Kounosuke Oisaki

Crystalline Covalent Organic Frameworks with Hydrazone Linkages

Condensation of 2,5-diethoxyterephthalohydrazide with 1,3,5-triformylbenzene or 1,3,5-tris(4-formylphenyl)benzene yields two new covalent organic frameworks, COF-42 and COF-43, in which the organic building units are linked through hydrazone bonds to form extended two-dimensional porous frameworks. Both materials are highly crystalline, display excellent chemical and thermal stability, and are permanently porous. These new COFs expand the scope of possibilities for this emerging class of porous materials.

A Metal-Organic Framework with Covalently Bound Organometallic Complexes

A procedure for making covalently linked organometallic complexes within the pores of metal-organic frameworks (MOFs) has been described. An N-heterocyclic carbene precursor containing link L0 was prepared and then constructed into a MOF-5-type structure (IRMOF-76). Attempts to produce covalently bound organometallic complexes in IRMOF-76 were unsuccessful. An alternative way of linking the first metalated link, L1, into the desired metalated MOF structure, IRMOF-77, was successful. IRMOF-76 and -77 were characterized by single-crystal X-ray studies. Demonstration of permanent porosity and successful substitution of the pyridine coligand in IRMOF-77 are also described.

Catalytic aerobic production of imines en route to mild, green, and concise derivatizations of amines

The development of a general, mild, and chemoselective catalytic aerobic oxidation of amines to imines is described. The combination of a less sterically demanding and electron-deficient new N-oxyl radical (ketoABNO: 5) and copper(I) salt is key for the high catalytic activity and allows for the use of molecular oxygen as the stoichiometric oxidant producing H2O as the sole side-product. The novel method is extendable to a direct α-derivatization of secondary amines via sequential aerobic oxidation of amines to imines followed by C–C bond-formation to the resulting imines, including the novel catalytic asymmetric aerobic cross-dehydrogenative coupling reaction. Mechanistic insight into the novel catalytic system is also discussed.

Identification of Modular Chiral Bisphosphines Effective for Cu(I)-Catalyzed Asymmetric Allylation and Propargylation of Ketones

New modular chiral phosphines effective for two distinct Cu(I)-catalyzed asymmetric tetrasubstituted-carbon-forming reactions, namely, allylation and propargylation of ketones, were identified. The optimized phosphine 8 was readily synthesized on a gram scale in high yield via three facile transformations (O-alkylation, bisaminal formation, and phosphination) from commercially available materials. In both reactions, excellent enantioselectivity (up to 98% ee) was produced from a range of substrates, including aromatic and aliphatic ketones, using 0.1-5 mol % catalyst loading. Specifically, catalytic enantioselective propargylation was the first example, affording synthetically useful chiral building blocks that have not been easily accessed to date. In addition to the enantioselectivity, the high catalytic activity of the CuOAc-8 complex is noteworthy. Preliminary studies to elucidate the structure-catalyst activity relationship suggested that the high catalytic activity of the Cu-8 complex is due to the extraordinarily wide bite angle ( angleP-Cu-P = 137.8 degrees ), leading to the stabilization of the active monomeric catalytically active species. Furthermore, mechanistically intriguing nonconventional hydrogen bonds existed between the acetate ligand of Cu and the bisaminal hydrogen atoms, stabilizing the distorted tetrahedral coordination state of the Cu atom.

