CHAPTER ONE Lycopodium Alkaloids – Synthetic Highlights and Recent Developments Peter Siengalewicz, Johann Mulzer, Uwe Rinner1 Institute of Organic Chemistry, University of Vienna, Währinger Straße 38, 1090 Vienna, Austria 1Corresponding author: E-mail: uwe.rinner@univie.ac.at Contents Introduction G eneral Background Isolation of Lycopodium Alkaloids and Their Biological Properties 3.1 L ycopodine Group 3.2 F awcettimine Group 3.3 L ycodine Group 3.4 M iscellaneous Alkaloids (Phlegmarine Group) T otal Synthesis of Lycopodium Alkaloids – Historic Aspects 4.1 F irst Synthesis of the Lycopodine Skeleton: (±)-12-epi-Lycopodine (Wiesner, 1967) 4.2 T he Quest for Lycopodine: Syntheses of Stork and Ayer, 1968 4.2.1 (±)-Lycopodine; Heathcock, 1978101 4.3 O ther Highlights in Lycopodium Synthesis 4.3.1 ( ±)-Fawcettimine; Heathcock, 1986107,108 4.3.2 (±)-Huperzine A; Kozikowski, 1993109–111 4.3.3 (−)-Magellanine, (+)-Magellaninone; Overman, 1993113 T otal Synthesis of Lycopodium Alkaloids – Recent Developments 5.1 L ycopodine Group 5.1.1 L ycopodine/Clavolonine/Deacetylfawcettiine/Acetylfawcettiine/ 7-Hydroxylycopodine 5.2 F awcettimine Group 5.2.1 F awcettimine/Fawcettidine/Lycoposerramine B and C/ Phlegmariurine A/Lycoflexine/Huperzine Q 5.2.2 Sieboldine 5.2.3 Serratinine/8-Deoxyserratinine/Serratezomine A 5.2.4 Lycopladine A/Lycoposerramine R 5.2.5 Magellanine/Magellinanone/Paniculatine 5.3 L ycodine Group 5.3.1 L ycodine/Complanadine A 5.3.2 Huperzine A 5.3.3 Huperzine B © 2013 Elsevier Inc The Alkaloids, Volume 72 ISSN 1099-4831, http://dx.doi.org/10.1016/B978-0-12-407774-4.00001-7 All rights reserved 6 12 12 12 12 25 26 29 31 31 32 34 36 36 36 51 51 74 80 84 91 96 96 103 108 Uwe Rinner et al 5.3.4 Fastigiatine 5.4 M iscellaneous Alkaloids (Phlegmarine Group) 5.4.1 5.4.2 5.4.3 5.4.4 5.4.5 ermizine C/Senepodine G C Cernuine/Cermizine D Lycoposerramine V/Lycoposerramine W/Lycoposerramine X/Lycoposerramine Z Lyconadin A/Lyconadin B Luciduline/Nankakurine A/Nankakurine B C onclusion Acknowledgment References 111 114 114 120 123 127 135 143 144 144 INTRODUCTION The genus Lycopodium comprises nearly 1000 different species, endemic to temperate and tropical climates, and particularly occurring in coniferous forests, mountainous areas, and marshlands Members of this genus are characterized as flowerless, terrestrial or epiphytic plants with small needle-like or scale-like leaves, covering stem and branches Lycopods are fern-like club-mosses, which reproduce either via gametes in an underground sexual phase, or in an alternating life cycle via spores These fascinating organisms have been identified as remnants of prehistoric ferns, with early fossils dating back as far as 300 million years (late Silurian to early Devonian period).1–4 In view of the wide distribution of club-mosses, it is no wonder that various species of this genus have been utilized in traditional folk medicine Pliny the Elder reported on a celtic harvesting ritual of selago, most likely the ancient name of Lycopodium clavatum5: “Similar to savin is the herb known as “selago.” Care is taken to gather it without the use of iron, the right hand being passed for the purpose through the left sleeve of the tunic, as though the gatherer were in the act of committing a theft The clothing too must be white, the feet bare and washed clean, and a sacrifice of bread and wine must be made before gathering it: it is carried also in a new napkin The Druids of Gaul have pretended that this plant should be carried about the person as a preservative against accidents of all kinds, and that the smoke of it is extremely good for all maladies of the eyes.”5 Hildegard of Bingen knew different recipes and formulas with clubmoss for the treatment of various medical conditions Skin irritations and acne were treated with a tea brewed from L clavatum and couch Lycopodium Alkaloids – Synthetic Highlights and Recent Developments grass (Agropyron repens L.) A tea from club-moss (L clavatum), greater burnet-saxifrage (Pimpinella major), common tormentil (Potentilla erecta), wormwood (Artemisia absinthium), and dandelion (Taraxacum officinale) was employed to medicate inflammation of the liver Other mixtures for the treatment of nosebleed, irritation of the intestinal tract, and kidney disorders, just to