Daisuke Urabe

Identification and Structure Determination of Novel Anti-inflammatory Mediator Resolvin E3, 17,18-Dihydroxyeicosapentaenoic Acid

Background: Endogenous mediators that control aberrant inflammation are of interest as potential targets of new therapeutics. Results: Here, we identified a novel omega-3 fatty acid-derived anti-inflammatory mediator 17,18-diHEPE, denoted as resolvin E3. Conclusion: Resolvin E3 has a potent inhibitory action on neutrophil chemotaxis both in vitro and in vivo. Significance: The significance of this study is the identification of a novel endogenous lipid mediator with a potent anti-inflammatory property. Bioactive mediators derived from omega-3 eicosapentaenoic acid (EPA) elicit potent anti-inflammatory actions. Here, we identified novel EPA metabolites, including 8,18-dihydroxyeicosapentaenoic acid (8,18-diHEPE), 11,18-diHEPE, 12,18-diHEPE, and 17,18-diHEPE from 18-HEPE. Unlike resolvins E1 and E2, both of which are biosynthesized by neutrophils via the 5-lipoxygenase pathway, these metabolites are biosynthesized by eosinophils via the 12/15-lipoxygenase pathway. Among them, two stereoisomers of 17,18-diHEPE, collectively termed resolvin E3 (RvE3), displayed a potent anti-inflammatory action by limiting neutrophil infiltration in zymosan-induced peritonitis. The planar structure of RvE3 was unambiguously determined to be 17,18-dihydroxy-5Z,8Z,11Z,13E,15E-EPE by high resolution NMR, and the two stereoisomers were assigned to have 17,18R- and 17,18S-dihydroxy groups, respectively, using chemically synthesized 18R- and 18S-HEPE as precursors. Both 18R- and 18S-RvE3 inhibited neutrophil chemotaxis in vitro at low nanomolar concentrations. These findings suggest that RvE3 contributes to the beneficial actions of EPA in controlling inflammation and related diseases.

Toolbox Approach to the Search for Effective Ligands for Catalytic Asymmetric Cr-Mediated Coupling Reactions

Chromium catalysts derived from chiral sulfonamides represented by A effect the couplings of aldehydes with vinyl, allyl, or alkyl halides. With three distinct sites for structural modification, A affords access to a structurally diverse pool of chiral sulfonamides. The Cr catalysts derived from these sulfonamides exhibit a broad range of catalyst-substrate matching profiles. A strategy is presented to search for a satisfactory chiral sulfonamide for a given substrate. In order to demonstrate the generality and effectiveness of this approach, five diverse C-C bond-forming cases have been selected from the halichondrin synthesis. For each of the cases, two ligands have been deliberately searched for, to induce the formation of (R)- and (S)-alcohols, respectively, at the arbitrarily chosen efficiency level of >or=80% yield with >or=20:1 stereoselectivity in the presence of <or=20 mol % of a Cr catalyst. For 9 out of the 10 cases studied, a satisfactory catalyst has been found within this pool of sulfonamides. Even for the remaining case, a Cr catalyst inducing stereoselectivity up to 8:1 has been identified.

Total synthesis and bioactivity of resolvin E2

Resolvin E2 is a potent anti-inflammatory compound, derived from eicosapentaenoic acid. The efficient total synthesis of resolvin E2 by taking advantage of its intrinsic pseudoenantiomeric substructures is reported. The synthetic resolvin E2 proved to be biologically active in blocking neutrophil infiltration and reducing proinflammatory cytokines in the acute peritonitis model.

New Syntheses of E7389 C14−C35 and Halichondrin C14−C38 Building Blocks: Reductive Cyclization and Oxy-Michael Cyclization Approaches

Cr-mediated coupling reactions are usually achieved with a slight excess of a given nucleophile. To develop a cost-effective use of this process, two different approaches have been studied. The first approach depends on two consecutive catalytic asymmetric Cr-mediated couplings, with use of coupling partners purposely being of unbalanced molecular size and complexity. The second approach rests on the success in identifying the nucleophile, which allows us to achieve the coupling satisfactorily with a 1:1 molar ratio of the coupling partners. The C23-O bond is stereospecifically constructed via reductive cyclization of the oxonium ion, or oxy-Michael cyclization. Both syntheses have a high overall efficiency: E7389 C14-C35 and halichondrin C14-C38 building blocks have been synthesized from the corresponding C27-C35 and C27-C38 aldehydes, respectively, in high overall yields with an excellent stereoselectivity. Because of operational simplicity, the synthesis outlined herein appears to be well suited for scaling.

