Diketopiperazines tryptophane-derived

L-tryptophan is compulsory, the biosynthetic machinery displays wide latitude in its ability to condense a second auxiliary amino acid—L-alanine in the case of (+)-ll,ll -dideoxyverticillin A (1)—to afford a tryptophan-derived diketopiperazine intermediate 13. Mirroring Woodward and Robinson s biogenetic hypothesis for the calycanthaceous alkaloids, single-electron oxidation of the electron-rich tryptophan residue would likely initiate an oxidative dimerization of the diketopiperazine precursor with concomitant cyclization to yield the octacyclic intermediate 17. Subsequent A-methylation of the amides would then yield an unembellished skeletal core of the dimeric epipolythiodiketopiperazine alkaloids. The first step en route... 

Bohn Rhoden CR, Westermann B, Wessjohann LA (2008) One-pot multicomponent synthesis of N-substituted tryptophan-derived diketopiperazines. Synthesis (Stuttg) 13 ... 

Rhoden CRB, Westermann B, Wessjoharm LA (2008) One-pot multicomponent synthesis of N-substituted tryptophan-derived diketopiperazines. Synthesis (Stuttg) (13) 2077-2082 Szardenings AK, Burkoth TS, Lu HH, Tien DW, Campbell DA (1997) A simple procedure for the solid phase synthesis of diketopiperazine and diketomorpholine derivatives. Tetrahedron 53(19) 6573-6593... 

Scheme 4 Tryptophane derived diketopiperazines by microwave vs. conventional heating...

Roquefortine, roquefortine C, a modified diketopiperazine produced by a number of Penicillium species. It is a common fungal metabolite, and is widely distributed in a range of blue cheeses. This diketopiperazine is derived from the condensation of tryptophan and histidine residues, and modified by heterocyclization and isoprenyl addition. Interestingly, roque-fortines A and B are structurally different from roquefortine C, and belong to the isofumigaclavines, whereas roquefortine D possesses the same core structure as roquefortine C [P. M. Scott etal, Experientia 1976, 32, 140 B. Clark et al., J. Nat. Prod. 2005, 68, 1661]. 

Chemoenzymatic synthesis. The transition metal-catalysed ferf-prenylations of indole will have to compete with enzymatic reactions. For instance, several pyrrolo [2,3-h]indoles have been synthesised by ierf-prenylation of tryptophan-derived diketopiperazines employing the recombinant prenyltransferases AnaPT [145] and CdpC3PT [146], respectively, from the fungus Neosartorya fischeri. Using the enzyme AnaPT it was also possible to 3-ferf-prenylate the benzodiazepindione 172, with subsequent cyclisation to the natural product aszonalenin (173) (Scheme 34). When epi-172 was used as substrate, a mixture of the corresponding epi-aszolenin and 2-tert- and 1-ferf-prenylated products was obtained [147]. 

The racemic tryptophan derivative 207 was condensed with optically pure proline derivatives following the BOP-Cl protocol. For the synthesis of notoamides C (213) and D (215), proline ethyl ester was used as coupling partner (Scheme 41), whereas the synthesis of stephacidin A (225) and notoamide B (227) employed hydroxyproline ethyl ester 219 (Scheme 43). Towards notoamides C (213) and D (215), the diaste-reomeric diketopiperazines 210 and 211 had to be separated by chromatography. The Fmoc can be replaced by a Boc protecting group and BOP-Cl by HATU [172]. 

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. 

III. Diketopiperazine Metabolites Derived from Tryptophan and Alanine... 

Few fungal metabolites consist of a diketopiperazine ring derived from tryptophan and an amino acid other than alanine and proline. Those known in Aspergillus species include ditryptophenaline and D-valyl-L-tryptophan anhydride. 

Ditryptophenaline (56), mp 204-205°C, was isolated from the mycelium of Asp. flavus during the investigation for food-borne mycotoxin by Biichi and coworkers (104). The chemical formula, C42H4QNg04, is assigned on the basis of the high-resolution mass spectrum (m/z 692.3095), and the NMR spectrum indicates a dimeric structure. It possesses a diketopiperazine ring derived from tryptophan and phenylalanine and has UV absorptions at 244 and 303 nm. The chemical structure was determined by single-crystal X-ray experiments. Later, Hino and co-... 

The authors started their synthesis with the preparation of diketopiperazine 672 from the commercially available D-tryptophan derivative 670 and known N-Chz-protected A-methyl-D-serine (671) (430). Tetracyclic derivative 673 was available through a stereoselective bromocyclization reaction with NBS. Treatment of 673 with more NBS and the radical initiator V-70 led to a two-fold bromination at the diketopiperazine ring ( 674). Hydrolysis with water afforded diol 675 as a major diastereomer in a mediocre yield with three other stereoisomers as side products. 

Studies with tryptophan and tyrosine derivatives and with tryptophan- or tyrosine-containing dipeptides or piperazine-2,5-diones (diketopiperazines, DKP) revealed structural moieties that affect the fluorescence quantum yield of these aromatic amino acids (for a review, see... 

Just as the penicillins and cephalosporins can be viewed as modified peptides so can the diketopiperazines. The diketopiperazine ring and various modifications are found in several fungal metabolites derived from two amino acids. Simple diketopiperazines such as the anhydride 3.20 of di-L-phenylalanine have been isolated from Penicillium nigricans. Echinulin (3.21), from Aspergillus echinu-latus and A. amstelodami, has been shown to be derived from L-alanine and L-tryptophan. The three isoprene units are formed from mevalonate. Flavacol... 

A weakly neurotoxic metabolite, neoxaline (58) 107), mp 202°C (dec.), —16.3° (CHCI3), is described here even though it does not possess a diketopiperazine system in the molecule. It was isolated from cultures of Asp. japonicus (yield, 230 mg/18 liters) (see this treatise, Vol. 22 (1984), p. 317) 108). Its physicochemical properties are very similar to oxaline (59), isolated from Pen. oxalicum, and the unique structure was determined by correlation with oxaline (709). The efficient conversion of roquefortine (60) to oxaline (24.3%) is known (770), and neoxaline is probably also biosynthesized from 60, which has been isolated from Pen. roquefortii 111) as a tremorgenic toxin and has a tryptophan-histidine-derived diketopiperazine system in the molecule. 

Ditryptophenaline (225) is a dimeric diketopiperazine derivative isolated from three strains of Aspergillus flavus. The structure (relative configuration only) was established by the X-ray method, and is simply derived from two molecules of tryptophan and two of iV-methylphenylalanine. Ditryptophenaline has no toxic... 

The synthesis started with the coupling of the N-sulfonylated tryptophan 660 (prepared from iV-Boc-tiyptophan in (me step) and L-alanine methyl ester 661 to give dipeptide 662. The c/s-diketopiperazine 663 was formed through cychzation with morpholine after treatment with trifluoroacetic acid. The reacticm of 663 with molecular bromine followed by N-alkylaticm with methyl iodide furnished monomeric tetracyclic bromide 664. The dimeric octacychc derivative 665 was available by cobalt(l)-mediated reductive dimerization. Due to the preference of the 5,5-ring system to build c/s-annelated products this method is an efficient strategy for the preparation of two vicinal quaternary stereogenic centers. 

Gliotoxin is a representative of a group of diketopiperazine-derived fungal toxins. It is formed from L-tryptophan and L-serine. A key intermediate is the cyclic dipeptide of these two amino acids (Fig. 334). The biosynthesis of the cyclo-hexadienol ring probably involves an epoxy intermediate. The incorporated sulfur may come from L-cysteine. 

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