Synthesis of lycopodium alkaloids

For color version of this figure, the reader is referred to the online version of this book... For color version of this figure, the reader is referred to the online version of this book

The Alkaloids, Volume 72

ISSN 1099-4831, http://dx.doi.org/10.1016/B978-0-12-407774-4.00001-7© 2013 Elsevier Inc.All rights reserved 1

Lycopodium Alkaloids – Synthetic

Highlights and Recent

Developments

Peter Siengalewicz, Johann Mulzer, Uwe Rinner 1

Institute of Organic Chemistry, University of Vienna, Währinger Straße 38, 1090 Vienna, Austria

1 Corresponding author: E-mail: uwe.rinner@univie.ac.at

1 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 Lyco-pods 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:

“Similartosavinistheherbknownas“selago.”Careistakentogatheritwithouttheuseofiron,therighthandbeingpassedforthepurposethroughtheleftsleeveofthetunic,asthoughthegathererwereintheactofcommittingatheft.Theclothingtoomustbewhite,thefeetbareandwashedclean,andasacrificeofbreadandwinemustbemadebeforegatheringit:itiscarriedalsoinanewnapkin.TheDruidsofGaulhavepretendedthatthisplantshouldbecarriedaboutthepersonasapreservativeagainstaccidentsofallkinds,andthatthesmokeofitisextremelygoodforallmaladiesoftheeyes.”5

Hildegard of Bingen knew different recipes and formulas with moss for the treatment of various medical conditions Skin irritations

club-and acne were treated with a tea brewed from L clavatum club-and couch

5.4.3 Lycoposerramine V/Lycoposerramine W/Lycoposerramine X/Lycoposerramine Z 123

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 kid-ney 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 diverg-

ing 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 ering isolation, physiological properties, as well as synthetic approaches have been published within this series.11–17 This contribution serves as

cov-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 thetic efforts with a brief excursion to early highlights of alkaloid synthesis

syn-One chapter of this review article summarizes recently isolated Lycopodium

alkaloids along with the reported biological data

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.19The same observation was attested by Muszynski who extended the investi-

gation 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

iso-late 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

eluci-dation 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

with 13C- and 14C-labeled substrates and alkaloid precursors with pods 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

lyco-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 decar-

boxylation of the intermediary formed β-ketoester (6) Most likely, letierine then reacts with (6) and phlegmarine (8), a general intermediate

pel-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),

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.)

fawcettimine (13), lycodine (11), and phlegmarine (7) (outlined in Fig 1.1).16While some authors prefer a different system with a larger number of pos-sible 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

3 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

lycopo-dine 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 biologi-cal properties; however, several compounds are structurally compel-

ling Thus, investigation of Lycopodium japonicum and H serrata revealed interesting N-oxides, whereas with the isolation of several lannotini-

dines (29–33) from L annotinum, structurally novel ring systems were

N

(–)-lycodine (11)

A

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.)

murine leukemia and KB human epidermoid carcinoma cells

murine leukemia and KB human epidermoid carcinoma cells

1321N1 human astrocytoma cells

1321N1 human astrocytoma cells

Continued

murine leukemia and KB human epidermoid carcinoma cells

1321N1 human astrocytoma cells

1321N1 human astrocytoma cells

1321N1 human astrocytoma cells

complana-tum Anitmicrobial activity against Cryptococcus neoformans (Minimal

inhibitory concentration (MIC):

0.26 µg/mL) and Aspergillus niger

(MIC: 4.16 µg/mL)

acterized over the last few years, all of which are displayed in Table 1.2 Again, the biological activity of these newly isolated natural products is unspectacular

or has not been assessed Interestingly, although isolated quite recently, several

of the alkaloids shown in Table 1.2 have already been accessed by total

syn-thesis Thus, lycoposerramine B (36), isolated in 2005 by Takayama,57 was thesized by Mukai in 2010.58 Lycopladine A (42) was successfully prepared by

syn-Toste (2006),59 Martin (2010),60 and Hiroya (2011),61 whereas the synthesis

of lycoposerramine R (47) was recently reported by Sarpong (2010).62

3.3 Lycodine Group

All newly isolated members of the lycodine group, a total of 14 compounds, are shown in Table 1.3 Remarkably, these alkaloids originated from two

Lycopodium species, namely L complanatum and Lycopodium casuarinoides The

substances depicted in Table 1.3 exhibit great structural variations While derivatives of huperzine are relatively simple natural products, complana-

dine B (57) and E (59) possess a challenging dimeric structure.

