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Lycopodium alkaloids    

             

TREBALL DE FI DE GRAU Lycopodium Alkaloids Marta Balañà Lucena Àrea principal: Química Orgànica Àrees secundàries: Botànica i fisiopatologia. 5-6-2012                                

                                                                                                                           


Lycopodium Alkaloids                                                                  

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Lycopodium Alkaloids     INDEX  

Abstract …………………………………………………………………………………………… 4 Introduction……………………………………………………………………………………….. 6 Objectives ………………………………………………………………………………………… 8 Materials and methods …...…...……..…….……………………………………...……………... 10 Lycopodium Alkalodis Taxonomic history and chemotaxonomy ……………………………………………… 12 Structure and nomenclature of Lycopodium alkaloids…………………………………. 13 Bioactivities of Lycopodium alkaloids ………………………………………………… 18 Proposed biosynthetic pathways ……………………………………………………….. 19 Results: Chemical syntheses of Lycopodium alkaloids ………………………………………… 21 Discussion ………………………………………………………………………………………. 46 Conclusions ………………………………………………………………………………………50 Acknowledgements ……...……………………………………………………………………… 52 Bibliography …………….………………………………………………………………………. 54

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Lycopodium Alkaloids                                                

                     

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Lycopodium Alkaloids     ABSTRACT  

  Lycopodium alkaloids are a diverse group of compounds identified in Lycopodium. The taxonomy of the genus is still not fixed. Lycopodiuim alkaloids are classified into four structural classes: the lycopodine class, the lycodine class, the fawcettimine class and the miscellaneous group. The lycopodium alkaloids are quinolizine or pyridine and α-pyridone type alkaloids. Some lycopodium alkaloids have been found to posses potent acethylcholinesterase inhibition activity and have potential as lead compounds in the treatment of neurogenerative diseases such as Alzheimer’s disease. A number of potential biosynthetic pathways to the lycopodium alkaloids have been proposed over the years. A chronological overview of the chemical syntheses of the Fawcettimine-like and lycopodinelike alkaloids are reviewed and compared showing the evolution of the synthetic strategies developed to date.

RESUM

 

Els alcaloides de licopodium són un grup divers de compostos identificats a Lycopodium. La taxonomia del gènere encara no ha estat fixada. Aquests alcaloides es classifiquen en quatre grups estructurals: el grup licopodina, el grup licodina, el grup faucetimina i el grup de miscel·lània. Els alcaloides de licopodium són de tipus quinolizina, piridina o α-piridona. S’ha descobert que alguns d’aquests alcaloides tenen una potent activitat inhibidora de l’acetilcolinesterassa, i que són compostos amb activitats potencials per al tractament de malalties neurodegeneratives com l’Alzheimer. Diferents possibles rutes biosintètiques dels alcaloides de licopodium han estat proposades durant els últims anys. Un recorregut cronològic de les síntesis químiques dels alcaloides del grup faucetimina i del grup licopodina és revisat i comparat en aquest escrit. Així mateix, es mostra l'evolució de les estratègies sintètiques desenvolupades fins ara.

                   

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Lycopodium Alkaloids  

                                                                                   

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Lycopodium Alkaloids  

INTRODUCTION

Lycopodium alkaloids are a structurally related, yet diverse group of compounds, identified in Lycopodium. To date, more than 200 Lycopodium alkaloids have been identified from 54 species of Lycopodium. These alkaloids commonly contain a skeleton comprised of 16 carbons, although they sometimes have as many as 32 carbons (apparent dimers) or less than 16 carbons (likely resulting from bond cleavage). The Lycopodium alkaloids are quinolizine, or pyridine and α-pyridone type alkaloids.1 The first investigations on Lycopodium alkaloids can be traced back to 1881. Bödeker separated lycopodine, the first identified Lycopodium alkaloid, from Lycopodium complanatum. 2 In 1938, Achmatowicz and Uzieblo isolated lycopodine, giving the correct molecular formula, and two new alkaloids. 3 Since the 1940s, several scientists have studied the isolation, structural elucidation, biogenesis, and chemical synthesis of Lycopodium alkaloids. W. A. Ayer was an outstanding chemist who spent the majority of his professional career investigating Lycopodium alkaloids and published many important articles and reviews on this topic. Through the mid 1980s, investigators studied the chemical constituents of various Lycopodium species, developed methods for chemical synthesis of several Lycopodium alkaloids, and proposed biochemical pathways for the production of these compounds. During the early 1980s, Chinese investigators screened Lycopodium species for new drugs for myasthenia gravis treatment.4 The period of 1986–1990 was a highlight in Lycopodium alkaloid research. During this time, some Lycopodium alkaloids were found to possess potent acetylcholinesterase inhibition activity.5,6 Lycopodium is a large group of species that are commonly known as club mosses. These plants are characterized by low, evergreen, coarsely and moss-like club-shaped strobili at the tips of mosslike branches. The taxonomy of the genus is still not fixed. These plants are not abundant, grow very slowly and are only found in very specialized habitats. No successful cultivation of these plants has been performed or reported. Tissue culture also seems to be very difficult. 7 , 8,9 A few investigations have been reported that have attempted to identify the biosynthetic pathway of Lycopodium alkaloids, particularly of lycopodine. However, these experiments have been limited to feeding experiments with radiolabeled precursors. In recent years, many researchers have developed total syntheses of the Lycopodium alkaloids, driven by the structurally challenging molecular architectures of the compounds and their potential biological activities.

