Hiromichi Fujioka

Asymmetric bromolactonization catalyzed by a C3-symmetric chiral trisimidazoline.

Halolactonization is one of the fundamental transformations in synthetic organic chemistry. This reaction provides synthetically useful products, which can be employed as synthetic intermediates for divergent transformations. A catalytic asymmetric version of this transformation would be very attractive. However, though a number of attempts to develop catalytic asymmetric halolactonization reactions have been made, and several related enantioselective halocyclizations have been developed, these reactions are still under development. Recently, highly enantioselective halolactonization reactions with organocatalysts were reported. Borhan and co-workers reported an enantioselective chlorolactonization of 4-substituted 4-pentenoic acids in the presence of hydroquinidine 1,4-phthalazinediyl diether ((DHQD)2PHAL), [4a] and Tang and co-workers reported an enantioselective bromolactonization of conjugated Z enynes with a bifunctional cinchona-alkaloid catalyst bearing a urea moiety. However, the former reaction was limited to chlorolactonization; bromoand iodolactonization were not successful, although Br and I are generally more readily transformed into various functional groups than Cl. The latter reaction is limited to particular substrates, such as conjugated Z enynes. Therefore, the development of a novel efficient method for catalytic asymmetric halolactonization is still important. During the preparation of this manuscript, Veitch and Jacobsen reported a tertiary-amine-catalyzed enantioselective iodolactonization. Herein, we present our study on organocatalytic asymmetric halolactonization. By using the structurally unique C3-symmetric trisimidazoline 1a, we developed a novel asymmetric bromolactonization of 5-substituted 5-hexenoic acids. Our working hypothesis for the development of the enantioselective bromolactonization is shown in Scheme 1. We assumed that if the alkenyl carboxylic acid and an appropriate chiral amine could form an ion pair, a chiral environment would be created. At the same time, the carboxylic acid should be activated. Bromolactonization would then proceed enantioselectively, because the olefin and the two possible bromonium intermediates would be in equilibrium in the presence of the brominating reagent, and the activated carboxylic acid, which would be in a chiral environment, should react preferentially with one of the two bromonium ions. This approach is different from recent successful approaches, which mainly involved the creation of chiral environments around the halo cations. The key to this hypothesis was the appropriate choice of a chiral amine that would have a good interaction with carboxylic acids. We envisioned that the C3-symmetric trisimidazoline 1a (Scheme 2), which we developed recently as a new organocatalyst entry, could be suitable for our working hypothesis, because an interesting interaction of the trisimidazoline derived from ethylenediamine with carboxylic acids led to the formation of 1:3 complexes in the field of material sciences (Scheme 2).

Asymmetric Dearomatizing Spirolactonization of Naphthols Catalyzed by Spirobiindane-Based Chiral Hypervalent Iodine Species

This report details the development of a spirobiindane-based chiral hypervalent iodine reagent, especially focusing on its structural elucidation for effective asymmetric induction of the chiral spiro center during the oxidative dearomatizing spirolactonization of naphthols. In this study we synthesized a new series of ortho-functionalized spirobiindane catalysts and demonstrated that the enantioselectivity can be dramatically improved by the presence of the substituents ortho to the iodine atom. The structural elucidation of a spirobiindane-based hypervalent iodine catalyst has led to further improvement in the stereoselective construction of the spiro center during the oxidative dearomatizing spirolactonization of naphthols. Thus, catalytic oxidation with the highest reported level of enantioselectivity in hypervalent iodine chemistry has been achieved with also an excellent level of asymmetric induction (92% ee for substrate 3a). As a result, this study, dealing with a series of modified iodine catalysts, can provide important clues about the transition state and reaction intermediate to help scientists understand the origin of the stereoselectivity. A plausible transition-state model and intermediate in the reaction for the stereoselective formation of spirolactone products are postulated by considering the ortho-substituent effect and the results of X-ray analysis. In this reaction model, the high enantiomeric excess obtained by using the spirobiindane catalysts could be well explained by the occupation of the equatorial site and extension of the surroundings around the hypervalent iodine bonds by the introduced ortho-substituent. Thus, this study would contribute to estimation of the chiral hypervalent iodine compounds in asymmetric reactions.

Unusual ipso Substitution of Diaryliodonium Bromides Initiated by a Single‐Electron‐Transfer Oxidizing Process

