Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Synthesis and clusterization of Gal beta(1 -> 3)[NeuAc alpha(2 -> 6)]GlcNAc beta(1 -> 2)Man motif of the N-glycan, as the molecular probes for their biological evaluation, are reported. Key step is the quantitative and the completely alpha-selective sialylation of the C5-azide N-phenyltrifluoroacetimidate with the disaccharide acceptor, Gal beta(1 -> 3) GlcNTroc. Clusterization of the 16 molecules of trisaccharide motif was also achieved by the 'self-activating click reaction'. These probes could efficiently be labeled by biotin and/or other fluorescenceor radioactive reporter groups through either cross metathesis, acylation, Cu(I)-mediated Huisgen [2+3]-cycloaddition, or the azaelectrocyclization to utilize the various biological techniques. (C) 2010 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmc.2010.04.067

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While elucidating the inhibitory mechanism of a hydrolytic enzyme by aldehyde-containing natural products, we discovered a reaction involving a rapid 6π-azaelectrocyclization of azatrienes generated from aldehyde with lysine residues. The electrocyclic reaction of the 1-azatriene system, a cyclization precursor, exhibited a substituent effect. Structure-reactivity studies showed that azaelectrocyclization, which usually proceeds in low yield at high temperatures, produced a quantitative yield in less than 5 min at room temperature. Asymmetric chiral piperidine synthesis and a one-pot library synthesis of pyridines on solid-supports were applied to synthesize pyridine/indole alkaloid-type natural products. Additionally, we developed lysine-based labeling of biomolecules based on the rapid 6π-azaelectrocyclization. Both DOTA as a metal chelating agent (either for MRI, PET, or other radiopharmaceutical purposes, e.g., SPECT with gamma emitters) as well as fluorescent groups were introduced efficiently and selectively into lysine residues within 10 min at concentrations as low as 10-8 m. The DOTA-labeled somatostatin and glycoproteins were then radiometallated with 68Ga to observe the receptor-mediated accumulation of somatostatin in pancreatic tissue. Furthermore, microPET visualized the oligosaccharide dependent circulatory residence of glycoproteins for the first time. © 2010 The Japan Chemical Journal Forum and Wiley Periodicals, Inc.

DOI： 10.1002/tcr.200900026

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Language：English   Publisher：SPRINGER  

Using recombinant tetanus toxin H-C fragment (rTT-H-C) as carrier, we prepared multimeric bivalent immunogens featuring the synthetic hexasaccharide fragment of O-PS of Vibrio cholerae O:1, serotype Ogawa, in combination with either the synthetic hexasaccharide fragment of O-PS of Vibrio cholerae O:1, serotype Inaba, or a synthetic disaccharide tetrapeptide peptidoglycan fragment as adjuvant. The conjugation reaction was effected by squaric acid chemistry and monitored in virtually real time by SELDI-TOF MS. In this way, we could prepare well-defined immunogens with predictable carbohydrate-carrier ratio, whose molecular mass and the amount of each saccharide attached could be independently determined. The ability to prepare such neoglycoconjugates opens unprecedented possibilities for preparation of conjugate vaccines for bacterial diseases from synthetic carbohydrates.

DOI： 10.1007/s10719-009-9259-4

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DOI： 10.1002/anie.201000892

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DOI： 10.1002/anie.201000892

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Publisher：Japan Radioisotope Association  

DOI： 10.3769/radioisotopes.59.721

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Language：English   Publisher：ELSEVIER ACADEMIC PRESS INC  