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Lycopodium Alkaloids                                                              

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Lycopodium Alkaloids     OBJECTIVES  

  1- To know the main characteristics of the group of alkaloids obtained from the vegetable genus Lycopodium.

2- To analyze the evolution of the chemical synthesis of the most representative molecules of the alkaloids families Fawcettimine and Lycopodine.

3- To acquire a general and comparative vision of these syntheses. 4- To know the botanical characteristics of the vegetable genus Lycopodium. 5- To find out the biological activity discovered to date of these alkcaloids. 6- To learn the methodology of developing a scientific article.

                                                         

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Lycopodium Alkaloids  

                                                                                           

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Lycopodium Alkaloids     MATERIALS  AND  METHODS  

For the realization of this study, the following steps were completed:

- Research of articles related to Lycopodium Alkaloids in scientific journals, such as Tethraedron Letters, Journal of Organic Chemistry, Journal of American Chemical Society and others. - Review of these articles to resume the main characteristics of the Lycopodium plants, the chemical structure of its representative alkaloids and their biological activities.   - Prospective analysis of the chemical syntheses of the representative alkaloids of the Fawcettimine and Lycopodine class.   - Representation of these syntheses by the computer programm ChemBioDraw Ultra.

- Analysis of the evolution of these syntheses by comparing the used chemical methods.

                                               

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Lycopodium Alkaloids  

                                               

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Lycopodium Alkaloids     10  

LYCOPODIUM ALKALOIDS  

1

Taxonomic history and chemotaxonomy

First of all, is needed to mention that the taxonomic system of the Lycopodiales is still not fixed. For a many years, species of Lycopodiales were put in the genus Lycopodium of Lycopodiaceae. Lycopodiaceae was considered to comprise two genera: Lycopodium and Phylloglossum. Two separate families, Lycopodiaceae and Urostachyaceae, were set up by Rothmaler11 in 1944 and based on differences in the prothallus. Under Rothmaler’s system, three genera belonged to Lycopodiaceae, and Urostachys was replaced by Huperzia in his system. In 1964, Holub12 published two novel genera: Lycopodiella and Phlegmariurus. A system with three families (Huperziaceae, Lycopodiaceae and Phylloglossaceae) was proposed by him in 1975.13 A study by Wilce based on an examination of lycopod spores suggested that one family, Lycopodiaceae, and two genera, Lycopodium and Phylloglossum, are adequate to describe the order. In 1978, a taxonomic system with two families (Huperziaceae and Lycopodiaceae) based on species of Lycopodiales in China and founded on Holub’s system (of 1975) was proposed by Ching.14 The former family included 2 genera (Huperzia and Phlegmariurus) and the latter had 6 genera. Holub published a new system15 in 1985 with two families (Huperziaceae and Lycopodiaceae), the former with only one genus, and the latter with 10 genera. Flavones are common in ferns. Voirin16 carried out a chemotaxonomic study on the Lycopodiales in 1967. His results shown that chrysoeriol was a common constituent in Lycopodiales. Voirin pointed out that possession of this compound was a primitive character of the Lycopodiales. In 1965, Towers and co-workers17 analyzed phenolic acids and lignins in 21 species of Lycopodiales. They found that Lycopodium and Diphasium had the same constituents and were easy to distinguish from Huperzia and Lepitotis, based on these chemical differences. Braekman and co-workers 18 discussed the alkaloid content of the Lycopodiales and the relationships of chemical constituents to the botanical classification of 40 species. Their results suggested that Huperzia (= Urostachys) and Lycopodiella (= Lepidotis, excl. L. deuterodensum) should be separated from Lycopodium Recently, Wikstromand Kenrick19 estimated divergence times in the Lycopodiaceae (Lycopsida) from rbcL gene sequences. They used nonparametric rate-smoothing to draw conclusions about the evolution of 64 species of different taxa. Their results demonstrated that Huperzia was obviously distinct from Lycopodium.

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Lycopodium Alkaloids  

2

Structure and nomenclature of Lycopodium alkaloids

A. W. Ayer separated the Lycopodium alkaloids into four structural classes: the lycopodine class, the lycodine class, the fawcettimine class and the miscellaneous group. Representative compounds for these structural classes are lycopodine, lycodine, fawcettimine and phlegmarine, respectively. Skeletons of these compounds are shown in Fig. 1. The carbon numbering system for the Lycopodium alkaloids is based on Conroy’s biogenetic hypothesis.20 In this hypothesis the alkaloids are made up of two 2-propylpiperidine units. These are joined as shown in 1 to give phlegmarine 2. Bond formation between C4 and C13 then gives the lycodane skeleton. Most examples of this class have ring A oxidized to a pyridine ring, as in lycodine 3. Detachment of C1 from Nα and reattachment to Nβ then gives the lycopodine skeleton 4. Finally migration of C4 from C13 to C12 gives the fawcettimine skeleton 5.