name a few, have been used similarly for hundreds of years Lycopods were highly valued herbal remedies in several early cultures all over the world Native American tribes employed L clavatum in wound care Thus, the standard treatment for injuries and lesions was the application of spores in the open wound Members of the Blackfoot tribe used Lycopodium complanatum for the treatment of pulmonary disease, while Iroquois believed in the ability of the plant to induce pregnancy.6 Today, Lycopodium plants and extracts are not commonly employed as herbal remedies as the side effects often exceed the benefits However, species of the genus Lycopodium have much to offer to different scientific areas; biologists are fascinated by the fact that lycopods are ancient relicts dating back to the carboniferous period and grant insight to prehistoric times.1–4 The isolation of biologically and structurally complex alkaloids exerts a fascination on phytochemists and rises the question how such simple plants are able to synthesize such complex and structurally diverging metabolites Several medicinally active Lycopodium constituents, the most notable being huperzine, raise interest among the pharmaceutically interested community while last, but not the least, synthetic chemists are intrigued by the challenging structural features of the various alkaloids isolated from lycopods The fascinating area of Lycopodium alkaloids has been summarized on several occasions,7–10,276 and so far, a total of seven review articles covering isolation, physiological properties, as well as synthetic approaches have been published within this series.11–17 This contribution serves as an update of this area since the last overview article in The Alkaloids by Kobayashi and Morita in 200517 and covers the literature until December 2011, with the exemption of two syntheses of fawcettimine, which have been reported in 2012 Key intermediates and key steps are depicted in blue color for clarity The main section of this article is devoted to the discussion of recent synthetic efforts with a brief excursion to early highlights of alkaloid synthesis One chapter of this review article summarizes recently isolated L ycopodium alkaloids along with the reported biological data Uwe Rinner et al GENERAL BACKGROUND The chemical interest in constituents of Lycopodium species started with the isolation of lycopodine from L complanatum by Bödeker in 1881.18 Later, Orechoff reported a high alkaloid content in Lycopodium annotinum L.19 The same observation was attested by Muszynski who extended the investigation to three additional Lycopodium species and furthermore reported the toxic effect of the newly isolated natural compounds on frogs.20 A few years after these findings (1938), Achmatowicz and Uzieblo investigated constituents of the species L clavatum and were able to isolate lycopodine along with clavatine and clavatoxine.21 A broader study of Lycopodium species was published by Marion and Manske who were able to isolate a large number of new alkaloids from various species.22–29 Interest in the isolation, characterization, and biological evaluation of structurally intriguing alkaloids of the Lycopodium family, as well as elucidation of the biosynthetic pathway, persisted and even increased over the next decades with Canadian scientists originating from the laboratory of W A Ayer, one of the pioneers of Lycopodium research Several milestone achievements are well worth mentioning: In 1967, Wiesner reported the preparation of 12-epi-lycopodine and was credited with the first synthesis of the tetracyclic skeleton of this important natural product.30 The seminal publication preceded the synthesis of lycopodine by only one year as 1968, Stork31 and Ayer32 completed their routes to lycopodine All three synthetic achievements are discussed in a later section of this review article Many other syntheses of Lycopodium alkaloids, published since Wiesner’s important contribution, may well be considered as synthetic and intellectual highlights and have been discussed in several review articles During the 1980s, much effort was devoted to the isolation of new metabolites, and this effort resulted in the identification of numerous structurally fascinating natural products Among the newly characterized