Total Synthesis of (+)-Silybin A.

We report the first total synthesis of silybin A (1). Key synthetic steps include the construction of the 1,4-benzodioxane neolignan skeleton, a modified Julia-Kocienski olefination reaction between m-nitrophenyltetrazole sulfone (m-NPT sulfone) 10 and aldehyde 21, the formation of the flavanol lignan skeleton 28 via a quinomethide intermediate under acidic conditions, and stepwise oxidation of the benzylic position of flavanol 29.

Asymmetric Fluorofunctionalizations with Carboxylate-Based Phase-Transfer Catalysts.

Fluorine is an attractive element in the field of pharmaceutical and agrochemical chemistry due to its unique properties. Considering the chiral environment in nature, where enantiomers often show different biological activities, the introduction of fluorine atom(s) into organic molecules to make chiral fluorinated compounds is an important subject. Herein, we describe the story of the development of our chiral carboxylate-based phase-transfer catalysts and their applications for asymmetric fluorocyclizations of alkenes bearing a carboxylic acid, an amide, and an oxime as an internal nucleophile with a dicationic fluorinating reagent, Selectfluor. We also describe dearomative fluorinations of indole derivatives, 2-naphthols, and resorcinols.

Amide-Ligand-Promoted Silver-Catalyzed C-H Fluorination via Radical/Polar Crossover.

We describe an efficient method for benzylic C-H fluorination via sequential hydrogen-atom transfer (HAT) and oxidative radical-polar crossover utilizing the Ag(I)/Selectfluor system. Amide ligands, such as benzamide and sulfonamide, substantially facilitate the processes leading to a carbocation intermediate, which subsequently reacts with nucleophilic fluorinating reagent to form a C-F bond. This protocol is applicable to the fluorination of all 1°, 2°, and 3° C-H bonds as well as to late-stage C-H fluorination of bioactive molecules.

Experimental and Computational Investigation of Facial Selectivity Switching in Nickel-Diamine-Acetate-Catalyzed Michael Reactions.

Chiral Ni complexes have revolutionized both asymmetric acid-base and redox catalysis. However, the coordination isomerism of Ni complexes and their open-shell property still often hinder the elucidation of the origin of their observed stereoselectivity. Here, we report our experimental and computational investigations to clarify the mechanism of ß-nitrostyrene facial selectivity switching in Ni(II)-diamine-(OAc)2-catalyzed asymmetric Michael reactions. In the reaction with a dimethyl malonate, the Evans transition state (TS), in which the enolate binds in the same plane with the diamine ligand, is identified as the lowest-energy TS to promote C-C bond formation from the Si face in ß-nitrostyrene. In contrast, a detailed survey of the multiple potential pathways in the reaction with α-keto esters points to a clear preference for our proposed C-C bond-forming TS, in which the enolate coordinates to the Ni(II) center in apical-equatorial positions relative to the diamine ligand, thereby promoting Re face addition in ß-nitrostyrene. The N-H group plays a key orientational role in minimizing steric repulsion.

Mechanistic Details of Asymmetric Bromocyclization with BINAP Monoxide: Identification of Chiral Proton-Bridged Bisphosphine Oxide Complex and Its Application to Parallel Kinetic Resolution.

The mechanism of our previously reported catalytic asymmetric bromocyclization reactions using 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) monoxide was examined in detail by the means of control experiments, NMR studies, X-ray structure analysis, and CryoSpray electrospray ionization mass spectrometry (ESI-MS) analysis. The chiral BINAP monoxide was transformed to a key catalyst precursor, proton-bridged bisphosphine oxide complex (POHOP·Br), in the presence of N-bromosuccinimide (NBS) and contaminating water. The thus-formed POHOP further reacts with NBS to afford BINAP dioxide and molecular bromine (Br2) simultaneously in equimolar amounts. While the resulting Br2 is activated by NBS to form a more reactive brominating reagent (Br2─NBS), BINAP dioxide serves as a bifunctional catalyst, acting as both a Lewis base that reacts with Br2─NBS to form a chiral brominating agent (P═O+─Br) and also as a Brønsted base for the activation of the substrate. By taking advantage of this novel concerted Lewis/Brønsted base catalysis by BINAP dioxide, we achieved the first regio- and chemodivergent parallel kinetic resolutions (PKRs) of racemic unsymmetrical bisallylic amides via bromocyclization.

