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Progress in the Synthesis of Iboga-alkaloids and their Congeners

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Progress in the Synthesis of Iboga-alkaloids and their CongenersGoutam Kumar Jana a , Sibasish Paul a & Surajit Sinha aa Department of Organic Chemistry, Indian Association for theCultivation of Science, Jadavpur, Kolkata-700032, IndiaVersion of record first published: 16 Nov 2011.

To cite this article: Goutam Kumar Jana, Sibasish Paul & Surajit Sinha (2011): Progress in theSynthesis of Iboga-alkaloids and their Congeners, Organic Preparations and Procedures International:The New Journal for Organic Synthesis, 43:6, 541-573

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Organic Preparations and Procedures International, 43:541–573, 2011Copyright © Taylor & Francis Group, LLCISSN: 0030-4948 print / 1945-5453 onlineDOI: 10.1080/00304948.2011.629563

Progress in the Synthesis of Iboga-alkaloidsand their Congeners

Goutam Kumar Jana, Sibasish Paul, and Surajit Sinha

Department of Organic Chemistry, Indian Association for the Cultivationof Science, Jadavpur, Kolkata-700032, India

I. Structure and Pharmacological Properties of Iboga-alkaloids ....... 5421. Structure of Iboga-alkaloids..................................................................5422. Newly Isolated Iboga-alkaloids..............................................................5443. Newly Isolated Iboga-lignan Conjugated Natural Products.....................5454. Pharmacological Properties of Iboga-alkaloids ......................................546

II. Syntheses of Ibogaine, Ibogamine (Ibogamine-19-ol) and theirAnalogues ..................................................................................... 5471. Brief Outline of the Retrosynthetic Strategies.........................................5472. Electrophilic C2–C16 Cyclization Approach...........................................5483. Fischer Indolization Approach ..............................................................5514. Mixed Metal-Mediated Cyclization Approach.........................................5535. Formation by Hydroazepine Ring ..........................................................5566. Decarboxylation of Coronaridine ..........................................................557

III. Syntheses of Coronaridine, Catharanthine and their Analogs........ 5571. Brief Outline of the Retrosynthetic Strategies.........................................5572. Synthesis from Ibogamine and Cleavamine............................................558

a) From Ibogamine............................................................................558b) From Cleavamines ........................................................................558c) Cleavamines .................................................................................559

3. Diels-Alder Reaction Mediated Synthesis ...............................................562

IV. Concluding Remarks .................................................................... 569Acknowledgements ....................................................................... 569References .................................................................................... 569

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542 Jana, Paul, and Sinha

Progress in the Synthesis of Iboga-alkaloidsand their Congeners

Goutam Kumar Jana, Sibasish Paul, and Surajit Sinha

Department of Organic Chemistry, Indian Association for the Cultivationof Science, Jadavpur, Kolkata-700032, India

I. Structure and Pharmacological Properties of Iboga-alkaloids

1. Structure of Iboga-alkaloids

Iboga alkaloids comprise a large group of pharmacologically important indole alkaloids,mostly isolated from Tabernanthe or Tabernaemontana species of plants belonging to theApocynaceae family.1–4 Members of this family of alkaloids have a characteristic indoleand isoquinuclidine ring fused by a seven membered indoloazepine ring. There are someeighty structurally closely related monoterpene indole alkaloids which belong to the iboga-alkaloid family and these can be categorized into three types based on the substitution onthe isoquinuclidine ring (Figure 1).

Ibogaine, 1 (Type 1) was the first member of this family isolated and identified inthe beginning of 20th century;5–8 the structures of this and related alkaloids were firstestablished about 60 years later.9 Iboga-alkaloids which have been isolated in the period of1900–2000 are shown in Figure 1.

The iboga- alkaloids in Figure 2 are the oxidized forms of the known alkaloids discussedin Figure 1 and have been isolated from different species of the Apocynaceae family. Di-hydroxycoronaridine 28,10 dehydrocoronaridine 2911 and 3-hydroxy-3,4-secocoronaridine3012 were isolated from Peschieru buchtien, Tabernaemontana markgrajiana and Er-vatamia polyneura, respectively. The iboga-alkaloids which have an ether linkage areepoxyibogaine 31,13 epoxyiboxygaine 32,13 epoxycoronaridine 33,14 heyneatine 3415 andobovamine 35.16 The other oxidized forms of this alkaloid are 3-ketopropyl-heyneanine 3614

and sarcopharyngine 3717 which were isolated from Tabernaemontana and Sarcopharyn-gia, respectively. The 3-position of the indole moiety is susceptible to oxidation andanother oxidized form of this alkaloid called 3-hydroxyindolenine has been isolated. Anumber of 3-hydroxyindolenine containing alkaloids are coronaridine hydroxyindolenine

Received March 11, 2011; in final form September 8, 2011.Address correspondence to Surajit Sinha, Department of Organic Chemistry, Indian Association

for the Cultivation of Science, Jadavpur, Kolkata 700032. E-mail: ocss5@iacs.res.in

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Synthesis of Iboga-alkaloids and their Congeners 543

Figure 1

38,10 voacangine hydroxyindolenine 39,11 heyneanine hydroxyindolenine 40,18 voacrsi-tine hydroxyindolenine 41,19 conopharyngine hydroxyindolenine 4220 and 3R/S-hydroxyconopharyngine hydroxyindolenine 43.20 Interestingly, the indole moiety lost its aromaticcharacter in these alkaloids.

