Synthesis of Rings DEF of Solanoeclepin A.

An improved synthesis of rings DEF of solanoeclepin A has been achieved from ent-Hajos Parrish ketone. A key tricyclo[5.3.2.01,6]decene intermediate having an additional vinyl group as a precursor of a hydroxyl functionality was synthesized, in which the key steps included (i) a [2,3]-Wittig rearrangement to provide trans-hydroindene with C11(R)-configuration, (ii) the introduction of a vinyl group as a masked OH at C6, (iii) an oxymercurative aldol to synthesize the tricyclo[5.3.2.01,6]decene moiety, (iv) an oxidative C-C bond cleavage to yield an aldehyde and an unsaturated methyl ketone, and (v) a radical cyclization for the cyclobutane ring formation to provide the tricyclo[5.2.1.01,6]decene compound.

Photochemically Induced Aryl Azide Rearrangement: Solution NMR Spectroscopic Identification of the Rearrangement Product.

Photolysis of ethyl 3-azido-4,6-difluorobenzoate at room temperature in the presence of oxygen results in the regioselective formation of ethyl 5,7-difluoro-4-azaspiro[2.4]hepta-1,4,6-triene-1-carboxylate, presumably via the corresponding ketenimine intermediate which undergoes a photochemical four-electron electrocyclization followed by a rearrangement. The photorearrangement product was identified by multinuclear solution NMR spectroscopic techniques supported by DFT calculations.

Multicomponent Strategy for the Synthesis of Prostaglandin E2 Methyl Ester under Anion Relay Chelation Control.

Starting with four components, the enantioselective synthesis of prostaglandin E2 methyl ester has been achieved through a highly stereoselective heteroatom-directed conjugate addition reaction and cyclopentanone ring cyclization as the key steps. This asymmetric strategy includes (i) an asymmetric Reformatsky reaction; (ii) conjugate addition of a chiral vinyllithium reagent; (iii) cyclization to form a sulfonylated cyclopentanone in one-pot; followed by (iv) allylation of the side chain. Four carbon-carbon bond-forming processes and three stereogenic centers were established, with the steps from (ii) to (iii) being achieved in a one-pot process.

Stereochemical Course of Wittig Rearrangements of Dihydropyran Allyl Propargyl Ethers.

[2,3]-Wittig rearrangements of sugar-derived dihydropyran allyl propargyl ethers located at the 2- or 4-position have been studied as useful means for extending the carbon chains of the 4- or 2-position with chirality transfer. The stereochemical course of these reactions depends on the following factors: (1) deprotonation of pro-R or pro-S-H, (2) equilibration of the lithiated stereogenic carbanion, (3) conformational inversion during the rearrangement, and (4) concerted [2,3]- or [1,2]-Wittig rearrangement. In some cases, a stepwise mechanism that involves the allyl-C-O bond cleavage is shared as the first step by both the [2,3]- and [1,2]-Wittig rearrangements. The stereochemical courses of the rearrangements are compared among the lithiated reactants to determine the reaction pathways. These mechanisms in the polyoxygenated dihydropyran ring system were further supported by DFT calculations.

Asymmetric synthesis of 3-azide-4-fluoro-l-phenylalanine.

The asymmetric synthesis of N-Fmoc-protected 3-azide-4-fluoro-l-phenylalanine as a photoactive phenylalanine analog has been achieved by Schöllkopf's alkylation.

Novel synthesis of the ABC rings of solanoeclepin A.

A stereocontrolled synthesis of the ABC rings of solanoeclepin A has been achieved. The seven-membered ring B was synthesized by an intramolecular Prins-ene reaction between an aldehyde and an enyne-dicobalthexacarbonyl complex. The acetylene in this synthesis plays multiple roles: to join the A and C rings, to allow stereoselective cyclization via dicobalthexacarbonyl complexation, and to facilitate Nicholas cation stabilization followed by deprotonation to form an endo-cyclic olefin (Nicholas-Prins cyclization).

Novel synthesis of right segment of solanoeclepin A.

The highly strained tricyclo[5.2.1.0(1,6)]decene skeleton of solanoeclepin A was synthesized through two key C-C bond forming processes; thus, a Hg(TFA)2-mediated oxymercuration followed an intramolecular aldol reaction to B and a SmI2-mediated cyclization of C between an aldehyde and an unsaturated ester to form the cyclobutane D having a tricyclo[5.2.1.0(1,6)]dodecene.

Molecular mechanism of Symplectoteuthis bioluminescence--part 4: chromophore exchange and oxidation of the cysteine residue.

