Immobilization of a flavin molecule onto poly(methacrylic acid)s and its application in aerobic oxidation catalysis: effect of polymer stereoregularity.

The isoalloxazine ring system, called flavin, was successfully immobilized on poly(methacrylic acid)s, PMAAs, with different tacticity via post-polymerization modification under suitable conditions. The resulting flavin-containing polymers showed catalytic activity for aerobic oxidation reactions, in which the polymer stereoregularity clearly influenced their catalytic activity.

Synthesis of Optically Active Polyguanidines by Polyaddition Reaction of Biscarbodiimides with Chiral Diamines.

Herein, we present the first study on the polyaddition reaction of biscarbodiimides with chiral diamines, which focuses on a definite case using optically active trans-4a,8a-decahydroquinoxaline and 1,4-phenylenebis(arylcarbodiimide)s, which readily react with each other under ambient and catalyst-free conditions. The specific reactivity allows for facile access to not only the corresponding chiral polyguanidines under balanced stoichiometry but also their oligomeric analogues under imbalanced stoichiometry via a step-by-step procedure. Spectroscopic, chromatographic, and computational characterization of the novel molecular chains containing arrayed guanidines have revealed their structural, optical, and conformational properties as well as the mechanism of polymerization assisted by molecular association. Their potential use as asymmetric catalysts is also described.

Determination of acid dissociation constants of flavin analogues by capillary zone electrophoresis.

Acid dissociation constants (pKa ) of nine kinds of flavin analogues as molecular catalyst candidates were determined by CZE. Although some of the analogues are instable and degradable under the light exposure or in alkaline aqueous solutions, the effective electrophoretic mobility of the flavin analogue of interest has been measured with the residual substance. The pKa values of the flavin analogues were analyzed through the changes in the effective electrophoretic mobility with varying pH of the separation buffer. One or two steps pKa values were determined by the analysis. One of the degraded species from the flavin analogues, lumichrome, was also detected in the CZE analysis, and its pKa values were also determined. While coexisting impurities generated over the storage conditions were found in some analogues, the pKa values of the target analogues were successfully determined with the help of the CZE separations. A pressure-assisted CZE was utilized for the determination or the estimation of the pKa values of such analogues as possessing carboxylic acid moiety.

An uncommon use of irradiated flavins: Brønsted acid catalysis.

We present that thioacetalization of aldehydes can be induced by blue light irradiation in the presence of a catalytic amount of riboflavin tetraacetate (RFTA) under aerobic conditions. Several control experiments have suggested that the reaction is more likely to be catalyzed by acidic species generated in situ upon light irradiation. We have proposed that single electron transfer from a thiol (RSH) to the excited state of RFTA can take place to give a one-electron oxidized thiol (RSH+˙) and the one-electron reduced RFTA (RFTA-˙), which can be trapped by molecular oxygen to be stabilized as Brønsted acids including the protonated RFTA-˙ (RFTAH˙). Finally, we have demonstrated that such acidic species can be prepared in advance as a solution and used as Brønsted acid catalysts for not only thioacetalization but also Mannich-type reactions.

Efficient Use of Photons in Photoredox/Enamine Dual Catalysis with a Peptide-Bridged Flavin-Amine Hybrid.

An isoalloxazine (flavin) ring system and a secondary amine have been integrated through a short peptide linker with the aim of using photons as efficiently as possible in photoredox/enamine dual catalysis. We herein report a peptide-bridged flavin-amine hybrid that can catalyze α-oxyamination of aldehydes with TEMPO under weak blue light irradiation to achieve an extremely high quantum yield of reaction (Φ = 0.80).

Flavinium and Alkali-Metal Assembly on Sulfated Chitin: A Heterogeneous Supramolecular Catalyst for H2 O2 -Mediated Oxidation.

Heterogeneous multiple-catalyst assemblies were developed in which the flavinium cation and Na or Li cations were easily immobilized on a chitin-derived anionic polymeric scaffold through noncovalent ionic interactions. The supramolecular flavinium catalysts were successfully employed in the environmentally friendly heterogeneous Baeyer-Villiger oxidation and sulfoxidation by H2 O2 . Owing to the cooperative catalytic effect of flavinium, alkali metal, and sulfated chitin, the supramolecular flavinium assembly showed higher catalytic activity for the Baeyer-Villiger oxidation of cyclic ketones than the corresponding homogeneous flavinium catalyst. Because the ionic assembly was stable under the reaction conditions, the catalyst could be readily recovered by simple filtration and reused.

Enzyme-like Regiodivergent Behavior of a Flavopeptide Catalyst in Aerobic Baeyer-Villiger Oxidation.

We recently developed a flavopeptide immobilized on polystyrene resin, Fl-Pep-PS, that could realize the first N5-unmodified neutral flavin (Fl)-catalyzed aerobic oxygenation reactions under non-enzymatic conditions. Although a key active species is assumed to be the corresponding 4a-hydroperoxyflavin (Fl4aOOH) from the unprecedented activity and unique chemoselectivity, further circumstantial support would be helpful to be sure since spectroscopic evidence is difficult to obtain due to the compound's insolubility. In this article, we report that the aerobic Baeyer-Villiger oxidation of a fused cyclobutanone, (±)-cis-bicyclo[3.2.0]hept-2-en-6-one (1), can be promoted with Fl-Pep-PS in a FMO-like chemoselectivity and regiodivergent manner via Fl-related catalytic intermediates, which delivers strong evidence of the involvement of Fl4aOOH as an active species in Fl-Pep-PS-catalyzed aerobic oxygenation reactions.

