Kimio Higashiyama

Stereocontrol at the quaternary center in 1-substituted 1-phenyl-2,2,2-trifluoroethylamines: stereospecific substitution with retention of a chiral cyclic fluoral N,O-acetal with organolithium reagents

Abstract The asymmetric synthesis of 1-substituted 1-phenyl-2,2,2-trifluoroethylamines from chiral 1,3-oxazolidines is described. The stereospecific substitution reaction with organolithium reagents of chiral 1,3-oxazolidines having a trifluoromethyl group proceeds with retention to control the newly created quaternary center.

Diastereoselective addition of organometallic reagents to chiral imines and 1,3-oxazolidines

Abstract The reaction of MeLi or MeMgBr with chiral aromatic imines and 2-aryl-1,3-oxazolidines derived from (R)-phenylglycinol afforded with good diastereoselectivity (R,R,) -amines from imines, but the (R,S) -amines from 1,3-oxazolidines, respectively.

Promoting effect of O-ethylmenthol on the percutaneous absorption of ketoprofen

The promoting effect of O-ethylmenthol (MET) on the percutaneous absorption of ketoprofen from alcoholic hydrogels was evaluated in rats in vitro and in vivo. Further, the anti-inflammatory action of ketoprofen hydrogels was evaluated with a rat paw edema test. The time course of the cumulative amounts of drug permeated through the rat skin in vitro exhibited a linear relation after an initial time lag. This was analyzed in a membrane diffusion model and the diffusion and partition parameters of ketoprofen were estimated. Both parameters were remarkably enhanced when a hydrogel containing a small quantity of MET (0.5%) was applied. However, at least 2% menthol was required to obtain the same activity as 0.25% MET. A pharmacokinetic model, which was derived on the assumption of a constant penetration rate (Rp) after a lag time, was employed to evaluate in vivo percutaneous absorption of ketoprofen from hydrogels containing MET. Further, the area under the plasma concentration-time curve (AUC0–8 h) was estimated. Similarly to the results observed in vitro, Rp and AUC0–8 h values were increased significantly by the administration of hydrogels containing a small amount of MET (0.25–0.5%). In order to obtain the significant inhibitory action of ketoprofen on the rat paw edema induced by carrageenan, at least 1% menthol was required in the hydrogel formulation. On the other hand, a small amount of MET (0.25–0.5%) was enough to bring about significant inhibitory action of ketoprofen. Distinguishable changes of the skin surface were microscopically observed with 0.5–2% MET, i.e. the spaces between the stratum corneum cells became extended and the shape of each cell became clear, whereas the morphological changes caused by menthol were relatively weak. Both MET and menthol may change the dense barrier structure of the stratum corneum of skin; however, the efficiency of MET is significantly greater than that of menthol.

Diastereoselective addition of chiral imines and 1,3-oxazolidines with Grignard reagents; Asymmetric synthesis of (R)-2-aryl- and (R,R)-2,5-bis(aryl)pyrrolidines

Abstract Asymmetric syntheses of (R)-2-aryl- and (R,R)-2,5-bis(aryl)pyrrolidines were described starting from chiral aromatic imines derived from (R)-phenylglycinol, in which the diastereoselective additions of Grignard reagents to the chiral imines and 1,3-oxazolidines were used as the key reaction step.

Stereocontrolled preparation of cis- and rans-2,6-dialkylpiperidines via diastereoselective reaction of 1-aza-4-oxabicyclo[4.3.0]nonane derivatives with Grignard reagents

Abstract We report here the syntheses of cis - and trans -2,6-disubstituted piperidines using chiral 1-aza-4-oxabicyclo[4.3.0]nonane synthon 1 , which shows high reactivity toward nucleophilic attack at its C-5 position. Bicyclic compounds resembling synthon 1 were transformed to cis - and trans -2,6-disubstituted piperidine derivatives via reactions with various Grignard reagents in a stereospecific manner. Using this methodology, (+)-solenopsin A ( 2b ) and both enantiomers of isosolenopsin A ( 3a and 3b ) were synthesized in an enantioselective manner from a single enantiomeric source.

