Journal of Chemistry
Volume 2015 (2015), Article ID 629085, 22 pages
http://dx.doi.org/10.1155/2015/629085

Review Article

Bioactive Phytochemicals: Bioactivity, Sources, Preparations, and/or Modifications via Silver Tetrafluoroborate Mediation

Matthew C. Achilonu and Dennis O. Umesiobi

Department of Agriculture, Central University of Technology, Free State, 1 Park Road, Bloemfontein 9300, South Africa

Received 12 August 2014; Accepted 5 March 2015

Academic Editor: Patricia Valentao

Copyright © 2015 Matthew C. Achilonu and Dennis O. Umesiobi. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

This review provides an overview of the biological activities, natural occurrences, and the silver tetrafluoroborate- (AgBF4-) mediated synthesis of proanthocyanidins, glycosides, N-heterocyclic alkaloid analogues (of pyrrole, morphine, quinoline, isoquinoline, and indole), furan analogues, and halocompounds. AgBF₄ has been reviewed as an effective reaction promoter, used extensively in the synthesis of relevant biologically active compounds via carbon-carbon and carbon-heteroatom bonds formation. The literatures from 1979 to April 2014 were reviewed.

1. Introduction

Naturally occurring bioactive compounds are ubiquitous in most dietary higher plants available to humans and livestock. The natural products such as plant extracts provide unlimited opportunities for new drug discoveries, mostly because of plethora of varieties of chemicals [1, 2]. Literally, relative to available synthetic medicines, thousands of accessible medicinal and agricultural phytochemicals are safer and largely more effective alternatives with less adverse effects. For this reason, coupled with advancing microbial resistance to the synthetic drugs, ethnopharmacognosy is rapidly gaining world recognition [2]. The strong growing value and interest in the crucial role that nutrition plays in maintaining human health, animal health, productivity, and reproductive performance of livestock and poultry are greatly recognised [3]. Sasidharan et al. (2011) and other authors have sturdily expressed useful biological activities of phytochemicals. They observed that plant chemicals exhibit anticancer, antimicrobial, antioxidant, antidiarrheal, analgesic, and wound healing actions on animals [2].

The most popular phytochemicals are the polyphenolics which consist of flavonoids and phenolic acids that form the building blocks for polymeric tannins (hydrolysable and condensed tannins or proanthocyanidins) [4]. Flavonoids are large collection of plant secondary metabolites whose chemical structures are based on a C₆-C₃-C₆ carbon ring system 1 and consist of five major subgroups: flavones 2, flavonols 3, flavanones 4, flavanols 5, and anthocyanidins 6 (Figure 1). Being universally distributed in green plant kingdom, flavonoids therefore form an integral part of human and animal diets. It is well known that flavonoids display a potpourri of biological activities in plants that biosynthesize them and in humans and livestock that feed on those plants and allied products. The bulk of animal feed, which is of plant origin, is known to contain a range of different biologically active compounds such as flavonoids, tocopherols, tocotrienols, and carotenoids [3]. Reports show that, in a particular animal feed portion, the bioactivity of flavonoids is about twice more than other bioactive source compounds [3]. Flavonoids play such important roles [5] in situ as signal 37 molecules [6], phytoalexins [7, 8], detoxifying agents [9–11] and stimulants for germination of spores [12–15]. Additionally, they also act as UV-filters [16, 17], in temperature acclimation [18], drought resistance [19], pollinator attractants [20] and allelochemical agents [21, 22]. For the scope of this review paper, our focus was limited to proanthocyanidins: polymers of flavanols (catechin) and the analogues (Figure 1) [23].

Figure 1: Base structure and subgroups of flavonoids.

Glycoside compounds are another important group of bioactive phytochemicals. They essentially constitute hormones, sweeteners, alkaloids, flavonoids, antibiotics, and so forth [24]. Literature revealed that amongst these glycosides are a range of natural polyphenolic flavonoid glycosides, richly found in legume plants (Figure 2) [25–28].

Figure 2: Natural polyphenolic flavonoid glycosides.

Typical alkaloids, mainly derived from plant sources, are a large group of secondary metabolites containing usually basic nitrogen in a heterocycle, which are broadly varied in chemical structure and in pharmacological action (Figure 3) [29]. The toxicity of some alkaloids is widely recognized; however they are a source of many biologically active phytochemicals with great potential for medicinal and agricultural uses. Many alkaloids have attractive pharmacological effects and are used as medications, such as recreational drugs, or in entheogenic rituals [30, 31].

Figure 3: Typical basic structure of alkaloids.

Furans, particularly 2,3-dihydrofurans, are one of the abundant structural motifs found in plants that possess impressive biological activities and, as a result, are extensively used in the pharmaceutical, flavour, insecticidal, and fish antifeedant industries [32–37].

Another group of phytochemical derivatives that are increasingly gaining attention in recent times in the agrochemical and pharmaceutical industries is the halocompounds. Though they are usually isolated from nature in low yields, the halogenated phytochemicals are known for their high bioactivity [38, 39].

Owing to the significance of these rare and sparsely available natural compounds to human health and biota, scientists have made desperate efforts to mimic nature and make these compounds more accessible through chemical synthetic methods. In that pursuit, silver tetrafluoroborate proved to be an efficient tool to achieve this purpose. AgBF₄ was found to promote a variety of reactions through its ability to complex with and activate electron rich atoms and bonds under mild conditions.

Our literature search for AgBF₄-promoted reactions thus revealed two reviewed papers published in 2008, covering silver-mediated reactions, including the AgBF₄-mediated reactions [40–43]. Abbiati and Rossi in their review [44] referred to the use of AgBF₄ by Liu (2011) to facilitate their 3-component cascade synthesis of bioactive Pyrrole-2-carboxaldehyde [44, 45]. These reports were concurrently summarized and therefore are excluded from the present review. A study of the available reports revealed that most of the compounds synthesized via AgBF₄ mediation are biologically active phytochemicals. With this revelation in mind, we summarized the publications with the aim of pursuing two objectives: firstly, to provide a brief overview of the bioactivity and natural occurrences of the main groups of the compounds within the scope of this paper; and, secondly, to review the AgBF₄-promoted synthesis of the compounds and/or analogues. Herein, we reviewed bioactivity and natural sources of some phytochemicals and formation of such compounds and/or analogues via AgBF₄-mediated reactions based on published information on AgBF₄-promoted carbon-carbon and carbon-heteroatom bond formation since 1979, when Fry and Migron record of its use in this regard appeared, until April 2014.

2. Proanthocyanidins

Proanthocyanidins, oligomers and/or polymers of flavan-3-ols, are among the most abundant naturally occurring polyphenolic plant metabolites. They are commonly available in different parts of plants (e.g., legumes, cocoa) and crops such as fruits (grapes, apples, and pears), nuts, seeds, flowers, and bark [46]. Proanthocyanidins display a wide range of biological activities, such as antioxidant, antibacterial, antiviral, antimutagenic, anti-inflammatory, hypertensive, and other heart related diseases [47, 48]. Their high significance in the general well-being of animals warranted intensive studies by researchers on their sources and accessibility. Hence, Steynberg and co-workers [49] (1998) and other research groups [50, 51] have widely exploited different ways of synthesizing the largely varied proanthocyanidin compounds.

A popular methodology in this regard involved using a substrate bearing a leaving group that contains oxygen or sulphur heteroatom. The affinity of AgBF₄ towards oxygen and sulfur is exploited to enhance capabilities of the leaving group [49–51]. This property has been explored to create good routes to obtain procyanidins 17 under neutral reaction conditions. The protocol involves treating a mixture of 4β-benzylsulfanylepicatechin 15 and catechin 16 in THF with AgBF₄ (2.5 equiv.) for 1 h at 0°C to obtain procyanidin B-1 in 38% yield (Scheme 1) [49].

Scheme 1: Interflavanyl bond formation in procyanidins under neutral conditions.

A 2-mercaptobenzothiazole is used to obviate the offensive odour associated with 4-thioderivatives. Then, condensation of 18 and 19 in dry THF in the presence of anhydrous AgBF₄ at 0°C yielded the procyanidin oligomers (20, 21, and 22), as presented in Scheme 2 [50].

