Synthesis of ω-Chloroalkyl Aryl Ketones via C-C Bond Cleavage of tert-Cycloalkanols with Tetramethylammonium Hypochlorite.

An oxidative C-C bond cleavage of tert-cycloalkanols with tetramethylammonium hypochlorite (TMAOCl) has been developed. TMAOCl is easy to prepare from tetramethylammonium hydroxide, and the combination of TMAOCl and AcOH effectively promoted the C-C bond cleavage in a two-phase system without additional phase-transfer reagents. Unstrained tert-cycloalkanols were transformed into ω-chloroalkyl aryl ketones in moderate to excellent yields under metal-free and mild reaction conditions.

(3+2) Cycloaddition of Heteroaromatic N-Ylides with Sulfenes.

A (3+2) cycloaddition of heteroaromatic N-ylides with sulfenes, which are generated in situ from sulfonyl chlorides, has been developed. A variety of ylides were transformed into the corresponding sulfone-embedded N-fused heterocycles in high yields. Hexafluoroisopropyl mesylate was demonstrated to be a suitable reactant for quinolinium ylides. Furthermore, this cycloaddition could be performed with an ylide prepared by a Cu-catalyzed ylide transfer reaction in a one-pot manner, extending the substrate scope to an unisolable ylide.

Copper-Catalyzed Asymmetric Sulfonylative Desymmetrization of Glycerol.

Glycerol is the main side product in the biodiesel manufacturing process, and the development of glycerol valorization methods would indirectly contribute the sustainable biodiesel production and decarbonization. Transformation of glycerol to optically active C3 units would be one of the attractive routes for glycerol valorization. We herein present the asymmetric sulfonylative desymmetrization of glycerol by using a CuCN/(R,R)-PhBOX catalyst system to provide an optically active monosulfonylated glycerol in high efficiency. A high degree of enantioselectivity was achieved with a commercially available chiral ligand and an inexpensive carbonate base. The optically active monosulfonylated glycerol was successfully transformed into a C3 unit attached with differentially protected three hydroxy moieties. In addition, the synthetic utility of the present reaction was also demonstrated by the transformation of the monosulfonylated glycerol into an optically active synthetic ceramide, sphingolipid E.

Electrochemical formal homocoupling of sec-alcohols.

Electrochemical pinacol coupling of carbonyl compounds in an undivided cell with a sacrificial anode would be a promising approach toward synthetically valuable vic-1,2-diol scaffolds without using low-valent metal reductants. However, sacrificial anodes produce an equimolar amount of metal waste, which may be a major issue in terms of sustainable chemistry. Herein, we report a sacrificial anode-free electrochemical protocol for the synthesis of pinacol-type vic-1,2-diols from sec-alcohols, namely benzyl alcohol derivatives and ethyl lactate. The corresponding vic-1,2-diols are obtained in moderate to good yields, and good to high levels of stereoselectivity are observed for sec-benzyl alcohol derivatives. The present transformations smoothly proceed in a simple undivided cell under constant current conditions without the use of external chemical oxidants/reductants, and transition-metal catalysts.

Organocatalytic Synthesis of Phenols from Diaryliodonium Salts with Water under Metal-Free Conditions.

The metal-free synthesis of phenols from diaryliodonium salts with water was developed by using N-benzylpyridin-2-one as an organocatalyst. In this process, sterically congested, functionalized, and heterocycle-containing iodonium salts were smoothly converted to the desired products, and the clofibrate and mecloqualone derivatives were also synthesized in high yields. In addition, the gram-scale experiment was successfully carried out with 10 mmol of a sterically congested substrate.

Copper-Catalyzed Asymmetric Oxidative Desymmetrization of 2-Substituted 1,2,3-Triols.

Asymmetric oxidative desymmetrization of 2-substituted glycerols has been achieved by using a new chiral bisoxazoline ligand/copper catalyst system with 1,3-dibromo-5,5-dimethylhydantoin and MeOH. The present transformation smoothly proceeds with readily accessible 2-(hetero)aryl- and alkyl-substituted glycerols and provides straightforward access toward various glycerate derivatives in good to high yields with high enantioselectivities. The synthetic utility of the present protocol was demonstrated by the transformation of the optically active glycerol into a glyceraldehyde derivative.

Electrophotochemical Ring-Opening Bromination of tert-Cycloalkanols.

An electrophotochemical ring-opening bromination of unstrained tert-cycloalkanols has been developed. This electrophotochemical method enables the oxidative transformation of cycloalkanols with 5- to 7-membered rings into synthetically useful ω-bromoketones without the use of chemical oxidants or transition-metal catalysts. Alkoxy radical species would be key intermediates in the present transformation, which generate through homolysis of the O-Br bond in hypobromite intermediates under visible light irradiation.

