Alkaloid structural elucidations

The antimalarial properties attributed to preparations from Dichroa febrifuga by the Chinese were confirmed about 1944 and two alkaloids, febrifugine (999) and isofebrifugine (1000), were isolated eventually. After difficult structural elucidations, syntheses of ( )-febrifugine followed it proved to be half as active as the natural material, itself far better than quinine, but the therapeutic index was disappointingly low (67HC(24-l)490). 

Hi) Dehydrogenation. j3-Carboline derivatives may be obtained from tetrahydro-)3-carbohnes by zinc dust distillation or high temperatmre dehydrogenation with selenium or palladium black. Many of the complex indole alkaloids may be degraded, with bond cleavage, to yield simple )3-carbolines under these conditions and this approach has become a standard method in structural elucidations. Examples are numerous but outside the scope of this review. 

Cleavage of the hetero ring in a number of extended tetrahydro-j8-carboline systems was observed in the course of structural elucidation of tetrahydro-jS-carboline alkaloids. A few examples only will be given. The indole derivative 287 was isolated as one of the products of the selenium dehydrogenation of yohimbine (358 R = and... 

Figure 5.49 shows the four HOHAHA spectra obtained at 20, 40, 60, and 100 ms of hyocyamine, an alkaloid isolated from Datura fastusa. The various short-range and long-range homonuclear connectivities established on the basis of HOHAHA spectra of hyoscyamine provided a powerful tool for structure elucidation. The spectrum obtained with a mixing time of... 

Preparative-scale fermentation of papaveraldine, the known benzyliso-quinoline alkaloid, with Mucor ramannianus 1839 (sih) has resulted in a stereoselective reduction of the ketone group and the isolation of S-papaverinol and S-papaverinol M-oxide [56]. The structure elucidations of both metabolites were reported to be based primarily on ID and 2D NMR analyses and chemical transformations [56]. The absolute configuration of S-papaverinol has been determined using Horeau s method of asymmetric esterification [56]. The structures of the compounds are shown in Fig. 7. 

Haliclonacyclamine F (25), arenosclerin D (26), and arenosclerin E (27) have been recently isolated from the sponge Pachychalina alcaloidifera endemic in Brazil [26]. The alkaloids 25-27 were isolated from the cytotoxic, antibiotic, and antituberculosis MeOH crude extract of P. alcaloidifera by a series of separations on silica-gel and cyanopropyl-bonded silica-gel columns. The structures of compounds 25-27 were established by the same approach employed for the structural elucidation of haliclonacyclamine E (13) and arenosclerins A-C (14-16) [18], as well as by comparison with NMR data for this last series of alkaloids. The alkaloids 25-27 displayed moderate cytotoxic activity against SF295 (human CNS), MDA-MB435 (human breast), HCT8 (colon), and HL60 (leukemia) cancer cell lines. 

The Hofmann degradation is the most well-known C—N bond cleavage reaction, and its value to structural elucidation of alkaloids has been demonstrated (76). Hofmann degradation of tetrahydroberberine methohy-droxide (1) led to two products base A (2), the C-14—N bond cleavage product, and base B (3), the C-6—N bond cleavage product (Scheme 2) (17,18). The former was the major product when 1 was heated under reduced pressure, but the latter, the thermodynamically controlled product, predominated when the reaction was carried out at atmospheric pressure or in an alkaline medium because base A recyclized back to the starting quaternary base through the transannular reaction. In fact, 2 was heated in aqueous alcohol to afford 1. The mechanism of this recyclization reaction was discussed by Kirby et al. (19). 

The seco amide alkaloids have been subjected to various transformations, mainly for structure elucidation purposes. When treated with lithium aluminium hydride, arnottianamide (206) was converted to the tertiary amine, deoxyarnottianamide (224), which on methylation with the Rodionow reagent gave deoxy-O-methylarnottianamide (225) (172,175). Arnottianamide (206) could be O-acetylated (174) as well as O-methylated with diazomethane in HMPA (172). Isoarnottianamide (208) was O-methylated to trimethoxy derivative 226, which under Bischler-Napieralski conditions recyclized to the benzophenantridine alkaloid, chelilutine (227) (176) (Scheme 33). 

A major study on 13C-NMR spectroscopy of hasubanan alkaloids was carried out by Matsui et al. (5) (Table III). They proposed assignments of all carbon atoms including the direct and long-range hetero coupling. The C-9 and JV-methyl carbons of hasubanan alkaloids reveal shifts of 6 and 20 ppm higher frequency than those reported for morphinan alkaloids (9). On the other hand, the iV-methyl carbons of hasubanans exhibit a lower frequency shift of 10 ppm relative to those of hasubanalactam-type alkaloids (5). These results have been utilized for structure elucidation in later works (4,7,10-12). 

Table VII gives a survey of alkaloids that exhibit the hasubanonine-type cleavage. The characteristic fragmentation pattern of this group, possessing an a,/ -unsaturated carbonyl group in ring C, is significantly different from other groups. In the case of hasubanonine (5) (3), the most abundant and nitrogen-free ion peak was observed at m/z 315, which is important for structure elucidation of this group (2,73).

Yashodharan K, Cox PJ, Jaspars M, Lutfun N, Satyajit DS. Isolation, structure elucidation and biological activity of hederacine A and B, two unique alkaloids from Gle-choma hederaceae. Tetrahedron 2003 59 6403-6407. 

