Regiospecific Bromination Research Articles

Production of Tyrian purple indigoid dye from tryptophan in Escherichia coli.

Tyrian purple, mainly composed of 6,6'-dibromoindigo (6BrIG), is an ancient dye extracted from sea snails and was recently demonstrated as a biocompatible semiconductor material. However, its synthesis remains limited due to uncharacterized biosynthetic pathways and the difficulty of regiospecific bromination. Here, we introduce an effective 6BrIG production strategy in Escherichia coli using tryptophan 6-halogenase SttH, tryptophanase TnaA and flavin-containing monooxygenase MaFMO. Since tryptophan halogenases are expressed in highly insoluble forms in E. coli, a flavin reductase (Fre) that regenerates FADH2 for the halogenase reaction was used as an N-terminal soluble tag of SttH. A consecutive two-cell reaction system was designed to overproduce regiospecifically brominated precursors of 6BrIG by spatiotemporal separation of bromination and bromotryptophan degradation. These approaches led to 315.0 mg l-1 6BrIG production from tryptophan and successful synthesis of regiospecifically dihalogenated indigos. Furthermore, it was demonstrated that 6BrIG overproducing cells can be directly used as a bacterial dye.

Concise syntheses and some biological activities of dl-2,5-di-O-methyl-chiro-inositol, dl-1,4-di-O-methyl-scyllo-inositol, and dl-1,6-dibromo-1,6-dideoxy-2,5-di-O-methyl-chiro-inositol.

The regio- and stereospecific synthesis of O-methyl-chiro-inositols and O-methyl-scyllo-inositol was achieved, starting from p-benzoquinone. After preparing dimethoxy conduritol-B as a key compound, regiospecific bromination of the alkene moiety of dimethoxy conduritol-B and acid-catalyzed ring opening of dimethoxydiacetate conduritol-B epoxide with Ac2 O afforded the desired new chiro-inositol derivatives and scyllo-inositol derivative, respectively. Spectroscopic methods were employed for the characterization of all synthesized compounds. The novel inositols (11-17) had effective inhibition profiles against human carbonic anhydrase isoenzymes I and II (hCA I and II) and acetylcholinesterase (AChE). The novel inositols 11-17 were found to be effective inhibitors against AChE, hCA I, and hCA II enzymes. Ki values were calculated in the range of 87.59 ± 7.011 to 237.95 ± 17.75 μM for hCA I, 65.08 ± 12.39 to 538.98 ± 61.26 μM for hCA II, and 193.28 ± 43.13 to 765.08 ± 209.77 μM for AChE, respectively. Also, due to the inhibitory effects of the novel inositols 11-17 against the tested enzymes, these novel inositols are potential drug candidates to treat some diseases such as glaucoma, epilepsy, leukemia, and Alzheimer's disease.

Regio- and stereospecific synthesis of dl-4,5-dibromo-4,5-dideoxy-3,6-O-methyl-chiro-inositol

The regio- and stereospecific synthesis of dl-4,5-dibromo-4,5-dideoxy-3,6-O-methyl-chiro-inositol is reported. Bromination of p-benzoquinone followed by reduction of the carbonyl groups with NaBH4 gave the corresponding trans-dibromodiol compound, which was reacted with sodium methoxide to produce dimethoxy conduritol-B. Regiospecific bromination of the alkene moiety furnished the desired chiro-inositol derivative.

Photon Funnels for One‐Way Energy Transfer: Multimetallic Assemblies Incorporating Cyclometallated Iridium or Rhodium Units Accessed by Sequential Cross‐Coupling and Bromination