Catharanthine, 44 (Figure 3) is another variant of the iboga-alkaloids. It is also apentacyclic indole alkaloid isolated from catharanthus roseus21,22 which belongs to theapocynaceae family having a carbomethoxy group at the C16 with an isolated double bond.It is the chemical and presumably the biogenetic precursor of the dimeric vinca alkaloidsvinblastine and vincristine, two drugs used in the treatment of a number of human cancers.

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Figure 2

2. Newly Isolated Iboga-alkaloids

Studies on the isolation and characterization of iboga alkaloids have been continuing. Thestructures of the newly isolated alkaloids are shown in (Figure 4). The alkaloids 45–4923

were isolated from Tabernaemontana corymbosa and 50–5424 were isolated from

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Synthesis of Iboga-alkaloids and their Congeners 545

Figure 3

Tabernaemontana divaricata, respectively. Though the compound 54 was isolated in1982,25 no experimental data was reported in that paper. The compounds 55–5626 belongto a new structural scaffold which was not discussed earlier.

3. Newly Isolated Iboga-lignan Conjugated Natural Products

More recently, iboga-conjugated natural products such as conoliferine (57a),27 isoconolif-erine (57b),27 conomicidines A and B (58a and b)28 and isoconomicidines A and B (59a

Figure 4

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Figure 5

and 59b)28 have been isolated from Tabernaemontana species as a mixture of (1′S, 2′S)-and (1′R, 2′R)-diastereomers (Figure 5). These natural products are the results of the conju-gation of ibogaine and hydroxycinnamyl alcohol moieties, and represent the first examplesof alkaloid-lignan conjugates.

4. Pharmacological Properties of Iboga-alkaloids

Psychoactive properties of ibogaine have been known for decades and its pharamacologicalproperties have been reviewed many times.1–3,29,30 Ibogaine has attracted attention becauseof its reported ability to reverse human addiction to multiple drugs of abuse, includingalcohol, heroin and cocaine.29 Human anecdotal reports assert that a single administrationof ibogaine reduces craving for opiates and cocaine for extended periods of time and reducesopiate withdrawal symptoms. The corresponding program was patented in the USA underthe trade name Lotsof Procedure.TM31 However, this therapy has not been admitted as aclinical method because of side-effects, such as hallucinations at high doses. In addition,ibogaine causes degeneration of cerebellar Purkinje cells32 and whole-body tremors andataxia in rats33 if the dose is high. In this connection, (−)-18-methoxycoronaridine (18 MC)(60) (Figure 6), a non-toxic iboga alkaloid congener was reported in 1996 by a team led byGlick and Kuehne.34 18-Methoxycoronaridine is a selective inhibitor of the α3β4 nicotinicreceptor whereas ibogaine affects many different neurotransmitter systems simultaneously.Apart from their anti-addictive properties, iboga-alkaloids and their congeners show awide variety of pharamacological effects, such as antifungal or antilipase,35 anti-HIV-1,36

anti-cholinesterasic37,38 and leishmanicide activities (against Leishmania amazonensi).39

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Synthesis of Iboga-alkaloids and their Congeners 547

Figure 6

II. Syntheses of Ibogaine, Ibogamine (Ibogamine-19-ol) and their Analogues

1. Brief Outline of the Retrosynthetic Strategies

Brief retrosynthetic strategies of iboga-alkaloids are depicted in Scheme 1. Since Buchi’s to-tal synthesis of ibogamine,40 the majority of the syntheses reported have adopted the strategyof generating β-(indolylacetyl or indolylethyl)isoquinuclidines or indolyl-isoquinuclidinesfollowed by electrophilic cyclization leading to the formation of hydroazepine ring. An alter-native approach involves the generation of isoquinuclidine fused seven-membered ketone,a key precursor followed by cyclization to the iboga-scaffold by the Fischer indolizationmethod. Trost developed a mixed-metal-mediated cyclization method for the formationof C2-C16 bond between indole and dehydroisoquinuclidine to obtain the iboga-scaffold.This method has been used by several other groups for the synthesis of ibogamine and itsanalogues. Grieco’s approach was the formation of the seven-membered hydroazepine ringfrom a suitably substituted tryptamine derivative and completion of the isoquinuclidine ringat the end of the synthesis (Scheme 1).

Scheme 1

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2. Electrophilic C2–C16 Cyclization Approach

Buchi and co-workers were the first to disclose a successful synthesis of racemic ibo-gaine and ibogamine as well as of the corresponding unnatural C(20)-epimers in 1965.40

Several other syntheses were then followed. In each of these syntheses, the formationof a 2-azabicyclo[2.2.2]octane (or isoquinuclidine) ring bearing a two-carbon chain atthe requisite position of the ring was the crucial step. Buchi’s method involved a Diels-Alder condensation between methyl vinyl ketone and unstable 3-carboxamido-N-benzyl-1,6-dihydropyridine. The dihydropyridine was synthesized from pyridinium salt 61. TheDiels-Alder adduct 62 was then converted to 2-azabicyclo[2.2.2.]octanone (63) in foursteps. Buchi’s synthetic route toward ibogamine following a cationic cyclization of 64 byPTSA and hot acetic acid was simple but it proceeded via the formation of rearrangementproduct 65 that was discussed in a subsequent paper.41 The rearranged product 65 was thenreduced with LiAlH4, followed by oxidation at C-19; a subsequent elimination affordedthe α,β-unsaturated ketone 66. Interestingly, compound 66 underwent rearrangement in thepresence of Zn/HOAc to yield the desired scaffold which was then converted to ibogamineand its epimer by Wolff-Kishner reduction (Scheme 2). Analogous procedures were usedto synthesize ibogaine and its epimer.