Symplectin is one of the few photoproteins, which forms covalent bonds with the dehydro-coelenterazine (DCL) at the binding sites and the active site. This binding takes place through the SH's of the cysteine residues via conjugate addition reaction. This photoprotein contains the chromophore molecules at the binding cites first, and then moves to the active cite Cys-390 for the luminescence. The current study focuses on these dynamic aspects of the chromophore using the natural photoprotein by analyzing the fluorescence changing of the DCL chromophores analogs with 8-(4'-methoxyphenyl)- or 8-(2'-naphthyl)-group and 2-(2',4'-difluorophenyl)-group. Exchanges of these chromophores were monitored the fluorescence at slightly acidic media and also from the luminescence function observed at the optimum pH 7.8. The non-fluorescent naphthyl analogs was even proven to make the covalent bond formation at pH 6.0 and evidently to obtain the corresponding luminescent product amide by liquid chromatographic detection from the spent solutions.

Synthesis of 5- and 8-deoxytetrodotoxin.

Tetrodotoxin, a toxic principle of puffer fish intoxication, is one of the most famous marine natural products owing to its complex structure and potent biological activity, which leads to fatal poisoning. Continuous synthetic studies on tetrodotoxin and its analogues to elucidate biologically interesting issues associated with tetrodotoxin have led to the development of versatile routes for a variety of tetrodotoxin derivatives. With the aim of investigating the structure-activity relationship of tetrodotoxin with voltage-gated sodium channels, this study describes the first total syntheses of 5-deoxytetrodotoxin, a natural analogue of tetrodotoxin, and 8-deoxytetrodotoxin, an unnatural analogue, from a newly designed, versatile intermediate in an efficient manner. An estimation of the biological activities of these compounds reveals the importance of the hydroxy groups at the C-5 and C-8 positions on the inhibition of voltage-gated sodium channels.

Total synthesis of chiriquitoxin, an analogue of tetrodotoxin isolated from the skin of a dart frog.

The first total synthesis of chiriquitoxin, the most structurally complex analogue of tetrodotoxin isolated from a Costa Rican dart frog, has been accomplished from a newly designed intermediate for a variety of tetrodotoxin derivatives. The synthesis includes the third total synthesis of tetrodotoxin in this laboratory, and its intermediate was transformed into chiriquitoxin by a stereocontrolled aldol reaction with a D-camphor-derived lactone for installation of the unique side chain, and a new deprotection of methylthiomethyl (MTM) ether by using a Pummerer rearrangement.

First identification of 5,11-dideoxytetrodotoxin in marine animals, and characterization of major fragment ions of tetrodotoxin and its analogs by high resolution ESI-MS/MS.

Even though tetrodotoxin (TTX) is a widespread toxin in marine and terrestrial organisms, very little is known about the biosynthetic pathway used to produce it. By describing chemical structures of natural analogs of TTX, we can start to identify some of the precursors that might be important for TTX biosynthesis. In the present study, an analog of TTX, 5,11-dideoxyTTX, was identified for the first time in natural sources, the ovary of the pufferfish and the pharynx of a flatworm (planocerid sp. 1), by comparison with totally synthesized (-)-5,11-dideoxyTTX, using high resolution ESI-LC-MS. Based on the presence of 5,11-dideoxyTTX together with a series of known deoxy analogs, 5,6, 11-trideoxyTTX, 6,11-dideoxyTTX, 11-deoxyTTX, and 5-deoxyTTX, in these animals, we predicted two routes of stepwise oxidation pathways in the late stages of biosynthesis of TTX. Furthermore, high resolution masses of the major fragment ions of TTX, 6,11-dideoxyTTX, and 5,6,11-trideoxyTTX were also measured, and their molecular formulas and structures were predicted to compare them with each other. Although both TTX and 5,6,11-trideoxyTTX give major fragment ions that are very close, m/z 162.0660 and 162.1020, respectively, they are distinguishable and predicted to be different molecular formulas. These data will be useful for identification of TTXs using high resolution LC-MS/MS.

Synthesis of tetrodotoxin, a classic but still fascinating natural product.

Tetrodotoxin, a toxic principle of puffer fish intoxication, is one of the most famous marine natural products due to its densely functionalized structure and potent toxicity. Despite its small molecular size (MW 319 g mol⁻¹), tetrodotoxin has long been well known as a formidable molecule in natural product synthesis. We have devoted more than twenty years to developing synthetic strategies for this molecule, resulting in the preparation of a variety of analogues of tetrodotoxin for biological experiments. This account describes a brief history of tetrodotoxin research and an overview of our synthetic efforts toward tetrodotoxin with the underlying logic and strategy.