Isokuraramine and (−)-7,11-dehydromatrine, lupin alkaloids from flowers of Sophora flavescens

Abstract Two new lupin alkaloids, isokuraramine and (−)-7, 11-dihydromatrine, were isolated from the fresh flowers of Sophora flavescens along with 16 kno

Antinociceptive effects of (+)-matrine in mice

The antinociceptive potency of matridin-15-one ((+)-matrine) was examined using the acetic acid-induced abdominal contraction test and the tail-flick test in mice. (+)-Matrine, at doses of 1 to 10 mg/kg, s.c., produced a marked and dose-dependent inhibition of the number of acetic acid-induced abdominal contractions in mice. The antinociceptive effect of (+)-matrine in the acetic acid-induced abdominal contraction test in mice was identical to that of pentazocine. Indeed, there was no significant difference in the ED50 (mg/kg with 95% confidence limits) values for the inhibition of acetic acid-induced abdominal contractions between (+)-matrine (4.7 (4.1-5.3)) and pentazocine (3.3 (2.2-5.0)). Furthermore, in the tail-flick assay, (+)-matrine at doses of 10 and 30 mg/kg, s.c., again produced a dose-dependent antinociceptive effect. When nor-binaltorphimine (20 mg/kg, s.c.), a selective kappa-opioid receptor antagonist, was administered 3 h before treatment with (+)-matrine, the antinociceptive effect of (+)-matrine was markedly antagonized. Furthermore, the antinociceptive effect of (+)-matrine was partially antagonized by pretreatment with beta-funaltrexamine, a selective mu-opioid receptor antagonist. Naltrindole, a selective delta-opioid receptor antagonist, had no effect on the antinociceptive effect of (+)-matrine. In conclusion, (+)-matrine produced an antinociceptive effect mainly through the activation of kappa-opioid receptors and partially through mu-opioid receptors.

(−)-Epilamprolobine and its N-oxide, lupin alkaloids from Sophora tomentosa☆

Abstract From the fresh leaves of Sophora tomentosa , three new lupin alkaloids, (−)-epilamprolobine, (+)-epilamprolobine N -oxide and 5-(3′-methoxycarbonylbutyroyl)aminomethyl- trans -quinolizidine N -oxide, have further been isolated along with (+)-matrine, (+)-matrine N -oxide, (+)-sophocarpine N -oxide, (−)-anagyrine, (−)- baptifoline, (−)-cytisine, (−)- N -methylcytisine, (−)- N -formylcytisine, (−)- N -acetylcytisine and (±)-ammodendrine. The absolute configurations of (+)-epilamprolobine N -oxide (1 R :5 R :6 S ) and (−)-epilamprolobine (5 R :6 S ) have also been established by spectroscopic data and by comparison with synthetic (+)-epilamprolobine (5 S :6 R )derived from (−)-lupinine (5 R :6 R ). (−)-Epilamprolobine is a diastereomer of (+)-lamprolobine (5 R :6 R ) in Lamprolobium fruticosum and 5-(3′-methoxycarbonylbutyroyl) aminomethyl- trans -quinolizidine N -oxide is presumed to be an artefact. A biosynthetic pathway for the formation of (−)-epilamprolobine is also proposed.

(+)-Kuraramine, a possible metabolite of (−)-N-methylcytisine in flowers of Sophora flavescens

Abstract From the flowers of Sophora flavescens , a new dipiperidine-type alkaloid, (+)-kuraramine, has been isolated together with (+ )-mamanine and the oth

Asymmetric synthesis of piperidine alkaloids utilizing diastereoselective reaction of 1,3-oxazolidine with Grignard reagents

A facile method of synthesizing enantiomerically pure piperidine alkaloids, (R)-(−)-coniine and (2R,6S)-(−)-dihydropinidine, has been explored by employing the highly diastereoselective reaction of a 1,3-oxazolidine with Grignard reagents