Progress in the Synthesis of Canthine Alkaloids ... - ACS Publications

Review pubs.acs.org/jnp

Progress in the Synthesis of Canthine Alkaloids and Ring-Truncated Congeners H. D. Hollis Showalter* Vahlteich Medicinal Chemistry Core, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1065, United States ABSTRACT: The canthines represent a fairly large subclass of βcarboline alkaloids, with the first members described 75 years ago. Over the last 60 years, many members of the parent compound, canthin-6-one (1), have been isolated from various plant sources, principally the Rutaceae and Simaroubaceae families, and recently from fungi. Structures isolated from these sources have been the subject of total synthesis, which continues to the present day. This review gives a broad overview of synthetic approaches to canthines over a 30-year period from 1982 to 2012 and summarizes recent reports on the synthesis of less well known ring-truncated congeners. These include C-ring-truncated (“ABD”, 2) and A-ring-truncated (“BCD”, 3) ring systems, which are providing new scaffolds for potentially useful therapeutic applications.

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erectile dysfunction,15 for cancer chemoprevention,16 and to reduce elevated levels of proinflammatory cytokines and nitric oxide production by lipopolysaccharide-stimulated macrophages.17 The first total synthesis of canthin-6-one (1) was reported in 196618 and was accomplished in poor overall yield via a classical Bischer−Napieralski approach starting from tryptophan. A related route utilizing a Pictet−Spengler reaction was reported by Mitscher et al. nine years later.19 Despite being longer, most reactions were clean and more efficient, resulting in a higher overall yield of canthin-6-one. Additional syntheses of canthin6-one and analogues were reported during the latter 1970s and early 1980s with almost all employing a classical Bischer− Napieralski or Pictet−Spengler approach starting from either tryptamine or tryptophan. This review will provide a broad overview of synthetic approaches to canthin-6-ones and selected isomers and examples of approaches to reduced congeners. The first section deals specifically with canthin-6-ones and isomers. It chronicles efforts over a 25-year period, profiling several syntheses of canthin-6-ones that are much more flexible and convergent than historical precedents. The second section deals with isolated reports of the synthesis of isomers of canthin-6-one (1) and C-ring deaza congeners. The third section discusses reduced congeners, which are less well known; thus a longer time frame (30 years) is covered. The last section summarizes synthetic approaches that have led to a number of examples of ring-truncated congeners of the canthin-6-ones. These include C-ring-truncated (“ABD” ring system, 2; Figure 1) and A-ringtruncated (“BCD” ring system, 3; Figure 1) compounds. Total synthesis within these cores has provided scaffolds on which

INTRODUCTION The canthines are a subclass of β-carboline alkaloids with an additional D-ring. The parent compound, canthin-6-one (1, 6H-indolo[3,2,1-de][1,5]naphthyridin-6-one; Figure 1), was

Figure 1. Canthin-6-one and ring-truncated congeners.

first isolated from Pentaceras australis in 1952.1 A literature search reveals that >150 compounds have the canthin-6-one core embedded within their framework, including pentacyclic derivatives, with >40 of these derived from natural sources. 4,5Dihydro tetracyclic congeners, many of which coexist with canthin-6-ones in natural sources, number considerably less at ∼25. Selected canthin-6-ones have been reported to have a wide range of potential therapeutic applications including, but not limited to, antiviral (HIV),2,3 anticancer,4,5 antiparasitic,6−8 antibacterial,9−11 and antifungal12−14 indications. More recent reports make claims for canthin-6-ones as agents to treat © 2013 American Chemical Society and American Society of Pharmacognosy

Special Issue: Special Issue in Honor of Lester A. Mitscher Received: October 27, 2012 Published: January 11, 2013 455

dx.doi.org/10.1021/np300753z | J. Nat. Prod. 2013, 76, 455−467

Journal of Natural Products

Review

Scheme 2. Rössler (199925)a

medicinal chemists have carried out recent structure−activity relationship (SAR) studies with exciting results, leading to potentially useful therapeutic applications. D-ring-truncated (“ABC” ring system, 4; Figure 1) compounds make up a venerable scaffold (β-carbolines) and have been extensively investigated. Synthetic endeavors into this ring system have been thoroughly reviewed20,21 and thus will not be covered.

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CANTHIN-6-ONES AND RING-FUSED CONGENERS Hagen et al.22,23 described a five-step synthesis of the cytotoxic alkaloid 1-methoxycanthine-6-one 9 (Scheme 1). Pictet− Scheme 1. Hagen (1988,22 198923); Czerwinski (200324)a

a Reagents and conditions: (i) triflic anhydride, Et3N, DCM, 0 °C (94% yield); (ii) E-3-(dimethylamino)acrylic acid methyl ester, 400 mV, DCM/ACN/LiClO4, rt (87% yield); (iii) Na/naphthalene, DME, 0 °C (60% yield); (iv) for 14b, MnO2, DCM, rt (74% yield; (v) 1. 2 N aq HCl, reflux; 2. Cu powder, pyridine, reflux, 5 h (50% yield over 2 steps).

radical cationic hetero [4+2] cycloaddition reaction, which occurred in high yield. A disadvantage of the synthesis is the required 5:1 ratio of 13 to the methyl acrylate in this step, although a reversal of this resulted in a relatively minor loss of yield (23%). French workers have described a flexible, low-cost preparation of canthin-6-one (1) and a series of analogues (Schemes 3−5).11,12 A few of these were prepared by semisynthesis using Scheme 3. Soriano-Agaton (200512); Fournet (200711)a

a

Reagents and conditions: (i) 6, MeOH, reflux, 20 h (92% yield); (ii) DDQ, aq THF, rt, 4.5 h (78% yield); (iii) conc HCl, HOAc, reflux, 3 h (88% yield); (iv) for 7c, (MeO)3CH, MeOH, p-TSA, reflux, 24 h (51% yield); (v) 1. 6% NH4OH/MeOH, reflux, 2 h then p-TSA, pdioxane/benzene, reflux, 48 h (82% yield); 2. DDQ, p-dioxane, reflux, 10 h (70% yield); (vi) 1. benzoyl chloride, NaOH, acetone rt (95% yield); 2. LAH, THF, reflux (98% yield); (vii) 10, benzene/p-dioxane, reflux (80% yield); (viii) 1. 10% Pd/C, HCO2NH4, MeOH, reflux, 36 h (83% yield); 2. MnO2, benzene/toluene, reflux, 60 h (78% yield).

a

Reagents and conditions: (i) RX (excess), rt (50% yield); (ii) MCPBA, DCM, rt, 18 h (75% yield); (iii) NaN3, ZnBr2, H2O/DMF, reflux, 48 h (70% yield).