The generation of multimetallic assemblies is a widely explored theme, owing to the relevance of controlling energy and electron transfer between metal centres to many fields of contemporary importance. Boronic acid substituted coordination and organometallic complexes have been shown to be useful synthons in the formation of such structures through cross‐coupling with halogenated complexes. In this work we used such a methodology to generate an octanuclear mixed‐metal compound of composition Ir7Ru having a dendrimer wedge‐like structure. The method combined cross‐coupling with regiospecific bromination of phenylpyridine (ppy) ligands at the position para to the C–Ir bond. The propensity of Ir(ppy)2‐based complexes to electrophilic bromination was found to be deactivated by the introduction of fluorine atoms. The coupling methodology was extended to rhodium‐containing systems, exemplified by a tetranuclear system of composition Rh2Ir1Ru1. The synthesis required the use of boronic acid appended RhIII complexes, which could be accessed by the introduction of a neopentyl boronate ester appended bipyridine into the coordination sphere of RhIII. The excited‐state energies of the constituent metal units in the resulting multinuclear complexes are such that unidirectional energy transfer occurs from the RhIII/IrIII branches to the RuII core. The luminescence thus resembles that of an isolated [Ru(bpy)3]2+ unit, but the ability of the structure to collect light is greatly enhanced.

Contributions of BrCl, Br2, BrOCl, Br2O, and HOBr to regiospecific bromination rates of anisole and bromoanisoles in aqueous solution.

When bromide-containing waters are chlorinated, conventional wisdom typically assumes HOBr is the only active brominating agent. Several additional and often-overlooked brominating agents (including BrCl, Br2, BrOCl, Br2O) can form in chlorinated waters, albeit at generally lower concentrations than HOBr. The extent to which these additional brominating agents influence bromination rates of disinfection byproduct precursors is, however, poorly understood. Herein, the influence of BrCl, Br2, BrOCl, Br2O, and HOBr toward rates of sequential bromination of anisole was quantified. Conditions affecting bromine speciation (e.g., pH, concentrations of chloride, bromide, and chlorine) were varied, and regiospecific second-order rate constants were calculated for reactions of each brominating agent with anisole, 2-bromoanisole, and 4-bromoanisole. The regioselectivity of anisole bromination changed with pH, consistent with the participation of more than one brominating agent. Under conditions representative of chlorinated drinking water, contributions to bromination rates decreased as BrCl > BrOCl > HOBr > Br2O (Br2 negligible). The second-order rate constant determined for net bromination of anisole by HOBr is up to 3000-times less than reported in previous studies (which assumed HOBr was the only active brominating agent). Accordingly, models that assume HOBr is the only kinetically relevant brominating agent in solutions of free bromine may be insufficient for reactions involving modestly nucleophilic organic compounds.

Environmentally-Benign and Rapid Bromination of Industrially-Important Aromatics Using an Aqueous CaBr2−Br2System as an Instant and Renewable Brominating Reagent

Selective bromination of various industrially and pharmaceutically important substituted aromatics using an aqueous CaBr2−Br2 system as an instant and renewable brominating reagent is disclosed. The direct bromination of anilines and phenols with molecular bromine in solution often results in polybromination, and when brominated in the presence of oxidants, they also get oxidized rather than undergoing substitution and, in some cases, require protection of the amino (−NH2) group. We report instantaneous, facile, and regiospecific bromination of industrially important substituted anilines, phenols, aldehydes, and anilides in excellent yields and purity under ambient conditions. The byproduct HBr waste has been utilized effectively, and the brominating reagent has been rejuvenated and reused in the subsequent brominations without any significant loss of reactivity.

Regiospecific Bromination of 2-Phenyl-3H-pyrimidin-4-ones

Three methods for the regiospecific bromination of 2-pnenyl-3H-pyrimidin-4-ones are presented: bromination or the 5-position of the pyrimidine ring, bromination of the 6-benzylic position and simultaneous bromination of both the 5-position of the pyrimidine ring and 6-benzylic position. Reactions were carried out using simple protocols and the brominated pyrimidines were obtained in good yields.