Fig. 1

Representative compounds of the four major classes of Lycopodium alkaloids

  2.1

Lycopodine class

Seventy of the known Lycopodium alkaloids belong to the lycopodine class. This is the largest group of known Lycopodium alkaloids, and appears to be the most widely distributed. The first Lycopodium alkaloid to be identified (lycopodine 4) belongs to this group. This class is characterized by four connected six-membered rings, with rings A and C being a quinolizidine ring system. The carbonyl group in ring B is generally at C5, although it may be found at C6, such as in huperzines E 6, F 721,22 and O 8.23 According to a biogenetic hypothesis,24 these compounds may be derived directly from lycopodine via sequential oxidations (see Fig 2). The most typical compound in this class is lycopodine 4. Positions C4 and C6, α to the C5 carbonyl of

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Lycopodium Alkaloids  

4, and the tertiary carbons at C7 and C12 are commonly oxygenated in this class (i.e. 6αhydroxyserratidine

9,

25

4α-hydroxyserratidine

10,30

4α,6α-dihydroxyserratidine

11,30

lycoposerramines G 12, H 13, I 14, K 15, L 16 and N 17,26 miyoshianine A 18,27 and serratezomine C 1928). Some compounds like lycoposerramine M 20,29 have hydroxyl functional groups at C11. In addition, the nitrogen of 4 can be oxygenated. Flabelline 21 and huperzine G 2232 are unusual derivatives of 4 with the C5 carbonyl being converted to an enamide (see Fig 2). Furthermore, the C5 carbonyl of 4 can be reduced to a hydroxyl group (i.e. miyoshianine B 23,32 selagoline 24,30 lyconesidine C 2531 and lycoposerramine O 2634). The A, B and C rings of the lycopodine class of compounds are stable. Skeletal variations are found mainly in the D ring (for example, the D ring is broken between C8 and C15 in annopodine 27 and annotinine 28, and between C7 and C8 in annotine 29, lyconnotine 30 and lyconnotinol 31) (see Fig 2).

Fig. 2

Mentioned compounds of the lycopodine class.

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Lycopodium Alkaloids  

2.2

Fawcettimine class

Sixty-five of the known Lycopodium alkaloids belong to the Fawcettimine class. This class of compounds can be regarded as the products of C4-C13 to C4 –C12 bond migration from lycopodine group precursor(s). TheC13–C14 double bond of fawcettidine 32, being an enamine, is easily hydrated to give a hydroxyl group on C13 (i.e. fawcettimine 5), which can then lead to C13–N bond-cleavage to form a carbonyl group. This been confirmed by demonstration of equilibrium between the carbinolamine form and the keto-amine form.32,33,34 (see Fig 3). 2.3.1

Carbinolamine form.

Compounds like fawcettimine in which the N is connected to C13 are the most common in the fawcettimine group and are referred to as the carbinolamine form (even though many of them are not in fact carbinolamines). This form can be divided into two sub-forms, depending on whether the C12– C13 bond is broken or not, with phlegmariurine B 33 and fawcettidine 32 , respectively, representing these subforms. (see Fig 3). 2.3.2

Keto-amine form.

Alkaloids of this form have the N- C13 bond of the carbinolamine form cleaved to give initially a ketoamine, although in many members of the form the ketone has subsequently been reduced or otherwise modified. This form also has two subforms having either three-ring (i.e. lobscurinol 34 (5α-OH) and epilobscurinol 35 (5β-OH)) or four-ring skeletons (i.e. serratinine 36 and its relatives, serratine 37, serratanidine 38 and 8-deoxyserratinine 39), depending on whether a N –C4 (or N –C17 ) bond has been made or not (see Fig 3)

Fig. 3

Mentioned compounds of the fawcettimine class.

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Lycopodium Alkaloids  

2.3

Lycodine class

Twenty-six of the known Lycopodium alkaloids belong to the lycodine class. So far, all of the Lycopodium alkaloids with acetylcholinesterase inhibition activity belong to this class (i.e. HupA 40 , huperzine B 41 , N-methyl-huperzine B 42 and huperzinine 43). This class also has four rings in general, with the B, C and D rings being the same as in the lycopodine class. However, the A ring is opened and rearranged to form a pyridine or pyridone ring. The representative compound of this group is lycodine 3. Complanadine A 44,35 is the second dimeric Lycopodium alkaloid reported so far, with a C1 to C2 linkage between two lycodine moieties. HupA 40, huperzinine 43, huperzines C 45 and D 46,36 6β-hydroxyhuperzine A 47, N-demethylhuperzinine 4837 and phlegmariurine M 49 are the products of C ring cleavage and elimination of C9, giving a C15N2 skeleton. Five-ring compounds (i.e. fastigiatine 50, and himeradine A 5138 ) with a C4–C10 bond are also uncommon (see Fig 4). Except for at C12, the lycodine class of compounds is rarely hydroxylated. Variations in structure are mainly due to dehydrogenation, skeletal additions (C-methylations), Nβ-methylation, Nα -acetylation and other substitutions. Conformational isomers are found in this class. The compounds in this class usually exist with the C/D rings in the trans configuration (i.e. α-obscurine 52). However, the C/D rings have been found in the cis configuration as well, as in sauroxine 53 (see Fig 4).

  Fig. 4

Mentioned compounds of the lycodine class.

