Prenylation, indoles

Peters, L Wright, A. D Kehraus, S., Giindisch, D., Tilotta, M. C. and Koning, G. M. 2004. Prenylated indole alkaloids from Flustra foliacea with subtype specific binding on NAChRs. Planta Medica, 70 883-886. 

The biosynthesis of many bis-indole alkaloids has been postulated to proceed by dimerisation of appropriate precursors, and there is now a substantial amount of experimental evidence to support this hypothesis. For example, treatment of the alcohol 1 with acid gives the alkaloid yuehchukene 2, and 1 could arise biogenetically by in vivo prenylation of indole followed by enzymatic oxidation. A study of related 2-prenylated indoles has confirmed the ease with which such molecules can "dimerise". Thus, treatment of the secondary alcohol 3 in benzene with silica gel impregnated with TsOH gave a complex mixture of products from which 4 (5.1%) and 5 (2.1%) were isolated (3 is very sensitive to acid, and is easily decomposed). Treatment of the isomeric tertiary alcohol 6 with a catalytic amount of TFA in anhydrous benzene gave much higher yields of the two "dimeric" products 7 (31%) and 8 (25%). 

Peters L, Wright AD, Kehraus S, Giindisch D, Tilotta MC, Konig GM (2004) Prenylated Indole Alkaloids from Flustra foliacea with Subtype Specific Binding on NAChRs. Planta Med 70 883... 

The alkaloids encountered in M myristica ate prenylated indoles isolated from the seeds. These were the first to be isolated from a higher plant. So far only two have been reported including the simple 6-(3,3-dimethylallyl)-indole and the dimeric 6-(7,7-dimethylallyl)-indoles (74, 75). 

Mould Metabolites.—In the search for later intermediates in the biosynthesis of echinulin and neochinulin three new prenylated indole derivatives have been isolated from the mycelium of Aspergillus amstelodami these are neoechinulin A (19), neoechinulin B (20), and neoechinulin C (cryptoechinulin A) (21). The isolation of neoechinulin A lends credence to the proposal that in the biosynthesis of echinulin the first isopentenyl group is introduced to position 2 of a preformed cyc/o-alanyltryptophan system, while the isolation of (19)—(21) suggests that neoechinulin (22) may be formed by a dehydrogenation followed by oxidative fission of the alanyl methyl group (CHMe —> C=CH2 C=0). ... 

Electrophilic N-prenylation of indole has, for instance, been employed in the synthesis of N-prenylindolactam-V (3, Scheme 1) [18], where the yield is only moderate, probably due to the simultaneous presence of the amide moiety. The natural product (—)-indolactam V (1) is a potent inhibitor of protein kinase C isozymes [28]. Other examples include the total syntheses of deformylflustrabromine B [11], of derivatives of physostigmine and debromoflustramine B [22], or of vulcanine and borrerine [24]. The key step of the synthesis of N-prenyltryprostatin B features N-prenylation with concomitant 3-prenylation (see Sect. 3.1) [29]. As a side reaction, prenylation of diketopiperazines, a frequent stmctural motif in prenylated indole alkaloids, was observed. 

Transition metal catalysed prenylation. There is a new one-step N-tert-prenylation of indole developed by Baran and co-workers [42] which still outcom-petes the chemoenzymatic approach (Scheme 5). Isobutene (21) as prenyl source is reacted with side-chain Fmoc-protected tryptophan methyl ester 20 in the presence of catalytic amounts of Pd(OAc)2 and superstoichiometric amounts of Ag(I) trifluoroacetate and Cu(II) acetate. The protocol also requires the presence of oxygen. After about 1 day at 35°C, the N-tert-prenylated indole is obtained in a yield of about 60%. The mechanism has not been elucidated, but may involve a 7i-allyl-Pd(II) complex which is coordinated by the indole nitrogen or by C3. In the latter case, a Pd-Claisen rearrangement of a 3-palladated indole would follow. Ag (I) functions as reoxidant of Pd(0). 

By building up the indole ring, A(-tert-prenylindole is also accessible. Willis and co-workers synthesised demethylasterriquinone A, isolated from the Congo fungus Pseudomassaria sp., from A-tert-prenyl indole which had been constmcted via Pd-catalysed condensation of 1,1-dimethylpropargylamine and a dihalogenated styrene derivative [62]. (9rt/jo-chlorinated alkynylbenzenes have been employed by Ackermann and co-workers in a Pd-catalysed N-arylation-hydroamination... 

Prenyl rearrangement. Efficient total syntheses of 3-ferf-prenylated indole alkaloids employ prenyl shifts fi om C2, which can be considered biomimetic, since it was shown by Williams that the biosynthesis of paraherquamide A (199) from Penicillium sp. proceeds via tert-prenyl shift fi om C2 to C3 starting from precursors like 198 (Scheme 39) [2, 165], in agreement with earlier proposals by Barrow [166] and by Gorst-Allman [167] for the biosynthesis of roquefortine. 

Very recently. She and co-workers reported the total synthesis of the 5-prenylated indole alkaloids tardioxopiperazine A, isoechinuhn A and variecolorin C, via Pd-catalysed coupling of an in situ-produced prenyUndium reagent with a 5-triflyloxytryptophan derivative in DMF at 100°C [206]. 

Still, there remain many open problems. It would be efficient to be able to prenylate or ferf-prenylate indole regioselectively at the benzene positions 4, 5 and 6 without having to rely on pre-functionalisation such as halogenation or hydroxylation. Here, deeper investigation of prenyl shifts and of CH functionalisation on indole is required. Enantioselective catalysis has to be explored further towards the synthesis of optically pure 3-prenylated or -tert-prenylated alkaloids. A chiral version of NBS would be helpful. In the case of conformationally flexible starting materials, the diastereoselectivity of oxidative cyclisations of tryptophan-derived diketopiperazines is still not convincing. In the area of chemoenzymatic synthesis, the number and availability of enzymes has to be enhanced and their substrate tolerance has to be elucidated in more detail. 

Li S-M (2009) Prenylated indole derivatives from fungi structure diversity, biological activities, biosynthesis and chemoenzymic synthesis. Nat Prod Rep 27 57-78... 

Biosynthesis Unknown, the racemic form of Y, however, is indicative of a non-enzymatic formation through condensation of the corresponding prenylated indoles. 

Prenylated indole alkaloids, 68-70 Pretazettine, 206-207 Primaquine, 215-216, 361 Procarpine, 110... 

Scheme 4. Corey s retrosynthetic analysis of reverse prenylated indole 9.

Me-53 and 54 displayed significant tumor promotion activity, which was found to be enhanced after the introduction of a further terpenoid side chain. )5-Me-53 was initially treated with prenylbromide to give the intermediate N-adduct 55. The subsequent aza-Claisen rearrangement gave rise to the formation of 7-prenyl indole 56 as one compound of a mixmre of regioisomers (35% yield overall. Scheme 10.14). 

This work demonstrates the first case where both a non face-selective and a face-selective addition to the tri-substituted olefinic portion of DMAPP has occurred within the same molecule. A related observation with respect to the loss of stereochemistry in the reverse prenylated indole alkaloids echinulin and roquefortine have been reported and are discussed elsewhere in this article. 

To rationalize this data, these workers speculate the intermediacy of the N-prenylated indole derivative A (Scheme 25) an aza-Claisen-type rearrangement would furnish B and a stereorandom [1,2]-migration of the isoprene moiety would result in the loss of the stereochemical integrity of the label in C-26 and C-27. An alternative pathway involving direct alkylation at C-3 of the... 

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