In this chapter, we describe synthetic studies on partial structures of lipopolysaccharide (LPS) and peptidoglycan (PGN), which work as tags for nonself recognition in innate immune system. Our previous studies demonstrated that lipid A is the endotoxic principle of LPS. The synthetic homogeneous preparations have enabled not only precise structure activity relationships, but also recognition mechanisms of LPS with innate immune receptor complexes, including the TLR4/MD-2 complex, to be studied. Synthetic studies of lipid A and Kdo-lipid A from parasitic Helicobacter pylori revealed their low inflammatory activities, suggesting the molecular evolution to escape from the host immune system. A synthetic study of the partial structures of PGN has also contributed to the understanding of the innate immune mechanism. The biological activities of the synthetic fragments have revealed that the intracellular receptor Nod2 recognizes partial structures containing the muramyl dipeptide (MDP) moiety. The PGN of Gram-negative bacteria and some Gram-positive bacteria contain meso-diaminopimelic acid (meso-DAP), and recent studies have revealed that the intracellular receptor Nod1 recognizes DAP-containing peptides. We have synthesized DAP-containing PGN fragments, including the first chemical synthesis of tracheal cytotoxin (TCT). The ability of these fragments to stimulate human Nod1 as well as differences in Nod1 recognition for various synthesized ligand structures was elucidated. Cell-surface glycans such as N-glycans and O-glycans on glycoproteins and glycoconjugates work as signaling molecules for self-recognition and control immune system. Our new strategy using glycan-imaging in whole-body system is expected to unveil the dynamics of glycans in the body. Positron emission tomography (PET) is a noninvasive method that visualizes the locations and levels of radiotracer accumulation. We developed the facile labeling of peptides and proteins for PET imaging. The labeled glycoproteins and glycoclusters were then subjected to PET imaging in order to examine their in vivo dynamics, visualizing the differences in the circulatory residence of glycoproteins and glycoclusters in the presence or absence of sialic acid residues.

DOI： 10.1016/S0076-6879(10)78016-2

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DOI： 10.1002/anie.201000892

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Publisher：Japan Radioisotope Association  

DOI： 10.3769/radioisotopes.59.721

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DOI： 10.5059/yukigoseikyokaishi.68.124

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Language：English   Publisher：JOHN WILEY & SONS INC  

While elucidating the inhibitory mechanism of a hydrolytic enzyme by aldehyde-containing natural products, we discovered a reaction involving a rapid 6 pi-azaelectrocyclization of azatrienes generated from aldehyde with lysine residues. The electrocyclic reaction of the 1-azatriene system, a cyclization precursor, exhibited a substituent effect. Structure-reactivity studies showed that azaelectrocyclization, which usually proceeds in low yield at high temperatures, produced a quantitative yield in less than 5 min at room temperature. Asymmetric chiral piperidine synthesis and a one-pot library synthesis of pyridines on solid-supports were applied to synthesize pyridine/indole alkaloid-type natural products. Additionally, we developed lysine-based labeling of biomolecules based on the rapid 6 pi-azaelectrocyclization. Both DO-FA as a metal chelating agent (either for MRI, PET, or other radiopharmaceutical purposes, e.g., SPECT with gamma emitters) as well as fluorescent groups were introduced efficiently and selectively into lysine residues within 10 min at concentrations as low as 10(-8) M. The DOTA-labeled somatostatin and glycoproteins were then radiometallated with (68)Ga to observe the receptor-mediated accumulation of somatostatin in pancreatic tissue. Furthermore, microPET visualized the oligosaccharide dependent circulatory residence of glycoproteins for the first time. (C) 2010 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 10: 119-139; 2010: Published online in Wiley InterScience (www.interscience.wiley. com) DOI 10.1002/tcr.200900026

DOI： 10.1002/tcr.200900026

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Language：English   Publisher：TAYLOR & FRANCIS INC  

[image omitted]Graphical Abstract Combined azaelectrocyclization and Staudinger ligation allowed proteins and living cells to be modified by small molecules (i.e., biotin or N-glycans). Chemically engineered lymphocytes modified by complex-type N-glycan targeted DLD-1 tissues implanted in nude mice at the whole-body level.

DOI： 10.1080/07328303.2010.483042

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DOI： 10.1016/S0076-6879(10)78016-2

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[image omitted]Graphical Abstract Combined azaelectrocyclization and Staudinger ligation allowed proteins and living cells to be modified by small molecules (i.e., biotin or N-glycans). Chemically engineered lymphocytes modified by complex-type N-glycan targeted DLD-1 tissues implanted in nude mice at the whole-body level.

