Combretastatins D series and analogues: from isolation, synthetic challenges and biological activities

• Jorge de Lima Neto and
• Paulo Henrique Menezes

Beilstein J. Org. Chem. 2023, 19, 399–427, doi:10.3762/bjoc.19.31

• called cyclic diaryl ether heptanoids (DAEH). This review is intended to highlight the structure elucidation, biosynthesis, and biological activity of these compounds as well as the use of different strategies for their synthesis. Keywords: combretastatin D; corniculatolide; isocorniculatolide

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

Germacrene B – a central intermediate in sesquiterpene biosynthesis

• Houchao Xu and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 186–203, doi:10.3762/bjoc.19.18

• Houchao Xu Jeroen S. Dickschat Kekulé-Institute of Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Straße 1, 53121 Bonn, Germany 10.3762/bjoc.19.18 Abstract Germacranes are important intermediates in the biosynthesis of eudesmane and guaiane sesquiterpenes. After their

• references. Keywords: biosynthesis; configuration determination; germacrene B; structure elucidation; terpenes; Introduction Terpenoids constitute the largest class of natural products with ca. 100,000 known compounds. Biosynthetically, all terpenoids are derived from only a few acyclic precursors

• combined computational and experimental approach that in this enzyme the main chain carbonyl oxygen of Gly182 near the helix G kink and an active site water are involved in the deprotonation–reprotonation sequence in the biosynthesis of 10 (Scheme 8B) [69]. γ-Selinene (10) has been synthesised from ketone

Identification and determination of the absolute configuration of amorph-4-en-10β-ol, a cadinol-type sesquiterpene from the scent glands of the African reed frog Hyperolius cinnamomeoventris

• Angelique Ladwig,
• Markus Kroll and
• Stefan Schulz

Beilstein J. Org. Chem. 2023, 19, 167–175, doi:10.3762/bjoc.19.16

• Information File 1). The same enantiomer was isolated from the wood oil of Cryptomeria japonica [17]. Therefore, the enantiomer R-14 from the frogs is different to the plant compound. This finding may point to a biosynthesis of 14 by the frogs themselves or by associated microorganisms, although uptake from

• synthesis and characterization showed that this compound is the opposite enantiomer of 14 known from plants. This may indicate biosynthesis in the frog, but more work has to be performed to establish this. Furthermore, a short diversity-oriented synthesis based on the work of Taber and Gunn [13] enabled

Revisiting the bromination of 3β-hydroxycholest-5-ene with CBr₄/PPh₃ and the subsequent azidolysis of the resulting bromide, disparity in stereochemical behavior

• Christian Schumacher,
• Jas S. Ward,
• Kari Rissanen,
• Carsten Bolm and
• Mohamed Ramadan El Sayed Aly

Beilstein J. Org. Chem. 2023, 19, 91–99, doi:10.3762/bjoc.19.9

• acts as fluidity buffer, permeability switch, and consequently in cell signaling pathways. Physiologically, cholesterol is the substrate for the biosynthesis of steroidal hormones, vitamin D and bile acids [1][2]. Although cholesterol can adopt 256 stereoisomeric structures, biological significances

• cholesterol biosynthesis (statins). However, the side effects of these drugs are controversial. Therefore, synthetic cholesterol derivatives came into focus for recent applications in chemical biology and materials science [6]. The advances have been summarized in comprehensive reviews [7][8]. In previous

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

• insertion of different amino acids, homologous extension and linear, isopropyl or isobutyl termination of fatty acid chains. Therefore, the biosynthesis of compound 1 is speculated to occur via a similar pathway like the surfactins, which is known to be modulated by four enzyme subunits SrfAA, SrfAB, SrfAC

• DMSO-d6, HRESIMSMS sequence tagging data with GNPS molecular networking and the advanced Marfey’s test. We proposed that the biosynthesis of compound 1 is similar to that of other surfactin-like lipopeptides previously reported in the literature. We found compound 1 to possess remarkable antiparasitic

Total synthesis of grayanane natural products

• Nicolas Fay,
• Rémi Blieck,
• Cyrille Kouklovsky and
• Aurélien de la Torre

Beilstein J. Org. Chem. 2022, 18, 1707–1719, doi:10.3762/bjoc.18.181

• known to date. Thus, we anticipate that in the future, organic chemists will keep focusing on highly enantioselective, efficient and flexible synthetic strategies towards grayanane natural products. General structure of grayanane natural products. Grayanane biosynthesis. Matsumoto’s relay approach