Lycopodium constituents, several ones expressed potent biological properties For instance, huperzine A, isolated from Huperzia serrata in 1986,33,34 showed potent acetylcholinesterase inhibition activity35,36 and as the compound increased the efficiency for learning and memory in animals, it is discussed as promising drug candidate for the treatment of Alzheimer’s disease and myasthenia gravis.37 Only limited information on the biosynthetic pathway of Lycopodium alkaloids is available as of until recently, cultivation of club-mosses was impossible Thus, Spenser and coworkers performed feeding experiments Lycopodium Alkaloids – Synthetic Highlights and Recent Developments Scheme 1.1 Proposed biosynthetic pathway in the synthesis of Lycopodium alkaloids (For color version of this figure, the reader is referred to the online version of this book.) with 13C- and 14C-labeled substrates and alkaloid precursors with lycopods in their natural habitat and analyzed the alkaloids with respect to their isotope content Although no enzymes taking part in the biosynthetic pathway have been identified with certainty, these studies are extremely important indications for future investigations.38–43 The proposed biosynthetic pathway is outlined in Scheme 1.1 in abbreviated form The route starts with the formation of cadaverine (2) via decarboxylation of lysine (1) Next, Δ1-piperideine (4) is generated via 5-aminopentanal (3), probably by action of the enzyme diamine oxidase.44 Subsequently, the imine is coupled to acetonedicarboxylic acid (5), or the corresponding CoA derivative, and converted to pelletierine (7) after decarboxylation of the intermediary formed β-ketoester (6) Most likely, pelletierine then reacts with (6) and phlegmarine (8), a general intermediate in the biosynthesis of all Lycopodium alkaloids, is generated Cyclization of phlegmarine to the tetracyclic lycodane skeleton (9) sets the stage for the formation of all structurally diverging alkaloids As the main focus of this review article rests on the chemical synthesis of Lycopodium alkaloids, further discussion of the biosynthesis is omitted Detailed information on proposed pathways have been previously reviewed by Ayer,7,16 MacLean,15 Blumenkopf,45 Hemscheidt,46 and Gang.10 Ayer and Trifonov divided all known Lycopodium alkaloids into four classes with a prominent alkaloid as lead substance, namely lycopodine (12), Uwe Rinner et al H H D C N D B A H O (–)-lycopodine (12) HO B O C N A (+)-fawcettimine (13) C N H A H D N H B A N (–)-lycodine (11) C D N H H (–)-phlegmarine (7) Figure 1.1 Parent compounds of the four classes of Lycopodium alkaloids as defined by Ayer and Trifonov (For color version of this figure, the reader is referred to the online version of this book.) fawcettimine (13), lycodine (11), and phlegmarine (7) (outlined in Fig 1.1).16 While some authors prefer a different system with a larger number of possible subgroups, the original system as introduced by Ayer is maintained throughout this article Noteworthy, the classification and group allocation of some newly isolated Lycopodium alkaloids is often challenging and not unambiguous as many products can be interconverted via simple skeletal rearrangements ISOLATION OF LYCOPODIUM ALKALOIDS AND THEIR BIOLOGICAL PROPERTIES Even after years of intense research, the isolation, characterization, and biological evaluation of Lycopodium alkaloids remain a fascinating and prolific research area Since the last major review article in this field, several compounds have been isolated and investigated The following section is devoted to the discussion of newly isolated natural products and a total of 80 Lycopodium alkaloids are listed, subdivided into the four distinct classes as described in the previous section 3.1 Lycopodine Group An overview of all newly isolated Lycopodium alkaloids of the lycopodine class is provided in Table 1.1 All results depicted in the table were obtained by Kobayashi and a number of Chinese researchers None of the structures outlined in Table 1.1 displayed highly promising biological properties; however, several compounds are structurally compelling Thus, investigation of Lycopodium japonicum and H serrata revealed interesting N-oxides, whereas with the isolation of several lannotinidines (29–33) from