Open access

Aspidosperma Terpenoid Alkaloids — Biosynthetic Origin, Chemical Synthesis and Importance

Written By

Pedro Gregório Vieira Aquino, Thiago Mendonça de Aquino, Magna Suzana Alexandre-Moreira, Bárbara Viviana de Oliveira Santos, Antônio Euzébio Goulart Santana and João Xavier de Araújo-Júnior

Submitted: 20 May 2014 Published: 30 September 2015

DOI: 10.5772/59758

From the Edited Volume

Phytochemicals - Isolation, Characterisation and Role in Human Health

Edited by A. Venket Rao and Leticia G. Rao

Chapter metrics overview

2,535 Chapter Downloads

View Full Metrics

1. Introduction

Since a long time ago health sciences and natural products have been linked by the use of remedies and poisons, and nowadays there is little doubt that humans used natural drugs long before the emergence of written history [1,2]. The Ebers Papyrus dating from about 1600 BC, is one of the oldest medical treatise, which documents natural product-derived drugs used by the Sumerians and Akkadians in the 3rd century BC. Today there is information on medicinal plants dating back over about 500 years, as documented in herbaria. Laboratory studies of medicinal natural products started only about 200 years ago, with the isolation of of morphine, an alkaloid, from opium (Papaver spp.) [2,3].

Aspisoperma genus (Apocynaceae) species are trees of a great diversity of sizes that grow in different habitats and are distributed mainly among the Americas; In Brazil about 50 species of this genus have been catalogued [46]. There are several reports in the literature concerning the folk utilization of plants of this genus, as in treatment of malaria, dysentery, appendicitis, wounds, fever, dyspnea, asthma, scabies, stomachache, cough, constipation, boils, rheumatism, leishmaniasis, toothache, urinary tract inflammation and dermatitis. However several studies show that some plants of the genus are not recommended for pregnant women because of their potential abortifacient and teratogenic effects [728].

Given the diversity of popular uses of plants of the genus Aspidosperma as well as the predominance of terpenoid-alkaloids production in this genus and the importance of these substances for organic synthesis, medicinal chemistry and for knowledge of the biosynthetic pathways used by plants to produce them, we propose to review the literature concerning the aspidosperma-type terpenoid-alkaloids chemical synthesis and their biological potential.


2. Biosynthesis of Aspidosperma terpenoid alkaloids

The isolation of alkaloids from species of Aspidosperma trees and their structural elucidation give rise to theories that attempt to explain their biosynthetic origin. In the field of indole-type alkaloids, one of the earliest theories to explain its biosynthesis arose in 1933, proposing that this type of alkaloid has origin in the reaction between tryptophan, phenylalanine and glicine (although at the time the proposed structures do not represent exactly the known reality today) [29]. Revisions of this theory lead to a new biosynthetic route, proposing that the indole-type alkaloids are derived from shikimic and prephenic acids and their interactions with seco-prephenate-formadehyde units and aromatic aminoacids as tryptamine and tryptophan (figure 1) [30,31]. As Aspidosperma type alkaloids were isolated theories that tried to explain their biosynthetic origin began to emerge, which, at this moment, were based on the chemical synthesis of such alkaloids, as done by several research groups [32].

Figure 1.

Early propositions for indole alkaloid precursors.

Early work on proof of terpenoid alkaloid biosynthesis were based on administration of deuterium-labelled precursors of alkaloids to the plants tested and analysis of the metabolites produced to confirm a proposed biosynthetic way. The earliest proposition for the biosynthesis of Aspidosperma terpenoid alkaloids was the synthesis via mevalonate pathway, demonstrated in 1966 by the administration of 1-[²H2]-geraniol and 2-¹4C-geraniol to Vinca rosea and mass spectrometry detection of labeled vindoline, what allowed the proposition of the biosynthetic route showed in figure 2 [33,34]. This biosynthetic way was refined two years later with the demonstration that administration of 14C-labelled loganin (produced by the administration of 2-¹4C-geraniol to Meyanthes trifoliata) to V. rosea and Rawfolia serpentina allowed the isolation of 14C-labeled catharantine, serpentine, ajmalicine, vindoline and perivine [35], whose biosynthetic mechanism was detailed elsewhere [36–47].

Figure 2.

Proposal to Aspidosperma terpenoid alkaloid biosynthesis (adapted from [1-2]).


3. Chemical synthesis of Aspidosperma terpenoid alkaloids

Since the structure elucidation of the first isolated Aspidosperma alkaloids, various alternatives and techniques have emerged, due mainly the great structural complexity of this family of alkaloids. One of the earliest syntheses of an Aspidosperma alkaloid was published by a group from Havard University in 1959, which obtained the recently-isolated alkaloid ellipticine from condensation of indole with 3-acetylpyridine followed by reduction and pyrolisis, as shown in figure 3 [48].

Figure 3.

First synthesis of ellipticine.

Many years later, a new synthesis of aspidosperma-type skeleton was published, in a very simple way using four steps (figure 4) [49]. Another example is the synthesis of quebrachamine, one way published in 1966, and another three ways, one of them based on alkylation of cyclic enamines, other starting with 1,3-propanediol and another based on the cleavage of a thioketal group (figure 5) [5053].

Figure 4.

Synthesis of 3-Methylaspidospermidine (adapted from [49]).

Figure 5.

Total synthesis of quebrachamine.

Despite the many synthetic routes described for obtaining quebrachamine, none was obtained with enantiomeric purity until the problem was addressed in 1980, with the development of a synthetic route to (+)-quebrachamine using L-glutamic acid as a chiral template (figure 6) [54].

Figure 6.

Enantioselective total synthesis of quebrachamine

Enamines were also utilized in the synthesis of aspidospermine, as showed in 1971 by a group from Rice University (figure 7) and other groups [55,56].

Figure 7.

Synthesis of aspidospermine.

In 1978 was published a work that introduced a conceptually new approach to the synthesis of Aspidosperma-type alkaloids, the photocyclization-rearrangement or heteroatom directed photoarylation of anilinocyclohexanones, exemplified by the synthesis of the indolines A and B shown in figure 8 [57], this concept being expanded many years later, with the demonstration of different techniques of photo-induced reactions [58–60].