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Lycopodium Alkaloids  

2.4

Miscellaneous group

Forty of the known Lycopodium alkaloids belong to the miscellaneous group. This group includes all of the Lycopodium alkaloids that do not belong in one of the first three classes, and represent quite a diversity of structural motifs. A representative and key compound belonging to this group is phlegmarine 2, and all of the compounds in this group can be viewed as being derived from it. Furthermore, phlegmarine appears to play a key role in the biosynthesis of the other Lycopodium alkaloids, perhaps being an intermediate in the formation of all Lycopodium alkaloids. In all of the miscellaneous group compounds, C4 remains unconnected to C12 or C13. In the three other classes, C4 of phlegmarine invariably forms a C–C bond with either C13 or C12 during the C–C coupling reaction that leads to the formation of these other classes. C13 is tertiary in the miscellaneous group and the compounds in this group generally have three rings in their structural backbones, instead of four or more as is common in the other classes. Although compounds in the other classes may contain only three rings, these are believed to be formed after the basic four ring backbone structure of the class is formed. In the miscellaneous group, the compounds begin with only three rings. Huperzine V 54,39 lucidine A 55 and oxolucidine A 56 are some of the exceptions that have six rings and a C27N3 skeleton. However, these structures appear to be the result of coupling of one additional pelletierine moiety and a C3 unit to the phlegmarine 2 skeleton. Senepodines A–E 57-6040,41 have a C22N2 skeleton. However, they still possess the core phlegmarine structure. Phlegmarine is an obvious candidate as precursor for these compounds. Cernuine 61, lycocernuine 62 and their N-oxides, have a large structural difference compared to phlegmarine 2. It is likely that they are formed by a 4+2 cycloaddition reaction with a derivative of phlegmarine 2 that has undergone opening of ring D via cleavage of the C7–C12 bond. In contrast, luciduline 63 and lucidulinone 64 are the products of elimination of Nα and the C1 to C4 carbons of phlegmarine and C–C bond formation between C5 and C10. Five two-ring alkaloids (i.e. huperzinine B 65,42 phlegmariurine N 66 and cermizine C 6743 ) have the simplest lycopodium alkaloid structures. Cermizines A 68 and B 6943 possess a very similar structure to phlegmarine 2, with differences only in subsitituents at Nα and C9.          

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Lycopodium Alkaloids  

 

  Fig. 5

Mentioned compounds of the miscellaneous class.

3

Bioactivities of Lycopodium alkaloids

Huperziaceae and Lycopodiaceae (Lycopodium s. l., club mosses), have a long history of use in Chinese folk medicine for the treatment of contusions, strains, swellings, schizophrenia, myasthenia gravis and organophosphate poisoning.44 In addition, in vitro and in vivo pharmacological studies have demonstrated that Lycopodium alkaloids produce definite effects in the treatment of diseases that affect the cardiovascular or neuromuscular systems, or that are related to cholinesterase activity. These alkaloids have been shown to have positive effects on learning and memory.45,46 The most potent of these is huperzine A (HupA) 40. HupA has been found to be a potent, reversible and selective acetylcholinesterase inhibitor (AChEI).47 It also crosses the blood–brain barrier smoothly, and shows high specificity for acetylcholinesterase (AChE) with a prolonged biological half-life.48 In fact, HupA is able to penetrate the blood–brain barrier better, has higher oral bioavailability, and possesses longer duration of AChEI action than galantamine, tacrine, rivastigmine or donepezil, all drugs approved for use in treating AD. HupA has been approved as the drug for treatment of AD in China, and is marketed in USA as a dietary supplement (as powdered H. serrata in tablet or capsule format).

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Lycopodium Alkaloids  

4

Proposed biosynthetic pathways

No enzymes have been identified in the Lycopodiaceae that might be involved in the production of the Lycopodium alkaloids. Nevertheless, the feeding experiments that have been performed have laid a very good framework for future work that will seek to identify the enzymes (and corresponding genes) that catalyze key transformations in the biosynthesis of Lycopodium alkaloids. Despite a lack of convincing direct biochemical evidence, a number of potential biosynthetic pathways to several of the Lycopodium alkaloids have been proposed over the years. Originally, these hypotheses were based on the identification of new members of the respective classes of Lycopodium alkaloids that were thought to represent putative intermediates in hypothesized pathways.49 Later, feeding experiments that sought to identify pathway intermediates were conducted. In these 14

13

experiments, C- and C- labeled precursors were fed to shoots of Lycopodium species growing in their natural habitat. A few days after application of the radio- or stable isotope- labeled putative precursor, the shoots of the plant were harvested and these tissues were then analyzed for the incorporation of label into end product alkaloids or into potential pathway intermediates. These experiments produced some interesting results that led to several conclusions about the biosynthetic pathway that produces the Lycopodium alkaloids (see Figs.6). First, feeding studies with lysine demonstrated that the entry point into the pathway is indeed through the decarboxylation of lysine (by lysine decarboxylase, enzyme A) to form cadaverine. Second, cadaverine is then transformed via 5aminopentanal to D1-piperideine,50 by the action of enzyme B (probably diamineoxidase). In the meantime, two molecules of malonyl-CoAare condensed by a ketosynthase type enzyme (C) to form acetonedicarboxylic acid (or its bisCoA ester). D1-Piperideine is then coupled to acetonedicarboxylic acid (or its bisCoAester) to form 4-(2-piperidyl) acetoacetate (4PAA) (or 4-(2-piperidyl) acetoacetylCoA, 4PAACoA)

