Takayuki Yakura

Ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes with amines: rapid access to 2-substituted 4-hydroxyindole.

An efficient ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes with primary amines has been developed. The reaction proceeded at room temperature without any additives to provide 2-substituted tetrahydroindol-4-ones in good to excellent yields without the formation of the 3-substituted isomers. The obtained product was readily converted into a 2-substituted 4-hydroxyindole derivative via a synthetically useful indoline intermediate.

STEREOSELECTIVE SYNTHESIS OF 5-SUBSTITUTED 2-ALLYL-3-OXOTETRAHYDROFURAN-2-CARBOXYLATES USING RHODIUM(II)-CATALYZED OXONIUM YLIDE FORMATION-12,3] SHIFT

- Reaction of 5-allyloxy-2-diazo-3-ketoesters 1 with catalytic amount of dirhodium(II) tetraacetate in dichloromethane proceeded in high yields with excellent stereoselectivities to give methyl 5-substituted 2-allyl-3-oxotetrahydrofuran-2-carboxylates 2, which are suitable intermediates for synthesis of heliespirones and their derivatives.

Involvement of c-Myc-mediated transient receptor potential melastatin 8 expression in oxaliplatin-induced cold allodynia in mice

BACKGROUNDnOxaliplatin, a platinum-based chemotherapeutic agent, induces acute cold allodynia and dysesthesia. Cold-sensitive transient receptor potential channels (TRPM8 and TRPA1) have been implicated as candidates to mediate oxaliplatin-induced cold allodynia and hyperalgesia, but precise roles of these channels remain unclear. In this study, we investigated the role of TRPM8 in oxaliplatin-induced cold allodynia.nnnMETHODSnOxaliplatin was injected intraperitoneally in mice. Cold allodynia was evaluated by the acetone test. Expression levels of TRPM8 mRNA and protein were measured using reverse transcription-polymerase chain reaction and Western blotting, respectively.nnnRESULTSnOxaliplatin-induced cold allodynia was alleviated by the TRPM8 blockers N-(2-aminoethyl)-N-[4-(benzyloxy)-3-methoxybenzyl]-N-(1S)-1-(phenyl) ethyl] urea and TC-I 2014. Oxaliplatin increased the expression levels of TRPM8 mRNA and protein in the dorsal root ganglia and plantar skin, respectively. Prophylactic administration of the c-Myc inhibitor 10058-F4 prevented cold allodynia and the increase of TRPM8 mRNA after oxaliplatin injection.nnnCONCLUSIONnThese results suggest that oxaliplatin induces cold allodynia through the increase of c-Myc-mediated TRPM8 expression in primary sensory neurons.

An Efficient Route to Highly Substituted Indoles via Tetrahydroindol-4(5H)-one Intermediates Produced by Ring-Opening Cyclization of Spirocyclopropanes with Amines

An efficient route to highly substituted indoles was developed. It included regioselective functionalization of tetrahydroindol-4(5H)-ones, prepared by ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes with primary amines, and subsequent oxidation. The 6-substituted indoles were synthesized from a readily available 5-substituted cyclohexane-1,3-dione-2-spirocyclopropane. The synthesis of 5- and 7-substituted indoles was achieved by regioselective electrophilic alkylation of tetrahydroindol-4(5H)-one, followed by oxidation. The 4-substituted indoles were synthesized by nucleophilic alkylation of the corresponding pyrrole derivative, which was prepared by partial oxidation of tetrahydroindol-4(5H)-one, and sequential oxidation. The synthesis of 4-substituted indoles was also accomplished by palladium-catalyzed coupling of 4-hydroxyindole-derived triflates. Furthermore, the synthesis of 4,5,6,7-tetrasubstituted indoles was achieved by using these regioselective alkylations.

