Researcher Profile and Settings

Affiliation

• Faculty of Environmental Earth Science　Materials Science　Biomaterials Chemistry

Job Title

• Associate Professor

URL

http://www.ees.hokudai.ac.jp/ems/stuff/matsuda/index.html

Research funding number

• 20503618

ORCID ID

•  https://orcid.org/0000-0003-4280-6574

J-Global ID

• 200901029220238284

Research Interests

• 含塩素化合物   全合成   クロロスルフォリピッド   有機合成化学   ブロモペルオキシダーゼ   ウラソゾ   紅藻   ハロゲン   付着生物   フジツボ   Laurencin   付着阻害   Omaezallene   ローレンシン   天然物合成   有機合成   Natural Product Synthesis   Organic Synthesis   

Research Areas

• Life sciences / Marine/Aquatic life sciences
• Nanotechnology/Materials / Molecular biochemistry

Educational Organization

•  Bachelor's degree program　School of Science
•  Master's degree program　Graduate School of Environmental Science
•  Doctoral (PhD) degree program　Graduate School of Environmental Science

Academic & Professional Experience

• 2013 Hokkaido University
• 2008 - 北海道大学大学院地球環境科学研究院 助教

Education

•        - 2006  Osaka City University
•        - 2006  Osaka City University  Graduate School, Division of Natural Science
•        - 2001  Osaka City University  Faculty of Science  Department of Material Science
•        - 2001  Osaka City University  Faculty of Science

Association Memberships

• 日本農芸化学会   THE SESSILE ORGANISMS SOCIETY OF JAPAN   有機合成化学協会   日本化学会   

Research Activities

Published Papers

• Formation pathway by by-products in methacrolein oxidation over H3PMo12O40 investigated by using 12C-labeled methacrolein

  Mitsuru Kanno, Jun Hirata, Taiki Umezawa, Wataru Ninomiya, Yuichi Kamiya

  Journal of the Japan Petroleum Institute 66 (4) 128 - 131 1346-8804 2023/07/01 [Refereed][Not invited]
  
• Syntheses and Biological Activities of Danicalipin A Derivatives.

  Taiki Umezawa, Takeshi Maeda, Takuya Akiyama, Nurcahyo Iman Prakoso, Jakia Jerin Mehjabin, Tatsufumi Okino, Fuyuhiko Matsuda

  Chemistry & biodiversity 20 (6) e202300400  2023/06 

  Synthesis of three derivatives of danicalipin A, tetrachloride, trisulfate and a fluorescent probe was achieved through Wittig reaction strategy. Toxicity of the derivatives against brine shrimp (Artemia salina) as also investigated to provide useful information for the biological activity; i) less chloride derivative showed similar toxicity to danicalipin A, ii) the amphiphilic property, a characteristic feature of danicalipin A, was crucial because trisulfate considerably decreased the toxicity and iii) fluorescent derivative kept brine shrimp toxicity of danicalipin A.
• Scope and limitations of absolute configuration determination of allenic natural products using the CCC stretching VCD signal.

  Tohru Taniguchi, Mutmainah, Shu Takimoto, Takahiro Suzuki, Soichiro Watanabe, Fuyuhiko Matsuda, Taiki Umezawa, Kenji Monde

  Organic & biomolecular chemistry 21 (3) 569 - 574 2023/01/18 

  The allene functional group in natural products isolated so far exists in a non-racemic form, but its axial chirality is difficult to elucidate. Allenes exhibit a characteristic antisymmetric CCC stretching mode at around 1950 cm-1, and their VCD properties have not been studied in detail. This work, for the first time, applied VCD spectroscopy to allenic natural products and allenic molecules with other asymmetric centers focusing on the antisymmetric CCC stretching mode. This vibrational mode yielded a negligibly weak VCD signal for several molecules, but in the presence of electron-withdrawing and/or conjugating substituents, it generated a stronger one. Its sign was found to be influenced by the nature of substituents. These findings should deepen the understanding of the VCD properties of the allene functional group and should be useful for future studies of chiral allenes.
• Model Study toward Total Synthesis of Mytilipin C

  Taiki Umezawa, Nurcahyo Iman Prakoso, Koichi Tsuji, Yosuke Ogura, Takumi Sato, Fuyuhiko Matsuda

  Bulletin of the Chemical Society of Japan 95 (10) 1491 - 1500 0009-2673 2022/10/15
• Nostosin G and Spiroidesin B from the Cyanobacterium Dolichospermum sp. NIES-1697

  Chin-Soon Phan, Jakia Jerin Mehjabin, Andrea Roxanne J. Anas, Masahiro Hayasaka, Reiko Onoki, Juting Wang, Taiki Umezawa, Kenji Washio, Masaaki Morikawa, Tatsufumi Okino

  Journal of Natural Products 0163-3864 2022/08/10
• Enantioselective Total Synthesis of Multifidene, a Sex Pheromone of Brown Algae

  Taiki Umezawa, Misaki Hara, Nana Kinoshita-Terauchi, Fuyuhiko Matsuda

  Organics 3 (3) 187 - 195 2022/07 

  The total synthesis of multifidene, a sex pheromone found in brown algae, is described. The synthesis features the highly enantioselective and diastereoselective addition reaction of an aldehyde to a nitroolefin in the presence of a Hayashi–Jørgensen catalyst and a Nef reaction initiated by visible light irradiation. These key reactions enabled the 11-step synthesis from commercially available compounds. The synthetic pheromones are examined with gametes.
• Effective Synthesis and Antifouling Activity of Dolastatin 16 Derivatives.

  Loida O Casalme, Keisuke Katayama, Yoshiki Hayakawa, Kensuke Nakamura, Arisa Yamauchi, Yasuyuki Nogata, Erina Yoshimura, Fuyuhiko Matsuda, Taiki Umezawa

  Marine drugs 20 (2) 2022/02/04 

  Some derivatives of dolastatin 16, a depsipeptide natural product first obtained from the sea hare Dolabella auricularia, were synthesized through second-generation synthesis of two unusual amino acids, dolaphenvaline and dolamethylleuine. The second-generation synthesis enabled derivatizations such as functionalization of the aromatic ring in dolaphenvaline. The derivatives of fragments and whole structures were evaluated for antifouling activity against the cypris larvae of Amphibalanus amphitrite. Small fragments inhibited the settlement of the cypris larvae at potent to moderate concentrations (EC50 = 0.60-4.62 μg/mL), although dolastatin 16 with a substituent on the aromatic ring (24) was much less potent than dolastatin 16.
• Efficient synthesis of α,β-dichlorinated ketones from α,β-dichlorinated Weinreb amides through a simple work-up procedure.

  Nurcahyo Iman Prakoso, Fuyuhiko Matsuda, Taiki Umezawa

  Organic & biomolecular chemistry 19 (36) 7822 - 7826 1477-0520 2021/09/22 

  An efficient synthesis of α,β-dichlorinated ketones from α,β-dichlorinated Weinreb amides is described. Quenching with nonaqueous HCl avoided side reactions associated with typical work-up procedures. The amide reacted with various nucleophiles to give the corresponding ketones in high yields. A novel reactivity of the Weinreb amide is also discussed.
• Assignment of Absolute Configuration of Bromoallenes by Vacuum-Ultraviolet Circular Dichroism (VUVCD).

  Taiki Umezawa, Nakaba Mizutani, Koichi Matsuo, Yuugo Tokunaga, Fuyuhiko Matsuda, Tatsuo Nehira

  Molecules (Basel, Switzerland) 26 (5) 2021/02/27 

  A new application of vacuum-ultraviolet circular dichroism (VUVCD), which enables the measurement of CD spectra in the vacuum-ultraviolet region (140-200 nm), for the assignment of the absolute configurations of bromoallenes is described. Bromoallene moieties are found in natural products obtained from many marine organisms. To date, the absolute configuration of bromoallenes has been assigned almost exclusively with Lowe's rule, which is based on specific rotation. However, exceptions to Lowe's rule have been reported arising from the presence of other substituents with large specific rotations. For the unambiguous assignment of the absolute configuration of the bromoallene moiety with its characteristic absorption wavelength at 180-190 nm due to the π-π* transition, VUVCD was applied to four pairs of bromoallene diastereomers prepared by modifying the synthetic scheme of omaezallene. The VUVCD spectra clearly showed positive or negative Cotton effects around 180-190 nm according to the configuration of the bromoallene employed, revealing the potential of VUVCD for determining absolute stereochemistry.
• Biosurfactants from Marine Cyanobacteria Collected in Sabah, Malaysia

  Jakia Jerin Mehjabin, Liang Wei, Julie G. Petitbois, Taiki Umezawa, Fuyuhiko Matsuda, Charles S. Vairappan, Masaaki Morikawa, Tatsufumi Okino