Spengler reaction between tryptamine hydrochloride (5a) and dimethyl α-ketoglutarate (6) provided lactam 7a. Pivotal steps were represented by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) oxidation of 7a to afford the 3-acylindole 7b and the conversion of 7c into the 4-methoxy-1-alkyl-β-carboline 8, which was subsequently converted into 9 as illustrated. The first four steps appear to be general and should enable access to other 1-alkoxy-substituted canthin-6-ones. A related highyielding sequence to canthin-6-one (1) was reported by Czerwinski et al. (Scheme 1).24 Tryptamine (5a) was converted to Nb-benzyltryptamine (5b) via reaction with benzoyl chloride and reduction using lithium aluminum hydride. Pictet− Spengler condensation with 2-ketoglutaric acid (10), removal of the protecting group by transfer hydrogenation, and aromatization with MnO2 afforded canthin-6-one (1) in 48% overall yield. Rössler et al. reported on a short, relatively efficient synthesis of canthin-6-one (1) starting from harmalane (12) (Scheme 2).25 After evaluating a number of N-activating groups (R = triflyl, tosyl, trifluoroacetyl) for 13, triflyl was determined to be the best for the key single electron transfer (SET) induced

simple reactions (Scheme 3). From canthin-6-one (1), a series of N-3 alkyl derivatives (16a−c) and the N-oxide (16d) were prepared in good yields. An original amination reaction, involving sodium azide and a zinc salt, was also exploited toward the synthesis of the 4-aminated analogue (17). A total synthesis of canthin-6-one (1) and analogues starting from tryptamines 5a and 18b−d is depicted in Scheme 4.11,12 Standard amidation with succinic anhydride followed by Bischler−Napieralski ring closure provided key intermediates 21a−d. Intramolecular cyclization to form the D-ring was accomplished by exposure of imines 21a−d to diazabicycloundecene (DBU) in dichloromethane, which led directly to canthin-6-ones 1 and 22b−d in good overall yields. Interestingly, complete oxidation (i.e., C-1/C-2 and C-4/C-5 bonds) of the tetracyclic intermediates following DBU ring closure occurred spontaneously, probably by contact with air. The same chemistry of Scheme 4 was applied to the synthesis of ring E cyclo[4,5]canthin-6-one congeners (25a−d) as well 456



Review

Scheme 4. Soriano-Agaton (200512); Fournet (200711)a

Scheme 6. Markgraf (200526)a

a

Reagents and conditions: (i) NaH, benzoyl chloride, DMAP, DMF, 70 °C, 15 h (91% yield); (ii) Bu3SnH, ACN, toluene, reflux, 3.5 h (74% yield).

Scheme 7. Suzuki (200527)a

a Reagents and conditions: (i) succinic anhydride, DCM, rt, 18 h (98− 99% yield); (ii) Amberlyst 15 (20% w/w), MeOH, reflux, 18 h (98% yield); (iii) for 20a−d: POCl3, benzene, reflux, 1 h; (iv) DBU, DCM, rt, 18 h (20−80% yield over 2 steps).

Scheme 5. Soriano-Agaton (200512); Fournet (200711)a

a Reagents and conditions: (i) Dibal-H, DCM, −40 °C, 5 min (70% yield); (ii) for 28b, LiHMDS/EtOAc, THF, −78 °C, 10 min and then EtOH quench (83−88% yield).

aldehyde, which upon ethanol quench forms an intermediate ester that is cyclized to the canthin-6-ones 1 and 9 via a 4,5dihydro-4-hydroxycanthin-6-one intermediate. Starting from readily available 4-(1H-indol-3-ylmethyl)-2trichloromethyl-1,3-oxazol-5(4H)-ones (29), derived from the corresponding tryptophan procedure by a variation of a literature procedure,29 the Bergman group in Sweden subjected these compounds to an intramolecular reaction in the presence of trifluoroacetic acid to afford β-carboline carboxylic acid products 30a in good yield (Scheme 8).30 Following conversion of these to methyl esters 30b, the dichloromethyl moiety was a

Scheme 8. Condie (200430)a

starting from the appropriate phthalic anhydrides as depicted in Scheme 5. All target compounds from Schemes 3−5 were tested for in vitro antifungal activities against five pathogenic fungal strains.11,12 None displayed better antifungal activities than canthin-6-one (1). Selected compounds were also tested in vitro against a number of Mycobacterium strains and in vivo against Mycobacterium bovis BCG.11 Only modest activity was observed relative to isoniazid control. A shorter and higher yielding synthesis of ring E benzocanthinone (25b) was reported by Markgraf et al.26 and utilized a radical-induced oxidative cyclization of 9-benzoyl-1-chloro-β-carboline (27) (Scheme 6). The reaction had broad generality to the synthesis of isomeric congeners in which the β-carboline pyridyl nitrogen was migrated into the E-ring. Suzuki et al.27 reported on a simple, two-step synthesis of canthinone (1) and 1-methoxycanthin-6-one (9) starting from the β-carboline-1-methyl esters 28a28 (Scheme 7). Dibal-H reduction to the carbaldehydes (28b) followed by the addition of lithium ketene acetal (derived from ethyl acetate and lithium hexamethyldisilazide) led to the direct formation of each product in good yield following an ethanol quench. The authors invoke a mechanism of initial aldol reaction on the

a Reagents and conditions: (i) TFA, −15 °C to reflux, 25 h (63−87% yield); (ii) CH2N2, ether, rt, 2 days (100% yield) or MeOH, anhyd HCl, reflux, 3 h (58−86% yield); (iii) for 30b, HCO2H: H2O (9:1), reflux, 3 h (78−82% yield); (iv) Ph3PCHCO2Et, toluene, reflux, 2 h (29% yield); (v) DMAD, Ph3P, DCM, rt, 20 h (76−89% yield).

Reagents and conditions: (i) ring E 1,2-anhydride, DCM, rt, 18 h (98% yield); (ii) POCl3, benzene, reflux, 1 h; (iii) DBU, DCM, rt, 18 h (50−80% yield over 2 steps).

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Review

Scheme 10. Puzik (201032)a

hydrolyzed to provide the methyl 1-formyl-β-carboline-3carboxylates 31. Subsequent reactions performed on these led either to 2-(methoxycarbonyl)canthin-6-one (32) in modest yield (via Wittig reaction) or to the substituted unsaturated canthine derivatives 33a and 33b in good yields (via dimethyl acetylenedicarboxylate and triphenylphosphine). An elegant and simple access to the canthin-6-one core by a Baylis−Hillman reaction on the 1-formyl-9H-β-carbolines (36b) was reported involving an unprecedented cascade cyclization reaction31 (Scheme 9). Optimization studies were Scheme 9. Singh (200931)a

Reagents and conditions: (i) methyl acrylate, K2CO3, DMF, 50 °C, 24 h (63% yield); (ii) n-BuLi, THF, −100 °C to rt, 15 h (29% yield); (iii) 2-aminobenzaldehyde, KOH, EtOH, reflux, 18 h (87% yield); (iv) MnO2, CHCl3, rt, 12 h (54−64% yield); (v) (Me2N)2CH(O-t-Bu), THF, 50 °C, 3 h (80% yield); (vi) guanidinium carbonate, DMF, reflux, 5 h (78% yield); (vii) HCO2NH4, HCONH2, HCO2H, 160 °C, 1 h (40% yield). a

