The chemistry of tryptanthrin and its derivatives

Tryptanthrin (indolo[2,1-b ]quinazoline-6,12-dione) is a natural product which shows significant biological activity as an antibacterial, antiparasitic, and antineoplastic agent. Historically, tryptanthrin has been found as a component of many dyes as well as a constituent of medicinal herbal treatments. This review describes the synthesis of tryptanthrin and some related compounds which also have a quinazoline ring fused to an indolo moiety as a core.


Introduction
The natural product tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione, Figure 1) is a weakly basic alkaloid.This bright yellow compound consists of a quinazoline ring fused to an indole moiety with carbonyl groups in the 6-and 12-positions.The name tryptanthrin is derived from the observation that this compound is produced by the yeast Candida lipolytica when grown in L-tryptophan-containing medium. 1 Occasionally the alternative spelling tryptanthrine is used to describe this compound.Chemical Abstracts appear to index both spellings.

Figure 1
This review describes the synthesis of compounds with a tryptanthrin core and selected reactions of this class of compounds. 2Tryptanthrin and its derivatives are of particular interest due to their biological activities.Tryptanthrin compounds have been shown to possess antibacterial 3 , antiparasitic 4 , and antineoplastic 5,6 properties.Extensive work has been put forth to elucidate the usefulness of tryptanthrin derivatives as dyes and pigments and as photoelectric materials. 7,8The physicochemical properties of tryptanthrin compounds deposited onto surfaces have also been investigated. 9n 1892 O'Neil described the formation of "silky golden-yellow crystals" that form upon oxidation of indigo with potassium permanganate. 10,11In 1915 Friedländer and Roschdestwensky were able to elucidate the structure of tryptanthrin, 12 which was verified 60 years later by X-ray crystallography. 13ryptanthrin has been isolated from numerous natural sources.In particular, tryptanthrin is found in plant material traditionally used as colorants including Chinese woad (Isatis tinctoria), 14,15 Japanese indigo (Polygonum tinctorium), 14,16 Assam indigo (Strobilanthes cusia), 17 Indigo naturalis (Strobilanthes formosanus), 18 and dyer's oleander (Wrightia tinctoria). 19Furthermore tryptanthrin has also been isolated from the fruits of the cannonball tree (Couroupita guaianensis), 20,21 the orchids Phaius mishmensis 22 and Calanthe discolor, 23 and the fungi Schizophyllum commune and Leucopaxillus cerealis, 24,25 and a strain of the bacterial Cytophaga genus. 26Tryptanthrin has also been found in mammals, specifically in the urine of the Asian elephant (Elephas maximus) 27 and the wing sac liquids of the bat Saccopteryx bilineata. 28everal compounds have been observed in nature with an indolo[2,1-b]quinazoline core in which the keto group in 6-position has been replaced with a different functional group (Figure 2).
In particular the orchid Phaius mishmensis was reported to be a rich source of such compounds. 22ryptanthrin derivatives 2-7 have all been isolated from this plant.Candidine (qingdainone, 6) a tryptanthrin based compound substituted with an additional indolo ring at the 6-position, has also been found in the Chinese herbal medicine qing dai, 29 Chinese woad 30 and in the fruits of the cannonball tree. 20,21In humans, uremic patients appear to form candidine (6) in very small amounts since this compound has been isolated from blood plasma, urine and haemofiltrate of such individuals. 31Bergman et al. have reported that 6 is also a minor product that is formed together with tryptanthrin upon digestion of L-tryptophan by the yeast Candida lipolytica. 32ethylisatoid (7) is the only 12-position modified tryptanthrin compound observed in nature. 22ryptanthrin compounds bearing substituents on the aromatic rings appear to be scarce in nature.Only a few examples have been observed, including phaitanthrin C (8) also isolated from Phaius mishmensis 22 and ophiuroidine, (9) found in the brittle star Ophiocoma riisei.

