Aspidofractinine

Part 7. Aspidofractinine-type alkaloids unsubstituted in position 3... 

Aspidofractinine, CXVII, C19H24N, x 102 Aspidofiline, CXXXVI, C21H26N2O2, r 79 0-Methyldea.cetylaspidofiline, CXXXIX, C20H2 N2O, y 48... 

Part 3. Aspidofractinine and kopsine-type alkaloids and their derivatives... 

The vast majority of indole alkaloids contain a tryptamine unit in which Nb is linked to the j9-position of the indole nucleus by an ethylene chain. On biogenetic grounds and also from the mass spectral similarity with aspidospermine (II), it is reasonable to expect this feature in the aspidofractinine-type alkaloids. Furthermore, in kopsine lactam A (CLXXV), in which C-ll is substituted by the C-3 bridge and C-10 has been oxidized (five-membered lactam), the residual hydrogen atom on C-ll shows as a singlet (2.82 S) in the NMR-spectrum and C-12 is therefore quaternary. 

Ten alkaloids have been isolated from A. populifolium, of which the greater part belong to the aspidofractinine group (48). They include (+ )-0-methyldeacetylaspidofiline [CXXXIX, optical enantiomer of that derived from aspidofiline (Section III, E)], its 16-methoxy analog, CXLI-A, and their respective A7a-formyl derivatives, CXLI-B and CXLI-C. The structures of all four compounds could be established by comparison of their IR-, UV-, NMR-, and especially mass spectra with... 

Although the alkaloids of Aspidosperma populifolium are preponderantly of the aspidofractinine type, one of them (CCXXIV-A) was clearly excluded from this class by its IR- (ACHCl3 5.98 and 6.25 p, MeC C—C=C) and UV- (Table III) spectra. The latter was somewhat similar to that of condylocarpine (CCXV), the differences being accountable to an aromatic methoxyl group whose presence was indicated by the NMR-spectrum (OCH3, 3.74 S, coincident with the CC Me peak 3 aromatic protons only). A further difference from condylocarpine and akuammicine lay in the presence of an ethyl (0.70 S, triplet) rather than ethylidene side chain. 

The abundance of the fragment of mass 124 [249] produced by a hydrogen shift123 is much lower than in aspidospermidine. The typical aspidofractinine pattern facilitated the structure determination of pyrifoline,139 refractidine,139 refractine,140 aspidofractine,140 aspido-filine,141 and kopsinine.123... 

The electrochemical oxidation of the aspidofractinine-type alkaloid kopsingine in a dichloromethane/acetonitrile medium at a platinum anode in the presence of 2,6-lutidine results in the intramolecular cyclization of an hydroxy group to the intermediate iminium ion of the tertiary amine structure. Thus, kopsidine A was formed in 72% yield [19]. 

Ban s synthetic work has been taken a stage further this year with the first total synthesis of aspidofractinine (207) (Scheme 28). The closely related alchohol (208), synthesized previously, could not be converted into aspidofractinine hence, an alternative synthesis was devised from the important intermediate (209), in which the sixth ring was introduced via a Diels-Alder addition of nitroethylene, which was highly regio- and stereo-selective, to the diene (210). 

Plants of the genus Kopsia have proven to be a particularly rich source of aspidofractinine-type alkaloids. Early studies in the sixties by Battersby (144,145) and Schmid (146,147) of Kopsia frulicosa, an ornamental Kopsia widely cultivated in Malaysia, yielded the heptacyclic bridged alkaloids, fruticosine (186), fruticosamine (187) and kopsine (188). 

Several new derivatives of kopsingine or kopsaporine with different aromatic substitution which were recently obtained include 11-hydroxykopsingine (193) [131], 11-methoxy-kopsingine (194) [131] and 11,12-methylenedioxykopsaporine (195) [132]. Another new aspidofractinine, kopsinol (196) [130] was readily shown to be the N(l)-decarbomelhoxy derivative of kopsaporine while compound 197 was assigned the structure 11-methoxy-12-hydroxykopsinol from the spectral data [131]. The position of the aromatic methoxy group in 197 was established to be at C(l I) from the observed NOE between H(10) and the aromatic OMe. 