Scheme 2: Synthesis of procyanidin oligomers using 4-[(2-benzothiazolyl)thio] derivative.

The ability of AgBF₄ to activate OH groups to synthesize ether-linked proanthocyanidins (proteracacinidin and promelacacinidin) was further explored. The protocol involved treating a mixture of the epioritin-4β 23 and 4α-ols 24 in dry THF at 0°C with AgBF₄ for 90 min under nitrogen before the reaction was quenched with water. After workup and purification processes including acetylation, the expected products epioritin-()-epioritin-4α-ol 25 (9.1%) and epioritin-()-epioritin-4α-ol 26 (7.8%) were obtained as the octa-O-acetyl derivatives, accompanied by a C-C-linked compound, epioritin-()-epioritin-4α-ol 27 (Scheme 3) [51].

Scheme 3: Synthesis of ether-linked proteracacinidins 25 and 26 and the C-C coupled analogue 27.

The AgBF₄ activating C-H group between carbonyl and aryl functional groups affords a novel synthesis of proanthocyanidins from 3-oxo-flavans, accessible from readily available flavan-3-ols via Dess-Martin periodinane oxidation, thus circumventing the need for C-4 functionalization. In contrast with flavan-3-ol based syntheses, where the C-3 stereochemistry determines the C-4 stereochemistry, the 3-oxo-flavans have no stereochemistry on C-3 and the C-2 determines absolute configuration on C-4, giving access in hitherto synthetically unavailable 3,4-cis procyanidins (Scheme 4) [52].

Scheme 4: Condensation reaction between 28 and 29.

The requirement of an excess of AgBF₄ and the observation of a silver mirror (reduction of Ag¹ to Ag⁰) may indicate an oxidative mechanism (Scheme 5) [53].

Scheme 5: Proposed mechanism for oxidative synthesis of 30 and 31 based on the model reaction.

The counter ion probably assists in stabilizing the 4-carbocation 34 via the quinone methide tautomer 36. Another major advantage of this synthesis is that no self-condensation was observed as was the case with the conventional syntheses based on a flavan-3-ol with a C-4 leaving group.

3. Glycosides

Natural occurring bioactive glycosides are many and are mainly essential class of compounds such as hormones, sweeteners, alkaloids, flavonoids, and antibiotics [24]. It is widely attested that the glycosidic moiety can be crucial for the compound’s activity or in certain cases it only improves its pharmacokinetic properties such as circulation, elimination, and concentration in the body fluid [24]. Glycosides are more water soluble than aglycons; therefore attaching glycosidic residue into the molecule will increase the compound’s hydrophilicity. Consequently, the effect will be seen in the compound’s pharmacokinetic activities such as inhibiting cell uptake of the glycoside by building placenta barrier, thus preventing foetal intoxication by metabolites of xenobiotics [24]. Varieties of natural polyphenolic flavonoid glycosides (Figure 2) are found in abundance in legume plants [28]. Glycoflavonoids, mainly isoflavonoids (e.g., quercetin 3-O-rhamnopyranosyl()-glucopyranoside-7-O-rhamnopyranoside 7) present in legumes such as Vicia faba and Lotus edulis (Leguminosae), are purported to exert chemopreventive actions [25] on certain cancer types (colon, breast, and prostate) [26] and cardiovascular diseases [27]. Flavonoid glycosides are prepared synthetically, usually for pharmaceutical purposes [24]. Anthocyanin glycosides improve the antioxidant and “deepening” colour stabilization controlled by the glycosyl residue. A typical molecule is the “heavy blue anthocyanidin,” peonidin acyl-glycoside 8. Another example is Silybin 9, a flavonolignan extracted from seeds of milk thistle (Silybum marianum) used as potent hepatoprotectant and an antidote in mushroom poisoning. However, the major drawback of water solubility of this phytochemical compound was dealt with by chemical glycosylation to afford compound 10 [24, 28]. The demand for biologically relevant and therapeutically active oligosaccharides is on the increase in recent times. This has spurred synthetic biologists and chemists to increase efforts in developing effective glycosylation methods for oligosaccharides.

A typical work is that of Kaeothip et al. (2008) who used silver tetrafluoroborate to activate glycosyl donors such as glycosyl halides, trichloroacetimidates, and thioimidates [53, 54]. Glycosyl thioimidates 40 and 41 could be selectively activated in the presence of thioglycosides to afford a simple one-pot synthesis of trisaccharides (Scheme 6). The glycosyl acceptor (S-ethyl glycoside) is expected to withstand AgBF₄ activation but later readily activated when N-iodosuccinimide (NIS) was added, followed by addition of new acceptor, methoxy glycoside 43.

Scheme 6: AgBF₄ as a potent promoter for chemical glycosylation.

4. Alkaloids

Alkaloids, typically derived from plant sources, are a large group of secondary metabolites containing usually basic nitrogen in a heterocycle. The types and occurrences of alkaloids [29] within the scope of this paper are as follows (Figure 3): pyrrole Coca spp. (Erythroxylaceae); quinolone Cinchona spp. (Rubiaceae), Remijia spp. (Rubiaceae), Angostura or cusparia bark, Galipea officinalis (Rutaceae); isoquinoline Papaver somniferum (Papaveraceae), Corydalis and Dicentra spp. (Fumariaceae), numerous genera of the Berberidaceae, Ranunculaceae and Papaveraceae, Cephaelis spp. (Rubiaceae), Curare obtained from plants of Menispermaceae, Papaver somniferum (Papaveraceae), Erythrina spp. (Leguminosae), Leucojum aestivum (Amaryllidaceae); and indole (benzopyrrole), Claviceps spp. (Hypocreaceae), Rivea corymbosa, Ipomoea violacea (Convolvulaceae), Physostigma venenosum (Leguminosae), Rauwolfia spp. (Apocynaceae), Aspidosperma spp. (Apocynaceae), Catharanthus roseus (Apocynaceae), and Strychnos spp. (Loganiaceae). Though many alkaloids are toxic, some have pharmacological effects and are used as medications, recreational drugs, or in religious rites [30, 31]. Only N-heterocyclic alkaloids synthesized via AgBF₄ mediation are summarized here.

4.1. Pyrroles

Pyrroles are a very important class of heterocyclic compounds serving as key structural characteristic of many bioactive natural products and pharmaceutical resources [55]. Many classical reaction methods requiring the use of prefunctionalized substrates to obtain bioactive pyrrole analogues have been developed [56].

In 2010, Buscemi et al. reported the use of ligand-AgBF₄ complex to synthesis substituted pyrrole not involving prefunctionalized substrate. This reaction allows hydroarylations of ethyl 3-phenylpropanoate 46 with 1-methylpyrrole 45 to obtain the ethyl 3-(1-methyl-1H-pyrrol-2-yl)-3-phenylacrylate 48 in 70% yield. The C-H bond functionalization of an aromatic heterocycles requires the chelating dicarbene Pd (II) ligand 47 to be activated by extraction of the halides with silver additives (AgBF₄) possessing a noncoordinating anion (Scheme 7) [56].

Scheme 7: Pd carbene complex AgBF₄-mediated synthesis of compound 48.

Reports on an efficient one-pot AgBF₄-catalyzed and phenyliodine diacetate- (PIDA-) mediated synthesis of polysubstituted pyrroles, in which dimethyl but-2-ynedioate was treated with various amines (via tandem reactions), afforded corresponding pyrroles in moderate to excellent isolated yields of 53–88% [55]. By the protocol, a facile and highly efficient C-N and C-C bond formation method to construct a direct pyrrole framework (Scheme 8) as described by the proposed reaction mechanism (Scheme 9) was established.

Scheme 8: Synthesis of polysubstituted pyrroles from various alkynoates and amines.

Scheme 9: A plausible mechanism for the addition/oxidative cyclization reaction in the formation of 52.

4.2. Morphine

Morphine, the major alkaloid in opium, a dried sap of the unripe seed capsule of poppy (Papaver somniferum), is an analgesic. However, it has serious side effects such as being additive and causing nausea, decrease in blood pressure, and depressed breathing [57]. Morphine was first isolated in 1805 and its first synthesis in the laboratory was in 1952.

