Lythraceae alkaloid

An interesting type of quinolizidine alkaloids occurs in the Lythraceae family and is not known in other plants (52). The alkaloids of woody plants of the genus Lagerstroemia are described here. 

Lagerstroemine and lagerine were isolated as major alkaloids together with decinine, decamine, dihydroverticillatine, and methyllagerine from Lagerstroemia indica. These alkaloids are concentrated in the seed pods, with trace amounts in 

The phenylquinolizidine alkaloids lasubine I and lasubine II were obtained from the leaves of Lagerstroemia subcostata as major alkaloids, together with the ester alkaloids subcosine I and subcosine II. These alkaloids are considered to be intermediates in the biogenetic route of the lactonic alkaloids. Thus, lysine, phenylalanine, and a C2 unit (acetate) produce the phenylquinolizidine alkaloids. These are then esterified with another phenylalanine unit to the ester alkaloids, followed by conversion to the lactonic alkaloids by oxidative coupling. 

There is still considerable activity in the synthesis of Lythraceae alkaloids, although no new methods have emerged this year. Details have appeared of two independent syntheses of the biphenyl ether alkaloid decaline. - Arata s approach to the synthesis of decaline (35) cf. Vol. 5) has been applied to lagarine (36), using a benzyl group to protect the phenolic hydroxyl substituent. 4-Arylquinolizid-2-ones, cf. (34), are important synthetic intermediates, and their synthesis from isopelletierine and a variety of 2-bromobenzaldehyde derivatives has been studied.  

The biphenyl alkaloid decinine (37) was synthesized by a route similar to that employed for methyldecinine cf. Vol. 6). The hydroxy-group was protected as its methyl sulphonate ester and calcium hydroxide was used in the reaction of the 

Hanaoka, N. Ogawa, and Y. Arata, Chem. and Pharm. Bull. (Japan), 1975, 23, 2140. 

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A tropical Old World family, its habitats are the mangrove and rain forest areas. It is related to the Lythraceae. Alkaloids have been recorded for Sonneraliu but they have not yet been characterized. 

Lythraceae Alkaloids.—Results showing that lysine (15) is a precursor for decodine (22) and decinine (23) in Decodon verticillatus, which were published in preliminary form (cf. Vol. 1, p. 6), are now available in a full paper.8 Label from either C-2 or C-6 of the amino-acid was found to be spread equally over C-5 and C-9 of the alkaloids, indicating that ring A derived from this amino-acid and that incorporation was via a symmetrical intermediate. Cadaverine (16),... 

A key stage in the biosynthesis of piperidine alkaloids is reached with the formation of A -piperideine. For the elaboration of diverse alkaloids, this intermediate undergoes condensation with a variety of nucleophiles, commonly a /3-keto-acid. (A similar situation is found for pyrrolidine alkaloid biosynthesis see, e.g., Scheme l).1,2 Existing evidence on Lythraceae alkaloid biosynthesis, taken up again below, indicated that condensation occurred in this case between A piperideine (17) and acetoacetic acid to give pelletierine (26), further elaboration yielding alkaloids like (22). In the event, however, labelled pelletierine was found not to be a precursor for (22) or (23).8 Negative evidence is always difficult to interpret, but is here made persuasive by the fact that other precursors that were fed concurrently were incorporated. Conclusive support for these results depended on others outlined below. 

The nature of the nucleophile which condenses with A piperideine (17) needs to be reconsidered. Very plausibly, this could be (18), which is formed as shown in Scheme 3 from phenylalanine (20) via cinnamic acid (19) and malonyl-CoA. A further unit of this type is found in alkaloids such as lythrumine (24). An outline biosynthetic route to Lythraceae alkaloids is given in Scheme 3.9... 

The first isolation of the Lythraceae alkaloids from Decodon verticillatus (L) Ell was reported by Ferris in 1962 (2). Those were lactonic biphenyl alkaloids (type A) decinine, decodine, verticillatine, decamine, vertine, lactonic ether alcaloids, decaline, and vertaline. 

In 1967, Fujita et al. (5,6) isolated three piperidine metacyclophane alkaloids (type B) from Lythrum anceps Makino. The third structural variant of the Lythraceae alkaloids, quinolizidine metacyclophane (type C), was... 