Two new aspidofractinine compounds M arbomethoxy-l7P-hydroxykopsinine (205) and -carbomethoxy-17 i-hydroxy-A -kopsinine (206) were obtained from K. deverrei and are characterized by the absence of the C(16) hydroxyl group when compared with kopsaporine. The assignments of the stereochemistry of the C(16) methyl ester and C(I7) hydroxyl substituents as P were based on the absence of W-coupling between H(I6) and H(I7) to any of the C( 18) and C(I9) hydrogens respectively. 

A new pleiocatpine derivative, 12-methoxypleiocarpine (222) was obtained from Kopsia griffilhii [58]. This plant furnished a diverse array of alkaloidal types which included the p-carboline compounds, harmane (55) and harmicine (56), the corynantheine alkaloids, tetrahydroalstonine and 16(R)-19,20- -isositsirikine 221, the aspidofractinine alkaloids, kopsilongine (223), kopsamine (224), kopsamine-Moxide, pleiocarpine (221), kopsinine (220), fV(l)-ntcthoxycarbonyl-12-melhoxy-A -kopsinine (216), -carbomethoxy-1 l-hydroxy-I2-methoxykopsinaline (225), Mcarboinethoxy-ll,12-dimethoxykopsinaline (226), the rare... 

Two aspidofractinine-type compounds, lahadinines A (233) and B (234), obtained from Kopsia pauciflora are remarkable for having a cyano-substituent at C(21) [162]. The mass-spectra of these alkaloids are characterized by a strong molecular ion (usually also the base peak), with the odd mass indicating the presence of a third nitrogen. Fragments attributable to loss of CN and HCN were also detected in the mass-spectrum and the IR spectrum showed a weak band at ca. 2250 cm. The characteristic H(21) signal was absent in the H NMR... 

Kopsia pauciflora also provided several new alkaloids (268 - 271) [174] possessing a pentacyclic skeleton similar to that of kopsijasminilam (272), deoxykopsijasminilam (273) and 14,15-dehydrokopsijasminilam (274) from the Thai species Kopsia Jasminiflora. The structure of272 was established by X-ray analysis [ISO]. These rare alkaloids can be considered as being derived from an aspidofractinine-type precursor by cleavage of the C(21)-C(20) bond. In pauciflorine A (268) and B (269), the double bond is located between C(19) and C(20) while in... 

A similar study of the anti-hypertensive activity of the alkaloids of Kopsia teoi were also carried out which were also prompted by positive results from preliminary screening of alkaloidal extracts. The major aspidofractinine alkaloid kopsingine (191) was found to produce dose-related decreases in mean arterial blood pressure and heart rate in anaesthetized spontaneously hypertensive rats (SHR) which were similar to those elicited in normotensive controls. The same depressor response was shown by the 12-demethoxy derivative (kopsaporine, 192) and the semisynthetic 14,15-dihydto derivative of kopsingine 252, indicating that minor modifications to the basic structure of kopsingine do not significantly alter... 

Aspidofractinine (146), the parent member of this third large subgroup of alkaloids of the aspidospermine group, does not occur widely, and the only recent report of its occurrence is in the stem bark and root bark of Hunteria elliottii Pichon (12). Its Na-methyl (147) and Na-methyl-14,15-didehydro (148) derivatives are new alkaloids, which have been found in the roots of Vinca sardoa (67). The ester alkaloids occur much more widely, and several new sources have been reported for (—)-kopsinine (149), (-)-venalstonine (150), (-)-venalstonidine (151), and several minor alkaloids (152-160) (Table I). Of the six reported isolations of 15a-hydroxykopsinine (154), one (16) does not spedfy the configuration of the hydroxyl group. Since it is described as a known alkaloid, it is presumed to be 15a-hydroxykopsinine, because 15/3-hydroxykopsinine is unknown as a natural product. 

K. Seco-Aspidofractinine Alkaloids, with or without Subsequent Cycuzation... 

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