Pseudallenes A and B, new sulfur-containing ovalicin sesquiterpenoid derivatives with antimicrobial activity from the deep-sea cold seep sediment-derived fungus Pseudallescheria boydii CS-793

• Zhen Ying,
• Xiao-Ming Li,
• Sui-Qun Yang,
• Hong-Lei Li,
• Xin Li,
• Bin-Gui Wang and
• Ling-Hong Meng

Beilstein J. Org. Chem. 2024, 20, 470–478, doi:10.3762/bjoc.20.42

• -rich fluid emissions and unique sulfur oxidation–reduction reactions [1]. Due to the unique habitat, microorganisms surviving in the deep-sea cold seeps may serve as promising sources of secondary metabolites with functional and structural diversity [2]. In particular, two indole diketopiperazine

• alkaloids containing an unprecedented spiro[bicyclo[2.2.2]octane-diketopiperazine] skeleton, chevalinulins A and B, and the first cytochalasin homodimer containing a thioether bridge, verruculoid A, were identified from deep-sea cold seeps-derived fungi and were described to have potent proangiogenic and

Synthesis of tryptophan-dehydrobutyrine diketopiperazine and biological activity of hangtaimycin and its co-metabolites

• Houchao Xu,
• Anne Wochele,
• Minghe Luo,
• Gregor Schnakenburg,
• Yuhui Sun,
• Heike Brötz-Oesterhelt and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 1159–1165, doi:10.3762/bjoc.18.120

• , People's Republic of China Institute of Inorganic Chemistry, University of Bonn, Gerhard-Domagk-Straße 1, 53121 Bonn, Germany 10.3762/bjoc.18.120 Abstract An improved synthesis for tryptophan-dehydrobutyrine diketopiperazine (TDD), a co-metabolite of the hybrid polyketide/non-ribosomal peptide

• ]. Another hangtaimycin co-metabolite in S. spectabilis [9] is tryptophan-dehydrobutyrine diketopiperazine (TDD, 4) that was already isolated several decades before the discovery of 1, and likewise reported to have no antibacterial activity [9]. The initially published structure was that of (E)-4 [9], but

Natural products in the predatory defence of the filamentous fungal pathogen Aspergillus fumigatus

• Jana M. Boysen,
• Nauman Saeed and
• Falk Hillmann

Beilstein J. Org. Chem. 2021, 17, 1814–1827, doi:10.3762/bjoc.17.124

• mellonella [66]. Fumitremorgins The class of fumitremorgins comprises several diketopiperazine alkaloids which are tremorgenic mycotoxins. However, there are several fumitremorgin-like indole alkaloids including tryprostatins, spiro- and cyclotryprostatins and verruculogen besides fumitremorgins themselves

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• , the authors found a high diastereoselectivity in the Ugi-4CR conducted with a carbonyl linked at C-17, a sterically crowed position very close to the axial methyl group placed of C-13. This step was implemented as part of the synthetic route toward steroidal 2,5-diketopiperazine 6, based on a strategy

• protocol provided a small library of steroidal 2,5-diketopiperazines 6 obtained as a single diastereomer, thus proving the high diastereoselection of the initial Ugi-4CR with the steroidal carbonyl substrate. In the 2,5-diketopiperazine ring, the configuration of the new asymmetric center C-3’ was S, a

• result confirmed by NOESY experiments. In comparison with the work described above, it can be suggested that in the case of the 2,5-diketopiperazine synthesis, the distance of the carbonyl moiety to the steroidal nucleus is determinant for the diastereoselection of the Ugi-type reaction. Thus, when the

Sequential Ugi reaction/base-induced ring closing/IAAC protocol toward triazolobenzodiazepine-fused diketopiperazines and hydantoins

• Robby Vroemans,
• Fante Bamba,
• Jonas Winters,
• Joice Thomas,
• Jeroen Jacobs,
• Luc Van Meervelt,
• Jubi John and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 626–633, doi:10.3762/bjoc.14.49