Construction of the quinazoline system
One common approach for the synthesis of tryptanthrin is the construction of the quinazoline system as the final key step.The starting materials for these procedures are derivatives of anthranilic acid (10) in particular isatoic anhydride, which reacts with compounds containing an indole core (11)in particular isatin or oxindole (Scheme 1).During the cyclization, bond formation occurs between N-5 and C-5a as well as N-11 and C-12

Scheme 2
Numerous reaction conditions have been developed to accomplish this transformation.The experimentally simplest methods involve heating 12 and 13 in a solvent such as toluene in the presence of triethylamine or pyridine. 6,21Alternative reactions conditions involve DBU/DMAP or an inorganic base such as a sodium hydride/DMF [37][38][39][40] or sodium hydroxide/dioxane. 41A solvent-free protocol under microwave conditions in the presence of potassium carbonate has also been reported. 42xcess isatoic anhydride has been found useful to catalyze the synthesis by scavenging any developing water. 426]44 Interestingly, in the presence of -cyclodextrin this procedure also works using water as a solvent. 43ormation of tryptanthrin also occurs during the oxidation of indigo (14), which can be explained by the presence of isatoic anhydride (12) and isatin (13) in the reaction mixture.A more recent example of indigo oxidation to tryptanthrin using ozone as the oxidant is shown in Scheme 3. 46 Under the reaction conditions the central double bond (C2-C2′-bond) of indigo ( 14) is cleaved to form isatin (13) as a primary oxidation product.Some isatin will then undergo further oxidation resulting in isatoic anhydride (12).Finally, condensation of these two oxidation products yielded tryptanthrin.The yields of tryptanthrin as an indigo oxidation byproduct are generally low. 46,47

Scheme 3
Several alternative means of synthesis have been developed that do not require isatoic anhydride.Recently, Jahng et al. described a one-pot synthesis of tryptanthrin using anthranilic acid (15, Scheme 4) as starting material. 48In this method 15 reacts with thionyl chloride to form a thio-analog of isatoic anhydride (16), which then condenses with isatin (13) to form tryptanthrin in excellent yield.

Scheme 4
Eguchi et al. investigated the preparation of tryptanthrin from 2-azidobenzoyl chloride (17)  with an intramolecular aza-Wittig reaction as the key step (Scheme 5). 49In this one-pot procedure 17 was reacted with isatin (13) to give the corresponding amide 18, which in the presence tributylphosphine formed the iminophosphorane (19).Subsequent cyclization gave tryptanthrin in 43% yield.

Scheme 5
Bergman et al. 36 approached the synthesis of tryptanthrin by using chloroindoleninone compound 20 as the indole core component (Scheme 6).For this procedure isatin (13) was treated with phosphoryl chloride to form 20. 50 Further reaction of 20 with anthranilamide (21)  produced tryptanthrin in excellent yield.

Scheme 6
Moskovkina developed a similar technique. 51However, after chloroindoline (20) had been formed, instead of adding an anthranilic acid derivative such as compound 21 excess of isatin (13) was used as its equivalent.In this modification compound 20 was generated in situ and condensed with the isatin.This procedure has been used to synthesize a perdeuterated derivative of tryptanthrin (Scheme 7). 52

Scheme 7
Dimerization of isatin has also been achieved electrochemically 53 , by radiation with laser light 54 or in the presence of an oxidizing agent such as potassium permanganate. 29The yields of these reactions are generally low.Closely related is the oxidative dimerization of 3-indole compounds.During the oxidation of the 5-bromo-3-acetoxyindole (25) with oxone the 2,8dibromo derivative of tryptanthrin (26) was observed as a minor product (Scheme 8). 55

Scheme 8
In a different approach tryptanthrin was prepared by the reaction of 2-aminobenzaldehyde (27) with O-methylisatin (28) resulting in the formation of dihydro tryptanthrin analog (29) in excellent yield (Scheme 9). 56Oxidation of 29 with CrO3 at room temperature gave tryptanthrin.
An alternative procedure for the synthesis of tryptanthrin was developed by Jahng et al. and used oxindole hydrochloride (30) and methyl anthranilate as starting materials (Scheme 10). 57pon treatment with phosphoryl chloride these two compound reacted to form the key intermediate 32.Further conversion of the 32 lead to the 6-benzylidene derivative 34, which was subjected to ozonolysis to give tryptanthrin.The key intermediate 32 is also known predominantly to yield tryptanthrin upon exposure to air. 56,58,59cheme 9