  Journal of Natural Products 83 (6) 1925 - 1930 0163-3864 2020/05/20 [Refereed][Not invited]
   

  Chemical investigation of the organic extract from Moorea bouillonii, collected in Sabah, Malaysia, led to the isolation of three new chlorinated fatty acid amides, columbamides F (1), G (2), and H (3). The planar structures of 1-3 were established by a combination of mass spectrometric and NMR spectroscopic analyses. The absolute configuration of 1 was determined by Marfey's analysis of its hydrolysate and chiral-phase HPLC analysis after conversion and esterification with Ohrui's acid, (1S,2S)-2-(anthracene-2,3-dicarboximido)cyclohexanecarboxylic acid. Compound 1 showed biosurfactant activity by an oil displacement assay. Related known fatty acid amides columbamide D and serinolamide C exhibited biosurfactant activity with critical micelle concentrations of about 0.34 and 0.78 mM, respectively.
• A Reliable Method to Create Adjacent Acid-Base Pair Sites on Silica through Hydrolysis of Pre-anchored Amide

  Wontae Kim, Loida O. Casalme, Taiki Umezawa, Fuyuhiko Matsuda, Ryoichi Otomo, Yuichi Kamiya

  Chemistry Letters 49 (1) 71 - 74 0366-7022 2020/01/05
• Neighboring Effect of Intramolecular Chlorine Atoms on Epoxide Opening Reaction by Chloride Anions.

  Taiki Umezawa, Masayuki Shibata, Ryutaro Tamagawa, Fuyuhiko Matsuda

  Organic letters 21 (19) 7731 - 7735 1523-7060 2019/10/04 

  We investigated the diastereoselectivity of ring openings for chloro vinyl epoxides with various chlorination reagents. In the chlorinolysis reactions using vinyl epoxides having an allyl alcohol, inversion:retention ratios varied depending on the chloride sources. In limited cases, the increase in retention ratio was consistent with the intervention of chloronium ions. In contrast, all vinyl epoxides bearing an α,β-unsaturated ester gave only the inversion products. These results suggest the electron-withdrawing property suppressed the chloronium ions.
• A brown algal sex pheromone reverses the sign of phototaxis by cAMP/Ca-dependent signaling in the male gametes of Mutimo cylindricus (Cutleriaceae)

  Kinoshita-Terauchi, Nana, Shiba, Kogiku, Umezawa, Taiki, Matsuda, Fuyuhiko, Motomura, Taizo, Inaba, Kazuo

  Journal of photochemistry and photobiology. B, Biology ELSEVIER SCIENCE SA 192 113 - 123 1873-2682 2019/03 [Refereed][Not invited]
   

  Male gametes of the brown alga Mutimo cylindricus show positive phototaxis soon after spawning in seawater but gradually change the sign of phototaxis with time. This conversion appears to need the decrease of intracellular Ca concentration. In this study, we revealed that the conversion of male gamete phototactic sign, positive to negative, was accelerated by mixing with female gametes. The supernatant after the centrifugation of female gamete suspension showed the same activity to change the phototactic sign, suggesting that a factor released from female gametes was responsible for the reaction. A known brown algal sex pheromone, ectocarpene, induced chemotaxis of male gametes of M. cylindricus. The addition of this compound induced the change of phototactic sign, clearly indicating that a sex pheromone is essential for the reversal. An inhibitor of phosphodiesterase, theophylline, inhibited the chemotaxis and phototactic sign reversion by a factor released from female gametes and ectocarpene. Measurements of cyclic nucleotides showed that the increase in intracellular concentration of cAMP, not cGMP, was parallel to the change of phototactic sign. The inhibition of phototactic s
• A brown algal sex pheromone reverses the sign of phototaxis by cAMP/Ca2+-dependent signaling in the male gametes of Mutimo cylindricus (Cutleriaceae)

  Kinoshita-Terauchi Nana, Shiba Kogiku, Umezawa Taiki, Matsuda Fuyuhiko, Motomura Taizo, Inaba Kazuo

  JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 192 113 - 123 1011-1344 2019/03 [Refereed][Not invited]
   

  Male gametes of the brown alga Mutimo cylindricus show positive phototaxis soon after spawning in seawater but gradually change the sign of phototaxis with time. This conversion appears to need the decrease of intracellular Ca2+ concentration. In this study, we revealed that the conversion of male gamete phototactic sign, positive to negative, was accelerated by mixing with female gametes. The supernatant after the centrifugation of female gamete suspension showed the same activity to change the phototactic sign, suggesting that a factor released from female gametes was responsible for the reaction. A known brown algal sex pheromone, ectocarpene, induced chemotaxis of male gametes of M. cylindricus. The addition of this compound induced the change of phototactic sign, clearly indicating that a sex pheromone is essential for the reversal. An inhibitor of phosphodiesterase, theophylline, inhibited the chemotaxis and phototactic sign reversion by a factor released from female gametes and ectocarpene. Measurements of cyclic nucleotides showed that the increase in intracellular concentration of cAMP, not cGMP, was parallel to the change of phototactic sign. The inhibition of phototactic sign by theophylline was not observed in low Ca2+ sea water. These results suggest that a signaling pathway mediated by cAMP and Ca2+ concentrations drives the interconversion between two important behaviors of male gametes, phototaxis and chemotaxis.
• Synthesis and Structure-Activity Relationship of Omaezallene Derivatives.

  Taiki Umezawa, Nurcahyo Iman Prakoso, Miho Kannaka, Yasuyuki Nogata, Erina Yoshimura, Tatsufumi Okino, Fuyuhiko Matsuda

  Chemistry & biodiversity 16 (1) e1800451  1612-1872 2019/01 [Refereed][Not invited]
   

  Omaezallene derivatives (nor-bromoallene, nor-bromodiene, and bromoenynes) were successfully synthesized. Their antifouling activity and toxicity to the cypris larvae of the barnacle Amphibalanus amphitrite and ecotoxicity to the marine crustacean Tigriopus japonicus were studied. It was revealed that the two side chains of omaezallene were essential to its antifouling activity because the activities of nor-bromoallene and nor-bromodiene were significantly diminished. The bromoenyne was found to exhibit potent antifouling activities comparable to omaezallene with low toxicity and ecotoxicity. Preparation of bromoenyne framework is much easier than that of bromodiene moiety in omaezallene. Based on the antifouling activities of the bromoenynes, the synthesis of fluorescent probes and evaluation of their biological activities were also carried out.
• Total synthesis of omaezallene toward structure determination

  Taiki Umezawa

  Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry 76 (5) 426 - 429 0037-9980 2018 [Refereed][Not invited]
   

  Details for the total synthesis of omaezallene, an antifouling natural product obtained from Laurencia sp, are described. Toward the total synthesis, tasks to be solved by total synthesis were determinations of relative configurations between bromoallene and THF ring, and the absolute configuration at C9 position. The use of an aldehyde, prepared from D-glucose in 5 steps, as a starting material was envisioned to accomplish these tasks. Although reactions for construction of the bromoallene and the THF ring were successful, extensive efforts to install the bromodiene unit were essential to overcome unexpected results.
• Antioxidants from the brown alga dictyopteris undulata

  Momochika Kumagai, Keisuke Nishikawa, Hiroshi Matsuura, Taiki Umezawa, Fuyuhiko Matsuda, Tatsufumi Okino

  Molecules 23 (5) 1420-3049 2018 [Refereed][Not invited]
   

  An investigation of anti-oxidative compounds from the brown alga Dictyopteris undulata has led to the isolation and identification of isozonarol, isozonarone, chromazonarol, zonaroic acid and isozonaroic acid. Their structures were identified by comparison of MS and NMR spectra. Full NMR assignment and absolute configuration of isozonaroic acid are described. Isozonarol showed the most potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity among the compounds isolated.
• Serinolamides and Lyngbyabellins from an Okeania sp Cyanobacterium Collected from the Red Sea

  Julie G. Petitbois, Loida O. Casalme, Julius Adam V. Lopez, Walied M. Alarif, Ahmed Abdel-Lateff, Sultan S. Al-Lihaibi, Erina Yoshimura, Yasuyuki Nogata, Taiki Umezawa, Fuyuhiko Matsuda, Tatsufumi Okino

  JOURNAL OF NATURAL PRODUCTS 80 (10) 2708 - 2715 0163-3864 2017/10 [Refereed][Not invited]
   