L annotinum, structurally novel ring systems were discovered Isolation Origin Biol Activity Lycopodium annotinum No activity against P388 and L1210 murine leukemia and KB human epidermoid carcinoma cells Lannotinidine I (15)47 Lycopodium annotinum No activity against P388 and L1210 murine leukemia and KB human epidermoid carcinoma cells Lannotinidine C (16)48 Lycopodium annotinum Enhanced NGF mRNA/β-actin in 1321N1 human astrocytoma cells Lannotinidine D (17)48 Lycopodium annotinum Enhanced NGF mRNA/β-actin in 1321N1 human astrocytoma cells Lannotinidine H (14)47 Continued Lycopodium Alkaloids – Synthetic Highlights and Recent Developments Table 1.1 Newly isolated alkaloids of the lycopodine subgroup Structure Name (18)49 Table 1.1 Newly isolated alkaloids of the lycopodine subgroup—cont’d Structure Name Isolation Origin Biol Activity N/A Malycorin B (19)50 Lycopodium phlegmaria N/A Malycorin C (20)50 Lycopodium phlegmaria N/A (12β)-12-Hydroxyhuperzine G (21)51 Huperzia serrata Thunb N/A Uwe Rinner et al Lycopodium obscurum Obscurumine B Huperzia serrata Thunb N/A Lycopladine E (23)52 Lycopodium complanatum Enhanced mRNA expressions for NGF in 1321N1 human astrocytoma cells Miyoshianine C (24)53 Lycopodium japonicum Thunb N/A N-Oxidehuperzine E (25)54 Huperzia serrata Thunb N/A N-Oxidehuperzine F (26)54 Huperzia serrata Thunb N/A Lycopodium Alkaloids – Synthetic Highlights and Recent Developments (5β,6β,15α)15-Methyllycopodane5,6-diol (22)51 Continued Biol Activity Lycopodium obscurum N/A Diphaladine A (28)55 Diphasiastrum complanatum N/A Lannotinidine J (29)47 Lycopodium annotinum No activity against P388 and L1210 murine leukemia and KB human epidermoid carcinoma cells Lannotinidine A (30)48 Lycopodium annotinum Enhanced NGF mRNA/β-actin in 1321N1 human astrocytoma cells Lannotinidine E (31)48 Lycopodium annotinum var acrifolium Enhanced NGF mRNA/β-actin in 1321N1 human astrocytoma cells Uwe Rinner et al Obscurumine A (27)49 10 Table 1.1 Newly isolated alkaloids of the lycopodine subgroup—cont’d Structure Name Isolation Origin Lycopodium Alkaloids – Synthetic Highlights and Recent Developments 137 eventually was traced back to the Diels–Alder precursors diene 669 and 2-chloroacrylonitrile (670) Four years later, Oppolzer reported an elegant asymmetric synthesis of luciduline from pulegone (274).264,265 The sequence featured an N-alkenyl nitrone cycloaddition as key step to elaborate the tricyclic ring system of the alkaloid with concomitant installation of the C6-oxygen functionality The third synthesis of luciduline (667) was reported by MacLean in 1979.266 5-Methyl-1,3-cyclohexanedione 253 was converted to cyanoethyl methylcyclohexenone 126, and then elaborated into the tricyclic natural product via a lactamization and a Peterson olefination and finally a Dieckmann condensation as key steps After the successful application of hexahydro-7-methylquinoline (679) in the preparation of lycopodine119 and α-obscurine,232 Schumann also devised a route to luciduline267 utilizing the same starting material As outlined in Scheme 1.91, bicyclic imine 679 was treated with malonic acid and then converted to lactam 682 via tetrahydroquinoline 681 before the synthesis was completed in analogy to MacLean’s protocol Comins’ strategy toward luciduline slightly differed from previously published efforts as the route commenced with the addition of a Grignard reagent to chiral acylpyridinium salt 683, thus preparing the substrate for an IMDA cycloaddition.268 The corresponding tricyclic reaction product was subjected to a retro-Mannich reaction (686) and the synthesis of luciduline was completed via a reductive cyclization reaction Three syntheses of luciduline (Barbe, 2011)269 and nankakurines A and B (Overman, 200880; Waters, 201081) were published within the reporting period, all of which are outlined in Scheme 1.92 and discussed in detail in the following section In 2008, Overman80,260 reported the first total synthesis of nankakurine A (89) and B (90) and thus verified the previously revised structure of the natural product.91 The route is based on the Diels–Alder cycloaddition reaction between enone (R)-124 and diene 687 to eventually establish hydrazide 688 The hydrazide moiety was then elegantly used to elaborate tricyclic heterocycle 