• together all necessary functionalities for further transformations. The Ugi adducts were then subjected to a base-induced ring closing and an intramolecular azide–alkyne cycloaddition reaction in succession to obtain highly fused benzodiazepine frameworks. Keywords: benzodiazepine; 2,5-diketopiperazine

• multiring-fused derivatives incorporating all these heterocyclic moieties. We hypothesized that 2,5-diketopiperazine-fused triazolobenzodiazepine could be obtained by proper functionalization of building blocks starting with an Ugi reaction; followed by two ring-closing steps, one being a base-induced

• diketopiperazine moiety 6 was obtained in 51% yield. Compound 6 bearing azide and alkyne functionalities was subjected to intramolecular azide–alkyne cycloaddition (IAAC) in EtOH at reflux conditions which afforded the target diketopiperazine-fused triazolobenzodiazepine 7a in 81% yield. The secondary path

Synthesis and biological evaluation of RGD and isoDGR peptidomimetic-α-amanitin conjugates for tumor-targeting

• Lizeth Bodero,
• Paula López Rivas,
• Barbara Korsak,
• Torsten Hechler,
• Andreas Pahl,
• Christoph Müller,
• Daniela Arosio,
• Luca Pignataro,
• Cesare Gennari and
• Umberto Piarulli

Beilstein J. Org. Chem. 2018, 14, 407–415, doi:10.3762/bjoc.14.29

• synthetic peptides or peptidomimetics containing these sequences have been prepared and show low nanomolar IC50 values for integrin αVβ3 binding [21][22][23][24][25][26][27]. A number of cyclic RGD and isoDGR ligands containing a bifunctional diketopiperazine (DKP) scaffold have been developed by the

A mechanochemical approach to access the proline–proline diketopiperazine framework

• Nicolas Pétry,
• Hafid Benakki,
• Eric Clot,
• Pascal Retailleau,
• Farhate Guenoun,
• Fatima Asserar,
• Chakib Sekkat,
• Thomas-Xavier Métro,
• Jean Martinez and
• Frédéric Lamaty

Beilstein J. Org. Chem. 2017, 13, 2169–2178, doi:10.3762/bjoc.13.217

• explained by DFT calculations. Using this method, an enantiopure disubstituted Pro–Pro diketopiperazine was synthesized in 4 steps, making 5 new bonds using a ball mill. Keywords: ball mill; DFT calculations; diketopiperazine; mechanochemistry; pyrrolidine; Introduction 2,5-Diketopiperazines (DKPs) are

• heterocyclic structures, usually derived from dipeptides, which find many applications in chemistry and biology, and have attracted attention in the last years [1][2]. The diketopiperazine backbone can be found in many natural products exhibiting various biological activities [3]. Consequently, medicinal

• a scaffold for the preparation of small compound libraries [15]. The Pro–Pro diketopiperazine can be prepared directly by dimerization of unprotected proline in a one-pot transformation, generally under harsh conditions [16]. Good results were indeed reported, although this procedure gives access

Three-component synthesis of highly functionalized aziridines containing a peptide side chain and their one-step transformation into β-functionalized α-ketoamides

• Lena Huck,
• Juan F. González,
• Elena de la Cuesta and
• J. Carlos Menéndez

Beilstein J. Org. Chem. 2016, 12, 1772–1777, doi:10.3762/bjoc.12.166

• -piperazinediones and involving a one-pot sequence of reactions achieving regioselective opening of the 2,5-diketopiperazine ring and diastereoselective generation of an aziridine ring. This method allows the preparation of N-unprotected, trisubstituted aziridines bearing a peptide side chain under mild conditions

• involve the base-promoted formation of the bicyclic aziridine 4, where nitrogen conjugation to the adjacent carbonyl would be geometrically constrained. The associated increase in reactivity for this carbonyl would explain the complete selectivity of the diketopiperazine ring opening, with concomitant