DOI： 10.1080/07328303.2010.483042

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Continuous flow synthesis for bioactive natural products is described. Efficient procedures using the microfluidic system were developed for the large-scale synthesis of important synthetic units of asparagine-linked oligosaccharide in glycoprotein. Advantageous aspects of microfluidic conditions, i.e., efficient mixing, fast heat transfer, and residence time control led to cation-mediated reactions, such as a-sialylation, β-mannosylation, and reductive opening of the benzylidene acetal groups in high yields. Microfluidic dehydration was developed for the industrial-scale synthesis of the immunostimulating natural terpenoid, pristane. The base-mediated aldol condensation in an aqueous biphasic system enabled the multigram synthesis of β-hydroxyketones in high yields. ©2009 American Chemical Society.

DOI： 10.1021/op900084f

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Language：English   Publisher：AMER CHEMICAL SOC  

Continuous flow synthesis for bioactive natural products is described. Efficient procedures using the microfludic system were developed for the large-scale synthesis of important synthetic units of asparagine-linked oligosaccharide in glycoprotein. Advantageous aspects of microfluidic conditions, i.e., efficient mixing, fast heat transfer, and residence time control led to cation-mediated reactions, such as alpha-sialylation, beta-mannosylation. and reductive opening of the benzylidene acetal groups in high yields. Microfluidic dehydration was developed for the industrial-scale synthesis of [fie immunostimulating natural terpenoid, pristane. The base-mediated aldol condensation in an aqueous biphasic system enabled the multigram synthesis of beta-hydroxyketones in high yields.

DOI： 10.1021/op900084f

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Language：English   Publisher：BEILSTEIN-INSTITUT  

Microfluidic conditions were applied to acid-mediated reactions, namely, glycosylation, reductive opening of the benzylidene acetal groups, and dehydration, which are the keys to the practical synthesis of N-glycans and the immunostimulating natural product, pristane. A distinctly different reactivity from that in conventional batch stirring was found; the vigorous micromixing of the reactants with the concentrated acids is critical especially for the "fast" reactions to be successful. Such a common feature might be due to the integration of all favorable aspects of microfluidic conditions, i.e., efficient mixing, precise temperature control, and the easy handling of the reactive intermediate by controlling the residence time. The microfluidic reactions cited in this review indicate the need to reinvestigate the traditional or imaginary reactions which have so far been performed and evaluated only in batch apparatus, and therefore they could be recognized as a new strategy in synthesizing natural products of prominent biological activity in a "practical" and a "industrial" manner.

DOI： 10.3762/bjoc.5.40

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Language：English   Publisher：GEORG THIEME VERLAG KG  

An integrated microfluidic/batch system was applied to the chemical N-glycosylation by the asparagine amide group, a key glycosyl bond-formation reaction in the synthesis of N-glycopeptides. By applying the advantageous features of microfluidic conditions, that is, efficient mixing and rapid heat transfer, the GlcNTroc beta Asn and the Fuc alpha(1-6)GlcNTroc beta Asn fragments were effciently prepared.

DOI： 10.1055/s-0029-1217343

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An integrated microfluidic/batch system was applied to the chemical N-glycosylation by the asparagine amide group, a key glycosyl bond-formation reaction in the synthesis of N-glycopeptides. By applying the advantageous features of microfluidic conditions, that is, efficient mixing and rapid heat transfer, the GlcNTrocβAsn and the Fuca(1-6)GlcNTrocβAsn fragments were efficiently prepared. © Georg Thieme Verlag Stuttgart.

DOI： 10.1055/s-0029-1217343

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Combined microfluidic/batch conditions were applied to -mannosylation, a key glycosylation for the synthesis of the Man(1-4)GlcNAc motif in N-glycan structures. By applying the advantageous features of microfluidic conditions (i.e., efficient mixing and fast heat transfer), the Man(1-4)GlcNTroc fragment was practically and reproducibly synthesized on the gram scale.

