Taiki Umezawa

Chemical Synthesis of the GHIJKLMNO Ring System of Maitotoxin.

As the largest secondary metabolite to be discovered as of yet, the polyether marine neurotoxin maitotoxin 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 3 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).

Asymmetric total synthesis of danicalipin A and evaluation of biological activity.

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.

Omaezallene from Red Alga Laurencia sp.: Structure Elucidation, Total Synthesis, and Antifouling Activity

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 Laurencia sp. 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.

Synthesis and biological activity of kalkitoxin and its analogues.

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-kalkitoxin, were achieved via oxazolidinone-based diastereoselective 1,4-addition reaction of a methyl group and efficient TiCl(4)-mediated thiazoline ring formation as the key steps. The biological activities of synthetic kalkitoxin and its analogues were evaluated with brine shrimp.

Synthesis of the QRSTU Domain of Maitotoxin and Its 85-epi- and 86-epi-Diastereoisomers

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.

Novel One-pot Three-component Coupling Reaction with Trimethylsilylmethyl-phosphonate, Acyl Fluoride, and Aldehyde through the Horner–Wadsworth–Emmons Reaction

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-β-ketophosphonate generated in situ by desilylation at the α-position of the α-silyl-β-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.

Confirmation of the configuration of 10-isothiocyanato-4-cadinene diastereomers through synthesis.

The marine sponge metabolite 10-isothiocyanato-4-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.

Total synthesis of 10-isocyano-4-cadinene and its stereoisomers and evaluations of antifouling activities.

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.

cDNA cloning and characterization of vanadium-dependent bromoperoxidases from the red alga Laurencia nipponica

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 Km 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. Graphical Abstract Two recombinant proteins of vanadium-dependent bromperoxidases from the red alga Laurencia nipponica catalyzed bromination and cyclization of the TMS-capped biosynthetic precursor of deacetyllaurencin.

Columbamides D and E: Chlorinated Fatty Acid Amides from the Marine Cyanobacterium Moorea bouillonii Collected in Malaysia

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 Marfeys analysis.