After three decades, a concise methodology to morphinan ring system 64 was described [58]. The reaction mechanism relies upon intramolecular trapping of an aziridinium cation generated in situ by the treatment of pyrrolidine 63 with AgBF₄. The protocol involves treatment of a solution of 63 (54 mg, 0.13 mmol) in 3 mL of toluene with AgBF₄ (56 mg, 0.29 mmol) in 2 mL of toluene, and an immediate formation of AgCl precipitate was purported to drive the reaction forward, affording the desired compound 64 (19 mg, 56%), following purification on silica gel preparative TLC (eluting with 12% MeOH/CH₂Cl₂) (Scheme 10).

Scheme 10: AgBF₄-mediated synthesis of morphinan.

4.3. Quinolines

Quinolines are made up of compounds that exhibit extensive bioactivities. According to the record of South and Liebeskind 1984, benzoquinones (methylbenzoquinone, ethylbenzoquinone) are defensive agents against predators in arthropods [59], while menaquinones play important role in blood clotting process [60], and many derivatives of natural products such as benzoquinone, naphthoquinone, and anthraquinone show significant antibiotic and/or antitumor properties [61]. It is widely recorded that polysubstituted dihydroquinolines are important building blocks in natural products, exhibiting a broad range of bioactivities (psychotropy, antiallergy, anti-inflammatory, and estrogen) and potential pharmaceutical applications [62–67].

The first example of a silver-catalyzed regioselective domino reaction between anilines and alkynes was reported to obtain partially hydrogenated quinoline moiety bearing different functional groups (polysubstituted 1,2-dihydroquinolines) [68]. The work involved treating Phenylethyne 65 (1.0 mmol) and phenylamine 66 (4.0 mmol) with AgBF₄ (9.7 mg, 0.05 mmol), HBF₄ (11.2 mg, 0.07 mmol), and BF₃·Et₂O (11.3 mg, 0.08 mmol) as cocatalysts, for 12 h at 160–190°C to yield 67 (77%) (Scheme 11). A proposed mechanism is given in Scheme 12.

Scheme 11: A silver-catalyzed efficient synthesis of 1,2-dihydroquinoline derivatives.

Scheme 12: Proposed mechanism for the synthesis of 67.

The works of Tang et al. (2010) demonstrated further ability of AgBF₄ in heteroatoms activation as well as alkyne group reactions. In the presence of AgBF₄, 2-alkynylbenzenamines and tetraalkylthiuram disulfides reacted via ammonolysis-cyclization tandem to produce quinoline thiaz-analogue 4-methylene-4H-benzo[d][1,3]thiazin-2-amines (Scheme 13) [69].

Scheme 13: Synthesis of 4-methylene-4H-benzo[d][1,3]thiazin-2-amines.

4.4. Isoquinoline

Crinine alkaloids are our focus here. They represent an important subclass (Galantamine) within the large family of Leucojum aestivum (Amaryllidaceae) alkaloids. Members of this subclass exhibit attractive biological properties including immune-stimulatory, cytotoxic, and antimalaria activities [70]. Accordingly, these natural products (e.g., maritinamine, erythramine, etc.) interests and synthetic studies have proved this since 1966 when it was first synthesised [70–83]. Cyclopropanes are ubiquitously basic structural moiety in a variety of the naturally occurring alkaloid compounds [84]. Banwell (2008) has demonstrated the use of AgBF₄ to open the strained cyclopropanes and trapped the resulting allylic cation by the carbamate nitrogen [70, 85] to synthesize maritinamine via an arylated hexahydroindole from 6,6-dichlorobicyclo[3.1.0]hexane (Scheme 14).

Scheme 14: Synthesis of epi-Maritinamine 78.

It was purported that deprotonation of gem-dihalopropane 79 with LiHMDS and subsequent reaction of the conjugate base with AgBF₄ affords a diastereoisomeric mixture of products 80 (26%) and its C-3 epimer 81 (30%) [85]; and the completion of the synthesis of erythramine 82 took three further steps as shown in Scheme 15.

Scheme 15: Synthesis of (-)-erythramine 82.

4.5. Indole

Indole ring system is a prevalent structural motif extensively present in naturally occurring compounds; and its derivatives display a broad variety of powerful and therapeutically fascinating biological activities [86]. For example, serotonin alkaloid is a bioactive alkaloid known as a neurotransmitter in the cardiovascular system, blood cells and the peripheral, and central nervous system. Psilocin and psilocybin are the main alkaloids in hallucinogenic mushrooms belonging to the genus Psilocybe [87]. In 1977, the first isolation of hallucinogenic bisindolylalkane was obtained and, subsequently, several bioactive bisindolylalkanes have been isolated from nature and this pulled a lot of scientific attention. Typically, some indole derivatives (3 substituted indoles) are known to exhibit various biological activities including antibacterial, cytotoxic, antioxidative, and insecticidal activities [88]. Following this line of thought, synthetic chemists in their pursuit for more efficient routes to synthesize the richly endowed indole molecules shifted from the common methods of preparing indole scaffold (Fischer, Bischler, Reissert, Madelung, and Smith methodologies) to organometallic reagents of which coinage metals (silver and gold) were the first choice [86].

Reports by Ko et al. (2013) established that stable bis-cyclometalated gold(III) catalysts 85 can exhibit high catalytic activity in organic synthesis via gold–silver dual catalysis for substrate activation [89]. They also supposed that silver salts can react synergistically with bis-cyclometalated gold(III) complexes in the indole alkylation. Thus, using 85 (2.5 mol%) with AgBF₄ (5.0 mol%), alkynyl alcohol 83 reacted with N-methylindole 84 to obtain the naturally occurring alkylated indole analogue (3-(tetrahydro-2-methylfuran-2-yl)-1-methyl-1H-indole) 86 in 80% isolated yield at room temperature in 2 h (Scheme 16). Poor yields (10–13%) or no product formation was found when only a single metal catalyst was used.

Scheme 16: Gold(III) complex silver-catalyzed cyclization-addition reactions of alkynyl alcohols 83 and substituted indoles 84.

Shaikh and Chen (2011) showed that carbonyl compounds 88 can be activated towards nucleophilic attack by indoles 87 with AgBF₄ to synthesise bisindolylmethanes 89 in excellent yields [88]. Thus, reaction of p-nitrobenzaldehyde and indole in the presence of AgBF₄ (10%) in methylene chloride gave a 96% yield at room temperature within 2 h (Scheme 17). The proposed mechanism is presented in Scheme 18.

Scheme 17: Synthesis of 3-substituted indole derivatives.

Scheme 18: AgBF₄-mediated synthesis of C-7 indole-substituted aminonitriles.

In the work of Grierson et al. (1992), it was discovered that condensation of allylic aminonitrile 93 and diacid 96 led to the production of 4-[bis(methoxycarbonyl)methyl]-3-(3-indolylmethyl)-1-methyl-1,4,5,6-tetrahydropyridine 97 [90]. The C-7 indole-substituted aminonitriles 93 or 95a,b, when treated with AgBF₄, yielded the desired reactive intermediate (5,6-dihydropyridinium salt 94), which on reaction with sodium dimethyl malonate 96 was converted to the 97 (76%) (Scheme 19).

Scheme 19: AgBF₄-mediated synthesis of C-7 indole-substituted aminonitriles.

Another example is AgBF₄-mediated cyclopropane ring opening and trapping of the intermediate cation in the synthesis of a diastereoisomeric mixture of Hapalindole C 100 (Scheme 20) [85].

Scheme 20: Synthesis of Hapalindole C.

Kuehne et al. (1991) recorded successful enantioselective synthesis of vinblastine [66], a natural occurring bioactive binary indole-indoline alkaloid. The compound generally has a long history of investigation and thus has been extensively reviewed since it was first synthesized in 1967 [91–94]. Here, we therefore summarize accessing the compound via the synthesis of the intermediate promoted by AgBF₄. The authors established that the reaction of the chloro-imine 101 with silver tetrafluoroborate and a natural compound, vindoline hydrofluoroborate, provided the tetracyclic C16′-C14′ parf indolenine 102 as white foam (Scheme 21) [95].