689, which was subsequently transformed to the desired Lycopodium alkaloids Waters also started with a Diels–Alder cycloaddition reaction which established bicyclic intermediate 692.81 A Mannich reaction was used to elaborate the tricyclic core of luciduline, which was further transformed to nankakurine A and B via a ring-closing metathesis reaction for the construction of the spiroannulated piperidine ring 138 Uwe Rinner et al Scheme 1.91 Strategic comparison of syntheses of luciduline (667) (For color version of this figure, the reader is referred to the online version of this book.) The so far latest contribution to this field was reported by Barbe in 2011.269 Starting from pyridine, bicyclic intermediate 695 was generated via a Diels–Alder cycloaddition Further key steps include a metathesis reaction, a Wacker oxidation, and an aldol condensation for the construction of the tricyclic alkaloid skeleton 5.4.5.1 (+)-Nankakurine A, (+)-Nankakurine B; Overman, 200880,260 Overman’s synthesis of nankakurine A (89) and nankakurine B (90),80,260 outlined in Scheme 1.93, began with cross-metathesis of alkyne 698 with ethylene to deliver diene 687 Next, diene 687 was allowed to react with Lycopodium Alkaloids – Synthetic Highlights and Recent Developments 139 Scheme 1.92 Strategic comparison of recent syntheses of (+)-luciduline [(+)-667], nankakurine A (89), and nankakurine B (90) (For color version of this figure, the reader is referred to the online version of this book.) Scheme 1.93 Overman’s synthesis of (+)-nankakurine B [(+)-90] (For color version of this figure, the reader is referred to the online version of this book.) enantiomerically pure enone 124, 1,2-bis(trimethylsiloxy)ethane, and TMSOTf in a Diels–Alder cycloaddition at low temperature, and acetal 699 was obtained in 64% yield as single stereoisomer This mild protocol (modification of a method reported by Gassman)270,271 became necessary to prevent the system from epimerization of the cis-decaline ring system to the thermodynamically more stable trans-isomer Cleavage of the acetal moiety in 699 with FeCl3 was then followed by condensation of the carbonyl 140 Uwe Rinner et al Scheme 1.94 Overman’s synthesis of originally proposed (+)-nankakurine A [(+)-668] (For color version of this figure, the reader is referred to the online version of this book.) group with benzoic hydrazide and subsequent reduction of the intermediary hydrazone to allow the isolation of hydrazide 688 in good overall yield With this material in hand, the way was paved for the key intramolecular azomethine imine cycloaddition reaction Thus, base-promoted reaction of hydrazide 688 with formaldehyde delivered the desired tetracyclic pyrazolidine 689 in high yield When the reaction was carried out in the absence of base, the corresponding tricyclic aza-Prins product was formed predominantly The following steps were devoted to the conversion of tetracycle 689 to nankakurine B (90) Samarium iodide-mediated cleavage of the N–N bond was followed by reductive methylation of the secondary amine Reduction of the amide with aluminum hydride and subsequent hydrogenolytic cleavage of the benzyl group delivered primary alcohol 690 Mesylation of the primary hydroxy moiety and subsequent intramolecular displacement of the mesylate was used to create the spiro-fused N-benzylpiperidine, from which nankakurine A (89; not shown in Scheme 1.93) was obtained after hydrogenolytic cleavage of the N-benzyl group Nankakurine A was further converted to nankakurine B (90) via reductive amination of the secondary nitrogen Noteworthy, Overman’s synthesis led to the correction of the originally proposed structure of nankakurine A (89) As briefly discussed above and shown in Fig 1.12, Kobayashi suggested compound 668 to be the actual natural product.90 Thus, Overman devised a route to 668, and was only able to detect the erroneously assigned structure when physical properties of the isolated and synthesized compounds did not match Overman’s initial effort is outlined in Scheme 1.94 in abbreviated form As the synthetic strategy between the syntheses of 89 and 668 only differ in the order of reactions, a discussion of this preliminary work is omitted 5.4.5.2 ( ±)-Luciduline, (±)-Nankakurine A, (±)-Nankakurine B; Waters, 201081 In 2010,Waters