The Dimeric Alkaloids of Calabash Curare

The structure of C-calebassine diiodide has been determined by X-ray crystallography 15). In this way the constitution and absolute stereochemistry of C-calebassine determined by chemical and spectroscopic methods (Volume VIII, p. 566) has been confirmed. 

Initial experiments showed that when nortoxiferine was heated in deuterioacetic acid (CHa-COOD) there was no exchange of deuterium with the alkaloid. Since these conditions were essentially those used for the dimerization of the Wieland-Gumlich aldehyde methochloride (Volume VIII, pp. 541, 547), dimerization of 17-deuterio Wieland-Gumlich aldehyde methochloride (XXV) to 17,17 -dideuteriotoxiferine-I (XXVI R = D central ring system only) should be possible without loss of deuterium. 

A comparison of the NMR-spectra of the deuterium derivatives with those of the corresponding protium species (XXVI R = H) shows conclusively that the signal from the 17,17 protons does indeed occur at the abnormally low field of 2.93 r, as previously postulated. 

Finally, deuterated toxiferine-I and C-dihydrotoxiferine-I were converted by air oxidation to 17,17 -dideuterio-C-alkaloid A and 17,17 - 

The hydrolysis of C-curarine to C-fluorocurarine (Vol. VIII, p. 569) with concentrated hydrochloric acid produces smaller amounts of two other compounds, ultracurine A and ultracurine B, notable for their very intense blue fluorescence in UV-light. The early investigations (16) led to the isolation of both of these degradation products as crystalline j8-anthraquinonesulfonates and the empirical formula C40H44N4++ or C44H44N4O++ was tentatively proposed for ultracurine A analyses of 

The method used to determine the molecular size involves pyrolysis of the alkaloid chloride LV to yield the corresponding nor base, that is, 

The success of this method depends upon the fact that the two basic Nb nitrogen atoms in the tertiary base (LVI) are sufficiently separated in space so that protonation or quaternization at one basic nitrogen atom does not greatly affect either of these processes at the second basic center. 

This same method, used initially for C-curarine, also showed C-calebas-sine to be and C-dihydrotoxiferine I to be C4oH4fiN + 

Tubocurarine (I) and the various synthetic curarizing agents such as succinylcholine (LXII) have two quaternary nitrogen atoms set some distance apart. The foregoing experiments allow the calabash curare alkaloids to be placed in the same class of compounds. 

C-Dihydrotoxiferine I chloride, C-tolKsN +Cl, [a]D —600° (1 1 aqueous alcohol), has two N-methyl groups attached at the quaternary Nb nitrogen atoms (39). Molecular distillation of the alkaloid chloride gives nordihydrotoxiferine with loss of methyl chloride this ditertiary base can be converted back into the bisquatemary alkaloid, as the diiodide, by methylation with methyl iodide (39). Dehydrogenation of C-dihydrotoxiferine I with sulfur or with zinc dust gives isoquinoline 

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The poisonous principle of calabash curare is C-curarine, a dimeric alkaloid derived from tryptophan.This alkaloid was first reported in 1937 [l],and total synthesis was achieved in 1964 [2]. C-Toxiferine I, an alkaloid with a structure similar to that of C-curarine, and with hydroxy groups at the 18 and 18 -positions, was isolated and characterized from the same plant [3,4].These alkaloids possess two of the strychnine-like moieties described in the previous section. The C of these alkaloids indicates the origin from calabash. 

The quaternary C-alkaloid D was first isolated (16) from a sample of calabash curare and was later encountered (24) as one of the products formed when C-dihydrotoxiferine I is treated with dilute acid in the presence of oxygen. Because of its low mobility on paper chromatograms, it was considered to be a dimeric alkaloid, and the formula C4oH48N4Or was proposed (116) on the basis of analyses of the several crystalline salts afforded by this alkaloid. Despite its bisquaternary nature, C-alkaloid D has a low curarizing activity, and in this respect it is similar to caracurine V dimethochloride mentioned earlier. C-Alkaloid D chloride shows [a]D — 51° (in 1 1 aqueous acetone). 

