Polycyclic aromatic alkaloid

During the last decade a series of structurally fascinating and biologically active fused polycyclic aromatic alkaloids has been isolated from marine sources. One such alkaloid, pan-therinine, has recently been synthesized using the Suzuki reaction (Eq. (32)) [62]. 

Much interest and research over the past 15 or so years has been directed towards ascidian metabolites because of the high incidence of pharmacological activity that they display. Few comprehensive reviews exist on the topic the only general ones being those produced by Davidson in 1993 [1,2] and the Marine Natural Product literature reviews by Faulkner which always contain a section on tunicate metabolites [3-13]. Although a number of non-nitrogenous metabolites have been isolated from the tunicates, the majority of compoimds isolated have been derived from amino acids. In particular, the two most commonly encountered classes are cyclic peptides and polycyclic aromatic alkaloids. 

Bowden, B,F McCool, B,J and Willis, R.H. (2004) lihouidine, a novel spiro polycyclic aromatic alkaloid from the marine sponge Suberea n,sp, (Aplysinellidae, Verongida). J. Org. Chem., 69, 7791-7793. 

Zeng, C.-M., Ishibashi, M., Matsiunoto, K., Nakaike, S., and Kobayashi, J. (1993) Two new polycyclic aromatic alkaloids from the Okinawan marine sponge Biemna sp. Tetrahedron, 49,8337-8342. 

Bracher, F. and Papke, T. (1996) Polycyclic aromatic alkaloids, XI. A convenient formal total synthesis of the cytotoxic marine alkaloid amphimedine. Liebigs Ann. Chem., 115-116. 

Bracher, F. (1992) Polycyclic aromatic alkaloids. 8. The structure of neocalliactine acetate proof by total synthesis. Eur. J. Org. Chem., 1205-1207. 

Cyclization of iminium ions onto arenes were first described by Pictet and Spengler in 1911, with the formation of tetrahydroisoquinoline 152 (Equation 10) [125]. This versatile transformation has been widely used in the diastereoselective synthesis of polycyclic aromatic alkaloids of biological interest, in particular of tetrahydro-/5-carbolines 154 (Equation 11) [126]. A few selected examples that highlight stereoselective Pictet-Spengler reactions are discussed below [9, 103, 127]. 

Removal of the amide function is much easier if the reaction is intramolecular, and —CONEt2 amides (sometimes even —CONPr-i2 amides) may be converted to lactones, lactams and other heterocycles in this way . Addition of an aldehyde or ketone as an electrophile generates a hydroxyl group (in some cases, atroposelectively, as it happens —though this is usually irrelevant to the stereochemistry of the product) which cyclizes to give a lactone via a benzylic cation in acid. This reaction has found wide use in the synthesis of polycyclic aromatics, particularly alkaloids. 

A very large number of substituted phenanthrenes have been made from stilbenes by this photocydization method, as have more complex polycyclic aromatic compounds by related reactions involving a single cydizatlon (e.g. 3.64 for chrysenes) or two, or more, successive cydizations le.g. 3.65). The reaction can be nicely adapted to provide a route from 1-benzylidenetetra-hydroisoquinolines to alkaloids of the aporphine family (e.g. 3.66). 

Intercalation has been demonstrated with a number of other compounds having a polycyclic aromatic system and groups capable of forming hydrogen bonds. Among such compounds are the antibacterial 9-aminoacridine, the antimalarials mepacrine and chloroquine, the veterinary trypanocide ethidium (246), the thioxanthone lucanthone (247 R = Me) and its more active metabolite hycanthone (247 R = CH20H), which are used in the treatment of schistosomiasis, and the antineoplastic alkaloid ellipticine (248). A number of antibiotics, including the actinomycins, echinomycin and bleomycin, also intercalate. 

Fused tetra- and pentacyclic aromatic alkaloids are a new, emerging group of compounds from marine organisms. Amphimedine (187) was isolated from a Pacific sponge (Amphimedon sp.) as a cytotoxic compound in 1983 and was the first example of a polycyclic alkaloid (158). A pigment from the sea anemone Calliactis parasitica, named calliactine, has been known for many years, but the structure elucidation of calliactine was a difficult problem (159). In 1987 the structure of calliactine was proposed to be 188 on the basis of modern spectroscopic methods as well as chemical... 

A variety of plant substances with planar, polycyclic, aromatic structures can intercalate with DNA, examples being the quinoline alkaloid camptothecin and the furanocoumarin phenolic psoralen (Table 12.1). A variety of plant-derived anthraquinones and naphthoquinones bind to DNA and it is notable that the structurally related anthraquinones mitox-antrone and adriamycin are clinically employed as anticancer drugs (Table 12.1). DNA-binding compounds that interfere with DNA repair, DNA replication and gene expression are cytotoxic and have potential as anticancer agents (see Chapter 9). 

The photocyclization of stilbenes (211) (including its in situ oxidation) to phenanthrenes (213) and that of conjugated arylalkenes to polycyclic aromatics constitute one of the most studied and widely used applications of organic photochemistry. Its potential synthetic utility is amplified by the existence of a number of natural products (mainly alkaloids) that contain a phenanthrene subunit in their structure. In view of the plethora of examples contained in several excellent reviews, only selected examples will be presented here with focus on the selectivity of the process. 

Due to the prevalence and diversity of pyrrole and indole alkaloids and the limitations of space, no attempt will be made to describe all of the synthetic efforts in this area. Of those syntheses wherein the construction of a pyrrole ring was of major importance, most efforts were devoted to the marine polycyclic aromatic lamellarin class of alkaloids and total syntheses of lamellarins-D, -G, -K and -O <97X5951, 97AGE155, 97CC2259, 97CC207> were reported Although not a total synthesis, Furstner reported a Pd-mediated route to the macrotricyclic core of the anti-leukemia alkaloid, roseophilin <97JA2944>. 

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