(1,7b,14-triazadibenzo[e,k]acephenanthrylene 44/45 and 1,7b,10,12-tetraazabenzo[e]acephenanthrylenes 47/49, respectively) using ring annulation reactions.32 The poorest step was the Parham cyclization from 42 to 43. An efficient workaround solution (not shown in Scheme 10) was to start from canthin-4one (70A, Scheme 14) and in two steps (platinum oxide catalytic hydrogenation followed by manganese dioxide oxidation) generate 43 in 49% overall yield. The new compounds represent hybrids between the canthinones and several bioactive aromatic alkaloids. Gollner et al. have recently reported on a convergent and flexible synthesis of canthin-6-one (1) that is suitable for the rapid generation of a diverse compound library of A-ring analogues for biological studies.33 They evaluated known strategies to canthin-6-one and identified a nonclassical route that revolves around constructing the B-ring via transitionmetal C−C and C−N coupling chemistry (Scheme 11). Canthin-6-one (1) and nine analogues, including the naturally occurring 9-methoxycanthin-6-one and amaroridine (11methoxycanthin-6-one), were prepared rapidly and in high yields via this strategy. The strategy relies on concomitant Pdcatalyzed Suzuki−Miyaura C−C coupling followed by a Cucatalyzed Buchwald C−N coupling that can be achieved either stepwise or in a novel one-pot protocol starting from the appropriate 8-bromo-1,5-naphthyridine. This laboratory published a follow-up study in which ethyl 4-bromo-6-methoxy-1,5naphthyridine-3-carboxylate (56) was used as a starting material for a series of eight ethyl canthin-6-one-1-carboxylates 57a bearing various substituents on the A-ring, together with the 8-aza and 9-aza analogues that constitute two members of previously unknown ring systems.34 The synthetic route that was used involved three key steps: (a) Suzuki−Miyaura arylation of the 4-bromonaphthyridine 56 to afford the ethyl 4-(2-haloaryl)-6-methoxy-1,5-naphthyridine-3-carboxylates analogous to 53, (b) TMSCl/NaI-mediated demethylation to give the ethyl 4-(2-haloaryl)-6-oxo-5,6-dihydro-1,5-naphthyr-

a

Reagents and conditions: (i) OHCCH(OMe)2, 5% TFA in DCM, rt, 15−72 h (96% yield); (ii) KMnO4, THF, rt, 15−120 h (90% yield); iii. AcOH/H2O (2:3), 120 °C, 45 min (86% yield); (iv) for 36a, Baylis− Hillman reaction with acrylates, DABCO, rt; (v) DABCO, acrylonitrile, rt, 3−5 h; (vi) K2CO3, DMF, rt, 0.5−3 h (57−63% yield).

performed with 36b (R = CO2Me) as a test compound and methyl acrylate as the alkene in the presence of 4diazabicyclo[2.2.2]octane (DABCO). Reaction conditions were adjusted such that mono or tandem Baylis−Hillman reaction products (37a and 37b, respectively) could predominate. Seeking experimental conditions in which the canthin-6one derivative (37b) was formed exclusively, several combinations of 36b, methyl acrylate, and DABCO were screened with optimum conditions yielding 37b as the sole product in 59% yield. Additional evaluation of 36b with ethyl, n-butyl, and tertbutyl acrylates revealed that, with the exception of tert-butyl acrylate, the corresponding canthin-6-one derivatives 37b could be isolated in good yields. For tert-butyl acrylate only the mono Baylis−Hillman products 37a were obtained. The authors proposed a possible mechanism for the formation of tandem products 37b. The Baylis−Hillman reaction of 36b was extended to acrylonitrile, which provided the mono adducts 38. Treatment of these with potassium carbonate in DMF smoothly gave the canthine products 39 by an intramolecular Michael reaction. The same chemistry was then applied to the synthesis of the novel C-ring benzo-fused congener 40. Following the synthesis of 5,6-dihydrocanthin-4-one (43), made from 1-bromo-β-carboline (41) as shown in Scheme 10, Puzik et al. constructed new hexa- and pentacyclic ring systems 458



Review

Scheme 11. Gollner (201033); Ioannidou (201134)a

Scheme 13. Ohashi (199937)a

a

Reagents and conditions: (i) 1-chlorobenzotriazole, DCM rt, 16 h, (85% yield); (ii) ethyl acrylate, Triton B, 0 °C, 5 min (67% yield); (iii) NaH, toluene, reflux 14 h (50% yield); (iv) 48% HBr, 80 °C, 4 h (78% yield); (v) for 67, R = alkaryl: aryl aldehyde, aq NaOH, EtOH, reflux, 15 min (10−16% yield); for R = H: DDQ, p-dioxane, reflux, 3 h (37% yield).

Scheme 14. Puzik (200939)a

a

Reagents and conditions: (i) ref 71 (86% yield) (ii) ref 72 (91% yield); (iii) ArB(OH)2, Pd(dppf)Cl2·CH2Cl2, K2CO3, p-dioxane/H2O (3:1), reflux (85−98% yields); (iv) aq HCl or HBr, p-dioxane, reflux (80−94% yield) (v) CuI, N1,N2-(dimethyl)ethylenediamine, Cs2CO3, H2O, p-dioxane, reflux (91−99% yield).

Scheme 12. Markgraf (199835); Snyder (200036)a a

Reagents and conditions: (i) for 68 (R = H): (Me2N)2CH(O-t-Bu), wet DMF reflux, 1 h (67% yield); (ii) for 68 (R = Et): t-BuOK (cat), anhyd DMF, reflux, 4 h (80% yield); (iii) (Me2N)2CH(O-t-Bu) or MeC(OMe)2NMe2, anhyd DMF, reflux, 3−24 h (52−74% yield).

ethyl esters 57a gave the corresponding canthin-6-one-1carboxylic acids (57b) in high yield.

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ISOCANTHINONES (C- AND D-RING ISOMERS) AND C-RING DEAZA CONGENERS The Markgraf laboratory featured an intramolecular Diels− Alder approach toward an efficient, four-step route to the Cring-modified isocanthin-6-ones 60b (Scheme 12).35,36 Starting from 3-formyl or 3-acetyl indole (58), the 1-aza-1,3-dienes 59b were accessed in two standard steps. Thermal cycloaddition of these was accompanied by loss of methanol to afford 4,5dihydroisocanthin-6-ones (60a), which were oxidized to 60b with palladium on activated carbon in refluxing sulfolane. The overall yield of the target isocanthin-6-ones (60b, R = H and Me) by this route was 43% and 52%, respectively. An attempt was made to synthesize the isocanthine compounds (62) via a similar sequence of reactions. Unfortunately, Diels−Alder cycloaddition proved to be quite difficult to achieve, so an alternative path was pursued utilizing 61. A two-step sequence of thioamide formation on 60a followed by Raney nickel reduction provided an acceptable solution. A Japanese group described a multistep synthesis of three target compounds (67a−c) in which the carbonyl of the D-ring

a

Reagents and conditions: (i) pent-4-ynoic acid, DCC, DMAP, DCM, rt, 3.5−5 h (88−96% yield); (ii) MeONH2·HCl, pyridine, EtOH, reflux, 3.5 h (94−96% yield); (iii) for 59b, toluene, 180 °C, 4−7 days (55−66% yield); (iv) 30% Pd/C, sulfolane, 285 °C, 2 h (86−93% yield); (v) for 60a, Lawesson’s reagent, toluene, 100 °C, 24 h (70− 84% yield); (vi) Ra Ni, EtOH, reflux, 2.5 h (26−29% yield).

