Intramolecular Cyclopropanation of Active Methylene Derivatives Based on FeCl2 or FeCl3-Promoted Radical-Polar Crossover Reactions.

Radical-polar crossover reactions were studied for the intramolecular cyclopropanation of active methylene derivatives. In the presence of FeCl3 as a stoichiometric oxidant and K2HPO4 as a base, the dehydrogenative cyclopropanation of active methylenes proceeded through the FeCl3-promoted oxidative radical cyclization followed by the ionic cyclization to give the bicyclic cyclopropanes. The use of α-chloro-active methylenes leads the subcatalytic cyclopropanation involving two redox pathways. In the presence of K2HPO4, the redox cyclopropanation proceeded by using FeCl2 (20 mol%) in combination with ligand (20 mol%).

Entry into Lithium Ynolates from α,α,α-Tribromomethyl Ketones: Synthesis of Cyclobutenes via the [2 + 2] Cycloaddition with α,ß-Unsaturated Carbonyls.

This study reports the synthesis of cyclobutene derivatives in good yields via the [2 + 2] cycloaddition between lithium ynolates and α,ß-unsaturated carbonyls. The ynolates are generated from α,α,α-tribromomethyl ketones and tert-butyl lithium via a simple and novel method, which does not produce any harmful byproducts, such as lithium alkoxide, which induces a polymerization reaction with α,ß-unsaturated carbonyls.

5-exo-Selective asymmetric bromolactonization of stilbenecarboxylic acids catalyzed by phenol-bearing chiral thiourea.

We developed a novel thiourea Lewis-base catalyst with phenol moieties for the enantioselective 5-exo-bromolactonization of stilbenecarboxylic acids to afford chiral 3-substituted phthalides. The phenol moieties are crucial for the enantio- and regio-selectivity.

Regiocontrol Using Fluoro Substituent on 3,6-Disubstituted Arynes.

The effect of fluoro substituent on the regioselectivity of several reactions of 3,6-disubstituted arynes was studied. These arynes contained another inductively electron-withdrawing substituent other than fluorine. A reasonable degree of regiocontrol was achieved in the (3 + 2) cycloaddition reaction of 3,6-disubstituted aryne containing both fluorine and bromine atoms with benzyl azide. Furthermore, the insertion reaction of aryne into Sn-F σ-bonds and the three-component coupling reaction involving the insertion of aryne into C=O π-bonds also led to the high degree of regiocontrol.

Rotaxane Synthesis by an End-Capping Strategy via Swelling Axle-Phenols.

A method for rotaxane synthesis by enlargement of the size of the terminal phenol group of the axle component by aromatic bromination has been developed. This method may be regarded as an end-capping strategy involving the swelling of the phenol group at the axle terminal. The advantages of the present strategy include: ready availability of axle components with a variety of swelling precursors, wide product scope (19 examples given including a [3]rotaxane), mild conditions for the swelling process, rich potential for the derivatization of the brominated rotaxanes, and possible release of the axle component by degradative dethreading of the thermally stable brominated rotaxanes under the basic conditions.

Remote electronic effect on the N-heterocyclic carbene-catalyzed asymmetric intramolecular Stetter reaction and structural revision of products.

The remote electronic effects of chiral N-heterocyclic carbene catalysts on the asymmetric intramolecular Stetter reaction are investigated. The reaction rate and enantioselectivity were markedly influenced by a substituent at a remote position of the catalyst. The absolute configurations of the products are revised on the basis of X-ray diffraction. Density-functional theory calculations rationalize the improvement of the enantioselectivity using an electron-deficient catalyst.

Development of Antimicrobial Peptide-Antibiotic Conjugates to Improve the Outer Membrane Permeability of Antibiotics Against Gram-Negative Bacteria.

Antibiotics have been widely used in the medical field as a treatment for infectious diseases, but they are not effective against all Gram-negative bacteria because of their low permeability to the outer membrane. One of the strategies to improve the antibacterial activity of antibiotics is the coadministration of antibiotics and membrane-perturbing antimicrobial peptides for their synergistic effects. However, because of their different pharmacokinetics, their coadministration may not exert expected effects in the clinical stage. Here, we designed various antimicrobial peptide-antibiotic conjugates as a novel approach to improve the antimicrobial activity of antibiotics. Ampicillin was chosen as a model antibiotic with poor outer membrane permeability, and the effects of the chemistry and position of conjugation and the choice of antimicrobial peptides were examined. One of the ampicillin conjugates exhibited significantly improved antimicrobial activity against ampicillin-resistant Gram-negative bacteria without exerting cytotoxicity against human cultured cells, demonstrating that our novel approach is an effective strategy to improve the antimicrobial activity of antibiotics with low outer membrane permeability.