reported the preparation of racemic nankakurine A (89) and B (90) via luciduline (667) as synthetic scaffold, thus validating a proposal by Overman in 2008.260 The alkaloids were assembled via a Diels–Alder Lycopodium Alkaloids – Synthetic Highlights and Recent Developments 141 Scheme 1.95 Waters’ synthesis of (±)-luciduline [(±)-667], (±)-nankakurine A [(±)-89], and (±)-nankakurine B [(±)-90)] (For color version of this figure, the reader is referred to the online version of this book.) reaction as a key step as outlined in Scheme 1.95.81 Aluminum-mediated cycloaddition of 5-methylcyclohex-2-en-1-one (124) and 2-tertbutyldimethylsiloxy-1,3-butadiene (691) afforded the desired cis-fused bicyclic ring system in excellent yield with only minor amounts of the undesired trans-fused material The octalinone derivative was then converted to N-methylamine decaline-derivative 692 via reductive amination With silyl vinyl ether 692 in hand, direct conversion to luciduline (667) could be attempted The corresponding carbonyl derivative has already been successfully converted to the natural product under forced conditions by Evans in 1972.263 In contrast to Evans’ protocol, Waters employed the silyl vinyl ether as substrate and allowed the compound to react with aqueous formaldehyde and luciduline (667) was isolated as major product after purification of the reaction mixture Thus, the natural product was successfully obtained in fair overall yield in only three steps from commercially available starting materials With the synthesis of luciduline achieved, Waters turned his attention to the preparation of nankakurine A (89) and B (90) The first step in the reaction sequence was devoted to the correct installation of the quaternary carbon ultimately resulting in the aza-spiro center This goal was achieved via aminoallylation of the carbonyl moiety in 667, and subsequent allylation of the intermediary obtained ketimine With bis-alkene 693 in hand, the piperidine ring could easily be assembled via RCM with Grubbs’ second generation catalyst Finally, hydrogenation of the double bond allowed the isolation of nankakurine A (89) after this short synthetic route in good overall yield Nankakurine B (90) was obtained via reductive amination of the secondary amine 142 Uwe Rinner et al Scheme 1.96 Barbe’s synthesis of (+)-luciduline [(+)-667] (For color version of this figure, the reader is referred to the online version of this book.) 5.4.5.3 (+)-Luciduline; Barbe, 2011269 So far, the latest contribution to this field was published by Barbe in 2011.269 Barbe intended to design a general protocol for the preparation of various structurally related Lycopodium alkaloids with enone 704 serving as common intermediate The synthesis, outlined in Scheme 1.96, differs somewhat from earlier approaches as pyridine served as starting material for the construction of azabicyclo[2.2.2]octane 695, which served as key intermediate and substrate for a tandem metathesis reaction to elaborate the cis-fused hydroquinoline core By adopting a protocol employed by Fukuyama in the preparation of tamiflu,272,273 pyridine was reduced with sodium borohydride in the presence of benzyl chloroformate to the corresponding Cbz-protected dihydropyridine Next, asymmetric Diels–Alder cycloaddition with acrolein in the presence of MacMillan’s catalyst (703)274,275 gave the desired bicyclic adduct with sufficient enantiomeric purity (92:8), which was converted to azabicyclo[2.2.2]octene 695 via allylation of the carbonyl moiety and subsequent silylation As the C10-hydroxy functionality was oxidized at a later stage of the synthesis, the stereochemical outcome of the allylation was inconsequential to the overall efficiency of this route Noteworthy, Barbe also developed an alternative but strongly related five-step sequence to 695 from pyridine, which had a higher yield and was better amendable to scaleup Despite the low overall yield, bicyclic adduct 695 became accessible in multigram quantities from inexpensive starting materials With bis-alkene 695 in hand, the tandem metathesis reaction could be attempted Exposure to Grubbs’ second generation catalyst furnished octahydroquinoline 696 in 81% yield Cleavage of the silyl ether and subsequent oxidation of the secondary alcohol resulted in