DOI： 10.1080/07328300802571129

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DOI： 10.3762/bjoc.5.40

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Language：English   Publisher：TAYLOR & FRANCIS INC  

[image omitted] Combined microfluidic/batch conditions were applied to -mannosylation, a key glycosylation for the synthesis of the Man(1-4)GlcNAc motif in N-glycan structures. By applying the advantageous features of microfluidic conditions (i.e., efficient mixing and fast heat transfer), the Man(1-4)GlcNTroc fragment was practically and reproducibly synthesized on the gram scale.

DOI： 10.1080/07328300802571129

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Language：English   Publisher：WILEY-V C H VERLAG GMBH  

A new solid-phase synthesis of N-linked glycans featuring 1.) highly stereoselective beta-mannosylation and microfluidic alpha-sialylation and 2) efficient glycosylation of the N-phenyltrifluoroacetimidate units on JandaJel resin is reported. Reagent concentration effects by a fluorous solvent are effectively applied,. and the use of these methods results in the first synthesis of a sialic acid containing complex-type N-glycan on a solid support.

DOI： 10.1002/asia.200800411

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Language：English   Publisher：WILEY-V C H VERLAG GMBH  

An efficient one-pot synthetic procedure for the synthesis of 2,4-disubstituted pyridines has been successfully established. The method proceeds through a 6n-azaelectrocyclization-aromatization sequence. Using this method, a wide variety of pyridine structures substituted at the 2-position have been rapidly constructed from vinyl stannanes, vinyl iodide, sulfonamide, and a palladium catalyst. The method was further applied to the solid-phase synthesis wherein the use of a "traceless" sulfonamide linker enabled the rapid preparation of a small library of pyridines with high purity, without any chromatographic separation.

DOI： 10.1002/asia.200900146

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Language：English  

DOI： 10.1002/cbic.200800336

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Language：English   Publisher：WILEY-V C H VERLAG GMBH  

DOI： 10.1002/cbic.200800336

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

A microfluidic system was applied to aldol reaction in aqueous biphasic medium. Advantageous aspects of microfluidic conditions, that is, efficient mixing, fast heat transfer, and residence time control led to the high-yielding reaction of acetone enolate with even of-proton-containing aldehydes in biphasic aqueous-acetone system, by minimizing the formation of self-condensation products. (c) 2008 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2008.01.057

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DOI： 10.2174/157019308785161684

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DOI： 10.1002/anie.200702989

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DOI： 10.2174/157019308785161684

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DOI： 10.1002/anie.200702989

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Acceleration of Cu(I)-mediated Huisgen 1,3-dipolar cycloaddition (Sharpless 'click reaction') by non-basic histidine derivatives was found. An efficient 'self-activating' click reaction between the azide- and acetylene-containing peptides on the solid-phase has also been achieved by introducing the Nim-benzylhistidine residue on the reacting peptides. © 2007 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2007.07.055

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Language：English   Publisher：TAYLOR & FRANCIS INC  

Highly alpha-selective sialylation of sialic acid N-phenyltrifluoroacetimidate with various galactose and lactose acceptors has been achieved by introducing the C-5 N-phthalyl group on the donor. The "fixed dipole effect" of the N-phthalyl group was proposed to explain the high reactivity and a-selectivity. The microfluidic system was applied to the present alpha-sialylation, which is amenable to large-scale synthesis. The N-phthalyl group was removed by treatment with methylhydrazine acetate, for which protocol can be readily applied to the synthesis of a variety of sialic acid-containing oligosaccharides.
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DOI： 10.1080/07328300701634796

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Language：English   Publisher：TAYLOR & FRANCIS INC  

Highly alpha-selective sialylation of sialic acid N-phenyltrifluoroacetimidate with various galactose and lactose acceptors has been achieved by introducing the C-5 N-phthalyl group on the donor. The "fixed dipole effect" of the N-phthalyl group was proposed to explain the high reactivity and a-selectivity. The microfluidic system was applied to the present alpha-sialylation, which is amenable to large-scale synthesis. The N-phthalyl group was removed by treatment with methylhydrazine acetate, for which protocol can be readily applied to the synthesis of a variety of sialic acid-containing oligosaccharides.
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DOI： 10.1080/07328300701634796