This contribution is an attempt to close this gap and therefore the organization of the chapter will be as follows. After a short outline of problems related to the nomenclature and delimitation of genera within the tribe Tabemaemontaneae, a summary of chemically investigated Tabernaemontana plants will be presented. Subsequently, the structure elucidation and chemistry of the most relevant alkaloids will be discussed. Finally, some noteworthly pharmacological activities will be outlined. 

The great number of different alkaloids found in Tabemaemontana precludes a discussion of the structure elucidation and chemistry of all of them. To keep the treatment concise, a major compromise was necessary. The alkaloids that have been reported in previous volumes of this treatise (as indicated in Table I) and their trivial modification will not be mentioned here. This compromise eliminates from the discussion well-established and long-known alkaloids that were isolated not only from Tabemaemontana but also from other genera. Moreover, the plumeran alkaloids isolated up to 1976 and ebuman-type and bisindole alkaloids isolated up to 1979 are covered in Volumes XVII and XX. The main efforts of this chapter will be focused on more recently isolated compounds, some of which are structurally and biogenetically relevant and have been found only in plants of the genus Tabemaemontana. 

The structural relationship among the above alkaloids was indicated by catalytic hydrogenation of 50, followed by mild Cr03-pyridine oxidation. This led to a mixture containing 44 as the major product and 45. The main work on structure elucidation was performed on 50, and this involved an interesting combination of chemical degradation and spectroscopy. 

During the past two decades a great number of papers have been published on the isolation, structure elucidation, synthesis and transformation, biogenesis, chemotaxonomy, and pharmacology of indole alkaloids. In this chapter we summarize the new results that appeared from 1968 to mid 1984 for the cory-nantheine-yohimbine group of monoterpene indole alkaloids with greater emphasis on their chemistry, excluding the related oxindoles and heteroyohimbines. 

Two important books on the biogenesis of indole alkaloids have been published (5, 6), therefore we do not intend to cover the literature of the biogenesis of corynantheine- and yohimbine-type alkaloids. Our chapter begins with the structure elucidation of the alkaloids isolated during the past two decades and proceeds with the synthesis, transformation, as well as spectroscopy of the alkaloids in question. 

A complex mixture of 10-methoxy-3,4,5,6-tetradehydro-18,19-dihydrocory-nantheol (17), 3,4,5,6-tetradehydroochropposinine (18), 10-methoxy-3,4,5,6-tetradehydrocorynantheol (19), and 3,4,5,6,18,19-hexadehydroochropposinine (20) has been isolated from the root bark of Neisosperma glomerata (Blume) Fosberg and Sachet (25). The approximative structure elucidation of alkaloids 17-20 was performed by H-NMR and mass spectral analysis of the unseparated mixture. 

Geissoschizine (30) (7) is one of the most widely investigated monoterpene indole alkaloids. Since the first structure elucidation, carried out by Rapoport... 

Kan-Fan and Husson reported the isolation and structure elucidation of 4,21-dehydrogeissoschizine chloride (32) from the leaves of Guettarda eximia (39). It has been suggested that this alkaloid is a biosynthetic intermediate of several... 

Adirubine (66), the first member of a new series of 5p-carboxy alkaloids having a corynane skeleton, has been isolated from Adina rubescens by Brown et al. (60). The first structure elucidation of adirubine, based on spectral data only, was incomplete (60). Final determination of the steric arrangement around ring D was performed by correlation with 5 p-methoxycarbonyldihydromancunine, and it proved to be alio (3a, 15a, 20a) (67). 

The application of chromatographic techniques to isolation, purification, structure elucidation, and identification procedures has created new possibilities and resulted in considerable progress in the important field of alkaloid research. 

In addition to the Annual Reports on NMR Spectroscopy monograph reviewing H-NMR and, 3C-NMR spectroscopy of alkaloids in three volumes (305), several books and reviews appeared concerning the 13C-NMR spectroscopy of naturally occurring substances (306-308). Therefore we would like to present only a limited number of examples of the exceptional applicability of these physical methods for structure elucidation and conformational analysis of complex molecules. 

In comparison with other spectroscopic methods, 13C-NMR spectroscopy affords the most valuable information for the stereochemical and conformational analysis of quinolizidine compounds. On the basis of the results, summarized in a review by Tourwe and van Binst (313) as well as in a series of publications (314-318), the steric structure elucidation of indolo[2,3-a]quinolizidine alkaloids has been facilitated. 

In the first place, the structure of the target molecule is submitted to a rational analysis in order to perceive the most significant structural features, and it may be useful to use different types of molecular models at this point. It should be remembered that a molecular structure has "thousand faces" and finding the most convenient perspective may greatly simplifly the synthetic problem. The synthesis of opium alkaloids, for instance, is much simplified if one realises that they are, in fact, derivatives of benzyltetrahydroisoquinoline (18) (see Scheme 3.8). This was indeed the inspired intuition of Sir Robert Robinson which led to the structural elucidation of morphine (19) and to a first sketch of the biogenetic pathway [22], and later on to the biomimetic synthesis of thebaine 20 [23] [24]. 

ISOLATION, STRUCTURE ELUCIDATION, AND BIOSYNTHESIS OF THE BISINDOLE ALKALOIDS OF CATHARANTHUS... 

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