Macralstonine

Macralstonine, C44H54N4O5, crystallizes as colorless, rectangular rods, mp 293° (dec.), [a]D +27.5°, and contains one methoxyl, at least two C-methyl, and three, or possibly four, methylimino groups (33, 36). Its IR-spectrum discloses the presence of an imino or hydroxyl group, an alkoxyacrylic ester chromophore (peaks at 1652 and 1628 cm-1), and an o-disubstituted benzene nucleus. The formation of a derivative with dinitrophenylhydrazine indicates the presence of a potential carbonyl function. Macralstonine has also been reported to possess a marked hypotensive activity (36). 

The alkaloid macrophylline,1 C45H54N4O5, mp 267°-268° (dec.), resembles macralstonine in both its mode of extraction and its physical properties (37), and was earlier assumed to be identical with it. Recently, however, the isolation of a base, mp 270°-272°, reported to be identical with macralstonine, has been described from A. macrophylla it is also 

1 Not to be confused with macrophylline, isolated from Senecio macrophyllus (93), or with macrophylline-A and macrophylline-B, isolated, as their picrates, from Strychnos macrophylla (94). 

Biogenetically, this interesting variant on the heteroyohimbine theme could originate from tryptamine and either dihydroxyphenylalanine (Robinson) or prephenic acid (LXXV) (Wenkert) as example, a possible route from prephenic acid via the seco-prephenate-formaldehyde unit (LXXVI) (97) is outlined below. A vital feature in this proposal (and 

Schlittler, H. Schwarz, and F. Bader, Helv. Chim. Acta 35, 271 (1952). 

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Alstonia macrophylla Wall. Villalstonine, macralstonine, macral-... 

Macralstonine, C44H54O5N4. This base is sparingly soluble in most solvents except chloroform, but can be crystallised from pyridine by addition of dry alcohol, in colourless, rectangular rods, m.p. 293° (dec.), [ ]d + 27 5° (CHCI3). The sulphate, B. H2SO4, forms prismatic rods, m.p. 263° (indef., dec.), [a]D — 36- 8° (H O). The base contains one methoxyl and three methylimino groups. 

Macoubea guyanensis macoubeine, 372 Macralstonidine macralstonine, 716, 719 Madagascar, 726... 

Apocynaceae Alstonia macrophylla Talcarpine Pleiocarp amine Alstoumerine 2-O-epiantirhine Alstonerine Alstophyline Macralstonine Alstomacrophyline Villalstonine Alstomacroline Macrocarpamine... 

Macarpine 203 Macralstonine 16, 37 Macrocarpamine 16, 37 Maculasine 24 Maculosine 9, 40 Magiioflorine 200 Mahanimbine 25 Malaxine 102... 

A partial synthesis101 of alstonerine (178) from macroline (179) (shown in Scheme 17) is of considerable interest, in view of the strategic position occupied by macroline as a possible precursor of both the monomeric Alstonia alkaloids (e.g. alstonerine) and the dimeric alkaloids (e.g. villalstonine and macralstonine). 

The third group of Alstonia species contains neither the alstonine nor the echitamine series of alkaloids hence, the genus appears to be divided into three clearly defined sections as far as alkaloid content is concerned. A. macrophylla Wall, contains villalstonine (33, 35), macralstonine (33, 36), macralstonidine, a base M which was obtained in minute amounts only (33), and macrophylline (37). A. villosa Blume contains villalstonine and base V, insufficiently characterized (33) A. somersetensis F. M. Bailey contains villalstonine and macralstonidine (33). 

A new vincamajine ester, 4 -hydroxy-3, S -dimethoxybenzoylvincamajine (90) was obtained from the roots of Alstonia angustifolia, in addition to nine other known alkaloids, alstonerine, alstophylline, vincamajine, villalstonine, macralstonine, pleiocarpamine, macrocarpamine, norfluorocurarine and 11-methoxyakuammicine [84]. The UV spectrum of 90 was similar to... 