Scheme 11
Akazome et al. used a slightly different approach to accomplish the cyclization step of the above sequence to produce tryptanthrin.Intermediate 37 was treated with a catalytic amount of triruthenium dodecacarbonyl (Ru3(CO)12) in a carbon monoxide atmosphere under vigorous conditions (140C, 40 kg/cm -2 (~39 atm) CO pressure, 16h). 45The yield (46%) for this transition metal catalyzed procedure was significantly lower than that reported by Kikumoto et al.
Zeide and Chelintsev 61 have reported a two step procedure that produced tryptanthrin in 62% overall yield (Scheme 12).This sequence significantly differs from any other approach outlined above because it does not involve isatin or oxindole precursors.The first step in this sequence involved a nucleophilic substitution of the 2-chloro-group in 2-chloroquinoline (38) by the amino group of anthranilic acid (15).An overall loss of water lead to the intermediate (39).In the second step of the reaction sequence, potassium permanganate induced an oxidative ring contraction to give tryptanthrin.

Construction of the indole system
Only a few synthetic approaches for tryptanthrin center on the bond formation within the indole system.All subsequent procedures involve the synthesis of a 3-arylquinazoline-4(3H)-one derivative, which is then cyclized to give the indolo[2,1-b]quinazoline moiety.
Potewar et al. initiated a two-step synthesis of tryptanthrin by preparation of the quinazolinone compound (41, Scheme 13), 62 which was achieved by the condensation of anthranilic acid (15) with methyl anthranilate (32) in the presence of triethyl orthoformate (40).Deprotonation of 41 with LDA led to the intermediary anion 42 which then cyclized to give tryptanthrin in 54% over two steps.

Scheme 13
Lygin and de Meijere have offered a one-pot variant of the preceding approach (Scheme 14) and used isocyanide 43 as the starting material. 63Lithiation of 43 followed by addition of isocyanate 44 gave the same intermediary anion 42 as above, which formed tryptanthrin in a yield greater than 80%.

Scheme 14
Bowman et al. used a different method with a related starting material for the cyclization step. 64In their approach the carboxylic acid 45 was converted into the phenylselenium compound 46, which was then subjected to ultraviolet light leading to the acyl radical 47.
Although the yield is poor, this may be one of the first examples of a 5-exo acyl radical cyclization onto a heterocycle.

Scheme 15
Staskun and Wolfe described a protocol that is based on the observation that the 2-methyl group in 48 (Scheme 16) is sufficiently acidic to be deprotonated with sodium amide. 59Both 2chloro and 3-chloro derivatives reacted to give 32.In situ air oxidation of this intermediate produced tryptanthrin in approximately 80% yield.Since the yield was independent of the position (2-or 3-) of the chlorine substituent the authors proposed the formation of the benzyne intermediate 49 as a possible mechanistic step for this reaction.

Scheme 17
The nitration of tryptanthrin has been shown to occur stepwise with the 8-position of tryptanthrin being more reactive than the 2-position. 6At 0 C, the addition of one equivalent of nitric acid selectively forms only 8-nitrotryptanthrin (51).

Scheme 18
3.1.2.Nucleophilic aromatic substitution.The substitution of amino groups onto the aromatic rings has been investigated by Baker and Mitscher (Scheme 19). 65The synthesis of a series of piperazine substituted tryptanthrin compounds has been achieved by nucleophilic aromatic substitution.These reactions have been found to be regioselective -halogens at the 8-or 10position do not undergo substitution.As indicated above compound 32 has been observed to be unstable in the presence of air and is easily oxidized back to tryptanthrin.

