Alkaloids of the Lythraceae

Reagents i, PhMe, reflux ii, MeSO Cl, pyridine iii, Zn, 50% AcOH, then AC2O, pyridine iv, NaOH, aq MeOH vii, 10% Pd/C, H 

0-methyl-lythridine (37) is initiation of ring closure by fluoro- 

Murakoshi, M.Watanabe, J.Haginiwa, S.Ohmiya, and H.Otoraasu, Phytochemistry, 

Kamaev, S.Kuchkarov, F.K.Kushmuradov, and Kh.A.Aslanov, Khim. Prir. Soedin., 1981, 604 (Chem. Abstr., 1982, 96, 123 059). 

Ohmiya, K.Higashiyama, H.Otomasu, J.Haginiwa, and I.Murakoshi, Phytochemistry, 1981, M, 1997. 

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Geminal and vicinal proton-proton couplings have been collected and applied by Hughes et al in their studies on the structure of six alkaloids of the Lythraceae group, i.e. decinine, decodine, decamine, verticillatine, decaline and vertaline, and by Krajewski et who studied solution conformation of the alkaloid chelidonine and its protonated form. 

Certain other groups of alkaloids that coincidentally have a quinolizidine ring system are discussed in other chapters. For example, the alkaloids of the Lythraceae are discussed in Chapter 37 and those of the genus Nuphar are discussed in Chapter 36. Yet other quinolizidine alkaloids (18 and 19) are known from the Ericaceae (Vaccinium myrtillus) and the Euphorbiaceae (Poranthera corymbosa) (see Piperidine... 

Simple quinolizidine alkaloids of the Lythraceae, "which include the well-known natural products (2S,4S,9aR)-(—)-lasubine I (1341) and (2S,4S,9aS)-(—)-lasubine II (1342) and substituted cinnamate esters thereof such as subcosines I and II, (1343) and (1344), are less common than those in which the quinolizidine forms part of a macroHde or cyclophane system containing a biaryl component (Figure 32). Since the macrocychc alkaloids are not pertinent to this review, they will not—with one exception—be discussed further vide infra). 

Figure 32 Simple quinolizidine alkaloids of the Lythraceae (-)-lasubine I (1341) —)-lasubine II (1342) (+)-subcosine I (1343) (+)-subcosine II (1344) (+)-sarusubine A (1347).

Lasubines I and II are alkaloids containing a 4-arylquinolizidine substructure that have been isolated from plants of the Lythraceae family and have attracted the attention of synthetic chemists for some time. While numerous racemic syntheses of these and related compounds have been reported, only a few enantioselective syntheses are known. Some examples of these syntheses are given below, and the strategies involved in these examples are summarized in Scheme 92. Three of these syntheses involve the creation of the quinolizidine system by formation of one bond at the a- or 7-positions, while the fourth approach is based on a ring transformation associated with a photochemical Beckmann rearrangement. 

Little of the chemistry of the Lythraceae was known prior to the 1960s beyond reports of the qualitative presence of alkaloids in a few genera. With the recognition of the novel alkaloid structures in Decodnn and Heimia, an examination of material from other genera gleaned from herbarium specimens was undertaken. The published results are included in those reported here. 

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... 

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). 

Lythraceae Alkaloids.— The rate at which quinolizidine alkaloids of the cryogenine (35) type are synthesized and degraded in Heimia salicifolia has been studied as has their sequence of appearance in growing plants. " The results do not yet add to the preliminary data so far obtained on these alkaloids. ... 

Alkaloids of the family Lythraceae were reviewed in Volumes 18 and 35 of this series (595, S). The latter review, published in 1989, was devoted to developments during the period 1979-1987, and overtyped to some extent with the review on simple indolizidine and quinolizidine alkaloids in Volume 28 (1). Also worth noting is a phytochemical and phytopharmacological review on the New World flowering shrub Heimia salicifolia, an important source of these alkaloids (596). 

Figure Structural types of the Lythraceae alkaloids 1 phenyl-quinolizkjinetype (10oH=lasubine 1,10/8H=lasubine II) 2 qui-nolizkSne-biphenyl lactone type (10uH=vertine, 1 -...