  NMR-and MS-guided fractionation of an extract of an Okeania sp. marine cyanobacterium, collected from the Red Sea, led to the isolation of four new metabolites, including serinolamides C (1) and D (2) and lyngbyabellins O (3) and P (4), together with the three known substances lyngbyabellins F (5) and G (6) and dolastatin 16 (7). The planar structures of the new compounds were determined using NMR and MS analyses. The absolute configurations of 1 and 2 were determined by Marfey's analysis of their hydrolysates. The absolute configuration of 3 was ascertained by chiral-phase chromatography of degradation products, while that of 4 was determined by comparison to 3 and 5. The cytotoxic and antifouling activities of these compounds were evaluated using MCF7 breast cancer cells and Amphibalanus amphitrite larvae, respectively. Compounds 3, 4, and 7 exhibited strong antifouling activity, and 3 and 7 were not cytotoxic. A structure-activity relationship was observed for the cytotoxicity of the lyngbyabellins with the presence of a side chain (4 is more active than 3) leading to greater activity. For the antifouling activity, the acyclic form without a side chain (3) was the most active.
• Total synthesis of (-)-kainic acid and (+)-allo-kainic acid through SmI2-mediated intramolecular coupling between allyl chloride and an alpha,beta-unsaturated ester

  Junya Suzuki, Natsumi Miyano, Shunpei Yashiro, Taiki Umezawa, Fuyuhiko Matsuda

  ORGANIC & BIOMOLECULAR CHEMISTRY 15 (31) 6557 - 6566 1477-0520 2017/08 [Refereed][Not invited]
   

  A 3,4-disubstituted pyrrolidine ring was effectively cyclized through SmI2-mediated reductive coupling between allyl chloride and an alpha,beta-unsaturated ester, although little has been reported about SmI2-promoted C-C bond formation of an allyl chloride with an alpha,beta-unsaturated ester. Selection of either the 3,4-cis- or 3,4-trans-selective cyclization can be accomplished simply by changing the additives from NiI2 to HMPA during reductive cyclization conducted in H2O-THF. Total synthesis of (-)-kainic acid and (+)-allo-kainic acid, which are pyrrolidine alkaloids used in neuroscience and neuropharmacology as useful molecular probes, was successfully achieved by using the stereo-complementary ring closure reactions promoted by SmI2 for the construction of the 2,3,4-trisubsituted pyrrolidine scaffold of kainoids.
• Columbamides D and E: Chlorinated Fatty Acid Amides from the Marine Cyanobacterium Moorea bouillonii Collected in Malaysia

  Julius Adam V. Lopez, Julie G. Petitbois, Charles S. Vairappan, Taiki Umezawa, Fuyuhiko Matsuda, Tatsufumi Okino

  ORGANIC LETTERS 19 (16) 4231 - 4234 1523-7060 2017/08 [Refereed][Not invited]
   

  Two new chlorinated fatty acid amides, columbamides D (1) and E (2), along with apratoxins A and C and wewakazole, were isolated from the organic extract of a Moorea bouillonii sample from Sabah, Malaysia. Structure elucidation was accomplished by a combination of MS and NMR analyses. The total synthesis of all four stereoisomers of 1 was completed, and the absolute configuration was determined by chiral-phase HPLC and Marfey's analysis.
• Design, Synthesis, and Antifouling Activity of Glucosamine-Based Isocyanides

  Taiki Umezawa, Yuki Hasegawa, Ira S. Novita, Junya Suzuki, Tatsuya Morozumi, Yasuyuki Nogata, Erina Yoshimura, Fuyuhiko Matsuda

  MARINE DRUGS 15 (7) 1660-3397 2017/07 [Refereed][Not invited]
   

  Biofouling, an undesirable accumulation of organisms on sea-immersed structures such as ship hulls and fishing nets, is a serious economic issue whose effects include oil wastage and clogged nets. Organotin compounds were utilized since the 1960s as an antifouling material; however, the use of such compounds was later banned by the International Maritime Organization (IMO) due to their high toxicity toward marine organisms, resulting in masculinization and imposex. Since the ban, there have been extensive efforts to develop environmentally benign antifoulants. Natural antifouling products obtained from marine creatures have been the subject of considerable attention due to their potent antifouling activity and low toxicity. These antifouling compounds often contain isocyano groups, which are well known to have natural antifouling properties. On the basis of our previous total synthesis of natural isocyanoterpenoids, we envisaged the installation of an isocyano functional group onto glucosamine to produce an environmentally friendly antifouling material. This paper describes an effective synthetic method for various glucosamine-based isocyanides and evaluation of their antifouling activity and toxicity against cypris larvae of the barnacle Amphibalanus amphitrite. Glucosamine isocyanides with an ether functionality at the anomeric position exhibited potent antifouling activity, with EC50 values below 1 mu g/mL, without detectable toxicity even at a high concentration of 10 mu g/mL. Two isocyanides had EC50 values of 0.23 and 0.25 mu g/mL, comparable to that of CuSO4, which is used as a fouling inhibitor (EC50 = 0.27 mu g/mL).
• Total synthesis and biological activity of dolastatin 16

  Loida O. Casalme, Arisa Yamauchi, Akinori Sato, Julie G. Petitbois, Yasuyuki Nogata, Erina Yoshimura, Tatsufumi Okino, Taiki Umezawa, Fuyuhiko Matsuda

  ORGANIC & BIOMOLECULAR CHEMISTRY 15 (5) 1140 - 1150 1477-0520 2017/02 [Refereed][Not invited]
   

  The total synthesis of dolastatin 16, a macrocyclic depsipeptide first isolated from the sea hare Dolabella auricularia as a potential antineoplastic metabolite by Pettit et al., was achieved in a convergent manner. Dolastatin 16 was reported by Tan to exhibit strong antifouling activity, and thus shows promise for inhibiting the attachment of marine benthic organisms such as Amphibalanus amphitrite to ships and submerged artificial structures. Therefore, dolastatin 16 is a potential compound for a new, environmentally friendly antifouling material to replace banned tributyltin-based antifouling paints. The synthesis of dolastatin 16 involved the use of prolinol to prevent formation of a diketopiperazine composed of L-proline and N-methyl-D-valine during peptide coupling. This strategy for the elongation of peptide chains allowed the efficient and scalable synthesis of one segment, which was subsequently coupled with a second segment and cyclized to form the macrocyclic framework of dolastatin 16. The synthetic dolastatin 16 exhibited potent antifouling activity similar to that of natural dolastatin 16 toward cypris larvae of Amphibalanus amphitrite.
• EFFECT OF SEX PHEROMONE ON THE SIGN OF PHOTOTAXIS IN BROWN ALGAL MALE GAMETES

  Kinoshita, N., Shiba, K., Inaba, K., Umezawa, T., Motomura, T.

  Phycologia 2017
• Total Synthesis of Natural Antifouling Products

  Taiki Umezawa, Keisuke Nishikawa, Tatsufumi Okino, Fuyuhiko Matsuda

  JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN 74 (7) 689 - 699 0037-9980 2016/07 [Refereed][Not invited]
   

  Biofouling is adverse growth of marine organisms on manmade submersible structures such as ships' hulls and cause significant economic and environmental problems. As a fouling inhibitor, tributyltin (TBT) has been widely used for controlling the sessile organisms since the early 1960s. Unfortunately, serious pollution of the marine environment due to the deleterious effect of TBT prompted the International Maritime Organization (IMO) to call in 2008 for a ban on the use of tributyltin (TBT) on ships. Since marine invertebrates prevent settlement of other benthic marine organisms through the use of natural substances with antifouling properties without causing serious environmental problems, natural antifouling products with good antifouling properties but without biocidal properties have attracted considerable attention. Among these, 10-isocyano-4-cadinene and omaezallene show promise as lead compounds for the development of new environmentally friendly antifouling agents due to its potent antifouling activity against the cypris larvae of the barnacle Amphibalanus amphitrite and low toxicity. 10-Isocyano-4-cadinene, an isocyanosesquiterpene, was isolated from nudibranchs of the family Phyllidiidae. On the other hand, omaezallene is a bromoallene-containing C-15-acetogenin isolated from the red alga Laurencia sp. Herein, we wish to describe our research on the isolations, structure elucidations, total syntheses, and evaluation of the antifouling activities of the natural products and their derivatives. The absolute configurations of the natural products were unambiguously established through our asymmetric total syntheses.
• Synthetic study on dolastatin 16: concise and scalable synthesis of two unusual amino acid units

  Taiki Umezawa, Akinori Sato, Yasuto Ameda, Loida O. Casalme, Fuyuhiko Matsuda

  TETRAHEDRON LETTERS 56 (1) 168 - 171 0040-4039 2015/01 [Refereed][Not invited]
   

  A convenient and scalable synthesis of two unusual amino acid units found in dolastatin 16, dolaphenvaline, and dolamethylleuine, is described. Dolastatin 16, which was first isolated from the sea hare Dolabella auricularia by Pettit, exhibits not only strong inhibition of growth for a variety of human cancer cell lines but also potent antifouling activity against the larvae of the barnacle Balanus amphitrite. The key element of the synthesis is an organocatalytic Mannich reaction to construct two contiguous stereocenters in the amino acid units with almost complete enantio- and diastereoselectivity. (C) 2014 Elsevier Ltd. All rights reserved.
• cDNA cloning and characterization of vanadium-dependent bromoperoxidases from the red alga Laurencia nipponica

