An Antimalarial Alkaloid From Hydrangea. Iii. Degradation

Abstract

The isolation of an antimalarial alkaloid from Hydrangea has been described (1). The elemental analysis indicated an empirical formula of Ci6HigN303-2HCl.Degradation studies were initiated even though only extremely small amounts of the alkaloid were available. The limited supply of the alkaloid made it imperative that maximum use be made of model compounds.1Through the following discussion it will become apparent that many of the postulates could have been decided by straightforward degradation reactions.However, with only a few milligrams of the alkaloid available at any one time, many of these approaches were not feasible. All exploratory reactions were run on 2-3 milligram samples, and because of the difficulty of isolating products or determining the course of a reaction, some of these ended in failures that would have been circumvented had larger samples been employed. As a descriptive summary of the approach to the problem, the course of the degradation has been more or less described as it evolved under the actual conditions.Determinations for N-methyl, O-methyl, and C-methyl groupings in the Hydrangea alkaloid were negative as were tests for isolated unactivated double bonds or for amino nitrogen. The alkaloid absorbed ultraviolet light with absorption maxima at 265, 275, 302.5, and 313 mg in 0.1 N sodium hydroxide and at 272.5 mg with an inflection at 295 µ in 0.1 N hydrochloric acid.When the alkaloid was subjected to alkaline hydrolysis, there was extensive coloration with marked changes in the ultraviolet absorption spectra. Concomitant with these changes an aromatic amine was formed that could be detected by the method of Bratton and Marshall (2). The rate and extent of amine formation was dependent on the concentration of alkali. One-tenth normal sodium hydroxide for 4 hours at 100°liberated 59% of theory, an amount that could not be further increased by prolonged hydrolysis. Two normal sodium hydroxide under similar conditions liberated 96% of theory. The rate of color

An Antimalarial Alkaloid From Hydrangea. Iv. Functional Derivatives of 3-Alkyl-4-Quinazolones

“…This was indeed found to be the case, indicating that the alkaloid had a ketone group on the /3-position of the side chain. This observation was checked quantitatively (1).…”

“…Early degradation experiments on the Hydrangea alkaloid (1) indicated that this molecule was a derivative of 4-quinazolone with a side chain on the 3-position containing one basic nitrogen and two oxygens. With this limited information on hand a number of 3-alkyl-4-quinazolones with functional groups in the side chain were synthesized in order to obtain (a) suitable models for degradation experiments (l), (b) compounds to be tested for antimalarial activity,' and (e) information on the synthesis and transformations of these functional groups.…”

“…This method is also limited to the introduction of a primary alkyl group, which will be discussed later. 0 0 /%R + RNH2 --+ 3 1 " I Ob" IV v .1\I/CCH3 \NyC CH, 1 The biological data will be published elsewhere. 2 Although a large number of 3-alkyl-4-quinazolones have been reported in the literature, only a few with functional groups in the side chain have been described, namely, 3-allyl-4-quinazolone (2) ; 4-quinazolone-3-acetic acid, its methyl ester, and methylamide (3) ; the alkaloid Rutaecarpine (4) ; 3-benzamidomethyl-4-quinazolone and its 2-methyl derivative (5, 11); and 2-methyl-3-(5-diethylamino-2-pentyl)-7,8-dimethoxy-4-quinazolone (6).…”

Concise Synthesis of dl-Febrifugine

“…[1][2][3][4] It is well known that d-1 and d-2 are related to each other's isomerization via waminoenone 5,6) (3) (Chart 1). Among reported methods [7][8][9][10][11][12][13][14][15][16][17][18][19][20] of d-1, we had believed that our method 10,13) was widely applicable to the synthesis of the derivatives needed to study the structure-activity relationship of d-1.…”

Re-revision of the Stereo Structure of Piperidine Lactone, an Intermediate in the Synthesis of Febrifugine

“…1). [1][2][3][4] The plane structure 5) of (ϩ)-1 and (ϩ)-2 was first proposed in 1950. Subsequently, their relative 6) and absolute 7) structures were proposed, based on Baker's synthetic work.…”