Of all compounds shown in Table 1.3, only lycopladine F (55) and G

(56) have been prepared and the total synthesis of these Lycopodium

constit-uents is discussed by Sarpong along with the preparation of complanadine

A, a dimeric alkaloid related to 55 and 56.71

3.4 Miscellaneous Alkaloids (Phlegmarine Group)

An overview of newly discovered Lycopodium alkaloids of the miscellaneous

or phlegmarine group is presented in Table 1.4 The compounds out of this

list synthesized so far are lycoposerramine V (69), W (70), X (71), and Z (73), all four of them prepared by Takayama,77,78 as well as lyconadin B (85),

which has been prepared by Smith in 2007.79 Nankakurine A (89) and B (90) have also been successfully synthesized by different workgroups.80,81

4 TOTAL SYNTHESIS OF LYCOPODIUM

ALKALOIDS – HISTORIC ASPECTS

The following section highlights milestone achievements in the area of

total synthesis of Lycopodium alkaloids Although these synthetic contributions

have been previously summarized, a detailed discussion of some syntheses seems

acetylcholinesterase from bovine extracts at the concentration of

200 µmol/L

Continued

1321N1 human astrocytoma cells

lymphoma L1210 cells

L1210 cells and human epidermoid carcinoma KB cells (IC50 > 10 µg/mL)

IC50 = 85 µM

Aspergillus niger (MIC: 2.05 µg/mL)

human astrocytoma cells

cytotoxic activity against L1210 cells (IC50: 7 µg/mL), antimicrobial activ-

ity against Cryptococcus neoformans (MIC: 0.52 µg/mL) and Aspergillus niger (MIC: 2.05 µg/mL)

Continued

human astrocytoma cells

human astrocytoma cells

Continued

murine leukemia and KB human epidermoid carcinoma cells (IC50 > 50 µg/mL)

1321N1 human astrocytoma cells

Continued

factors (1321N1 cells) and promote neuronal differentia-tion of PC-12 cells

appropriate in order to illustrate the development in this area and to appreciate the scientific value and impact of these early accomplishments The study of early synthetic contributions appears even more striking when considering the limited repertoire of synthetic procedures available to chemists only few decades ago.

4.1 First Synthesis of the Lycopodine Skeleton:

(±)-12-epi-Lycopodine (Wiesner, 1967)

In 1967, Wiesner reported the synthesis of 12-epi-lycopodine (104).30With this seminal publication, the Wiesner group achieved the first syn-thesis of the lycopodine ring system The epimer of the natural product was first described by Ayer,94 who obtained the unnatural alkaloid together

with lycopodine (12) upon catalytic hydrogenation of anhydrolycodoline

Wiesner’s synthesis of 12-epi-lycopodine is outlined in Scheme 1.2

Scheme 1.2 Wiesner’s synthesis of (±)-12-epi-lycopodine [(±)-104] (For color version of

this figure, the reader is referred to the online version of this book.)

employed in a [2+2]-photocyclization reaction with allene to deliver the

bridged tricyclic ring system 96 in fair yield Ketalization was followed by

epoxidation of the exo-methylene functionality (97) before lithium

boro-hydride reduction delivered tertiary alcohol 98, the precursor for the aldol addition reaction Exposure of ketal 98 to acidic conditions resulted

retro-in the liberation of the ketone and simultaneously mediated the retro-aldol

addition (99) Next, the B-ring of the alkaloid was generated upon reaction

of 99 with dilute sodium hydroxide in ethanol The bridgehead hydroxy functionality in 100 was then converted to the corresponding chloride

before ketalization and reduction with sodium in a mixture of ether and

liquid ammonia delivered lactam 101 Reaction with lithium aluminum

hydride and exposure to dilute hydrochloric acid gave the corresponding

amine, which was reacted with acryloyl chloride (102) to deliver 103 The

lycopodine skeleton was obtained via reaction of the enolized ketone in

103 with the newly installed Michael acceptor Reduction with lithium

aluminum hydride and reoxidation of the secondary alcohol resulted in the

formation of the C12-epimer of the Lycopodium alkaloid.