Scheme 2

Huffman’s strategy was the opening of cyclic epoxy ester by tryptamine at high tem-perature to obtain a tryptamine-isoquinuclidone conjugate in one step. Further syntheticmanipulations provided deethylibogamine42,43 and ibogamine,44 respectively (Scheme 3).Using a similar approach and at the same time, Kuehne and Reider45 reported the synthesisof ibogamine via the formation of lactam 69a which was derived from a mixture of thesame epoxides, 68.

Huffman’s synthetic approach toward epoxides, 68 was different from that of Kuehne.Huffman started with readily available allylic bicyclic lactone and obtained 68 in 43%

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Synthesis of Iboga-alkaloids and their Congeners 549

Scheme 3

overall yield whereas Kuehne started from diethyl methylenemalonate that after conden-sation with 1-pyrrolidino-1-butene gave 72. Further synthetic manipulation of 72 affordedcis/trans-mixture of epoxides in 21% overall yield (Scheme 4).

Scheme 4

Nagata and coworkers developed an alternative synthesis of isoquinuclidine (75) bythe cleavage of a bridged aziridine ring 74 with β-indolyl acetic anhydride. The hydroxycompound 75, after oxidation and PTSA-mediated cyclization followed by methanolysisgave methoxy lactam 76a. The methoxy group was removed by LiAlH4 and further reactionsequences led to the formation of deethylibogamine.46 This approach was then applied tothe synthesis of dl-ibogamine and epiibogamine,47 respectively. The conversion of 76 toibogamine was successfully achieved in a single step by reduction with AlH3

48 (Scheme 5).

Scheme 5

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Imanishi et al.49,50 synthesized 2-azabicyclo-[2.2.2]octane via an intramolecularMichael addition reaction of unsaturated ester 77 which was derived from ethyl 1,6-dihydro-3(2H)-pyridinone-1-carboxylate. The ratio of the endo and exo isomers from Michael addi-tion products 78 was 2:1; these were then used separately for the conversion to epiibogamineand ibogamine, respectively. Yields were reported here for the endo-isomer which led tothe formation of epiibogamine. Similarly, the exo-isomer of 78 gave ibogamine in 10%overall yield (Scheme 6).

Scheme 6

The synthesis of the dimethyl acetal of compound 80 was also reported by Herdeis andHartke-Karger group51 where the dimethyl acetal of isoquinuclidone was synthesized by theDiels-Alder addition of 1-benzyl-5-benzyloxy-2-pyridone to 1,2-diphenylsulfonylethylene.

Krow’s group developed a synthetic route52 to lactam 80 starting from Diels-Alderadduct 81.40,41 The tosylhydrazone of the endo compound was separated out as a crystallinesolid from a mixture of endo/exo products. The endo-isomer was wrongly assigned toexo-isomer by Krow and co-workers and the configuration of the ethyl group wasconfirmed by Hodgson’s group based on the single-crystal X-ray structure.53 The 5,6-dehydroisoquinuclidine (82) was then treated with benezeneselenenyl chloride followedby dehydrohalogenation and hydrolysis of the intermediate (vinyl selenide) affordedisoquinuclidin-6-one 83 regioselectively, which was used for the synthesis of lactam 80(Scheme 7).

The earlier syntheses were restricted to very simple representatives, namely ibogamineand ibogaine. In 2006, Borschberg’s group reported the first enantioselective synthesis of(−)-(19R)-ibogamin-19-ol.4,54 The key intermediate 9054,55 was synthesized in opticallyactive form starting from L-glutamic acid and (2S)-but-3-en-2-ol. The synthesis of 90shown in (Scheme 8) involves two key steps, an Ireland–Claisen rearrangement and anintramolecular nitrone-olefin 1,3-dipolar cycloaddition reaction. The C2-C16 cyclizationin the synthesis of ibogamine was achieved earlier with PTSA in boiling benzene,50 however,this procedure gave poor yield in the cyclization of 92. After some unsuccessful attempts,acetyl chloride in strictly anhydrous glacial acetic acid was found to be suitable for the

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Synthesis of Iboga-alkaloids and their Congeners 551

Scheme 7

cyclization of 92 to give 93 in 72% yield. Deacetylation, selective dehydration and lactamreduction yielded (−)-ibogamin-19-ol (45) in 20% overall yield from 90 (Scheme 8).

Rosenmund and his group used polyphosphoric acid mediated cyclization of the C-6-C-7 bond in the synthesis of deethylibogamine,56 ibogaine, epiibogamine and ibogamine,57

respectively (Scheme 9).

3. Fischer Indolization Approach

There are other approaches which have led successfully to ibogamine. Sallay58 developed acompletely new stereocontrolled route toward the synthesis of dl-ibogamine, which involvedthe formation of the seven-membered ring first, then completion of the isoquinuclidine andindole ring closures at the end of the synthesis. It was claimed that this method is moreversatile, as the formation of side-products is minimized and several steps produced goodyields. According to this approach, the cis-enedione 95 was converted to a Beckmann-rearranged product 96. Epoxidation using perbenzoic acid takes place from the convexside of the molecule and the resultant epoxide on treatment with LAH gave the hydroxycompound 97. Further synthetic manipulations gave the tricyclic ketone 101 which wasthen transformed to racemic ibogamine by Fischer indolizations (Scheme 10).

