The conversion of syn-(methy1,hydro)bimane (1) to products was between 50% and loo%, based on the recovery of 1. The yields of 2 were between 25% and 30%, of 3 between a trace and 5%, and of 4 from 50% to 60%.Kinetic Measurements. syn-(CH,,F)B (2) was dissolved in CH3CN. An aliquot (100 pL) was added rapidly to aqueous buffer, pH 10.2, maintained at 50.0 "C in a thermostated quartz cell located in the cell compartment of a Cary 17 spectrophotometer. The decrease of absorption at 360 nm was followed with time for more than 10 half-lives. The second-order rate constant for the reaction of the bimane with hydroxide ion was obtained from the experimental curve from the slope of the plot of log (Dt -Dinf) vs. time and dividing by the temperature corrected hydroxide ion concentration.Regeneration of 2 from the Pyrazolinoylacrylic Acid. A mixture of the acid (obtained from base-catalyzed ring opening of syn-(CH,,F)B and acidification) (1 mg) and thionyl chloride (10 rL) was stirred for 24 h. After removal of thionyl chloride under vacuum, the residue was shown to be identical with authentic syn-(CH,,F)B (2) in absorption maximum (340 nm; dioxane), emission maximum (433 nm; dioxane), and thin-layer chromatographic behavior.Acknowledgment. The aid of M. Ben-Shoshan and Y. Menachem in preparing the syn-(CH3,H)B is acknowledged.
The total synthesis of enantiomerically pure (-)-crinine (1) in 10 steps and 6% overall yield from cyclopentene oxide is reported. The key step was the rearrangement of 7 upon reaction with AgNO, at 25 "C to give cis-perhydroindolone 8 in 81 % yield.Although the total synthesis of Amaryllidaceae alkaloids has been the object of intense in~estigation,)~), few methods have been developed for preparing these alkaloids in optically active form. To our knowledge, the pioneering synthesis of (+)-maritidine by the Yarnada group [4] represents the only published enantioselective synthesis of a member of the widely occurring 5,l Ob-ethanophenanthridine class of Amaryllidaceae alkaloid?). In this paper, we report the first efficient method for preparing enantiomerically pure alkaloids of this type. Specifically, we detail the total synthesis of (-)-crinine (1)6) in 10 steps and 6 % overall yield from cyclopentene oxide.The starting point for the synthesis of 1 (see Scheme) was aminoalcohol 3, which is available on a large scale from the reaction [7] of cyclopentene oxide with the aluminium amide 2 formed from (R)-a-methylbenzylamine and trimethylal~minium~).Although this reaction gave 3 and its (lS, 2s)-diastereoisomer 4 in equal amounts, these aminoalcohols were easily separated by chromatography on silica gel to afford 3 (m.p. 7475°C) in 45% yield. Reaction of the hydrochloride salt of 3 with paraformaldehyde and KCN [ I] provided the oily aminoacetonitrile 5 in 92 % yield. Swern oxidation [lo] of 5 followed by recrystallization of the crude product from CH,Cl,/hexane afforded the 0x0 derivative 6 (m.p. 83-84°C) in 95% yield. Crystalline 6 could be stored at 0 "C without epimerization, however attempted purification on silica gel yielded a 1 : 1 Part 14 in the series 'Synthesis Applications of Aza-Cope Rearrangements'; for Part 13, see [l]. On sabbatical leave from the Agricultural Chemicals Research Laboratories of the Sunkyo Company, Tokyo, Japan. For recent reviews, see [2]. For new approaches for preparing these alkaloids in racemic form, see, inter uliu, [3]. Several enantioselective syntheses of structurally related Sceletium alkaloids have been described, see [5]. For the determination of the absolute configuration of this alkaloid, see [6]. A wide variety of enantiomerically pure 2-aminoalcohols are easily prepared in this way [8]. The absolute configuration of 3 was established [8] by conversion to (-)-(lR, 2R)-2-aminocyclopentanol[9].
Starting from milbemycin D (1), milbemycin A4 (2) and milbemycin A3 (3), a series of 5-keto-5-oxime derivatives were synthesized by selective oximation at the a,/?-conjugated carbonyl function of the 5-ketomilbemycins (4-6). The activities of the synthesized compoundswere studied in dogs naturally infested with microfilariae of Dirofilaria immitis. The 5-keto-5-oximes of milbemycin D (7), A4 (8) and A3 (9) had quite high efficacy to control the microfilariae and more potency than their parents, while the 5-O-acyl oximes (ll-15) also exhibited high activity. The synthesis of the 5-keto-5-oxime derivatives is shown in Scheme 1. The 5-keto intermediates ofmilbemycin A3 (6) and A4 (5) were also isolated from a culture broth of Streptomyces hygroscopicus, and were named 2615 milbemycin J and K, respectively
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