One year after this seminal disclosure, Wiesner reported an improved

route to 12-epi-lycopodine.95 The discussion of this work is omitted herein

4.2 The Quest for Lycopodine: Syntheses of Stork and Ayer, 1968

Shortly after Wiesner’s preparation of 12-epi-lycopodine, Ayer32 and Stork31 nearly simultaneously achieved the synthesis of racemic lycopo-

dine Both syntheses were published back to back in the Journal of the American Chemical Society in 1968.

Ayer’s synthesis of lycopodine (12) is outlined in Scheme 1.3 With

thal-lin (105) as starting material, Ayer efficiently generated tricyclic iminium salt 106 in only three synthetic operations.97,98 With the ABC-ring system

in hand, stereoselective addition of Grignard reagent 107 introduced the four-carbon-containing handle (108), which on a later stage was converted

into the D-ring of the alkaloid Next, epimerization at C4 was achieved

via a five-step sequence after which the C15 epimers (109 and 110) could successfully be separated Alcohol 110 was then converted to lactam 111

before addition of base effected the desired intramolecular attack of the enolate anion onto the mesylate with concomitant closure of the D-ring

of lycopodine The interim formation of the lactam became necessary as mesylation of the amino compound resulted in the formation of quaternary ammonium salts via internal ring closure on the nitrogen.

Reduction of the lactam was followed by reoxidation of the C6 hydroxy

group and tetracycle 112 was obtained Finally, lycopodine (±12) was

iso-lated after selenium dioxide-mediated oxidation of C5 and subsequent reduction with hydrazine hydrate in diethylene glycol

Ayer’s synthesis suffers from low-yielding reactions and the unselective introduction of the carbon handle as synthon for the D-ring of the natural product Nevertheless, he succeeded to prepare the alkaloid in only 17 steps and presented a remarkable synthetic achievement

Stork’s strategy toward lycopodine required the preparation of

hexa-hydroquinolone 119, (Scheme 1.4) Exposure of m-methoxybenzaldehyde

(113) to ethyl acrylate in the presence of triphenylphosphine afforded

β,γ-unsaturated ester 114 Mechanistically, this reaction proceeds via proton

migration of the initially formed Baylis–Hillman adduct and subsequent formation of an ylide that then undergoes Wittig olefination.99 Next, iso-merization of the double bond was followed by Michael addition of ethyl

acetoacetate (115) and intramolecular acylation, hydrolysis, and ylation to establish the D-ring of the alkaloid as 1,3-diketone 116 Forma-

decarbox-tion of the vinylogous ethyl ester, reducdecarbox-tion to the α,β-enone, and conjugate

cuprate addition led to cyclohexanone 117, which was converted to the first key intermediate, namely hexahydroquinolone 119, via an annelation

reaction of the corresponding enamine and subsequent Michael addition

to acrylamide The desired material (119) was obtained as a 1:1 mixture

Scheme 1.3 Ayer’s synthesis of (±)-lycopodine [(±)- 12] (For color version of this figure,

the reader is referred to the online version of this book.)

with regioisomer 118 Cyclization with a mixture of phosphoric acid and formic acid gave lactam 120 in 55% yield, along with minor amounts of

the isomer resulting from attack at the ortho-position.

The following steps were devoted to the elaboration of the A-ring of the alkaloid The carbon atoms required for the installation of the six- membered ring were already contained in the anisol moiety Thus, reduction of amide

120 to the corresponding amine was followed by Birch reduction of the

aromatic nucleus, base catalyzed isomerization of the double bond, and

protection of the secondary amine as carbamate (121) Next, ozonolysis

delivered the corresponding aldehyde ester, which was converted to enol

formate 122 upon a Baeyer–Villiger-type oxidation with selenium dioxide

and hydrogen peroxide Hydrolysis of the enol formate released the carbonyl

at C5 before zinc-mediated reductive cleavage of the carbamate-protecting

Scheme 1.4 Stork’s synthesis of (±)-lycopodine [(±)-12] (For color version of this figure,

the reader is referred to the online version of this book.)

group delivered the free amine which spontaneously cyclized to afford the

desired lactam 123, thus completing the tetracyclic lycopodine skeleton The synthesis of the target alkaloid [(±)-12] was completed via reduction of

the lactam moiety and subsequent reoxidation of the C5 alcohol

Shortly after this seminal publication, Stork reported an improved

syn-thesis of key intermediate 119, Scheme 1.5.100 Conjugate addition of the

m-methoxybenzyl bromide-derived cuprate to enone 124 and subsequent

trapping of the intermediary enolate anion with allyl bromide gave keto

acid 125 after a hydroboration/oxidation sequence The material could then

be converted to quinolone 119 via reaction with ammonia in methanol

The new route saved steps, and also solved the selectivity issues in the

prep-aration of 119, discussed above.

