Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• engineered P450 enzymes catalyzed the site- and stereoselective oxidative modifications enabling further chemical transformations. Since the scaffolds of terpenes and ribosomally synthesized and post-translationally modified peptides (RiPPs) are first biosynthesized and then modified, the strategy of late

• , efficiency, and robustness of these biocatalysts are expected to enhance their usefulness and generality as synthetic tools. Apart from oxygenated terpenes and RiPPs, chemo-enzymatic approaches for polyketides and non-ribosomal peptides (NRPs) are considered more suitable for the second and third strategies

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry

• Maria-Paula Schröder,
• Isabel P.-M. Pfeiffer and
• Silja Mordhorst

Beilstein J. Org. Chem. 2024, 20, 1652–1670, doi:10.3762/bjoc.20.147

• allowing methylation at various positions. The different possible acceptor regions in ribosomally synthesised peptides are described in this article. Furthermore, we will discuss the potential application of these methyltransferases as powerful biocatalytic tools in the synthesis of modified peptides and

• -translational modifications; ribosomal peptides; SAM-dependent enzymes; Introduction In the complex landscape of natural product biosynthesis, ribosomally synthesised and post-translationally modified peptides (RiPPs) stand out as a fascinating class of compounds with both structural diversity and unique

• ; this reaction is catalysed by S-adenosylmethionine (SAM or AdoMet)-dependent methyltransferases (MTs). These enzymes are known for their excellent chemo-, regio-, and stereoselectivity [3][4][5][6]. Their ability to introduce methyl groups at specific positions within ribosomal peptides equips the

Polymer degrading marine Microbulbifer bacteria: an un(der)utilized source of chemical and biocatalytic novelty

• Weimao Zhong and
• Vinayak Agarwal

Beilstein J. Org. Chem. 2024, 20, 1635–1651, doi:10.3762/bjoc.20.146

• classes of natural products isolated from Microbulbifer to date include alkaloids [15], fatty acid and polyketides [16][17], and non-ribosomally synthesized peptides [3][4][7]. These findings validate the potential for secondary metabolite discovery from Microbulbifer genus. This review will cover the

• publicly available which are typically 5 Mbp in size. Computational mining these genomes with antiSMASH reveals that these bacteria, though not endowed with the biosynthetic prowess of actinomycetes, do still possess BGCs encoding NRPS-derived peptides, polyketides, RiPPs, and siderophores [4][147]. A

Regio- and stereochemical stability induced by anomeric and gauche effects in difluorinated pyrrolidines

• Ana Flávia Candida Silva,
• Francisco A. Martins and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2024, 20, 1572–1579, doi:10.3762/bjoc.20.140

• of the pyrrolidine ring in proline motifs has been found to induce significant conformational changes that impact the structure and biological roles of modified peptides and proteins. Vicinal difluorination of fluoroproline, for example, in (3S,4R)-3,4-difluoroproline, serves to mitigate the inherent

• pervade biochemistry in peptides and proteins. The chemical and biological properties of substituted pyrrolidine derivatives, along with many other compounds, hinge on the relative stereochemistry. It is well established that the presence of fluorine in an organic molecule can significantly influence the

Mining raw plant transcriptomic data for new cyclopeptide alkaloids

• Draco Kriger,
• Michael A. Pasquale,
• Brigitte G. Ampolini and
• Jonathan R. Chekan

Beilstein J. Org. Chem. 2024, 20, 1548–1559, doi:10.3762/bjoc.20.138

• transcriptomic data sets, we uncover the potential distribution of split burpitide precursor peptides in Streptophyta. Metabolomic analysis of target plants confirms our bioinformatic predictions of new cyclopeptide alkaloids from both known and new sources. Keywords: burpitides; natural products; plants; RiPPs

• ; transcriptome mining; Introduction Plants are prolific producers of cyclic peptide natural products, making 1000s of different molecules [1]. While the orbitide [2] and cyclotide [3] classes of peptides are well known, it has been recently discovered that a new class of molecules called burpitides are also

• prevalent in plants [4]. Like all known plant peptides, burpitides fall under the ribosomally synthesized and post-translationally modified peptides (RiPPs) superclass of natural products (Figure 1). The typical pathway for a RiPP starts with a precursor peptide made by the ribosome that undergoes post