Scheme 21: Synthesis of indolenine 102.

5. Furans

Furan structural motif occurs in a variety of natural products, and the 2,3- and 3,4-substitutions are the most abundant in nature [96, 97]. Typically, 2,3-dihydrofurans are amongst the structural units ubiquitously found in natural products and they exhibit impressive biological activities. Accordingly, they are extensively used in the pharmaceuticals, as flavourant, insecticidal, and fish antifeedant industries [32]. Thus, researchers are prompted to search for better methods to synthesize or modify the natural products.

Hence, Xia et al. (2011) reported their investigation in the use of AgBF₄ to generate carbenes from diazo compounds [32]; namely, (1) several Ag(I) containing catalysts were used for the synthesis of 2,3-dihydrofurans starting from 2-diazo-5,5-dimethyl cyclohexanedione 103 and styrene 104; (2) Ag₂O, Ag₂CO₃, AgNO₃, AgClO₄, and AgOSO₂CF₃ at 70°C for 10 h gave no cycloadducts, while, with AgBF₄ (10 mol%) in toluene at room temperature for 48 h, the expected product 105 was produced in 22% yield (Scheme 22); and (3) raising the temperature to 70°C increased the yield to 47%, but, by using the ionic liquid, 1-butyl-3-methylimidazolium tetrafluoroborate ([Bmim]BF₄), as a cocatalyst, the yield was increased to 71%. The general procedure for the synthesis involves addition of silver tetrafluoroborate (0.10 mmol) and (Bmim) BF₄ (0.1 mL) to a solution of cyclic diazodicarbonyl compound 103 (1.0 mmol) and the corresponding olefin 104 (5.0 mmol) in toluene (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 24 h or at 70°C for 5 h, and the mechanism is given in Scheme 23.

Scheme 22: Synthesis of 2,3-dihydrofurans 105.

Scheme 23: Proposed reaction mechanism to afford the 2,3-dihydrofuran.

AgBF₄ has also been used to activate trimethylsilyl enols as nucleophiles in substitution reactions. In a study [96], 2,3-diiodo-1-(phenylsulfonyl)-1-propene (DIP) 109 and (cyclohex-1-enyloxy)trimethylsilane (CH-TMS) 110 were treated at 25°C in methylene chloride (0.05 M), with 2.0 equivalents of AgBF₄ to obtain iodo-(phenylsulfonyl) ketone 111. Addition of triethylamine in THF at 25°C cyclized the ketone compound to form the 2-phenylsulfonylmethyl substituted furan 112 (Scheme 24).

Scheme 24: Synthesis of substituted furans 112.

6. Organohalogen Compounds

According to Gribble (2012), the number of naturally occurring organohalogen compounds (particularly, halogenated alkaloids) has grown from a dozen in 1954 to >5000 at the time [98]. However, not many compounds containing fluorine atom(s) have been found in nature [39–100]. Nevertheless, it is widely recognised that these compounds exhibit interesting biological activities [101–106]. A typical example is kinamycin D [101], produced by Streptomyces murayamaensis (5-diazobenzo[b]fluorine), which is a naturally occurring diazo compound that possesses modest antitumor properties and antibiotic activity against Gram-positive organisms [101–105]. Again, record shows that introducing fluorine into organic molecules, more often than not, significantly improves their physical, chemical, and biological properties [106]. These reactions have been demonstrated in some compounds such as steroids. Steroids are important naturally occurring bioactive compounds. Unfortunately most of these compounds lack methods for their synthesis; and fluorination has been a gateway to access these rare compounds [107]. The report of Wang et al. (2013) and other authors expressed that arene compounds with fluorine or a trifluoromethyl substituent display unique pharmaceutical properties such as improved metabolic stability and lipophilicity. For this reason, a large number of drug candidates containing ArF and ArCF₃ are routinely evaluated in modern drug discovery [108–111]. Given that fluorinated compounds are notably sparsely available from nature, their chemical synthesis are highly challenging [112, 113]. Accordingly, fluorination of molecules has gained a prestigious position in the design and synthesis of biologically active compounds [39].

Studies by Wang et al. (2013) [108] revealed that AgBF₄ in a nonpolar solvent (such as toluene) was most effective in promoting the substrate cyclization and subsequent fluorination to afford 96% product yield. The general procedure for the stoichiometric fluorination reaction involves dissolving 113 (0.1 mmol) and AgBF₄ (0.15 mmol) in 5.0 mL of toluene under inert atmosphere, and the resulting mixture was stirred at 90°C for 2 h. Thereafter, the crude reaction mixture was filtered through a small column packed with silica gel and the required product 114 was isolated by column chromatography on silica gel (Scheme 25). A proposed reaction mechanism is shown in Scheme 26.

Scheme 25: Synthesis of compound 114.

Scheme 26: A proposed reaction mechanism for compound 108.

It was recently illustrated [107] that P₂Pt-dicationic catalysts can mediate enantioselective cation-olefin 120 cyclization/fluorination reactions of the polyenes to yield C3-fluorinated carbocycles. Their catalyst formulation is comprised of 10 mol% (S)-(xylyl-phanephos)PtI₂, 25 mol% AgBF₄, 30 mol% NCC₆F₅, and stoichiometric quantities of XeF₂ and TMSOMe, which at 0°C provided moderate to quantitative yields of 121 (49–80%) with enantiomeric excess (10–81%) and low to trace yields of 122 (22%-trace) (Scheme 27).

Scheme 27: Catalytic cyclization and C3-fluorination of polyene.

The fluoride in the can be liberated as an F⁻ nucleophile. Following this line of thought, α-fluorocarbonyl molecules 124 can be prepared via the substitution of carbonyl α-bromo substituents (Scheme 28), presumably via neighbouring group participation by the carbonyl oxygen (Scheme 29) to obtain α-fluorocarbonyl compounds [114].

Scheme 28: Synthesis of α-fluorocarbonyl compounds 124.

Scheme 29: Proposed reaction mechanism for α-fluorocarbonyl compounds.

Another example of participation in fluorination reaction via halogen-exchange is in the synthesis of trifluoromethyl sulfides [115], gem-difluorides, and trifluorides [116]. For the sulfides, the general procedure involved treatment of aprotic solution of mercaptan 126 with a base (NaH) and thereafter with CF₂Br₂ or CF₂BrCl. The resulting bromodifluoromethyl sulfide 127 was subsequently treated with AgBF₄ to obtain desired trifluoromethyl sulfide 128 in moderate yield (41%) (Scheme 30) [115].

Scheme 30: AgBF₄-mediated synthesis of trifluoromethyl sulfide.

The reaction conditions for the formation of the gem-difluorides and trifluorides involved treating respective substrate 129 or 131 with AgBF₄ (1.1 molar equiv. per halide) in CH₂Cl₂ for 1 hour at room temperature followed by workup to obtain 35–84% yields (Scheme 31). Bloodworth et al. suggested that the reactions proceeded via cationic intermediates as demonstrated by the proposed mechanism in Scheme 32 [116].

Scheme 31: Exchange-fluorination by reaction with AgBF₄.

Scheme 32: Mechanism of exchange-fluorination by reaction with AgBF₄.

In another study [117], direct electrophilic fluorination reaction of aryl silanes 138 with F-TEDA-BF₄ 139 catalyst afforded less than 4% yield. Not only did addition of AgBF₄ to the reaction system improve the yield to 11% but also regiospecific fluorination was observed. Intriguingly, Ag(I) oxide was identified as the silver salt that resulted in the highest yield of aryl fluoride (60–90%) (Scheme 33).

Scheme 33: Silver-mediated synthesis of 4-fluorobiphenyl.

In addition to the reactivities of AgBF₄ described above, an effective electrophilic trifluoromethylating reagent, being (trifluoromethyl)dibenzotellurophenium salt, was developed [39, 108]. The experimental protocol aimed to afford the salt consisting of treatment of telluride 141 with an equimolar mixture of triflic anhydride and DMSO at 0°C, followed by anion exchange with AgBF₄ [118]. Synthesized trifluoromethylated arenes 145 (53–88% yields) were obtained by reacting substituted arenes 144 with Umemoto reagents 143, Pd(OAc)₂, and Cu(OAc)₂ at 110°C in a mixture of dichloroethane (DCE) and 10 equiv. of trifluoroacetic acid (TFA) (Scheme 34) [39].

