Naphthalene-isoquinoline alkaloids

In this chapter, ephedrine and related alkaloids, the khat alkaloids (which are related to the ephedrines), and two other types of alkaloids are described. One of them is the naphthalene-isoquinoline alkaloids, which are described in Section 16.3.These alkaloids might also be classified as alkaloids derived from phenylalanine because they possess an isoquinoline skeleton. However, an extra Cj unit has been joined to the carbon to which the nitrogen is attached, as occurs in the case of ephedrine. Therefore, it is considered that the formation of these alkaloids might involve a biosynthetic pathway not utilizing phenylalanine. The other alkaloids are capsaicin and related alkaloids, which are described in Section 16.4. 

Two naphthalene-isoquinoline groups of alkaloids, ancistrocladidine (53) and ancistrotectorine (54), were isolated from Ancistrocladus heyneanus Wall [295], and A. tectorius (Lour.) Merr [296], respectively. The members of the plant family, ancistrocladaceae, are distributed in tropical Asia and Western Africa. Some are regarded as traditionally medicinal plants. The root of A. tectorius has been used to treat dysentery and malaria [296],... 

Additional strong evidence of the chemical plausibility of joint in vivo formation of both naphthalenes and isoquinolines from common p-polycarbonyl precursors was obtained from the in vitro imitation of the proposed biosynthetic pathway in the laboratory. These model reactions, which simultaneously allowed first total syntheses of naphthyl isoquinoline alkaloids, are depicted in Section V. 

Following the postulated biogenetic pathway (see Scheme 3), a chemical in vitro imitation, aiming at a biomimetic first synthesis of naphthyl isoquinoline alkaloids, had to consist of essentially four crucial steps (1) synthesis of suitable P-polycarbonyl precursors, (2) their primary cyclization to monocyclic diketones like 31 or 32, (3) the further differentiation to naphthalenes and isoquinolines, and (4) their mixed coupling to the complete natural alkaloids. 

This unusual biosynthetic pathway—the synthesis and regio-controlled cyclization of p-polyketones, optionally leading to tetrahydro-, dihydro-, or fully conjugated isoquinolines, or to naphthalenes and respective naphthoquinones— could be imitated effieiently in vitro. The smooth course of these chemical model reaetions underlines the chemieal plausibility of the proposed biogenetie scheme and simultaneously provides the basis for a first and variable total synthesis of naphthyl isoquinoline alkaloids. 

About 20 species of plant are known in the genus Ancistrocladus (Ancistro-cladaceae), which grows wild in the tropical areas of Asia, Malaysia, and West Africa. From this genus of plants, as well as two genera of the Dionchophyl-laceae family, naphthalene-isoquinoline-type alkaloids have been isolated. This type of alkaloid is quite rare, and only about 20 such alkaloids have been reported [1]. 

Replacing one carbon atom of naphthalene with an a2omethene linkage creates the isomeric heterocycles 1- and 2-a2anaphthalene. Better known by their trivial names quinoline [91-22-5] (1) and isoquinoline [119-65-3] (2), these compounds have been the subject of extensive investigation since their extraction from coal tar in the nineteenth century. The variety of studies cover fields as diverse as molecular orbital theory and corrosion prevention. There is also a vast patent Hterature. The best assurance of continuing interest is the frequency with which quinoline and isoquinoline stmctures occur in alkaloids (qv) and pharmaceuticals (qv), for example, quinine [130-95-0] and morphine [57-27-2] (see Alkaloids). 

Several tetra- and pentacyclic systems were prepared from Pro, which was first -substituted with naphthalene or phenanthrene rings whereupon the cyclization took place. Such reactions were used for synthetic ap-proaehes toward alkaloids vinceten from Cynachum vincetoxicum (the tetrahydrobenzo /]pyrrolo[l,2-Z ]isoquinoline system 146) (79LA1212 84AJC819) or tylophorine (65T2573). 

As mentioned, naphthylisoquinoline alkaloids are structurally unusual on account of the methyl group at the 3-position and oxygenation at the 8- and/or 6-position of the isoquinoline ring which points to a polyketide origin. This postulate has been supported by extensive studies conducted by Btingmann on the in vitro biomimetic synthesis of the naphthalene and isoquinoline portions of these compounds (ref. 13,14) and this work is worth briefly mentioning in a discussion on the total synthesis of these compounds. 

The first total synthesis of a naphthylisoquinoline alkaloid, the 7-1 linked O-methyltetradehydrotriphyophylline (55) isolated from the Dioncophyllaceae family (ref. 44), was reported in 1984 by Bringmann and coworkers (ref. 45). The requisite naphthalene 12 and isoquinoline 13 segments where available from biomimetic synthesis as previously detailed but attempted intermolecular coupling between the two moieties in their brominated forms under classical Ullmann type conditions (ref. 46) afforded only traces of the desired coupled product. Therefore, an intermolecular coupling approach utilising a temporary ether bridge was undertaken. 

The analogous cyclization of 75 allowed a specific synthesis of the monomethyl ether 73, the naphthalene part of 7-2 coupled alkaloids like 21 and 22 (36,55). All three naphthalenes 34, 73, and 74 also have been found free, not coupled to isoquinolines, for example, in tropical Ebenaceae (64,65). The ring closure reaction to 34, or, respectively, to 73, was found to be regiospecific the... 

Following the proposed biogenetic scheme (see Section IV,A), completion of a first total synthesis of entire alkaloids still required a regioselective coupling of sterically highly crowded naphthalenes with isoquinolines. Thus, as expected, direct methods like the classical Ullmann reaction of 94 and 95 failed, giving the desired mixed coupling product 96 only in traces (7) (see Scheme 22). 

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