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Acceleration of Cul(I)-mediated Huisgen 1,3-dipolar cycloaddition (Sharpless 'click reaction') by non-basic histidine derivatives was found. An efficient 'self-activating' click reaction between the azide- and acetylene-containing peptides on the solid-phase has also been achieved by introducing the N-im`-benzylhistidine residue on the reacting peptides. (c) 2007 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2007.07.055

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Language：English   Publisher：AMER CHEMICAL SOC  

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An efficient protocol of dehydration was developed under microfluidic conditions. The method was applied to a multikilogram synthesis of pristane, a biologically important natural product, which is now widely used as an adjuvant for monoclonal antibody production.

DOI： 10.1021/ol062777o

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DOI： 10.1016/j.jmb.2007.03.046

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DOI： 10.1016/j.tetlet.2007.07.055

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DOI： 10.1016/j.jmb.2007.03.046

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Language：English   Publisher：AMER CHEMICAL SOC  

A one-pot procedure for tetracyclic chiral aminoacetals, the useful precursors for substituted piperidine synthesis, has been established via Stille-Migita coupling, 6 pi-azaelectrocyclization, and aminoacetal formation from readily prepared vinylstannanes, vinyliodides, and cis-aminoindanol derivatives. Based on the method, chiral 2,4-disubstituted 1,2,5,6-tetrahydropyridines, bearing a variety of aromatic substituents at the C-2 position, have been prepared.

DOI： 10.1021/ol061405c

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Language：English   Publisher：AMER CHEMICAL SOC  

The structural and photochemical changes in rhodopsin due to absorption of light are crucial for understanding the process of visual signaling. We investigated the structure of trans-retinal in the metarhodopsin I photointermediate (MI), where the retinylidene cofactor functions as an antagonist. Rhodopsin was regenerated using retinal that was H-2-labeled at the C5, C9, or C13 methyl groups and was reconstituted with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine. Membranes were aligned by isopotential centrifugation, and rhodopsin in the supported bilayers was then bleached and cryotrapped in the MI state. Solid-state H-2 NMR spectra of oriented rhodopsin in the low-temperature lipid gel state were analyzed in terms of a static uniaxial distribution (Nevzorov, A. A.; Moltke, S.; Heyn, M. P.; Brown, M. F. J. Am. Chem. Soc. 1999, 121, 7636-7643). The line shape analysis allowed us to obtain the methyl bond orientations relative to the membrane normal in the presence of substantial alignment disorder ( mosaic spread). Relative orientations of the methyl groups were used to calculate effective torsional angles between the three different planes that represent the polyene chain and the beta-ionone ring of retinal. Assuming a three-plane model, a less distorted structure was found for retinal in MI compared to the dark state. Our results are pertinent to how photonic energy is channeled within the protein to allow the strained retinal conformation to relax, thereby forming the activated state of the receptor.

DOI： 10.1021/ja058738+

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Language：English   Publisher：AMER CHEMICAL SOC  

Stereocontrolled synthesis of 2,4,6-trisubstituted piperidine diastereomers has been realized from common intermediates, obtained by a one-pot azaelectrocyclization protocol. Based on the method, the asymmetric synthesis of an indolizidine alkaloid, (-)-dendroprimine, was achieved.