51

via the action of unknown enzyme D. 4PAA/4PAACoA is then

decarboxylated (4PAACoA is perhaps hydrolyzed first) by unknown decarboxy-lase E to form pelletierine, the first general intermediate to Lycopodium alkaloids.51,

52

Pelletierine and

4PAA/4PAACoA, or some derivatives thereof are then coupled (see Fig.6), accompanied by requisite decarboxylation, by an unknown enzyme(s), to form phlegmarine, the second general intermediate to all Lycopodium alkaloids. 53 ,52 From phlegmarine, two options are possible: on the one hand, fragmentation at C4-C5 or C7-C12 leads to compounds of the misscellaneous class such as 62 or 64; on the other hand, cyclization joining C-4-C13 of phlegmarine gives lycodane, which upon oxidation of the piperidine ring leads to lycodine. Alternatively, if the partially oxidised piperidine is hydrolized and the C1-C3 carbon attached to the other nitrogen, lycopodine skeleton results. Ring contraction of lycopodine (C4-C13 → C4-C12 migration) followed by hydration then leads to the Fawcettimine skeleton. Further oxidations then lead to wide variety of structures in each class (see Fig. 2 and Fig. 3).

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Lycopodium Alkaloids  

Fig.6

Proposed biosynthetic pathways

20  


Lycopodium Alkaloids     RESULTS   4

Chemical syntheses of Lycopodium alkaloids.

Due to the large number of syntheses of the Lycopodium alkaloids, this review will concentrate principally on compounds of the fawcettimine and lycopodine class of lycopodium alkaloids, although a number of compounds of the miscellaneous class have been included. The syntheses of each class are arranged in chronological order in order to illustrate the evolution of the strategies developed.

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Lycopodium Alkaloids  

(±)-Fawcettimine synthesis. Clayton H. Heathcock, Karl M. Smith, and Todd A. Blumenkopf. 1986.54

The stereoselective total synthesis of fawcettimine by Heathcock is not only the first synthesis but remains one of the best. The synthesis also showed that the C4 stereochemistry proposed by Ayer55 and Inubushi56 was correct. Fawcettimine was achieved in 12 steps from the cyanoenone X and proceeded in 9% overall yield. The synthesis involved a Sakurai reaction57 to install the key carbons for the B ring and an Arndt-Eistert homologation to introduce the remaining carbon of the A ring. A notable feature was that no protecting groups were employed.

22  


Lycopodium Alkaloids  

(±)-Fawcettimine synthesis. Clayton H. Heathcock, Karl M. Smith, and Todd A. Blumenkopf. 1988.58

In 1988 Heathcock refined his total synthesis of (±)-Fawcettimine. 13 steps from the cyano enone were required, with an overall yield of 16.6%. Again, it was notable that no protecting groups were required.

23  


Lycopodium Alkaloids  

Magellanine synthesis. Yen, C.; Liao, C. 200259

This is a complete an efficient total synthesis of racemic magellanine. It illustrates the power of the masked o-benzoquinone Diels-Alder protocol and serves to show how highly condensed molecular architectures can be synthesized from simple 2-methoxyphenols. It is noteworthy that all 13 carbon atoms of the tricyclic skeleton, including the aceto functionality, served in its elaborate functionalization to the target molecule. The other salient features of the current synthesis include the photochemical ODPM rear-rangement60, intramolecular cyclization of an alkenyl ketone, and the selective oxidative cleavage and double reductive amination61.

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Lycopodium Alkaloids  

(-)-Magellanine, (+)-Magellaninone, and (+)-Paniculatine syntheses. Kozaka, T.; Miyakoshi, N.; Mukai, C. 200762

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Lycopodium  Alkaloids  

This is a total syntheses of three Lycopodium alkaloids, (-)-magellanine (1), (+)-magellaninone (2), and (+)-paniculatine (3), from diethyl L-tartrate in a stereoselective manner (1, 43 steps, 1.7% overall yield; 2, 43 steps, 1.9% overall yield; 3, 45 steps, 2.8% overall yield). The noteworthy tactical feature of the synthesis involves the two PKR of enynes63, which enabled to accomplish the total synthesis of these three alkaloids.

26 Â


Lycopodium Alkaloids  

(+)- Fawcettidine synthesis. Jennifer A. Kozak and Gregory R. Dake 2008.64

The first total synthesis of (+)-fawcettidine was carried out in 16 steps by using (R)-(+)-pulegone as the chiral starting material. Key features of this synthesis included a platinum (II)-catalyzed 65 annulation reaction of a highly functionalized enamide, and a one-pot Ramberg–Bäcklund

66 , 67

reaction to form a seven-membered ring. The tolerance of platinum (II) chloride catalysis to the functional groups presented in this synthesis bodes well for the use of the annulation strategy in the synthesis

of

other

complex

natural

products.

.