Structure Dependence in Asymmetric Deprotonative Fluorination and Fluorocyclization Reactions of Allylamine Derivatives with Linked Binaphthyl Dicarboxylate Phase-Transfer Catalyst.

The asymmetric fluorofunctionalization of γ,γ-disubstituted allylamine derivatives (e.g., 3, 7, and 8) was investigated using our dianionic phase-transfer catalyst. Depending on the substituents on the alkene moiety, the reaction afforded chiral allylic fluorides and fluorinated dihydrooxazines in a highly enantioselective manner (up to 99% ee). The absolute stereochemistry of these products was found to be opposite to that in our previously reported fluorocyclization of γ-monosubstituted allylic amides (e.g., 13 and 14). To probe this interesting phenomenon, we investigated the influence of the substitution pattern of the alkene moiety on the reaction by means of NMR experiments and kinetic studies. The rate laws of the deprotonative fluorination and the fluorocyclization of γ,γ-disubstituted substrates were v = k[cat]0.6, while that of the fluorocyclization of γ-monosubstituted substrates was v = k[substrate][cat]0.4. An exponent of less than 1 suggests the involvement of an aggregated state of the catalyst ion pair in the catalytic cycle. Interestingly, a positive nonlinear effect was observed in the reactions of the γ,γ-disubstituted substrates, while a negative nonlinear effect was observed in the case of the γ-monosubstituted substrates. Thus, the reaction pathway depends on the presence or absence of an alkyl substituent at the γ position of the substrates, and on the basis of our mechanistic studies we propose that the active catalytic species for γ,γ-disubstituted substrates is a catalyst ion pair aggregate, whereas that for γ-monosubstituted substrates is the more active monomeric catalyst ion pair species, even though its concentration would be low.

Enhancement of target toxin neutralization effect in vivo by PEGylation of multifunctionalized lipid nanoparticles.

Protein-protein (e.g., antibody-antigen) interactions comprise multiple weak interactions. We have previously reported that lipid nanoparticles (LNPs) bind to and neutralize target toxic peptides after multifunctionalization of the LNP surface (MF-LNPs) with amino acid derivatives that induce weak interactions; however, the MF-LNPs aggregated after target capture and showed short blood circulation times. Here we optimized polyethylene glycol (PEG)-modified MF-LNPs (PEG-MF-LNPs) to inhibit the aggregation and increase the blood circulation time. Melittin was used as a target toxin, and MF-LNPs were prepared with negatively charged, hydrophobic, and neutral amino-acid-derivative-conjugated functional lipids. In this study, MF-LNPs modified with only PEG5k (PEG5k-MF-LNPs) and with both PEG5k and PEG2k (PEGmix-MF-LNPs) were prepared, where PEG5k and PEG2k represent PEG with a molecular weight of 5000 and 2000, respectively. PEGylation of the MF-LNPs did not decrease the melittin neutralization ability of nonPEGylated MF-LNPs, as tested by hemolysis assay. The PEGmix-MF-LNPs showed better blood circulation characteristics than the PEG5k-MF-LNPs. Although the nonPEGylated MF-LNPs immediately aggregated when mixed with melittin, the PEGmix-MF-LNPs did not aggregate. The PEGmix-MF-LNPs dramatically increased the survival rate of melittin-treated mice, whereas the nonPEGylated MF-LNPs increased slightly. These results provide a fundamental strategy to improve the in vivo toxin neutralization ability of MF-LNPs.

Design of synthetic polymer nanoparticles that inhibit glucose absorption from the intestine.