Scheme 34: Synthesis of Umemoto reagent and ortho-trifluoromethylation of heterocycle-substituted arenes.

The AgBF₄ activates alkyne moieties viaπ-complexes as exemplified in the regio- and stereoselective difunctional synthesis of (Z)-β-haloenol acetates from terminal alkynes (Scheme 35) [119]. Interestingly, reaction of phenylacetylene 146 and N-halosuccinimide in acetic anhydride in the presence of AgBF₄ at 120°C affords 60–90% yield of (Z)-β-haloenol acetate compounds 147. These vinyl halides are thus important starting materials for transition-metal-catalyzed cross coupling reactions and halogen-metal exchange reactions [120].

Scheme 35: Highly regio- and stereoselective synthesis of (Z)-β-haloenol acetates.

Reports indicate that AgBF₄ and NXS catalysed electrophilic cascade cyclization of halo-substituted benzo[a]fluorenols 149 under mild conditions (Scheme 36) [38]. Into a CH₂Cl₂ (0.5 mL) mixture of N-iodosuccinimide (0.24 mmol) and AgBF₄ (0.01 mmol) at 10°C, was added a CH₂Cl₂ (1.0 mL) solution of benzodiyne 148 (0.20 mmol) under nitrogen. After 12 h, the reaction mixture was quenched with saturated ammonium chloride solution (3 mL) and flash column chromatography (ethyl acetate/n-hexane, 1 : 50) purification afforded 149 (76%) as a light yellow solid. A plausible mechanism is depicted in Scheme 37. The fused fluorenol derivatives 149 are well known to be widely applied in optoelectronic materials because of their highly conjugated rigid systems. They are extensively found as structural moieties in numerous natural products such as kinamycin D, recognised as 5-diazobenzo[b]fluorine, a naturally occurring diazo compound that possesses antitumor properties and antibiotic activity against Gram-positive organisms [38].

Scheme 36: Synthesis of halo-substituted benzo[a]fluorenols.

Scheme 37: Mechanism for AgBF₄-catalyzed sequential electrophilic cyclization reaction.

7. Conclusions

Phytochemicals have generally been noted to exhibit important health effects such as anticancer, antimicrobial, antioxidant, antidiarrheal, analgesic, and wound healing actions to humans and animals. Accordingly, a number of AgBF₄-mediated syntheses of biologically active phytochemicals have been described over the past six years; in addition to these there are those not reviewed in the previous reviews [40–43]. Hence, herein we reviewed the bioactivity and natural occurrences of some phytochemicals synthesized through AgBF₄-promoted reactions from 1979, when Fry and Migron published its use in this regard, until April 2014.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgment

Financial support from Research and Innovation Fund (3319/4351) of the Central University of Technology, Free State is hereby acknowledged with great appreciation.

References

P. Cos, A. J. Vlietinck, D. V. Berghe, and L. Maes, “Anti-infective potential of natural products: how to develop a stronger in vitro ‘proof-of-concept’,” Journal of Ethnopharmacology, vol. 106, no. 3, pp. 290–302, 2006.

S. Sasidharan, Y. Chen, D. Saravanan, K. M. Sundram, and L. Y. Latha, “Extraction, isolation and characterization of bioactive compounds from plants' extracts,” African Journal of Traditional, Complementary and Alternative Medicines, vol. 8, no. 1, pp. 1–10, 2011.

P. F. Surai, “Natural antioxidants in poultry nutrition: new developments,” in Proceedings of the 16th European Symposium on Poultry Nutrition, World Poultry Science Association, Strasboury, France, 2007.

R. Puupponen-Pimiä, L. Nohynek, H.-L. Alakomi, and K.-M. Oksman-Caldentey, “Bioactive berry compounds—novel tools against human pathogens,” Applied Microbiology and Biotechnology, vol. 67, no. 1, pp. 8–18, 2005.

A. Samanta, G. Das, and S. K. Das, “Roles of flavonoids in plants,” International Journal of Pharmaceutical Science and Technology, vol. 6, pp. 12–35, 2011.

W. A. Peer and A. S. Murphy, The Science of Flavonoids, Springer, New York, NY, USA, 2006.

A. Fawe, M. Abou-Zaid, J. G. Menzies, and R. R. Bélanger, “Silicon-mediated accumulation of flavonoid phytoalexins in cucumber,” Phytopathology, vol. 88, no. 5, pp. 396–401, 1998.

D. J. McNally, K. V. Wurms, C. Labbé, and R. R. Bélanger, “Synthesis of C-glycosyl flavonoid phytoalexins as a site-specific response to fungal penetration in cucumber,” Physiological and Molecular Plant Pathology, vol. 63, no. 6, pp. 293–303, 2003.

H. Yamasaki, Y. Sakihama, and N. Ikehara, “Flavonoid-peroxidase reaction as a detoxification mechanism of plant cells against H₂O₂,” Plant Physiology, vol. 115, no. 4, pp. 1405–1412, 1997.

M. A. K. Jansen, R. E. van den Noort, M. Y. Adillah Tan, E. Prinsen, L. M. Lagrimini, and R. N. F. Thorneley, “Phenol-oxidizing peroxidases contribute to the protection of plants from ultraviolet radiation stress,” Plant Physiology, vol. 126, no. 3, pp. 1012–1023, 2001.

A. Michalak, “Phenolic compounds and their antioxidant activity in plants growing under heavy metal stress,” Polish Journal of Environmental Studies, vol. 15, no. 4, pp. 523–530, 2006.

S. Bagga and D. Straney, “Modulation of cAMP and phosphodiesterase activity by flavonoids which induce spore germination of Nectria haematococca MP VI (Fusarium solani),” Physiological and Molecular Plant Pathology, vol. 56, no. 2, pp. 51–61, 2000.

D. Morandi, B. Branzanti, and V. Gianinazzi-Pearson, “Effect of some plant flavonoids on in vitro behaviour of an arbuscular mycorrhizal fungus,” Agronomie, vol. 12, no. 10, pp. 811–816, 1992.

B. W. Shirley, “Flavonoids in seeds and grains: physiological function, agronomic importance and the genetics of biosynthesis,” Seed Science Research, vol. 8, no. 4, pp. 415–422, 1998.

K. S. Gould and C. Lister, “Flavonoid functions in plants,” in Flavonoids, Ø. M. Andersen and K. R. Markham, Eds., pp. 397–442, CRC Press, Boca Raton, Fla, USA, 2006.

A. Lanot and P. Morris, “Elicitation of isoflavan phytoalexins,” in Lotus Japonicus Handbook, A. J. Marquez, Ed., pp. 355–361, Springer, Amsterdam, The Netherlands, 2005.

F. D. Vergas and O. P. Lopez, Natural Colorants for Food and Nutraceutical Uses, CRC Press, New York, NY, USA, 2003.

F. Kaplan, J. Kopka, D. W. Haskell et al., “Exploring the temperature-stress metabolome of Arabidopsis,” Plant Physiology, vol. 136, no. 4, pp. 4159–4168, 2004.

I. Hernández, L. Alegre, and S. Munné-Bosch, “Drought-induced changes in flavonoids and other low molecular weight antioxidants in Cistus clusii grown under Mediterranean field conditions,” Tree Physiology, vol. 24, no. 11, pp. 1303–1311, 2004.

T. Iwashina, “Flavonoid function and activity to plants and other organisms,” Biological Sciences in Space, vol. 17, no. 1, pp. 24–44, 2003.

A. P. Mamolos and K. L. Kalburtji, “Significance of allelopathy in crop rotation,” in Allelopathy in Agroecosystems, pp. 197–218, Food Products Press, Binghamton, NY, USA, 2001.

S. O. Duke, “The emergence of grass root chemical ecology,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 43, pp. 16729–16730, 2007.

M. C. Achilonu, Novel synthetic approaches toward procyanidins and bioflavonoids [Ph.D. thesis], University of the Free State, Bloemfontein, South Africa, 2009.