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Lycopodium Alkaloids  

Lycoposerramine-C and Phlegmariurine-A syntheses. Atsushi Nakayama, Noriyuki Kogure, Mariko Kitajima, and Hiromitsu Takayama 2009.68

The first asymmetric total synthesis of lycoposerramine-C69 was carried out in 21 steps and with a 12.6% of overall yield. The highlights of this synthesis are: first of all, the stereoselective construction of a 6-5 bicyclic α,β-unsaturated ketone by cobalt-mediated Pauson-Khand reaction70; secondly the stereoselective reduction of enone with CBS reagent

71

and the subsequent vinyl Claisen

rearrangement; thirdly the construction of an azonane ring with the Ns strategy[72]; and finally, formation of the 1-azabicyclo[4.3.1]decane ring system by deprotection of the N group and C4 isomerization. Biomimetic transformation of lycoposerramine-C into phlegmariurine was also successful.

28


Lycopodium Alkaloids  

(+)-Fawcettimine synthesis. Michael E. Jung and Johan J. Chang. 2010.73

Here is reported that the process of a stepwise Mukaiyama-Michael addition of the silyl enol ether of an

acetylcyclopropane-1,1-dicarboxylate, Wittig

olefination, and

final Lewis-acid-promoted

cyclopropane opening affords hydrindanones in good yield and with complete diastereocontrol. Furthermore, it is shown that this process proceeds via an “SN2-like” mechanism and is therefore completely diastereospecific with full retention of the stereochemistry of the cyclopropyl center. This intermediate intersected with that reported by Heathcock and the subsequent steps to reach Fawcettimine were carried out in an analogous manner.

29


Lycopodium  Alkaloids  

(+)-Fawcettimine, (+)-Fawcettidine and (-)-Deoxyserratinine syntheses. Li, H.; Wang, X.; Lei, X. 201074

This synthesis demonstrated the feasibility of collective total syntheses of both fawcettimine and serratinine-type Lycopodium alkaloids (+)-fawcettimine, (+)-fawcettidine, and (-)-8-deoxyserratinine from a common precursor (all syntheses were accomplished in 12 steps). Key features of this synthesis are : first, an intramolecular C alkylation to install the challenging spiro-configured quaternary carbon center and the aza-cyclono-nane ring 75; secondly, a hydroxy-directed SmI2-mediated pinacol coupling to establish the correct relative stereochemistry of the oxa-substituted quaternary center;76 and lastly, the tandem transannular N-alkylation and removal of the Boc group.

30 Â


Lycopodium Alkaloids  

(+)-Fawcettimine and (+)-Lycoposerramine-B synthesis. Yasunari Otsuka, Fuyuhiko Inagaki, and Chisato Mukai. 2010.77

This is a total syntheses of two Lycopodium alkaloids, (+)-Fawcettimine and (+)-Lycoposerramine-B, in a stereoselective manner from a lactone derivative, which was derived from a Pauson-Khand reaction.

31


Lycopodium Alkaloids  

(-)-8-Deoxyserratinine, (+)-Fawcettimine, and (+)-Lycoflexine syntheses. Yu-Rong Yang, Liang Shen, Jiu-Zhong Huang, Tao Xu, and Kun Wei. 2010.78

32


Lycopodium Alkaloids  

This is an efficient, general and unified strategy for the total synthesis of the Lycopodium alkaloids ()-8-deoxyserratinine, (+)-fawcettimine, and (+)-lycoflexine. The key features include a highly efficient Helquist annulation 79 to assemble the cis-fused 6/5 bicycle, facile construction of the aza ninemembered ring system employing double N-alkylation strategy, providing access to the common tricyclic skeleton, asymmetric Shi epoxidation80, delivering the desired β-epoxide stereospecifically to furnish (-)-8-deoxyserratinine, SmI2 reduction of dihydroxylation derivative to enable formation of (+)-fawcettimine, and a rapid biomimetic transformation of (+)-fawcettimine into (+)- lycoflexine via an intramolecular Mannich cyclization.

33


Lycopodium Alkaloids  

(+)-Lycoflexine synthesis. Jurgen Ramharter, Harald Weinstabl, and Johann Mulzer. 2010.81

This is the first total synthesis of (+)-lycoflexine. In this case, the extensive use of tandem and one-pot reactions ( Sakurai / aldol, 82 enynene RCM 83 / hydrogenation tandem catalysis, hydroboration /oxidation84, N-Boc deprotection / transannular Mannich cyclization85) makes the sequence remarkably concise and efficient (eigh steps from cyclohexenone with an overall yield of 13%). It is flexible and therefore has been suitable for the synthesis of several other Lycopodium alkaloids as well.

34


Lycopodium Alkaloids  

Huperzine-Q synthesis. Atsushi Nakayama, Noriyuki Kogure, Mariko Kitajima, and Hiromitsu Takayama. 2011.86

This is the first asymmetric total synthesis of (-)-huperzine-Q, and was achieved in 19 steps and 16.4% overall yield starting from methyl-4-chloro-4-oxobutylate. The synthesis involved a novel stereoselective Pauson–Khand reaction87 utilizing a silyl-tethered substrate, the construction of a quaternary carbon center through a vinyl Claisen rearrangement, and a biomimetic spiroaminal formation.