idine-3-carboxylates analogous to 54, and (c) copper-catalyzed Buchwald cyclization to provide the target ethyl canthinone-1carboxylates 57a. For the latter coupling, trans-N1,N2-dimethyl1,2-cyclohexanediamine (DMCDA) was found to be a better ligand for chloro-substituted substrates than N1,N2-dimethylethylenediamine (DMEDA). Furthermore, base hydrolysis of 459



Review

of canthin-6-one has been transposed (Scheme 13).37 Starting from the readily available β-carboline nitrile 63a,38 a series of standard reactions was carried out in good overall yield to provide dihydro intermediate 65. DDQ oxidation of 66 then inserted the D-ring olefin in modest yield for R = H, whereas installation of an alkaryl functionality at the same position from base-catalyzed condensation of 66 with the appropriate aldehyde proceeded poorly. The sequence was repeated on 63a to provide deschloro congeners corresponding to 67a−c in comparable yields. The compounds are claimed to be potent and selective inhibitors of cyclic GMP phosphodiesterase. A short route to canthin-4-one (70a), as well as 6-methyl (70b, norisotuboflavine) and 5-ethyl (70c, tuboflavine) congeners, via use of Bredereck reagents has been described (Scheme 14).39 Depending on the degree of hydration of the commercial source of DMF, the reaction could be tailored to go stepwise via an enamino ketone intermediate (exemplified for 69a) or proceed directly to products 70a−c. In the reaction leading directly to 70a−c, the catalytic amount of alkoxide essential for the cyclization is provided by heterolytic cleavage of Bredereck’s reagent into an intimate ion pair. There are only a few examples in the literature of C-ring deaza congeners of canthin-6-one (1). The structures (71a,40,41 71b,40 71c,42 7243) are shown in Figure 2 and are accessed in a straightforward manner by synthesis.

converted to the tryptamide 74, which was cyclized followed by dehydrogenation to give chiral 4,4-disubstituted product 75b. Reaction of optically pure (S)-dimethyl butanedioate 73b in a similar sequence of reactions led to the (S)-(−)-5,5disubstituted congeners 76a and 76b. In a study to make ring-contracted analogues of the vinca alkaloid vincamone,46 racemates of two diastereomers of 3,4diethyl-1,2,3,3a,4,5-hexahydrocanthin-6-one (82) were prepared.47 The synthesis is shown in Scheme 16 and proceeds Scheme 16. De Bruyn (198547)a

a

Reagents and conditions: (i) 10:1 benzene/HOAc, reflux, 16 h (79% yield); (ii) 1. Na-t-amylate, toluene, rt, 15 min (100% yield); 2. Fractional crystallization; (iii) for 80: Na-t-amylate, t-Bu-ONO, toluene, rt, 2 h (98% yield); (iv) 1. NaOH, 2-ethoxyethanol, reflux, 16 h; 2. 3 N aq HCl, reflux, 1 h (43% yield over 2 steps).

in two annulation steps from N-ethyltryptamine (77). Ring closure of 78 generates a 1:2 mixture of diastereomers 79 and 80, which is separated by fractional crystallization. Stereochemical assignments about the 3a,4-position carbons were made by 1H NMR spectroscopy. Each diastereomer was then converted to its corresponding perhydrocanthin-6-one congener (shown only for 80) through a Beckmann rearrangement of oxime intermediate 81. This occurs through a putative eightmembered acylimide intermediate followed by basic hydrolysis to a probable open-chain carboxylic acid. Acid-catalyzed ring closure would then form the D-ring lactam of 82. Compounds related to 82 are claimed to “show interesting properties concerning hemodynamic action and cerebral metabolism”.47 Chinese workers described the synthesis of optically active 1,2,3,3a,4,5-hexahydrocanthin-6-one derivatives 84b−d48 by a simple two-step process starting from optically active tryptophan-based precursor 83a49 (Scheme 17). The Padwa group demonstrated the [4+2] cycloaddition chemistry of 5-amino-substituted oxazoles as an approach

Figure 2. C-ring deaza congeners of canthin-6-ones.

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DIHYDROCANTHINONES, CANTHINES, AND REDUCED CONGENERS Czech workers have described the synthesis of optically active 4,4- and 5,5-disubstituted 4,5-dihydro-6H-canthin-6-ones starting from tryptamine, 5a (Scheme 15).44,45 Thus, (R)-(+)-2ethyl-2-methyl-3-(methoxycarbonyl)propionic acid (73a) was Scheme 15. Hajicek (198244,45)a

Scheme 17. Liu (199048)a

Reagents and conditions: (i) (COCl)2, benzene, 40 °C, and then 5a, pyridine, rt, 7.5 h (58% yield); (ii) POCl3, PPA, 120 °C, 1.3 h (44% yield); (iii) Se powder, 300 °C, in vacuo, 9 min (71% yield); (iv) KOH, aq MeOH, 50 °C. a

a Reagents and conditions: (i) RBr, NaHCO3, ACN, reflux, 15 h; (ii) for 83b−d: NaH, THF, reflux, 2 h or HMPA, 0 °C, 1 h (70−98% yield).

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Review

toward the construction of β-carbolines, which was applied to the synthesis of 2-methyl-4,5-dihydrocanthin-6-one 91 (Scheme 18).50 They proposed a mechanism in which

Scheme 19. Benson (199251); Li (199452); Lindsley (200353)a

Scheme 18. Chughtai (201150)a

Reagents and conditions: (i) KH, γ-butyrolactone or δ-valerolactone (>90% yield); (ii) CH2N2 (72−100%); (iii) NH3, PPE; (iv) for 93c, PPE (44−60% yield over 2 steps); (v) NaNHNH2; (vi) for 94b, R1COCOR2 (52−73% yield over 2 steps); (vii) refluxing p-dioxane, diglyme, or triisopropylbenzene, 1.5−20 h (38−93% yield). a

a

Reagents and conditions: (i) 2-iodoaniline, DCC, cat DMAP, DCM, rt, 24 h (74% yield); (ii) TFA, DCM, rt, 2 h; (iii) Ac2O, pyridine, THF, rt, 4 h (89% yield over 2 steps); (iv) for 88: TFAA, TFA, DCM, rt, 36 h (98% yield); (v) n-Bu3SnCHCH2, PdCl2(PPh3)2, CsF, DMF, 100 °C, 14 h (60% yield); (vi) p-TsOH, toluene, reflux, 15 h (75% yield).