Figure 8.

Photoarylation in the synthesis of Aspidosperma-type substructures.

Given the biosynthetic route proposed by Wenkert [30], a group from Yale University developed a synthetic route for obtaining the alkaloid minovine in a biogenetically modeled way (figure 9), refined many years later by the same group [61,62].

Figure 9.

Synthesis of minovine.

Based on the fact that the Aspidosperma alkaloids share common structural features, a group from the Chinese Academy of Synthesis developed a strategy to aspidophytine enantioselective and stereo-controlled synthesis that could be applied to the synthesis of several other alkaloids of this family by simply varying the initial aniline (figure 10) [63].

Figure 10.

Aspidophytine synthesis (adapted from [63]).

Another powerful technique for the Aspidosperma alkaloids skeleton is the utilization of aza-Cope rearrangements, utilized for the first time in 1981 for the stereoselective synthesis of 9a-arylhydrolilolidines precursors of vindoline (figure 11) and later expanded to other alkaloids [6466].

Figure 11.

Application of aza-Cope rearrangement (adapted from [64]).

Based on the premise that Heck reaction is a powerful method for the construction of quaternary carbon centers, researchers from Kyoto University decided to apply this methodology to the entantioselective synthesis of (-)-epieburnamonine (figure 12) [67].

Figure 12.

Utilization of Heck reaction on the construction of intermediates in terpenoid alkaloids synthesis (adapted from [67]).

Exploiting the possibilities of C-H bond functionalization on the pyrrole ring, a group from Cambridge University recently proposed the total synthesis of rhanizilam-type alkaloids as precursors to Aspidosperma-type alkaloids, as shown in figure 13 [68].

Figure 13.

Metal-catalyzed C-H bond functionalization on terpenoid alkaloid synthesis (adapted from [68]).

3.1. Aspidosperma alkaloid precursors

Another field of great interest is in synthesis of precursors which can serve to the achieve greater structural diversity from common structures. Various approaches have been utilized in this field, such as ketone annelation of endocyclic enamines [69] (figure 14) and the utilization of photochemistry with the one pot synthesis of a 9-membered ring system that could be applied not only in the synthesis of Aspidosperma-type alkaloids, but also Strychnos, Schizozygane and Eburnamine-types, as shown in figure 15 [70].

Figure 14.

Ketone annelation of endocyclic enamines on the synthesis of alkaloids.

Figure 15.

Photochemistry on the synthesis of alkaloids.

Another approach relied on the conversion of para-substituted anisoles into 4,4-dissubstitued cyclohexenones via cyclohexadiene-Fe(CO)3 complexes, to obtain the tetrasubstituted carbon of Aspidosperma-type alkaloids, as demonstrated by the synthesis shown in figure 16 [71]. The iron complexes were also utilized in the synthesis of limaspermine derivatives, as shown in figure 17 [72]. Iron [73] and others metals were also utilized in Aspidosperma alkaloids synthesis, such as rhodium [74–77], copper [75,78], ruthenium and molybdenum [79], titanium [80] and palladium [81,82].

Figure 16.

Synthesis of alkaloids with functionalised C(20) substituents via diene-Fe(CO)3 complex (adapted from [71]).

Figure 17.

Utilization of organoiron chemistry in limaspermine synthesis.

Another precursor of Aspidosperma type alkaloids was synthesized in 1978, from azocetones or iminomalonates via acid-catalysed and Birch reduction reactions (figure 18) [83].

Figure 18.

Synthesis of synthons for Aspidosperma alkaloids synthesis (adapted from [83]).

3.2. Novel strategies

One of the main concerns of chemists worldwide is the development of more efficient and “green” procedures in organic synthesis procedures. Among the procedures developed we can cite the so-called domino synthesis, where several bonds are formed in sequence, without isolation of intermediates, addition of reagents or changes in reaction conditions, so that the subsequent reaction result as a consequence of the functionality formed in the previous step [84]. One example of domino synthesis application to Aspidosperma alkaloids synthesis was recently published, where the alkaloids (-)-aspidospermidine, (-)-tabersonine and (-)-vincadifformine were synthesized in an asymmetric domino Michael/Mannich/N-alkylation sequence, as shown in figure 19 [85].

Figure 19.

Domino Michael/Mannich/N-alkylation sequence to Aspidosperma alkaloids synthesis (adapted from [85]).

The majority of synthetic strategies employed to obtain natural products are based on the construction of a single target skeleton, in contrast with the strategy utilized by plants, where divergent molecular cyclizations of a polyunsaturated common intermediate produce different scaffolds, as recently demonstrated in two different papers, by the synthesis of different Aspidosperma alkaloids[81] and diverse indole alkaloids skeletons [86] from a common intermediate in a biogenetically-inspired way, as shown in figure 20 [86].

Figure 20.

Synthesis of indole alkaloids in a biogenetically-inspired way (adapted from [86]).


4. Biological importance of Aspidosperma terpenoid alkaloids

One of the research interests of our group is the isolation of alkaloids from Aspidosperma species with pharmacological potential. From a chemotaxonomic point of view, alkaloids are substances of great potential in malaria treatment [87,88]. In this perspective, we decided to study the alkaloids produced by A. pyrifolium, resulting in the isolation of the alkaloids 15-demethoxypyrifoline, aspidofractinine and N-formylaspidofractinine [89]. We have identified in A. pyrifolium insecticidal [90], antibacterial [91] and hypotensive activities [92]. Another plant studied by our group was A. tomentosum, which showed great anti-hipertensive [93,94], antinociceptive, anti-inflammatory and analgesic [95–98] and A. macrocarpum, which showed anti-hypertensive activity in spontaneously hypertensive mice [99].