35


Lycopodium Alkaloids  

(±)-Alopecuridine and (±)-Sieboldine A. syntheses. Xiao Ming Zhang, Yong-Qiang Tu, Fu-Min Zhang, Hui Shao, and Xing Meng. 2011.88

This is the first total synthesis of alopecuridine, achieved in 13 steps, and a biomimetic synthesis of sieboldine A achieved in 15 steps through a common convergent route from known iodide cyclohexenone. Key features of this synthesis included a semipinacol rearrangement of a functionalized medium-sized ring and a intramolecular pinacol coupling mediated by SmI2.89 The biogenetic pathway from alopecuridine to sieboldine A was also validated for the first time.

36


Lycopodium Alkaloids  

Synthesis of dl-Lycopodine. Stork. 1968 90

The synthesis of Stork uses an aromatic ring to form the B ring via a Friedel Craft type reaction. Reduction and cleavage of the aromatic ring provide a side chain, which is cyclised into the nitrogen in a manner that is reminiscent of the biosynthesis of lycopodine from lycodine.

37


Lycopodium Alkaloids  

Synthesys of (±)-lycopodine. Albert Padwa, Michael A. Brodney, Joseph P. Marino, Jr., and Scott M. Sheehan. 199791

A new strategy for the synthesis of (±)- lycopodine was developed by Albert Padwa, and was based on a sequential dipolar cycloaddition-N-acyliminium ion cyclization. This approach was particularly attractive as the starting α-diazo imide can be prepared efficiently on a large scale, and the cycloaddition and cyclization reactions are highly stereospecific.

38


Lycopodium Alkaloids  

Synthesis of clavolonine. David A. Evans and Jonathan R. Scheerer 2005.92

The synthesis of clavolonine by Evans highlights the conversion of functionalized linear carbon chains into polycyclic architectures. The end products of the synthesis included not only the target structure but also a diverse array of complex nitrogen-containing polycyclic structures that are accessible from simple Michael– Mannich reaction cascades.

39


Lycopodium Alkaloids  

Synthesis of lycopodine. Hua Yang, Rich G. Carter, and Lev N. Zakharov, 2008.93

This is the first enantioselective total synthesis of lycopodine. Key to this strategy was the diastereoselective intramolecular Michael addition of the acyclic sulfunamide and the Heathcock-inspired Mannich cyclization to form the CBD tricycle.

40


Lycopodium Alkaloids  

Synthesis of (±)-7-hydroxylycopodine. Hong-Yu Lin, Robert Causey, Gregory E. Garcia, and Barry B. Snider.201294

A seven-step synthesis of (±)-7-hydroxylycopodine that proceeds in 5% overall yield has been achieved. The key step is a Prins reaction in 60% sulfuric acid that gave the key tricyclic intermediate with complete control of the ring fusion stereochemistry. A one-pot procedure orthogonally protected the primary alcohol as an acetate and the tertiary alcohol as a methylthiomethyl ether.

      41  


Lycopodium Alkaloids  

Lycoposerramines-V and –W syntheses. Shigeyama, T.; Katakawa, K.; Kogure, N.; Kitajima, M.; Takayama, H. 200795

42


Lycopodium Alkaloids  

Those are asymmetric total syntheses of lycoposerramine-V (1) (22 steps, 4.3% overall yield) and lycoposerramine-W (3) (23 steps, 1.4% overall yield) starting from (α)-3-methylcyclohexanone, which enabled to determine unambiguously the structures including the absolute configurations of two novel Phlegmarine-type alkaloids newly isolated from Lycopodium serratum.

                          43  


Lycopodium Alkaloids  

Lycoposerramines  -­‐X  and  –Z.  Tanaka,  T.;  Kogure,  N.;  Kitajima,  M.;  Takayama,  H.  2009.  96

44


Lycopodium Alkaloids  

The total syntheses of cyclic nitrone-containing phlegmarine-type Lycopodium alkaloids, lycoposerraminesX and -Z, were accomplished starting from (α)-3-methylcyclohexanone via Pd-catalyzed Suzuki-Miyaura coupling,

97

Johnson-Claisen rearrangement,

98

stereoselective hydroboration-oxidation reaction,

99

and

Mitsunobu reaction, thereby establishing the structures including the absolute configuration of these two alkaloids.

 

45


Lycopodium Alkaloids     DISCUSSION   Overview of Total Syntheses of the Fawcettimine type:

To date there have been many syntheses of Fawcettimine and closely related products. After Heathcock’s classic syntheses in the eighties (in racemic form) the field underwent a resurgence around 2010 when multiple syntheses were reported in close succession, the majority being enantioselective. As can be seen from the table the most common order of ring construction is D→B→A→C or minor variations thereof. The most common methods for introducing sterochemistry into the initially formed D ring was via the use of cyclohexanones available from the chiral pool or by use of chiral auxillaries to introduced the chirality into an acyclic precursor which is then cyclised. No method used asymmetric catalysis as the source of chirality.