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

• combination of all genome mining approaches will pave the way towards a more comprehensive understanding of the full biosynthetic repertoire encoded in microbial genome sequences. Keywords: genome mining; natural product biosynthesis; non-canonical pathways; PKS; NRPS; RiPP; Introduction In 2002, the genome

• bioinformatic analysis of (meta-)genomes to identify gene clusters involved in the biosynthesis of NPs [3]. NPs have been shown to act as signaling metabolites (e.g., acylhomoserine lactones (1) [6]), siderophores (e.g., pyoverdines (2) [7]), virulence factors (e.g., malleicyprol (3) [8][9][10]), toxins (e.g

• biosynthetic concepts. NP biosynthesis follows two fundamentally different principles: NPs can either be produced in an assembly line-like fashion (Figure 2A) or by discrete, multi-enzymatic assemblies (Figure 2B). Discrete, multi-enzymatic assemblies utilize monofunctional enzymes for the consecutive build-up

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

• products. For example, the mycolic acid-containing bacterium Tsukamurella pulmonis TP-B0596 can influence the biosynthesis of cryptic natural products [3]. Additionally, we have developed several highly sensitive labeling reagents to detect and identify scarce and cryptic natural products [4]. Integrating

• ] and provides insights into the biosynthesis pathways of these peptides [14]. However, the biosynthetic gene clusters of compounds 1–4 remain unidentified. Therefore, the least sterically hindered amine, namely the amino group of glycine, was selected as a nucleophile of the cyclization reaction in

Characterization of a new fusicoccane-type diterpene synthase and an associated P450 enzyme

• Jia-Hua Huang,
• Jian-Ming Lv,
• Liang-Yan Xiao,
• Qian Xu,
• Fu-Long Lin,
• Gao-Qian Wang,
• Guo-Dong Chen,
• Sheng-Ying Qin,
• Dan Hu and
• Hao Gao

Beilstein J. Org. Chem. 2022, 18, 1396–1402, doi:10.3762/bjoc.18.144

• become a promising strategy for targeted discovery of natural products [10][11][12], which can also provide enzymatic tools toward combinatorial biosynthesis [13][14]. As terpene synthases play a fundamental role in constructing molecular skeletons, great efforts have been devoted to mining novel

• analyze the function of TadA, we introduced tadA into the quadruple auxotrophic host Aspergillus oryzae NSAR1 (niaD−, sC−, ∆argB, adeA−) (Supporting Information 1, Tables S1 and S2) [26], which has been widely used for biosynthesis of fungi-derived natural products due to its genetic tractability [27

• cytotoxic FC-type diterpenoid isolated from T. purpurogenus PP-414 [7]. It will be important to elucidate the biosynthetic pathway of roussoellol C, providing enzymatic tools for expanding the chemical diversity of talaro-7,13-diene related FC-type diterpenoids via combinational biosynthesis [14

Synthesis of C6-modified mannose 1-phosphates and evaluation of derived sugar nucleotides against GDP-mannose dehydrogenase

• Sanaz Ahmadipour,
• Alice J. C. Wahart,
• Jonathan P. Dolan,
• Laura Beswick,
• Chris S. Hawes,
• Robert A. Field and
• Gavin J. Miller

Beilstein J. Org. Chem. 2022, 18, 1379–1384, doi:10.3762/bjoc.18.142

• pathogen in these cases is mucoid Pseudomonas aeruginosa. Such infections are characterised by overproduction of the exopolysaccharide alginate. We present herein the design and chemoenzymatic synthesis of sugar nucleotide tools to probe a critical enzyme within alginate biosynthesis, GDP-mannose

• , starting from fructose 6-phosphate and its synthesis ultimately arrives at the limiting step in alginate precursor biosynthesis, the action of GDP-mannose dehydrogenase (GMD), which oxidises GDP-mannose 1 to 5 (Figure 1a). GMD oxidation is suggested to have four discrete steps, first oxidising C6 to an

Cytochrome P450 monooxygenase-mediated tailoring of triterpenoids and steroids in plants

• Karan Malhotra and
• Jakob Franke

Beilstein J. Org. Chem. 2022, 18, 1289–1310, doi:10.3762/bjoc.18.135

• pharmaceuticals, food, cosmetics, and agricultural industries. In this review, we provide a full overview of 149 functionally characterised CYPs involved in the biosynthesis of triterpenoids and steroids in primary as well as in specialised metabolism. We describe the phylogenetic distribution of triterpenoid