Some species have been the subject of research in order to identify its pharmacological properties and other biological activities. In vitro assay with aqueous extracts of the aerial parts and roots of A. pachypterum against Staphylococcus aureus and the Human Immunodeficiency Virus (HIV), respectively, showed that this species exhibited a moderate activity [100,101]. The methanolic extract of the aerial parts of A. ramiflorum was active in vitro against gram-negative bacterium Escherichia coli [102] and against the fungus Cryptococcus neoformans (causing opportunistic infections in humans) [103] while the methanol extract of the stem bark of the same species was found to be moderately active against gram-positive bacteria and inactive against gram-negatives ones [104]. Studying tailings from the processing of hardwoods in Paraná (Brazil), it was found that the methanol extract of the wood of the plant identified as Peroba pink (Aspidosperma sp.) had a composition rich in phenols and alkaloids as well as strong activity against gram-negative bacteria Proteus mirabilis [105]. In two trials conducted with various plant species, among them five from Aspidosperma genre, it was observed that the ethanol extract of the stem bark of A. excelsum, A. megalocarpon, A. oblongum and A. marcgravianum were active against gram-positive bacteria Bacillus subtilis and that the same extracts and also the ethanol extract of the stem bark of A. album were active against gram-positive S. aureus [106,107]. In a study of Peruvian plants, it was reported that the extract of the bark of A. rigidum showed antibacterial activity against B. subtilis [108].

Another reported activity for species was the anti-Leishmania, where in vitro assay for Leishmania amazonensis promastigotes ahead and L. braziliensis, the fraction rich in alkaloids obtained from the stem bark proved to be active, with the highest activity observed against the first species [109]. Yet in order to find alternatives for the treatment of neglected diseases, the methanol extract of the bark of A. megalocarpon was tested against the D2 and F32 Plasmodium falciparum strains, being active [110]. The dichloromethane extract of the roots of A. tomentosum was active front P. falciparum (strain FcB1/Colombia) with a selectivity index of 67.5 compared with the activity front NIH-3T3 cells. In relation to substances with antifungal properties, it was seen that the ethanol extract of the stem of A. polyneuron was capable of inhibiting Cladosporium herbarum (pathogen of plants) [111].

In order to find alternatives for the treatment of cancer, the dichloromethane extract of the aerial parts of A. tomentosum was capable of inhibiting the proliferation of cell lines MCF-7 (breast cancer), UACC62 (melanoma), NCIADR (breast cancer phenotype with resistance to multiple drugs and NCl460 (lung cancer), and we observed that the activity was concentrated in fractions rich in terpenes and species of high polarity [112].

In vivo assay of the ethanol extract of the stem of A. nitidum showed significant anti-inflammatory activity when evaluated in the trial of edema induced by carrageenan in mice. Prospecting for sources of antioxidant compounds, the hot aqueous extract of A. quebracho-blanco was tested for oxidation power / ferric reduction, showing a low activity and is therefore not considered as potential producer of antioxidant compounds [113].

It was observed that administration of a fraction rich in alkaloids obtained from the root bark of A. ulei exerted pro-erectile effect in rats and suggested a mechanism of action via blocking presynaptic α2-adrenergic receptors, the activation of the dopaminergic system and release of nitric oxide [114]. When the same fraction was tested in corpus cavernosum penis obtained from rabbit, its ability to cause relaxation was observed and the proposed mechanism blocking the influx of calcium into the cells [115]. In assay using α-adrenergic receptors isolated from human penis, it was shown that the crude extract and four fractions obtained from the bark of A. quebracho-blanco were able to block them, and the magnitude of interaction directly proportional to the content of the alkaloid yohimbine [116].

Despite reports of low toxicity associated with the use of plants of the genus Aspidosperma [109,110,117–119], some studies show a contrary position regarding the species A. pyrifolium [89,120]. In a study of the species A. pyrifolium cases of abortion in goats were reported due to ingestion of parts of the plants and when the ethanol extract of the leaves was administered to pregnant rats reduced fetal weight and maternal toxicity was observed, as well as hemolysis and toxicity test the front microcrustacean Artemia salina [120]. In a toxicity study with the microcrustacean A. franciscana with several species found in the Brazilian Amazon, among them seven species of Aspidosperma, it was reported that the bark extracts of A. marcgravianum, A. vargasii, A. nitidum and A. sprucenaum led to mortality of 100, 94, 70 and 65% of the crustaceans, whilst extracts from the bark of A. desmanthum, A. sandwithianum and A. shultesii led to a mortality rate of 6, 0 and 0% crustaceans, showing the potential toxicity of some species gender [121]. In another test with brine shrimp, both the dichloromethane extract and the methanol extract of the bark of A. excelsum showed toxicity [14].


5. Conclusion

The present literature review shows the importance of the study of Aspidosperma type alkaloids due to the widespread usage of plants that produce these substances in folk medicine and the great array of potential biomedical applications that these substances exhibit. Beyond this it is clear the importance of developments in synthetic organic chemistry to obtain these substances without the necessity of extraction from natural sources.



We would like to thank the financial support given by CNPq, CAPES, FINEP and FAPEAL agencies.