Design of peptide-containing N5-unmodified neutral flavins that catalyze aerobic oxygenations.

Simulation of the monooxygenation function of flavoenzyme (Fl-Enz) has been long-studied with N5-modified cationic flavins (FlEt+ ), but never with N5-unmodified neutral flavins (Fl) despite the fact that Fl is genuinely equal to the active center of Fl-Enz. This is because of the greater lability of 4a-hydroperoxy adduct of Fl, FlOOH , compared to those of FlEt+ , FlEtOOH , and Fl-Enz, FlOOH-Enz. In this study, Fl incorporated into a short peptide, flavopeptide (Fl-Pep), was designed by a rational top-down approach using a computational method, which could stabilize the corresponding 4a-hydroperoxy adduct (FlOOH-Pep) through intramolecular hydrogen bonds. We report catalytic chemoselective sulfoxidation as well as Baeyer-Villiger oxidation by means of Fl-Pep under light-shielding and aerobic conditions, which are the first Fl-Enz-mimetic aerobic oxygenation reactions catalyzed by Fl under non-enzymatic conditions.

Facile Preparation of Flavinium Organocatalysts.

We developed a safe, simple, inexpensive, and environmentally benign method for preparing N(5)-ethylated flavinium organocatalysts without using hazardous reagents or inert conditions as previously required. 5-Ethyl-3-methyllumiflavinium cation was prepared from its reduced form by NaNO2 -free aerobic oxidation, which was subsequently extracted onto commercial cation-exchange resins under NaClO4 -free conditions. The resulting resin-immobilized flavinium salts were found to be effective organocatalysts for aerobic oxidation reactions.

Organocatalytic stereoselective synthesis of acyclic γ-nitrothioesters with all-carbon quaternary stereogenic centers.

A method for the stereoselective synthesis of acyclic thioesters bearing adjacent quaternary and tertiary stereogenic centers under mild organocatalytic conditions was developed. α-Substituted monothiomalonates (MTMs) were used as thioester enolate equivalents. They reacted cleanly with nitroolefins in the presence of 1-6 mol % of cinchona alkaloid urea derivatives, and provided access to γ-nitrothioesters with quaternary stereocenters in high yields and diastereo- and enantioselectivities. Mechanistic investigations provided insight into the parameters that determine the stereoselectivity and showed that the diastereoselectivity can be controlled by the nature of the MTM substrate. The different reactivities of the three functional groups (oxoester, thioester, nitro moieties) within the conjugate addition products allowed for straightforward access to other compounds with quaternary stereogenic centers, such as γ-nitroaldehydes and γ-butyrolactams.

Peptide-catalyzed 1,4-addition reactions of aldehydes to nitroolefins.

Conjugate addition reactions of aldehydes to nitroolefins provide synthetically useful gamma-nitroaldehydes. Here we summarize our research on peptide-catalyzed conjugate addition reactions of aldehydes to differently substituted nitroolefins. We show that peptides of the general type Pro-Pro-Xaa (Xaa = acidic amino acid) are not only highly active, robust and stereoselective catalysts but have also remarkable chemoselectivities.

Enamine catalysis in flow with an immobilized peptidic catalyst.

Pep talk: An immobilized peptidic catalyst achieves more than 600 turnovers in a continuous-flow system, allowing the production of chiral γ-nitroaldehydes with excellent stereoselectivities on a scale of >450 mmol (>100 g). Such a high efficiency opens the way for more practical applications of enamine catalysis.

Asymmetric transfer hydrogenation of imines catalyzed by a polymer-immobilized chiral catalyst.

The asymmetric transfer hydrogenation of imines was performed with the use of a polymer-immobilized chiral catalyst. The chiral catalyst, prepared from crosslinked polystyrene-immobilized chiral 1,2-diamine monosulfonamide, was effective in the asymmetric transfer hydrogenation of N-benzyl imines in CH(2)Cl(2) to give a chiral amine in high yield and good enantioselectivity. Furthermore, an amphiphilic polymeric catalyst prepared from crosslinked polystyrene containing sulfonated groups successfully catalyzed the asymmetric transfer hydrogenation of cyclic imines in water. Enantioenriched secondary amines with up to 94% ee were obtained by using a polymeric catalyst.

A patient with primary biliary cirrhosis complicated with slowly progressive insulin-dependent diabetes mellitus.

We report a case of primary biliary cirrhosis (PBC) complicated by slowly progressive insulin-dependent diabetes mellitus (SPIDDM). A 67-year-old woman was diagnosed as having PBC based on clinical manifestations and a positive result of anti-mitochondrial antibody. Furthermore, SPIDDM was diagnosed by her clinical course and a positive result of anti-glutamic acid decarboxylase antibody. Both PBC and SPIDDM are considered to be autoimmune diseases. However, the coexistence of PBC and SPIDDM is extremely rare. Liver cirrhosis sometimes accompanies hyperglycemia. When the etiology of liver cirrhosis is an autoimmune disorder such as PBC, SPIDDM should be considered as a cause of hyperglycemia.