demonstrated, and reaction times were markedly reduced over standard solution methods. The Benson and Lindsley work has been reviewed.54 On the basis of the fact that intramolecular cyclizations of N(9)-acyliminium salts of 3,4-dihydro-β-carbolines had never been investigated, Malamidou-Xenikaki et al.55 decided to investigate this reaction (Scheme 20). Thus, a series of homologous 2-[1-(ω-nitroalkyl)-1H-indol-3-yl]ethylformamides (99a−c) were synthesized and transformed in high yield to the corresponding annulated tetrahydro-βcarbolines 100b,c through a diastereoselective intramolecular aminoalkylation reaction and/or to tricyclic 9-(ω-nitroalkyl)4,9-dihydro-3H-β-carbolines (101a−c). Intramolecular N-acyliminium cyclization of 101a−c afforded a diastereoisomeric mixture of tetracyclic diazacycloalkano[jk]fluorenes (103a−c and C-5 epimer) with moderate selectivity, whereas direct acryloylation of 100b,c provided 103b,c directly in good yield. Conjugate addition reaction on 103a,b then provided pentacyclic indolo[3,2,1-de]pyrido[3,2,1-jk]naphthyridinone (104a) or diazabenzo[a]naphtho[2,1,8-cde]azulenone (104b). Katritzky et al. prepared a small series of optically pure ethyl 6-substituted-2,3,3a,4,5,6-hexahydro-1H-indolo[3,2,1-de][1,5]naphthyridine-2-carboxylates (107a−d), which in turn were prepared from the addition of allyl- or (allyloxy)silanes to ethyl 6-benzotriazolyl-2,3,3a,4,5,6-hexahydro-1H-indolo[3,2,1-de][1,5]naphthyridine-2-carboxylate (106, Scheme 21).56 The products were obtained as a separable mixture of diastereomers highly enriched in 107a−d. Structural assignments were confirmed by X-ray crystallography and showed that the silane nucleophiles underwent dominant attack on the same face of the molecule as the 4-axial hydrogen of 106, possibly because in the incipient iminium cation the benzotriazole anion shields the other face.

following Stille vinylation of 89, in situ thermolysis led to an initial [4+2] cycloadduct followed by a cascade of ringopening/semipinacol-type rearrangement to furnish 9H-pyrido[3,4-b]indole 90. Treatment of this with p-TsOH then gave rise to the 4,5-dihydrocanthin-6-one 91 in good overall yield. This chemistry was not tested for the synthesis of other canthin-6one analogues. Benson et al. reported on an intramolecular inverse electron demand cycloaddition of two indole substrates with a range of substituted 1,2,4-triazines connected by a tri- or tetramethylene tether linking the indolic N-1 position with the triazinyl 3position (Scheme 19).51 This successfully produced the canthine skeleton (96, n = 1) and the homologous sevenmembered D-ring congener (96, n = 2). It also allowed for the relatively facile introduction of diverse substituents at the C-1 and C-2 positions of the C-ring. In a follow-up report from this laboratory, the authors provided representative examples wherein canthine cycloadducts (96, n = 1) were cleanly oxidized to corresponding canthin-6-ones in modest yields (∼65%) with triethylbenzylammonium permanganate (BTAP) in 5:1 glacial acetic acid/dichloromethane.52 Lindsley et al.53 extended the utility of Benson’s cycloaddition reaction by developing a microwave-mediated protocol for the synthesis of the basic canthine skeleton. Utilizing a single-mode “one-pot” protocol, a generalized synthesis of several C-1/C-2-substituted canthines (96, n = 1) was completed in moderate to excellent yields with diaryl analogues proceeding in overall 60−80% yields and dialkyl analogues in lower yields (ca. 30%). A complementary “two-pot” microwave-accelerated procedure was developed to improve the yields of dialkyl congeners (55% overall yield). Unnatural canthin-6-one alkaloid congeners could also be obtained by selective oxidation following the BTAP procedure described by Li and Snyder.52 Thus, in Lindsley’s work, high-yielding access to a number of previously unknown C-1/C-2 canthine and canthin-6-one alkaloids was

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C-RING-TRUNCATED CANTHINES (“ABD” RING SYSTEM) Kato et al. synthesized a series of 7-substituted 8,9-dihydro-7Hpyrido[1,2-a]indol-6-ones and evaluated them for 5-HT3 461



Review

Scheme 20. Malamidou-Xenikaki (200655)a

Scheme 22. Kato (199457)a

a

Reagents and conditions: (i) 4-R2-C6H4NHNH2, aq H2SO4, toluene (50−52% yield); (ii) Method A: 1. LDA, Het-CHO, THF, −70 °C, 1 h (13−95% yield); 2. Ac2O, pyridine, rt, 20 h (100% yield); 3. DBU, toluene, 55 °C, 6 h (22−94% yield); 4. 10% Pd/C, HCO2NH4, AcOH, 90 °C, 2 h (50−91% yield) or 10% Pd/C, H2, DMF/EtOH (6:1), rt, 6 h (63−93% yield) or Zn, AcOH, reflux, 2.5 h (50−91% yield); Method B: 1. LDA, CH2N+(Me)2I−, THF, −40 °C, 1.5 h (45% yield); 2. 2-methylimidazole, 2-PrOH, 2 N aq HCl, reflux, 3 h (54% yield).

Reagents and conditions: (i) Br(CH2)mBr, NaOH, Bu4NBr, benzene, rt, 1−1.5 h (52−63% yield); (ii) AgNO2, THF, rt, 2 days (38−56% yield); (iii) for 99a−c, POCl3, ACN, reflux, 1 h; (iv) acryloyl chloride, Et3N, DCM, rt, 2 h; (v) NaH, MeOH, THF, rt, 4 h (55−88% yield).

labeled methyl group at the 10-position (R1 = 14CH3; R2 = H) for metabolism studies.58 A Mannich reaction followed by hydrogenolysis of the dimethylaminomethyl group allowed for an efficient introduction of the methyl group. The synthesis developed for this purpose is shown in Scheme 23 for coldlabeled compound.

Scheme 21. Katritzky (199956)a

Scheme 23. Kato (199558)a

a

Reagents and conditions: (i) NBS, (PhCO2)2, CCl4, 85 °C, 1.5 h (84% yield); (ii) PPh3, CHCl3, reflux, 48 h (93% yield); (iii) for 113: DBU, DMF, 110 °C, 2 h (51% yield); (iv) 35% HCHO, 50% aq NHMe2, AcOH, 50 °C, 24 h (67% yield); (v) 10% Pd/C, HCO2NH4, EtOH, 75 °C, 3 h (62% yield). a

a Reagents and conditions: (i) 2,5-(OMe)2-tetrahydrofuran, HOAc, rt, (60% yield); (ii) allyl- or (allyloxy)silanes, BF3·OEt2, ACN (∼80% yield).

