Leuco Ethyl Violet as Self-Activating Prodrug Photocatalyst for In Vivo Amyloid-Selective Oxygenation.

Aberrant aggregates of amyloid-ß (Aß) and tau protein (tau), called amyloid, are related to the etiology of Alzheimer disease (AD). Reducing amyloid levels in AD patients is a potentially effective approach to the treatment of AD. The selective degradation of amyloids via small molecule-catalyzed photooxygenation in vivo is a leading approach; however, moderate catalyst activity and the side effects of scalp injury are problematic in prior studies using AD model mice. Here, leuco ethyl violet (LEV) is identified as a highly active, amyloid-selective, and blood-brain barrier (BBB)-permeable photooxygenation catalyst that circumvents all of these problems. LEV is a redox-sensitive, self-activating prodrug catalyst; self-oxidation of LEV through a hydrogen atom transfer process under photoirradiation produces catalytically active ethyl violet (EV) in the presence of amyloid. LEV effectively oxygenates human Aß and tau, suggesting the feasibility for applications in humans. Furthermore, a concept of using a hydrogen atom as a caging group of a reactive catalyst functional in vivo is postulated. The minimal size of the hydrogen caging group is especially useful for catalyst delivery to the brain through BBB.

Unimolecular Chemiexcited Oxygenation of Pathogenic Amyloids.

Pathogenic protein aggregates, called amyloids, are etiologically relevant to various diseases, including neurodegenerative Alzheimer disease. Catalytic photooxygenation of amyloids, such as amyloid-ß (Aß), reduces their toxicity; however, the requirement for light irradiation may limit its utility in large animals, including humans, due to the low tissue permeability of light. Here, we report that Cypridina luciferin analogs, dmCLA-Cl and dmCLA-Br, promoted selective oxygenation of amyloids through chemiexcitation without external light irradiation. Further structural optimization of dmCLA-Cl led to the identification of a derivative with a polar carboxylate functional group and low cellular toxicity: dmCLA-Cl-acid. dmCLA-Cl-acid promoted oxygenation of Aß amyloid and reduced its cellular toxicity without photoirradiation. The chemiexcited oxygenation developed in this study may be an effective approach to neutralizing the toxicity of amyloids, which can accumulate deep inside the body, and treating amyloidosis.

Quantitative Assays for Catalytic Photo-Oxygenation of Alzheimer Disease-Related Tau Proteins.

Catalytic photo-oxygenation of tau amyloid is a potential therapeutic approach to tauopathies, including Alzheimer disease (AD). However, tau is a complex target containing great molecular size and heterogeneous isoforms/proteoforms. Although catalytic photo-oxygenation has been confirmed when using catalyst 1 and recombinant tau pretreated with heparin, its effects on tau from human patients have not yet been clarified. In this study, focusing on the histidine residues being oxygenated, we have constructed two assay systems capable of quantitatively evaluating the catalytic activity when used on human patient tau: (1) fluorescence labeling at oxygenated histidine sites and (2) LC-MS/MS analysis of histidine-containing fragments. Using these assays, we identified 2 as a promising catalyst for oxygenation of human tau. In addition, our results suggest that aggregated tau induced by heparin is different from actual AD patient tau in developing effective photo-oxygenation catalysts.

Attenuation of α-synuclein aggregation by catalytic photo-oxygenation.

We developed catalyst 11 to promote selective photo-oxygenation of α-synuclein amyloid and attenuate its aggregation. Catalyst 11 effectively oxygenated both small and large aggregates. The oxygenated α-synuclein exhibited lower seeding activity than intact α-synuclein. This study corroborates the feasibility of catalytic photo-oxygenation as an anti-synucleinopathy strategy.

A Catalytic Alkylation of Ketones via sp3 C-H Bond Activation.

