One Substrate – Seven Products with Different Prenylation Positions in One‐Step Reactions: Prenyltransferases Make it Possible

Prenylated indole alkaloids derived from L ‐tryptophan are widely distributed in nature and show diverse biological and pharmacological activities, usually distinct from their non‐prenylated precursors. Prenyltransferases catalyze the transfer reactions of prenyl moieties onto the indole nucleus and contribute largely to the structural diversity of these compounds. In this study, we demonstrate the acceptance of cyclo‐L ‐homotryptophan‐D ‐valine, an unnatural cyclic dipeptide, by eight prenyltransferases of the dimethylallyltryptophan synthase superfamily. Seven products with one prenyl moiety at each position of the indole nucleus and one diprenylated derivative were isolated from enzyme assays of cyclo‐L ‐homotryptophan‐D ‐valine with dimethylallyl diphosphate. To the best of our knowledge, this is the first report for production of seven monoprenylated products from one substrate by one‐step reactions.

     

Highly Efficient Molybdenum(II)‐Catalyzed Intramolecular Allylic Alkylation of Arenes

The Friedel–Crafts‐type intramolecular allylic alkylation of simple arenes is performed in the presence of a catalytic amount of [Mo(II) (CO)₄Br₂]₂ (2.5 mol%). The moisture‐tolerant protocol provided a mild and direct access to a large library of functionalized 4‐vinyl‐1,2,3,4‐tetrahydronaphthalenes in high yields.     

Site‐Selective Iron(III) Chloride‐Catalyzed Arylation of 4‐Aryl‐4‐methoxy‐2,5‐cyclohexadienones for the Synthesis of Polyarylated Phenols

The iron(III) chloride‐catalyzed Friedel–Crafts arylation of 4‐aryl‐4‐methoxy‐2,5‐cyclohexadienones, which were easily prepared by the phenyliodine(III) diacetate (PIDA)‐mediated oxidation of 4‐arylphenols in methanol, proceeded site‐selectively to form meta‐terphenyl (2,4‐diarylphenol) derivatives in good yields. The subsequent PIDA‐mediated oxidation and iron(III) chloride‐catalyzed Friedel–Crafts arylation of the resulting products gave the corresponding 2,4,6‐triarylphenol derivatives. The present method provides useful highly substituted polyarylated compounds.

     

Novel Enantiocomplementary C2‐Symmetric Chiral Bis(imidazoline) Ligands: Highly Enantioselective Friedel–Crafts Alkylation of Indoles with Ethyl 3,3,3‐Trifluoropyruvate

Enantioselective Friedel–Crafts alkylations of a variety of indoles with ethyl 3,3,3‐trifluoropyruvate catalyzed by novel chiral m‐phenylenebis(imidazoline)‐copper(II) complexes or the bis(imidazoline)‐achiral acid combination afforded products with high enantioselectivity. Both enantiomers of indole derivatives can be prepared with high enantioselectivities by tuning the N‐substituents of the imidazoline.     

Iron‐Catalyzed Regio‐ and Stereoselective Conjugate Addition of Aryl‐Grignard Reagents to α,β,γ,δ‐Unsaturated Sulfones and its Synthetic Application

The iron‐catalyzed δ‐addition of aryl‐Grignard reagents to α,β,γ,δ‐unsaturated sulfones proceeded in a regio‐ and stereoselective manner to give cis‐4‐aryl‐2‐alkenyl sulfones. Allylic alkylation of the resultant products was performed without isomerization of the cis‐olefin to give cis‐4‐aryl‐1,1‐dialkyl‐2‐alkenyl sulfones, which upon intramolecular Friedel–Crafts reaction with aluminum chloride gave 1,4‐dihydronaphthalenes having a quaternary carbon center.     

Development of Diphenylamine‐Linked Bis(imidazoline) Ligands and Their Application in Asymmetric Friedel–Crafts Alkylation of Indole Derivatives with Nitroalkenes

The new diphenylamine‐linked bis(imidazoline) ligands were prepared through Kelly‐You’s imidazoline formation procedure mediated by Hendrickson’s reagent in good yields. The novel ligands were tested in the asymmetric Friedel–Crafts alkylation of indole derivatives with nitroalkenes. In most cases, good yields (up to 97%) and excellent enantioselectivities (up to 98%) can be achieved. The optimized bis(imidazoline) ligand with trans‐diphenyl substitution on the imidazoline ring gave better enantioselectivity than the corresponding bis(oxazoline) ligand.     