• - and steroid-modifying CYPs across the plant CYPome, present a structure-based summary of their reactions, and highlight recent examples of particular interest to the field. Our review therefore provides a comprehensive up-to-date picture of CYPs involved in the biosynthesis of triterpenoids and

• steroids in plants as a starting point for future research. Keywords: biosynthesis; CYPs; cytochrome P450 monooxygenases; plants; steroid; sterol; triterpene; triterpenoid; Introduction Triterpenoids are a large class of natural products derived from precursors containing 30 carbon atoms and composed of

Make or break: the thermodynamic equilibrium of polyphosphate kinase-catalysed reactions

• Michael Keppler,
• Sandra Moser,
• Henning J. Jessen,
• Christoph Held and
• Jennifer N. Andexer

Beilstein J. Org. Chem. 2022, 18, 1278–1288, doi:10.3762/bjoc.18.134

• PPK2. They are structurally unrelated and use different catalytic mechanisms. PPK1 enzymes prefer the usage of adenosine 5'-triphosphate (ATP) for polyphosphate (polyP) synthesis while PPK2 enzymes favour the reverse reaction. With the emerging use of PPK enzymes in biosynthesis, a deeper understanding

• frequently used in ATP regeneration systems as well as in cascade reactions for NTP biosynthesis [22][23][39][44][50][58][59][60]. Therefore, the results presented here can serve to further tune and improve these multi-enzyme reactions and the yield of biomimetic NTP synthesis systems. Usually, reactions for

• polyP-dependent ATP regeneration as well as NTP biosynthesis are carried out under conditions comparable to the ones used for this study [22][39][50][52]. Overall, we can clearly see a preference of the thermodynamic system towards ATP. This behaviour was not impacted by the choice of PPK, regardless of

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

• , Department of Microbial Bioactive Compounds, University of Tübingen, Auf der Morgenstelle 28, 72076 Tübingen, Germany Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and School of Pharmaceutical Sciences, Wuhan University, No. 185 East Lake Road, Wuhan, 430071

Enzymes in biosynthesis

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 1131–1132, doi:10.3762/bjoc.18.116

• Jeroen S. Dickschat Kekulé-Institut für Organische Chemie und Biochemie, Rheinische Friedrich-Wilhelms-Universität Bonn, Gerhard-Domagk-Straße 1, 53121 Bonn, Germany 10.3762/bjoc.18.116 Keywords: biosynthesis; enzymes in biosynthesis; Enzymes are fascinating biocatalysts that can accelerate

• different aspects of studying the roles of enzymes in the biosynthesis of natural products. Also contributions showing the application of enzymes in synthetic organic chemistry will be welcome. I am grateful to all colleagues who have contributed to this issue and to the Editorial Team of the Beilstein

• -Institut for their professional support. I wish the readers of this issue some stimulating new insights into enzyme research in natural product biosynthesis. Jeroen S. Dickschat Bonn, August 2022

A Streptomyces P450 enzyme dimerizes isoflavones from plants

• Run-Zhou Liu,
• Shanchong Chen and
• Lihan Zhang

Beilstein J. Org. Chem. 2022, 18, 1107–1115, doi:10.3762/bjoc.18.113

• , which extends the insights into P450-mediated biaryl coupling reactions in biosynthesis. Keywords: biaryl coupling; cytochrome P450; dimerization; isoflavone; natural product; Introduction Dimerization is a ubiquitous biotransformation in nature. Almost all forms of life, including bacteria, fungi

• dimers or cross-coupling products, starting from simple monomers [17][18][19]. Nevertheless, our knowledge of enzyme-mediated dimerization is still limited in contrast to the numerous reported dimeric natural products. Phenol coupling in plant polyphenol biosynthesis is one of the earliest documented

• coclaurine [28]. The absence of the product 1 in vitro is reasonable because the biosynthesis of 1 requires an additional methyltransferase from S. cattleya for the methoxy group formation. Substrate scope and reaction mechanism After identification of CYP158C1 as the isoflavone dimerization enzyme, we next

New azodyrecins identified by a genome mining-directed reactivity-based screening

• Atina Rizkiya Choirunnisa,
• Kuga Arima,
• Yo Abe,
• Noritaka Kagaya,
• Kei Kudo,
• Hikaru Suenaga,
• Junko Hashimoto,
• Manabu Fujie,
• Noriyuki Satoh,
• Kazuo Shin-ya,
• Kenichi Matsuda and
• Toshiyuki Wakimoto