Synthesis and Fate of o-Carboxybenzophenones in the Biosynthesis of Aflatoxin

o-Carboxybenzophenones have long been postulated to be intermediates in the oxidative rearrangement of anthraquinone natural products to xanthones in vivo. Many of these Baeyer-Villiger-like cleavages are believed to be carried out by cytochrome P450 enzymes. In the biosynthesis of the fungal carcinogen, aflatoxin, six cytochromes P450 are encoded by the biosynthetic gene cluster. One of these, AflN, is known to be involved in the conversion of the anthraquinone versicolorin A (3) to the xanthone demethylsterigmatocystin (5) en route to the mycotoxin. An aryl deoxygenation, however, also takes place in this overall transformation and is proposed to be due to the requirement that an NADPH-dependent oxidoreductase, AflM, be active for this process to take place. What is known about other fungal anthraquinone --> xanthone conversions is reviewed, notably, the role of the o-carboxybenzophenone sulochrin (25) in geodin (26) biosynthesis. On the basis of mutagenesis experiments in the aflatoxin pathway and these biochemical precedents, total syntheses of a tetrahydroxy-o-carboxybenzophenone bearing a fused tetrahydrobisfuran and its 15-deoxy homologue are described. The key steps of the syntheses entail rearrangement of a 1,2-disubstituted alkene bearing an electron-rich benzene ring under Kikuchi conditions to give the 2-aryl aldehyde 43 followed by silyltriflate closure to a differentially protected dihydrobenzofuran 44. Regiospecific bromination, conversion to the substituted benzoic acid, and condensation with an o-bromobenzyl alcohol gave esters 47 and 50. The latter could be rearranged with strong base, oxidized, and deprotected to the desired o-carboxybenzophenones. These potential biosynthetic intermediates were examined in whole-cell and ground-cell experiments for their ability to support aflatoxin formation in the blocked mutant DIS-1, defective in its ability to synthesize the first intermediate in the pathway, norsolorinic acid. Against expectation, neither of these compounds was converted into aflatoxin under conditions where the anthraquinones versicolorin A and B readily afforded aflatoxins B1 and B2. This outcome is evaluated further in a companion paper appearing later in this journal.

General Facile Synthesis of 2,5‐Diarylheteropentalenes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

General facile synthesis of 2,5-diarylheteropentalenes

Palladium-catalyzed cross-coupling reactions of various heteropentalene derivatives were systematically studied. A general three-step synthesis of 2,5-diarylheteropentalenes involving two Suzuki or Negishi couplings and a regiospecific bromination was developed. Nonsymmetrical 2,5-diaryl-furans, thiophenes, pyrroles, 1,3-thiazoles, 1,3-oxazoles, 1,3,4-thiadiazoles, and 1,3,4-oxadiazoles were prepared in 31–67% isolated yield (three steps).

The Synthesis and X-ray Crystal Structure of 6-Bromo-2,4,4-Trimethyl-Cyclohex-2-Enone

Regiospecific bromination of 2,4,4-trimethyl-cyclohex-2-enone was achieved and the X-ray crystal structure of 6-bromo-2,4,4-trimethyl-cyclohex-2-enone is presented.

A concise synthesis of topsentin A and nortopsentins B and D.

[reaction: see text] A concise synthesis of topsentin A (R(1) = R(2) = H) and nortopsentins B (R(1) = Br, R(2) = H) and D (R(1) = R(2) = H) is described from oxotryptamine 5 via reduction of acyl cyanide 4. Regiospecific bromination of 3-cyanoindole afforded 6-bromo-3-cyanoindole (10) as the major product.

ChemInform Abstract: Environment Friendly Regiospecific Bromination of Aromatic Ethers by N‐Bromosuccinimide in Presence of Montmorillonite.