  Kensuke Kaneko, Kenji Washio, Taiki Umezawa, Fuyuhiko Matsuda, Masaaki Morikawa, Tatsufumi Okino

  BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY 78 (8) 1310 - 1319 0916-8451 2014/08 [Refereed][Not invited]
   

  The marine red alga genus Laurencia is one of the richest producers of unique brominated compounds in the marine environment. The cDNAs for two Laurencia nipponica vanadium-dependent bromoperoxidases (LnVBPO1 and LnVBPO2) were cloned and expressed in Escherichia coli. Enzyme assays of recombinant LnVBPO1 and LnVBPO2 using monochlorodimedone revealed that they were thermolabile but their K-m values for Br- were significantly lower than other red algal VBPOs. The bromination reaction was also assessed using laurediol, the predicted natural precursor of the brominated ether laurencin. Laurediol, protected by trimethylsilyl at the enyne, was converted to deacetyllaurencin by the LnVBPOs, which was confirmed by tandem mass spectrometry. Native LnVBPO partially purified from algal bodies was active, suggesting that LnVBPO is functional in vivo. These results contributed to our knowledge of the biosynthesis of Laurencia brominated metabolites.
• Recent progress toward synthesis of chlorosulfolipids: total synthesis and methodology

  Taiki Umezawa, Fuyuhiko Matsuda

  TETRAHEDRON LETTERS 55 (19) 3003 - 3012 0040-4039 2014/05 [Refereed][Not invited]
   

  Chlorosulfolipids (CSLs) are an intriguing family of natural products featuring highly chlorinated linear hydrocarbon skeletons. Although CSLs were first isolated in 1962, chemical synthesis of CSLs was hampered because relevant methods for stereoselective construction of the polychlorinated motifs of CSLs were scarce. Since Carreira's first total synthesis of the CSL mytilipin A in 2009, several groups, including our own, have reported total syntheses of CSLs. As a result of these total syntheses, important progress has been made in the development of reliable synthetic methods for stereoselective polychlorination. In this digest, we summarize the total syntheses of CSLs by focusing on synthetic methods for stereoselective polychlorination of the organic frameworks of CSLs. (c) 2014 Published by Elsevier Ltd.
• Omaezallene from Red Alga Laurencia sp.: Structure Elucidation, Total Synthesis, and Antifouling Activity

  Taiki Umezawa, Yuko Oguri, Hiroshi Matsuura, Shohei Yamazaki, Masahiro Suzuki, Erina Yoshimura, Takeshi Furuta, Yasuyuki Nogata, Yukihiko Serisawa, Kazuyo Matsuyama-Serisawa, Tsuyoshi Abe, Fuyuhiko Matsuda, Minoru Suzuki, Tatsufumi Okino

  ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 53 (15) 3909 - 3912 1433-7851 2014/04 [Refereed][Not invited]
   

  Natural antifouling products have been the subject of considerable attention. We screened marine algae for antifouling activity and discovered omaezallenes, the new bromoallene-containing natural products isolated from the red alga Laurenciasp. Described is the isolation, structure elucidation, and total syntheses of omaezallenes. The relative and absolute configurations of natural omaezallenes were unambiguously established through total synthesis. The antifouling activities and ecotoxicity of omaezallenes were also evaluated.
• Bromoperoxidases from Laurencia species

  Kaneko Kensuke, Washio Kenji, Umezawa Taiki, Kobayashi Daiki, Tang Xiaorong, Matsuda Fuyuhiko, Morikawa Masaaki, Okino Tatsufumi

  Symposium on the Chemistry of Natural Products, symposium papers 天然有機化合物討論会実行委員会 56 Poster53  2014 

  The genus of red alga Laurencia is one of the richest producers of halogenated compounds (mostly brominated) ³⁾. Murai et al ⁴⁾ and Butler et al ⁹⁾ showed enzymatic bromination of Laurencia C₁₅acetogenins including laurencin (1) ^1,2)and sesquiterpenoids snyderols using partially purified bromoperoxidase (BPO) from L. nipponica and vanadium-dependent BPO (VBPO) from a mixture of red algae including L. pacifica. However, since the lack of information of sequences, the structural information and biochemical aspects of BPO from L. nipponica and VBPO from L. pacifica remains unknown. Here, we report cDNA cloning of VBPOs from L. nipponicaand in vitro enzymatic bromination of putative biosynthetic precursors using recombinant enzymes. Two VBPOs (LnVBPO1 and LnVBPO2) were cloned from L. nipponica and recombinant LnVBPOs were prepared. Recombinant LnVBPOs were subjected to enzyme activity assay. A general substrate, monochlorodimedone (MCD), was utilized for K_m determination for H₂O₂ and , essential for bromination of organic substrate. K_m for H₂O₂was 0.03 mM in both LnVBPOs, K_m for were 0.53 mM for LnVBPO1 and 0.35 mM for LnVBPO2, respectively. A derivative of putative precursor of laurencin (1), TMS-capped (3E, 6R, 7R)-laurediol (4) was subjected to LnVBPOs enzymatic bromination and gave similar MS/MS spectrum of deacetylaurencin (3). Since the compound 3 is considered to be the final precursor of 1, it is suggested that VBPO catalyzes bromination in Laurenciametabolites. We also cloned VBPOs from other Laurencia spp. which produce brominated sesquiterpenoids (L. okamurae) and triterpenoids (L. saitoi). We will discuss in vitro enzymatic bromination of these two LaurenciaVBPOs.
• Total Synthesis of Omaezallene and Determination of its Absolute Stereochemistries

  Umezawa Taiki, Yamazaki Shohei, Oguri Yuko, Matsuura Hiroshi, Suzuki Masahiro, Okino Tatsufumi, Matsuda Fuyuhiko

  Symposium on the Chemistry of Natural Products, symposium papers 天然有機化合物討論会実行委員会 55 Oral24  2013 

  Omaezallene (1) was isolated from Laurencia sp. and showed strong antifouling activity against the larvae of the barnacle amphitrite. Although organotin compounds, such as tributyltin (TBT), had been widely used as a fouling inhibitor, the use of TBT was prohibited by IMO in 2008 due to its toxicity. Therefore, the development of the potent nontoxic fouling inhibitor is desired strongly, and 1 is expected to be a lead compound as the fouling inhibitor. Although the relative and absolute structure of 1 was assumed using 1D- and 2D-NMR experiments, the relative configurations have not been determined completely, especially the configuration at C9 position. To determine the relative configurations as well as the absolute configuration, the synthetic study toward 1 was started. The synthesis commenced with the known aldehyde 3, derived from D-glucose in 5 steps, which was transformed into the unsaturated ester 8 with E geometry. The ester 8 was next converted to the hemiacetal 10 in 3 steps. The treatment of ethynylmagnesium chloride to 10 afforded the desired propargy alcohol 4 as a major diastereomer. Cyclization of 4 with NBS furnished the construction of the two contiguous stereocenters to give bromoether 11 in a highly stereoselective manner, which was then derived to the aldehyde 6 in 4 steps. 6 was successfully converted to 1via cyanohydrin formation, HWE reaction, and Wittig reaction involving in-situ bromination of reagent. By the total synthesis, the absolute configuration of 1was unambiguously determined as shown in scheme 5.
• Confirmation of the Configuration of 10-Isothiocyanato-4-cadinene Diastereomers through Synthesis

  Keisuke Nishikawa, Taiki Umezawa, Mary J. Garson, Fuyuhiko Matsuda

  JOURNAL OF NATURAL PRODUCTS 75 (12) 2232 - 2235 0163-3864 2012/12 [Refereed][Not invited]
   

  The marine sponge metabolite 10-isothiocyanato4-cadinene (1) was first isolated by Garson et al. from Acanthella cavernosa in 2000. The same structure 1 was later reported by Wright et al. from the nudibranch Phyllidiella pustulosa and its sponge diet, but with different NMR data. The syntheses of both enantiomers of 1 were accomplished through the isothiocyanation of 10-isocyano-4-cadinene (2) previously synthesized by our group. The correct spectroscopic data and specific rotation value of the structure 1 were determined on the basis of the syntheses. The NMR data of synthetic 1 matched those of the isothiocyanate isolated by Garson and differed from those reported by Wright. The spectroscopic data and specific rotation values of 10-epi-10-isothiocyanato-4-cadinene (6) and di-1,6-epi-10-isothiocyanato-4-cadinene (8) were also established through the syntheses of these diastereomers. Structure 6 has been reported as a natural product by Mitome et al., but the NMR data for the synthetic sample of 6 differ from those of the natural isolate.
• P-11 Three-component Coupling Reaction with Aldehyde, Acyl Fluoride and Trimethylsilylmethylphosphonate(Poster Presentation)