Beilstein J. Org. Chem. 2022, 18, 1017–1025, doi:10.3762/bjoc.18.102

• vitro assay elucidated the tailoring step of azodyrecin biosynthesis, which is mediated by the S-adenosylmethionine (SAM)-dependent methyltransferase Ady1. This study paves the way for the targeted isolation of aliphatic azoxy natural products through a genome-mining approach and further investigations

• of their biosynthetic mechanisms. Keywords: biosynthesis; methyltransferase; natural azoxides; reactivity-based screening; Streptomyces; Introduction Azoxy natural products are a rare yet intriguing class of natural products with various beneficial biological properties, such as antibacterial

• nitrogen radical coupling mechanism in the biosynthesis of azoxymycins [12][13], which are aromatic azoxy natural products. A similar mechanism has been envisioned for the autoxidation and spontaneous dimerization of aliphatic hydroxylamines via the azoxy linkage in malleobactin D biosynthesis [14]. A

Isolation and biosynthesis of daturamycins from Streptomyces sp. KIB-H1544

• Yin Chen,
• Jinqiu Ren,
• Ruimin Yang,
• Jie Li,
• Sheng-Xiong Huang and
• Yijun Yan

Beilstein J. Org. Chem. 2022, 18, 1009–1016, doi:10.3762/bjoc.18.101

• daturamycins was identified through gene knockout and biochemical characterization experiments and the biosynthetic pathway of daturamycins was proposed. Keywords: biosynthesis; diarylcyclopentenone; polyporic acid synthetase; p-terphenyl; Streptomyces; Introduction Natural products containing a terphenyl

• Streptomyces species [1][2][3][4]. Meanwhile, these types of compounds exhibit a broad spectrum of bioactivities, including antitumor [5][6], antibacterial [7][8], antioxidant [9][10][11][12], immunosuppressive [13], and antithrombotic activities [14]. The biosynthesis of the p-terphenyls has been studied

• since the 1960s [15][16]. Stable-isotope labeling experiments confirmed that ʟ-tyrosine or ʟ-phenylalanine are involved in the biosynthesis of p-terphenyl as metabolic origin. The precursors undergoing deamination are converted to the corresponding α-keto acid, then a quinone intermediate arises by

Understanding the competing pathways leading to hydropyrene and isoelisabethatriene

• Shani Zev,
• Marion Ringel,
• Ronja Driller,
• Bernhard Loll,
• Thomas Brück and
• Dan T. Major

Beilstein J. Org. Chem. 2022, 18, 972–978, doi:10.3762/bjoc.18.97

• Translational Neuroscience – DANDRITE, Universitetsbyen 81, 8000 Aarhus C, Denmark 10.3762/bjoc.18.97 Abstract Terpene synthases are responsible for the biosynthesis of terpenes, the largest family of natural products. Hydropyrene synthase generates hydropyrene and hydropyrenol as its main products along with

Morita–Baylis–Hillman reaction of 3-formyl-9H-pyrido[3,4-b]indoles and fluorescence studies of the products

• Nisha Devi and
• Virender Singh

Beilstein J. Org. Chem. 2022, 18, 926–934, doi:10.3762/bjoc.18.92

• large number of natural products are reported representing this scaffold [9][10][11][12][13][14][15][16]. The key precursor used in the biosynthesis of β-carboline is ʟ-tryptophan which forms the basis of great abundance of β-carboline-containing natural products [17]. A broad spectrum of biological

Anti-inflammatory aromadendrane- and cadinane-type sesquiterpenoids from the South China Sea sponge Acanthella cavernosa

• Shou-Mao Shen,
• Qing Yang,
• Yi Zang,
• Jia Li,
• Xueting Liu and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2022, 18, 916–925, doi:10.3762/bjoc.18.91

• ) [32], the terpene precursor of compounds 4–6. Meanwhile, direct deprotonation of cadinyl cation (J) generates the double bond Δ9,10 of 1,5-cadinadiene (N) [32], the precursor of compound 7. Compounds 4–7 belong to the phenolic sesquiterpenes family, and the biosynthesis of the phenolic group has not

• characterized the function of a P450 enzyme CYP76AH1 which was responsible for the formation of the aromatic ring of ferruginol in the biosynthesis pathway of tanshinones [34]. Hence, we proposed that the oxidation occurred on L to furnish the aromatic ring of calamenene (M) [29], followed by the hydroxylation

Efficient production of clerodane and ent-kaurane diterpenes through truncated artificial pathways in Escherichia coli