V. Křen and L. Martínkové, “Glycosides in medicine: the role of glycosidic residue in biological activity,” Current Medicinal Chemistry, vol. 8, no. 11, pp. 1303–1328, 2001.

C. Spanou, G. Bourou, A. Dervishi et al., “Antioxidant and chemopreventive properties of polyphenols compounds derived from Greek legume plant extracts,” Journal of Agricultural and Food Chemistry, vol. 56, no. 16, pp. 6967–6976, 2008.

J. C. Mathers, “Pulses and carcinogenesis: potential for the prevention of colon, breast and other cancers,” British Journal of Nutrition, vol. 88, no. 3, pp. S273–S279, 2002.

L. H. Kushi, K. A. Meyer, and D. R. Jacobs Jr., “Cereals, legumes, and chronic disease risk reduction: evidence from epidemiologic studies,” The American Journal of Clinical Nutrition, vol. 70, no. 3, pp. 451–458, 1999.

C. Spanou, A. S. Veskoukis, T. Kerasioti et al., “Flavonoid glycosides isolated from unique legume plant extracts as novel inhibitors of xanthine oxidase,” PLoS ONE, vol. 7, no. 3, Article ID e32214, 2012.

W. C. Evans, “Pharmacopoeial and related drugs of biological origin. Alkaloids,” in Trease and Evans' Pharmacognosy, G. E. Trease and W. C. Evans, Eds., WB Saunders, London, UK, 14th edition, 1996.

G. C. L. Ee, C. M. Lim, M. Rahmani, K. Shaari, and C. F. J. Bong, “Pellitorine, a potential anti-cancer lead compound against HL60 and MCT-7 cell lines and microbial transformation of piperine from Piper nigrum,” Molecules, vol. 15, no. 4, pp. 2398–2404, 2010.

T. M. Godlaski, “Gods of drugs: the God within,” Substance Use and Misuse, vol. 46, no. 10, pp. 1217–1222, 2011.

L. Xia, Y. R. Lee, S. H. Kim, and W. S. Lyoo, “AgBF₄/[Bmim]BF₄-Catalyzed [3+2] cycloaddition of cyclic diazodicarbonyl compounds: efficient synthesis of 2,3-dihydrofurans and conversion to 3-acylfurans,” Bulletin of the Korean Chemical Society, vol. 32, no. 5, pp. 1554–1558, 2011.

F. M. Dean, “Recent advances in furan chemistry,” in Advances in Heterocyclic Chemistry, A. R. Katritzky, Ed., vol. 30, pp. 167–238, Academic Press, New York, NY, USA, 1982.

F. M. Dean and M. V. Sargent, Comprehensive Heterocyclic Chemistry, vol. 4 of edited by: C. W. Bird, G. W. H. Cheeseman, part 3, Pergamon, New York, NY, USA, 1984.

K. Nakanishi, Natural Products Chemistry, Kodansha, Tokyo, Japan, 1974.

G. Vernin and G. M. F. Vernin, “Heterocyclic aroma compounds in foods: occurrence and organoleptic properties,” in Chemistry of Heterocyclic Flavoring and Aroma Compounds, G. Vernin and C. Párkányi, Eds., pp. 72–150, Ellis Horwood, Chichester, UK, 1982.

G. Schulte, P. J. Scheuer, and O. J. McConnell, “Two furanosesquiterpene marine metabolites with antifeedant properties,” Helvetica Chimica Acta, vol. 63, no. 8, pp. 2159–2167, 1980.

Z. Chen, M. Zeng, J. Yuan, Q. Yang, and Y. Peng, “Novel silver tetrafluoroborate catalyzed electrophilic cascade cyclization reaction: a facile approach to the synthesis of halo-substituted benzo[a]fluorenols,” Organic Letters, vol. 14, no. 14, pp. 3588–3591, 2012.

N. Shibata, A. Matsnev, and D. Cahard, “Shelf-stable electrophilic trifluoromethylating reagents: a brief historical perspective,” Beilstein Journal of Organic Chemistry, vol. 6, no. 65, 19 pages, 2010.

M. Álvarez-Corral, M. Muñoz-Dorado, and I. Rodríguez-García, “Silver-mediated synthesis of heterocycles,” Chemical Reviews, vol. 108, no. 8, pp. 3174–3198, 2008.

Z. Li and C. He, “Recent advances in silver-catalyzed nitrene, carbene, and silylene-transfer reactions,” European Journal of Organic Chemistry, vol. 2006, no. 19, pp. 4313–4322, 2006.

J.-M. Weibel, A. Blanc, and P. Pale, “Ag-mediated reactions: coupling and heterocyclization reactions,” Chemical Reviews, vol. 108, no. 8, pp. 3149–3173, 2008.

P. Belmont, “Silver-catalyzed cycloisomerization reactions,” in Silver in Organic Chemistry, M. Harmata, Ed., pp. 143–165, John Wiley & Sons, Hoboken, NJ, USA, 2010.

G. Abbiati and E. Rossi, “Silver and gold-catalyzed multicomponent reactions,” Beilstein Journal of Organic Chemistry, vol. 10, pp. 481–513, 2014.

J. Zeng, Y. Bai, S. Cai, J. Ma, and X.-W. Liu, “Direct synthesis of pyrroles via a silver-promoted three-component reaction involving unusual imidazole ring opening,” Chemical Communications, vol. 47, no. 48, pp. 12855–12857, 2011.

L. J. Porter, The Flavonoids: Advances in Research Since 1986, edited by J. B. Harborne, Chapman & Hall, London, UK, 1994.

B. Tanwar and R. Modgil, “Flavonoids: dietary occurrence and health benefits,” Spatula DD, vol. 2, no. 1, pp. 59–68, 2012.

J. W. T. Selway, “Antiviral activity of flavones and flavans,” in Plant Flavonoids in Biology and Medicine: Biochemical, Pharmacological and Structure Activity Relationships, V. Cody, E. Middleton, and J. B. Harborne, Eds., pp. 521–536, Alan R. Liss, New York, NY, USA, 1986.

P. J. Steynberg, R. J. J. Nel, H. Van Rensburg, B. C. B. Bezuidenhoudt, and D. Ferreira, “Oligomeric flavanoids. Part 27. Interflavanyl bond formation in procyanidins under neutral conditions,” Tetrahedron, vol. 54, no. 28, pp. 8153–8158, 1998.

A. P. Kozikowski, W. Tückmantel, G. Böttcher, and L. J. Romanczyk Jr., “Studies in polyphenol chemistry and bioactivity. 4. Synthesis of trimeric, tetrameric, pentameric, and higher oligomeric epicatechin-derived procyanidins having all-4β,8-interflavan connectivity and their inhibition of cancer cell growth through cell cycle arrest,” The Journal of Organic Chemistry, vol. 68, no. 5, pp. 1641–1658, 2003.

L. Bennie, E. Malan, J. Coetzee, and D. Ferreira, “Structure and synthesis of ether-linked proteracacinidin and promelacacinidin proanthocyanidins from Acacia caffra,” Phytochemistry, vol. 53, no. 7, pp. 785–793, 2000.

M. C. Achilonu, S. L. Bonnet, and J. H. van der Westhuizen, “Synthesis of proanthocyanidins. Part 1. The first oxidative formation of the interflavanyl bond in procyanidins,” Organic Letters, vol. 10, no. 17, pp. 3865–3868, 2008.

P. Pornsuriyasak and A. V. Demchenko, “S-thiazolinyl (STaz) glycosides as versatile building blocks for convergent selective, chemoselective, and orthogonal oligosaccharide synthesis,” Chemistry, vol. 12, no. 25, pp. 6630–6646, 2006.

S. Kaeothip, P. Pornsuriyasak, and A. V. Demchenko, “Silver(I) tetrafluoroborate as a potent promoter for chemical glycosylation,” Tetrahedron Letters, vol. 49, no. 9, pp. 1542–1545, 2008.

W. Liu, H. Jiang, and L. Huang, “One-pot silver-catalyzed and PIDA-mediated sequential reactions: synthesis of polysubstituted pyrroles directly from alkynoates and amines,” Organic Letters, vol. 12, no. 2, pp. 312–315, 2010.