  Umezawa Taiki, Seino Tomoya, Matsuda Fuyuhiko

  Symposium on the Chemistry of Natural Products, symposium papers 天然有機化合物討論会 (54) 297 - 302 2012/09/01 

  Horner-Wadsworth-Emmons reaction (HWE reaction) is known as a reliable and powerful method for carbon-carbon bond formation by coupling between β-ketophosphonate and aldehyde to give α,β-unsaturated compound with high stereoselectivity. In general, the β-ketophosphonate used as the HWE reaction precursor is needed to be synthesized from a readily accessible material. However, these procedures sometimes encounter troubles in purification due to its high polarity or side products. To avoid these problems, we planned one-pot synthesis of the α,β-unsaturated ketone with aldehyde, acyl fluoride and trimethylsilylmethylphosphonate through HWE reaction according to the sequential reaction illustrated in Scheme 1. The reaction conditions were optimized by examining bases, reaction time, and equivalent of reagents as shown in Table 1. With the optimized conditions (Table 1. Entry 7), wide variety of substrates (aldehyde, acyl fluoride, and phosphonate) bearing various functional groups were coupled to give α,β-unsaturated ketone in high yields with E geometry. (Table 2) Z-α,β-Unsaturated ketones were also prepared with high stereoselectivity by using one-pot procedure. (Table 3)
• Thrombin Inhibitors from the Freshwater Cyanobacterium Anabaena compacta

  Andrea Roxanne J. Anas, Takaya Kisugi, Taiki Umezawa, Fuyuhiko Matsuda, Marc R. Campitelli, Ronald J. Quinn, Tatsufumi Okino

  JOURNAL OF NATURAL PRODUCTS 75 (9) 1546 - 1552 0163-3864 2012/09 [Refereed][Not invited]
   

  Bioassay-guided investigation of the cyanobacterium Anabaena compacta extracts afforded spumigin J (1) and the known thrombin inhibitor spumigin A (2). The absolute configuration of 1 was analyzed by advanced Marfey's methodology. Compounds 1 and 2 inhibited thrombin with EC50 values of 4.9 and 2.1 mu M, and 0.7 and 0.2 mu M in the cathepsin B inhibitory assay, respectively. The MM-GBSA methodology predicted spumigin A with 2S-4-methylproline as the better thrombin inhibitor.
• Novel One-pot Three-component Coupling Reaction with Trimethylsilylmethylphosphonate, Acyl Fluoride, and Aldehyde through the Horner-Wadsworth-Emmons Reaction

  Taiki Umezawa, Tomoya Seino, Fuyuhiko Matsuda

  ORGANIC LETTERS 14 (16) 4206 - 4209 1523-7060 2012/08 [Refereed][Not invited]
   

  A novel three-component coupling between trimethylsilylmethylphosphonate, acyl fluoride, and aldehyde has been developed. A sequential nucleophilic addition of lithio-trimethylsilylmethylphosphonate to the acyl fluoride and Horner-Wadsworth-Emmons reaction of an aldehyde with the lithio-beta-ketophosphonate generated in situ by desilylation at the alpha-position of the alpha-silyl-beta-ketophosphonate by fluoride took place cleanly in a one-pot operation. Various E- and Z-enones were obtained in high yields with high stereoselectivities by this one-pot procedure.
• Synthesis and Biological Activity of Kalkitoxin and its Analogues

  Taiki Umezawa, Manabu Sueda, Takao Kamura, Teppei Kawahara, Xuerong Han, Tatsufumi Okino, Fuyuhiko Matsuda

  JOURNAL OF ORGANIC CHEMISTRY 77 (1) 357 - 370 0022-3263 2012/01 [Refereed][Not invited]
   

  Total syntheses of kalkitoxin, isolated from the Caribbean Lyngbya majuscula, and its analogues, 3-epi-, 7-epi-, 8-epi-, 10-epi-, 10-nor-, and 16-nor-kalldtcocin, were achieved via oxazolidinone-based diastereoselective 1,4-addition reaction of a methyl group and efficient T1C14-mediated thiazoline ring formation as the key steps. The biological activities of synthetic kalkitoxin and its analogues were evaluated with brine shrimp.
• Asymmetric Total Synthesis of Danicalipin A

  Umezawa Taiki, Shibata Masayuki, Matsuda Fuyuhiko

  Symposium on the Chemistry of Natural Products, symposium papers 天然有機化合物討論会 (52) 1 - 6 2010/09/01 

  Danicalipin A (1), a major component of chlorosulfolipids (CSLs) from Ochromonas danica, was first isolated more than four decades ago along wigh its congeners 2-6. Although the planar structure of 1 was reorted in 1973, the absolute and relative stereochemistries of 1 have not been determined until 2009; total synthesis by Vanderwal and NMR analysis of natural sample by Okino. Due to the unprecedent structure of CSLs, CSLs have attracted much attention of synthetic chemists and total syntheses of 1, 7, and 8 were achieved by three groups. In this presentation, asymmetric total synthesis of Danicalipin A (1) will be described. The synthesis commenced with the known optically active epoxide 14, derived via Sharpless-Katsuki asymmetric epoxidation, which was transformed into the α,β-unsaturated ester 15. (Scheme 2) At this stage, the enantiomeric excess of 15 was enhanced from 85% ee to >99% ee by recrystallization. Four transformations involving regioselective epoxy opening reaction gave the aldehyde 13. After diastereoselective α-chlorination of 13 with 19, the aldehyde 10 was synthesized in 2 steps. Wittig reaction between 10 and the phosphonium salt 11, derived from the known aldehyde 12, afforded the alkene 24. E-olefin for the trans-dichloride at C15 and 16 was installed by Wiitg olefination, furnishing the α,β-unsaturated ester 26. After introduction of n-hexyl group from ester, trans addition of chlorine equivalent into E-olefin at 80℃ gave the adduct 29, which was successfully converted to Danicalipin A.
• Synthesis and Biological Activity of Kalkitoxin and its Analogues

  Umezawa Taiki, Kamura Takao, Kawahara Teppei, Sueda Manabu, Kan Setsuyo, Okino Tatsufumi, Matsuda Fuyuhiko

  Symposium on the Chemistry of Natural Products, symposium papers 天然有機化合物討論会 (51) 329 - 334 2009/09/01 

  Kalkitoxin (1) was isolated from cyanobacterium Lyngbya majuscule in the Caribbean Sea. It is reported that 1 posssesses some intersting biological activities. For example, 1 shows a strong ichtyotoxic activity toward the common gold fish and brine shrimp. Also, kalkitoxin has a strong neurotoxicity (LC_<50>=3.86nM) in cerebellar granule neouron (CGN) as an inhibitor N-methyl-D-aspartate (NMDA) receptor antagonists and is a highly potent blocker of the voltage-depending sodium channel in mouse neuro-2a cells (EC_<50>=1nM). We have been attracted by the structure-activity relationship of kalkitoxins. In present paper, we describe the synthesis of kalkitoxin and its analogues (epimer and demethylated kalkitoxins (nor form) and their biological activity with brine shrimp. The synthesis was started from 15, which was converted to α,β-unsaturaed imide 14 with phosphonate 17. 1,4-Addition reaction to 14 with methyl curprate gave imide 18 as 10 : 1 mixture of diastereomers. The imide 18 was transformed into second 1,4-addition precursor 11 in 9 steps. The conjugate addition reaction of 11 proceeded smoothly to give imide 26 as a single diastereomer, which was derived to 1 via condensation with amine 10, synthesize without racemization by novel method, and highly efficient thiazoline formation with TiCl_4. Kalkitoxin analogues 2-7 were synthesized in the similar manner by simply changing the chiral auxiliary or chiral building block. Finally, the biological activity with 1-7 was evaluated as LC_<50> toward brine shrimp.
• P-80 Total Synthesis of Isocyanocadinene(Poster Presentation)

  Nishikawa Keisuke, Shirokura Yousuke, Nakahara Hiroshi, Umezawa Taiki, Matsuda Fuyuhiko

  Symposium on the Chemistry of Natural Products, symposium papers 天然有機化合物討論会 (50) 777 - 782 2008/09/01 

  10-Isocyano-4-cadinene (1), a marine sesquiterpene isolated from nudibranchs of the family Phyllidiidae by Okino et al., exhibits potent antifouling activity against the larvae of the barnacle Balanus amphitrite (EC_<50> 0.14μg/mL). 10-Isocyano-4-cadinene (1) is expected to be new nontoxic antifouling agents. Furthermore, the absolute stereochemistry of 1 has not been determined. To access these issues, we started the enantioselective total synthesis toward 1. The synthesis toward 1 was commenced with known imide 6, which was converted into dieneacetate 5c in 9 steps. The Diels-Alder reaction between 5c and methyl acrylate with MeAlCl_2 afforded cyclohexene 11c as a mixture of four diasereomers. This mixture was epimerized to two isomers, desired carboxylic acid 12 as a major product and ester 13, by the treatment of NaOMe followed by selective hydrolysis with 1N HCl in one-pot. Carboxylic acid 12 was transformed into aldehyde 14, which was cyclized by SmI_2-induced Barbier-type reaction to give alcohol 15. To introduce the functional groups at C10, homologation of 15 with TosMIC afforded aldehyde 16, which was treated with t-BuOK and 21 to give MPM ether 22 in stereoselective fashion. Wolff-Kishner reaction followed by Curtis rearrangement of 24 gave isocyanate 25, C10 was fully functionalized. Total synthesis was completed by reduction of isocyano group with NaBH_4 and dehydration with POCl_3. The absolute configuration of 1 was determined as (1R, 6R, 7S, 10R) by the comparison with the optical rotation between natural and synthetic samples.