DOI： 10.1021/ol0614065

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DOI： 10.5059/yukigoseikyokaishi.64.382

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DOI： 10.5059/yukigoseikyokaishi.64.382

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The aglycon, or so-called 'warhead' portion, of several potent 10-membered ring enediyne antitumor antibiotics contain dienonecarbamate and enediyne chromophores in an unusual bicyclic ring structure in which these two subunits are essentially orthogonal to each other. The circular dichroism (CD) spectra of the calicheamicin, esperamicin, and shisijimicin A families, all of which contain this bicyclic ring system, exhibit a characteristic negative exciton coupled CD at about 3 10 and 270 nm. This signature CD feature suggested the absolute stereochemical relationship between these chromophores as originally assigned and which was later confirmed by stereospecific total synthesis. Because of the unique nature of this chromophoric interaction and the importance of using this CD spectral feature in the assignment of the absolute stereochemistry of other related enediynes, we report here simulations of the CD spectra of the calicheamicin aglycon A, and of two other truncated models, B and C, by using density functional theory (DFT) and the DeVoe coupled oscillator approach. The DFT calculations provide a strong theoretical basis that the planar enediyne chromophore alone gives a negligible CD contribution, while that coming from the twisted dienonecarbamate is much more substantial. However, the shape and the largest part of the intensity of experimental CD spectrum can only be reproduced when the two unsaturated moieties are simultaneously present. Thus, the exciton coupling between the two chromophores provides the most important contribution to the experimental CD spectrum of calicheamicin. This conclusion is in full agreement with the results from the DeVoe calculation. (c) 2005 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmc.2005.04.007

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Language：English   Publisher：AMER CHEMICAL SOC  

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Ab initio calculations of the optical rotatory power of the natural cytokine modulator cytoxazone 1 and its trans-diastereomer 2, as well as the structural isomers cis-3 and trans-4 isocytoxazones, have been performed at four different wavelengths (589, 546, 435, and 405 nm) by Density Functional Theory. The calculation of ORD curves provides a reliable method for the assignment of absolute configuration of these conformationally flexible molecules. The absolute configurations of isocytoxazones has been established as (+)-(4R,5S)-cis-3 and (+)-(4S,5S)-trans-4.

DOI： 10.1021/jo048023+

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Language：English   Publisher：AMER CHEMICAL SOC  

The absolute configuration of gymnocin-B has been determined to be (S)-10 and (S)-37. Three challenges toward the configurational assignment of this largest of the polyether marine toxin include (i) introduction of p-(meso-triphenylporphyrin)-cinnamate group (TPPcinnamate) on sterically hindered 10-, 37-hydroxyls under mild conditions, (ii) conformational analysis in the presence of TPPcinnamates at C-10 and C-37 positions on the flexible seven-membered rings embodied in a large polyether ladder-like scaffold structure, and (iii) determination of the chirality at C-10 and C-37 on the basis of porphyrin/porphyrin circular dichroism exciton-coupled interaction over a large distance. The experimentally obtained positive exciton couplet by CD and FDCD of the bis-TPPcin derivative of gymnocin-B is in good agreement with that of theoretically calculated CD of the MMFF optimized structures, by employing DeVoe's coupled oscillator approach, thus establishing the full absolute configuration of gymnocin-B.

DOI： 10.1021/ja0512677

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：SPRINGER WIEN  

In collaboration with Jasco Corporation we have recently developed an FDCD (fluorescence detected circular dichroic) instrument J-465, which eliminates the photoselection artifacts and efficiently collects the emitted light from the sample solution based on the ideal ellipsoidal mirror principle. Using the J-465 we have investigated a variety of fluorophores with/without polarization for exciton-coupled FDCD stereochemical analysis. The following three cases extend the FDCD methodology to new challenging areas beyond the limits of conventional CD: (1) substrates containing C=C double bonds, (2) molecules with sterically hindered hydroxyls, and (3) substrates beating remote stereogenic centers. The pico- to nano-level FDCD analysis described in this paper leads to promising opportunities for the stereochemical analysis of a wide range of natural products with minuscule amounts of sample available.

