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

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. AgBF 4 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.


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 C 6 -C 3 -C 6 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][10][11] and stimulants for germination of spores [12][13][14][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].
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].
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.AgBF 4 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 AgBF 4 -promoted reactions thus revealed two reviewed papers published in 2008, covering silver-mediated reactions, including the AgBF 4 -mediated reactions [40][41][42][43].Abbiati and Rossi in their review [44] referred to the use of AgBF 4 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 AgBF 4 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 AgBF 4 -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 AgBF 4 -mediated reactions based on published information on AgBF 4 -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.

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 AgBF 4 towards oxygen and sulfur is exploited to enhance capabilities of the leaving group [49][50][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 4benzylsulfanylepicatechin 15 and catechin 16 in THF with AgBF 4 (2.5 equiv.)for 1 h at 0 ∘ C to obtain procyanidin B-1 in 38% yield (Scheme 1) [49].
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 AgBF 4 at 0 ∘ C yielded the procyanidin oligomers (20, 21, and 22), as presented in Scheme 2 [50].
The AgBF 4 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 3oxo-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].The requirement of an excess of AgBF 4 and the observation of a silver mirror (reduction of Ag 1 to Ag 0 ) may indicate an oxidative mechanism (Scheme 5) [53].
The BF 4 − 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.

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(1 → 2)-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 AgBF 4 activation but later readily activated when N-iodosuccinimide (NIS) was added, followed by addition of new acceptor, methoxy glycoside 43.

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 .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 AgBF 4 mediation are summarized here.

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].
Reports on an efficient one-pot AgBF 4 -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.PIDA (1.2 equiv.) Scheme 8: Synthesis of polysubstituted pyrroles from various alkynoates and amines.
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 AgBF 4 .The protocol involves treatment of a solution of 63 (54 mg, 0.13 mmol) in 3 mL of toluene with AgBF 4 (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/CH 2 Cl 2 ) (Scheme 10).
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]
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 biscyclometalated 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 ).Poor yields (10-13%) or no product formation was found when only a single metal catalyst was used.Shaikh and Chen (2011) showed that carbonyl compounds 88 can be activated towards nucleophilic attack by indoles 87 with AgBF 4 to synthesise bisindolylmethanes 89 in excellent yields [88].Thus, reaction of p-nitrobenzaldehyde and indole in the presence of AgBF 4 (10%) in methylene chloride gave a 96% yield at room temperature within 2 h (Scheme 17).The proposed mechanism is presented in Scheme 18.
Another example is AgBF 4 -mediated cyclopropane ring opening and trapping of the intermediate cation in the synthesis of a diastereoisomeric mixture of Hapalindole C 100 (Scheme 20) [85].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][92][93][94].
Here, we therefore summarize accessing the compound via the synthesis of the intermediate promoted by AgBF 4 .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].

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.

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 .Nevertheless, it is widely recognised that these compounds exhibit interesting biological activities [101][102][103][104][105][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][102][103][104][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 ArCF 3 are routinely evaluated in modern drug discovery [108][109][110][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 AgBF 4 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 AgBF 4 (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.
Another example of BF 4 − 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 CF 2 Br 2 or CF 2 BrCl.The resulting bromodifluoromethyl sulfide 127 was subsequently treated with AgBF 4 to obtain desired trifluoromethyl sulfide 128 in moderate yield (41%) (Scheme 30) [115].
The reaction conditions for the formation of the gemdifluorides and trifluorides involved treating respective substrate 129 or 131 with AgBF 4 (1.1 molar equiv.per halide)   in CH 2 Cl 2 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].
Reports indicate that AgBF 4 and NXS catalysed electrophilic cascade cyclization of halo-substituted benzo[a]fluorenols 149 under mild conditions (Scheme 36) [38].Into a CH 2 Cl 2 (0.5 mL) mixture of N-iodosuccinimide (0.24 mmol) and AgBF 4 (0.01 mmol) at 10 ∘ C, was added a CH 2 Cl 2 (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].

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 AgBF 4mediated 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][41][42][43].Hence, herein we reviewed the bioactivity and natural occurrences of some phytochemicals synthesized through AgBF 4 -promoted reactions from 1979, when Fry and Migron published its use in this regard, until April 2014.

Figure 1 :
Figure 1: Base structure and subgroups of flavonoids.

Scheme 5 :
Scheme 5: Proposed mechanism for oxidative synthesis of 30 and 31 based on the model reaction.
Scheme 26: A proposed reaction mechanism for compound 108.
Scheme 12: Proposed mechanism for the synthesis of 67.
••Scheme 9: A plausible mechanism for the addition/oxidative cyclization reaction in the formation of 52.