Ban and coworkers used an alternative approach (Scheme 11) to the synthesis oftricyclic ketone 101 and its epimer 101a which were then converted to ibogamine (2)59 andepiibogamine (2a),60 respectively using the Fischer indolization method. Compound 102underwent tautomerization in the presence of a base to give a mixture of imine 103a andenamine 103b which after hydrolysis and diazomethane treatment gave the tricyclic ketone104. The tricyclic ketone was then converted to 101a in four steps.

The strategy of White’s group for the enantioselective synthesis of (−)-ibogamine61

was based on an asymmetric Diels-Alder reaction as a key step. The chiral Diels-Alderadduct 107 was synthesized using benzoquinone as the dienophile in the presence ofthe Ti-complex of (S)-BINOL 106 as the catalyst. Diketone 107 was reduced under theLuche conditions to give allylic alcohol 108. The reduction of olefinic double bonds wasaccomplished by hydrogenation over rhodium on alumina and subsequent oxidation of thediol then gave diketone 109. Selective protection of the less hindered ketone, reprotection

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O

HO OMe

O

O

(-)-87

OHL-Glutamic acid

Mitsunobu react. OBn

OMe

OMe

OMe

OBn

6 steps

86

OMe

NH

OBn

O

H

MeN OBn

H

O

H

Me

+

+

HN

H

OBn

HO

H

Me

(-)-88

(+)-89 (-)-89(+)-90

1. LDA, HMPTTBDMSCl, reflux2. LiAlH4

3. Swern oxid.4. NH2OH.HCl5. NaBH3CN

HN

OH

OBn

OMe

OMe

HN

OH

OBn

OMe96 : 4 (65 %)

96 : 4

1.5 M H2SO4 Zn, HOAc(+)-89

NMeO

AcOH

Me

NH

O

NMeO

AcO

H

Me

N

O

Ts

NAcO

H

Me

NH

O

NHO

H

Me

NH

OAc

(+)-90

(+)-91 (+)-92

(+)-93 (+)-94

4 steps

MeO

1. LAH

2. BF3.OEt2 HO

NHO

H

Me

NH

LAH, AlCl3(-)-Ibogamine-19-ol (45)

(+)-88

(-)-87

Na/Hg

MeOH

85 %

67 %94 %

68 %

85 %

67% MeOKH2PO4

72%

AcCl, MeOH (cat.)

72 %

HOAc, 45 oC

Scheme 8

Scheme 9

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Synthesis of Iboga-alkaloids and their Congeners 553

O

O

O

O

NH

O

1. HO(CH2)2OH

3. Beckmannrearrangement

1. Perbenzoicacid

O

O

NH

O

2. LiAlH4

1) Sarett oxidation90%

2) Wittig olefination

O

O

NH

O 1) Hydroboration90%

2) LiAlH4, 90 %

3) CbzCl4) TsCl

O

O

NCbz

OTs

HBr-AcOH

NH.HBr

X

O

OH

N

O

Fischer indolesynthesis

Isoamylalcohol

95 9697

98 99100

101

Ibogamine (2)

2. NH2OH

X = OTs or Br

58 % (3 steps)55 % (2 steps) 82 %

quantitative

Scheme 10

Scheme 11

of the primary alcohol, oxime formation and subsequent Beckman rearrangement gavelactam 110. The silyl deprotection followed by tosylation and intramolecular cyclizationof the tosyl compound in the presence of NaH furnished 111. After transketalization of111, the resultant keto lactam was subjected to Fischer indolization to yield 112. Reductionof the lactam 112 with borane gave crystalline (−)-ibogamine in 9.9% overall yield from105 (Scheme 12).

4. Mixed Metal-Mediated Cyclization Approach

Trost has reported the synthesis of dehydroisoquinuclidine moiety 115 via Pd-catalyzedallylations of suitably substituted amines. The cyclization between C2 and C16 was effectedby Ag-Pd-catalyzed olefin arylation and the organo-palladium intermediate was reducedby NaBH4 to give deethylibogamine62,63 in 40–50% yield (Scheme 13).

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Scheme 12

Scheme 13

Extension of this method to the enantioselective synthesis of ibogamine was alsoreported in 1978 by Trost’s group63 where the Diels-Alder addition step was carried outenantioselectively using a chiral auxiliary. The enantioselectivity was maintained until thefinal step of the synthesis (Scheme 14). Trost also reported64 the synthesis of racemicibogamine and epiibogamine from achiral diene (R = CH3) using this protocol. The Pd-mediated cyclization method was also used by Tomisawa and coworkers65 to synthesizeepiibogamine.

Neier and coworkers66 developed an alternative synthetic route toward the synthesis ofa 2-azabicyclo[2.2.2]oct-5-ene derivative 115 which was used as a precursor in the synthesisof an iboga-scaffold 70 (Scheme 15).