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• photosensitive arylketone catalyst in the fluorination of phenylalanine residues in peptides (Figure 27) [72]. This work demonstrated high yields and selectivity for peptides bearing phenylalanine residues, including tripeptides, such as 16. In 2015, Britton and co-workers reported a photochemical HAT-guided

• fluorination in continuous flow. Photochemical phenylalanine fluorination in peptides. Decatungstate-photocatalyzed versus AIBN-initiated selective benzylic fluorination. Benzylic fluorination using organic dye Acr+-Mes and Selectfluor. Palladium-catalysed benzylic C(sp3)–H fluorination with nucleophilic

Discovery and biosynthesis of bacterial drimane-type sesquiterpenoids from Streptomyces clavuligerus

• Dongxu Zhang,
• Wenyu Du,
• Xingming Pan,
• Xiaoxu Lin,
• Fang-Ru Li,
• Qingling Wang,
• Qian Yang,
• Hui-Min Xu and
• Liao-Bin Dong

Beilstein J. Org. Chem. 2024, 20, 815–822, doi:10.3762/bjoc.20.73

• biocatalysts, capable of catalyzing a wide range of reactions and processing a variety of substrates [35][36]. They effectively recognize different structural types, including aromatic compounds, polyketides, terpenes, peptides, and carbohydrates [37][38][39][40]. To investigate the substrate spectrum of CavA

Synthesis and characterization of water-soluble C₆₀–peptide conjugates

• Yue Ma,
• Lorenzo Persi and
• Yoko Yamakoshi

Beilstein J. Org. Chem. 2024, 20, 777–786, doi:10.3762/bjoc.20.71

• of hydrophilic oligopeptide anchors (oligo-Lys, oligo-Glu, and oligo-Arg) were synthesized. A previously reported Prato reaction adduct of a biscarboxylic acid-substituted C60 derivative was subjected to a solid phase synthesis for amide formation with N-terminal amines of peptides on resin to

• C60–peptide conjugates in this study. In addition to the water solubility introduced by the peptides, these conjugates have a superior biocompatibility compared to those with synthetic polymers, such as PEG and PVP. We utilized the previously reported biscarboxylic acid derivative 3, which was

• suitable for the coupling to peptides on resin, prepared by solid-phase peptide synthesis (SPPS) [35]. The detailed conditions for the amide-forming reaction were optimized using biscarboxylic acid-substituted C60 derivative 3 and a similar peptide with a primary amine derived from γ-aminobutyric acid

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• .20.66 Abstract Chemoenzymatic strategies that combine synthetic and enzymatic transformations offer efficient approaches to yield target molecules, which have been increasingly employed in the synthesis of bioactive natural products. In the biosynthesis of macrocyclic nonribosomal peptides, polyketides

• for these natural products that aim to address the common issues in classical synthetic approaches and increase synthetic efficiencies, which have the potential to facilitate further pharmaceutical research. Keywords: biosynthesis; chemoenzymatic synthesis; macrocyclic peptides; macrocyclic

• polyketides; thioesterase; Introduction Nonribosomal peptides, polyketides, and their hybrids exhibit significant diversity and a broad spectrum of bioactivities [1][2][3]. Particularly, macrocycles from these three categories of natural products are vital resources for developing pharmaceuticals and drug

Development of a chemical scaffold for inhibiting nonribosomal peptide synthetases in live bacterial cells

• Fumihiro Ishikawa,
• Sho Konno,
• Hideaki Kakeya and
• Genzoh Tanabe

Beilstein J. Org. Chem. 2024, 20, 445–451, doi:10.3762/bjoc.20.39

• ; Introduction Nonribosomal peptides (NRPs) exhibit various biological activities and have been used as therapeutic agents, such as antibiotics, anticancer agents, and immunosuppressants [1]. Additionally, NRPs function as virulence factors, such as siderophores and genotoxins [2]. Therefore, inhibiting their

Discovery of unguisin J, a new cyclic peptide from Aspergillus heteromorphus CBS 117.55, and phylogeny-based bioinformatic analysis of UngA NRPS domains

• Sharmila Neupane,
• Marcelo Rodrigues de Amorim and
• Elizabeth Skellam

Beilstein J. Org. Chem. 2024, 20, 321–330, doi:10.3762/bjoc.20.32

• heptapeptides isolated predominantly from Aspergillus sp. [1][2][3][4][5][6][7][8]. Distinctive features of these cyclic peptides include the non-proteinogenic amino acid γ-aminobutyric acid (GABA) and the incorporation of up to five ᴅ-amino acids (Figure 1) [1][2][3][4][5][6][7][8]. The amino acids at