  1. 1. Newman DJ, Cragg GM, Snader KM. The influence of natural products upon drug discovery. Natural Products Report 2000;17:215–34.
  2. 2. Kinghorn AD. Drug discovery form natural products. In: Lemke TL, Williams DA, Roche VF, Zito SW, editors. Foye’s Principles of Medicinal Chemistry 6th ed., Philadelphia: Lippincott Williams & Wilkins; 2008, p. 12–25.
  3. 3. De Pasquale A. Pharmacognosy: the oldest modern science. Journal of Ethnopharmacology 1984;11:1–16.
  4. 4. Amorim IL De, Sampaio EVSB, Araújo E de L. Flora e estrutura da vegetação arbustivo-arbórea de uma área de caatinga do Seridó, RN, Brasil. Acta Botânica Brasileira 2005;19:615–23.
  5. 5. Corrêa MP. Diccionário das Plantas Úteis do Brasil e das Exóticas Cultivadas. Volumes I a VI. Rio de Janeiro: Imprensa Nacional; 1984.
  6. 6. Oliveira VB, Freitas MSM, Mathias L, Braz-Filho R, Vieira IJC. Atividade biológica e alcalóides indólicos do gênero Aspidosperma (Apocynaceae): uma revisão. Revista Brasileira de Plantas Medicinais Botucatu 2009;11:92–9.
  7. 7. Agra MF, Baracho GS, Nurit K, Basílio IJLD, Coelho VPM. Medicinal and poisonous diversity of the flora of “Cariri Paraibano”, Brazil. Journal Ethnopharmacology 2007;111:383–95.
  8. 8. Botsaris AS. Plants used traditionally to treat malaria in Brazil: the archives of Flora Medicinal. Journal of Ethnobiology and Ethnomedicine 2007;3:1.
  9. 9. Bourdy G, DeWalt SJ, Chávez de Michel LR, Roca a, Deharo E, Muñoz V, et al. Medicinal plants uses of the Tacana, an Amazonian Bolivian ethnic group. Journal Ethnopharmacology 2000;70:87–109.
  10. 10. Bourdy G, Chāvez de Michel LR, Roca-Coulthard a. Pharmacopoeia in a shamanistic society: the Izoceño-Guaraní (Bolivian Chaco). Journal of Ethnopharmacology 2004;91:189–208.
  11. 11. Brandão MGL, Grandi TSM, Rocha EMM, Sawyer DR, Krettli AU. Survey of medicinal plants used as antimalarials in the Amazon. Journal of Ethnopharmacology 1992;36:175–82.
  12. 12. De Almeida CDFCBR, Ramos MA, de Amorim ELC, de Albuquerque UP. A comparison of knowledge about medicinal plants for three rural communities in the semi-arid region of northeast of Brazil. Journal of Ethnopharmacology 2010;127:674–84.
  13. 13. Dele Vitto LA, Petenatti EM, Petenatti ME. Recursos herbolarios de San Luis (República Argentina) primera parte: plantas nativas. Multequina 1997;6:49–66.
  14. 14. Desmarchelier C, Mongelli E, Coussio J, Ciccia G. Studies on the cytotoxicity, antimicrobial and DNA-binding activities of plants used by the Ese’ejas. Journal of Ethnopharmacology 1996;50:91–6.
  15. 15. Filipov A. Medicinal plants of the Pilagá of central Chaco. Journal of Ethnopharmacology 1994;44:181–93.
  16. 16. Goleniowski ME, Bongiovanni G a, Palacio L, Nuñez CO, Cantero JJ. Medicinal plants from the “Sierra de Comechingones”, Argentina. Journal of Ethnopharmacology 2006;107:324–41.
  17. 17. Hajdu Z, Hohmann J. An ethnopharmacological survey of the traditional medicine utilized in the community of Porvenir, Bajo Paraguá Indian Reservation, Bolivia. Journal of Ethnopharmacology 2012;139:838–57.
  18. 18. Kvist LP, Christensen SB, Rasmussen HB, Mejia K, Gonzalez a. Identification and evaluation of Peruvian plants used to treat malaria and leishmaniasis. Journal of Ethnopharmacology 2006;106:390–402.
  19. 19. Martínez GJ, Barboza GE. Natural pharmacopoeia used in traditional Toba medicine for the treatment of parasitosis and skin disorders (Central Chaco, Argentina). Journal of Ethnopharmacology 2010;132:86–100.
  20. 20. Monteles R, Pinheiro CUB. Plantas medicinais em um quilombo maranhense: uma perspectiva etnobotânica. Revista Biologia e Ciências da Terra 2007;7:38–48.
  21. 21. Muñoz V, Sauvain M, Bourdy G, Arrázola S, Callapa J, Ruiz G, et al. A search for natural bioactive compounds in Bolivia through a multidisciplinary approach Part III. Evaluation of the antimalarial activity of plants used by Alteños Indians. Journal of Ethnopharmacology 2000;71:123–31.
  22. 22. Rodrigues E. Plants of restricted use indicated by three cultures in Brazil (Caboclo-river dweller, Indian and Quilombola). Journal of Ethnopharmacology 2007;111:295–302.
  23. 23. Ruiz L, Ruiz L, Maco M, Cobos M, Gutierrez-Choquevilca A-L, Roumy V. Plants used by native Amazonian groups from the Nanay River (Peru) for the treatment of malaria. Journal of Ethnopharmacology 2011;133:917–21.
  24. 24. Sanz-Biset J, Cañigueral S. Plant use in the medicinal practices known as “strict diets” in Chazuta valley (Peruvian Amazon). Journal of Ethnopharmacology 2011;137:271–88.
  25. 25. Sanz-Biset J, Campos-de-la-Cruz J, Epiquién-Rivera M a, Cañigueral S. A first survey on the medicinal plants of the Chazuta valley (Peruvian Amazon). Journal of Ethnopharmacology 2009;122:333–62.
  26. 26. Scarpa GF. Medicinal plants used by the Criollos of Northwestern Argentine Chaco. Journal of Ethnopharmacology 2004;91:115–35.
  27. 27. Schmeda-Hirschmann G. Magic and medicinal plants of the Ayoreos of the Chaco Boreal (Paraguay). Journal of Ethnopharmacology 1993;39:105–11.