Shono-Type Oxidation for Functionalization of N-Heterocycles.

The development of facile synthetic methods for stereodefined aliphatic cyclic amines is an important research field in synthetic organic chemistry since such scaffolds constitute a variety of natural products and biologically active compounds. N-Acyl cyclic N,O-acetals which prepared by electrochemical oxidation of the corresponding cyclic amines have proven to be useful and versatile precursors for the synthesis of such skeletons. In this Personal Account, we introduce our efforts toward the development of synthetic strategies for the diastereo- and/or enantioselective synthesis of cyclic amines by using electrochemically prepared cyclic N,O-acetals. In addition, the investigation of the "memory of chirality" in the electrooxidative methoxylation of N-acyl amino acid derivatives, the strategy for the synthesis of chiral azabicyclic compounds by utilizing electrochemical oxidation, and halogen cation-mediated synthesis of nitrogen-containing heterocycles are also described.

Copper-Catalyzed Enantioselective Synthesis of Oxazolines from Aminotriols via Asymmetric Desymmetrization.

A copper-catalyzed enantioselective transformation of tris(hydroxymethyl)aminomethane-derived aminotriols was developed to provide multisubstituted oxazolines with a tetrasubstituted carbon center. The present transformation consisted of sequential reactions involving mono-sulfonylation of aminotriols, subsequent intramolecular cyclization to afford prochiral oxazoline diols, and sulfonylative asymmetric desymmetrization of resultant oxazoline diols. In addition, the kinetic resolution process would be involved in the sulfonylative asymmetric desymmetrization step, which would amplify the enantiopurities of the desired products. Various aminotriols were tolerated in the present reaction, affording the desired oxazolines in good to high yields with excellent enantioselectivities. The synthetic utility of the present reaction was demonstrated by the transformation of the optically active oxazoline into a chiral α-tertiary amine motif.

N- and O-arylation of pyridin-2-ones with diaryliodonium salts: base-dependent orthogonal selectivity under metal-free conditions.

Metal-free N- and O-arylation reactions of pyridin-2-ones as ambident nucleophiles have been achieved with diaryliodonium salts on the basis of base-dependent chemoselectivity. In the presence of N,N-diethylaniline in fluorobenzene, pyridin-2-ones were very selectively converted to N-arylated products in high yields. On the other hand, the O-arylation reactions smoothly proceeded with the use of quinoline in chlorobenzene, leading to high yields and selectivities. In these methods, a variety of pyridin-2-ones in addition to pyridin-4-one and a set of diaryliodonium salts were accepted as suitable reaction partners.

Anodic Oxidation for the Stereoselective Synthesis of Heterocycles.

Stereodefined aliphatic heterocycles are one of the fundamental structural motifs observed in natural products and biologically active compounds. Various strategies for the synthesis of these building blocks based on transition metal catalysis, organocatalysis, and noncatalytic conditions have been developed. Although electrosynthesis has also been utilized for the functionalization of aliphatic heterocycles, stereoselective transformations under electrochemical conditions are still a challenging field in electroorganic chemistry. This Account consists of four main topics related to our recent efforts on the diastereo- and/or enantioselective synthesis of aliphatic heterocycles, especially N-heterocycles, using anodic oxidations as key steps. The first topic is the development of stereoselective synthetic methods for multisubstituted piperidines and pyrrolidines from anodically prepared α-methoxy cyclic amines. Our strategies were based primarily on N-acyliminium ion chemistry, and the key electrochemical transformations were diastereoselective anodic methoxylation, diastereoselective arylation, and anodic deallylative methoxylation. Furthermore, we found a unique property of the N-cyano protecting group that enabled the electrochemical α-methoxylation of α-substituted cyclic amines. The second topic of investigation is memory of chirality in electrochemical decarboxylative methoxylation. We observed that the electrochemical decarboxylative methoxylation of oxazolidine and thiazolidine derivatives with the appropriate N-protecting group occurred in a stereospecific manner even though the reaction proceeded through an sp2 planar carbon center. Our findings demonstrated the first example of memory of chirality in N-acyliminium ion chemistry. The third topic is the synthesis of chiral azabicyclo-N-oxyls and their application to chiral organocatalysis in the electrochemical oxidative kinetic resolution of secondary alcohols. The final topic is stereoselective transformations utilizing anodically generated halogen cations. We investigated the oxidative kinetic resolution of amino alcohol derivatives using anodically generated bromo cations. We also developed an intramolecular C-C bond formation of keto amides, a diastereoselective bromoiminolactonization of α-allyl malonamides, and an oxidative ring expansion reaction of allyl alcohols. It is noteworthy that most of the electrochemical reactions were performed in undivided cells under constant-current conditions, which avoided a complicated reaction setup and was beneficial for a large-scale reaction. In addition, we developed some enantioselective electrochemical transformations that are still challenges in electroorganic chemistry. We hope that our research will contribute to the further development of diastereo- and/or enantioselective transformations and the construction of valuable heterocyclic compounds using an electrochemical approach.