We identified a ternary hybrid catalyst system composed of an acridinium photoredox catalyst, a thiophosphoric imide (TPI) catalyst, and a titanium complex catalyst that promoted an intermolecular addition reaction of organic molecules with various ketones through sp3 C-H bond activation. The thiyl radical generated via single-electron oxidation of TPI by the excited photoredox catalyst abstracted a hydrogen atom from organic molecules such as toluene, benzyl alcohol, alkenes, aldehydes, and THF. The thus-generated carbon-centered radical species underwent addition to ketones and aldehydes. This intrinsically unfavorable step was promoted by single-electron reduction of the intermediate alkoxy radical by catalytically generated titanium(III) species. This reaction provided an efficient and straightforward route to a broad range of tertiary alcohols and was successfully applied to late-stage functionalization of drugs or their derivatives. The proposed mechanism was supported by both experimental and theoretical studies.

Lewis Acid-Conjugated Pyrene Photoredox Catalyst Promoting the Addition Reaction of α-Silyl Amines with Benzalmalononitriles.

We developed the addition reaction of α-silyl amines with benzalmalononitriles catalyzed by a Mg2+-conjugated pyrene catalyst under visible light irradiation. The catalytic activity of this complex was higher than pyrene alone, a Mg2+ Lewis acid alone, and the sum of these two independent catalytic elements. The observed enhancement in catalytic activity was likely due to electrostatic interactions of the Mg2+ Lewis acid with the pyrene radical anion, which was generated through photoinduced single electron transfer from α-silyl amines to the catalyst's pyrene moiety.

Site-Selective α-Alkylation of 1,3-Butanediol Using a Thiophosphoric Acid Hydrogen Atom Transfer Catalyst.

Herein, we developed secondary-alcohol-selective C-H alkylation of 1,3-butane diol by combining an acridinium photoredox catalyst and a thiophosphoric acid hydrogen atom transfer (HAT) catalyst. The use of non-coordinating solvent such as dichloromethane (DCM) improved secondary α-alkoxy C-H selectivity by lowering bond dissociation energy (BDE) through intramolecular hydrogen bonding.

Identification of a Self-Photosensitizing Hydrogen Atom Transfer Organocatalyst System.

We developed organocatalyst systems to promote the cleavage of stable C-H bonds, such as formyl, α-hydroxy, and benzylic C-H bonds, through a hydrogen atom transfer (HAT) process without the use of exogenous photosensitizers. An electronically tuned thiophosphoric acid, 7,7'-OMe-TPA, was assembled with substrate or co-catalyst N-heteroaromatics through hydrogen bonding and π-π interactions to form electron donor-acceptor (EDA) complexes. Photoirradiation of the EDA complex induced stepwise, sequential single-electron transfer (SET) processes to generate a HAT-active thiyl radical. The first SET was from the electron-rich naphthyl group of 7,7'-OMe-TPA to the protonated N-heteroaromatics and the second proton-coupled SET (PCET) from the thiophosphoric acid moiety of 7,7'-OMe-TPA to the resulting naphthyl radical cation. Spectroscopic studies and theoretical calculations characterized the stepwise SET process mediated by short-lived intermediates. This organocatalytic HAT system was applied to four different carbon-hydrogen (C-H) functionalization reactions, hydroxyalkylation and alkylation of N-heteroaromatics, acceptorless dehydrogenation of alcohols, and benzylation of imines, with high functional group tolerance.

Titanium(IV) Chloride-Catalyzed Photoalkylation via C(sp3)-H Bond Activation of Alkanes.

Despite the sophistication of C-H functionalization as one of the most powerful tools in organic synthesis, methodology for performing hydrogen-atom transfer of unactivated alkanes remains rather scarce. Herein, we describe chlorine radical-catalyzed C(sp3)-H photoalkylation using titanium(IV) chloride via a ligand-to-metal charge transfer process. Enabled by the unique properties of this abundant metal salt, the reaction not only effected the coupling of various alkanes with radical acceptors but also was shown to be applicable to direct photoalkylation of aromatic ketones.

Siloxy Esters as Traceless Activators of Carboxylic Acids: Boron-Catalyzed Chemoselective Asymmetric Aldol Reaction*.