• small peptides [3][4][9], however, unguisin A has been shown to bind a series of anions [10]. Recently the biosynthesis of unguisins A and B from Aspergillus violaceofuscus CBS 115571 was reported [5]. A seven module non-ribosomal peptide synthetase (NRPS; UngA) was heterologously expressed in

• discovered that linearized the cyclic unguisins to linear peptides during in vitro investigations, although the linear peptides were not detected from the fungal cultures. NRPS enzymes are large multifunctional enzymes that often synthesize very important bioactive molecules [11][12]. These enzymes consist

Optimizations of lipid II synthesis: an essential glycolipid precursor in bacterial cell wall synthesis and a validated antibiotic target

• Milandip Karak,
• Cian R. Cloonan,
• Brad R. Baker,
• Rachel V. K. Cochrane and
• Stephen A. Cochrane

Beilstein J. Org. Chem. 2024, 20, 220–227, doi:10.3762/bjoc.20.22

• ramoplanin [2]. It is also the target for a host of other antimicrobials (mostly non-ribosomal peptides), including the tridecaptins [3], nisin [4], teixobactin [5], clovibactin [6], malacidin [7], and cilagicin [8]. Despite significant progress in the chemical synthesis of lipid II and its analogues, the

• study the mechanism of action of antimicrobial peptides that kill bacteria through binding to these polyprenyls [21][28][29][30][31][32][33][34]. Lipid II has been of particular interest, and during our synthesis of multiple different lipid II analogues, we have developed several optimizations, which we

Unprecedented synthesis of a 14-membered hexaazamacrocycle

• Anastasia A. Fesenko and
• Anatoly D. Shutalev

Beilstein J. Org. Chem. 2023, 19, 1728–1740, doi:10.3762/bjoc.19.126

• ., vitamin B12, chlorophyll, metalloproteins, cyclic peptides, etc). PAMs themselves and their metal complexes exhibit various useful properties [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31], particularly, they possess a wide range of biological activities and are used as contrast

N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• acid organocatalysts were evaluated for sulfenylation on C3, or C2 position of N-heterocycles 115, including indoles, peptides, pyrrole, and 1-methyl-1H-pyrrolo[2,3-b]pyridine. The authors hypothesized a mechanism for the activation of N-sulfanylsuccinimides 1 or 14 by conjugate Lewis base Brønsted

• , peptides, drugs and saccharides reacted smoothly with N-alkynylthiophthalimides in the presence of TFA as a catalyst. Also, aliphatic and aromatic thiols reacted with N-alkynylthiophthalimide and sulfoxide 149 to obtain acyl disulfides 151 through alkynylthiolation and hydrative oxyarylation in the

Asymmetric tandem conjugate addition and reaction with carbocations on acylimidazole Michael acceptors

• Brigita Mudráková,
• Renata Marcia de Figueiredo,
• Jean-Marc Campagne and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 881–888, doi:10.3762/bjoc.19.65

• solubility in water. Among exceptional properties belongs to easy post-transformation of acylimidazoles to common carbonyl analogs. These tunable properties allow the use of acylimidazoles in chemical biology research, which includes chemical synthesis of proteins/peptides, structure analysis, and functional

Non-peptide compounds from Kronopolites svenhedini (Verhoeff) and their antitumor and iNOS inhibitory activities

• Yuan-Nan Yuan,
• Jin-Qiang Li,
• Hong-Bin Fang,
• Shao-Jun Xing,
• Yong-Ming Yan and
• Yong-Xian Cheng

Beilstein J. Org. Chem. 2023, 19, 789–799, doi:10.3762/bjoc.19.59

• activity have revealed the presence of antimicrobial peptides [5], defensive alkaloids [6], and defensive long chain alcohol acetates [7]. Historically, in China, numerous records documented the utilization of animals like arthropods for medicinal purposes. Millipedes hereby represent a traditional Chinese

Palladium-catalyzed enantioselective three-component synthesis of α-arylglycine derivatives from glyoxylic acid, sulfonamides and aryltrifluoroborates

• Bastian Jakob,
• Nico Schneider,
• Luca Gengenbach and
• Georg Manolikakes

Beilstein J. Org. Chem. 2023, 19, 719–726, doi:10.3762/bjoc.19.52

• , sulfonamides and aryltrifluoroborates is described. This process provides modular access to the important α-arylglycine motif in moderate to good yields and enantioselectivies. The formed α-arylglycine products constitute useful building blocks for the synthesis of peptides or arylglycine-containing natural