  28. 28. Alves M, Silva B, Melo LVL, Ribeiro R V. Levantamento etnobotânico de plantas utilizadas como anti-hiperlipidêmicas e anorexígenas pela população de Nova Xavantina-MT, Brasil. Revista Brasileira de Farmacognosia 2010;20:549–62.
  29. 29. Barger G, Scholz C. Über Yohimbin. Helvetica Chimica Acta 1933;16:1343–54.
  30. 30. Wenkert E. Biosynthesis of Indole Alkaloids. The Aspidosperma and Iboga Bases. Journal of the American Chemical Society 1962;84:98–102.
  31. 31. Wenkert E, Bringi N V. A Stereochemical Interpretation of the Biosynthesis of Indole Alkaloids 1. Journal of the American Chemical Society 1959;81:1474–81.
  32. 32. Kutney JP, Piers E. The Chemistry of Cleavamine: A Novel Transannular Cyclization Relating to Biosynthesis of Aspidosperma Alkaloids. Journal of the American Chemical Society 1964;86:953–5.
  33. 33. Hall ES, McCapra F, Money T, Fukumoto K, Hanson JR, Mootoo BS, et al. Concerning the terpenoid origin of indole alkaloids: biosynthetic mapping by direct mass spectrometry. Chemical Communications 1966:348–50.
  34. 34. Battersby AR, Brown RT, Kapil RS, Martin JA, Plunkett AO. Role of loganin in the biosynthesis of indole alkaloids. Chemical Communications 1966;22:812–3.
  35. 35. Battersby AR, Kapil RS, Martin JA, Mo L. Loganin as Precursor of the Indole Alkaloids. Chemical Communications 1968:133–4.
  36. 36. Battersby AR, Byrne JC, Kapil RS, Martin JA, Payne TG, Arigoni D, et al. The Mechanism of Indole Alkaloid Biosynthesis. Chemical Communications 1968:951–3.
  37. 37. Battersby AR, Burnett AR, Parsons PG. Preparation of secologanin: its conversion into ipecoside and its role in indole alkaloid biosynthesis. Chemical Communications 1968:1280–1.
  38. 38. Qureshi AA, Scott AI. Interconversion of Coryanthe, Aspidosperma, and Iboga alkaloids. A model for indole alkaloid biosynthesis. Chemical Communications 1968:945–6.
  39. 39. Kutney JP, Cretney WJ, Hadfield JR, Hall ES, Nelson VR, Wigfield DC. Indole alkaloid biosynthesis. Journal of the American Chemical Society 1968;90:3566–7.
  40. 40. Scott AI, Qureshi AA. Biogenesis of Strychnos, Aspidosperma, and Iboga alkaloids. Structure and reactions of preakuammicine. Journal of the American Chemical Society 1969;91:5874–6.
  41. 41. Qureshi AA, Scott AI. Biosynthesis of indole alkaloids: sequential precursor formation and biological conversion in Vinca rosea. Chemical Communications 1968:948.
  42. 42. Battersby AR, Burnett AR, Parsons PG. Alkaloid biosynthesis. Part XV. Partial synthesis and isolation of vincoside and isovincoside: Biosynthesis of the three major classes of indole alkaloids from vincoside. Journal of Chemical Society 1969:1193–200.
  43. 43. Battersby AR, Burnett AR, Parsons PG. Alkaloid biosynthesis. Part XIV. Secologanin: Its cnversion into ipecoside and its role as biological precursor of the indole alkaloids. Journal of Chemical Society 1969:1187–92.
  44. 44. Kutney JP, Ehret C, Nelson VR, Wigfield DC. Studies on indole alkaloid biosynthesis. II. Journal of the American Chemical Society 1968;90:5929–30.
  45. 45. Kutney JP, Nelson VR, Wigfield DC. Indole alkaloid biosynthesis. III. Journal of the American Chemical Society 1969;91:4278–9.
  46. 46. Kutney JP, Nelson VR, Wigfield DC. Indole alkaloid biosynthesis. IV. Journal of the American Chemical Society 1969;91:4279–80.
  47. 47. Kutney JP, Beck JF, Eggers NJ, Hanssen HW, Sood RS, Westcott ND. Indole alkaloid biosynthesis. VII. Later stages of Aspidosperma alkaloid biosynthesis. Journal of the American Chemical Society 1971;93:7322–4.
  48. 48. Woodward RB, Iacobucci GA, Hochstein IA. The synthesis of ellipticine. Journal of the American Chemical Society 1959;81:4434–5.
  49. 49. Barton JED, Harley-Mason J. Total synthesis of Hunteria and Aspidosperma alkaloids from a common intermediate. Chemical Communications 1965:298–9.
  50. 50. Kutney JP, Abdurahman N, Le Quesne P, Piers E, Vlattas I. A New Total Synthesis of dl-Quebrachamine and dl-Aspidospermidine. A General Entry into the Aspidosperma Alkaloids. Journal of the American Chemical Society 1966;88:3656–7.
  51. 51. Ziegler FE, Zoretic PA. The alkylation of cyclic enamines: A synthesis of the quebrachamine skeleton. Tetrahedron Letters 1968:2639–41.
  52. 52. Kutney JP, Abdurahman N, Gletsos C, Le Quesne P, Piers E, Vlattas I. Total synthesis of indole and dihydroindole alkaloids. V. Total synthesis of dl-quebrachamine and dl-aspidospermidine. General entry into the aspidosperma alkaloids. Journal of the American Chemical Society 1970;92:1727–35.
  53. 53. Takano S, Hatakeyama S, Ogasawara K. Synthesis of the non-tryptamine moiety of the aspidosperma-type indole alkaloids via cleavage of cyclic.alpha.-diketone monothioketal. An efficient synthesis of (dl)-quebrachamine and a formal synthesis of (dl)-tabersonine. Journal of the American Chemical Society 1976;98:3022–3.
  54. 54. Takano S, Chiba K, Yonaga M, Ogasawara K. Enantioselective Synthesis of (+)-Quebrachamine using L-glutamic acid as chiral template. Chemical Communications 1980:616–7.