Works

• 若手研究者のための有機合成セミナー

  2008

MISC

• マリンバイオマス由来付着阻害剤の構造―活性相関研究

  梅澤大樹, 長谷川裕己, SARI Ira Novita, 鈴木惇也, 諸角達也, 野方靖行, 吉村えり奈, 松田冬彦  マリンバイオテクノロジー学会大会講演要旨集  19th-  80  2017/06/03  [Not refereed][Not invited]
  
• グルコサミン由来の付着阻害剤の合成と付着阻害活性

  梅澤大樹, 長谷川裕己, SARI Ira Novita, 鈴木惇也, 諸角達也, 松田冬彦, 野方靖行, 吉村えり奈  Sessile Organisms  34-  (2)  2017
• Synthetic study on dolastatin 16: concise and scalable synthesis of two unusual amino acid units

  Taiki Umezawa, Akinori Sato, Yasuto Ameda, Loida O. Casalme, Fuyuhiko Matsuda  TETRAHEDRON LETTERS  56-  (1)  168  -171  2015/01  [Not refereed][Not invited]
   

  A convenient and scalable synthesis of two unusual amino acid units found in dolastatin 16, dolaphenvaline, and dolamethylleuine, is described. Dolastatin 16, which was first isolated from the sea hare Dolabella auricularia by Pettit, exhibits not only strong inhibition of growth for a variety of human cancer cell lines but also potent antifouling activity against the larvae of the barnacle Balanus amphitrite. The key element of the synthesis is an organocatalytic Mannich reaction to construct two contiguous stereocenters in the amino acid units with almost complete enantio- and diastereoselectivity. (C) 2014 Elsevier Ltd. All rights reserved.
• Recent progress toward synthesis of chlorosulfolipids: total synthesis and methodology

  Taiki Umezawa, Fuyuhiko Matsuda  TETRAHEDRON LETTERS  55-  (19)  3003  -3012  2014/05  [Not refereed][Not invited]
   

  Chlorosulfolipids (CSLs) are an intriguing family of natural products featuring highly chlorinated linear hydrocarbon skeletons. Although CSLs were first isolated in 1962, chemical synthesis of CSLs was hampered because relevant methods for stereoselective construction of the polychlorinated motifs of CSLs were scarce. Since Carreira's first total synthesis of the CSL mytilipin A in 2009, several groups, including our own, have reported total syntheses of CSLs. As a result of these total syntheses, important progress has been made in the development of reliable synthetic methods for stereoselective polychlorination. In this digest, we summarize the total syntheses of CSLs by focusing on synthetic methods for stereoselective polychlorination of the organic frameworks of CSLs. (c) 2014 Published by Elsevier Ltd.
• 紅藻ウラソゾLaurencia nipponica由来バナジウム依存型ブロモペルオキシダーゼの性状解析

  KANEKO KENSUKE, WASHIO KENJI, UMEZAWA DAIKI, MATSUDA FUYUHIKO, MORIKAWA MASAAKI, OKINO TATSUFUMI  日本水産学会大会講演要旨集  2014-  119  2014/03/27  [Not refereed][Not invited]
  
• Danicalipin A誘導体の合成研究

  MAEDA TAKESHI, UMEZAWA TAIKI, MATSUDA FUYUHIKO  日本化学会講演予稿集  94th-  (4)  1492  2014/03/12  [Not refereed][Not invited]
  
• Dolastatin16の全合成研究

  SATO AKINORI, UMEZAWA TAIKI, MATSUDA FUYUHIKO  日本化学会講演予稿集  94th-  (4)  1468  2014/03/12  [Not refereed][Not invited]
  
• 効率的ビニグロールの合成研究

  UMEZAWA DAIKI  上原記念生命科学財団研究報告集(CD-ROM)  27-  ROMBUNNO.11  -4  2013/12/10  [Not refereed][Not invited]
  
• 紅藻ウラソゾLaurencia nipponica由来バナジウム依存型ブロモペルオキシダーゼの性状解析

  KANEKO KENSUKE, WASHIO KENJI, UMEZAWA DAIKI, MATSUDA FUYUHIKO, MORIKAWA MASAAKI, OKINO TATSUFUMI  マリンバイオテクノロジー学会大会講演要旨集  15th-  68  2013/06/01  [Not refereed][Not invited]
  
• Mytilipin Cの全合成研究

  UMEZAWA TAIKI, SEINO TOMOYA, MATSUDA FUYUHIKO  日本化学会講演予稿集  93rd-  (4)  1202  2013/03/08  [Not refereed][Not invited]
  
• アルデヒド,酸フッ化物,トリメチルシリルメチルホスホネートの3成分カップリング反応

  UMEZAWA TAIKI, SEINO TOMOYA, MATSUDA FUYUHIKO  日本化学会講演予稿集  92nd-  (4)  1156  2012/03/09  [Not refereed][Not invited]
  
• Stereoselective Total Syntheses of Chlorosulfolipids

  Taiki Umezawa, Fuyuhiko Matsuda  JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN  69-  (10)  1122  -1133  2011/10  [Not refereed][Not invited]
   

  Chlorosulfolipids (CSLs) represent an unusual family of natural products that were first isolated from the freshwater alga Ochromonas danica in the 1960s. They have drawn considerable attention as substances of toxicological concern, because some of them display modest cytotoxic activity and are associated with seafood poisoning. CSLs are unique in featuring hydrocarbon framework which possess chlorine-substituted multiple stereogenic centers. Due to the unprecedented structure and interesting biological activity of CSLs, this fascinating class of natural products has recently garnered interest as targets of total synthesis and inspired methodology for stereoselective chlorination. In 2009, Carreira accomplished the total synthesis of hexachlorosulfolipid. After this total synthesis, other three groups including our group have achieved total syntheses of CSLs: Malhamensilipin A and danicalipin A by Vanderwal, hexachlorosulfolipid and danicalipin A by Yoshimitsu and Tanaka, and danicalipin A by authors. This review deals with these total syntheses of CSLs, focusing the development of synthetic methods to stereoselectively incorporate acyclic polychlorinated arrays into hydrocarbon skeletons of CSLs.
• Stereoselective total syntheses of chlorosulfolipids

  Taiki Umezawa, Fuyuhiko Matsuda  Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry  69-  (10)  1122  -1133  2011/10  [Not refereed][Not invited]
   

  Chlorosulfolipids (CSLs) represent an unusual family of natural products that were first isolated from the freshwater alga Ochromonas danica in the 1960s. They have drawn considerable attention as substances of toxicological concern, because some of them display modest cytotoxic activity and are associated with seafood poisoning. CSLs are unique in featuring hydrocarbon framework which possess chlorine-substituted multiple stereogenic centers. Due to the unprecedented structure and interesting biological activity of CSLs, this fascinating class of natural products has recently garnered interest as targets of total synthesis and inspired methodology for stereoselective chlorination. In 2009, Carreira accomplished the total synthesis of hexachlorosulfolipid. After this total synthesis, other three groups including our group have achieved total syntheses of CSLs: Malhamensilipin A and danicalipin A by Vanderwal, hexachlorosulfolipid and danicalipin A by Yoshimitsu and Tanaka, and danicalipin A by authors. This review deals with these total syntheses of CSLs, focusing the development of synthetic methods to stereoselectively incorporate acyclic polychlorinated arrays into hydrocarbon skeletons of CSLs.
• オマエザレンの全合成

  UMEZAWA TAIKI, SUZUKI MASAHIRO, OGURI YUKO, MATSUURA HIROSHI, OKINO TATSUFUMI, MATSUDA FUYUHIKO  天然有機化合物討論会講演要旨集  53rd-  637  -642  2011/09/02  [Not refereed][Not invited]
  
