Ervatamia Alkaloids

Ervatamine, 20-epiervatamine, and 19, 20-dehydroervatamine have been obtained from Ervatamia orientalis (Apocynaceae), a small tropical tree, and from other Ervatamia species (89). 

These 2-acyl indole alkaloids are peculiar in that there are three carbon atoms between the indole nucleus and the N, atom. These alkaloids are thought to be biosynthesized from vobasine-type 2-acyl indole alkaloids. 

Applying the Potier-Polonovski reaction, vobasine-type indole alkaloids such as vobasine, dregamine, and tabernaemontanine could be transformed into dehydroervatamine, 20-epiervatamine, and ervatamine, respectively (70). 

These transformations can be related to a biogenetic process, which is supported by the fact that both types of alkaloids exist in the same plant. 

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The above sequence mimics the proposed biosynthesis of Ervatamia alkaloids and in this context Thai and Mansuy (190) set out to determine whether an enzyme preparation would be able to promote the same transformation. By incubation of dregamine hydrochloride with a suspension of liver microsomes from a rat pretreated with phenobarbital (as a good inducer of P-450 cytochromes) in the presence of NADPH and 02, 20-epiervatamine (45) was formed together with the major metabolite Nl -demethyldregamine. It is well known that microsomal reaction on tertiary amines results in Af-oxide formation or N-deal-kylation. Thus it is likely that 45 was derived either from a rearrangement of dregamine JV4-oxide, catalyzed by the iron cytochrome P-450 or from one-electron oxidation of 30. 

In China, the bark and leaves are used for the treatment of fractures. The roots are used in Malaysia to recover from childbirth and exhaustion, and a paste of the plant is used to treat orchitis. The plant contains indole alkaloids such as conodurinine, 19 (S) hydroxyconoduramin, 19 (S)-hydroxyervahanine A, and related iboga alkaloid congeners, and like the species mentioned earlier, and in fact the genera Ervatamia, in general, would be worth investigating for serotoninergic activities (17). 

In 1971, Knox and Stobbe isolated, from T. orientalis (Ervatamia orientalis), ervatamine (44, C21H26N203, MP 98°C), 20-epi-ervatamine (45, C2IH26N203, MP 187°C, [a]D —22°), and 19,20-dehydroervatamine (50, C21H24N203, MP 200°C, [a]D +53°C), which were the first examples of a novel class of 2-acylindole alkaloids, lacking the most common indolylethylamine moiety (151). 

A new amorphous alkaloid has been recently isolated from the Chinese plant T. bufalina (Ervatamia hainanensis) collected on Hainan Island (53). Its mass spectrum showed a molecular ion at m/z 382, corresponding to C23H30N2O3. From the fragmentation pattern, this compound would appear to be a coronaridine derivative in which a C2H50 unit is attached to the aliphatic moiety of the molecule. The structure 111 with (S) configuration at C-3 was determined by a detailed analysis of its H-NMR spectrum (Table IV) in comparison with the data of other ibogan alkaloids. 

The related alkaloids ervaticine (15) and apparicine (16a) have been isolated from the leaves of Ervatamia coronaria (85H(23)2975) and from the wood of Vallesia antillana (77MI249), respectively. The latter exhibits high antibacterial activity. Subsequently, 16(S)-hydroxy-16,22-dihydroapparicine (16b) was isolated from the leaves of T. dichotoma (84JNP835). 

Tabernanthe orientalis. This plant is now called Ervatamia orientalis, and is found in Western Australia. The leaves contain ibogaine, along with six minor alkaloids that are closely related, structurally. 

Ervatamia, Gabunia, Hazunta, Muntafara, Pagiantha, Pandaca, Peschiera, Phrissocarpus, and Stenosolen, All of these contain alkaloids related to Ibogaine. 

The first extractions of Strempeliopsis strempelioides K. Schum. (Family Apo-cynaceae), from Cuba, reveal that it is rich in alkaloids. The leaves and stem bark contain, amongst others, (+)-tubotaiwine and (+)-condylocarpine, and the stem bark also contains (-)-apparicine.80 Apparicine (pericalline) also occurs, together with O-acetylvallesamine, 19,20-dihydrocondylocarpine, and eleven other alkaloids, in the wood and stem bark of Ervatamia heyneana (Wall.) T. Cooke,81 and... 

Camptothecin Group.—Camptothecin and 9-methoxycamptothecin are two of the major cytotoxic alkaloids of the wood and stem bark of Ervatamia hey-neana. li3°... 