Lewis Acid-Catalyzed Diastereoselective Domino Reaction of Ene-Ynamide with Trimethylsilyl Cyanide to Construct Spiroindolines.

The Zn(OTf)2-catalyzed domino reaction of enamide-ynamides in the presence of trimethylsilyl cyanide as an external nucleophile to construct spirocyclic indolines was developed. This domino reaction involved cyclization of enamide to ynamide to generate 4',5'-dihydrospiro[indoline-3,3'-pyrrol]-1'-ium followed by cyanide addition to produce spiroindolopyrrolidines with good diastereoselectivity.

Oxidative ß-Cleavage of Fused Cyclobutanols Leading to Hydrofuran-Fused Polycyclic Aromatic Compounds.

Treatment of aryl-fused bicyclo[4.2.0]octanols with an oxidant such as phenyliodine diacetate (PIDA) or hypochlorous acid gave dihydrofuran-containing polycyclic aromatic compounds by selective ß-cleavage of the cyclobutanol moiety. Mechanistic studies suggest that the oxygen atom of the hydrofuran ring is incorporated from the hydroxy group of the substrate via intramolecular addition. The oxidative transformation should serve as a new method to prepare functionalized polycyclic aromatic compounds.

Total Synthesis of (-)-Sigillin A: A Polychlorinated and Polyoxygenated Natural Product.

The total synthesis of (-)-sigillin A, a highly chlorinated and oxygenated octahydroisocoumarin, is described herein. A hexahydroisocoumarin skeleton was constructed from (R)-4-(trichloromethyl)oxetan-2-one in seven steps. Its unique manganese oxidation provided an enone as the key intermediate of sigillin A. Stereoselective installation of two hydroxy groups and formation of gem-dichloroalkene from the corresponding ketone led to the total synthesis of (-)-sigillin A in a total of 16 steps.

Helical Nanographenes Embedded with Contiguous Azulene Units.

The azulene moiety, composed of contiguous pentagonal and heptagonal rings, is a structural defect that alters the electronic, magnetic, and structural properties of graphenes and graphene nanoribbons. However, nanographenes embedded with an azulene cluster have not been widely investigated because these compounds are difficult to synthesize in their pure form. Herein, azulene-embedded nanographenes bearing a unique cove-type edge were synthesized by a novel synthetic protocol. Experimental and theoretical investigations revealed that this cove edge imparts stable helical chirality, unlike normal cove edges. The in-solution self-association behavior and the structural, electronic, and electrochemical properties were also described in detail.

Synthesis of Polycyclic Spirocarbocycles via Acid-Promoted Ring-Contraction/Dearomative Ring-Closure Cascade of Oxapropellanes.

We report herein the development of an acid-promoted rearrangement of oxa[4.3.2]propellanes to afford polyaromatic-fused spiro[4.5]carbocycles. DFT calculations suggest that the reaction pathway involves generation of a cyclobutyl cation, ring contraction to the cyclopropylcarbinyl cation, and dearomative ring closure by an internal 2-naphthol moiety. The resulting spirocarbocycles are synthetically valuable, as they could be transformed into two different polycyclic aromatic hydrocarbons via skeletal rearrangement. Syntheses of optically pure spirocarbocycles via a central-to-axial-to-central chirality transfer are also described.

Total Syntheses of Allelopathic 4-Oxyprotoilludanes, Melleolides, and Echinocidins.

Stereocontrolled total syntheses of allelopathic 4-oxyprotoilludane sesquiterpenes, melleolide, melleolide F, and echinocidins B and D were achieved. The curved 5/6/4 tricyclic system with an angular hydroxy group was built via three key transformations: (1) Me3Al-catalyzed [2 + 2] cycloaddition of a ketene silyl acetal with a propiolate, (2) reductive ring-opening of a cyclic hemiketal, and (3) the intramolecular Morita-Baylis-Hillman reaction. This synthetic route represents a new and reliable strategy to obtain protoilludanes with several oxy-functional groups.