• 支部発 話題欄 1 天然有機化合物の化学 含ハロゲン化合物の全合成

  UMEZAWA TAIKI  化学と工業  64-  (9)  688  -689  2011/09/01  [Not refereed][Not invited]
  
• Total Synthesis of 10-Isocyano-4-cadinene and Its Stereoisomers and Evaluations of Antifouling Activities

  Keisuke Nishikawa, Hiroshi Nakahara, Yousuke Shirokura, Yasuyuki Nogata, Erina Yoshimura, Taiki Umezawa, Tatsufumi Okino, Fuyuhiko Matsuda  JOURNAL OF ORGANIC CHEMISTRY  76-  (16)  6558  -6573  2011/08  [Not refereed][Not invited]
   

  The first enantioselective total synthesis of 10-isocyano-4-cadinene, a marine sesquiterpene isolated from nudibranchs of the family Phyllidiidae, and determination of its absolute stereochemistry were achieved. 10-Isocyano-4-cadinene is expected to be a novel nontoxic antifouling agent. In the synthesis, intermolecular Diels-Alder reaction and samarium diiodide induced Barbier-type cyclization were employed as key steps. The absolute configuration of 10-isocyano-4-cadinene was determined as (1S,6S,7R,10S) by comparison of the optical rotations between natural and synthetic samples. In addition, the authors successfully synthesized 10-epi- and di-1,6-epi-10-isocyano-4-cadinene through the same synthetic pathway. Antifouling activities against Balanus amphitrite with the cadinenes were also evaluated.
• Asymmetric Total Synthesis of Danicalipin A and Evaluation of Biological Activity

  Taiki Umezawa, Masayuki Shibata, Kensuke Kaneko, Tatsufumi Okino, Fuyuhiko Matsuda  ORGANIC LETTERS  13-  (5)  904  -907  2011/03  [Not refereed][Not invited]
   

  Asymmetric total synthesis of danicalipin A was achieved. The synthesis was characterized by diastereoselective introduction of chlorine atoms. Biological activities with synthetic danicalipin A, its enantiomer, and racemate were also evaluated toward brine shrimp. Both enantiomers of danicalipin A showed almost the same activity.
• Synthesis of C-13-Labeled 5,6,11-Trideoxytetrodotoxin

  Taiki Umezawa, Tetsuro Shinada, Yasufumi Ohfune  CHEMISTRY LETTERS  39-  (12)  1281  -1282  2010/12  [Not refereed][Not invited]
   

  The synthesis of (1) C-labeled 5,6,11-trideoxytetrodotoxin has been successfully achieved This is the first example of the C-13-labeled analogs in tetrodotoxin congeners
• Mild and Catalytic Transesterification Reaction Using K2HPO4 for the Synthesis of Methyl Esters

  Tetsuro Shinada, Makoto Hamada, Kota Miyoshi, Masato Higashino, Taiki Umezawa, Yasufumi Ohfune  SYNLETT  (14)  2141  -2145  2010/09  [Not refereed][Not invited]
   

  K2HPO4 is an efficient catalyst for the transesterification reaction to produce methyl esters. Various functional groups are compatible under the mild reaction conditions.
• Synthesis of the QRSTU Domain of Maitotoxin and Its 85-epi- and 86-epi-Diastereoisomers

  K. C. Nicolaou, Christine F. Gelin, Jae Hong Seo, Zhihong Huang, Taiki Umezawa  JOURNAL OF THE AMERICAN CHEMICAL SOCIETY  132-  (28)  9900  -9907  2010/07  [Not refereed][Not invited]
   

  A devised synthetic strategy toward the QRSTU ring system 4 of the marine-derived biotoxin maitotoxin (1) delivered, in addition to 4, its diastereoisomers 85-epi-QRSTU and 86-epi-QRSTU ring systems 5 and 6. The convergent route to these maitotoxin fragments involved coupling of UT and Q building blocks 9 (obtained from 2-deoxy-D-ribose) and 10 (obtained from D-ribose) followed by ring-closing metathesis to afford enol ether 8, whose elaboration to the targeted QRSTU ring system 4 required its conversion to hydroxy ketone 7. The latter compound (7) was transformed to the final product through a hydroxy dithioketal cyclization, followed by oxidation/methylation of the resulting O,S-mixed ketal to install the last of the five methyl groups contained within the target molecule (4). (13)C NMR spectroscopic analysis of synthesized fragments 4, 5, and 6 and comparisons with maitotoxin provided strong support for the originally assigned structure of the QRSTU domain of the natural product.
• Isocyanocadinene及びその立体異性体の合成とそれらの着生阻害活性の評価

  西川慶祐, 代蔵陽介, 野方靖行, 吉村えり奈, 梅澤大樹, 沖野龍文, 松田冬彦  日本化学会講演予稿集  90th-  (4)  1043  2010/03/12  [Not refereed][Not invited]
  
• Total Synthesis of 10-Isocyano-4-cadinene and Determination of Its Absolute Configuration

  Keisuke Nishikawa, Hiroshi Nakahara, Yousuke Shirokura, Yasuyuki Nogata, Erina Yoshimura, Taiki Umezawa, Tatsufumi Okino, Fuyuhiko Matsuda  ORGANIC LETTERS  12-  (5)  904  -907  2010/03  [Not refereed][Not invited]
   

  The first enantioselective total synthesis of 10-isocyano-4-cadinene, a marine sesquiterpene isolated from nudibranchs of the family Phyllidiidae, was achieved. The cadinene is expected to be a novel nontoxic antifouling agent. In the synthesis, an intermolecular Diels-Alder reaction and a SMl(2)-induced Barbier-type reaction were employed as key steps. The absolute configuration of 10-isocyano-4-cadinene was determined to be (1S, 6S, 7R, 10S) on the basis of the total synthesis. Antifouling activities against Balanus amphitrite with both enantiomers of 10-isocyano-4-cadinene were also evaluated.
• テルペン類の全合成 : 骨格形成法の新展開

  松田 冬彦, 梅澤 大樹  ファルマシア  44-  (10)  959  -964  2008/10/01
• Chemical synthesis of the GHIJKLMNO ring system of maitotoxin

  K. C. Nicolaou, Michael O. Frederick, Antonio C. B. Burtoloso, Ross M. Denton, Fatima Rivas, Kevin P. Cole, Robert J. Aversa, Romelo Gibe, Taiki Umezawa, Takahiro Suzuki  JOURNAL OF THE AMERICAN CHEMICAL SOCIETY  130-  (23)  7466  -7476  2008/06  [Not refereed][Not invited]
   

  As the largest secondary metabolite to be discovered as of yet, the polyether marine neurotoxin maiitotoxin constitutes a major structural and synthetic challenge. After its originally proposed structure (1) had been questioned on the basis of biosynthetic considerations, we provided computational and experimental support for structure 1. In an effort to provide stronger experimental evidence of the molecular architecture of maitotoxin, its GHIJKLMNO ring system 21 was synthesized. The (13)C NMR chemical shifts of synthetic 3 matched closely those corresponding to the same domain of the natural product providing strong evidence for the correctness of the originally proposed structure of maitotoxin (1).
• Total synthesis of (-)-5,6,11-trideoxytetrodotoxin and its 4-epimer

  Taiki Umezawa, Toshihiro Hayashi, Hiroshi Sakai, Hidetoshi Teramoto, Takeshi Yoshikawa, Masashi Izumida, Yoshinori Tamatani, Tadashi Hirose, Yasufumi Ohfune, Tetsuro Shinada  ORGANIC LETTERS  8-  (21)  4971  -4974  2006/10  [Not refereed][Not invited]
   

  The first total synthesis of 5,6,11-trideoxytetrodotoxin (1) and its 4-epimer were achieved. The synthesis is characterized by the stereoselective construction of the quaternary amino carbon center at C8a by an asymmetric transferring Strecker synthesis and the highly efficient conversion of cyanohydrin 4 to 1 via intramolecular cyclization reactions.
• P-107 TOTAL SYNTHESIS OF 5,6,11-TRIDEOXYTETRODOTOXIN

  Shinada Tetsuro, Umezawa Taiki, Hayashi Toshihiro, Sakai Hiroshi, Kawakami Tadashi, Teramoto Hidetoshi, Yoshikawa Takeshi, Izumida Masashi, Tamatani Yoshinori, Hirose Tadashi, Ohfune Yasufumi  International Symposium on the Chemistry of Natural Products  2006-  "P  -107"  2006/07/23  [Not refereed][Not invited]
  
