Naphthyl isoquinoline alkaloids

Using a set of 40 naphthyl-isoquinoline alkaloids, Bringmann and Rummey (56) compared two different methods of generating alignments automatically. Typically, data are divided into a training set used to optimize the parameters of the model and a test set that does not influence the model in any way but is used for evaluation of the predictive abilities of the final model. In this study, all available compounds were used for model development, and given that the researchers synthesized and tested new compounds on a continuous basis, the test set consisted of newly synthesized chemical compounds. When seven newly synthesized compounds were evaluated and predictions were made, a poor correlation was seen between actual and predicted IC50 values (r 0.279). If instead, the results are evaluated as a classification of active or inactive, five of the seven structures are predicted correctly. 

The ingenious elucidation of naphthyl isoquinoline alkaloids has been reviewed very proficiently by Govindachari and Parthasarathy (11). Nonetheless, some of the numerous degradation reactions on which the structural proposal 1 for ancistrocladine was founded are briefly sketched in Schemes 1 and 2. 

Beside the Ancistrocladaceae, only one other plant family so far has been found to produce naphthyl isoquinoline alkaloids (see also Section IV,B), the Dionchophyllaceae (31-33). Triphyophyllum peltatum (Hutch, et Dalz.) Airy Shaw is a large liana (34), endemic to the rain forests of West Africa. From the twigs of this plant, Bruneton and Cave isolated a new alkaloid, named tri-phyophylline (57), which, in contrast to all kno n Ancistrocladus alkaloids (see Section II), has only one oxygen function on the isoquinoline part of the molecule. No degradation reactions have been described for any of the Triphyophyllum alkaloids. Based exclusively on spectral evidence, triphyophylline was assigned the structure 23 (see Table II). The stereochemistry of the two... 

Naphthyl Isoquinoline Alkaloids from Ancistrocladus Plants ... 

Bruneton s last communication (55) on naphthyl isoquinoline alkaloids includes work on the related plant D. tholonii Baill., also belonging to the Di-onchophyllaceae. It is not clear, however, which of the alkaloids 24, 25, 26, or 29, mentioned above, occur in this species. 

Scheme 3. Proposed biogenetic scheme for naphthyl isoquinoline alkaloids (S5,36).

Scheme 4. A possible nitrogen source for naphthyl isoquinoline alkaloids 38).

Apart from this preliminary report, Triphyophyllum peltatum and Dioncho-phyllum tholonii are the only species outside the Ancistrocladaceae that contain naphthyl isoquinoline alkaloids. The characteristic biochemical difference, that... 

Outside these two families, however, no other plants have been found to produce real tetrahydro-, dihydro-, and fully aromatic isoquinoline alkaloids in a polyacetate way. Closely related, but chemically a lactam, is siamine (40) from Cassia siamea Lam. (Leguminosae) (42). The structure suggests a biogenesis from a pentaketide precursor 41 (Fig. 2), thus requiring one acetate unit less than each of the naphthyl isoquinoline alkaloid moieties. 

Scheme 6. Possible biosynthetic relationship between naphthyl isoquinoline alkaloids and cooccurring naphthoquinones.

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. 

Neither 30 nor any of the terminally protected polyketones 46, 51, or 55 could be used as a basis for a total synthesis of naphthyl isoquinoline alkaloids. Synthetic efforts thus focused on a derivation of the central carbon atom of the polycarbonyl chain (54-56). 

Thus, the postulated diketo precursors 70 had become accessible by complementary biomimetic and nonbiomimetic synthetic pathways. Starting from these joint monocyclic key intermediates, the biomimetic synthesis of both bicyclic molecular moieties of naphthyl isoquinoline alkaloids was readily achieved 35,36,54.55). 

D. The Mixed Aryl Coupling to Naphthyl Isoquinoline Alkaloids... 

After these described biomimetic syntheses of racemic naphthyl isoquinoline alkaloids, optically active synthetic material had to be prepared in enan-tiomerically pure form, not only for a systematic screening of biological activity of the minor alkaloids, but also for a thorough reinvestigation of several published, obviously uncertain structures that could not be determined by X ray. For these purposes, an enantiomeric separation of the racemic material as obtained from the biomimetic syntheses seemed uneconomical, given the fact that all... 

The first naphthyl isoquinoline alkaloid to be synthesized in optically active form was ancistrocladine (1) itself, the most important and widespread of all the Ancistrocladus alkaloids (see Scheme 31). The effectivity of the ester bridge assisted aryl coupling method (as presented in Section V.D.) was demonstrated by the regioselective formation of the highly strained lactone 124, which— different from the corresponding triphyophylline precursor 108 (see Scheme... 

Naphthyl isoquinoline alkaloids have proved to be a novel group of structurally intriguing natural products. Their extraordinary substitution pattern seems to correspond to an unprecedented biosynthesis of isoquinolines from acetate units via P-polycarbonyl precursors. 

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. 

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