• double bond in readily available 3-arylmethylene-2,5-piperazinediones, followed by a domino process involving three consecutive nucleophilic attacks that achieve regioselective opening of the diketopiperazine ring and diastereoselective generation of the aziridine ring. The protocol described here

Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides

• Andrew W. Truman

Beilstein J. Org. Chem. 2016, 12, 1250–1268, doi:10.3762/bjoc.12.120

• to produce peptidic secondary metabolites, including non-ribosomal peptide synthetases [1][2] (NRPSs) and diketopiperazine-forming cyclases [3][4]. Alternatively, peptides synthesised by the ribosome can be post-translationally modified into secondary metabolites [5]. These are termed ribosomally

Opportunities and challenges for direct C–H functionalization of piperazines

• Zhishi Ye,
• Kristen E. Gettys and
• Mingji Dai

Beilstein J. Org. Chem. 2016, 12, 702–715, doi:10.3762/bjoc.12.70

• aerobic conditions with copper salt catalysts [67]. For example, when the antipsychotic drug aripiprazole (96) was treated with a catalytic amount of CuI under air or oxygen in DMSO at 120 °C, 2,3-diketopiperazine 97 was produced in 30% yield along with a 15% yield of urea product 98 (Figure 16). This

Recent highlights in biosynthesis research using stable isotopes

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2015, 11, 2493–2508, doi:10.3762/bjoc.11.271

• via NMR. It turned out that the label was incorporated into the N-methoxy group, and not into the presumptive glycine unit of the diketopiperazine structure. In summary, these results support an unusual conversion of one phenylalanine-derived side chain to a glycin-like moiety. The observed

Asymmetric Ugi 3CR on isatin-derived ketimine: synthesis of chiral 3,3-disubstituted 3-aminooxindole derivatives

• Giordano Lesma,
• Fiorella Meneghetti,
• Alessandro Sacchetti,
• Mattia Stucchi and
• Alessandra Silvani

Beilstein J. Org. Chem. 2014, 10, 1383–1389, doi:10.3762/bjoc.10.141

• post-Ugi cyclization, namely an intramolecular aza-Michael [24] reaction, which afforded compound 18 bearing the privileged spiro-diketopiperazine scaffold (Scheme 2). Spiro-diketopiperazines are present in many natural products [38][39][40] and have recently received much attention as

Substitution effect and effect of axle’s flexibility at (pseudo-)rotaxanes

• Friedrich Malberg,
• Jan Gerit Brandenburg,
• Werner Reckien,
• Oldamur Hollóczki,
• Stefan Grimme and
• Barbara Kirchner

Beilstein J. Org. Chem. 2014, 10, 1299–1307, doi:10.3762/bjoc.10.131

• also witnessed for diketopiperazine-based amide rotaxanes [57]. In Table 2, also the Hammett σ parameters are given. These substituent parameters [43] are the difference of the pKa values of substituted and non-substituted benzoic acids, they can be correlated with the interaction energies resulting in

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• of the 2-cyano-N-acylpyrrolidinyl motif (2.73) is its inherent susceptibility towards diketopiperazine formation (2.74, Scheme 29) [80], however, one way to inhibit this transformation is to position a bulky substituent on the secondary amine nucleophile as is the case in vildagliptine (2.72). A

Development of peptidomimetic ligands of Pro-Leu-Gly-NH₂ as allosteric modulators of the dopamine D₂ receptor

• Swapna Bhagwanth,
• Ram K. Mishra and
• Rodney L. Johnson

Beilstein J. Org. Chem. 2013, 9, 204–214, doi:10.3762/bjoc.9.24

• . Instead, 53 had a propensity to convert to the diketopiperazine 54. Also, the methyl ester of 52 resisted direct amidation under a variety of standard conditions. Rather, 52 had to be hydrolyzed to the acid and then coupled to NH3 with 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium

The diketopiperazine-fused tetrahydro-β-carboline scaffold as a model peptidomimetic with an unusual α-turn secondary structure

• Francesco Airaghi,
• Andrea Fiorati,
• Giordano Lesma,
• Manuele Musolino,
• Alessandro Sacchetti and
• Alessandra Silvani

