Mikio Takeda

Highly enantioselective reduction of Meso-1,2-dicarboxylic anhydrides

Abstract Optically active lactones ( 2a–2g ) were synthesized by highly enantioselective reduction of readily available meso -1,2-dicarboxylic anhydrides ( 1a–1g ) using lithium aluminum hydride-ethanol-1,1′-bi-2-naphthol complex (BINAL-H).

Reaction of 3-phenylglycidic esters. Part 1. Stereoselective opening of the oxirane ring of trans-3-phenylglycidic esters with 2-nitrothiophenols and the effect of various catalysts thereon

In the reaction of 2-nitrothiophenol (2) with trans-3-phenylglycidic esters carrying various substituents on the benzene ring, both reactivity and stereoselectivity of the oxirane ring-opening of the glycidates were markedly influenced by the electronic nature of the substituents. The presence of electron-donating groups was favourable for both reactivity and the preferential formation of cis-opening products, while the reverse was true for electron-withdrawing groups. As a result of our investigation on the catalytic effect of various Lewis acids in the reaction of the 4-methoxy derivative (1) with (2), tin compounds were found to be effective catalysts for cis-opening and readily produced the threo-nitro ester (3a), a key intermediate for the synthesis of diltiazem (5).Isolation of the crystalline complex (adduct A) from the reaction of (2) with SnCl4 and its efficient catalytic activity similar to that of SnCl4 suggest that the transition state involves co-ordination of tin derivatives both with (2) and the epoxy oxygen of (1) to cause highly specific cis-opening.

Asymmetric reduction of cyclic imines with chiral sodium acyloxyborohydrides

Asymmetric reduction of prochiral cyclic imines with chiral sodium acyloxyborohydrides (5a–i), which are easily prepared by the reaction of NaBH4 with various N-acyl α-amino-acids, has been investigated. Of these new reducing agents, triacyloxyborohydrides (5c–f), derived from NaBH4(1 equiv.) and (S)-N-acylproline (3 equiv.), were found to reduce 3,4-dihydropapaverine (2) in tetrahydrofuran to (S)-norlaudanosine (3) hydrochloride in 60% optical yield. The N-benzyloxycarbonyl derivative (5c) could be isolated as a powder and characterized. The effect of solvents on this asymmetric reduction has been examined by the use of the isolated reagent (5c); halogenated alkane solvents such as CH2Cl2 or CHCl2CH3 gave a better optical yield of compound (3)(70% e.e.). The reagent (5c) also reduced other cyclic imines (6a–c) and (8) to the corresponding alkaloids (7a–c) and (9) in excellent optical yields (70–86% e.e.), providing an effective route to the asymmetric synthesis of these alkaloids. A possible reaction path for this reduction is also presented.

Reaction of 3-phenylglycidic esters. Part 2. Stereo- and regio-selectivity in the oxirane ring opening of methyl trans-3-(4-methoxyphenyl)glycidate with various thiophenols and the effects of solvent and temperature

The effects of the solvent and temperature on the reaction of the trans-glycidate (1) with various substituted thiophenols (2) in the presence or absence of a catalyst have been investigated. The temperature had a surprisingly large effect on the stereochemistry of the oxirane ring-opening of (1). At room temperature, the erythro-isomer (4)(trans-opening product) was obtained as a major product in the absence of catalyst, while the cis-opening product (3)(threo-isomer) was produced predominantly at higher temperature. On the other hand, in a dipolar aprotic solvent, the regioisomer (5) was formed, the yield increasing with the electron-donating ability of the substituents on (2). The formation of compound (5) may involve single-electron transfer as a key step.

A New Class of Nitrosoureas. VI. Synthesis and Antitumor Activity of 3-Substituted-1-(2-chloroethyl)-3-(methyl-α-D-glucopyranosid-2-yl)-1-nitrosoureas

A series of five 3, 3-disubstituted nitrosoureas having the nitrosoureido group at the C-3 position of methyl glucoside were prepared and tested for antitumor activities. Heating of methyl 2, 3-anhydro-α-D-allopyranoside (I) with various alkylamines followed by reaction with 2-chloroethyl isocyanate gave two regioisomers (II and III). The major product (II) and the minor product (III) were determined to be the ureido derivatives of methyl glucoside and methyl altroside, respectively. Nitrosation of II with dinitrogen tetroxide gave 3-substituted 1-(2-chloroethyl)-3-(methyl α-D-glucopyranosid-3-yl)-1-nitrosoureas (VI) in good yields. All the nitrosoureas obtained were remarkably active against leukemia L-1210 and Ehrlich ascites carcinoma. The structure-activity relationships of positional isomers with respect to the nitrosoureido group are discussed.