Some of the most difficult structural problems in the indole alkaloid field are associated with the bisindole alkaloids of the vobtusine type. Since 1955, vobtusine has been isolated on numerous occasions, often in large quantities, from the Apocynaceae species Callichilia, Conopharyngia, Rejoua, and Voacanga A correct molecular formula could only be determined by high-resolution mass spectrometry. In 1966 a partial structure was proposed for the alkaloid and later in the same year a complete structure was put forward. An unambiguous structural proof is, however, still lacking. The difficulty arises from the complete resistance of the alkaloid and its derivatives to cleavage, in contrast, for example, to the dimers of the voacamine and vinblastine types. Non-cleavable dimers occur also in calabash-curare but in these cases chemical correlation with cleavable alkaloids has been possible (see Section 2, p. 209). To date no bisindole alkaloid related to vobtusine has been found which can be split into monomeric units. 

An analysis of the chromophore of the dimer and dimeric derivatives is a basic necessity since cleavage reactions often result in modification of one or both of the monomeric chromophores present in the alkaloid itself. Such behaviour is shown by the bisindole alkaloids of the calabash-curare, presecamine, pycnanthine, Alstonia, and pleiomutine-umbellamine groups. Such chromo-phoric changes are of paramount importance in determining the mode of coupling. 

The alkaloid content of curare is from 4% to 7%. The most important constituent in menispermaceous curare is the bis-benzyltetrahydroisoquinoline alkaloid (+)-tubocurarine (Figure 6.48). This is a monoquaternary ammonium salt, and is water soluble. Other main alkaloids include non-quaternary dimeric structures, e.g. isochondrodendrine and curine (bebeerine) (Figure 6.48), which appear to be derived from two molecules of (R)-N-methylcoclaurine, with the former also displaying a different coupling mode. The constituents in loganiaceous curare (from calabash curare, i.e. Strychnos toxifera) are even more complex, and a series of 12 quaternary dimeric strychnine-like alkaloids has been identified, e.g. C-toxiferine (toxiferine-1) (see page 359). 

Streptomyces distallicus the structure elucidation and synthesis have also been made by them.165 A wide variety of porphyrins which are derivatives of porphin (125 R = H) occur in nature and exert three biological functions (a) oxygen storage and transport, as in hemoglobin, (b) cellular respiration as in the cytochromes, and (c) photosynthesis, as in the chlorophylls for detailed discussion of structures and synthesis of naturally occurring porphyrins, see references.166 Recent developments in the chemistry of polypyrrolic compounds have been reviewed.167 Several naturally occurring indole alkaloids have dimeric structures of type B,168 an example of which is c-toxiferine-I, a calabash curare alkaloid found in South American species of Strychnos.169... 

On the basis of structure the dimers can be clearly divided into two groups. The first is comprised of alkaloids with identical or very closely related components in which the same centres act as linkage positions. The Calycanthaceous and Calabash-curare-South American Strychnos alkaloids make up this group. The second group consists of dimeric bases in which the alkaloid components are of a different structural type (e.g. geissospermine, vinblastine, and tubulosine) or in which two similar halves are linked unsymmetrically through two different centres e.g. macralstonine). The bisindole alkaloids will be discussed in this order. ... 

All dimeric curare alkaloids are derived from the monomeric units Wieland-Gumlich aldehyde (32) and 18-desoxy-Wieland-Gumlich aldehyde (34) or their respective iV(j,)-metho-salts (33) and (35). The key substance for the synthesis of the dimeric calabash alkaloids is therefore Wieland-Gumlich aldehyde (32). Under the name caracurine VII it has been isolated from the South American Strychnos toxifera F. Schomb. and S. subcordata Spruce in the form of its V(j,)-metho-salt (= alkaloid 8 = hemitoxiferine = caracurine VII metho-salt). 

The presentation here has been primarily concerned with the synthetic relationships between the dimeric calabash-curare alkaloids. Literature is only cited when it is not contained in the recently published review articles. In these works all the arguments leading to the structural classification of the alkaloids are fully discussed and the important contributions of the schools of H. Wieland and P. Karrer indicated. 

In continued studies73 of the dimerization of tetrahydrocarbazole derivatives to give the central chromophoric section of the calabash curare alkaloids, it has been shown that the presence of an ethylamino-side-chain can be tolerated thus (83a) gives (84a) and (83b) gives (84b) (Scheme 30). 

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