Beilstein J. Org. Chem. 2013, 9, 147–154, doi:10.3762/bjoc.9.17

• , piazza Leonardo da Vinci 32, 20132 Milano, Italy 10.3762/bjoc.9.17 Abstract Aiming at restricting the conformational freedom of tryptophan-containing peptide ligands, we designed a THBC (tetrahydro-β-carboline)-DKP (diketopiperazine)-based peptidomimetic scaffold capable of arranging in an unusual α

• that characterizes the α-turn structure is confirmed by 1H NMR conformational studies. To the best of our knowledge, this scaffold represents one of the rare examples of a designed constrained α-turn mimic. Keywords: α-turn; conformational analysis; diketopiperazine; peptidomimetics; tetrahydro-β

• ]. Moreover, recently some tetracyclic β-carbolines have been described to act as selective inhibitors in the anticancer field [8][9], or to be endowed with antimalarial properties [10]. 2,5-Diketopiperazine (DKP)-based compounds are heterocyclic scaffolds structurally similar to peptides. They have attracted

Synthesis of multivalent host and guest molecules for the construction of multithreaded diamide pseudorotaxanes

• Nora L. Löw,
• Egor V. Dzyuba,
• Boris Brusilowskij,
• Lena Kaufmann,
• Elisa Franzmann,
• Wolfgang Maison,
• Emily Brandt,
• Daniel Aicher,
• Arno Wiehe and
• Christoph A. Schalley

Beilstein J. Org. Chem. 2012, 8, 234–245, doi:10.3762/bjoc.8.24

• . Equipping our wheels with better solubilizing groups and using diketopiperazine axles should therefore help us to go beyond the limitations encountered in the present study. Hunter/Vögtle-type tetralactam macrocycle 1 bearing an iodo substituent at one of the isophthaloyl groups, and the diamide axle piece

Synthesis of enantiomerically enriched (R)-¹³C-labelled 2-aminoisobutyric acid (Aib) by conformational memory in the alkylation of a derivative of L-alanine

• Stephen P. Fletcher,
• Jordi Solà,
• Dean Holt,
• Robert A. Brown and
• Jonathan Clayden

Beilstein J. Org. Chem. 2011, 7, 1304–1309, doi:10.3762/bjoc.7.152

• hydrogenation and cyclized by refluxing in methanol [56] to yield diketopiperazine 8. The major isotopomer displayed a 13C label in the more downfield of the two diastereotopic methyl groups (Figure 3) indicating that the more shielded methyl group, cis to the phenyl ring, is the principally unlabelled one

• , 129.5, 169.7, 174.5; IR νmax: 3278, 3064, 2948, 1742, 1703, 1658, 1547 cm–1; MS (ES+, MeOH): 422 ([M + Na]+, 100%), 400 ([M + H]+, 20%). HRMS (ES+, MeOH): Calcd for C2113C1H27N2O5 + Na+: 400.1949; found, 400.1960. Deprotection and cyclization of 7 to yield diketopiperazine 8: 7 (59 mg, 0.15 mmol) was

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• methyl ester to form the indolopiperidine motif 135 via a Pictet–Spengler reaction followed by a double condensation to install the additional diketopiperazine ring (Scheme 28) [38][39]. To achieve the high levels of cis selectivity required from the Pictet–Spengler reaction, an extensive investigation

Synthesis of glycosylated β³-homo-threonine conjugates for mucin-like glycopeptide antigen analogues

• Florian Karch and
• Anja Hoffmann-Röder

Beilstein J. Org. Chem. 2010, 6, No. 47, doi:10.3762/bjoc.6.47

• pseudo-glycopeptide was assembled in an automated synthesiser by the Fmoc-strategy on a TentaGel S resin 5 equipped with a bulky trityl linker [38] to avoid diketopiperazine formation and pre-loaded with Fmoc-proline (Scheme 2). The first 13 amino acids of the MUC1 sequence were coupled under standard