Securinega Alkaloids: Complex Structures, Potent Bioactivities, and Efficient Total Syntheses
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Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2017 Securinega Alkaloids : Complex Structures, Potent Bioactivities, and Efficient Total Syntheses Wehlauch, Robin ; Gademann, Karl Abstract: The Securinega alkaloids feature a compact tetracyclic structural framework and can be divided into four subclasses characterized by either a bridged [2.2.2]‐ or a [3.2.1]‐bicyclic core with two homologous series in each subclass. In the last two decades, many innovative strategies to chemically access the Securinega alkaloids have been developed. This Focus Review discusses the selected structures and syntheses of representative members of the Securinega alkaloids. Ring‐closing metathesis has enabled the syntheses of securinine and norsecurinine, and different cycloaddition approaches were key to the syntheses of nirurine and virosaines A and B. Virosine A was accessed through a Vilsmeier–Haack/Mannich reaction cascade. A bio‐inspired vinylogous Mannich reaction has enabled the synthesis of allosecurinine and this strategy has been extended by an intramolecular 1,6‐addition to obtain bubbialidine and secuamamine E. A rearrangement process of the latter two alkaloids has furnished allonorsecurinine and allosecurinine, respectively. Finally, an expanded model for the biogenesis of the Securinega alkaloid subclasses is discussed. DOI: https://doi.org/10.1002/ajoc.201700142 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-150835 Journal Article Published Version Originally published at: Wehlauch, Robin; Gademann, Karl (2017). Securinega Alkaloids : Complex Structures, Potent Bioactiv- ities, and Efficient Total Syntheses. Asian Journal of Organic Chemistry, 6(9):1146-1159. DOI: https://doi.org/10.1002/ajoc.201700142 DOI:10.1002/ajoc.201700142 Focus Review NaturalProduct Synthesis Securinega Alkaloids:Complex Structures, Potent Bioactivities, and Efficient Total Syntheses RobinWehlauchand Karl Gademann*[a] Asian J. Org. Chem. 2017, 6,1146 –1159 1146 2017 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Focus Review Abstract: The Securinega alkaloids feature acompacttetra- proaches were key to the syntheses of nirurine and viro- cyclic structuralframework and can be divided into four sub- saines Aand B. Virosine Awas accessed through aVilsmei- classes characterized by either abridged [2.2.2]- or a[3.2.1]- er–Haack/Mannich reactioncascade. Abio-inspired vinylo- bicyclic core with two homologous series in each subclass. gous Mannich reactionhas enabled the synthesis of allose- In the last two decades, many innovative strategies to chem- curinine and this strategy has been extendedbyanintramo- ically access the Securinega alkaloidshave been developed. lecular 1,6-addition to obtain bubbialidine and This Focus Reviewdiscusses the selected structures and syn- secu’amamine E. Arearrangementprocess of the latter two theses of representative members of the Securinega alka- alkaloids has furnished allonorsecurinine and allosecurinine, loids. Ring-closing metathesis has enabled the syntheses of respectively.Finally,anexpanded model for the biogenesis securinine and norsecurinine, and different cycloaddition ap- of the Securinega alkaloid subclasses is discussed. 1. Introduction China,[5] and also in Central Africa.[6] In West Africa, it serves as astomachic.[3,7] Severalgroups have reportedonthe isolation Securinega alkaloids have fascinated chemists for decades. This of Securinega alkaloids from samples of P. niruri collected in obsessionarises from the large structuralvariety in these alka- India[8] and Thailand.[9] However,these alkaloidswere not loids, their complexarchitecture,and their potent biological found in samples of the same species collected in Brazil.[10] This activity,which has even resulted in clinical use. These facts trig- result might be explained by the different environmental con- gered the synthetic efforts of many researchgroups,culminat- ditions in which the plants grow.Recently,itwas shown that ing in fascinating, efficient and instructive total syntheses of plant growth regulators influence the alkaloid content of S. suf- many Securinega alkaloids. The goal of this Focus Review is to fruticosa callus cultures,and promotion as well as inhibition of introduce the readertothe structural complexity of these com- alkaloid production was observed.[11] To date, no report has pounds,and to illustrate recent synthetic approaches towards been published on the isolation of Securinega alkaloids from their preparation.Although this review is by no means com- aplant sample collected in the Americas. Interestingly, Securi- prehensive, it may serve as an introductory overview to the nega alkaloids have been obtained from Zygogynum pauciflo- field, and we refer the interested reader to excellent surveys rum,[12] aspecies of the Winteraceae family found in New Cale- that have been publishedpreviously.