  55. 55. Michael J, Zimmerman L. General methods of alkaloid synthesis. A new approach to functionalized Hydrolulolidone aspidosperma alkaloid precursors. A formal synthesis of (+-)-aspidospermine. Chemical Communications 1971:857–8.
  56. 56. Martin SF, Desai SR, Philips GW, Miller AC. General methods for alkaloid synthesis via intramolecular [4+2] cycloaddition reactions of enamides. A new approach to the synthesis of Aspidosperma alkaloids. Journal of the American Chemical Society 1980;102:3294–6.
  57. 57. Schultz AG, Chiu I-C. Heteroatom directed photoarylation; an approach to the synthesis of Aspidosperma alkaloids. Journal of Chemical Society Chemical Communications 1978:29.
  58. 58. Ban Y, Yoshida K, Goto J, Oishi T. Novel photoisomerization of 1-acylindoles to 3-acylindolenines. General entry to the total synthesis of Strychnos and Aspidosperma alkaloids. Journal of the American Chemical Society 1981;103:6990–2.
  59. 59. Ibrahim-Ouali M, Sinibaldi M-E, Troin Y, Guillaume D, Gramain J-C. Diastereoselective photochemical synthesis of 3,3’-dissubstituted indolines. Tetrahedron 1997;53:16083–96.
  60. 60. Ibrahim-Ouali M, Sinibaldi M-E, Troin Y, Gramain J-C. Photocyclization of enaminoesters: Access to 2,3-dihydroindoles spiroimides. Tetrahedron Letters 1996;37:37–8.
  61. 61. Ziegler FE, Spitzner EB. The biogenetically modeled total synthesis of (+-)-Minovine. Journal of the American Chemical Society 1970;92:3492–4.
  62. 62. Ziegler FE, Spitzner EB. Biogenetically modeled synthesis via an indole acrylic ester. Total synthesis of (+-)-minovine. Journal of the American Chemical Society 1973;95:7146–9.
  63. 63. Yang R, Qiu FG. General entry to aspidosperma alkaloids: enantioselective total synthesis of (-)-aspidophytine. Angewandte Chemie International Edition English 2013;52:6015–8.
  64. 64. Overman LE, Sworin M, Bass LS, Clardy J. Synthesis applications of aza-cope rearrangements. Tetrahedron 1981;37:4041–5.
  65. 65. Overman LE, Sworin M, Burk RM. Synthesis applications of aza-Cope rearrangements. Part 10. A new approach for the total synthesis of pentacyclic Aspidosperma alkaloids. Total synthesis of dl-16-methoxytabersonine. Journal of Organic Chemistry 1983;48:2685–90.
  66. 66. Overman LE, Robertson GM, Robichaud AJ. Use of aza-Cope rearrangement-Mannich cyclization reactions to achieve a general entry to Melodinus and Aspidosperma alkaloids. Stereocontrolled total syntheses of (.+-.)-deoxoapodine, (.+-.)-meloscine, and (.+-.)-epimeloscine and a formal synthesis of (. Journal of the American Chemical Society 1991;113:2598–610.
  67. 67. Yasui Y, Takeda H, Takemoto Y. Toward general access to the aspidosperma-type terpenoid indole alkaloids: synthesis of the key 3,3-disubstituted piperidones through enantioselective intramolecular heck-type reaction of chloroformamides. Chemical and Pharmaceutical Bulletin (Tokyo) 2008;56:1567–74.
  68. 68. McMurray L, Beck EM, Gaunt MJ. Chemical synthesis of Aspidosperma alkaloids inspired by the reverse of the biosynthesis of the rhazinilam family of natural products. Angewandte Chemie International Edition English 2012;51:9288–91.
  69. 69. Stevens R V, Mehra RK, Zinmerman RL. Synthesis of Aspidosperma Alkaloid Precursors. A New Application of the Methyl Vinyl Ketone Annelation of Endocyclic Enamines in Alkaloid Synthesis. Chemical Communications 1969:877–8.
  70. 70. Ban Y, Toshida K, Goto J, Oishi T, Takeda E. A synthetic road to the forest of Strychnos, Aspidosperma, Schizozygane and Eburnamine alkaloids by way of the novel photoisomerization. Tetrahedron 1983;39:3657–68.
  71. 71. Pearson AJ, Ress DC. New synthetic approaches to Aspidosperma alkaloids with functionalised C(20) substituents: Some key intermediates via diene-Fe(CO)3 complexes. Tetrahedron Letters 1980;21:3937–40.
  72. 72. Pearson AJ, Rees DC. Total synthesis of (.+-.)-limaspermine derivatives using organoiron chemistry. Journal of the American Chemical Society 1982;104:1118–9.
  73. 73. Kuehne ME, Bandarage UK, Hammach A, Li Y, Wang T. Application of Ferrocenylalkyl Chiral Auxiliaries to Syntheses of Indolenine Alkaloids: Enantioselective Syntheses of Vincadifformine, ψ-and 20-epi-ψ-Vincadifformines, Tabersonine, Ibophyllidine, and Mossambine. Journal of Organic Chemistry 1998;63:2172–83.
  74. 74. Padwa A, Price AT. Synthesis of the Pentacyclic Skeleton of the Aspidosperma Alkaloids Using Rhodium Carbenoids as Reactive Intermediates. Journal of Organic Chemistry 1998;63:556–65.
  75. 75. Edwankar R V, Edwankar CR, Namjoshi O a, Deschamps JR, Cook JM. Brønsted acid mediated cyclization of enaminones. Rapid and efficient access to the tetracyclic framework of the Strychnos alkaloids. Journal of Natural Products 2012;75:181–8.
  76. 76. Mejía-Oneto JM, Padwa A. Application of the Rh(II) cyclization/cycloaddition cascade for the total synthesis of (+/-)-aspidophytine. Organic Letters 2006;8:3275–8.
  77. 77. Hong X, Mejía-oneto JM, France S, Padwa A. Preparation of 2-diazo-2-oxopiperidin-3-yl-3-oxopropanoates. Useful reagents for Rh (II)-catalyzed cyclization-cycloaddition chemistry. Arkivoc 2007:125–38.