Solid Acid‐Catalysed Michael‐Type Conjugate Addition of Indoles to Electron‐Poor CC Bonds: Towards High Atom Economical Semicontinuous Processes

In this paper a novel application of solid acid catalysts in the chemoselective Friedel–Crafts (FC) alkylation of indoles is reported. The optimal protocol allows highly functionalised indolyl compounds to be synthesised in excellent yields through conjugate addition of indoles with α,β‐unsaturated ketones and nitro compounds. Finally, the use of commercial Amberlyst‐15 as the heterogeneous catalyst for highly atom efficient continuous and semicontinuous Friedel–Crafts processes is described.     

Enantioselective Construction of Cyclic Indolyl α‐Amino Esters via a Friedel–Crafts Alkylation Reaction

An enantioselective Friedel–Crafts alkylation reaction of indoles with cyclic N‐sulfonyl ketimino esters was developed. Under the optimized conditions using a chiral copper(II) triflate‐bisoxazoline complex as the catalyst, a range of N‐sulfonyl ketimino ester derivatives and indoles reacted smoothly to afford indole‐containing chiral cyclic α‐amino esters bearing tetrasubstituted α‐stereogenic centers [3‐ethoxycarbonyl‐3‐(3‐indolyl)‐2,3‐dihydrobenzo[d]isothiazole 1,1‐dioxides] in excellent yields and with high enantioselectivities (up to 99% ee). Pyrrole and N,N‐dimethylaniline were also investigated as aromatic substrates to afford the corresponding products with good results. An asymmetric induction model was then proposed on the basis of the observed absolute configuration of the product 3‐ethoxycarbonyl‐3‐(5‐bromo‐3‐indolyl)‐2,3‐dihydrobenzo[d]isothiazole 1,1‐dioxide. Synthetic transformations to convert the products into cyclic chiral N‐sulfonamido alcohols and the deprotection of the sulfonamides were performed. This study provides an efficient approach to chiral α‐tetrasubstituted indolic α‐amino acids as potential building blocks for peptides and biologically active molecules.

     

Gold‐Catalyzed Intermolecular Reactions of (Z)‐Enynols with Indoles for the Construction of Dihydrocyclohepta[b]indole Skeletons through a Cascade Friedel–Crafts/Hydroarylation Sequence

An efficient domino approach for the synthesis of indole‐fused carbocycles and their analogues from the reactions of suitably substituted (Z)‐enynols with indoles or pyrroles under mild reaction conditions was developed. This methodology is realized by a tandem reaction using Au/Ag catalysts, which could catalyze both of the Friedel–Crafts and the hydroarylation reaction in the same vessel.     

Synthesis of (all‐rac)‐α‐Tocopherol Using Fluorinated NH‐Acidic Catalysts

The synthesis of (all‐rac)‐α‐tocopherol starting from trimethylhydroquinone and isophytol using fluorinated NH‐acidic catalysts is described. Scope and limitations of this type of catalysts are discussed. Advantages of this new procedure are high yield and selectivity, no waste problem and mild reaction conditions. Best results in the synthesis of (all‐rac)‐α‐tocopherol (94% yield) using NH‐acidic compounds are obtained in polar solvents. The used catalyst could be recovered.     

Asymmetric Friedel–Crafts Reaction of Indoles with Ethyl Trifluoropyruvate Using a Copper(I)‐Bisoxazolidine Catalyst

Bisoxazolidine 1 is an effective ligand in the copper(I)‐catalyzed Friedel–Crafts reaction of alkyl trifluoropyruvates and indoles. A range of ethyl 2‐(3′‐indolyl)‐3,3,3‐trifluoro‐2‐hydroxypropanoates was produced in up to 99% yield and 94% ee within 30 min to 4 h. The effect of temperature on conversion and enantioselectivity proved to be substrate specific and was optimized individually. Of particular interest is that this method tolerates the presence of substituents in various positions in the indole ring. Yields ranging from 90–97% and ee values between 90 and 94% were obtained at optimized temperatures with substrates carrying substituents in position 1 or 7.     

Enzymatic Redox Cascade for One‐Pot Synthesis of Uridine 5′‐Diphosphate Xylose from Uridine 5′‐Diphosphate Glucose