• P-216 SYNTHESIS OF STELLETTADINE A BY NOVEL METHOD FOR THE SYNTHESIS OF N-ACYL-N'-SUBSTITUTED GUANIDINES

  Kozuma Hayato, Umezawa Taiki, Ando Takeshi, Shinada Tetsuro, Ohfune Yasufumi  International Symposium on the Chemistry of Natural Products  2006-  "P  -216"  2006/07/23  [Not refereed][Not invited]
  
• On the stereoselectivity of asymmetric strecker synthesis in a cyclohexane system: Synthesis of optically active cis- and trans-1-amino-2-hydroxycyclohexane-1-carboxylic acids

  Tetsuro Shinada, Tadashi Kawakami, Hiroshi Sakai, Hiromi Matsuda, Taiki Umezawa, Masaki Kawasaki, Kosuke Namba, Yasufumi Ohfune  BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN  79-  (5)  768  -774  2006/05  [Not refereed][Not invited]
   

  Stereoselective synthesis of both optically active cis- and trans-1-amino-2-hydroxycyclohexane-1-carboxylic acids (Ahhs) 1a and 1b was accomplished by an asymmetric version of the Strecker synthesis. Stereochemical aspects of their chiral induction processes are investigated.
• On the stereoselectivity of asymmetric strecker synthesis in a cyclohexane system: Synthesis of optically active cis- and trans-1-amino-2-hydroxycyclohexane-1-carboxylic acids

  Tetsuro Shinada, Tadashi Kawakami, Hiroshi Sakai, Hiromi Matsuda, Taiki Umezawa, Masaki Kawasaki, Kosuke Namba, Yasufumi Ohfune  BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN  79-  (5)  768  -774  2006/05  [Not refereed][Not invited]
   

  Stereoselective synthesis of both optically active cis- and trans-1-amino-2-hydroxycyclohexane-1-carboxylic acids (Ahhs) 1a and 1b was accomplished by an asymmetric version of the Strecker synthesis. Stereochemical aspects of their chiral induction processes are investigated.
• A new entry for the synthesis of N-acyl-N '-substituted guanidines

  T Shinada, T Umezawa, T Ando, H Kozuma, Y Ohfune  TETRAHEDRON LETTERS  47-  (12)  1945  -1947  2006/03  [Not refereed][Not invited]
   

  An efficient synthesis of N-acyl-N'-substituted guanidines by condensation reaction of thiourea and (Me3Si)(2)NH in the presence of EDCI is described. Various guanidines were synthesized in a simple manner. (c) 2006 Elsevier Ltd. All rights reserved.
• 14 Total Synthesis of 5,6,11-Trideoxytetrodotoxin

  Umezawa Taiki, Shinada Tetsuro, Ohfune Yasufumi  Symposium on the Chemistry of Natural Products, symposium papers  47-  (0)  77  -82  2005  [Not refereed][Not invited]
   

  Tetrodotoxin (TTX) is a toxic principle of puffer fish poisoning. TTX is a useful biological tool because of its specificity for blocking voltage-dependent sodium channels. 5,6,11-Trideoxy TTX (1), one of the congeners of TTX, has also been isolated from ovaries of puffers, Fugu poecilonotus, by Yasumoto et al. in 1995 and received significant interests in view of biosynthetic relationship with TTX. Synthetic studies of TTX and its congeners have been extensive due to their biological activities as well as their molecular complexity consisting of a quaternary carbon center attached to an amino group, concomitant polyol system, a cyclic guanidine containing an aminal, and an ortho acid for TTX or a δ-lactone for some of the congeners. In this report, we wish to describe the first total synthesis of 5,6,11-trideoxy TTX (1) and its 4-epimer 2. The synthesis was commenced with the known triol 7, prepared from (-)-quinic acid in 4 steps, which was converted to Strecker precursor 6 in 6 steps. 6 was subjected to an asymmetric transferring Strecker synthesis for the diastereoselective construction of a quaternary carbon center involving an amino group at C8a. Installation of a hydroxy group to C7 was accomplished by the Mislow-Evans rearrangement to give 20. Initial hydrogenation of 20 for the introduction of β-methyl group at C6 and subsequent pyrrolidine ring opening via lactam 24 gave alcohol 25. The hydroxyethyl group of 25 was transformed to a vinyl group in 3 steps to give 26. Inversion of the hydroxy group at C7 was performed by oxidation to a diketone followed by diastereoselective reduction to give cis-diol 4, This was converted to aldehyde 28, which, upon treatment with TMSCN in the presence of Et_3N, gave a cyanohydrin as an inseparable mixture of diastereomers. The mixture was guanidylated to give 29. Ozonolysis of the desired (9S)-29 followed by exposure to 20% TFA afforded a mixture of 5,6,11-trideoxyTTX (1), and its 4-epimer 2 and anhydro derivative 31. Thus, the total syntheses of 1 and 2 were accomplished.

Research Grants & Projects

• 環境にやさしい付着阻害剤の開発を指向した天然物誘導体合成と付着阻害メカニズム解明

  科研費：基盤研究（B)

  Date (from‐to) : 2018/04 -2022/03 

  Author : 梅澤 大樹
• Construction of active sites composed of multi-functional groups with precisely controlled distance by use of decomposition reaction

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2019/06 -2021/03 

  Author : Kamiya Yuichi

   

  Adjacent acid-base pair sites, which were consisted of carboxyl and amine groups, were constructed on silica surface by hydrolysis of an amide compound, which were anchored on the silica in advance. It was found that this catalyst showed extremely high catalytic activity for cross-aldol condensation of 4-nitrobenzaldehyde with acetone. The acid-base pair sites that were three methylene groups away from each other, which were constructed using an diamide compound that contains three methylene groups in the structure, showed less activity for the reaction that the catalyst with adjacent acid-base pair sites, demonstrating that the distance between acid and base functional groups was important factor for the reaction.
• Chemical Biology of Halogenated Antifouling Compounds

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2016/04 -2020/03 

  Author : Okino Tatsufumi

   

  Reaction condition of vanadium-dependent bromoperoxidase from the red alga Laurencia saitoi was optimized to propose its products by MS. Chlorinated compounds were isolated from marine cyanobacteria.
• 海洋生物の防御機能を模倣したバイオマス循環型船底付着阻害剤の合成的探索研究

  環境省：環境総合研究推進費

  Date (from‐to) : 2016/04 -2018/03 

  Author : 梅澤 大樹
• Biosynthetic enzymes of antifouling halogenated compounds

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2012/04 -2016/03 

  Author : Okino Tatsufumi, MATSUDA Fuyuhiko, UMEZAWA Taiki, NOGATA Yasuyuki, WASHIO Kenji

   

  Vanadium dependent bromoperoxidase (VBPO) was cloned from the red alga Laurencia nipponica which produces a halogenated compound, laurencin. The enzyme catalyzed cyclization and bromination of a precursor of laurencin. Bromination activity of recombinant enzyme was investigated. A similar type of VBPO was cloned from L. okamurae which produces a halogenated sesquiterpenoid, laurinterol. The recombinant enzyme showed bromination activity. In addition, another type of VBPO was cloned from L. saitoi which produces a halogenated triterpenoid. Its properties were investigated by using its recombinant protein. The structure of bromoallene containing C15 compound, omaezallene was reported. Its totaly syntehsis was successfully achieved.
• Synthetic study on fluorecent probe of antifouling natural products toward elucidation of molecular mechanism

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2015 -2016 

  Author : Umezawa Taiki

   

  This study aims syntheses of fluorescent probe of antifouling natural products. As lead compounds for antifouling materials, omaezallene (brominated compound) and dolastatin 16 (cyclic peptide) are selected becuase these exhibit strong antifouling activity along with very low toxicity toward cypris larvae of Amphibalanus amphitrite. Elucidation of molecular mechanism of antifouling activity expects the development of ideal antifouling material. Syntheses of omaezallene derivatives was achieved, which includes fluorescent derivative. A new synthetic pathway to dolastatin 16 and the antifouling activity of synthetic sample were revealed. Functionalization method toward fluorescent compound was also developed.
• Synthetic Study on Chlorosulfolipid toward elucidation of toxicity

  Ministry of Education, Culture, Sports, Science and Technology：Grants-in-Aid for Scientific Research(若手研究(B))

  Date (from‐to) : 2011 -2012 

  Author : Taiki UMEZAWA

   

  According to the plan, the synthesis of two fragments for the chlorosulfolipid and a coupling reaction conditions with the fragments were examined. As a results of the examinations, the efficient synthesis of one fragment was developed, and a new synthetic method for the synthesis of another fragment was established. The method is used for the synthesis of, -unsaturated ketone with aldehyde, trimethylsilylmethyl phosphonate, and acyl fluoride in one step, and published from a journal, Organic Letters. Synthesis of chlorosulfolipid is currently underway using the method.

Educational Activities

Teaching Experience