Asymmetric Reductive Mannich Reaction to Ketimines Catalyzed by a Cu(I) Complex

A highly diastereoselective reductive Mannich coupling of ketimines and alpha,beta-unsaturated esters was developed using CuOAc-PPh(3) or CuOAc-MePPh(2) complex as a catalyst (5 mol %) and pinacolborane as a reducing reagent. The reaction was easily conducted at room temperature, and the substrate generality was broad. This platform methodology was extended to the first catalytic asymmetric reductive Mannich reaction of ketimines using CuOAc-DIFLUORPHOS as the catalyst (10 mol %). Switching the reducing reagent from pinacolborane to (EtO)(3)SiH was key to inducing the high enantioselectivity (82-93% ee). High diastereoselectivity was also maintained (3:1 approximately 30:1). Thus, products containing contiguous tetra- and trisubstituted carbons were catalytically synthesized with high stereoselectivities. Products were converted to alpha,beta,beta-trisubstituted (beta(2,3,3)) amino acid derivatives without any racemization and epimerization through simple treatment under acidic conditions. This method is the first entry of the catalytic asymmetric synthesis of beta(2,3,3)-amino acid derivatives, which constitute important chiral building blocks of biologically significant molecules.

Iron-Catalyzed Oxidative C(3)–H Functionalization of Amines

Fe-catalyzed direct dehydrogenative C(3)-functionalization of tertiary arylamines was developed via activation of the sp(3) C(3)-H bond. The reaction is applicable to both cyclic and acyclic amines. The key process is the catalytic desaturative enamine formation from tertiary amines and position-selective C-C bond formation (addition to nitro olefins) at the β-carbon. Products can be converted to versatile and unique nitrogen-containing molecules.

Catalytic Migratory Oxidative Coupling of Nitrones

A Cu(I)-catalyzed migratory oxidative coupling between nitrones and heterocycles or a methylamine is described. Selective C-C bond-formation proceeds through cleavage of two C(sp(3))-H bonds concomitant with C═N double bond-migration. The reaction provides an alternating nitrone moiety, allowing for further synthetically useful transformations. Radical clock studies suggest that the nucleophilic addition of nitrones to an oxidatively generated carbocation is a key step.

Cu(I)-catalyzed hetero-Diels-Alder reaction between Danishefsky-type siloxy dienes and ketones.

A general catalytic method for the hetero-Diels-Alder reaction between Danishefsky-type siloxy dienes and ketones was developed. Optimum results were produced with a catalyst generated from CuOTf x (C6H6)1/2 and TBAT with Ph 3PO as the catalytic additive. This reaction was extended to an asymmetric variant, using a Cu(I)-Walphos catalyst.

Transition Metal-Free Tryptophan-Selective Bioconjugation of Proteins

Chemical modifications of native proteins can facilitate production of supernatural protein functions that are not easily accessible by complementary methods relying on genetic manipulations. However, accomplishing precise control over selectivity while maintaining structural integrity and homogeneity still represents a formidable challenge. Herein, we report a transition metal-free method for tryptophan-selective bioconjugation of proteins that is based on an organoradical and operates under ambient conditions. This method exhibits low levels of cross-reactivity and leaves higher-order structures of the protein and various functional groups therein unaffected. The strategy to target less abundant amino acids contributes to the formation of structurally homogeneous conjugates, which may even be suitable for protein crystallography. The absence of toxic metals and biochemically incompatible conditions allows a rapid functional modulation of native proteins such as antibodies and pathogenic aggregative proteins, and this method may thus easily find therapeutic applications.

Switchable photooxygenation catalysts that sense higher-order amyloid structures

Proteins can misfold into amyloid structures that are associated with diseases; however, the same proteins often have important biological roles. To degrade selectively the amyloid form without affecting the fraction of functional protein is, therefore, an attractive goal. Here we report target-state-dependent photooxygenation catalysts that are active only when bound to the cross-β-sheet structure that is characteristic of pathogenic aggregated amyloid proteins. We show these catalysts can selectively oxygenate the amyloid form of amyloid β-protein (Aβ) 1-42 in the presence of non-amyloid off-target substrates. Furthermore, photooxygenation with a catalyst that bears an Aβ-binding peptide attenuated the Aβ pathogenicity in the presence of cells. We also show that selective photooxygenation is generally applicable to other amyloidogenic proteins (amylin, insulin, β2-microglobulin, transthyretin and α-synuclein) and does not affect the physiologically functional non-aggregate states of these proteins. This is the first report of an artificial catalyst that can be selectively and reversibly turned on and off depending on the structure and aggregation state of the substrate protein.