DOI： 10.1007/s00706-004-0276-5

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

It has been found that NaBH4 smoothly reduces the alpha-hydroxy-lactone moieties in ginkgolide and F-seco-ginkgolides to lactols. The reaction is rapid and stops at the lactol stage: the coordination of NNaBH4 to the conformationally rigid cage structure is involved in both the initiation and termination stages. This facile reduction of ginkgolide lactones yield a variety of new ginkgolide lactols. (C) 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2004.10.113

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DOI： 10.1366/0003702052940459

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DOI： 10.1246/bcsj.78.1843

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DOI： 10.1055/s-2005-872269

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DOI： 10.1055/s-2005-872269

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DOI： 10.1366/0003702052940459

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DOI： 10.1246/bcsj.78.1843

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Language：English   Publisher：AMER CHEMICAL SOC  

The conformation of retinal bound to the G protein-coupled receptor rhodopsin is intimately linked to its photochemistry, which initiates the visual process. Site-directed deuterium (H-2) NMR spectroscopy was used to investigate the structure of retinal within the binding pocket of bovine rhodopsin. Aligned recombinant membranes were studied containing rhodopsin that was regenerated with retinal H-2-labeled at the C-5, C-9, or C-13 methyl groups by total synthesis. Studies were conducted at temperatures below the gel to liquid-crystalline phase transition of the membrane lipid bilayer, where rotational and translational diffusion of rhodopsin is effectively quenched. The experimental tilt series of H-2 NMR spectra were fit to a theoretical line shape analysis [Nevzorov, A. A., Moltke, S., Heyn, M. P., and Brown, M. F. (1999) J. Am. Chem. Soc. 121, 7636-7643] giving the retinylidene bond orientations with respect to the membrane normal in the dark state. Moreover, the relative orientations of pairs of methyl groups were used to calculate effective torsional angles between different planes of unsaturation of the retinal chromophore. Our results are consistent with significant conformational distortion of retinal, and they have important implications for quantum mechanical calculations of its electronic spectral properties. In particular, we find that the beta-ionone ring has a twisted 6-s-cis conformation, whereas the polyene chain is twisted 12-s-traps. The conformational strain of retinal as revealed by solid-state H-2 NMR is significant for explaining the quantum yields and mechanism of its ultrafast photoisomerization in visual pigments. This work provides a consensus view of the retinal conformation in rhodopsin as seen by X-ray diffraction, solid-state NMR spectroscopy, and quantum chemical calculations.

DOI： 10.1021/bi0491191

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The synthesis of new chiral auxiliaries, 7-alkyl substituted cis-1-amino-2-indanol derivatives, was established by the Diels-Alder reaction of 1-substituted dienes with cyclopentenone followed by the asymmetric epoxidation of the resulting indene derivatives and then the Ritter reaction. These bulky cis-aminoindanol derivatives are very effective as chiral auxiliaries and nitrogen sources in the asymmetric 6pi-azaelectrocyclization. The corresponding 4-alkyl derivative was also prepared using a similar method. (C) 2003 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetasy.2003.10.029

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Development of Highly Stereoselective Asymmetric 6p-Azaelectrocyclization of Conformationally Flexible Linear 1-Azatrienes. From Finding of Multi-Functional Chiral Amines, 7-Alkyl cis-1-Amino-2-indanols To Application as a New Synthetic Strategy; Formal Synthesis of 20-Epiuleine

DOI： 10.1021/jo049381f

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Language：English   Publisher：ROYAL SOC CHEMISTRY  

Coumarins are associated with a variety of pharmacological activities which have led to the synthesis of numerous derivatives. However, no general method for determination of the absolute configuration of chiral coumarins is known. This has now been achieved for a series of dihydrofuroangelicins bearing a variety of C-8 substituted double bonds, synthesized in the racemic form and resolved through enantioselective chromatography. A combined chemical/chiroptical protocol has been developed in which the C=C double bonds are replaced with a styrenoid chromophore through either (i) cross metathesis, (ii) Heck reaction, or (iii) a combined method of cross metathesis and Heck reaction with about 1 mg sample under mild conditions. The coupling between the styrenoid and coumarin chromophores gives rise to clear-cut exciton coupled CD curves, suitable for assignments of absolute configurations. The solution conformation of the styrenoid derivatives is determined by NMR and DFT molecular modeling; the electronic structure of the 7-hydroxy coumarin chromophore is also clarified by semi-empirical and TDDFT methods. The conformation thus derived, in conjunction with quantitative DeVoe's coupled-oscillator CD calculation, establishes the absolute configurations of the coumarins. The theoretical study described herein justifies the straightforward approach of the current chemical/exciton chirality protocol to this type of dihydrofuroangelicins.

