Macroline

Ein anderes Beispiel ergab sich im Zusammenhang mit der Strukturauf-klarung des dimeren Alkaloides Villalstonin 19, 31). N(b)-Trideutero-methyl-macrolin-chlorid (17) wurde auBerhalb des Massenspektrometers... 

Tabelle 3. Gegenuberstellung der wichtigsten Peaks in den Massenspektren von Macrolin (18) und dem Pyrolysat von N - Trideuleromethyl-macrolin-chlorid 17). In( )relative Intensitdten in %... 

Thymocyte stimulating factor [NAM SY] Lymphocyte mitogenic factor [NAM SY] Macrolin [NAM TR used in France, perhaps other European countries]... 

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 absolute configuration of (-t-)-macroline, obtained by degradation of the dimeric alkaloid villalstonine, follows70" from its transformation into a mixture of the tetracyclic base (138) and its C-20 epimer. Base (138) was also obtained by degradation of ajmaline (139), as outlined in Scheme 21 the C-20 epimer of (138) was similarly obtained from isoajmaline, which is epimeric with ajmaline at both C-20 and C-21. 

The partial synthesis70 of macroline (136) from normacusine B (140) was inspired by its postulated biosynthesis from a sarpagine-type precursor. Normacusine B (140), prepared by a previously published route from perivine, was protected at the primary alcohol group and then methylated on Na. Direct epoxidation of the product (141) failed however, osmylation gave the desired diol together with the related oxindole obtained by simultaneous oxidation of the indole double-bond, followed by rearrangement. Conversion of these diols into the related epoxides gave a mixture of (142) and (143), from which the desired epoxide (142) could be separated satisfactorily by fractional crystallization. 

Isomerization then gave a / -amino-ketone (144), whose methosulphate readily suffered / -elimination and loss of the protecting group, with formation of the unsaturated amino-ketone identified as macroline (136) (Scheme 22).706... 

Pandicine (312), an air-sensitive, amorphous alkaloid from the leaves of Pandacastrum saccharatum Pichon, has a novel structure composed of macroline and highly oxygenated tabersonine units.135 Its structure was elucidated mainly by comparison of its H and 13C n.m.r. spectra with those of the macroline unit in villalstonine and the oxygenated tabersonine unit in cryophylline. There is at present no definitive proof for the relative stereochemistry of the two components of the pandicine molecule that depicted in (312) is simply based on the stereochemistry deduced for related monomers, namely talcarpine and hazuntinine. Presumably the ease of oxidation of pandicine is due to the facile formation of the quinonoid species (313). 

The amino acid derived carboxy group can be utilized as a functionality for further synthetic manipulations, e.g. for cyclization reactions to 1,3-bridged P-carbolines, using the Dieckmann reaction, a promising stereocontrolled approach to macroline-related alkaloids (Scheme 14). > ... 

Liu, X., Cook, J. M. General Approach for the Synthesis of Sarpagine/Macroline Indole Alkaloids. Enantiospecific Total Synthesis of the Indole Alkaloid Trinervine. Org. Lett. 2001, 3,4023-4026. 

In another study of the leaves of the same plant, several new monomeric alkaloids were obtained (in addition to bisindoles, vide infra) including the macroline alkaloid, 19,20-dehydro-... 

Of a total of 31 alkaloids isolated from the leaves and stem-bark of Alstonia angustifolia, 11 were new and of these, eight were dimeric alkaloids, all of which possessed the macroline unit (83]. The predominant alkaloid present was the known dimeric alkaloid villalstonine (289). 

A possible biogenesis of the macroline-cabucraline dimers derives from a Michael reaction of the nucleophilic C(IO ) of cabucraline (299) with the unsaturated aldehyde 300 (which may be regarded as an opened form of talcarpine) to give an addition product 301, which on subsequent hemiketalization or ketalization furnishes the dimeric compounds 296 and 297 [83]. 

A number of novel nitrogenous derivatives have also been obtained in recent years from several Malaysian plants. An unusual nitrogenous compound angustimaline was obtained from Alstonia angustifolia [192]. The spectral data led to the structure 321 which showed that angustimaline retains all the features of the non-indole portion of a type-B macroline unit except for the presence of an additional oxygenated carbon. It is probably derived from fragmentation of a macroline-type precursor, possibly alstophylline or its oxindole. 

The stem-bark extract of the Malayan Alstonia macrophylla provided in addition to seven known alkaloids, three new indole alkaloids, lO-methoxyaflinisine (334), 10-methoxy-cathafoline (335) and alstonerinal (336) [226]. The latter is a type A macroline and coeluted with the known type B macroline, alstonerine (337) during chromatography, and proved resistant to further resolution by chromatography or fractional crystallization. Eventually a pure sample was obtained by reduction of a mixture of 336 and 337 to yield the isomeric alcohols 338 and 339, followed by oxidation of338 to yield alstonerinal (336). 

Le Quesne and coll. 156, 157, 165) found that when macroline (141) and quebrachidine (36) were allowed to stand for 72 h in a dilute aqueous HCI solution at room temperature, they were converted into alstomacroline (80), which is claimed... 

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. 

The mass spectrum of villamine is extremely informative. Apart from the molecular ion (M" = 660) the spectrum is virtually a summation of the mass spectra of pleiocarpamine (196, C20H22O2N2, = 322) and the base macroline... 

These data show that villamine is a 2,7-dihydropleiocarpamine derivative. The thermal cleavage to pleiocarpamine (196) and macroline (215) is considered to be of the retro-Diels-Alder type. 

Finally, the more important arguments leading to the structure of macroline (215), C21H26O2N2, will be discussed the presence of the groupings... 

The monomeric cleavage base alstophylline (221) occurs naturally in Alstonia macrophylla Wall. Macroline (215) was previously isolated from villalstonine (213). The cleavage ketone, C20H26O2N2, has been assigned structure (222) based on the following considerations it is an indole and contains... 

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