Digyalipopeptide A, an antiparasitic cyclic peptide from the Ghanaian Bacillus sp. strain DE2B

• Adwoa P. Nartey,
• Aboagye K. Dofuor,
• Kofi B. A. Owusu,
• Anil S. Camas,
• Hai Deng,
• Marcel Jaspars and
• Kwaku Kyeremeh

Beilstein J. Org. Chem. 2022, 18, 1763–1771, doi:10.3762/bjoc.18.185

• data, mass spectrometry sequence tagging, advanced Marfey’s analysis, and the GNPS molecular networking we solved the full structure of digyalipopeptide A (1). We found that compound 1 is a member of a somewhat homologous series of peptides produced as a mixture by the strain containing the same amino

• , 1H, H-7), 4.53 (ov., 1H, H-12), 4.52 (ov., 1H, H-16), 4.18 (ov., 1H, H-22), 4.08 (dd, J = 8.8, 6.0 Hz, 1H, H-33), and 4.44 (ov., 1H, H-27) which were indicative of the presence of α-hydrogens belonging to amino acid residues typical for peptides. Using 1H,1H homonuclear correlation spectroscopy (COSY

• − 99Val) provided the needed sequence information for the structure of compound 1. Stereochemistry determination Historically, the determination of the regiochemistry of enantiomeric amino acid residues within natural product peptides has proved challenging sometimes requiring the strenuous efforts of de

Navigating and expanding the roadmap of natural product genome mining tools

• Friederike Biermann,
• Sebastian L. Wenski and
• Eric J. N. Helfrich

Beilstein J. Org. Chem. 2022, 18, 1656–1671, doi:10.3762/bjoc.18.178

• conserved across all 40 plus RiPP families [32]. However, each RiPP BGC family features genes encoding characteristic tailoring enzymes, or precursor peptides, that show a high degree of sequence conservation within the family. These conserved genes can be utilized for the targeted, family-specific

• alignments with known genes and domains using algorithms like BLAST (Figure 4) [42]. BLAST detects similar sequences to a given query sequence [42]. The first version of the tool BAGEL utilized BLAST analysis, among others, to identify putative BGCs of bacteriocins (= antimicrobial peptides and proteins) [43

• sequences derived from tailoring enzymes or precursor peptides (Figure 3C and D). These family-specific pHMMs are likewise used in tools like BAGEL or RODEO and enable the identification of novel members of known RiPP families [46][69]. RRE-Finder, which is integrated into the antiSMASH platform and RODEO

Simple synthesis of multi-halogenated alkenes from 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane)

• Yukiko Karuo,
• Atsushi Tarui,
• Kazuyuki Sato,
• Kentaro Kawai and
• Masaaki Omote

Beilstein J. Org. Chem. 2022, 18, 1567–1574, doi:10.3762/bjoc.18.167

• an aryl or alkynyl unit [16][17][18][19][20][21][22]. In a biological context, the fluoroalkenyl motif could be incorporated into peptides with the expectation that the fluoroalkenyl unit could serve as a peptide isostere and prevent unexpected hydrolysis of these compounds. Recent studies have shown

Solid-phase total synthesis and structural confirmation of antimicrobial longicatenamide A

• Takumi Matsumoto,
• Takefumi Kuranaga,
• Yuto Taniguchi,
• Weicheng Wang and
• Hideaki Kakeya

Beilstein J. Org. Chem. 2022, 18, 1560–1566, doi:10.3762/bjoc.18.166

• .18.166 Abstract Longicatenamides A–D are cyclic hexapeptides isolated from the combined culture of Streptomyces sp. KUSC_F05 and Tsukamurella pulmonis TP-B0596. Because these peptides are not detected in the monoculture broth of the actinomycete, they are key tools for understanding chemical

• developed [4]. Among the isolated longicatenamides, compound 1 exhibits weak but preferential antimicrobial activity against Bacillus subtilis. Because peptides 1–4 are not detected in the monoculture broth of Streptomyces sp. KUSC_F05, they are key tools for understanding chemical communication in the

• chemical communication. The retrosynthesis of peptide 1 is displayed in Scheme 1. First, the cyclic peptide 1 was linearized by retrosynthesis, and acid-labile protecting groups were attached onto the reactive side chain. The biomimetic synthesis of cyclic peptides often enables efficient synthesis [12][13