DOI： 10.1039/b312542d

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Development of Highly Stereoselective Asymmetric 6p-Azaelectrocyclization of Conformationally Flexible Linear 1-Azatrienes. From Finding of Multi-Functional Chiral Amines, 7-Alkyl cis-1-Amino-2-indanols To Application as a New Synthetic Strategy; Formal Synthesis of 20-Epiuleine

DOI： 10.1021/jo049381f

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Language：English   Publisher：AMER CHEMICAL SOC  

DOI： 10.1021/ja036847n

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

New Wittig reagents, furanmethylids b-e were successfully developed. Their preparation, reactivity, and application toward the natural products synthesis are described in detail. (C) 2003 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4020(03)00763-4

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Language：English   Publisher：AMER CHEMICAL SOC  

DOI： 10.1021/ja026464+

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DOI： 10.1021/ja026464+

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Language：English  

The remarkable acceleration of 6π-azaelectrocyclization due to the combination of the C4-carbonyl and the C6-alkenyl or phenyl substituents in 1-azatrienes was found. This observation was rationalized by considering the remarkable orbital interaction between the HOMO and LUMO of 1-azatrienes, which were obtained by molecular orbital calculations. The formal synthesis of the unusual retinal metabolite, A2-E, was achieved by two types of the new one-pot synthesis of substituted pyridines by utilizing the obtained facile 6π-azaelectrocyclization, one of which is compatible with the proposed metabolic pathway of A2-E.

DOI： 10.1021/jo005779+

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PubMed

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DOI： 10.1021/jo005779+

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DOI： 10.1021/jo005779+

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Language：English  

(Formula Presentation) The formal synthesis of the ocular age pigment A2-E was achieved by the efficient one-pot preparation of the substituted pyridine, which involves the aza-6π-electrocyclization of the Schiff base derived from (E)-3-carbonyl-2,4,6-trienal followed by oxidation.

DOI： 10.1021/ol991320u

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PubMed

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DOI： 10.1021/ol991320u

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DOI： 10.1021/ol991320u

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

We established the stereoselective synthesis of (E)-3-methoxycarbonyl-2,4,6-trienal compound A and discovered that the compound A showed more powerful inhibitory activity toward phospholipase A(2)(PLA(2)) from bovine pancreas than manoalide which is a typical PLA(2) inhibitor. As the inhibitory mechanism of PLA(2) by A, the irreversible formation of dihydropyridine derivative resulting from the reaction of A with lysine residues in PLA(2) was proposed based on the model reactions. Furthermore, A was found to selectively modify Lys56 which is included in the interfacial recognition site of this enzyme by the MALDI-TOF-MS peptide mapping analyses. (C) 1999 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4020(98)01197-1

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DOI： 10.1016/S0040-4039(99)00039-8

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DOI： 10.1016/S0040-4020(98)01197-1

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DOI： 10.5059/yukigoseikyokaishi.57.876

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DOI： 10.1016/S0040-4039(99)00039-8

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DOI： 10.1016/S0040-4020(98)01197-1

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DOI： 10.1016/S0040-4039(99)00039-8

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DOI： 10.5059/yukigoseikyokaishi.57.876

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Language：English   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

3-(E)-Methoxycarbonyl-2,4,6-trienal compound A was stereoselectively synthesized and found to show strong inhibitory activity toward phospholipase A(2) (PLA(2)) from bovine pancreas. As the inhibitory mechanism of PLA(2) by A, the irreversible formation of dihydropyridine resulting from the reaction of A with lysine residues in PLA(2) is proposed based on the model reactions. (C) 1998 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4039(97)10805-X

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DOI： 10.1016/S0040-4039(97)10805-X

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DOI： 10.1016/S0040-4039(97)10805-X

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Country：Japan

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Country：Japan

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Country：Japan

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