Practical Synthesis of Pachastrissamine (Jaspine B), 2-epi-Pachastrissamine, and the 2-epi-Pyrrolidine Analogue

The practical syntheses of pachastrissamine (jaspine B), 2-epi-pachastrissamine, and the 2-epimer of the pyrrolidine analogue were accomplished via the stereoselective reduction of an allylketone derived from commercially available diethyl D-tartrate and the cross-metathesis of an allyltetrahydrofuran or allypyrrolidine with 1-tridecene as key steps.

Synthesis of 10b-fluorinated analogues of protubonine A and its 11a-epimer via fluorocyclisation of tryptophan-containing dipeptides

The synthesis of 10b-fluorinated analogues of protubonine A and its 11a-epimer was accomplished using fluorocyclisation of tryptophan-containing dipeptides with N-fluoro-2,4,6-trimethylpyridinium triflate to 3a-fluoropyrrolo[2,3-b]indoles as a key step. Acetylation of the indole nitrogen and the following diketopiperazine formation gave the 10b-fluorinated analogues of protubonine A and its 11a-epimer.

Total Synthesis of Sphingofungin E and 4,5-Di- epi -sphingofungin E

Total synthesis of sphingofungin E and 4,5-di-epi-sphingofungin E was achieved from an intermediate same as that of myriocin and mycestericin D via antipodal stereoselective dihydroxylations.

Synthetic Studies on a Pachastrissamine Sulfur Analogue: Synthesis of a 4-epi-Sulfur Analogue

A versatile synthetic procedure for a sulfur analogue of pachastrissamine (jaspine B), which involves the tandem thiolation-cyclization of a 1,4-ditosylate to construct a tetrahydrothiophene ring, was developed. Nucleophilic amino substitution of a tetrahydrothiophene-4-sulfonate with unexpected retention of the configuration afforded the sulfur analogue of 4-epi-pachastrissamine.

Dirhodium(II)-catalysed intramolecular carbon–hydrogen insertion reaction of α-diazo ketones: stereoselective synthesis of 2,3-cis-2-alkyl-5-oxo-3-silyloxycyclopentanecarboxylates

Methyl 5-(tert-butyldimethylsilyloxy)-2-diazo-3-oxoheptanoate 2a, upon treatment with 1 mol% of dirhodium(II) tetraacetate in dichloromethane under reflux, gives a mixture of methyl (1R*,2R*,3S*)-3-(tert-butyldimethylsilyloxy)-2-methyl-5-oxocyclopentanecarboxylate 3a and its (1S*,2S*,3S*) isomer 4a in a ratio of 79∶21 and 87% combined yield. Similarly, 5-(tert-butyldimethylsilyloxy)-2-diazo-3-oxoalkanoates 2c–g give 2,3-cis-2-alkyl- (or 2-phenyl)-3-(tert-butyldimethylsilyloxy)cyclopentanecarboxylates 3c–g as the major products. The presence of both the keto and ester groups in the precursors was found to be essential for this site- and stereo-selective C–H insertion to take place. A possible interpretation for the observed stereoselectivity is presented.

2-Iodo-N-isopropyl-5-methoxybenzamide as a highly reactive and environmentally benign catalyst for alcohol oxidation

Several N-isopropyliodobenzamides were evaluated as catalysts for the oxidation of benzhydrol to benzophenone in the presence of Oxone® (2KHSO5·KHSO4·K2SO4) as a co-oxidant at room temperature. A study on the substituent effect of the benzene ring of N-isopropyl-2-iodobenzamide on the oxidation revealed that its reactivity increased in the following order of substitution: 5-NO2 < 5-CO2Me, 3-OMe < 5-OAc < 5-Cl < H, 4-OMe < 5-Me < 5-OMe. The oxidation of various benzylic and aliphatic alcohols using a catalytic amount of the most reactive 5-methoxy derivative successfully resulted in moderate to excellent yields of the corresponding carbonyl compounds. The high reactivity of the 5-methoxy derivative at room temperature is a result of the rapid generation of the pentavalent species from the trivalent species during the reaction. 5-Methoxy-2-iodobenzamide would be an efficient and environmentally benign catalyst for the oxidation of alcohols, especially benzylic alcohols.