Stereocontrolled total synthesis of polygalolide†A.

The total synthesis of polygalolide A, a secondary metabolite that was isolated from a Chinese medicinal plant, is reported. A key issue in this synthesis was construction of an oxabicyclo[3.2.1] skeleton, which was solved by the development of an intramolecular Ferrier-type C-glycosylation of a glucal with siloxyfuran as an internal nucleophile. The substrate was prepared from D-glucal by the introduction of trimethylsilylacetylene and siloxyfuran groups. Although C-glycosylation did not occur under the conditions found from model experiments, further examination revealed that the combination of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2,4,6-collidine successfully afforded the desired product as a single diastereomer. The siloxy group at the C3 position played a crucial role in the stereocontrol of this reaction. The product was further transformed into a tetracyclic compound as follows: The vinyl ether and acetylenic moieties were reduced and the siloxy group was removed with a Barton-McCombie reaction. The construction of the six-membered ether and the γ-lactone provided the tetracyclic compound. Finally, a phenolic moiety was introduced by using a Mukaiyama aldol reaction to furnish polygalolide A.

An improved synthesis of (-)-5,11-dideoxytetrodotoxin.

We describe an improved synthesis of (-)-5,11-dideoxytetrodotoxin from an enone, which was used for synthesis of tetrodotoxin and its analogues in this laboratory. One of the major modifications was to establish a two-step guanidinylation of trichloroacetamide of a highly functionalized intermediate, which allowed us to prepare (15)N(2)-labeled 5,11-dideoxytetrodotoxin for biosynthetic investigations.

Cobalt-mediated synthesis of the tricyclo[5.2.1.0(1,6)]decene framework in solanoeclepin A.

The stereocontrolled synthesis of the highly strained, tricyclo[5.2.1.0(1,6)]decene skeleton (C) of solanoeclepin A has been achieved through two key transformations: a [2,3]-Wittig rearrangement of allylpropargyl ether (A) to propargyl alcohol (B) having a trans-fused perhydroindane framework and the formation of the cyclobutane via a cobalt-mediated Hosomi-Sakurai type cyclization of an acetylene dicobalthexacarbonyl complex.

Total synthesis of polygalolide A.

The total synthesis of polygalolide A was accomplished through intramolecular C-glycosylation of glucal modified with siloxyfuran. The siloxyfuran group and siloxy substituent at the C-3 position played crucial roles in allowing direct access to the highly substituted oxabicyclo[3.2.1] core skeleton with correct quaternary stereogenic centers.

Dynamic chirality determines critical roles for bioluminescence in symplectin-dehydrocoelenterazine system.

Symplectin is a photoprotein containing the dehydrocoelenterazine (DCL) chromophore, which links to a cysteine residue through a covalent bond with the emission of blue light. This study focuses on the stereochemical process of the emerging stereogenic centers. Two isomeric fluorinated DCL analogs (2,4-diF- and 2,6-diF-DCL) were employed owing to their different bioluminescence activities, these being 200% and 20% compared to natural DCL, respectively. Each of these diF-DCLs was found to exchange with the natural DCL in symplectin at pH 6.0. The emerging stereogenic carbons were racemic at the binding sites. Changing the pH of this storage form to the protein's optimum solubility pH (pH 7.8) resulted in 2,4-diF-DCL-bound symplectin luminescence, and the spent solutions were then analyzed and coelenteramide-390-CGLK-peptide and coelenteramine were detected after a peptidase digestion. The same analysis of the 2,6-diF-DCL-bound symplectin, on the other hand, afforded coelenteramine only but no coelenteramide. When the racemic storage diF-DCLs moved to the active site at pH 7.8, a change in the chirality with the 390-Cys residue resulted. Model experiments using L-cysteine-containing CGLK-peptide supported two diastereoisomers from each diF-DCL. The significant difference in the luminescence from these two chromophores is attributed to a plausible mechanism including the dynamically variable stereogenic center emerging at the storage and then the active site on the symplectin. It is concluded that such dynamic chirality plays a significant role in the symplectoteuthis bioluminescence.

Chiral cyclobutane synthesis by exploiting a heteroatom-directed conjugate addition.

The syntheses of both enantiomers of cyclobutanes B and ent-B are achieved through heteroatom-directed conjugate addition (HADCA) of nucleophiles to the epoxyvinylsulfone-substituted carbohydrates A and ent-A, which provided carbanions that intramolecularly attacked the epoxide with concomitant formation of the cyclobutane ring.