Three dimeric alkaloids from Alstonia angusHfoHa, macrocarpamine (293), macralstonine acetate and villalstonine (289) possess significant in vitro activity against Entamoeba histolytica and Plasmodium falciparum, protozoans causing amoebic dysentery and cerebral malaria, respectively [211]. The EDso/gM of the compounds against . histolytica were macrocarpamine... 

On the basis of structure the dimers can be clearly divided into two groups. The first is comprised of alkaloids with identical or very closely related components in which the same centres act as linkage positions. The Calycanthaceous and Calabash-curare-South American Strychnos alkaloids make up this group. The second group consists of dimeric bases in which the alkaloid components are of a different structural type (e.g. geissospermine, vinblastine, and tubulosine) or in which two similar halves are linked unsymmetrically through two different centres e.g. macralstonine). The bisindole alkaloids will be discussed in this order. ... 

Certain Alstonia species of the family Apocynaceae contain bisindole alkaloids of interesting construction. These are (+)-villalstonine from Alstonia macro-phylla Wall., A. muelleriana, A. somersetensis F.M. Bailey and A. villosa Blume, (+ )-macralstonine from A. macrophylla Wall., and macralstonidine from A. macrophylla Wall, and A. somersetensis F.M. Bailey. A common unit of all three dimers is the monomeric indolic base macroline. 

Macralstonine (220). — The dextrorotatory macralstonine, C43H52O5N4, is a bisindole alkaloid which is composed of two similar halves. As with villalstonine (213) the alkaloid undergoes fission in 2N-HC1. The results are summarised in Scheme 15. 

Since macroline (215) does not give ketone (222) under the above conditions, macralstonine (220) must break down by acid catalysis via two distinct processes from one are formed alstophylline (221) and macroline (215), from the other alstophylline, ketone (222), and formaldehyde (Scheme 15). The two modes of cleavage can be understood in terms of structure (220) as shown in Scheme 16. 

When heated at 300-350 °C under high vacuum, macralstonine (220) loses water to give anhydromacralstonine (225), which can also be obtained by treat-... 

Macralstonine is the water-addition product of (225). This addition cannot be at the 8-keto-enol ether system of the alstophylline half since macralstonine shows the same u.v. absorption as the anhydro-compound (225), bands at 1646 and 1615 cm in the i.r. spectrum, and the low-field singlet of the C(21 )-proton in its n.m.r. spectrum. Hydration must therefore be at the double bond of the macroline component, resulting in structure (220) for macralstonine. In chloroform both the ring-open and ring-closed forms are present [singlets for the — C(18)H3 grouping at 1.67 and 1.49 p.p.m. (total 3H) and a medium ketone band at 1706 cm ]. The presence of two distinct species causes other n.m.r. signals to be doubled, a fact which does not facilitate interpretation. 

The biosynthesis of macralstonine is considered to involve a Michael-type coupling of the nucleophilic centre of alstophylline to macroline. 

Simultaneous production of ketone (222) and formaldehyde strongly suggests that a building block of macralstonidine, as with villalstonine (213) and macral-stonine (220), is the base macroline (215). In addition, it is probable that the mechanism of the cleavage process corresponds to that of macralstonine which leads to the formation of alstophylline (221), ketone (222), and formaldehyde (see Scheme 16). 

The following discussion is restricted to aromatic chromophores. Although the same applies to additional chromophores, e.g. the amino-acrylic-ester chromo-phore (roxburghines, Section 5), the alkoxy-acrylic-ester chromophore (serpen-tinine, Section 15), and the alkoxy-acrolein chromophore (macralstonine. Section 12, p. 269), these are as a rule readily recognised from characteristic i.r. and n.m.r. absorptions. 

Macralstonine (220) shows, as does its monomeric unit alstophylline (221), an intense dirty blue colour reaction—non-hydroxylated or methoxylated indoles give only a weak ceric reaction. 

Two bis-indohomotropane alkaloids, macralstonine (188) and anhy-dromacralstonine (189), were isolated from the stem bark and leaves of Alstonia macrophylla (82). Root bark of the same plant was recently reported to contain macralstonine (188) (88). 

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