Microelectrode arrays, electrosynthesis, and the optimization of signaling on an inert, stable surface

• Kendra Drayton-White,
• Siyue Liu,
• Yu-Chia Chang,
• Sakashi Uppal and
• Kevin D. Moeller

Beilstein J. Org. Chem. 2022, 18, 1488–1498, doi:10.3762/bjoc.18.156

• . For example, consider a pair of molecules (Figure 1) that selectively inhibit the Gq11-signaling pathway in cells [15][16]. The molecules are complex cyclic peptides, and the construction of analogs of the molecules to probe the basis of their activity is a significant challenge. In an ideal situation

• chosen as the ligand for Gαi1 because it was known to bind the target with a binding constant of KD = 60 nM [21]. The binding data shown in Figure 5 compared interactions between Gαi1 and two surface bound peptides; R6A (MSQTKRLDDQLYWWEYLC) and a scrambled R6A sequence (QLSEDTYLLMRWDYWQK). The two

• peptides were placed on the array along with a fluorescent dye (LRSC, lissamine rhodamine) that was used to make sure the placement chemistry was working. The array used was coated with the borate ester diblock copolymer (Figure 2), and the peptides were attached to this polymer through a PEG-6 linker in

Computational model predicts protein binding sites of a luminescent ligand equipped with guanidiniocarbonyl-pyrrole groups

• Neda Rafieiolhosseini,
• Matthias Killa,
• Thorben Neumann,
• Niklas Tötsch,
• Jean-Noël Grad,
• Alexander Höing,
• Thies Dirksmeyer,
• Jochen Niemeyer,
• Christian Ottmann,
• Shirley K. Knauer,
• Michael Giese,
• Jens Voskuhl and
• Daniel Hoffmann

Beilstein J. Org. Chem. 2022, 18, 1322–1331, doi:10.3762/bjoc.18.137

• interactions with other proteins. Here, we use a computational approach to predict the binding sites of the designed hybrid compound featuring aggregation-induced emission luminophores as a potential supramolecular ligand for 14-3-3ζ in the presence and absence of C-Raf peptides. Our results suggest that the

• area above and below the central pore of the dimeric 14-3-3ζ protein is the most probable binding site for the ligand. Moreover, we predict that the position of the ligand is sensitive to the presence of phosphorylated C-Raf peptides. With a series of experiments, we confirmed the computational

• that identified putative binding sites of 1 on 14-3-3ζ. These predictions can then be tested in a targeted way. Using this approach, we tried to answer basically two questions: (a) where does compound 1 bind on 14-3-3ζ, and (b) how would the presence of phosphorylated C-Raf peptides in the binding

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

• hangtaimycin, TDD and the hangtaimycin degradation product HTM222 are given. Keywords: antibiotics; enantioselective synthesis; peptides; racemisation; Streptomyces; Introduction Hangtaimycin (1, Scheme 1) was first isolated from Streptomyces spectabilis and shown to possess weak antimicrobial activity

• DBU is a common strategy for the dehydration of serine and threonine units in peptides [16], but unfortunately the acetylation of 10 failed. Interestingly, the direct treatment of 10 with LiClO4 and DBU under prolonged reaction times (3 days) resulted in the elimination of water. This reaction

First series of N-alkylamino peptoid homooligomers: solution phase synthesis and conformational investigation

• Maxime Pypec,
• Laurent Jouffret,
• Claude Taillefumier and
• Olivier Roy

Beilstein J. Org. Chem. 2022, 18, 845–854, doi:10.3762/bjoc.18.85

• -substituted glycines [1][2]. They retain the same backbone as peptides except that the side chains are located on the nitrogen atoms of the amide bonds and thus represent an important class of peptide biomimetics [3][4][5], generally with improved cell permeability [6] and proteolytic resistance [7][8

• ]. Beyond their resemblance to peptides, the obvious interest in this family of peptidomimetics arises from their ease of synthesis by the modular submonomer protocol [9] which enables the incorporation of numerous primary amine synthons in a sequence-controlled manner [10], and application of solid

• -supported combinatorial approaches [11][12][13]. The most relevant comparison of peptoids with peptides is in fact with polyprolines due to the presence of backbone tertiary amide linkages, much more prone to cis/trans equilibria than secondary amides. Indeed, in proteins, cis-amide bonds are most often