Lactone alkaloids

Lactone Alkaloids from Amaryllidaceae W. Dopke, Heterocycles, 1977, 6, 551-582. 

A number of spectroscopic studies have been completed, and 13C-NMR spectroscopy continues to be a useful analytical tool for structural elucidation. Furthermore, CD spectroscopy has proved to be an effective means for providing stereochemical information for the lactone alkaloids of die lycorenine class (33). 

Clivojuline (195) (10) represents an unusual structural type since it lacks the 9,10-aromatic oxygenation pattern, which is ubiquitious among the other lactone alkaloids. The structure of the related alkaloid cliviahaksine (196) was assigned on the basis of spectral comparisons with 195 although its stereochemistry was not specifically indicated (15). Since cliviaaline (197) was isolated in only very small amounts, its structure was deduced principally from its IR spectrum and its mass spectral fragmentation pattern however, the possibility that it was an artifact was not rigorously excluded (14). 

Oxidation of the open chain tetrapeptide 62 could afford 63 which on cyclization should immediately lead to ergosecaline (64), a novel type of lactone alkaloid. It was isolated only once from Spanish rye but not sufficiently characterized (89). Hydrolysis of 64 and subsequent decarboxylation would finally give the desired 61. 

The X-ray analysis of lycorenine methiodide has established the a (steroid notation) configuration of the hydroxy group at position 7. From considerations of the specific and molecular rotations of analogous hemiacetal and lactonic alkaloids it has been inferred that oduline (109), nerinine (99), krigeine (105), unsevine (112), and krigmamine (104) all possess an a-hydroxy group at position 7 (20). 

Similarly, from Crinum powellii, avoiding basic treatment, criwelline (241) was not obtained but the amorphous precriwelline (243) whose hydrochloride melted at 199-201° was isolated. The sequence leading from 243 to 245 and 247, the known alkaloid macronine (Vol. XI, p. 381), and its synthetic iV-demethyl derivative, respectively, established structure 243. The compound 247 was isolated from Crinum erubescens along with the carbamate 253 which probably arose from 247 during the extraction by the action of chloroform and ethanol. Epimacronine (246), another lactonic alkaloid of this series, was obtained in small amounts from 8. formosissima (50, 51). 

This report was followed by isolation of other lactonic alkaloids from Heimia salicifolia Link and Otto by Schwarting et al. (1, J) and from Heimia myrtifolia Cham and Schl. and H. salicifolia by Douglas et al. (4). 

The methoxylation pattern of lactonic alkaloids was established by a combination of spectral and chemical studies. Methoxyl groups at positions ortho to the biphenyl link (at C-17 or C-21) resonate at relatively high field (<5 3.8 — 3.7 ppm) because of shielding by the adjacent aromatic ring. Methoxyl groups at the other positions absorb at <5 3.95 — 3.85 ppm. Formation of an internal ether demonstrates the presence of 17-OH (24). 

The NMR spectra of /V-oxides of biphenyl lactonic alkaloids (O-methyl and O-acetyl derivatives) show the signal of low-field aromatic proton H-24 at 5 8.1 -8.7 ppm. The Dreiding models indicate that this proton is deshielded by the N—O group. H-24 resonates in the cis-fused derivatives at 0.13-0.28 ppm lower field than in the corresponding trans forms (24). The same relation is observed in the NMR spectra of biphenyl ether alkaloids where H-24 absorbs at 5 7.6-8.2 ppm (25, 36). 

Occurrence of simple quinolizidone alkaloids, ester alkaloids, and lactonic alkaloids in the same Heimia salicifolia plant species provides further evidence in support of current biogenetic hypothesis. 

Lythraceae plant family and suggests that the metacyclophane and lactonic alkaloids have a common biosynthesis. 

In the lactonic alkaloid molecule one can find three synthons pelle-tierine, a 4-methoxybenzaldehyde derivative, and p-hydroxycinnamic acid. In all published syntheses of lactonic Lythraceae alkaloids they are the building blocks. 

Several biogenetic schemes have been suggested to account for the origin of biphenyl and biphenyl ether lactonic alkaloids (52, 62, 83, 84). The proposals differ in the mode of biogenesis of the phenylquinolizidine moiety. Steps common to all the proposals are the reduction of oxo group in the phenylquinolizidone (130) followed by esterification with of / -coumaric acid (C6 C3) unit derived from phenylalanine via cinnamic acid. 

Attempts to construct the framework of lactonic alkaloids by an intramolecular phenol coupling with vanadium(V) oxidizing agents were unsuccessful (27). 

The biphenyl group in both lactonic and metacyclophane alkaloids poses an interesting question about chirality. Ferris et al. (39) reported that the biphenyl moiety in lactonic alkaloids was inherently dissymmetric. Its chirality was determined by comparison of the circular dichroism (CD) curves with those of di-hydrothebaines with known chiralities. The biphenyl group of metacyclophane alkaloids with a piperidine ring, however, should exist as an equilibrium between two rotamers with (R) chirality (126a) and (5) chirality (126b) in solution as... 

T. A. Henry, The Plant Alkaloids. Churchill, London, 1949. Lactonic alkaloids ... 

The above syntheses of the parent spiroamine system establish the skeleton of the aromatic alkaloids. A synthesis of a derivative of jS-erythroidine (III) with the intact spiro skeleton, achieved in Boekel-heide s laboratory (15), provides similar confirmation for the lactonic alkaloids. 

A number of new alkaloids are closely related to vobtusine. These include vobtusine lactone (alkaloid V) and desoxyvobtusine lactone (alkaloid IV) from Voacanga africana Stapf. and desoxyvobtusine, voafoline (alkaloid VII), isovoafoline, voafolidine (alkaloid IX), and folicangine (alkaloid VIII) from the same plant. From Callichilia (Hedranthera) barteri (Hook.f.) Pichon owerreine, goziline (= desoxyvobtusine ), and amataine have been isolated. 

Lappaconine (11) is the first bisnor (C g) diterpene alkaloid to be found. The presence of the hydroxy-group on C-4 suggests that removal of C-19 is by a Baeyer-Villiger t q)e process. The biosynthesis of the lactone alkaloids such as heteratisine (137) also may involve such a step. 

NMR data of Homolycorine type compounds lactone alkaloids. 

Acids and lactones Alkaloids (brucine, strychnine, quinidine, quinine, chinchonine, chinchonidine, dehydroabietylamine, quinotoxine, cinchotoxine), terpene derivatives (endo-bomylamine, 1 R-3-endo-aminobomeol, pinelylamines, (+)-3-aminomethylpinane) ephedrine and ephedrine analogs, synthetic amines (d-methyl-benzylamine and its derivatives, d-l-naphthylethyl-amine, 2-amino-l,2-diphenylethanol), amino acids and bases derived thereof [15-19] [20-23] [24,25-27] [28-31]... 

Cimiciphytine and norcimiciphytine are two minor, lactonic alkaloids isolated from Haplophyton cimicidum. ° Both alkaloids contain an unrearranged canthiphytine unit, since cimiciphytine (269) can be obtained by mild reduction of haplophytine in acid solution (Zn-AcOH), and norcimiciphytine (270) affords... 

Alkaloids of the group have been reviewed/ and an account of lactone alkaloids of the Amaryllidaceae has been published/ A concise account of recent developments in the synthesis of Amaryllidaceae alkaloids has appeared/ Contrary to previous practice, Sceletium alkaloids and related compounds are classified as pyrrolidine derivatives and discussed in Chapter 2. The Amaryllidaceae alkaloid cherylline is included in the account of isoquinoline alkaloids (Chapter 8). 

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