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Synthesis of Iboga-alkaloids and their Congeners 555

Scheme 14

CO2MeSCN

+

CO2Me

NCS

NH

O

SH

NH

O

Benzene, reflux

1) LiAlH4

2) PPh3, CCl4Et3N, CH3CN

Lewis acid

Toluene, 110 oC

NH

CO2Me118 119

115

Overall 21 %

71 %60 %

Scheme 15

In 2005, Hodgson’s group reported53 an enantioselective synthesis of dehydro-isoquinuclidine (124) by desymmetrization of a tropenone in the presence of a chirallithium amide. The synthesis of this dehydroisoquinuclidine was reported earlier by Krow’sgroup,52 that was in racemic form (Scheme 7) The optically active ibogamine precursor117 was synthesized from 124 and was then converted to (+)-ibogamine by Trost’s method(Scheme 16).

Trost’s mixed metal mediated cyclization method63 has been recently used by theSinha group for the synthesis of the iboga-scaffold67 (Scheme 17) and its analogue68

(Scheme 18). The key intermediate indole-dehydroisoquinuclidine conjugates 128a and128b were synthesized from internal alkynes 127a and 127b, respectively, by Larock’s

Scheme 16

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556 Jana, Paul, and Sinha

heteroannulation reaction. The key intermediates were then converted to iboga-scaffolds129a and 129b by Trost’s cyclization method. Both the heteroannulation and cyclizationsteps worked well for the exo-isomer. The overall yield was 21% from N-Boc-2-iodoaniline,whereas the endo-isomer 129b was obtained in 5.3% overall yield from N-Ts-2-iodoaniline(Scheme 17).

Scheme 17

Iboga-analogues 132a and 132b were synthesized from the corresponding exo- andendo-substituted intermediates 131a and 131b. The Pd-catalyzed Sonogashira couplingof Boc-2-iodoaniline with terminal alkynes 130a and 130b, followed by treatment withtetrabutylammonium fluoride, gave the key intermediates 131a and 131b, respectively.After cyclization, these gave iboga-analogues (Scheme 18).

NCO2Me

HN

N

BocN

NCO2Me

CO2Me

130a: exo130b: endo

131a: exo (63%)131b: endo (61%)

Pd(PPh3)2Cl2 (5 mol%),CuI (10 mol%), Et3N,

C6H6

1. Boc-2-iodoaniline,

2. TBAF, THF,reflux, 12 h

1. Trost's cyclization

2. 20% TFA inCH2Cl2, rt, 3 h

132a: exo (48%)132b: endo (37%)

Scheme 18

5. Formation by Hydroazepine Ring

In 1996, Grieco et al.69 reported the synthesis of racemic ibogamine along with epi-ibogamine. Their approach involved the initial formation of 2-substituted tryptamine134 by the reaction with suitably substituted cyclic allyl acetate 133 in the presence ofLi[Co(B9C2H11)2] as a catalyst. Hydroboration oxidation afforded the alcohol which wasthen converted to ketone 135 by oxidation. CBz deprotection and reductive amination af-forded 136. Heating at 220◦C followed by reduction with LiAlH4 gave dl-epiibogamine asa major and dl-ibogamine as a minor isomer, respectively (Scheme 19).

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Synthesis of Iboga-alkaloids and their Congeners 557

NH

NHCBz

CO2MeAcO

+

Li[Co(B9C2H11)2]

NH

NHCBz

R1. Hydroboration

oxidation

NH

R

CO2Me

O 1) Pd/C,Cyclohexene

2) NaBH3CN,CF3CO2H

NH

R

CO2Me

NH

1. 220 oC

134

135 136

Ibogamine (2) (58 %)Epiibogamine (2a)

R

133

2. LAH

CO2Me

R = Et

NHCBz

2. Oxidation

OI

HO O

F3C CF3

60 %

Overall yield 75 %

Overall yield 51 %

Scheme 19

6. Decarboxylation of Coronaridine

One step conversion of coronaridine to ibogamine was achieved by decarboxylation70–73

which occurred either in the presence of hydrazine hydrate or by a saponification method(Scheme 20).

Scheme 20

III. Syntheses of Coronaridine, Catharanthine and their Analogs

1. Brief Outline of the Retrosynthetic Strategies

Coronaridine and catharanthine are the iboga-alkaloids having a carbomethoxy group atC-16; retrosyntheses of such iboga-scaffolds are shown in (Scheme 21). Initially, thesealkaloids were synthesized from ibogamine or cleavamines or dihydrocleavamines. Sub-sequently, several methods have been reported for the synthesis of coronaridine or catha-ranthine and their analogues. All the syntheses involved either inter- or intra-molecularDiels-Alder reaction in making the carbomethoxy-substituted isoquinuclidine ring, a keycomponent present in these alkaloids. Subsequent cyclization completed the synthesses(Scheme 21).

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Scheme 21

2. Synthesis from Ibogamine and Cleavamine

a) From Ibogamine

Ibogamine precursor 7648 was converted to coronaridine where the tosyl group at C-16was replaced by a carbomethoxy group via cyanation followed by saponification andesterification with diazomethane (Scheme 22).

Scheme 22

b) From Cleavamines

Cleavamine is considered a biological precursor that affords various iboga-alkaloidsthrough a rearrangement processes. Coronaridine and catharanathine have been preparedin the laboratory by transannular oxidative cyclization of substituted cleavamines via the

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Synthesis of Iboga-alkaloids and their Congeners 559

formation of iminium intermediates in the presence of mercuric acetate and acetic acid(Scheme 23).74,75

Scheme 23

c) Cleavamines

A one-step preparation of carbomethoxydihydrocleavamine albeit in poor yield76 was re-ported using Zn-HOAc reduction of catharanthine. The synthetic procedures77–80 towardcleavamines were similar in which the key component 141 was synthesized from malonicester derivatives. Compound 140 was obtained from 139 in 32% overall yield after 3 steps(LAH→reduction, Hg(OAc)2→cyclization, debenzylation). The same compound 140 wasobtained from 139a in 27% overall yield by saponification (10% KOH/MeOH), decarboxy-lation, followed by esterification and reduction. The pentacyclic quaternary ammoniumsalt was then converted to dihydrocleavamine (142) and carbomethoxydihydrocleavamine(137), respectively (Scheme 24).