Heathcock

Ring Construction Strategy D→B→A→C

Racemic/ Enantiopure racemic

Fawcettimine

Heathcock

D→B→A→C

racemic

2002

Magellanine

Liao

racemic

2007

Magellanine

Mukai

enantiopure

Year

Natural Product(s)

Author

1986

Fawcettimine

1988

+ (Magellaninone &

-

Paniculatine) 2008

Fawcettidine

Dake

D→C→B→A

enantiopure

2009

Lycoposerramine-C

Takayama

acyclic→DB→A→C

enantiopure

+ (Phlegmariurine-A) 2010

Fawcettimine

Jung

D→B→A→C

enantiopure

2010

Fawcettimine +

Li

D→A→B→C

enantiopure

(Fawcettidine and Deoxyserratinine) 2010

Fawcettimine +(Lycoposerramine-B)

Mukai

acyclic→DB→A→C

enantiopure

2010

Fawcettimine +(8-Deoxyserratinine &

Wei

D→B→A→C

enantiopure

Lycoflexine) 2010

Lycoflexine

Mulzer

D→BA→C

enantiopure

2011

Huperzine-Q

Takayama

acyclic→DB→A→C

enantiopure

2012

Alopecuridine + (Sieboldine-A)

Meng

D→A→B→C

racemic

46


Lycopodium Alkaloids  

Overview of Total Syntheses of the Lycopodine Type: In the same way that in the majority of cases the reported total syntheses of Fawcettimine followed a common pattern, so do the syntheses for the construction of the Lycopodine skeleton where the sequence of D→C→B→A dominates. Of further note, despite there being numerous reported syntheses it was not until 2008 that an enantioselective synthesis of Lycopodine was reported using a chiral auxillary approach. However it should be noted that most could be made chiral by use of the enantiopure methylcyclohexenone which has been employed in numerous syntheses of Fawcettimine. Year

Natural Product

Author

1967*

12-epi-Lycopodine

Weisner

Ring Construction Strategy D→C→B→A

Racemic/ Enantiopure racemic

1968*

12-epi-Lycopodine

Weisner

D→C→A→B

racemic

1968

Lycopodine

Stork

D→CB→A

racemic

1968*

Lycopodine

Ayer

B→A→C→D

racemic

1978*

Lycopodine

Heathcock

D→C→B→A

racemic

1982*

Lycopodine

Schumann

D→C→B→A

racemic

1984*

Lycopodine

Wenkert

C→A→B→D

racemic

1985*

Lycopodine

Kraus

D→B→C→A

racemic

1998*

Lycopodine

Grieco

B→A→D→C

racemic

1997

Lycopodine

Padwa

acyclic→CD→B→A

racemic

2005

Clavolonine

Evans

acyclic→DC→B→A

enantiopure

2008

Lycopodine

Carter

D→C→B→A

enantiopure

2012

7-hydroxylycopodine

Snider

D→C→B→A

racemic

*these syntheses have not been covered in this review but are included here for comparsion.

47


Lycopodium Alkaloids  

Overview of Total Syntheses of Phlegmarine type: As in the syntheses of Fawcettimine and Lycopodine one strategy dominates: D→C→A with the chirality in the D-ring originating from methylcyclohexenone available from the chiral pool. The alternative approach by Comins used a chiral auxillary approach. Year 1981*

Natural Product Nα-methyl-Nβ-

Author Maclean

Ring Construction Strategy D→C→A

Racemic/ Enantiopure racemic

Comins

C→D→A

enantiopure

Takayama

D→C→A

enantiopure

Takayama

D→C→A

enantiopure

acetylphlegmarine 1999*

Nα-Acetyl-Nβmethylphlegmarine

2007

Lycoposerramine-V +(Lycoposerramine W)

2009

Lycoposerramine-X +(Lycoposerramine Y)

*these syntheses have not been covered in this review but are included here for comparsion.

48


Lycopodium Alkaloids                                                                  

49


Lycopodium Alkaloids     CONCLUSIONS    

1- The main characteristics of the group of alkaloids obtained from the vegetable genus Lycopodium have been analyzed. 2- The evolution of the chemical syntheses of the most representative molecules of the alkaloids f families Fawcettimine and Lycopodine have been discussed. 3-

A general, chronological and comparative vision of these syntheses have been represented.

4-

The botanical characteristics of the vegetable genus Lycopodium have been analyzed.

5-

The biological activities discovered to date of these alkaloids have been analyzed.

6-

A first approach to the methodology of developing a scientific article has been developed.

             

         

50


Lycopodium Alkaloids                                                                  

51


Lycopodium Alkaloids     ACKNOWLEDGEMENTS  

I would like to express my gratitude to all those who gave me the possibility to complete this review:

The special thank goes to my helpful supervisors, professors Ben Bradshaw and Josep Bonjoch, for their assistance and guidance in getting this project started on the right foot, and for providing me with advice, all the necessary help and time, and for sharing with me part of their valuable knowledge in organic chemistry.

My grateful thanks also goes to my parents, Xavier and Antonia Maria, for keeping reminding me that I always have a lot of work to do.

And last (but not least) I would like to thank Albert Llorens for his support, comprehension, and for his endless patience.

                     

52


Lycopodium Alkaloids  

         

                                                                             

53


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Lycopodium Alkaloids  

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Lycopodium Alkaloids  

                                                                                                                                                                                                                                                                                                                                                       

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Lycopodium Alkaloids  

TREBALL DE FI DE GRAU Lycopodium Alkaloids