Scheme 21
Treatment of tryptanthrin with hypophosphorous acid resulted in a reductive dimerization to yield compound 57 (Scheme 22). 5857 readily underwent dehydrogenation to yield the violet dimer 58.

Scheme 22
Reduction of tryptanthrin with lithium aluminum hydride led to compound 59 (Scheme 23), which was characterized as the diacetyl ester 60. 58 The structure of 60 has been confirmed by Xray crystallography.Alternatively, partial oxidation of 59 by manganese dioxide led to compound 61. 68Scheme 23 3.2.3Oxidation.Tryptanthrin and its ring substituted derivatives appear to be stable towards chemical oxidation agents including potassium permanganate 10,29,61 , chromium trioxide 56 , oxone 55 and ozone. 46Ring oxidation has been observed in many biological systems and Lee et al. concluded that 8-hydroxytryptanthrin (62, Scheme 24)along with an unidentified dihydroxy tryptanthrin derivativeis a phase I metabolite of tryptanthrin in an in vitro rat liver model. 38Scheme 24 3.2.4.Reactions with nitrogen nucleophiles.Tryptanthrin and its substituted derivatives react with nitrogen nucleophiles including hydrazines, hydroxyl amine and alkoxy amines to give the corresponding 6-hydrazones 7, 40, 60, 66 and 6-oximes. 6In particular 6-oximes and 6-imines have received particular attention due to their biological properties.Suitably substituted 6-oxime esters and ethers of tryptanthrin have been shown to increase bioavailability.The oxime ether 64 has been shown to possess a bioavailability of 76% at a 20 mg/kg dose in mice. 6

Scheme 25
The single step synthesis of 6-aryl imines from the corresponding tryptanthrin compounds has been reported with low to moderate yields. 7An alternative procedure involves the reaction of isatin-3-imine compounds including isatin imine 65 and isatoic anhydride (15) in the presence of a catalytic amount of KF-Al2O3 under microwave conditions as shown in Scheme 26. 69Scheme 26 3.2.5 Reactions with CH-acidic compounds.Racemic phaitanthrin A (4) was obtained from tryptanthrin by treatment with acetone in the presence of diethylamine (Scheme 27). 22Acetone serves both as solvent and as a reactant.If acetone is replaced by 2-decanone, the reaction adds selectively at the 1-methyl group.The cyclopentanone substituted derivative was found to be unstable.

Scheme 27
When a suspension of tryptanthrin (1) in acetone is treated with hydrazine the azine 67 is obtained (Scheme 28) 70 .When crystallized this compound adopts Z-configuration.

Scheme 28
Guentner et al. investigated a series of tryptanthrin derivatives as potential dyes and pigments. 7Their work included the preparation of tryptanthrin derivatives with extended πsystems.In the reaction of tryptanthrin with 1,4-diacetylpiperazine-2,5-dione (68, Scheme 29)  the bridged dimer of tryptanthrin (69) was isolated in excellent yield.

Scheme 30
The synthesis of candidine ( 6) can be achieved by treatment of tryptanthrin with indoxyl acetate (70, Scheme 30).Under the reaction conditions shown a mild hydrolysis occurs. 32For this synthesis N,O-diacetylindoxyl has also been used. 29Reaction with oxindole gave to candidine isomeric compound 71. 32ryptanthrin reacts with malonitrile to form dicyanomethylene derivative 72. 32,34,42 Tis derivative has been also obtained in one-pot microwave reaction. 42

Scheme 31
Grandolini et al. showed that tryptanthrin undergoes a Darzens reaction to yield compound 73 (Scheme 32). 40Nucleophilic ring opening then the resulted in the chlorohydrin 74.Scheme 32 3.2.6Reactions with Grignard reagents.Tryptanthrin and 8-bromotryptanthrin (75) add Grignard reagents to the 6-carbonyl group in moderate yields. 71Thus the reaction of 75 with methylmagnesium bromide led to the tertiary alcohol 76 as the only product in 64% yield (Scheme 33).