The diaryliodonium salts ArIArX , which have two aryl groups bound to an iodine atom as a ligand, represent one of the most popular classes of hypervalent iodine compounds and they have application as important arylating agents in organic synthesis. In general, the arylation of nucleophiles with these iodonium salts is assumed to involve the tricoordinated intermediate A before the final ligand-coupling (LC) steps. Owing to the competition of the two LC pathways of Ar and Nu (LCAr ) or Ar and Nu (LCAr ) at the iodine atoms in the intermediates, a mixture of two types of arylated products, Ar Nu and Nu Ar, are potentially obtained in the unsymmetrical salts (Ar1⁄46 Ar) during the aromatic substitution. Previous studies have revealed that the product produced from these pathways should be effected by both electronic and steric factors exerted by the two differential aryl rings of the initial salts—where the nucleophiles would preferentially react with a relatively electron-deficient aryl ring and/or sterically congested ipso carbon atom (i.e. the so-called “ortho effect”). Therefore, the introduction of nucleophiles to an electron-rich heteroaromatic ring is known to be particularly difficult through typical thermal LC processes, which involve the collapse of the intermediate A. Despite their rich chemistry, the utility of diaryliodonium salts as a heteroaryl transfer agent in LC processes has been somewhat limited. Herein, we report a unique single-electron-transfer (SET) oxidizing strategy using diaryliodonium salts as selective heteroaryl transfer agents during ipso substitution. Recently, our research group has reported a metal-free C H coupling method of thiophenes and aromatic compounds using iodonium salts. The method, using TMSBr in hexafluoroisopropanol (HFIP), is useful for the coupling reaction of the thiophene iodonium salts and introduces aromatic nucleophiles to the g positions of the iodine(III)–carbon bonds [Eq. (1)]. However, this reaction is not suitable for coupling through the ipso substitution of the thiophene iodonium salts 1a-X [X = OTs, Br; Eq. (2)].

Clean and efficient benzylic C-H oxidation in water using a hypervalent iodine reagent: activation of polymeric iodosobenzene with KBr in the presence of montmorillonite-K10.

We have found that unreactive and insoluble polymeric iodosobenzene [PhIO] n induced aqueous benzylic C-H oxidation to effectively give arylketones, in the presence of KBr and montmorillonite-K10 (M-K10) clay. Water-soluble and reactive species 1 having the unique I(III)-Br bond, in situ generated from [PhIO]n and KBr, was considered to be the key radical initiator during the reactions.

C3‐Symmetric Trisimidazoline‐Catalyzed Enantioselective Bromolactonization of Internal Alkenoic Acids

A method for conducting enantioselective bromolactonization reactions of trisubstituted alkenoic acids, using the C(3)-symmetric trisimidazoline 1 and 1,3-dibromo-5,5-dimethyl hydantoin as a bromine source, has been developed. The process generates chiral δ-lactones that contain a quaternary carbon. The results of studies probing geometrically different olefins show that (Z)-olefins rather than (E)-olefins are favorable substrates for the process. The method is not only applicable to acyclic olefin reactants but can also be employed to transform cyclic trisubstituted olefins into chiral spirocyclic lactones. Finally, the synthetic utility of the newly developed process is demonstrated by its application to a concise synthesis of tanikolide, an antifungal marine natural product.

C3-Symmetric Chiral Trisimidazoline: Design and Application to Organocatalyst

C(3)-symmetric chiral trisimidazoline was designed and synthesized as a new entry of organocatalyst with the concept of constructing C(3)-symmetric molecules with three C(2)-symmetric chiral components, and the application of this novel catalyst to asymmetric conjugate addition of beta-ketoesters to nitroolefins was described.

Metal-Free C–H Cross-Coupling toward Oxygenated Naphthalene-Benzene Linked Biaryls

The intermolecular C-H cross-coupling between aromatic ethers has been achieved for the first time using perfluorinated hypervalent iodine(III) compounds as extreme single-electron-transfer (SET) oxidants. The demonstrations of this specific coupling could provide a direct route to valuable oxygenated mixed naphthalene-benzene biaryls 3 only, without formation of other biaryl-derived byproducts.

Metal-Free Regioselective Oxidative Biaryl Coupling Leading to Head-to-Tail Bithiophenes: Reactivity Switching, a Concept Based on the Iodonium(III) Intermediate

A new synthetic concept for obtaining unsymmetrical biaryl coupling products by an oxidative method is reported. Our synthetic strategy casts light on the reaction intermediate for switching the reactivity of 3-substituted thiophenes. On the basis of this strategy, a novel direct method for the synthesis of head-to-tail bithiophenes using hypervalent iodine(III) reagents has been developed.

Concise asymmetric synthesis of a model compound, (4S,5S,6S)-6-(2,2-dimethoxy)ethyl-4,5-epoxy-6-hydroxy-2-cyclohexenone, for the cyclohexenone core of scyphostatin

Abstract The optically pure cyclohexenone core of scyphostatin ( 1 ) has been synthesized from cyclohexadiene acetal 5 . The crucial aspects of our synthesis include the intramolecular bromoetherification of 5 , the SeO 2 oxidation of 7 , and the enone formation of 13 to 4 in the final step.

Asymmetric synthesis of anthracyclinones using chiral acetal: synthesis of a new chiral AB-synthon, ()-2-bromo-6-ethynyl-6-hydroxy-5, 6, 7, 8-tetrahydro-1, 4-naphthoquinone, and its application for ()-7-deoxydaunomycinone

Abstract A synthesis of a new chiral AB-synthon ( 4 ) for preparing the optically active anthracyclinones was attained through a stereospecific nucleophilic addition of trimethylsilylethynylmagnesium chloride to the chiral 2-tetralone-1-acetal ( 2 ). Synthesis of ( )-7- deoxydaunomycinone ( 1c ) was achieved by a regiospecific cycloaddition of 4 to 4-acetoxy-8-methoxyhomophthalic anhydride ( 5 ).