the formation of the Lycopodium Alkaloids – Synthetic Highlights and Recent Developments 143 corresponding α,β-unsaturated ketone after the double bond was shifted into conjugation upon reaction with basic alumina The synthesis of key intermediate 697 proceeded with conjugate cuprate addition, which stereoselectively introduced the C8-methyl group Wacker oxidation then set the stage for the envisaged intramolecular aldol condensation, delivering enone 706 in 62% yield Hydrogenation of the carbamate and concomitant in situ reductive amination completed the synthesis of luciduline (667) Barbe thus presented a 12-step route to luciduline (667) from pyridine The advantage of the approach clearly lies in the intended utilization of enone 704 for the preparation of various structurally related Lycopodium alkaloids Recently, two additional syntheses of lycopodium alkaloids have been reported Snider et al published a synthesis of racemic 7-hydroxylycopodine (283) and Fukuyama et al reported the preparation of (–)-lycoposerramineS (284) CONCLUSION Plants of the genus Lycopodium have long attracted considerable attention among researchers of different areas The isolation of structurally intriguing natural products from various plants of this genus also triggered the interest of synthetic organic chemists who soon started to pursue the preparation of these challenging alkaloids Pioneered by Canadian chemists, groups all over the world joined the scientific endeavor, which soon resulted in the preparation of structurally complex alkaloids Several of those early syntheses are today considered milestone achievements in organic chemistry and are discussed within this chapter After the seminal disclosures by Wiesner, Heathcock, Schumann, and others, the interest in the isolation and preparation of novel alkaloids from Lycopodium plants further increased and is still growing This ongoing interest is evidenced by the numerous synthetic contributions and the continuously increasing number of known metabolites Boosted by the isolation of huperzine A, which proved to be a highly potent acetylcholinesterase inhibitor, this research area experienced a further growth within the last few years, which is evidenced by this review article The literature is covered between 2005 and early 2012, and within this period, more than 40 syntheses of Lycopodium alkaloids have appeared and are discussed in detail Furthermore, nearly 80 new metabolites of Lycopodium species have been identified and to some extent evaluated for their biological activities 144 Uwe Rinner et al In many cases, the enormous activity in this field has led to numerous approaches to one and the same compound and this often allows a direct comparison of different routes Syntheses published prior to the reporting period are briefly covered to facilitate this strategic comparison and to outline the development of organic chemistry over the last decades as very often organocatalysis and transition metal chemistry have gained importance over “traditional methodology” It is also interesting to observe that some long-known protocols, such as Mannich type cyclizations, still play a major role in alkaloid synthesis Even after more than 40 years of active research, Lycopodium alkaloid synthesis continues to be an important testing ground for synthetic methodology With the enormous activity in this field, we certainly can look forward to some great new developments and achievements in Lycopodium chemistry in the near future ACKNOWLEDGMENT The authors thank Prof Edda Gössinger for careful proofreading of the manuscript REFERENCES Nickrent, D L.; Parkinson, C L.; Palmer, J D.; Duff, R J Mol Biol Evol 2000, 17, 1885–1895 Wikstrom, N.; Kenrick, P Mol Phylogenet Evol 2001, 19, 177–186 Tanabe,Y.; Uchida, M.; Hasebe, M.; Ito, M J Plant Res 2003, 116, 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Although... experiments Lycopodium Alkaloids – Synthetic Highlights and Recent Developments Scheme 1.1 Proposed biosynthetic pathway in the synthesis of Lycopodium alkaloids (For color version of this figure,... analysis of (±)-lycopodine [(±)-12] and structurally related Lycopodium alkaloids – part (For color version of this figure, the reader is referred to the online version of this book.) Lycopodium Alkaloids