bacterium designated KU5D5(T) was isolated from seawater that was obtained from the coastal region of the Goto Islands, Japan, on the basis of its ability to utilize cyclohexylacetate as the sole source of carbon and energy. Strain KU5D5(T) grew at pH 6.0-8.0 and 10-35 °C in the presence of 1.0-5.0 % (w/v) NaCl. Analysis of the 16S rRNA gene sequence revealed that this strain was affiliated to the family Rhodobacteraceae in the class Alphaproteobacteria and was related most closely to Lutimaribacter saemankumensis (96.6 % similarity) and Oceanicola pacificus (96.6 %). The predominant respiratory lipoquinone was ubiquinone-10 and the major cellular fatty acids were C(18:1) ω7c (66.7 %), C(16:0) (7.7 %), C(12:1) 3-OH (6.1 %), and C(17:0) (6.1 %). The DNA G+C content was 58.9 mol %. On the basis of physiological, chemotaxonomic, and phylogenetic data, strain KU5D5(T) is suggested to represent a novel species of the genus Lutimaribacter, for which the name Lutimaribacter litoralis sp. nov. is proposed. It is also proposed that O. pacificus should be transferred to the genus Lutimaribacter as Lutimaribacter pacificus comb. nov. The type strain of L. litoralis is KU5D5(T) (=JCM 17792(T) = KCTC 23660(T)) and the type strain of L. pacificus is W11-2B(T) (=CCTCC AB 208224(T) = LMG 24619(T) = MCCC 1A01034(T)).

Accessing unnatural α-amino acids with tetrasubstituted stereogenic centers via catalytic enantioselective reactions of ketimine-type α-iminoesters/α-iminoamides.

Catalytic enantioselective synthesis methodologies have been actively explored and developed owing to the significance of chiral molecules and their utilities. In particular, unnatural α-amino acids with tetrasubstituted stereogenic carbon centers (α-tertiary amino acids; ATAAs) are undoubtedly among the most valuable compounds. Asymmetric addition to an α-iminoester or α-iminoamide is widely recognized as a straightforward, powerful, and atom-economical strategy for accessing optically active α-amino acids and their derivatives. However, this type of chemistry, which relies on ketimine-type electrophiles, was quite limited only a few decades ago owing to low reactivities and difficulties associated with enantiofacial control. This feature article comprehensively overviews this research field and highlights the significant progress that has been made. In particular, it focuses on the chiral catalyst system and the transition state as the key parameters for such reactions.

Asymmetric synthesis of tetrasubstituted cyclic amines via aza-Henry reaction using cinchona alkaloid sulfonamide/zinc(II) catalysts.

The first enantioselective aza-Henry reaction of non-activated cyclic iminoesters, derived from cyclic amino acids, has been developed. Good yields and enantioselectivities were observed for the reaction using our original cinchona alkaloid sulfonamide/zinc(II) catalyst. The transition state was proposed to explain the stereoselectivity based on experiments and DFT calculations.

Gold-Catalyzed Tandem Oxidative Coupling Reaction between ß-Ketoallenes and Electron-Rich Arenes to 2-Furylmethylarenes.

A tandem oxidative coupling reaction of ß-ketoallenes and arenes was developed, which leads to the formation of 2-furylmethylarenes using AuCl3 and phenyliodine diacetate. The AuIII salt catalyzed the cyclization of ß-ketoallenes to form a 2-furylmethyl gold intermediate, and the subsequent C-H functionalization of arenes proceeded smoothly. During the oxidative coupling, nucleophilic additions occurred at the center and terminal carbon atoms of the allene moiety to form C-O and C-C bonds.

Copper-Catalyzed Aqueous N-O Bond Cleavage of 2-Oxa-3-Azabicyclo Compounds to Cyclic cis-1,4-Amino Alcohols.

The N-O bond cleavage of 2-oxa-3-azabicyclo substrates, which are readily prepared by the hetero Diels-Alder reaction between nitroso dienophiles and cyclic 1,3-dienes, was effectively catalyzed by heterogeneous copper-on-carbon (Cu/C) under aqueous conditions to give the corresponding cyclic cis-1,4-amino alcohol derivatives. The present method was applied to the direct incorporation of the hydroxy and amino groups derived from a nitroso substrate into cyclic 1,3-dienes with cis-selectivity by the combination of the in situ formation of 2-oxa-3-azabicyclo compounds and following Cu/C-catalyzed N-O bond cleavage. The obtained cis-4-aminocyclohexenols, derived from cyclohexadiene as a cyclic 1,3-diene, could be selectively oxidized by using the ruthenium-on-carbon (Ru/C) catalyst under oxygen atmosphere to the corresponding 4-aminocyclohexenones at 50-65 °C or para-iminoquinones at 100-110 °C as useful reactive synthetic precursors.

Birch-Type Reduction of Arenes in 2-Propanol Catalyzed by Zero-Valent Iron and Platinum on Carbon.

Catalytic arene reduction was effectively realized by heating in 2-propanol/water in the presence of Pt on carbon (Pt/C) and metallic Fe. 2-Propanol acted as a hydrogen source, obviating the need for flammable (and hence, dangerous and hard-to-handle) hydrogen gas, while metallic Fe acted as an essential co-catalyst to promote reduction. The chemical states of Pt and Fe in the reaction mixture were determined by X-ray absorption near-edge structure analysis, and the obtained results were used to suggest a plausible reaction mechanism, implying that catalytic reduction involved Pt- and Fe-mediated single-electron transfer and the dehydrogenation of 2-propanol.

Stainless Steel-Mediated Hydrogen Generation from Alkanes and Diethyl Ether and Its Application for Arene Reduction.

Hydrogen gas can be generated from simple alkanes (e.g., n-pentane, n-hexane, etc.) and diethyl ether (Et2O) by mechanochemical energy using a planetary ball mill (SUS304, Fritsch Pulverisette 7), and the use of stainless steel balls and vessel is an important factor to generate the hydrogen. The reduction of organic compounds was also accomplished using the in-situ-generated hydrogen. While the use of pentane as the hydrogen source facilitated the reduction of the olefin moieties, the arene reduction could proceed using Et2O. Within the components (Fe, Cr, Ni, etc.) of the stainless steel, Cr was the metal factor for the hydrogen generation from the alkanes and Et2O, and Ni metal played the role of the hydrogenation catalyst.

Palladium on Carbon-Catalyzed Chemoselective Oxygen Oxidation of Aromatic Acetals.

The development of an unprecedented chemoselective transformation has contributed to forming a novel synthetic process for target molecules. Chemoselective oxidation of aromatic acetals has been accomplished using a reusable palladium on carbon catalyst under atmospheric oxygen conditions to form ester derivatives with tolerance of aliphatic acetals and ketals.