Ten years after the first total syntheses of lycopodine by Ayer and Stork, Heathcock achieved a highly efficient synthesis of lycopodine, which counts

as one of the highlights in alkaloid synthesis The first generation synthesis

is shown in Scheme 1.6.101 With nitrile 126 as an easily available starting

Scheme 1.5 Improved preparation of intermediate 119 (For color version of this figure,

the reader is referred to the online version of this book.)

Scheme 1.6 Heathcock’s synthesis of (±)-lycopodine [(±)-12] (For color version of this

figure, the reader is referred to the online version of this book.)

material, Heathcock decided to elaborate the alkaloid from the C-ring The B- and D-rings were established simultaneously via an intramolecular Man-nich reaction, while the A-ring was introduced last.

Cuprate addition to cyanoenone 126102 delivered dione 128 as a

1:1-C12-epimeric mixture after ozonolytic cleavage of the double bond The configuration at C12 was found to be inconsequential as only the desired isomer was able to perform the ring-closing reaction at a later stage

of the synthesis while the undesired isomer epimerized in the course of the reaction thus driving the cyclization to completion Importantly, the afore-

mentioned cuprate addition stereoselectively introduced the side-chain anti

to the on-ring methyl group

Next, both carbonyl functionalities in 128 were protected as ketals before the nitrile was hydrolyzed to the corresponding carboxylic acid 129

Amide formation with O-benzyl protected propanol amine was followed

by reduction of the amide to secondary amine 130 This sequence fulfilled

a dual purpose, namely the incorporation of the basic nitrogen and the installation of the C3-handle, which was later used in the formation of the A-ring of lycopodine Now the stage was set for the key Mannich cycli-

zation Thus, exposure of ketal 130 to acidic conditions (refluxing 3.2 M

hydrochloric acid for 14 days) released both ketone functionalities and

triggered the Mannich reaction to tricyclic ketone 132 in good yield As

already mentioned above, epimerization of the stereocenter at C12 tinuously replenished the isomer with the required configuration for the ring-closing reaction Hydrogenolytic cleavage of the benzyl group fol-lowed by Cannizzaro oxidation delivered the corresponding ketoaldehyde from which the A-ring was established via an aldol condensation reaction Hydrogenation of the resulting C3–C4 double bond finally afforded lyco-

con-podine in only 11 steps from cyanoenone 126.

An improved route to lycopodine (12) was reported in a full paper, four

years later.103 The strategy, in principle, remained the same; however, the carbon chain eventually leading to the formation of the A-ring was already

Scheme 1.7 Heathcock’s second generation synthesis of (±)-lycopodine [(±)-12] (For

color version of this figure, the reader is referred to the online version of this book.)

introduced during the cuprate addition at an early stage of the synthesis As shown in Scheme 1.7, reaction of cyanoenone 126 with the cuprate derived from 133 followed by ketalization of both carbonyl moieties and reduction

of the nitrile delivered primary amine 134 as mixture of C12-epimers, with

the newly introduced side-chain again anti to the on-ring methyl group As

discussed before, the formation of C12-epimers had no negative effect on the synthesis The cyclization took place upon heating the substrate in the

presence of hydrochloric acid for 18 days and 135 was obtained in good

overall yield The second generation synthesis of lycopodine was concluded

after exposure of methyl ether 135 to hydrobromic acid, resulting in closure

of the A-ring, and subsequent basification

4.3 Other Highlights in Lycopodium Synthesis

In 1959, Burnell isolated a novel alkaloid from Lycopodium fawcetti that was

originally referred to as base A.104 Later, the compound was renamed to fawcettimine105 and extensive research was devoted to the structural char-acterization of this fascinating compound In 1980, Inubushi reported the first total synthesis of fawcettimine.106 However, the configuration of C4 could not be unambiguously defined as the presence of a carbonyl moiety

at C5 effected epimerization at this center The ultimate structural proof was finally provided by Heathcock and coworkers who reported their total synthesis of fawcettimine in 1986.107,108