G. Buscemi, A. Biffis, C. Tubaro, M. Basato, C. Graiff, and A. Tiripicchio, “C-H bond functionalization of aromatic heterocycles with chelating dicarbene palladium (II) and platinum (II) complexes,” Applied Organometallic Chemistry, vol. 24, no. 4, pp. 285–290, 2010.

H. Hart, L. E. Craine, and D. J. Hart, Organic Chemistry: A Short Course, Houghton Mifflin Company, Boston, Mass, USA, 1999.

C. A. Broka and J. F. Gerlits, “Aziridinium cation mediated cyclizations. New routes to the morphinan ring system,” Journal of Organic Chemistry, vol. 53, no. 10, pp. 2144–2150, 1988.

R. A. Morton, Biochemistry of Quinones, Academic Press, New York, NY, USA, 1965.

R. H. Thomson, Naturally Occurring Quinones, Academic Press, New York, NY, USA, 2nd edition, 1971.

J. S. Driscoll, G. F. Hazard Jr., H. B. Wood Jr., and A. Goldin, “Structure-antitumor activity relationships among quinone derivatives,” Cancer Chemotherapy Reports. Part 2, vol. 4, no. 2, pp. 1–362, 1974.

M. Ramesh, P. S. Mohan, and P. Shanmugam, “A convenient synthesis of flindersine, atanine and their analogues,” Tetrahedron, vol. 40, no. 20, pp. 4041–4049, 1984.

K. M. Witherup, R. W. Ransom, S. L. Varga, S. M. Pitzenberger, V. J. Lotti, and W. J. Lumma, “Pyrroloquinoline bradykinin antagonist,” US Patent 5,288,725, 1994

N. B. Perry, J. W. Blunt, J. D. McCombs, and M. H. Munro, “Discorhabdin C, a highly cytotoxic pigment from a sponge of the genus Latrunculia,” Journal of Organic Chemistry, vol. 51, no. 26, pp. 5476–5478, 1986.

N. M. Williamson, D. R. March, and A. D. Ward, “An improved synthesis of 2,2-disubstituted-1,2-dihydroquinolines and their conversion to 3-chloro-2,2-disubstituted-tetrahydroquinolines,” Tetrahedron Letters, vol. 36, no. 42, pp. 7721–7724, 1995.

N. Yamada, S. Kadowaki, K. Takahashi, and K. Umezu, “MY-1250, a major metabolite of the anti-allergic drug repirinast, induces phosphorylation of a 78-kDa protein in rat mast cells,” Biochemical Pharmacology, vol. 44, no. 6, pp. 1211–1213, 1992.

K. Faber, H. Stuckler, and T. Kappe, “Non-steroidal antiinflammatory agents. 1. Synthesis of 4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl alkanoic acids by the wittig reaction of quinisatines,” Journal of Heterocyclic Chemistry, vol. 21, no. 4, pp. 1177–1181, 1984.

Y. Luo, Z. Li, and C.-J. Li, “A silver-catalyzed domino route toward 1,2-dihydroquinoline derivatives from simple anilines and alkynes,” Organic Letters, vol. 7, no. 13, pp. 2675–2678, 2005.

R.-Y. Tang, P.-S. Luo, X.-G. Zhang, P. Zhong, and J.-H. Li, “Silver-catalyzed tandem ammonolysis-cyclization of 2-alkynylbenzenamines with tetraalkylthiuram disulfides to 4-methylene-4 h -benzo[d][1,3]thiazin-2-amines,” Synlett, no. 9, pp. 1345–1350, 2010.

M. G. Banwell, J. E. Harvey, and K. A. Jolliffe, “π-Allyl cation cyclisations initiated by electrocyclic ring-opening of gem-dihalocyclopropanes: application to the first total syntheses of the crinine-type alkaloids maritinamine and epi-maritinamine,” Journal of the Chemical Society, Perkin Transactions 1, no. 17, pp. 2002–2005, 2001.

M. A. Schwartz and R. A. Holton, “Intramolecular oxidative phenol coupling. II. Biogenetic-type synthesis of (+-)-maritidine,” Journal of the American Chemical Society, vol. 92, no. 4, pp. 1090–1092, 1970.

H. Irie, S. Uyeo, and A. Yoshitake, “The total synthesis of dihydrocrinine and related compounds,” Journal of the Chemical Society C: Organic, vol. 14, pp. 1802–1804, 1968.

H. Muxfeldt, R. S. Schneider, and J. B. Mooberry, “A total synthesis of (±)-crinine,” Journal of the American Chemical Society, vol. 88, no. 15, pp. 3670–3671, 1966.

H. W. Whitlock Jr. and G. L. Smith, “Total synthesis of dl-crinine,” Journal of the American Chemical Society, vol. 89, no. 14, pp. 3600–3606, 1967.

R. V. Stevens, “General methods of alkaloid synthesis,” Accounts of Chemical Research, vol. 10, no. 6, pp. 193–198, 1977.

J. B. P. A. Wijnberg and W. N. Speckamp, “Total syntheses of dl-mesembrine, dl-dihydromaritidine and dl-epi-dihydromaritidine via regioselective NaBH₄/H⁺ reduction of imides,” Tetrahedron, vol. 34, no. 16, pp. 2579–2586, 1978.

G. E. Keck and R. R. Webb II, “Alkaloid synthesis via intramolecular ene reaction. 2. Application to dl-mesembrine and dl-dihydromaritidine,” Journal of Organic Chemistry, vol. 47, no. 7, pp. 1302–1309, 1982.

I. H. Sánchez, F. J. López, H. J. Flores, and M. I. Larraza, “Novel conformational effects of the N-benzyloxycarbonyl-cis-3a-aryl-octahydroindole nucleus. Formal total synthesis of racemic elwesine and epielwesine,” Heterocycles, vol. 20, no. 2, pp. 247–254, 1983.

S. F. Martin and C. L. Campbell, “Total syntheses of (±)-crinine and (±)-buphanisine,” Journal of Organic Chemistry, vol. 53, no. 14, pp. 3184–3190, 1988.

J. P. Michael, A. S. Howard, R. B. Katz, and M. I. Zwane, “Formal syntheses of (±)-mesembrine and (±)-dihydromaritidine,” Tetrahedron Letters, vol. 33, no. 40, pp. 6023–6024, 1992.

R. M. Burk and L. E. Overman, “Total synthesis of the Amaryllidaceae alkaloid (±)-epielwesine. The importance of vinylsilane stereochemistry in iminium ion-vinylsilane cyclizations,” Heterocycles, vol. 35, no. 1, pp. 205–225, 1993.

W. H. Pearson and F. E. Lovering, “Assembly of 3α-arylperhydroindoles by the intramolecularcycloaddition of 2-azaallyl anions with alkenes. Total syntheses of (±)-crinine, (±)-6-epicrinine, (−)-amabiline, and (−)-augustamine,” Journal of Organic Chemistry, vol. 63, no. 11, pp. 3607–3617, 1998.

A. Padwa, M. A. Brodney, M. Dimitroff, B. Liu, and T. Wu, “Application of furanyl carbamate cycloadditions toward the synthesis of hexahydroindolinone alkaloids,” Journal of Organic Chemistry, vol. 66, no. 9, pp. 3119–3128, 2001.

Y. R. Lee and J. H. Choi, “Rh₂(Opiv)4-catalyzed reactions of diazo compound derived from Meldrum's acid and styrenes. Efficient synthesis of cyclopropanes,” Bulletin of the Korean Chemical Society, vol. 27, no. 4, pp. 503–507, 2006.

M. G. Banwell, “New processes for the synthesis of biologically relevant heterocycles,” Pure and Applied Chemistry, vol. 80, no. 4, pp. 669–679, 2008.

P. A. Suryavanshi, V. Sridharan, and J. C. Menéndez, “Expedient, one-pot preparation of fused indoles via CAN-catalyzed three-component domino sequences and their transformation into polyheterocyclic compounds containing pyrrolo[1,2-a]azepine fragments,” Organic & Biomolecular Chemistry, vol. 8, no. 15, pp. 3426–3436, 2010.