Synthetic polymers prepared using several functional monomers have attracted attention as cost-effective protein affinity reagents and alternative to antibodies. We previously reported the synthesis of poly NIPAm-based nanoparticles (NPs) using several functional monomers that can capture target molecules. In this study, we designed NPs for capturing glucose and inhibiting intestinal absorption in living mice. For capturing glucose, we focused on the Maillard reaction between primary amines and aldehyde residues. We hypothesized that the primary amine-containing NPs can capture the open-chain structure of glucose via the Maillard reaction and inhibit intestinal absorption. NPs were prepared by the precipitation polymerization of NIPAm, N-tert-butylacrylamide (TBAm), trifluoroacetate-protected N-(3-aminopropyl)methacrylamide (T-APM), and N,N'-methylenebisacrylamide. Then, T-APM in NPs was deprotected by NH3 (aq). The amount of glucose captured by NPs depended on the percentage of TBAm and APM in vitro. After 24 h, only 2% of orally administered NPs remained in the body after administration, suggesting that many NPs were excreted without being absorbed. The prepared NPs significantly inhibited an increase in blood glucose concentration after the oral administration of glucose and NPs, indicating that NPs capture glucose and inhibit intestinal absorption. These results show the potential of using synthetic polymer nanoparticles for inhibiting postprandial hyperglycemia.

18F-Labeled dihydromethidine: positron emission tomography radiotracer for imaging of reactive oxygen species in intact brain.

Dihydromethidine (DHM) labeled with 18F at the para position of the peripheral benzene ring was designed as a positron emission tomography (PET) radiotracer for non-invasive imaging of reactive oxygen species (ROS). This compound readily crosses the blood-brain barrier and is oxidized by ROS, and the oxidation product is retained intracellularly. PET imaging of ROS-producing rat brain microinfused with sodium nitroprusside identified specific brain regions with high ROS concentrations. This tracer should be useful for studies of the pathophysiological roles of ROS, and in the diagnosis of neurodegenerative diseases.

Asymmetric Dearomative Fluorination of 2-Naphthols with a Dicarboxylate Phase-Transfer Catalyst.

A linked dicarboxylate phase-transfer catalyst enables smooth asymmetric dearomative fluorination of 2-naphthols with Selectfluor under mild conditions to give the corresponding 1-fluoronaphthalenone derivatives in a highly enantioselective manner. This reaction, which is compatible with a range of functional groups, is the first example of catalytic asymmetric fluorination of 2-naphthols, and is expected to be useful in the synthesis of bioactive molecules.

Practical and Scalable Organic Reactions with Flow Microwave Apparatus.

Microwave irradiation has been used for accelerating organic reactions as a heating method and has been proven to be useful in laboratory scale organic synthesis. The major drawback of microwave chemistry is the difficulty in scaling up, mainly because of the low penetration depth of microwaves. The combination of microwave chemistry and flow chemistry is considered to overcome the problem in scaling up of microwave-assisted organic reactions, and some flow microwave systems have been developed in both academic and industrial communities. In this context, we have demonstrated the scale-up of fundamental organic reactions using a novel flow microwave system developed by the academic-industrial alliance between the University of Shizuoka, Advanced Industrial Science and Technology, and SAIDA FDS. In this Personal Account, we summarize the recent progress of our scalable microwave-assisted continuous synthesis using the SAIDA flow microwave apparatus.

Design of Synthetic Polymer Nanoparticles Specifically Capturing Indole, a Small Toxic Molecule.

Synthetic polymers are of interest as stable and cost-effective biomolecule-affinity reagents, since these polymers interact with target biomolecules both in vitro and in the bloodstream. However, little has been reported about orally administered polymers capable of capturing a target molecule and inhibiting its intestinal absorption. Here, we describe the design of synthetic polymer nanoparticles (NPs) specifically capturing indole, a major factor exacerbating chronic kidney disease, in the intestine. N-isopropylacrylamide-based NPs were prepared with various hydrophobic monomers. The amounts of indole captured by NPs depended on the structures and feed ratios of the hydrophobic monomers and the polymer density but not on the particle size. The combination of hydrophobic and quadrupole interaction was effective to enhance the affinity and specificity of NPs for indole. The optimized NPs specifically inhibited intestinal absorption of orally administered indole in mice. These results showed the potential of synthetic polymer NPs for inhibiting the intestinal absorption of a target molecule.

Thiocyanation of Aromatic and Heteroaromatic Compounds with 1-Chloro-1,2-benziodoxol-3-(1H)-one and (Trimethylsilyl)isothiocyanate.