Heathcock’s synthesis not only helped to clarify stereochemical issues but also served as prominent example when strategic considerations were discussed and taken into account Several syntheses of fawcettimine are out-lined in Section 5.2.1 of this review article and despite the application of newly developed methodologies, strategic similarities to Heathcock’s route become obvious upon closer inspection In this respect, initial formation of the hydrindane moiety (A- and B-rings of the alkaloid) followed by elabo-ration of the nine-membered heterocyclic ring and subsequent formation

of the hemiaminal proved to be a valid and highly efficient route to this alkaloid Heathcock’s synthesis of fawcettimine is outlined in Scheme 1.8

The synthesis started with cyanoenone 126, which was already utilized

in the preparation of lycopodine Sakurai reaction with allylsilane 136 afforded allylic alcohol 137 in 94% yield Oxidation of the alcohol to the corresponding aldehyde (138) was followed by Wittig reaction and base catalyzed Michael cyclization to hydrindanone 140 Arndt–Eistert homolo- gation and lithium aluminum hydride reduction gave amino alcohol 141 as

a 9:1 mixture of C13 diastereomers Reaction with p-toluenesulfonyl chloride gave the N,O-ditosylate, which was cyclized with potassium hydride to the

desired nine-membered heterocyclic ring 142 in fair yield N-Detosylation

and oxidation with Jones’ reagent delivered the requisite amine 143

Note-worthy, this material did not show any tendency for cyclization and nolamine formation This observation was seen as strong indication for the originally proposed stereochemical configuration of the C4-center, oppo-

carbi-site to the configuration present in 143 Ozonolysis of the double bond in

143 allowed C4-epimerization, and fawcettimine (±13) was isolated after

spontaneous hemiaminal formation

Heathcock’s synthesis led to the natural product in 12 steps and 9%

overall yield from enone 126 (15 steps from commercially available starting

materials) This is an example that is hard to beat even with today’s sibilities

Huperzine A (10) was isolated in 1986 from H serrata (Thunb.) and was

identified as an acetylcholinesterase inhibitor and thus, a promising didate for the treatment of Alzheimer’ disease Consequently, huperzine

can-A attracted considerable attention, and several syntheses of this important natural product have been reported

Kozikowski published an elegant synthesis of huperzine A in 1989.109,110Two years later, an improved route was reported.111 The high impact and biological relevance justify a detailed discussion of Kozikowski’s synthesis of

this Lycopodium alkaloid, even more as this route comprises steps and

strate-gies that have been utilized by several groups in subsequent synthetic studies

Scheme 1.8 Heathcock’s synthesis of (±)-fawcettimine [(±)-13] (For color version of this

figure, the reader is referred to the online version of this book.)

A key step in Kozikowski’s first generation synthesis109,110 was the lation of the unsaturated carbon bridge via addition of methacrolein to the bicyclic β-ketoester 148, followed by dehydration Ketoester 148 was pre-

instal-pared via an annelation reaction to monoprotected cyclohexane-1,4-dione

(144) as starting material Throughout the sequence, the pyridone moiety

was protected as the corresponding methoxypyridine, a strategy adopted by several research groups The primary amine was introduced via a Curtius rearrangement, again imitated by other groups as well The second genera-tion synthesis, as outlined below,111 simplified the endgame of the synthesis and led to a more efficient route to the natural product Instead of the aforementioned addition of methacrolein, a palladium-catalyzed reaction was employed to complete the carbon skeleton of huperzine A

As outlined in Scheme 1.9, the reaction sequence started with treatment

of the monoethylene ketal of cyclohexane-1,4-dione (144) with

pyrro-lidine and acrylamide effecting an annelation reaction via the intermediary

formed enamine, and a mixture of pyridones 145 and 146 was obtained

in a ratio of 85:15 favoring 145 Benzylation of the nitrogen and

subse-quent dehydrogenation by α-selenation and subsequent selenoxide nation and epimerization afforded the corresponding pyridone in high

elimi-Scheme 1.9 Kozikowski’s synthesis of (±)-huperzine A [(±)-10] (For color version of this

figure, the reader is referred to the online version of this book.)