  78. 78. Temme O, Taj S-A, Andersson PG. Highly Enantioselective Intermolecular Cu(I)-Catalyzed Cyclopropanation of Cyclic Enol Ethers. Asymmetric Total Synthesis of (+)-Quebrachamine. Journal of Organic Chemistry 1998;63:6007–15.
  79. 79. Sattely ES, Meek SJ, Malcolmson SJ, Schrock RR, Hoveyda AH. Design and stereoselective preparation of a new class of chiral olefin metathesis catalysts and application to enantioselective synthesis of quebrachamine: catalyst development inspired by natural product synthesis. Journal of the American Chemical Society 2009;131:943–53.
  80. 80. Cheng X, Duhaime CM, Waters SP. Total synthesis of the Aspidosperma alkaloid (±)-subincanadine F via a titanium-mediated intramolecular nucleophilic acyl substitution strategy. Journal of Organic Chemistry 2010;75:7026–8.
  81. 81. Shen X, Zhao R, Mo M, Peng F, Zhang H, Shao Z. Catalytic enantioselective and divergent total synthesis of (+)-10-oxocylindrocarpidine, (+)-cylindrocarpidine, (-)-N-acetylcylindrocarpinol, and (+)-aspidospermine. Journal of Organic Chemistry 2014;79:2473–80.
  82. 82. Jiao L, Herdtweck E, Bach T. Pd(II)-catalyzed regioselective 2-alkylation of indoles via a norbornene-mediated C-H activation: mechanism and applications. Journal of the American Chemical Society 2012;134:14563–72.
  83. 83. Takano S, Shishido K, Sato M, Yuta K, Ogasawara K. New synthetic routes to synthons for the synthesis of functionalized aspidosperma alkaloids. Journal of Chemical Society Chemical Communications 1978:943.
  84. 84. Tietze LF. Domino Reactions in Organic Synthesis. Chemical Reviews 1996;96:115–36.
  85. 85. Zhao S, Andrade RB. Domino Michael/Mannich/N-alkylation route to the tetrahydrocarbazole framework of aspidosperma alkaloids: concise total syntheses of (-)-aspidospermidine, (-)-tabersonine, and (-)-vincadifformine. Journal of the American Chemical Society 2013;135:13334–7.
  86. 86. Mizoguchi H, Oikawa H, Oguri H. Biogenetically inspired synthesis and skeletal diversification of indole alkaloids. Nature Chemistry 2014;6:57–64.
  87. 87. Wright CW. Plant Derived Antimalarial Agents: New Leads and Challenges. Phytochemistry Reviews 2005;4:55–61.
  88. 88. Foley M, Tilley L. Quinoline antimalarials: mechanisms of action and resistance. International Journal of Parasitology 1997;27:231–40.
  89. 89. Araújo-Jr. JX, Antheaume C, Trindade RCP, Schmitt M, Bourguignon J-J, Sant’Ana AEG. Isolation and characterisation of the monoterpenoid indole alkaloids of Aspidosperma pyrifolium. Phytochemistry Reviews 2007;6:183–8.
  90. 90. Trindade RCP, da Silva PP, Araújo-Júnior JX, de Lima IS, de Paula JE, Sant’Ana AEG. Mortality of Plutella xylostella larvae treated with Aspidosperma pyrifolium ethanol extracts. Pesquisa Agropecuária Brasileira 2008;43:1813–6.
  91. 91. Pessini GL, Aquino PG V, Bernardo VB, Costa MA, Nakamura C V, Ribeiro EAN, et al. Evaluation of antimicrobial activity of three Aspidosperma species. PharmacologyOnLine 2012;1:112–9.
  92. 92. Araújo-Júnior JX, Oliveira DA, Oliveira MP, Aquino PG V, Sant’Ana AEG, Ribeiro EAN. Evaluation of cardiovascular response induced by ethanolic extract of Aspidosperma pyrifolium (Apocynaceae) wood on arterial pressure in spontaneously hypertensive rats. XX Congr. Italo-Latinoamericano Etnomedicina, Fortaleza: 2011.
  93. 93. Furtado FF, Herculano EA, Araújo-Júnior JX, Sat’Ana AEG, Ribeiro EAN, Medeiros IA, et al. Vasorelaxant effect induced by ethanolic extract of Aspidosperma tomentosum in the isolated rat mesenteric artery. XVII Congr. Italo-Latinoamericano di Etnomedicina, Palermo: 2008.
  94. 94. Furtado FF, Tenorio EP, Sant’Ana AEG, Araújo-Júnior JX, Aquino PG V, Ribeiro EAN, et al. Antihypertensive and vasorelaxant activities of Aspidosperma tomentosum are mainly through calcium channel blockade. XIX Italo-Latinamerican Congr. Etnomedicine, Villassimius: 2010.
  95. 95. Aquino AB De, Cavalcante-Silva LHA, Matta CBB Da, Epifânio WADN, Aquino PGV, Santana AEG, et al. The antinociceptive and anti-inflammatory activities of Aspidosperma tomentosum (Apocynaceae). ScientificWorldJournal 2013;2013:218627.
  96. 96. Aquino AB, Queiroz AC, Oliveira MP, Epifanio WAN, Junior WB, Sant’Ana AEG, et al. Avaliação da atividade antinociceptiva e antiinflamatória da espécie Aspidosperma tomentosum (Apocynacea). 40o Congr. Bras. Farmacol. e Ter. Exp., Águas de Lindóia: 2008.
  97. 97. Epifanio WAN, Oliveira MP, Melo GMA, Silva SAS, Moreira MSA, Sant’Ana AEG, et al. Isolamento de flavonóide das cascas do caule de Aspidosperma tomentosum e atividade analgésica preliminar. 30a Reun. Anu. da Soc. Bras. Química, Águas de Lindóia: 2007.
  98. 98. Oliveira MP, Silva DJC, Aquino AB, Epifanio WAN, Araújo-Júnior JX, Sant’Ana AEG, et al. Evaluation of the anti-nociceptive and antiinflammatory activities of Aspidosperma tomentosum (Apocynaceae). XVI Congr. Italo-latinoamericano Etnomedicina, La Plata: 2007.
  99. 99. Araújo-Júnior JX, Oliveira MP, Paulino JVS, Aquino PG V, Sant’Ana AEG, Ribeiro EAN. Anti-hypertensive activity of Aspidosperma macrocarpum on spontaneously hypertensive rats. XX Congr. Italo-Latinoamericano Etnomedicina, Fortaleza: 2011.