Computational study of the competitive binding of valproic acid glucuronide and carbapenem antibiotics to acylpeptide hydrolase.

The efficacy of the antiepileptic drug VPA is decreased by co-administered carbapenems (CBPMs). The mechanism of CBPM selective inhibition of acylpeptide hydrolase (APEH) hydrolysis of VPA-glucuronide (VPA-G) to VPA is unclear due to the lack of APEH structural information. Here we performed homology modeling of the three-dimensional structure of APEH and subsequent docking simulations with a modeled structure to understand this mechanism. Docking simulations indicated that four groups of binding structures were involved in the binding of VPA-G, panipenem, and meropenem to APEH, but only one or two binding structures were involved in the binding of meropenem with an open ß-lactam ring structure and other antibiotics involving ampicillin. One of the four VPA-G binding structures was close enough to the APEH catalytic triad to facilitate VPA-G hydrolysis. This binding structure was also the most stable binding structure for panipenem, suggesting potential inhibition of VPA-G hydrolysis by panipenem. Fragment molecular orbital calculations of interaction energies of amino acid residues of APEH with VPA-G, panipenem, and meropenem indicated that the binding structure for panipenem closest to the catalytic triad is stabilized upon APEH interaction. These data suggest that APEH binding characteristics with CBPMs may help explain the selective inhibition of APEH by CBPMs.

Deuterodechlorination of Aryl/Heteroaryl Chlorides Catalyzed by a Palladium/Unsymmetrical NHC System.

The catalytic deuterodechlorination of aryl/heteroaryl chlorides was developed with a palladium/unsymmetrical NHC system, and the precisely controlled introduction of deuterium into a variety of aryl/heteroaryl compounds was achieved with a high level of efficiency, selectivity, and deuteration degree. This method was also successfully applied to the transformation of bioactive agents even in a gram-scale synthesis. The crystal structure analysis of Pd-NHC complexes led to the observation of Pd-arene interaction.

Palladium-catalyzed synthesis of heterocycle-containing diarylmethanes through Suzuki-Miyaura cross-coupling.

The heterocycle-containing diarylmethane synthesis from chloromethyl(hetero)arenes with (hetero)arylboron reagents was attained using the palladium/ether-imidazolium chloride system. This coupling process tolerated a diverse range of heteroaromatic moieties with sufficient catalytic activity to achieve the efficient synthesis of various diheteroarylmethanes in good to excellent yields.

Synthesis and biological evaluation of N-(2-fluorophenyl)-2ß-deoxyfuconojirimycin acetamide as a potent inhibitor for α-l-fucosidases.

In this study we revealed that the addition of an N-phenylacetamide substituent to the C-1 position of 1-deoxyfuconojirimycin (DFJ) can lead to highly potent inhibitors of α-l-fucosidases. A structure-activity relationship study showed that a fluoro group on the phenyl ring greatly increased its potency and selectivity. In contrast the addition of two or three fluoro groups decreased their inhibition potency. Consequently, N-(2-fluorophenyl)-2ß-DFJ acetamide (18j) was found to display very potent and selective inhibition of bovine kidney, rat epididymis, and human lysosome α-l-fucosidases, with IC50 value of 0.012, 0.044, and 0.0079µM respectively. It is noteworthy that our designed N-phenyl-2ß-DFJ acetamide derivative exhibited about 18-fold stronger effects on human lysosomal α-l-fucosidase than original DFJ and it occupied the active-site of this enzyme. We therefore expect that this compound may find applications in new therapeutic trials against genetic deficiency disorders.

Ether-imidazolium carbenes for Suzuki-Miyaura cross-coupling of heteroaryl chlorides with aryl/heteroarylboron reagents.

Easily accessible and handled ether-imidazolium chlorides were developed as ligand precursors. The coupling reactions of heteroaryl chlorides with aryl/heteroarylboronic acids and esters were catalyzed by the palladium/ether-imidazolium chloride system with high substrate tolerance to give various heterobiaryls in good to excellent yields.

Organotin-catalyzed highly regioselective thiocarbonylation of nonprotected carbohydrates and synthesis of deoxy carbohydrates in a minimum number of steps.

Nonprotected carbohydrates: The catalytic regioselective thiocarbonylation of carbohydrates by using organotin dichloride under mild conditions was demonstrated. The reaction afforded various deoxy saccharides in high yields and excellent regioselectivity in a minimum number of steps. The regioselectivity of the thiocarbonylation is attributed to the intrinsic character of the carbohydrates based on the stereorelationship of their hydroxy groups (see scheme).