Brief references to the Lythraceae alkaloids have been made in Volumes X, XII, and XIV of this treatise. A short review on the alkaloids from Lythrum anceps was published in Japanese (14). A review on the Lythraceae alkaloids has appeared recently, covering mainly structure elucidation (15). 

The numbering system used for lactonic Lythraceae alkaloids is that introduced by Spenser (10) and originally employed by Schopf et at. (11). The system closely corresponds to the that introduced by Fujita et al. (12, 13) for metacyclophane alkaloids (B and C). The new system is attractive since the carbon atoms that correspond in biogenetic origin to the three types (A, B, C) maintain corresponding numbers. 

The methoxyl groups of nesodine absorb in the NMR at 3 3.98 and 3.69 ppm. The former signal may be assigned to 22-OMe and the latter to 21-OMe. The data do not eliminate an alternative structure (16) (structure 1 with R1 = H, R2 = OH, R3 = Me) for nesodine. Ferris et al. preferred 5 to 16 on the basis of the fact that no naturally occurring Lythraceae alkaloid has a 21-OMe. It would, however, be necessary to confirm this structure by internal ether formation. 

The Lythraceae alkaloids have four centers of chirality—three chiral carbon atoms at the quinolizidine ring C-l, C-3, and C-5, and the dissy-metric biphenyl or biphenyl ether link. The chirality of the biphenyl system in all alkaloids of the group is the same. The chirality of the biphenyl ether link is also the same for all alkaloids in this class (22, 23, 32). 

Lagerine was isolated by Ferris et al. from Lagerstroemia indica (17), and methyllagerine was isolated by Hanaoka et al. (42) from L. indica grown in Japan. The structure of lagerine is unique since it was not possible to convert this base to any known Lythraceae alkaloid. The basic skeletons of O-methyllagerine and vertaline are the same since the mass spectra of the two alkaloids are almost identical. The alkaloids differ in the substitution pattern on the biphenyl ether chromophore, a fact which is reflected in the UV spectra. 

The common intermediate in two published biomimetic routes to Lythraceae alkaloids was substituted 4-phenylquinolizid-2-one. In one approach based on a biogenetic hypothesis of Ferris et al. (62), Wrobel and Gol biewski condensed pelletierine (126) with isovanillin (128) and obtained a transfused quinolizidine derivative (130, jS H-5) (64) in 75% yield. A model condensation of pelletierine (126) with benzaldehyde which resulted in a mixture of quinolizidones was reported earlier by Matsunaga et al. (65). In another approach Rosazza et al. (52) condensed A -pjperideine (132) with /J-ketoester 133 to get 134. The next stage in both approaches was reduction of the ketone and esterification or transesterification with derivatives of p-hydroxycinna-mic acid (135 or 136). Investigations into the oxidative coupling of 137 were unsuccessful. 

This is a key stage in the synthesis of lactonic Lythraceae alkaloids published by Hanaoka et al., Loev et al., and Wrobel and Gol biewski. This reaction was studied by several groups of chemists (64, 66-69). It proceeds in good yield for a variety of aromatic aldehydes usually in dilute aqueous or alcoholic solutions of sodium hydroxide to yield 2-quinolizidones. Two diastereomers, 138 and 139, defined by the relative stereochemistry at C-4 and C-10 are formed in the condensation In the trans-quinolizidone (139) the C-4 and C-10 hydrogens are trans to one another. In the cw-quinolizidone (138) they are cis. 

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. 

Decaline (43) was the first synthesized Lythraceae alkaloid. The synthesis was achieved independently and concurrently by a Japanese and a Polish group. Three approaches were used in these syntheses. In the first method,... 

Most of the work on the biosynthesis of Lythraceae alkaloids has been done by Spenser et al. (10, 84-87). First, the validity of the pelletierine hypothesis (c) of Ferris et al. (62) has been tested. The pelletierine (126) nucleus is generated from L-lysine (181) via cadaverine (182), and presumably A -piperideine (132) and its side chain originate from the acetate. Incorporation of radioactivity from 14C-labeled samples of these precursors to decodine (6) and decinine (2) in Decodon verticilatus has been investigated (85, 87). 

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