Partial degradation of the lythraceae alkaloids decodine (22) and decimine (23), isolated from Decodon verticillatus after being fed either 2-14c or 6 4c-lysine, indicated that the amino acid enters the alkaloid in a non-random fashion through a symmetrical intermediate. It was also demonstrated that two fragments derived from phenylalanine are incorporated into decodine. 

About 45 alkaloids from the above-ground parts of members of the Lythraceae have been studied (Golebiewski and Wro-bel, 1981). Several of these alkaloids contain quinolizidine... 

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),... 

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... 

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 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. 

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. 

Five new alkaloids have been isolated from the Lythraceae plant Lythrum Lanceolatum by Wright et al. (9). The structure and absolute configuration of two of these bases, lythrumine (123) and monoacetyllythrumine (124), were established on the basis of the X-ray analysis on lythrumine hydrobromide. On acetylation both the alkaloids yielded the same diacetate (125). 

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. 

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). 

The chirality of a precursor product relationship was determined by the use of doubly labeled lysine, in which one enantiomer was labeled only with tritium and the other with tritium and 14C (55). Comparison of the 3H/14C ratios of substrate and products demonstrated that decodine and decinine were derived from L-lysine, whereas pipecolic acid (186) was derived from D-lysine. Thus, pipecolic acid does not serve as a precursor of Lythraceae alkaloids (57). 

This body of evidence led to the conclusion that two intact C6-C3 units derived from phenylalanine are incorporated into lactonic Lythraceae alkaloids. One unit is the precursor of the phenylpropanoid part of the alkaloids (C-l 1 to C-19) and the other gives rise to the C-3 to C-l, C-20 to C-25 segment of the phenylquinolizidine part ... 

This volume of The Alkaloids presents timely reviews of three groups, the Erythrina, Lythraceae, and C20-diterpenoid alkaloids. The chapters are organized in the traditional manner and cover all aspects of the recent chemistry of these groups. A useful catalogue of C20-diterpenoid alkaloids is also included. One chapter is devoted to a discussion of the 13Carbon spectra of benzylisoquinolines and the fifth chapter collects and reviews work on the microbial and in vitro transformations of the alkaloids. Both subjects have attracted increasing attention in recent years. 

Once again the azaphenalene, Nuphar, and Lythraceae alkaloids are included in this Chapter. Perhaps the most notable achievement of the year is the synthesis of azaphenalenes of ladybird beetles by Ayer and co-workers.Amongst the new alkaloids, the novel pyridone quinoiizidine, mamanine (3) and its tetrahydro-derivative, pohakuline (5) are of special interest. ... 

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. ... 

Recent biosynthetic studies on the Lythraceae kaloids have concentrated on the macrolide alkaloids. Of interest is a demonstration that the cis- and /rnns-fused quinolizidinones 913 and 914 were effective and specific precursors for biaryl macrolide alkaloids such as vertine (915) and lythrine (916) in H. salicifolia, respectively, whereas the four possible monomethyl ethers of 913 and 914 were not incorporated effectively (597). Another in vitro incorporation study on H. salicifolia with labeled lysine, phenylalanine, and />-coumaric acid showed that 4-arylquinolizidinols, their /i-coumarate esters, and biaryl macrolide alkaloids are formed from different precursor pools, but cis- and trans-fased alkaloids within each class originate from a common metabolic pool (59S). 

Lythraceae Alkaloids.—Cryogenine (18) has been shown to incorporate [3- " C]-phenylalanine in Heimia salicifolia. Oxidative degradation established the incorporation of labels at the positions shown in (18) the difference in incorporation of the two units may be a function of the stage at which they normally enter the biosynthetic pathway. Although ring d and the whole of its C3 side chain are probably derived from phenylalanine, it is not yet clear whether this precursor supplies three or only one carbon atom of the quinolizidine system. 

Anti-inflammatory Compounds.—Claims for anti-inflammatory activity of alkaloids appear in the literature from time to time, but in view of the difficulties connected with the testing of such compounds, positive results should be viewed with caution. Recently it has been stated that cryogenine from Heimia salicifolia (Lythraceae) has anti-inflammatory activity. Lythraceae have been investigated broadly during recent years, probably because of an early claim that these alkaloids have hallucinogenic properties. The structure (31) has been proposed for cryogenine. ... 

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