NH

NO

Malonic ester derivatives

O

BnOH2C

dl-Dihydrocleavamine (R = H) (142)

Carbomethoxydihydrocleavamine (137)

Tryptamine

NH

NO

CO2Et

CH2CHCO2Me

NH

N

CH2CHCH2OH

Et

NH

NNH

NNa/liq.NH3

1. KCN, digol, R = CN, 10 %

2. MeOH, HCl, R = CO2Me

139, 77 %

141

or

(ref 79, 80)

(ref 77, 78)

or

139aEt

R

CO2Et

OBn

EtO2C

EtO2C CO2Et

EtO

EtO

CO2Me

1) LiAlH42) Hg(OAc)2

3) H2, Pd-C

OMs

140

72 %90 %

quantitative

1) MsCl, Et3N2) CH3CN, reflux

ref 80

Scheme 24

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Buchi’s group described the synthesis of cleavamine in connection with the synthesis ofcatharanthine.81 Isoquinuclidine was chosen as the starting material as it was used previouslyin the synthesis of iboga-alkaloids.41 The unstable diketone 145 was reduced with excessNaBH4 to give diol 146 as a major product which this was reduced to 147, a precursor ofdihydrocleavamine. Catharanthine (44) was also synthesized from 144a. The crucial stepwas the insertion of the ethyl group. Treatment of 144a with ethylmagnesium bromide gavea number of products whereas vinylmagnesium bromide afforded a single product whichupon reduction gave hydroxy compound 148. Compound 148 gave 3-chloroindolenine in thepresence of t-butyl hypochlorite. The crude intermediate was converted to the hydroxynitrile149 on treatment with potassium cyanide in N,N-dimethylacetamide. Dehydration of 149by sulfuric acid at room temperature gave a mixture of the unsaturated nitrile and thecorresponding primary amide. The mixture was then treated with potassium hydroxide indiethyleneglycol at 150◦C for complete conversion to the corresponding acid which afteresterification with diazomethane gave catharanthine (44) (Scheme 25).

Scheme 25

Kuehne et al. developed a synthetic route73 toward dl-coronaridine. The monoprotecteddialdehyde 150 was condensed with indoloazepine 151 in methanol to give a diastereomericmixture of bridged azepines 152 in good yield. These amines 152 were treated, withoutisolation, with benzyl bromide and the resultant quaternary salts underwent fragmentation inthe presence of triethylamine. Spontaneous cyclization of the fragmented product providedthe tetracyclic product 153 in a diastereomeric mixture. After treatment with NaBH4, theindoloazonines 154 were obtained. Debenzylation by hydrogenolysis and hydrolysis of theacetal function provided the cyclized compound 138a. On storage under vacuum for fivedays, enamine 138a was converted quantitatively to racemic coronaridine (8) (Scheme 26).

In an extension of the above synthetic strategy, Kuehne’s group reported the synthesisof 18-hydroxy, 18-methoxy, 18-benzyloxycoronaridine and several other derivatives of 18-substituted coronaridine.82 Condensation of acetal 150a with indoloazepine 151a underheating conditions gave an intermediate which after treatment with NaBH4 in hot acetic

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Synthesis of Iboga-alkaloids and their Congeners 561

Scheme 26

acid followed by N-debenzylation provided secondary amine 154a. Hydrolysis of the acetalfunction followed by heating gave 18-methoxy- or 18-benzyloxycoronaridine (155 and 156,respectively).

Debenzylation occurred by catalytic transfer hydrogenation to obtain 158 which wasthen converted to 18-hydroxyibogamine (159) and several other derivatives of coro-naridine 160a–c (Scheme 27). They have extended the same methodology to the syn-thesis of (−) coronaridine and (−) 18-methoxycoronaridine using chiral Nb-substitutedindoloazepines.83

OHC OR

R = Me or Bn

OO

Synthesized in 11 steps frommonoprotected ethylene glycol

+NH

NBn

CO2Me

NBn-Indoloazepine

NH

NH

H

CO2Me

H

OR

O O

H

NH

N

CO2Me

OR

NH

N

CO2Me

OH

NH

N

CO2Me

R' = OCH2OCH2CH2OCH3;160a (64 %)

= OAc; 160b (75 %)= OCO(CH2)10CH3;

160c (71 %)

NH

NOH

18-Hydroxyibogamine (159)

150a 151a

158

154a

N2H4, EtOHheat

1) Toluene, reflux2) NaBH4, HOAc

3) Pd-C, H2EtOAc, HOAc

10 % HClMeOH

HCO2NH4Pd-C

MeOH

R = Bn (71 %)= Me (65 %)

R = Me; 155 (76 %)= Bn; 156 (86 %)

70%

87 %

n = 2

n = 2

R'

Scheme 27

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3. Diels-Alder Reaction Mediated Synthesis

Sundberg and coworkers used an intermolecular Diels-Alder reaction approach towardthe synthesis of (±)-catharanathine (44),84 deethylcatharanthine (44b)72,84,85 and dihy-drodeethylcatharanthine (44c)72 and also extended this route to the synthesis of severalother analogues as shown below. Photocyclization and detosylation were carried out usingtheir intra-molecular photocyclization method86 to obtain the cyclized product 166 whichwas then converted to catharanthine (44) and its analogues (Scheme 28).

