Jun Shimokawa

Total synthesis of gelsemoxonine.

The first total synthesis of gelsemoxonine (1) has been accomplished. Divinylcyclopropane-cycloheptadiene rearrangement of the highly functionalized substrate was successfully applied to assemble the spiro-quaternary carbon center connected to the bicyclic seven-membered core structure. A one-pot isomerization reaction of the α,β-unsaturated aldehyde to the saturated ester via the TMSCN-DBU reagent combination allowed a facile diastereoselective introduction of the latent nitrogen functionality of the unique azetidine moiety.

Total synthesis of tryprostatins A and B.

Multiple-drug resistance toward cell-cycle inhibitors frequently becomes an obstacle in cancer chemotherapy. One strategy for circumventing this problem is to develop antimitotic agents that operate by a new mode of action. Two such compounds, tryprostatins A and B, were isolated in 1995 from the fermentation broth of Aspergillus fumigatus BM939 by Osada and co-workers. Tryprostatin A holds great promise, because it selectively arrests the cell cycle at the mitotic phase in tsFT210 cells. Interesting biological activity combined with an apparently simple structure has stimulated the synthetic community, and several total syntheses have already been reported. 4] Our research group has long been involved with the radical-mediated construction of a variety of indole cores and the application of these methods to natural product synthesis. We envisioned that our method could also be applied to the synthesis of the 2,3-disubstituted indole moiety of the tryprostatins. The interesting structural features as well as the therapeutic potential of tryprostatin A analogues indicated in a recent structure–activity-relationship study prompted us to launch a program toward the synthesis of tryprostatins. We reasoned that radical-mediated cyclization and subsequent palladium-mediated coupling with a prenyl-group donor would enable facile construction of the 2,3-disubstituted indole core structure 3 (Scheme 1). The requisite orthoalkenyl isocyanide 4 would be prepared from the alkyne 5, which in turn could be accessed by Sonogashira coupling of the aromatic iodide 6 with the terminal alkyne 7. To enable synthesis of the target compounds with high enantiomeric purity, the alkyne 7 derived from the Garner aldehyde (8) was employed as a latent amino acid unit to be incorporated into the diketopiperazine. Initially, we focused our efforts on the synthesis of the isocyanide 12 as a radical-cyclization precursor (Scheme 2). The alkyne 7 was prepared from 8 according to the known protocol with a slight modification. After the Sonogashira coupling between 7 and 2-iodoformanilide (9), partial reduction of the triple bond was examined. Whereas the use of the Lindlar catalyst, Pd/C, nickel boride, or diimide resulted in no reaction or overreduction, treatment with Zn/LiCuBr2 in ethanol gave the desired product 11 along with the corresponding amine. The use of 2,2,2-trifluoroethanol as the solvent suppressed the undesired solvolysis and improved the yield of 11 to 99 %. Subsequent dehydration with bis(trichloromethyl) carbonate (triphosgene) gave the ortho-alkenyl isocyanide 12 and thus set the stage for a radical-mediated cyclization. When isocyanide 12 thus obtained was subjected to our previously established radical-cyclization conditions, the desired 5-exo adduct 13 was obtained in moderate yield after acidic treatment with silica gel along with a considerable amount of products 14 and 15 of a 6-endo cyclization– cleavage process (Scheme 3). We were aware of the tendency of this imidoyl-radical cyclization to give a mixture of the 5-exo and 6-endo products if the intermediate radical of the Scheme 1. Retrosynthetic analysis. Boc = tert-butoxycarbonyl.

O-TBS-N-tosylhydroxylamine: A Reagent for Facile Conversion of Alcohols to Oximes

A variety of oximes were synthesized from the corresponding alcohols, alkyl halides, or alkyl sulfonates without using external oxidants. With this simple two-step procedure involving substitution with readily available TsNHOTBS and subsequent treatment with CsF, a range of oximes were prepared including the ones hardly preparable with conventional procedures.

Experimental evaluation of the pathogenicity of Perkinsus olseni in juvenile Manila clams Ruditapes philippinarum.