and O-methylation with silver carbonate and methyl iodide delivered the

desired methylated hydroxypyridine in excellent yield With this material

in hand, the key substrate for the palladium-catalyzed installation of the remaining ring could easily be obtained after deketalization and carbo-methoxylation

Following the procedure on palladium-catalyzed bicycloannelation by Huang and Lu,112 β-ketoester 148 was reacted with allylic diacetate 152

in the presence of palladium acetate, triphenylphosphine, and ramethylguanidine as base in refluxing dioxane to allow the isolation of

1,1,3,3-tet-the methylene-bridged adduct 149 in excellent yield Next, Wittig nation of ketone 149 with ethylidenetriphenylphosphorane installed the

olefi-C13–C14 side-chain as isomeric mixture of (Z )- and (E )-alkenes in a ratio

of 1:9 As the desired (E )-isomer was only present as minor component, the

mixture was isomerized with thiophenol and azobisisobutyronitrile (AIBN)

to the (E )-stereoisomer.

As mentioned above, the primary amine in (±)-huperzine A (±10) was introduced via a Curtius rearrangement Thus, saponification of 150

was followed by treatment of the acid with diphenyl phosphorazidate and

triethylamine, and carbamate 151 was obtained after methanolysis of the

resulting isocyanate Interestingly, the saponification only yielded the desired (E )-acid, while traces of the (Z )-ester present in the reaction mixture were

found to be unreactive and could be recovered

The synthesis of (±)-huperzine A (±10) was concluded after

trimethyl-silyl iodide-mediated deprotection of the methoxypyridine and tion of the exocyclic double bond to the desired endocyclic olefin

In 1993, the Overman group contributed to the area of Lycopodium

alka-loids with a short and highly efficient route to magellanine (162) and magellaninone (164).113 The synthesis of these two alkaloids, outlined in

Scheme 1.10, featured a Prins-pinacol rearrangement as the key step and represents an early and beautiful example of the synthetic utility of this reaction for the elaboration of complex natural products First described

in 1969 by Mousset,114,115 the Prins-pinacol rearrangement became an important tool in the Overman group as evidenced by numerous synthetic applications.116

Following a procedure developed by Cohen and coworkers,117

enan-tiomerically pure bicyclic ketone 153 was treated with [bis(methylthio)

methyl]lithium before exposure of the resulting alcohol to copper(II) flate induced Wagner–Meerwein ring expansion to α-sulfenyl ketone 154

tri-in high yield The sulfenyl ketone was converted to vtri-inyl triflate 155 via

sequential treatment with Li–NH3, trimethylsilyl chloride, methyllithium,

and N-phenyltriflimide Thus, the methylthio functionality introduced

dur-ing the rdur-ing expansion reaction served as a regioselective handle to install

the second double bond of the bicyclic system Triflate 155 was converted

to the corresponding vinyl iodide and then metalated to the organolithium

derivative which was added to ketone 165 (also accessible from bicyclic ketone 153 following a four-step protocol comprising of hydrogenation,

Baeyer-Villiger oxidation, reduction of the lactone, selective silylation of

the primary alcohol, and subsequent Swern oxidation) Diol 156 was

obtained stereoselectively after exposure of the reaction product to

tetra-n-butylammonium fluoride (TBAF).

The substrate for the key Prins-pinacol rearrangement was prepared

by bis-silylation and selective oxidation of the primary silyl ether to the

Scheme 1.10 Overman’s synthesis of (−)-magellanine [(−)-162] and (+)-magellaninone 164] (For color version of this figure, the reader is referred to the online version of this book.)

[(+)-in 57% yield [(+)-in a 2:1 ratio Noteworthy, this Pr[(+)-ins-p[(+)-inacol rearrangement

established the core structure of the Lycopodium alkaloids and defined three

of the six stereocenters Although separation of the epimers was possible

at this stage, Overman and coworkers decided to carry the mixture to the final stage of the synthesis before the isomers were separated and converted

to magellanine from β-isomer 158 and magellaninone from α-isomer 159.