T. Aniszewski, “Alkaloids—secrets of life,” in Alkaloid Chemistry, Biological Significance, Applications and Ecological Role, p. 112, Elsevier, Amsterdam, The Netherlands, 2007.

A. C. Shaikh and C. Chen, “An easy and efficient synthesis of bisindolylmethanes and tetraindolylmethane Tröger's base catatlyzed by AgBF₄,” Journal of the Chinese Chemical Society, vol. 58, no. 7, pp. 899–905, 2011.

H.-M. Ko, K. K.-Y. Kung, J.-F. Cui, and M.-K. Wong, “Bis-cyclometallated gold(III) complexes as efficient catalysts for synthesis of propargylamines and alkylated indoles,” Chemical Communications, vol. 49, no. 78, pp. 8869–8871, 2013.

D. S. Grierson, J.-L. Bettiol, I. Buck, H.-P. Husson, M. Rubiralta, and A. Diez, “Synthesis of 20-deethylsilicine from a second-generation 2-cyano--piperidine synthon,” Journal of Organic Chemistry, vol. 57, no. 24, pp. 6414–6421, 1992.

M. E. Kuehne and I. Marko, The Alkaloids, vol. 37 of edited by: A. Brossi, M. Suffness, Academic Press, New York, NY, USA, 1990.

A. U. Basha, A. Basha, and M. Ghazala, “Synthetic studies of anti-leukaemic alkaloids. VII the partial synthesis of vinblastine,” Tetrahedron Letters, vol. 17, pp. 2351–2354, 1976.

G. A. Cordell, Heterocyclic Compounds: The Monoterpenoid Indole Alkaloids, vol. 25, John Wiley & Sons, New York, NY, USA, 1983, edited by J. E. Saxton.

M. Lounasmaa and A. Nemes, “The synthesis of bis-indole alkaloids and their derivatives,” Tetrahedron, vol. 38, no. 2, pp. 223–243, 1982.

M. E. Kuehne, P. A. Matson, and W. G. Bornmann, “Enantioselective syntheses of vinblastine, leurosidine, vincovaline, and -epi-vincovaline,” Journal of Organic Chemistry, vol. 56, no. 2, pp. 513–528, 1991.

A. Padwa and M. Ishida, “Silver tetrafluoroborate induced reaction of trimethylsilyl enol ethers with 2,3-diiodo-1-(phenylsulfonyl)-1-propene as a method for preparing substituted furans,” Tetrahedron Letters, vol. 32, no. 41, pp. 5673–5676, 1991.

W. H. Lewis and M. P. F. Elvin-Lewis, Medical Botany, John Wiley & Sons, New York, NY, USA, 1977.

G. W. Gribble, “Occurence of halogenated alkaloids,” The Alkaloids: Chemistry and Biology, vol. 71, pp. 1–165, 2012.

T. Yamazaki, T. Taguchi, and I. Ojima, “Introduction: basic aspects of fluorine in chemistry and biology,” in Fluorine in Medicinal Chemistry and Chemical Biology, I. Ojima, Ed., pp. 1–47, Wiley-Blackwell, London, UK, 2009.

P. Kirsch, Modern Fluoroorganic Chemistry, Wiley-VCH, Weinheim, Germany, 2004.

S. J. Gould, C. R. Melville, M. C. Cone, J. Chen, and J. R. Carney, “Kinamycin biosynthesis. Synthesis, isolation, and incorporation of stealthin C, an aminobenzo[b]fluorene,” Journal of Organic Chemistry, vol. 62, no. 2, pp. 320–324, 1997.

S. J. Gould, N. Tamayo, C. R. Melville, and M. C. Cone, “Revised structures for the kinamycin antibiotics: 5-diazobenzo[b]fluorenes rather than benzo[b]carbazole cyanamides,” Journal of the American Chemical Society, vol. 116, no. 5, pp. 2207–2208, 1994.

S. Mithani, G. Weeratunga, N. J. Taylor, and G. I. Dmitrienko, “The kinamycins are diazofluorenes and not cyanocarbazoles,” Journal of the American Chemical Society, vol. 116, no. 5, pp. 2209–2210, 1994.

S. Omura, A. Nakagawa, H. Yamada, T. Hata, A. Furusaki, and T. Watanabe, “Structures and biological properties of kinamycin A, B, C, and D,” Chemical and Pharmaceutical Bulletin, vol. 21, no. 5, pp. 931–940, 1973.

A. Furusaki, M. Matsui, T. Watanabé, S. Ōmura, A. Nakagawa, and T. Hata, “The crystal and molecular structure of kinamycin C-p-bromo-benzoate,” Israel Journal of Chemistry, vol. 10, no. 2, pp. 173–187, 1972.

J.-P. Bégué and D. Bonnet-Delpon, Bioorganic and Medicinal Chemistry of Fluorine, John Wiley & Sons, Hoboken, NJ, USA, 2008.

N. A. Cochrane, H. Nguyen, and M. R. Gagne, “Catalytic enantioselective cyclization and C3-fluorination of polyenes,” Journal of the American Chemical Society, vol. 135, no. 2, pp. 628–631, 2013.

K.-P. Wang, S. Y. Yun, P. Mamidipalli, and D. Lee, “Silver-mediated fluorination, trifluoromethylation, and trifluoromethylthiolation of arynes,” Chemical Science, vol. 4, no. 8, pp. 3205–3211, 2013.

K. Müller, C. Faeh, and F. Diederich, “Fluorine in pharmaceuticals: looking beyond intuition,” Science, vol. 317, no. 5846, pp. 1881–1886, 2007.

H.-J. Böhm, D. Banner, S. Bendels et al., “Fluorine in medicinal chemistry,” ChemBioChem, vol. 5, no. 5, pp. 637–643, 2004.

C. Isanbor and D. O'Hagan, “Fluorine in medicinal chemistry: a review of anti-cancer agents,” Journal of Fluorine Chemistry, vol. 127, no. 3, pp. 303–319, 2006.

D. O'Hagan and D. B. Harper, “The fluorinated natural products,” Natural Product Reports, vol. 11, no. 2, pp. 123–133, 1994.

C. D. Murphy, C. Schaffrath, and D. O'Hagan, “Fluorinated natural products: the biosynthesis of fluoroacetate and 4-fluorothreonine in Streptomyces cattleya,” Chemosphere, vol. 52, no. 2, pp. 455–461, 2003.

A. J. Fry and Y. Migron, “A convenient new synthesis of α-fluorocarbonyl compounds,” Tetrahedron Letters, vol. 20, no. 36, pp. 3357–3360, 1979.

M. Suda and C. Hino, “Preparation of bromodifluoromethyl sulfide and its conversion to trifluoromethyl sulfide,” Tetrahedron Letters, vol. 22, no. 21, pp. 1997–2000, 1981.

A. J. Bloodworth, K. J. Bowyer, and J. C. Mitchell, “A mild, convenient, halogen-exchange route to gem-difluorides and trifluorides,” Tetrahedron Letters, vol. 28, no. 44, pp. 5347–5350, 1987.

P. Tang and T. Ritter, “Silver-mediated fluorination of aryl silanes,” Tetrahedron, vol. 67, no. 24, pp. 4449–4454, 2011.

T. Umemoto and S. Ishihara, “Power-variable electrophilic trifluoromethylating agents. S-, Se-, and Te-(trifluoromethyl)dibenzothio-, -seleno-, and -tellurophenium salt system,” Journal of the American Chemical Society, vol. 115, no. 6, pp. 2156–2164, 1993.

Z. Chen, J. Li, H. Jiang, S. Zhu, Y. Li, and C. Qi, “Silver-catalyzed difunctionalization of terminal alkynes: highly regio- and stereoselective synthesis of (Z)-β-Haloenol acetates,” Organic Letters, vol. 12, no. 14, pp. 3262–3265, 2010.

X. Chen, D. Chen, Z. Lu, L. Kong, and G. Zhu, “Palladium-catalyzed coupling of haloalkynes with allyl acetate: a regio- and stereoselective synthesis of (Z)-β-haloenol acetates,” Journal of Organic Chemistry, vol. 76, no. 15, pp. 6338–6343, 2011.