[1] donia.Since this familyisnot related to Phyllanthaceae, the The Securinega alkaloids comprise agroup of more than 60 study revealed ararecase of metabolic convergence. The Phyl- known natural products found in plants of the Phyllanthaceae lanthaceaefamily of plants represents one of several Euphor- family and more precisely in the Flueggea, Margaritaria, Phyl- biaceae segregates and was classified in 2006.[13] Nevertheless, lanthus and Securinega genera.[1] These plants are commonly the Securinega alkaloids have often been assigned to the Eu- found in the subtropical zones of the Americas, Africa and phorbiaceae in the recent literature. Asia, and are broadlyappliedastraditional medicinesinthese In 1956, securinine (1)was isolated from S. suffruticosa by regions.For example, the species Securinega suffruticosa and Murav’eva and Ban’kovskii as the first memberofthis alkaloid Flueggea virosa—two rich and well-studied sourcesofSecurine- family (Figure1).[14] Being the mostabundant and best-studied ga alkaloids—havebeen applied in Chinese folk medicine to Securinega alkaloid, it has been the major representative ever treat avariety of symptomssuch as lumbago, indigestion,im- since. Thetetracyclic structureof1 was elucidated independ- potence, rheumatism,infantile paralysis, and eczema.[2] Prepa- ently by two research groups in 1962,[15] and the correct abso- rations from F. virosa have served as treatments for complica- lute configuration was established by chemical degradation tions of the liver, kidneys, gall bladder,bladder and genitalsas studies[16] and an X-ray crystal structure of securinine hydrobro- well as bilharzia in Senegalese medicine. In India, this plant has been used against diabetes.[3] Margaritaria discoidea has been utilized in Guineanfolk medicine to treat malaria,diabetes and diarrhea among others.[4] Phyllanthus niruri has been used for the treatment of malaria and other diseases in India and [a] Dr.R.Wehlauch, Prof. Dr.K.Gademann Department of Chemistry University of Zurich Winterthurerstrasse 190, 8057 Zurich (Switzerland) E-mail:[email protected] The ORCID identification number(s) for the author(s) of this articlecan be found under https://doi.org/10.1002/ajoc.201700142. This manuscript is part of the Board Membersspecial issue celebrating the 5th anniversary and the success of Asian Journal of Organic Chemistry. Figure 1. Two- and three-dimensional representations of securinine (1)and Click here to see the Table of Contents of the specialissue. its stereoisomers. Asian J. Org. Chem. 2017, 6,1146 –1159 www.AsianJOC.org 1147 2017 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Focus Review mide.[17] Total synthesis of the racemic natural product and to 4.Thus, securinol A(6)was assigned a15-hydroxy-14,15-di- chiral resolution by recrystallization with (+)-10-camphorsul- hydrosecurinane-type structure. More than 25 years later, fonic acid confirmed the structural and stereochemical assign- Arbain,Sargentand co-workersinvestigated the alkaloid con- ments.[18] Another alkaloid isolated from S. suffruticosa showed tent of Margaritaria indica and revisedthe structure of 6.[24] similarities to 1[15b] and was identified as the epimer allosecuri- Based on acomparison of NMR spectroscopic data of 6 and nine (2), in which the Aand Brings are fused in an opposite other Securinega alkaloids, andultimately on X-ray crystallo- configuration.[19] Surprisingly,the investigation of the alkaloid graphic analysis of securinolA hydrobromide, the neosecuri- content of F. virosa (synonymous with S. virosa)yielded another nane-type structure shown in Figure 2was established. stereoisomer of 1,which was found to be its enantiomer viro- Besides the four groups described so far,severalalkaloids securinine (3).[20] Asystematic study of the two plant species have been isolatedpossessing unprecedented structures, and their metabolites then led to the discovery of the fourth which do not fit the general motifs (Figure 3). Nirurine(8)was possible stereoisomerviroallosecurinine (4), the enantiomer of 2.[21] The study showed that whereas S. suffruticosa contained only 1 and 2, S. virosa contained exclusively their optical anti- podes 3 and 4.However,leaves of the male plant of S. suffruti- cosa var. amamiensis contained both 1 and 3 along with 2.[21] Besides the unusualdistribution of stereoisomers, these obser- vations also demonstrate the high diversity of alkaloid constit- uents in the different plants. Figure 3. Examples of Securinega alkaloids with unusual carbon skeletons. The Securinega alkaloidscan be divided into