  100. 100. Suffredini IB, Varella D, de Oliviera a a, Younes RN. In vitro anti-HIV and antitumor evaluation of Amazonian plants belonging to the Apocynaceae family. Phytomedicine 2002;9:175.
  101. 101. Suffredini IB, Bacchi EM, Mary T, Sakuda K, Ohara MT, Younes RN, et al. Antibacterial activity of Apocynaceae extracts and MIC of Tabernaemontana angulata stem organic extract. Revista Brasileira de Ciências Farmacêuticas 2002;38:89–94.
  102. 102. Agripino DG, Leite EML, da Silva RM, Meda CI, Bolzani V da S, Cordeiro I, et al. Screening of brazilian plants for antimicrobial and DNA-damaging activities. I. Atlantic rain forest-Ecological station Juréia-Itatins. Biota Neotropica 2004;4:1–15.
  103. 103. De Souza ACM, Hasimoto e Souza LK, Silva MRR, Oliveira CMA, Kato L, da Silva CC, et al. Propriedades antifúngicas dos alcalóides de Aspidosperma ramiflorum. 29a Reun. Anu. da Soc. Bras. Química, vol. 46, Águas de Lindóia: 2006.
  104. 104. Tanaka JCA, da Silva CC, de Oliveira AJB, Nakamura C V, Dias Filho BP. Antibacterial activity of indole alkaloids from Aspidosperma ramiflorum. Brazilian Journal of Medicine and Biological Research 2006;39:387–91.
  105. 105. Granato D, Nunes DS, Mattos PP De, Moura E De, Samples W. Chemical and Biological Evaluation of Rejects from the Wood Industry Microbiological activity of the extracts. Brazilian Archives of Biology and Thecnology 2005;48:237–41.
  106. 106. Verpoorte R, Tsoi ATA, Doorne HVAN, Svendsen AB. Medicinal plants of Suriname. I. Antimicrobial activity of some medicinal plants. Journal of Ethnopharmacology 1982;5:221–6.
  107. 107. Verpoorte R, Van Beek TA, Thomassen PHAM, Aandewiel J, Svendsen AB. Screening of antimicrobial activity of some plants belonging to the Apocynaceae and Loganiaceae. Journal of Ethnopharmacology 1983;8:287–302.
  108. 108. Rojas R, Bustamante B, Bauer J, Fernández I, Albán J, Lock O. Antimicrobial activity of selected Peruvian medicinal plants. Journal of Ethnopharmacology 2003;88:199–204.
  109. 109. Ferreira ICP, Lonardoni MVC, Machado GMC, Leon LL, Gobbi Filho L, Pinto LHB, et al. Anti-leishmanial activity of alkaloidal extract from Aspidosperma ramiflorum. Memórias do Instituto Oswaldo Cruz 2004;99:325–7.
  110. 110. Weniger B, Robledo S, Arango GJ, Deharo E, Aragón R, Muñoz V, et al. Antiprotozoal activities of Colombian plants. Journal of Ethnopharmacology 2001;78:193–200.
  111. 111. Ferreira DT, da Silva Jr. J V, Soeira LS, Zanolli LA, Ishikawa NK, Barbosa AM, et al. Avaliação da atividade antifúngica dos extratos etanólicos de raiz, caule e folha de Aspidosperma polyneuron. An. do XI Encontro Química da Região Sul, 2003, p. QO83.
  112. 112. Kohn LK, Pizão PE, Foglio MA, Antônio MA, Amaral MCE, Bittric V, et al. Antiproliferative activity of crude extract and fractions obtained from Aspidosperma tomentosum Mart. Revista Brasileira de Plantas Medicinais Botucatu 2006;8:110–5.
  113. 113. Borneo R, León a. E, Aguirre a., Ribotta P, Cantero JJ. Antioxidant capacity of medicinal plants from the Province of Córdoba (Argentina) and their in vitro testing in a model food system. Food Chemistry 2009;112:664–70.
  114. 114. Campos AR, Lima RCP, Uchoa DE a, Silveira ER, Santos F a, Rao VSN. Pro-erectile effects of an alkaloidal rich fraction from Aspidosperma ulei root bark in mice. Journal of Ethnopharmacology 2006;104:240–4.
  115. 115. Campos a R, Cunha KM a, Santos F a, Silveira ER, Uchoa DE a, Nascimento NRF, et al. Relaxant effects of an alkaloid-rich fraction from Aspidosperma ulei root bark on isolated rabbit corpus cavernosum. International Journal of Impotency Research 2008;20:255–63.
  116. 116. Sperling H, Lorenz A, Krege S, Arndt R, Michel MC. An extract from the bark of Aspidosperma quebracho blanco binds to human penile alpha-adrenoceptors. Journal fo Urology 2002;168:160–3.
  117. 117. Goloni R, Alves NM, Garrote CFD, Paula JR, Valadares MC, Bara MTF, et al. Estudo da toxicidade aguda do Aspidosperma subincanum Martius. Revista Eletrônica de Farmácia 2005;2:89–91.
  118. 118. Pereira MDM, Jácome RLRP, Alcântara AFC, Alves RB, Raslan DS. Alcaloides indólicos isolados de espécies do gênero Aspidosperma (APOCYNACEAE). Quimica Nova 2007;30:970–83.
  119. 119. Santos SR, Rangel ET, Lima JCS, Silva RM, Lopes L, Noldin VF, et al. Toxicological and phytochemical studies of Aspidosperma subincanum Mart. stem bark (Guatambu). Pharmazie 2009;64:836–9.
  120. 120. De Souza Lima MCJ, Soto-Blanco B. Poisoning in goats by Aspidosperma pyrifolium Mart.: biological and cytotoxic effects. Toxicon 2010;55:320–4.
  121. 121. Quignard ELJ, Pohlit AM, Nunomura SM, da Silva Pinto AC, dos Santos EVM, de Morais SKR, et al. Screening of plants found in amazonas state for lethality towards brine shrimp. Acta Amazonica 2003;33:93–104.

Written By

Pedro Gregório Vieira Aquino, Thiago Mendonça de Aquino, Magna Suzana Alexandre-Moreira, Bárbara Viviana de Oliveira Santos, Antônio Euzébio Goulart Santana and João Xavier de Araújo-Júnior

Submitted: 20 May 2014 Published: 30 September 2015