• Fang-Ru Li,
• Xiaoxu Lin,
• Qian Yang,
• Ning-Hua Tan and
• Liao-Bin Dong

Beilstein J. Org. Chem. 2022, 18, 881–888, doi:10.3762/bjoc.18.89

• reconstructed two-step artificial pathway efficiently produced IPP and DMAPP and thus can be used to overproduce the clerodane and ent-kaurane diterpenes in E. coli. Collecting the essential genes in the biosynthesis of terpentetriene and ent-kaurene Terpentetriene and ent-kaurene are labdane-related diterpenes

• ]. In the biosynthesis of terpentetriene, GGDP was first cyclized by a class II DTS (Cyc1) that contains a conserved DxDD motif to form terpentedienyl diphosphate (TDP) via a syn-labda-13-en-8-yl+ diphosphate intermediate (Figure 2), which, prior to deprotonation, can be followed by rearrangement to

• Information File 1) [31]. These results demonstrated that the two-step artificial pathway coupled with downstream genes for the terpentetriene and ent-kaurene biosynthesis was successful and efficient. Though a single plasmid expression system might lower the host cell burden, our results showed that the two

The stereochemical course of 2-methylisoborneol biosynthesis

• Binbin Gu,
• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 818–824, doi:10.3762/bjoc.18.82

• 2-methylisoborneol from (S)-2-Me-LPP may be explained by isomerization to 2-Me-GPP and then to (R)-2-Me-LPP. Keywords: biosynthesis; enantioselective synthesis; enzyme mechanisms; gas chromatography; terpenoids; Introduction After its first discovery from Streptomyces [1][2], it has been

• ]. Recent research on its chemical ecology demonstrated that arthropodes are attracted by compound 1 which helps in the dispersion of Streptomyces spores [20]. The absolute configuration of (–)-1 has been established through a synthesis from (+)-camphor [21]. The biosynthesis of compound 1 was initially

• biosynthesis of 1 can also be reconstituted in vitro through coupling of dimethylallyl diphosphate (DMAPP) with 2-methyl-IPP (2-Me-IPP; IPP = isopentenyl diphosphate) to 2-Me-GPP using farnesyl diphosphate synthase (FPPS), followed by cyclization through 2MIBS to 1 [26]. A recently described methyltransferase

Identification of the new prenyltransferase Ubi-297 from marine bacteria and elucidation of its substrate specificity

• Jamshid Amiri Moghaddam,
• Huijuan Guo,
• Karsten Willing,
• Thomas Wichard and
• Christine Beemelmanns

Beilstein J. Org. Chem. 2022, 18, 722–731, doi:10.3762/bjoc.18.72

• preferences. While the microbial UbiA Ptase catalyzes the C–C-bond formation between an isoprenyl chain and the meta-position of p-hydroxybenzoate (PHB) in the ubiquinone-Coenzyme Q10 biosynthesis (Figure 1), Ptases of type MenA perform the key step in the menaquinone biosynthesis by prenylating 1,4-dihydroxy

• ) contained close homologs of the bacterial MenA family (EC 2.5.1.74) (50–100% pairwise identity) catalyzing the key step in the menaquinone biosynthesis [2]. As marine bacteria such as Zobellia barbeyronii [16] Marinithermus hydrothermalis [17], Marinobacter litoralis [18], and Marinobacter flavus [19] have

• been reported to produce menaquinone 6 (MK-6), it can be speculated that G1-Ptases of this group are likely involved in its biosynthesis. The second group of Ptases (G2) included yet poorly described UbiA-like Ptases (EC 2.5.1.39) with 43–99% pairwise identity. The third cluster of Ptases (G3) (20–100

Structural basis for endoperoxide-forming oxygenases

• Takahiro Mori and
• Ikuro Abe

Beilstein J. Org. Chem. 2022, 18, 707–721, doi:10.3762/bjoc.18.71

• endoperoxygenase NvfI. Keywords: biosynthesis; endoperoxide; enzyme; natural products; X-ray crystallography; Introduction Endoperoxide-containing compounds form a large group of natural products with cyclic peroxide structures [1][2][3][4][5]. These compounds are widely distributed in nature, and many

• endoperoxide-containing natural products, numerous synthetic analyses and biosynthesis of endoperoxide compounds have been reported [18][19][20][21]. In some cases; e.g., in the biosynthesis of artemisinin and ergosterol peroxides, a reactive oxygen species (ROS) such as singlet oxygen, which is generated by

• photosensitizers or visible light, non-enzymatically reacts with the biosynthetic intermediates to produce endoperoxide structures [16][22][23]. However, over the past three decades, only a few endoperoxide-forming enzymes have been identified, including the cyclooxygenases in the biosynthesis of prostaglandins