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Synthesis of Novel Polysiloxanes Containing Charge Transporting and Second-Order Nonlinear Optical Functionalities with Atom Economical Constructs

Novel, highly functionalized polysiloxanes were prepared in which each repeat unit bears, on average, one charge transporting and one to two second-order nonlinear optical chromophores. Covalent attachment of charge-transporting carbazole or diphenylamine derivatives was realized through efficient Pt-catalyzed hydrosilylation. Poly(hydrogen methylsiloxane) was reacted with 9-(2-propenyl)carbazole or (N-phenyl-N-2-propenylamino)benzene, affording poly[methyl-3-(9-carbazolyl)propylsiloxane] and poly[methyl-3-(N,N-diphenylamino)propylsiloxane], respectively. Rather remarkable regiospecific bromination of the two arylamine-containing siloxane polymers was achieved using benzyltrimethylammonium chlorobromate, resulting in the formation of poly[methyl-3-(N(3,6-dibromocarbazolyl))propylsiloxane] and poly[methyl-3-(N,N-bis(4-bromophenyl)amino)propylsiloxane]. Pd-catalyzed Heck-type coupling of the arylbromide-bearing polysiloxanes with either vinylbenzenephosphonic acid diethyl ester or 4-nitrostyrene afforded st...

ChemInform Abstract: Regiospecific Bromination of 3‐Methylindoles with NBS and Its Application to the Concise Synthesis of Optically Active Unusual Tryptophans Present in Marine Cyclic Peptides.

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Process Development of a Novel Anti-Inflammatory Agent. The Regiospecific Bromination of 4‘-Acetylmethanesulfonanilide

An efficient, practical synthesis of a novel antiinflammatory agent (FK3311, 1) which is acceptable environmentally and could be used for pilot plant manufacture is described. Regiospecific bromination of 4‘-acetylmethanesulfonanilide, allowing selective side chain or nuclear halogenation, also has been investigated. Development efforts focused on the optimized Ullmann coupling reaction conditions and the isolation and purification of 1 to give satisfactory quality product (99.8% purity) according to the new and concise synthetic route.

Regio-selective bromination of multiflorine and structures of 3-bromomultiflorine and its molecular complex with succinimide

The regio-specific bromination of multiflorine, an alkaloid isolated from Lupinus albus is described. The bromomultiflorine and its molecular complex with succinimide have been characterized by IR and NMR spectroscopy, as well as by X-ray diffraction. The conformation in solution and in the solid state has been determined. The molecular complex formation between 3-bromomultiflorine and succinimide molecules is the first case in the class of lupine alkaloids. Both molecules of this complex are held together by an intermolecular hydrogen bond NH⋯N which leads to a conversion of alkaloid nitrogen atom configuration. As a consequence, ring C adopts a chair conformation, whereas it is in a boat form in 3-bromomultiflorine.

Enantiospecific Synthesis of Optically Active 6-Methoxytryptophan Derivatives and Total Synthesis of Tryprostatin A1

A concise preparation of optically active l or d-6-methoxytryptophan ethyl ester 21 was developed via the Fischer indole/Schöllkopf protocol from 6-methoxy-3-methylindole 16 (four steps, 58% overall yield). This method was extended to the enantiospecific total synthesis of tryprostatin A (11) via a regiospecific bromination process as a key step. In addition, 6-methoxy-2-bromotryptophan ethyl ester (32), a potential intermediate for indole alkaloid synthesis, was prepared via this strategy.

Regiospecific Bromination of 3-Methylindoles with NBS and Its Application to the Concise Synthesis of Optically Active Unusual Tryptophans Present in Marine Cyclic Peptides(1).

A regiospecific bromination of substituted 3-methylindoles at either the C(3) alkyl moiety or the C(2) position was achieved via a free radical bromination or electrophilic process, respectively. The regiospecificity of the bromination could be controlled by variation of both the substituent and the N(1) protecting group on the indole ring. In addition, enantiospecific syntheses of 5-methoxytryptophan (20) and 5-hydroxy-6-chlorotryptophan (21c) as well as concise syntheses of optically active 2-bromotryptophan ethyl esters 26a,b or their substituted derivatives in three steps from bifunctional dibromoindoles were achieved via the above regiospecific process.

Enantiospecific total synthesis of tryprostatin A

The 3-methyl-6-methoxyindole 3 was converted into tryprostatin A ( 1) via a regiospecific bromination process coupled with the Schöllkopf chiral auxillary 7 to provide the 2-bromo-6-methoxy-tryptophan 8a as a key intermediate.