Catharanthine—Ibogamine-Cleavamine Group. Catharanthine is one of the alkaloids produced in suspension cultures of the 200 GW cell line of Catharanthus roseus, 2a and ibogamine has been found in the stem and root bark of Hazunta modesta var. modesta subvar. montana.62 Four Ervatamia species have been shown to contain several alkaloids of this group.64 Thus, E. orientalis (R. Brown) Domin contains voacangine, conopharyngine, pandine, and pandoline, E. daemeliana... 

The seeds of Centaurea moschata contain alkaloids with a 5-hydroxyindole structural unit, namely moschamine 87, moschamindole 88, and moschaminindolol 89 <1997MI189>. Ervatamine-type indole alkaloids, for example, 6-oxo-16,20-episilicine 90, 16,20-episilicine, and 6,16-didehydro-20-episilicine have been isolated from Ervatamia officinalis <2005HCA2537>. 

Six new monomeric alkaloids were isolated from the root bark and leaves of Ervatamia hirta, of which five (105,106, 109 - 111) possess the normacusine B-afTinisine skeleton while the other (112), is the N-oxide of norfluorocurarine [91]. Compounds 105 and 106 were readily identified as the C(I6) epimers of normacusine B and affmisine, respectively, by comparison of their NMR spectral data with that of normacusine B (107) and affinisine (108). Similarly, compounds 109 and 110 were readily shown to be the O-acetyl derivative of 16-epi-affinisine and the N-oxide of affinisine, respectively. The remaining new alkaloid, dehydro- 16- pi-... 

The second dimeric alkaloid conophyllidine (304) is identical in all respects with conophylline except for replacement of the epoxide function at positions 14 and IS of the tabersonine epoxide unit by a double bond. Conophylline has also been subsequently isolated from the South American species, Tabernaemontana glandulosa [182], and from the Thai species, Ervatamia microphylla [183]. It has also been reported from another Malaysian species, Ervatamia polyneura, under the name polyetvine [184]. The leaf extract of Ervatamia polyneura also yielded the related dimer, polyervininc (306), which is similar to conophylline except for the aromatic portion of the vincadifformine unit which now possesses an indoline dione chromophore, existing predominantly in its zwitterionic quinoniminium form. 

Conofoline has also been isolated from another Malaysian Tabemaemontana species (Ervatamia peduncularis) under the name pedunculine [185]. The same plant also furnished another dimeric alkaloid, peduncularidine (307), which shares the common oxygenated tabersonine-P-epoxide moiety of conofoline but differs in the second unit which is now an opened form of (-)-mehranine, with a trans diol functionality at position 14 and 15 instead of a P-epoxide function. The epoxide ring opening by a water molecule is anticipated to occur preferentially at the less hindered carbon (14 ) resulting in a H(14 P), H(15 a) configuration. This proposal was supported by the ROESY spectrum which showed correlations between the axial H(2 ) and H( 17 ) with H(14 ), indicating that the latter has p stereochemistry. 

Several new sources of quebrachamine (5) (10-16) and, particularly, voaphylline (conoflorine, 6) (15,17-34) have been found in recent years. Other known alkaloids encountered in recent extractions include vincadine (7) (35,36), 14,15-didehydro-epivincadine (8) (37), rhazidine (9) (38), and 12-methoxyvoaphylline (10) (39-41). New alkaloids include quebrachamine hydroxyindolenine (strictanol, 11), which has been found in the fruits (42) and leaves (43) of R. stricta, and voaphylline hydroxyindolenine (12), for which five sources have been reported (20,22,27,34,44). In common with many other hydroxyindolenine derivatives of easily oxidized alkaloids, these may well prove to be artifacts of the extraction process. Ervayunine (13), the enantiomer of voaphylline, occurs in the roots of Ervatamia yunnanensis... 

The recent reports of the occurrences of these alkaloids are given in Table II. Pandoline (657) has been isolated from the leaves and stems of Melodinus polyadenus (Baill.) Boiteau 99, 373), from Ervatamia obtusius-cula Mgf. (373), and from the leaves of E. lifuana Boiteau 374), Tabemae-montana citrifolia L. 32), Stenosolen heterophyllus (Vahl) Mgf. 29, 375), and E. orientalis (R. Brown) Domin 374). 20-Epipandoline (658) occurs in the first four of these species, and pandine ( 9) in the last four, and also in the stems and leaves of Tabernaemontana pandacaqui Poir 376). 

Quite the most intriguing new indole alkaloidal structural type to appear this year is that of ervatamine (17b) which occurs, together with 20-epi-ervatamine (17c) and 19,20-dehydroervatamine (17a), in Ervatamia orientalis.26a A description of the degradations (Scheme 5) which led to the structural assignments is included in this sub-section on the basis of a possible biogenetic relationship to alkaloids in this class (see below). 

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