Scheme 28

The carbamate deprotection of Diels-Alder adduct 164a using p-TsOH in CH3CNgave 167, which was converted to 20-deethyl-6-norcatharanthine (168) in the presence offormaldehyde followed by treatment with sodium amalgam87 (Scheme 29).

Scheme 29

A similar approach was also used by the same group for the synthesis of 20-deethyl-15-oxo-analogues of iboga alkaloids, such as (±)-20-deethyl-l5-oxocoronaridine, (±)-20-deethyl-15-oxo-5-norcoronaridine, and (±)-6,7-seco-20-deethyl-15-oxocoronaridine.88

The simultaneous cleavage of the Cbz and the methyl vinyl ether groups was carried out inthe presence of trimethylsilyl iodide (TMSI) to obtain keto amine 169a, used as a precursorfor the synthesis of various cyclized products. The 15-oxo coronaridine analogue 170 wassynthesized either by photocyclization or an electrophilic cyclization method. Compound169a underwent ethylation to yield the seco-derivative 171. Similarly, 169a was convertedto the nor-derivative 172 (Scheme 30).

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Synthesis of Iboga-alkaloids and their Congeners 563

NSO2Ph

CO2R NSO2Ph

N

CO2Me

CbzOMe

NSO2Ph

N

CO2Me

RX

NH

N

CO2Me

O

164c

170

1. Photocyclization, 69%169c

NSO2Ph

N

CO2Me

C2H5O

Seco-derivative; 171

Scheme 29 Ethylation169a

NH

N

CO2Me

Nor-derivative; 172

O

NCbz OMe

Xylene, 70 oC55 %

169a; R = H, X = O169b; R = H, X = (OMe)2169c; R = ClCH2CO, X = (OMe)2169d; R = HOCH2CH2, X = O169e; R = OCHCH2, X = O2. Reduction via thioamide

formation, 12%

Swern oxidation169d 169e

1. Electrophilic cyclization by BF3OEt2

Quantitative yield 2. NaBH3CN, 44 % (2 steps)170

3. Detosylation, 81 %

Scheme 30

Diels-Alder adduct 164c was also used as a precursor for the synthesis of 5,6-homologues of the iboga alkaloid skeleton.89 Three different methods such as electrophilic,palladium-catalyzed (Heck reaction), and radical reactions were used for closure of theeight-membered C ring between the isoquinuclidine nitrogen and the 3-position of the indolering by introduction of a three-carbon bridge. Electrophilic cyclization of N-unsubstitutedindole 173 (a or b or c) proceeded in the presence of BF3·OEt2 to give 30–53% yields(Scheme 31).

Scheme 31

An intramolecular Heck reaction between a 3-iodinated indole ring and N-acryloyl orN-allyl (Z = CO2Et) derivatives of the isoquinuclidine ring was carried out. The reactionis efficient only when the indole is N-methylated and the allyl moiety is substituted with anelectron-withdrawing group (Z = CO2Et). In the case of intramolecular radical cyclization,

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unsubstituted indole 176 (R = H) worked well to give 178 in 70% yield when Z = SOPh.The sulfone group was removed by sodium amalgam in liquid ammonia (Scheme 32).Neither simple allyl nor propargyl derivatives underwent such a cyclization reaction.

Scheme 32

In 1991, Sundberg’s group reported90 another improved reaction sequence for thesynthesis of iboga-analogues. The sequence features selective reduction of N-methoxy-N-methylacetamide derivatives to the corresponding aldehyde followed by a facile acid-catalyzed cyclization. (±)-20-Deethylcatharanthine 44b (Scheme 33) and 15-oxygenatedderivatives 183 were prepared by use of this protocol (Scheme 34).

Scheme 33

In 1998, Sundberg and coworkers84 reported the synthesis of two new types of racemiccatharanthine-analogues that differ from catharanthine in the fusion of the indole ring tothe non-aromatic portion of the iboga skeleton. The [2,3] fusion present in catharanthine isreplaced by [2,1] 185 and [3,2] fusions 188, respectively (Scheme 35).

Szantay’s group91–93 and Raucher’s group94,95 reported the synthesis of catharanathineand deethycatharanathine using photocyclization to form the C2-C16 bond. Photocycliza-tion of 190 led to 166 and a regioisomer 191 respectively in a 1:1 ratio. Treatment of 166

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Synthesis of Iboga-alkaloids and their Congeners 565

Scheme 34

Scheme 35

with NaBH4 and BF3·OEt2 led to the formation of catharanathine (44) and deethylcatha-ranthine (44b), respectively (Scheme 36).

In Raucher’s synthesis, photocyclization was carried out on the thioamide 192 insteadof the amide 190 and a better yield of 193 (41%) was obtained. Reaction of an endo/exo-mixture (3:1) of 190 with Lawesson’s reagent provided a 79% yield of the thioamide

Scheme 36

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566 Jana, Paul, and Sinha

exclusively as the endo-isomer 192. Interestingly, the conversion of a pure sample ofexo-190 to thioamide was not successful under the same conditions (Scheme 37).