The catalytic asymmetric aldol reaction is among the most useful reactions in organic synthesis. Despite the existence of many prominent reports, however, the late-stage, chemoselective, catalytic, asymmetric aldol reaction of multifunctional substrates is still difficult to achieve. Herein, we identified that in situ pre-conversion of carboxylic acids to siloxy esters facilitated the boron-catalyzed direct aldol reaction, leading to the development of carboxylic acid-selective, catalytic, asymmetric aldol reaction applicable to multifunctional substrates. Combining experimental and computational studies rationalized the reaction mechanism and led to the proposal of Si/B enediolates as the active species. The silyl ester formation facilitated both enolization and catalyst turnover by acidifying the α-proton of substrates and attenuating poisonous Lewis bases to the boron catalyst.

Chromium-Catalyzed Linear-Selective Alkylation of Aldehydes with Alkenes.

We developed a chromium-catalyzed, photochemical, and linear-selective alkylation of aldehydes with alkylzirconium species generated in situ from a wide range of alkenes and Schwartz's reagent. Photochemical homolysis of the C-Zr bond afforded alkyl radicals, which were then trapped by a chromium complex catalyst to generate the alkylchromium(III) species for polar addition to aldehydes. The reaction proceeded with high functional group tolerance at ambient temperature under visible-light irradiation.

Catalytic Allylation of Aldehydes Using Unactivated Alkenes.

Simple feedstock organic molecules, especially alkenes, are attractive starting materials in organic synthesis because of their wide availability. Direct utilization of such bulk, inert organic molecules for practical and selective chemical reactions, however, remains limited. Herein, we developed a ternary hybrid catalyst system comprising a photoredox catalyst, a hydrogen-atom-transfer catalyst, and a chromium complex catalyst, enabling catalytic allylation of aldehydes with simple alkenes, including feedstock lower alkenes. The reaction proceeded under visible-light irradiation at room temperature and with high functional group tolerance. The reaction was extended to an asymmetric variant by employing a chiral chromium complex catalyst.

Catalytic Acceptorless Dehydrogenation of Aliphatic Alcohols.

We developed the first acceptorless dehydrogenation of aliphatic secondary alcohols to ketones under visible light irradiation at room temperature by devising a ternary hybrid catalyst system comprising a photoredox catalyst, a thiophosphate organocatalyst, and a nickel catalyst. The reaction proceeded through three main steps: hydrogen atom transfer from the α-C-H bond of an alcohol substrate to the thiyl radical of the photo-oxidized organocatalyst, interception of the generated carbon-centered radical with a nickel catalyst, and ß-hydride elimination. The reaction proceeded in high yield under mild conditions without producing side products (except H2 gas) from various alcohols, including sterically hindered alcohols, a steroid, and a pharmaceutical derivative. This catalyst system also promoted acceptorless cross-dehydrogenative esterification from aldehydes and alcohols through hemiacetal intermediates.

Photocatalytic redox-neutral hydroxyalkylation of N-heteroaromatics with aldehydes.

Hydroxyalkylation of N-heteroaromatics with aldehydes was achieved using a binary hybrid catalyst system comprising an acridinium photoredox catalyst and a thiophosphoric acid organocatalyst. The reaction proceeded through the following sequence: (1) photoredox-catalyzed single-electron oxidation of a thiophosphoric acid catalyst to generate a thiyl radical, (2) cleavage of the formyl C-H bond of the aldehyde substrates by a thiyl radical acting as a hydrogen atom transfer catalyst to generate acyl radicals, (3) Minisci-type addition of the resulting acyl radicals to N-heteroaromatics, and (4) a spin-center shift, photoredox-catalyzed single-electron reduction, and protonation to produce secondary alcohol products. This metal-free hybrid catalysis proceeded under mild conditions for a wide range of substrates, including isoquinolines, quinolines, and pyridines as N-heteroaromatics, as well as both aromatic and aliphatic aldehydes, and tolerated various functional groups. The reaction was applicable to late-stage derivatization of drugs and their leads.

Copper(I)-Catalyzed Stereodivergent Propargylation of N-Acetyl Mannosamine for Protecting Group Minimal Synthesis of C3-Substituted Sialic Acids.