Kappe et al. described the synthesis of a series of substituted 8-hydroxy-10,10-dimethyl-10H-pyrido[1,2-a]indol-6-ones 11759 and 118,60 which were each made in a two-step sequence as shown in Scheme 24. Selected congeners of 117 (X = H, Cl; R = Ph) and 118 (X = H, Cl) were then entered into a range of electrophilic (halogenation, nitration) and hydrolysis reactions, respectively, leading to products 119 in which further substitution (E) was installed at each of the C-7−C-9 positions on the pyridone ring. Imase and Tanaka have developed a very simple route to the 10,10-dimethyl-10H-pyrido[1,2-a]indol-6-one skeleton utilizing

receptor antagonist activity.57 The core template 109 was prepared in one step from the 2-substituted cyclohexane-1,3dione 108 by the Fischer indole reaction (Scheme 22). Further elaboration via standard homologation reactions on the 7position provided a series of analogues (110) for biological testing. One compound was shown to have potent receptor activity and was a very effective antiemetic agent against cisplatin-induced emesis in dogs. A follow-up study by the same group reported on an improved synthesis of 109 toward providing a better route that would permit introduction of a 462



Review

Scheme 24. Kappe (2002,59 200360)a

Scheme 26. Patil (201162); Phun (201263)a

a Reagents and conditions: (i) 3-methyl-2-butanone, AcOH, reflux, 2 h (∼60% yield); (ii) Method A: 2-substituted diethylmalonate, Ph2O, 220−250 °C, 1−4 h (10−81% yield); Method B: 2-substituted bis(2,4,6-trichlorophenyl)malonate, 200−220 °C (53−63% yield); (iii) diethylmalonate (2 equiv), Ph2O, 200−250 °C, 1.5−2 h (68−78% yield); (iv) halogenation, nitration; (v) aq NaOH, ethylene glycol, reflux, 1 h (93% yield).

a

Reagents and conditions: (i) NaH, methyl malonyl chloride, THF, 0 °C; (ii) TsN3, Et3N, ACN, (iii) for 123b: 1 mol % Rh2esp2, alkene, DCM, 0 °C (≤70% yields over 3 steps); (iv) (a) for 124, 30 mol % In(OTf)3, DCM/rt or 1,2-DCE/reflux (50−99% yield); (b) for 126, 5 mol % In(OTf)3, DCM, rt, 6 h (69% yield); (v) for 123b, 1 mol % Rh2esp2, 4-ethynylanisole, DCM, rt, 3 h (67% yield).

a cationic gold(I)/PPh3-catalyzed cycloisomerization reaction.61 Thus, reaction of the 1,5-enyne 120, readily prepared from phenylpropiolic acid and commercially available 2,3,3trimethyl-3H-indole (116, X = H), gave the 8-phenylsubstituted product 121 in 52% yield under the conditions shown in Scheme 25. No other examples of this heterocycle

A closely related study was carried out by Phun et al.63 as part of a program to generate highly functionalized heterocycles (Scheme 26). Several examples showing Lewis acid-catalyzed cycloisomerization of cyclopropene-3,3-dicarbonyl substrates provided a wide array of benzo-fused heteroaromatics and heterobiaryls, including the substituted 6-hydroxy-10methylpyrido[1,2-a]indole (127). Thus, treatment of the Nindolyl α-diazo β-amidoester 123b with rhodium catalyst and 4ethynylanisole produced the cyclopropene 126, which was then cycloisomerized in the presence of In(OTf)3 to afford the pyrido[1,2-a]indole product 127 in good yield over two steps. While the methodology is reasonably efficient and provides direct entry to a fully oxidized tricylic system as compared to the work of Patil,62 its application to the generation of diverse analogues of 127 remains to be demonstrated.

Scheme 25. Imase (200961)a

a

Reagents and conditions: (i) phenylpropiolic acid, Me2C CClNMe2, DCM, 0 °C, 1 h and then 116 (X = H), Et3N, 0 °C to rt, 1 h (40% yield); (ii) 5 mol % AuCl(PPh3)/AgBF4, DCM, rt, 12 h (52% yield).

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were exemplified, but it is likely that this reaction would have generality for a range of analogues with variable substitution on the benzenoid and pyridone rings. In a demonstration of chemistry with broad generality, Patil et al. reported on an efficient catalytic cyclopropane ringopening/Friedel−Crafts alkylation sequence for the facile construction of hydropyrido[1,2-a]indole-based derivatives (125a and 125b) in good to excellent yields (48−99%). These were obtained in four steps from readily available indoles (122) and a range of alkenes (Scheme 26).62 The methodology is highly modular, operationally simple, and amenable to a large variety of functional groups and substitution patterns. Mechanistically, the protocol involves cyclopropane ringopening in the presence of In(III) catalyst, followed by an intramolecular Friedel−Crafts alkylation of the indole moiety. The cyclization proceeds through an aza-cationic intermediate, which incorporates a nitrogen atom into the newly formed ring. Products are formed with a generally high trans:cis diastereomeric ratio for 125a, and a number of cyclic adducts (125b) with an all-cis configuration are reported, including ones incorporating heteroatoms.

A-RING-TRUNCATED CANTHINES (“BCD” RING SYSTEM) A patent application by Glaxo, UK, reported on the synthesis of a series of 4-substituted-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5naphthyridin-7-ones (134) as antibacterial agents (Scheme 27).64 The most distinguishing feature of their strategy was to use two different pathways to introduce an acrylate function at the 8-position of the 1,5-naphthyridine starting compounds 128a and 128b. The resultant intermediates 129 were then entered into a Michael reaction with primary and secondary amines to generate an SAR representing a wide range of elaborate heterocyclic side chains. While yields generally were good to excellent for each reaction, the overall scheme lacks convergence, requiring 5−8 steps for each derivative made. Compounds of this invention were tested for antibacterial activity against a wide range of common Gram-positive and Gram-negative pathogens. For at least one strain of each organism tested, at least one derivative displayed an MIC ≤ 2 μg/mL with the exception of strains of Pseudomonas aeruginosa, 463



Review

Scheme 27. Brooks (200764)a

framework for annulation onto the 1,5-naphthyridine core to provide tricylic scaffold 137. This was then transformed to either optical isomer of diol 138a by AD mix α or β. Activation of the C-4 primary alcohol of 138a via tosylation then provided key intermediate 138b, which was engaged in an SN2 displacement reaction with a wide range of heterocyclic amines. Additional examples are provided in which some of the target derivatives are further treated with diethylaminosulfur trifluoride to provide derivatives with fluoro in place of the tertiary hydroxy. All compounds of the invention were evaluated for cellular activity against Mycobacterium tuberculosis H37Rv, with the best ones exhibiting MIC values of ≤1.7 μg/ mL. Subsequent to the above patent disclosures, a Glaxo process chemistry group published an efficient enantioselective total synthesis of the novel antibiotic GSK966587 (Scheme 29), Scheme 29. Voight 201066)a

a

Reagents and conditions: (i) for 128a, 2-(tributylstannanyl)-2propenoate, Pd(PPh3)4, CuI, LiCl, DMF, rt, 1 h (93% yield); (ii) method A: NaH, dimethyl malonate, DMF, 1 h and then 128a, 50 °C, 12 h (81% yield); method B: NaH, dimethyl malonate, p-dioxane, 75 °C, 2 h and then 128b, CuBr, 100 °C, 18 h, (97% yield); (iii) LiCl, H2O (0.5 equiv), DMSO, 100 °C, 16−24 h (94% yield); (iv) paraformaldehyde, K2CO3, Et3(CH2Ph)NCl, cyclohexane, 80 °C, 24 h (89% yield); (v) NHR1R2, 1,1,3,3-tetramethylguanidine, DMF, 70−80 °C, 1−7 h, (58−100% yield); (vi) LAH, THF, −78 to 0 °C, 0.5−3 h (38−54% yield); (vii) mesyl chloride, Et3N, DCM, rt, 1 h; (viii) for 133b, DBU, CHCl3, 50 °C, 1 h to 3 days (22−79% yield over 2 steps).

