Chapter 2 - The Sarpagine Group of Indole Alkaloids

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Introduction

The sarpagine alkaloids have been reviewed only twice previously in “The Alkaloids” series (1,2). As both of these articles appeared in the sixties, they are relatively obsolete and the need for a new review in the series is clear. A somewhat more recent review article appeared in 1983 in the series “Progress in the Chemistry of Organic Natural Products” (3), and that is now also out-of-date. Yearly summaries have been compiled by Saxton (4), and short reviews have occasionally appeared in connection with other topics (3., 4., 5., 6., 7., 8., 9.). This chapter covers the literature up to the end of 1997. The number of known monomelic structures has grown markedly in recent years to a present count of 80. Of these, perhaps 10 may be artifacts and a few structures have not been convinc-ingly determined (discussed later). In addition, nine bisindole alkaloids containing at least one monomeric sarpagan unit have been isolated, increasing the total number to 89.

All sarpagine alkaloids contain the polycyclic sarpagan ring system as a structural element. The “biogenetic numbering” of Le Men and Taylor (10) is used throughout this article (Fig. 1). The 3-oxygenated sarpagine derivatives, which exist in part in the 2-acylindole form and thus behave in a different manner, are not included in this review (Scheme 1). Readers with a special interest in these compounds are referred to articles given in Kingston and Ekundays (11).

Section snippets

Occurrence

The sarpagine alkaloids occur mainly in the plant family Apocynaceae, the most important genus being Rauvolfia* and they are also found in the family Loganiaceae. To date, sarpagine alkaloids have been found in the following genera: Alstonia, Amsonia, Aspidosperma, Cabucala, Catharan-thus, Diplorhynchus, Ervatamia, Gabunia, Geissospermum, Gonioma, Ha-zunta, Hunteria, Lochnera (Vinca), Melodinus, Neisosperma, Ochrosia, Pandaca, Peschiera, Picralima, Pleiocarpa, Rauvolfia, Rhazya, Stemmade-nia,

VAN TAMELEN SYNTHESIS OF THE “DEOXYAJMALAL SYSTEM”;18,19-DlHYDRO-Na-METHYLVELLOSIMINE (102a) AND ITS C-16 EPIMER (102b)

About thirty years ago van Tamelen and Oliver (201,202) presented a synthetic study, based on their biosynthetic suggestions (discussed later), that they claimed to lead via a sarpagan ring system (“deoxyajmalal system”) to the six-ring indole alkaloid ajmahne (99). The “crucial steps” in their approach to the sarpagan ring system were the regioselective formation of the Δ4(5)-iminium ion 100 (realized by decarbonylation; 101 → 100), and subsequent spontaneous bond formation between C-5 and

Reactions

Many reactions and transformations that in earlier days played an important role in the structure determinations of the sarpagine derivatives, have been presented in previous reviews (1,2). These are less important today, when structural determinations are made in other ways, and interested readers are referred to Koskinen and Lounasmaa (3) and Saxton (4). A titre d’examples, here are some recent transformations.

E-Akuammidine (53) can be transformed to vellosimine (1) as shown in Scheme 13 (19

Biosynthesis and Biogenesis

The general role played by strictosidine (151) (Fig. 8) in the biosynthesis of all monoterpenoid indole alkaloids is firmly established (220., 221., 222., 223., 224.). In the biogenetic formation of sarpagine (and ajmaline) alkaloids, the van Tamelen proposal (201,202) has been generally accepted (213,222,223), that is, that formation of a bond between C-5 and C-16 in the intermediate 4,5dehydrogeissoschizine (Δ4(5)-iminium system) (152) leads to the sarpagan skeleton (152 → 51). In explaining

1H NMR SPECTROSCOPY

Modern high-field 1H NMR techniques (correlated spectroscopy (COSY), heteronuclear chemical shift correlation (HETCOR), nuclear Overhauser enhancement (NOE), etc.), which generally permit determination of the chemical shifts and coupling constants of all protons (and connectivities between certain groups), have greatly simplified the structural determination of organic natural products (e.g., 231., 232., 233., 234., 235.). This has certainly been the case in the field of sarpagine alkaloids.

The

Pharmacology

Very few pharmacological effects have been indicated for the alkaloids of the sarpagine group. Normacusine B (2) has sedative and ganglion blocking activity (256). Lochnerine (25) shows hypoglycemic activity (257), and pericyclivine (18) has been indicated to have weak cytotoxic activity against leukemia P-388 (112). Gardnutine (20), gardnerine (26), and hydroxygard-nutine (42) have been shown to have ganglion blocking effects (258).

The mixture of constituents [e.g., normacusine B (2),

Perspectives

Altogether 89 alkaloids belonging to the sarpagine group (sensu stricto) have been isolated from plant sources. It can be expected that the intensity of the search for new alkaloids of the sarpagine type will continue. Recently, considerable effort has been concentrated on the biogenetic formation of sarpagine alkaloids. Although considerable progress has been made (vide supra), several crucial problems still remain. The research on cell culture methods towards the preparation of sarpagine

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