First total synthesis of murisolinElectronic Supplementary Information (ESI) available: characterization data of synthetic murisolin (1), and 1H and 13C NMR spectra of compounds 9, 12 and 1. See http://www.rsc.org/suppdata/cc/b3/b312362f/

The first and concise total synthesis of murisolin (1) was accomplished using asymmetric alkynylation and Sonogashira coupling as the key steps. The threo/trans/threo-type THF ring moiety was constructed with excellent stereoselectivity by asymmetric alkynylation of 1,6-heptadiyne to alpha-tetrahydrofuranic aldehyde, which was also prepared via the asymmetric alkynylation.

Application of α-Alkoxy Bridgehead Radical for Coupling of Oxygenated Carbocycles

A new coupling methodology for assembly of highly oxygenated carbocycles was developed. An α-alkoxy bridgehead radical was employed as the key reactive intermediate due to its potent reactivity, minimum steric interaction, and predestined stereochemical outcome. The radical of the trioxadamantane structure, generated from the O,Se-acetal, was reacted with electron-deficient cyclic olefins of various ring sizes. Intermolecular formation of sterically congested linkages between two tetrasubstituted carbons and application of the method to a three-component coupling were two significant achievements.

Total Synthesis of Resiniferatoxin Enabled by Radical-Mediated Three-Component Coupling and 7-endo Cyclization

Resiniferatoxin (1) belongs to a daphnane diterpenoid family and has strong agonistic effects on TRPV1, a transducer of noxious temperature and chemical stimuli. The densely oxygenated trans-fused 5/7/6-tricarbocycle (ABC-ring) of 1 presents a daunting challenge for chemical synthesis. Here we report the development of a novel radical-based strategy for assembling 1 from three components: A-ring 9, allyl stannane 18b, and C-ring 17b. The 6-membered 17b, prepared from d-ribose derivative 19, was designed to possess the caged orthoester structure with α-alkoxy selenide as a radical precursor. Upon treatment of 17b with 18b, 9, and V-40, the potently reactive α-alkoxy bridgehead radical was generated from 17b and then sequentially coupled with 9 and 18b to yield 16b. This first radical reaction formed the hindered C9,10-linkage between the A and C-rings and extended the C4-chain on the A-ring in a stereoselective fashion. After derivatization of 16b into 15, the remaining 7-membered B-ring was cyclized in the presence of n-Bu3SnH and V-40 by utilizing the xanthate on the C-ring as the radical precursor and the allylic dithiocarbonate as the terminator. The second radical reaction thus enabled not only the 7-endo cyclization but also construction of the C8-stereocenter and the C6-exo olefin. Tricycle 14 was elaborated into the targeted 1 by a series of highly optimized chemoselective reactions. The present total synthesis of 1 demonstrates the advantages of radical reactions for linking hindered bonds within carbocycles without damaging preexisting functionalities, thereby offering a new strategic design for multistep target-oriented synthesis.

Intermolecular radical reaction of O,Se-acetals generated via seleno-Pummerer rearrangement.

A new general protocol for the synthesis of O,Se-acetals using the seleno-Pummerer reaction has been developed, and their radical-based two- and three-component coupling reactions were studied. The three-component coupling employed the O,Se-acetal, cyclopentenone, and an allylstannane derivative, and enabled stereoselective installations of α-acyloxy alkyl and functionalized allyl groups to generate the 2,3-trans-disubstituted cyclopentanone in a single operation. The obtained highly functionalized structure was used as an intermediate for facile assembly of the zedoarondiol carboskeleton.

ASYMMETRIC SYNTHESES OF HIGHLY FUNCTIONALIZED BICYCLO[2.2.2]OCTENE DERIVATIVES

Highly functionalized bicyclo[2.2.2]octene derivatives bearing two quaternary carbon centers were synthesized in an asymmetric fashion. The key transformations were the regioselective Diels-Alder reaction between 3,6-dimethyl-o-quinone monoacetal and 1,1-diethoxyethylene and the subsequent enzymatic resolution. The optically active bicyclo[2.2.2]octene derivatives obtained should serve as versatile chiral building blocks for highly functionalized natural products such as ryanodine.

Symmetry-Driven Total Synthesis of Merrilactone A and Resolvin E2

Abstract In this chapter, we described the asymmetric total synthesis of merrilactone A and resolvin E2 based on the symmetry-driven strategy. The enantio- and diastereoselective transannular aldol reaction of the meso eight-membered diketone led to the efficient total syntheses of both enantiomers of merrilactone A, and the convergent assembly of the pseudo-enantiomeric fragments, prepared through the enantioselective solvolysis of the meso intermediate, resulted in total synthesis of resolvin E2. These syntheses demonstrate the power and generality of the symmetry-driven strategy for construction of both multicyclic and linear natural products.