We evaluated the pathogenicity of Perkinsus olseni towards the Manila clam, Ruditapes philippinarum, by an experimental challenge. For production of prezoosporangia of P. olseni, we injected uninfected Manila clams with cells of a pure strain of P. olseni and reared them for 7d. Prezoosporangia were isolated from the soft tissue of the injected clams after culturing in Rays fluid thioglycollate medium. Hatchery-reared, uninfected juvenile clams (3-10 mm shell length) were challenged by immersion in one of two concentrations of a prezoosporangial suspension of P. olseni for 6d. The challenged clams had significantly higher mortality at both the concentrations than the unchallenged clams. The mortality due to infection dose-dependently began approximately 4 weeks and 7 weeks after challenge in the higher and lower concentrations, respectively. This is the first experimental evidence that P. olseni causes direct mortality in Manila clams. The lethal level of infection was estimated at approximately 10⁷ pathogen cells/g soft tissue weight.

Experimental challenges of wild Manila clams with Perkinsus species isolated from naturally infected wild Manila clams

Manila clams, Ruditapes philippinarum, are widely harvested in the coastal waters in Japan. However, there have been significant decreases in the populations of Manila clams since the 1980s. It is thought that infection with the protozoan Perkinsus species has contributed to these decreases. A previous study demonstrated that high infection levels of a pure strain of Perkinsus olseni (ATCC PRA-181) were lethal to hatchery-raised small Manila clams, however, the pathogenicity of wild strain Perkinsus species to wild Manila clam is unclear. To address this, we challenged large (30-40 mm in shell length) and small (3-15 mm in shell length) wild Manila clams with Perkinsus species isolated from naturally infected wild Manila clams. We report high mortalities among the small clams, but not among the large ones. This is the first report to confirm the pathogenicity of wild isolate of Perkinsus species to wild Manila clams.

Synthesis of the Common Core Structure of the Stemofoline Alkaloids

A novel synthetic route to the common core structural motif of the stemofoline alkaloids has been developed. The key transformations include (1) an intramolecular 1,3-dipolar cycloaddition reaction of a highly functionalized nitrone, (2) the subsequent formation of a caged structure via lithiated allylic sulfoxide, and (3) the concomitant sila-Pummerer reaction of α-silylalkenyl sulfoxide to prepare a thioester precursor. A series of stereochemistries on the highly caged core structure characteristic of the stemofoline alkaloids was successfully assembled.

Stereoselective synthesis of spirotryprostatin A

The asymmetric synthesis of spirotryprostatin A was achieved by employing an intramolecular Heck reaction to introduce the quaternary spiro center. The stereochemistry of the reaction was controlled by a tethering system, which was selectively introduced by taking advantage of the unique and as yet mysterious characteristics of the cyclo-(Pro–Pro) diketopiperazine moiety.

Development of a Divergent Synthetic Route to the Erythrina Alkaloids: Asymmetric Syntheses of 8-Oxo-erythrinine, Crystamidine, 8-Oxo-erythraline, and Erythraline.

A general synthetic methodology toward the erythrina alkaloids has been developed. Inspired by a proposed biosynthetic mechanism, the medium-sized chiral biaryl lactam was asymmetrically transformed into the common core A-D rings by a stereospecific singlet oxygen oxidation of the phenol moiety, followed by a transannular aza-Michael reaction to the dienone functionality. The late-stage manipulation of the oxidation and oxygenation states of the functional groups on the peripheral moieties enabled the flexible syntheses of the erythrina alkaloids.

TMSCN/DBU-mediated facile redox transformation of α,β-unsaturated aldehydes to carboxylic acid derivatives.

Redox transformation of an α,β-unsaturated aldehyde to a carboxylic acid derivative by means of a combination of TMSCN and DBU was investigated. In addition to the wide use of the carboxylic acid derivatives provided by this reaction, temperature-dependent control of the kinetic or thermodynamic protonation pattern was found to selectively switch the stereochemistry of the acyl group in the product.

Unified Total Synthesis of Five Gelsedine-Type Alkaloids: (−)-Gelsenicine, (−)-Gelsedine, (−)-Gelsedilam, (−)-14-Hydroxygelsenicine, and (−)-14,15-Dihydroxygelsenicine

The systematic arrangement of a two-carbon unit, hydrogen atom, and oxygen atom on the versatile enal moiety of a non-natural synthetic intermediate successfully led to the unified access to the gelsedine-type alkaloids. The development and use of this new synthetic hub and an array of site-selective transformations resulted in the asymmetric synthesis of (-)-gelsenicine, (-)-gelsedine, (-)-gelsedilam, (-)-14-hydroxygelsenicine, and (-)-14,15-dihydroxygelsenicine.