Synthetic ways towards uridine 5′‐diphosphate (UDP)‐xylose are scarce and not well established, although this compound plays an important role in the glycobiology of various organisms and cell types. We show here how UDP‐glucose 6‐dehydrogenase (hUGDH) and UDP‐xylose synthase 1 (hUXS) from Homo sapiens can be used for the efficient production of pure UDP‐α‐xylose from UDP‐glucose. In a mimic of the natural biosynthetic route, UDP‐glucose is converted to UDP‐glucuronic acid by hUGDH, followed by subsequent formation of UDP‐xylose by hUXS. The nicotinamide adenine dinucleotide (NAD⁺) required in the hUGDH reaction is continuously regenerated in a three‐step chemo‐enzymatic cascade. In the first step, reduced NAD⁺ (NADH) is recycled by xylose reductase from Candida tenuis via reduction of 9,10‐phenanthrenequinone (PQ). Radical chemical re‐oxidation of this mediator in the second step reduces molecular oxygen to hydrogen peroxide (H₂O₂) that is cleaved by bovine liver catalase in the last step. A comprehensive analysis of the coupled chemo‐enzymatic reactions revealed pronounced inhibition of hUGDH by NADH and UDP‐xylose as well as an adequate oxygen supply for PQ re‐oxidation as major bottlenecks of effective performance of the overall multi‐step reaction system. Net oxidation of UDP‐glucose to UDP‐xylose by hydrogen peroxide (H₂O₂) could thus be achieved when using an in situ oxygen supply through periodic external feed of H₂O₂ during the reaction. Engineering of the interrelated reaction parameters finally enabled production of 19.5 mM (10.5 g L ⁻¹) UDP‐α‐xylose. After two‐step chromatographic purification the compound was obtained in high purity (>98%) and good overall yield (46%). The results provide a strong case for application of multi‐step redox cascades in the synthesis of nucleotide sugar products.

     

Development of Fe‐, Sb‐, Bi‐ and Al‐impregnated silica catalysts using rice husk silica as a support for Friedel–Crafts benzylation of arenes

The milling by‐product of rice, rice husk, constitutes a major waste of the agricultural industry. It is mainly used as a fuel additive for various purposes, leaving behind residual ash which is rich in silica (Biogenic silica). In the present project, rice husk silica was impregnated with Fe³⁺, Sb³⁺, Bi³⁺ and Al³⁺ from both their aqueous and organic solutions. The resultant catalysts were activated at 120 °C and 550 °C and used for the Friedel–Crafts benzylation of benzene using benzyl chloride. Copyright © 2003 Society of Chemical Industry     

Efficient Synthesis of 9‐Tosylaminofluorene Derivatives by Boron Trifluoride Etherate‐Catalyzed Aza‐Friedel–Crafts Reaction of in situ Generated N‐Tosylbenzaldimines

An efficient and expeditious boron trifluoride etherate (BF₃⋅Et₂O) catalyzed one‐pot reaction for the synthesis of N‐tosyl‐9‐aminofluorenes and anthracene derivatives from in situ generated N‐tosylbenzaldimines via an aza‐Friedal–Crafts reaction has been developed. The catalytic reaction shows high substrate tolerance with excellent yields.     

Geranylation of Cyclic Dipeptides by the Dimethylallyl Transferase AnaPT Resulting in a Shift of Prenylation Position on the Indole Ring

The dimethylallyl transferase AnaPT from Neosartorya fischeri is involved in the biosynthesis of acetylaszonalenin and catalyses the regioselective and stereospecific C3α‐prenylation of (R)‐benzodiazepinedione in the presence of dimethylallyl diphosphate. This enzyme also converts several tryptophan‐containing cyclic dipeptides to C3α‐prenylated indolines. In this study, we demonstrate the geranylation of (R)‐benzodiazepinedione and five other cyclic dipeptides by AnaPT in the presence of geranyl diphosphate (GPP). Interestingly, structure elucidation by NMR and MS analyses revealed that, with GPP, the geranyl moiety is attached to C‐6 or C‐7 rather than C‐3 of the indole ring of the enzyme products. For (R)‐benzodiazepinedione, one dominant C6‐geranylated derivative was obtained, whereas the other five substrates yielded both C6‐ and C7‐geranylated products. Neither acceptance of GPP by a dimethylallyl transferase from the dimethylallyltryptophan synthase superfamily, nor the alkylation shift from C‐3 to the benzene ring of the indole nucleus has been reported previously.     

One‐Pot Assembly of Highly Functionalized Cyclopenta[b]pyrroles via a Calcium(II)‐ and Copper(II)‐Catalyzed Reaction Sequence

A user‐friendly, calcium(II)‐ and copper(II)‐catalyzed one‐pot reaction sequence to furnish cyclopenta[b ]pyrroles with a high level of complexity is depicted. The reaction involves the following sequential transformations: (i) an aza‐Piancatelli cyclization, (ii) a hydroamination/isomerization process and (iii) a subsequent Friedel–Crafts‐type reaction to afford the desired compounds from readily available 2‐furylcarbinols, anilines and secondary alcohols with a minimum of precautions.