Synthesis of Functionalized Medium-Sized trans-Cycloalkenes by 4π Electrocyclic Ring Opening/Alkylation Sequence.

Development of a novel synthetic method for medium-sized trans-cycloalkenes (TCAs) is described. Functionalized TCAs are readily prepared from simple cycloalkanones in a few steps, namely, enol silyl ether formation, [2+2] cycloaddition, and domino 4π electrocyclic ring opening/alkylation (conjugate addition). The first example of central-to-planar chirality transfer from enantiomerically enriched cyclobutenes to TCAs is also described.

Rapid Assembly of Protoilludane Skeleton through Tandem Catalysis: Total Synthesis of Paesslerin A and Its Structural Revision.

A multicomponent domino reaction involving three mechanistically distinct Tf2NH-catalyzed reactions was developed. The reaction cascade enables the assembly of a skewed 5/6/4 tricyclic motif with migration of the reactive site with the assistance of a catalyst. The tricyclic product was used to achieve the first total synthesis of cytotoxic paesslerin A by regioselective C-H insertion of the sulfonyl carbenoid and base-promoted olefin isomerization. Our results led to the revision of the originally proposed tricyclic structure of paesslerin A.

Synthesis and Properties of Tribenzocarbazoles via an Acid-Promoted Retro (2+2)-Cycloaddition of Azapropellanes.

We describe herein the development of a new method to synthesize tribenzocarbazoles via an acid-promoted retro (2+2)-cycloaddition of azapropellanes, which were prepared by potassium hexamethyldisilazide (KHMDS)-promoted (2+2)-cycloaddition. The tribenzocarbazoles showed strong fluorescence both in solution and the solid state. The structural, electronic, and optical properties of the synthetic tribenzocarbazoles are also described.

Synthesis of π-Extended Fluoranthenes via a KHMDS-Promoted Anionic-Radical Reaction Cascade.

An unprecedented KHMDS-promoted domino reaction to furnish hydroxyfluoranthenes is described. Biaryl compounds bearing acyl and naphthylalkenyl moieties are transformed into 9-hydroxydibenzo[j,l]fluoranthenes in a single step through the formation of an aromatic and a pentagonal ring system. A variety of fluoranthenes including those with extended π-conjugation, a heteroaromatic ring, and unsymmetrical substituents could be synthesized. Mechanistic studies reveal a unique reaction cascade where KHMDS acts as both a base and a single-electron donor.

Synthesis and biological evaluation of steroidal derivatives bearing a small ring as vitamin D receptor agonists.

A novel series of 3-ketolithocholic acid derivatives as well as estrone derivatives bearing a small ring for the conformational fixation of the side chain were synthesized by using a catalytic [2+2] cycloaddition and a ring-contraction rearrangement. The steroidal derivatives were evaluated for transcriptional activation of vitamin D receptor by luciferase reporter assays. Among them, two estrone derivatives showed a higher efficacy of the transactivation of vitamin D receptor than 3-ketolithocholic acid, and the small ring moieties were found to be important for the efficacy.

Site-selective benzoin-type cyclization of unsymmetrical dialdoses catalyzed by N-heterocyclic carbenes for divergent cyclitol synthesis.

A highly site-selective N-heterocyclic carbene (NHC)-catalyzed benzoin-type cyclization of unsymmetrical dialdoses is developed to enable a divergent cyclitol synthesis. The choice of chiral NHCs and protecting groups affects the site-selectivity. The resulting inososes are converted into epi-, muco- and myo-inositols, and their chiral protected derivatives are formed in good yields.

Efficient Synthesis of Polyaromatic Hydrocarbon via a Formal [2+2] Cycloaddition.

A potassium base-promoted formal [2+2] cycloaddition of 2-acyl-2'-vinyl-1,1'-biaryls was developed to afford benzo-fused polycyclic cyclobutanols in a highly stereoselective manner. We demonstrated synthesis of substituted polycyclic aromatic hydrocarbons and these heterocyclic derivatives via this cyclization, followed by an acid-promoted rearrangement. Furthermore, asymmetric total synthesis of phenanthroindolizidine alkaloid (-)-tylophorine was achieved using our methodology and late-stage asymmetric hydrogenation of a cyclic imine.