Thiocyanation of aromatic compounds has been investigated using the combination of 1-chloro-1,2-benziodoxol-3-(1H)-one (1) and (trimethylsilyl)isothiocyanate (TMSNCS). The reaction with electron rich aromatic compounds proceeded smoothly to provide the thiocyanated products in high yield, while electron deficient heteroaromatic compounds were not suitable for this reaction. In these reactions, the regioselectivity was generally high. Transformations of the products were also investigated to demonstrate the utility of the reaction. Based on NMR experiments, we propose that thiocyanogen chloride is generated in situ as an active species.

Enantioselective 5-exo-Fluorocyclization of Ene-Oximes.

The enantioselective 5-exo-fluorocyclization of ene-oxime compounds was demonstrated under phase-transfer catalysis. Although deprotonative fluorinations competed, the chemical yields and the ee values of the desired isoxazoline products were generally moderate to good. The absolute stereochemistry of the major isomer was determined to be S by comparison with the literature after transformation of the product to the corresponding iodinated isoxazoline.

Dianionic Phase-Transfer Catalyst for Asymmetric Fluoro-cyclization.

Inspired by the dicationic nature of the electrophilic fluorinating reagent, Selectfluor (1), we rationally designed a series of dicarboxylic acid precatalysts (2), which, when deprotonated, act as anionic phase-transfer catalysts for asymmetric fluorination of alkenes. Among them, 2a having the shortest linker moiety efficiently catalyzed unprecedented 6-endo-fluoro-cyclization of various allylic amides, affording fluorinated dihydrooxazine compounds with high enantioselectivity (up to 99% ee). In addition to cyclic substrates, acyclic trisubstituted alkenes underwent the reaction with good diastereoselectivity, whereas low diastereoselectivity was observed for linear disubstituted alkenes. Results suggest that the reaction proceeds via a fluoro-carbocation intermediate.

Enantioselective Synthesis of Nelfinavir via Asymmetric Bromocyclization of Bisallylic Amide.

We describe a concise enantioselective synthesis of the HIV-protease inhibitor nelfinavir (1) via a new route in which the key step is construction of the central optically active 1,2-amino alcohol framework via asymmetric bromocyclization of bisallylic amide with N-bromosuccinimide in the presence of a catalytic amount of ( S)-BINAP or ( S)-BINAP monoxide. The remaining alkene and bromo functionalities were used to install the requisite thioether and chiral perhydroisoquinoline units, respectively.

C-Alkylation of N-alkylamides with styrenes in air and scale-up using a microwave flow reactor.

C-Alkylation of N-alkylamides with styrenes is reported, proceeding in ambient air/moisture to give arylbutanamides and pharmaceutically-relevant scaffolds in excellent mass balance. Various amide and styrene derivatives were tolerated, rapidly affording molecular complexity in a single step; thus highlighting the future utility of this transformation in the synthetic chemistry toolbox. Reaction scalability (up to 65 g h-1 product) was demonstrated using a Microwave Flow reactor, as the first example of a C-alkylation reaction using styrenes in continuous flow.

Asymmetric Fluorination of Cyclic Tetrasubstituted Alkenes with a Pendant Amide Groups under Dianionic Phase-Transfer Catalysis.

Asymmetric fluorination of cyclic tetrasubstituted alkenes with a pendant amide group was investigated under dianionic phase-transfer catalysis. Fluorination proceeded with high face selectivity, affording the corresponding allylic fluorides with a chiral tetrasubstituted carbon center with up to 97% enantiomeric excess (ee). It should be noted that deprotonative fluorination occurred mainly in preference to intramolecular nucleophilic attack of the amide group.

Desymmetrization of Bisallylic Amides through Catalytic Enantioselective Bromocyclization with BINAP Monoxide.

We report the first desymmetrization of bisallylic amides by enantioselective bromocyclization with BINAP monoxide as a catalyst. Depending upon the substitution pattern of the alkene moieties, densely functionalized, optically active oxazoline or dihydrooxazine compounds were obtained in a highly stereoselective manner. The remaining alkene moiety was subjected to various functional group manipulations to afford a diverse array of chiral molecules with multiple stereogenic centers.