for which at least some of the compounds had an MIC ≤ 4 μg/ mL. Another patent application by a Glaxo group reported on the synthesis of a series of 4-substituted-3-fluoro-4-hydroxy-4,5dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-ones for the treatment of tuberculosis (Scheme 28).65 Thus, palladiumcatalyzed isopropenylation of 135 provided the carbon Scheme 28. Ballell-Pages (200865)a a Reagents and conditions: (i) n-butyl acrylate, 2 mol % Pd(OAc)2, HP(t-Bu)3BF4, Cy2NMe, cumene, 150 °C, 4−5 h (76% yield); (ii) SOCl2, (n-Bu)2NCHO, toluene, 85 °C, 1 h; (iii) MeOH, 20−40 °C, 24 h; (iv) for 142b:, (i-Pr)2NZnEt2Li, THF, −30 to 25 °C; (v) 2bromopropen-3-ol, LDA, THF, −30 °C, and then Pd2dba3·CHCl3, tri(2-furyl)phosphine, THF, 45 °C, 1 h (68% yield from 141); (vi) Ti(Oi-Pr)4, L-DIPT, 4 Å mol sieves, cumene hydroperoxide, DCM, 0 °C, 5.5 h; (vii) conc HCl, < 5 °C, 1.7 h; (viii) n-PrCN, 100 °C, 2.5 h (63% yield from 144); (ix) C4F9SO2F, Et3N, Et3N, ACN, rt 1 h; (x) amine side chain, ACN, rt, 16 h (76% yield from 147).

which was chosen for further development due to its potent activity against Gram-positive and Gram-negative bacteria.66 Starting from commercially available 139, a three-step sequence was optimized to provide key naphthyridine 142b, which was then entered into a Negishi coupling reaction through the intermediacy of 143, readily prepared from the zincate reagent (i-Pr)2NZnEt2Li. To introduce the single asymmetric center of

a

Reagents and conditions: (i) pyridine-tris(triisopropenyl)boroxin, Pd(PPh3)4, K2CO3, DME, reflux, 10 h (95% yield); (ii) aq NaOCl, CeCl3, t-BuOH, rt, 30 min (58% yield); (iii) for 136b, NaI, acetone, reflux, 18 h, (36% yield); (iv) AD mix α or β, aq t-BuOH, rt, 16 h (100% yield); (v) p-TsCl, Et3N, DCM/THF/DMF (1:1:1), rt, 16 h (100% yield). 464



Review

Scheme 31. Hubschwerlen (201068)a

GSK966587, a Sharpless epoxidation of allylic alcohol 144 was used, which provided 145 in 90% ee. The synthesis of GSK966587 was then completed via SN2 ring-opening of spiro epoxide 148, which was easily prepared from 145 in two simple steps. The target antibiotic was isolated in 25% overall yield with three isolated intermediates and gave high chemical and optical purity (98.7% and 98% ee, respectively). The biological target of this class of antibacterial agents has not been disclosed either in Glaxo or in other publications. In another patent application related to the Glaxo work above, the ethano bridge of the tricyclic core of 152 was constructed as shown in Scheme 30.67 An attractive feature of

Reagents and conditions: (i) NaN3, NH4Cl, aq MeOH, 65 °C, 4 h; (ii) 10% Pd/C, H2, THF/MeOH (1:1), 1 h; (iii) Boc2O, DCM, rt, 2 h (43% yield over 3 steps); (iv) mesyl chloride, Et3N, 1,2-DCE, 1 h, rt; (v) for 154d, 45 °C, 72 h (47% yield over 2 steps); (vi) 4 N aq HCl/pdioxane, rt, overnight (52% yield). a



a

Reagents and conditions: (i) allyltributyltin, Pd(PPh3)4, CuI, LiCl, DMF, 100 °C, 2 h (98% yield); (ii) K2OsO4·2H2O, NMO, aq DCM, rt, 16 h (69% yield); (iii) TBSCl, imidazole, THF, rt, 3 h (100% yield); (iv) mesyl chloride, Et3N, DCM, 0 °C, 1 h (75−96% yield); (v) for 151c: toluene/1,2-DCE, 110 °C, 2 h (21% yield); (vi) NaN3, DMF, 50 °C, 20 h (71% yield); (vii) PPh3, THF, aq acid, 70 °C, 2 days (39% yield).

this route is that the intermediate 8-allyl-1,5-naphthyridine 150 can be engaged in an asymmetric dihydroxylation reaction utilizing AD-mix α or β to provide either R- or Sstereochemistry of the 4-aminomethyl side chain of 152d. This intermediate was then reacted with a range of tosylate or mesylate side chains to generate a number of derivatives for biological testing. The best compounds displayed an MIC of ≤0.063 mg/L vs Moraxella catarrhalis. Yet another strategy toward generating the 7-oxo-5,7dihydro-4H-pyrrolo[3,2,1-de][1,5]naphthyridine ring system is outlined in a patent application by Actelion Pharmaceuticals, Ltd.68 Several synthetic schemes were presented in which a functionalized dihydropyrrole moiety is annulated onto an 8functionalized-2-methoxy-1,5-naphthyridine precursor. These are exemplified in Schemes 31 and 32 for three cores incorporating amino side chains of variable length at the 4position of the dihydropyrrole ring. Essentially the same synthetic methodology is presented in additional schemes (not shown) to incorporate functionality (e.g., OH) at either or both of the 4- and 5-positions of the dihydropyrrole ring. The use of chiral precursors, as shown for 153, is exemplified for many examples, permitting the generation of optically active cores with a 4- (R) and (S) amino functionality. Amino cores 155b and 160b (n = 1, 2) were alkylated with a variety of side chains to provide target compounds that were evaluated for

a Reagents and conditions: (i) NaH, diethyl malonate, p-dioxane, rt and then 156, CuBr, 100 °C, 6 h, (90% yield); (ii) LiCl, H2O (1.2 equiv), DMSO, 110 °C, 32 h (87% yield); (iii) LiHMDS, BrCH2NPht, −78 °C to rt, THF (43% yield); (iv) for 157c, aq NH2NH2, EtOH, rt, 2 h (82% yield); (v) Boc2O, Et3N, THF, rt, 1 h (62−83% yield); (vi) LAH, THF, −10 °C to rt, 3 h (100% yield); (vii) mesyl chloride, Et3N, 1,2-DCE, 1 h, rt; (viii) for 159b, 162c, 45 °C, 72 h (100% yield over 2 steps); (ix) Et3SiH, TFA, DCM, rt, 1 h (13−49% yield); (x) 157b, LiHMDS, THF, −78 °C, 2 h and then BrCH2CN, −78 °C, 2 h (76% yield); (xi) AlCl3, LAH, THF, −78 °C to −30 °C, 2 h (25% yield).