Copper(I)-catalyzed stereodivergent nucleophilic propargylation at the anomeric carbon of unprotected N-acetyl mannosamine was developed using 3-substituted allenylboronates as a nucleophile. The homopropargylic alcohol products contained two contiguous stereocenters, and two stereoisomers out of the four possible isomers were selectively obtained in a catalyst-controlled manner by applying either basic conditions: a MesCu/(R,R,R)-Ph-SKP catalyst with a B(OiPr)3 additive or acidic conditions: a CuBF4/(S,S,S)-Ph-SKP catalyst with an MeB(OiPr)2 additive. Mechanistic studies suggested the presence of distinct active nucleophilic species depending on the conditions: an allenylcopper species under the basic conditions or an allenylboronate activated by the Lewis acidic copper catalyst under the acidic conditions. The propargylation products were concisely transformed into C3-substituted sialic acids in two steps without the use of protecting groups.

Amine-tethered phenylboronic acid-enabling ring-opening strategy for carbon chain elongation from double aldol cyclic hemiacetals.

The addition of carbon nucleophiles to cyclic hemiacetal forms of double aldols is a promising approach toward the synthesis of structurally attractive 1,3-polyol derivatives. Cyclic hemiacetals are generally unreactive to carbon nucleophiles under neutral conditions, however, because the electrophilic aldehyde function is masked. Here we developed an amine-tethered phenylboronic acid 7g, which transforms double aldol cyclic hemiacetals to ring-opened linear aldehydes. Combined with the previously-developed copper-catalysed asymmetric double aldol reaction (L. Lin, K. Yamamoto, H. Mitsunuma, Y. Kanzaki, S. Matsunaga and M. Kanai, J. Am. Chem. Soc., 2015, 137, 15418), this method produced synthetically useful chiral building blocks containing a 1,3-di- or tri-ol moiety.

Catalytic asymmetric allylation of aldehydes with alkenes through allylic C(sp3)-H functionalization mediated by organophotoredox and chiral chromium hybrid catalysis.

We describe a hybrid system that realizes cooperativity between an organophotoredox acridinium catalyst and a chiral chromium complex catalyst, thereby enabling unprecedented exploitation of unactivated hydrocarbon alkenes as precursors to chiral allylchromium nucleophiles for asymmetric allylation of aldehydes. The reaction proceeds under visible light irradiation at room temperature, affording the corresponding homoallylic alcohols with a diastereomeric ratio >20/1 and up to 99% ee. The addition of Mg(ClO4)2 markedly enhanced both the reactivity and enantioselectivity.

Acceptorless Dehydrogenation of Hydrocarbons by Noble-Metal-Free Hybrid Catalyst System.

A hybrid catalysis that comprises an acridinium photoredox catalyst, a thiophosphate organocatalyst, and a nickel catalyst-enabled acceptorless dehydrogenation of hydrocarbons is reported. The cationic nickel complex played a critical role in the reactivity. This is the first example of acceptorless dehydrogenation of hydrocarbons by base metal catalysis under mild reaction conditions of visible light irradiation at room temperature.

Catalytic Asymmetric Iterative/Domino Aldehyde Cross-Aldol Reactions for the Rapid and Flexible Synthesis of 1,3-Polyols.

We report here catalytic asymmetric iterative and domino cross-aldol reactions between aldehydes, endowed with a high level of robustness, flexibility, and generality. A Cu(I)-DTBM-SEGPHOS complex catalyzes an asymmetric cross-aldol reaction between acceptor aldehydes and boron enolates derived from donor aldehydes, which are generated through Ir-catalyzed isomerization of allyloxyboronates. The unit process can be repeated using the aldol products in turn as acceptor substrates for the subsequent asymmetric aldol reaction. The donor aldehydes and stereoselectivity can be flexibly switched in a stepwise manner for the double-aldol reaction. Furthermore, asymmetric triple- and quadruple-aldol reactions are possible in one-pot using the appropriate amounts of donors and amine additives, rapidly elongating the carbon skeleton with controlling up to eight stereocenters. The method should be useful for straightforward synthesis of enantiomerically and diastereomerically enriched 1,3-polyols.