Scheme 37

Szantay’s group extended their methodology toward the synthesis of optically ac-tive catharanthine93 and deethylcatharanthine.92 The optical resolution of isoquinuclidinebase 189 was achieved in the presence of dibenzoyl-L-tartaric acid in 96% yield. Theoptically pure isomers were then used for the synthesis of (+)-catharanthine, (16S)-20-deethylcatharanthine and (16R)-20-deethylcatharanthine, respectively (Scheme 38).

Scheme 38

Szantay’s group has also applied the same methodology to the synthesis ofallocatharanthine.93 A mixture of dihydropyridine derivatives gave 194 and 189, respec-tively, in a ratio of 55:45. The same reaction sequence led to catharanthine (44) andallocatharanthine (44d) (Scheme 39).

Using the Diels-Alder approach reported earlier by Sundberg85 (Scheme 28), Daset al.96 have synthesized key intermediate 197 from a reaction between indole-2-acrylate196 and 3-ethyl-1,6-dihydropyridine (Scheme 40). Prior to the synthesis of catharanthine,these authors reported the synthesis of 20-deethycathernathine by the same route usingunsubstituted dihydropyridine.97

Kutney and coworkers used Cr(CO)3 complexes of dihydropyridine as the precursorof catharnathine.98 Compound 198 was synthesized by Fisher indole synthesis of levulinicacid with phenylhydrazine followed by reduction with LiAlH4 and the resultant alcohol wasprotected with benzyl chloride. Methanolysis of 199 followed by addition of 3-ethylpyridine

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Synthesis of Iboga-alkaloids and their Congeners 567

N

CbzCbzN

NH

N

CO2Me

N NaBH4

CbzCl

N

Cbz

+Cl

CO2Me

CbzN

Cl

CO2Me

+

55 : 45

20%

R1

R2

R1 = ethyl, R2 = H Catharanthine (44)R1 = H, R2 = ethyl Allocatharanthine (44d)

189194

Cl

Cl

O

1) HBr.AcOH2) Indole acetic

anhydride

3) hv, 30% inboth cases

O

P2S5, MeI

NH

N

CO2MeR1

R2

S

NaBH4, NaCNBH3BF3OEt2

~98% in bothcases

Sundberg'smethod, ref 72

56% from 19478% from 189

Scheme 39

gave the salt 200 in 10% overall yield from phenylhydrazine. The chromium complexesof dihydropyridines were obtained after controlled reduction by NaBH4 and subsequenttreatment with tris-acetonitriletricarbonylchromium (0). The mixture of the complexes wastreated with KH and Eschenmoser’s salt followed by decomposition with K2CO3 to givethe dehydrosecodine complexes 201 and 202, respectively. When isomeric mixtures of 201and 202 were decomposed with ethylenediamine, followed by treatment with acetic acidand NaBH4, a poor yield of 1-benzylcatharnathine resulted along with the formation ofother two products 203 and 204, respectively (Scheme 41).

Synthesis of catharanathine was reported by Kuehne et al.99 using an intramolecularDiels-Alder reaction. When compound 206 was treated with DBU and TBSOTf, it wasconverted to the corresponding silyl enol ether 207, which was then cyclized to 208 in very

Scheme 40

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Scheme 41

good yield. The synthesis of catharanthine was completed in 39.5% overall yield from 205by the desulfurization of thioenol ether 209 in the presence of Raney nickel (Scheme 42).

Scheme 42

Reding and Fukuyama100 reported a stereocontrolled total synthesis of (±) catha-ranathine. The key component 214, a suitably substituted indole, was synthesized from 213using their radical-based indole cyclization methods (Scheme 43).

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Synthesis of Iboga-alkaloids and their Congeners 569

NH2

HO N

OO

HO2C

Cbz

+NH

O N

AcOCbz

OO

I

1) Zn, HOAc2) CH2N2

3) Lawesson'sreagent

NH

N

AcO Cbz

CO2Me

AIBN, H3PO2

PropanolS

1) K2CO3, MeOH2) CH3SO2Cl

3) Et3SiH, Pd(OAc)279 % (3 steps)N

H

N

Cbz

CO2Me

44

211 212

213 214

I

210

1) CarbodiimideNEt3, CH2Cl2

2) Ac2O, Py

40-50 %

AcO

74 % (2 steps) 71 % (3 steps)

Scheme 43

IV. Concluding Remarks

This review has updated the progress in the synthesis of iboga-alkaloids and their analogsemphasizing the key intermediates as well as the key steps. Though there are reports onthe isolation of eighty structurally related iboga-alkaloids, most of the synthetic efforts,except very few, are for simple representatives such as ibogamine, ibogaine, coronaridineand catharanthine and their analogues. Few methods have been reported for the synthesisof optically active compounds. In the majority of cases, construction of the rigid isoquinu-clidine ring involves Diels-Alder reaction as one of the steps followed by cyclization leadsto the formation of the hydroazepine ring. The reported methods lack flexibility in orderto achieve several other iboga-alkaloids that are closely related to each other. We hope thisreview will provide appropriate background for the development of new methodologies forthe synthesis of iboga-alkaloids in the context of alkaloid chemistry.

Acknowledgements

S. S. thanks DST, India for financial support through grant SR/S1/OC-38/2007. G. K. J.and S. P. are thankful to CSIR for their fellowships.

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