Next, the heterocyclic D-ring of the alkaloid was elaborated ylation of the remaining double bond and subsequent periodate cleavage

Dihydrox-was followed by reductive amination and azatetracycle 160 Dihydrox-was isolated in good overall yield The methyl ether in 160 was displaced by a TBS group

and the benzhydryl moiety by a carbamate before the A-ring was alized Saegusa oxidation was followed by cuprate addition before a second Saegusa oxidation completed this sequence The synthesis of magellanine

function-(162) was completed after cleavage of the Boc-functionality, methylation of

the nitrogen, desilylation, and separation of the C5-epimers Magellaninone

(164) became accessible via Jones oxidation of the C5 α-isomer

Overman’s synthesis of magellanine (162) and magellaninone (164)

clearly deserves discussion in this section as the route impresses by the cise design The key Prins-pinacol rearrangement is perfectly suited for the

pre-elaboration of the tetracyclic skeleton of these Lycopodium alkaloids without

necessitating additional synthetic operations to adjust the reaction product according to structural requirements of the target molecule Also worth mentioning is the elegant independent conversion of the bicyclic starting material to both coupling partners

5 TOTAL SYNTHESIS OF LYCOPODIUM

ALKALOIDS – RECENT DEVELOPMENTS

Lycopo-petition between the research groups of Wiesner, Stork and Ayer led – in

1968 – to the first total synthesis of a Lycopodium alkaloid In the following

years, lycopodine served as playground for many other synthetic groups

To date, 15 syntheses of lycopodine and structurally highly related Lycopodium

alkaloids have been published The retrosynthetic analysis and key steps for all syntheses are outlined in Schemes 1.11–1.13 All syntheses published after 2005 (see Scheme 1.13) are discussed in detail within this section;

a brief overview of older contributions is outlined below Ayer’s, Storck’s and Heathcock’s classical contributions have already been discussed in detail in Section 4.2

Ayer’s approach32 toward lycopodine (12) is shown in the first line

of Scheme 1.11 The authors envisaged the D-ring to be elaborated at a very late stage of the synthesis via an alkylation reaction The requisite

substituted hydrojulolidone core was prepared from iminium ion 106, which could be traced back to thallin (105) Thus, Ayer’s synthesis is

unique as it is the only approach starting from the BC-ring system of the alkaloid

Stork31 decided for a completely different strategy and performed the closure of the A-ring as last major synthetic operation This general strategy was later adopted by several other groups as evidenced in Schemes 1.11–1.13 Tricyclic intermediate 122 was prepared from aromatic precursor 119

via an acyliminium cyclization and ozonolytic cleavage of the aromatic ring

as key steps Noteworthy, the aromatic ring served as scaffold for the tion of the A-ring of the alkaloid at a later stage of the synthesis Diketone

elabora-116 became accessible from m-methoxybenzaldehyde via a sequence

featur-ing a modified Baylis–Hillman reaction/Wittig olefination cascade

Ten years after Ayer’s and Stork’s pioneering contributions, Kim118reported a synthesis of lycopodine Again, the A-ring of the alkaloid was

constructed last via N-alkylation leading back to tricyclic amide 170 This material was prepared from carbamate 169 utilizing a malonate conden-

sation and a Corey–Chaykovsky reaction as key steps A [3,3]-Robinson annelation and subsequent Curtius rearrangement served as methods of

choice for the preparation of tricyclic lactam 170.

In 1982, Heathcock103 (second generation synthesis; the first eration synthesis was published in 1978)101 and Schumann119 presented highly efficient syntheses of lycopodine Unquestionably, both routes are considered classic examples and highlights of alkaloid synthesis, and Heathcock’s contribution is described in detail in Section 4.2 While the endgame with the construction of the A-ring of lycopodine is similar in

gen-both routes, the synthesis of the requisite tricyclic precursor (132 and

173, respectively) clearly differs Heathcock started with a conjugate

Scheme 1.11 Retrosynthetic analysis of (±)-lycopodine [(±)-12] and structurally related

Lycopodium alkaloids – part 1 (For color version of this figure, the reader is referred to

the online version of this book.)

Scheme 1.12 Retrosynthetic analysis of (±)-lycopodine [(±)-12] and structurally related

Lycopodium alkaloids – part 2 (For color version of this figure, the reader is referred to

the online version of this book.)

Scheme 1.13 Retrosynthetic analysis of lycopodine (12) and structurally related

Lycopodium alkaloids – part 3 (For color version of this figure, the reader is referred to

the online version of this book.)