antibacterial activity. Against Moraxella catarrhasis A894, the best compounds exhibited MIC values of ≤0.031 mg/L. In another patent application, Gilead Sciences, Inc. detailed the synthesis of a large series of compounds in which a range of five- to seven-membered rings were fused onto the N-1 and C-8 positions of a 4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine3-carboxylate core.69 The resultant tricyclic systems included the 9-hydroxy-4,4-dialkyl-7-oxo-5,7-dihydro-4H-pyrrolo[3,2,1de][1,5]naphthyridine-8-carboxylate and 9-hydroxy-4-alkyl-7oxo-7H-pyrrolo[3,2,1-de][1,5]naphthyridine-8-carboxylate 465



Review

congeners available only by organic synthesis. While endeavors employing a classical Bischer−Napieralski or Pictet−Spengler approach are still popular, more recent syntheses are utilizing strategies that are much more flexible and convergent. This has opened the possibility of generating libraries of analogues for pharmacological evaluation in an efficient manner, especially for diversity within the A- and C-rings. Synthetic advances allowing access to reduced canthine scaffolds are also providing a range of analogues of potential medicinal interest, especially those compounds with chiral centers embedded in the C- and Drings. Additionally, recent campaigns at generating A- and Cring-truncated congeners of canthines show that there still are opportunities to explore new directions within this venerable template. With the exciting biological results being reported for some of these truncates, one would expect to see considerably more medicinal chemistry activity in this area, as evidenced by the number of patent applications claiming therapeutic utility. Finally, one area that has not been significantly explored within the parent or truncated canthine templates is the replacement of various rings, especially the A- and C-rings, with other heterocycles. Current synthetic methodologies should now make these readily accessible.

cores exemplified in compounds 167 and 171, respectively (Scheme 33). Their synthesis followed a strategy of first Scheme 33. Aktoudianakis (201069)a

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AUTHOR INFORMATION

Corresponding Author

*Tel: 1-734-764-5504. Fax: 1-734-647-8430. E-mail: showalh@ umich.edu. Notes

The authors declare no competing financial interest.

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a

Reagents and conditions: (i) NaHDMS and then 3-Br-2-methylpropene (for 163a) or allyl bromide (for 163b), DMF, 0 °C to rt, 0.5−1 h (90−100% yield); (ii) 1−10% Pd(OAc)2, NaOAc, NaOCHO, Et4NCl, 80 °C, 1.5−16 h (27−90% yield); (iii) 10% Pd/C, NaOAc, H2, MeOH/EtOAc (2:1), rt, 1 h, (100% yield); (iv) 1,2-DCE-TFA (4:1), 25−55 °C, 1.5−2 h (100% yield); (v) ethyl 3-chloro-3-oxopropionate, 1,2-DCE, 25−80 °C, 0.5−1 h (90−100% yield); (vi) NaOEt, EtOH, rt, 2 h (100% yield); (vii) Ag2O, BnBr, DCM, rt, 4h (70% yield).

ACKNOWLEDGMENTS Generous support by the University of Michigan College of Pharmacy Ella and Hans Vahlteich Research Fund is gratefully acknowledged.

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DEDICATION Dedicated to Dr. Lester A. Mitscher, of the University of Kansas, for his pioneering work in the discovery of bioactive natural products and their derivatives.

building a five-membered ring onto precursor bromopyridine (164a) by a reductive Heck reaction to give the 3,3-dimethyl2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-7-carboxylate 165c and then further elaborating this intermediate into desired tricyclic core 167 via a Claisen condensation reaction on 166. Similar chemistry was carried out on 164b, but through a different ordering of reactions and through the use of a Heck reaction under nonreductive conditions to provide target intermediate 171. Compound 171 is the only example in the literature of a fully oxidized 7-oxo-7H-pyrrolo[3,2,1-de][1,5]naphthyridine ring system. The carboxylic ester of both 167 and 171 was then amidated with a wide variety of amines to provide analogues for biological evaluation. Selected compounds were assayed for activity in MT-2 cells infected with HIV-IIIb, with better ones showing an EC50 = 0.1 nM.

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REFERENCES

(1) Haynes, H. F.; Nelson, E. R.; Price, J. R. Aust. J. Sci. Res., Ser. A 1952, 5, 387−400. (2) Brahmbhatt, K. G.; Ahmed, N.; Sabde, S.; Mitra, D.; Singh, I. P.; Bhutani, K. K. Bioorg. Med. Chem. Lett. 2010, 20, 4416−4419. (3) Xu, Z.; Chang, F.-R.; Wang, H.-K.; Kashiwada, Y.; McPhail, A. T.; Bastow, K. F.; Tachibana, Y.; Cosentino, M.; Lee, K.-H. J. Nat. Prod. 2000, 63, 1712−1715. (4) Peduto, A.; More, V.; de Caprariis, P.; Festa, M.; Capasso, A.; Piacente, S.; De Martino, L.; De Feo, V.; Filosa, R. Mini-Rev. Med. Chem. 2011, 11, 486−491. (5) Miyake, K.; Tezuka, Y.; Awale, S.; Li, F.; Kadota, S. Nat. Prod. Commun. 2010, 5, 17−22. (6) Ferreira, M. E.; Nakayama, H.; de Arias, A. R.; Schinini, A.; de Bilbao, N. V.; Serna, E.; Lagoutte, D.; Soriano-Agaton, F.; Poupon, E.; Hocquemiller, R.; Fournet, A. J. Ethnopharmacol. 2007, 109, 258−263. (7) Takasu, K.; Shimogama, T.; Saiin, C.; Kim, H.-S.; Wataya, Y.; Brun, R.; Ihara, M. Chem. Pharm. Bull. 2005, 53, 653−661. (8) Kuo, P.-C.; Shi, L.-S.; Damu, A. G.; Su, C.-R.; Huang, C.-H.; Ke, C.-H.; Wu, J.-B.; Lin, A.-J.; Bastow, K. F.; Lee, K.-H.; Wu, T.-S. J. Nat. Prod. 2003, 66, 1324−1327. (9) O’Donnell, G.; Gibbons, S. Phytother. Res. 2007, 21, 653−657. (10) Ostrov, D. A.; Prada, J. A. H.; Corsino, P. E.; Finton, K. A.; Le, N.; Rowe, T. C. Antimicrob. Agents Chemother. 2007, 51, 3688−3698.

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CONCLUSION Natural products containing the canthine ring system are a special subclass of β-carboline alkaloids and are intriguing from a taxonomic, synthetic, and medicinal perspective.12,34,70 Synthetic efforts over a 45-year period have resulted in the availability of many canthin-6-ones and reduced congeners for biological study. These include compounds that have been isolated from natural sources as well as a number of unnatural 466



Review

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Progress in the Synthesis of Canthine Alkaloids ... - ACS Publications

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