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

• analysis (Figure 4b). In these experiments, CavA was found to hydroxylate drim-8-ene-11-ol (6) at the C-3 and C-7 positions to produce 8 and 9, respectively, while albicanol (5) was modified only at the C-3 position. Compound 7 is a known natural product, and its chemical structure was determined by

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

Beilstein J. Org. Chem. 2024, 20, 787–814, doi:10.3762/bjoc.20.72

• natural product dictyophlebine (60) [57]. Surprisingly, the reported hydrochlorination conditions for the synthesis of 60 differ significantly from the original protocol by Boudjouk (2500 equivalents of H2O instead of 1.5 equiv). A surface-mediated hydrochlorination reaction was reported by Kropp and co

Methodology for awakening the potential secondary metabolic capacity in actinomycetes

• Shun Saito and
• Midori A. Arai

Beilstein J. Org. Chem. 2024, 20, 753–766, doi:10.3762/bjoc.20.69

• was determined by total synthesis. The biological activities of these maniwamycins were also evaluated, and they showed antiviral activity against influenza (H1N1) virus and the causative agent of COVID-19, SARS-CoV-2. This was the first report of such activity for a natural product having an azoxy

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

• chemoenzymatic approaches involving TE-catalyzed macrocyclization will keep expanding in scope and depth to explore previously inaccessible chemical space for discovering important therapeutically active natural product drug leads. Brief introduction of thioesterase (TE) domain. (a) NRPS and PKS assembly lines

• biomimetic linker to imitate peptide-S-PCP [46], which not only employed in the efficient cyclization of tyrocidine A (1) but also worked on hundreds of other linear substrates, some of which exhibited broad-spectrum activity against both Gram-positive and Gram-negative organisms. By combining natural

• -product biosynthesis and combinatorial solid-phase chemistry, this strategy has expanded the sequence space of macrocyclic peptides significantly (Scheme 2c). The daptomycins The calcium-dependent antibiotic (CDA, 11), daptomycin (12), and A54145 are acidic lipopeptides isolated from Streptomycetes, which

A myo-inositol dehydrogenase involved in aminocyclitol biosynthesis of hygromycin A

• Michael O. Akintubosun and
• Melanie A. Higgins

Beilstein J. Org. Chem. 2024, 20, 589–596, doi:10.3762/bjoc.20.51

• family containing Hyg17 and discuss genome mining strategies that target this protein family to identify biosynthetic clusters for natural product discovery. Keywords: aminocyclitol; biosynthesis; hygromycin A; inositol dehydrogenase; myo-inositol; Introduction Hygromycin A is a natural product that

• Hyg17 sequences with other members of the oxidoreductase family and inositol dehydrogenases and discuss specialized genome mining approaches using these sequences to identify new natural product biosynthetic clusters. Results and Discussion Hyg17 enzyme activity We found that Hyg17 formed inclusion

• enzymes can have distinct biological functions, such as sugar metabolism and LPS biosynthesis [19][20][21][22][23]. By contrast, other members are involved in natural product biosynthetic pathways similar to Hyg17 [24][25][26]. Although many of the PF01408 enzymes have reported activities, the SSN shows

A new analog of dihydroxybenzoic acid from Saccharopolyspora sp. KR21-0001

• Rattiya Janthanom,
• Yuta Kikuchi,
• Hiroki Kanto,
• Tomoyasu Hirose,
• Arisu Tahara,
• Takahiro Ishii,
• Arinthip Thamchaipenet and
• Yuki Inahashi

Beilstein J. Org. Chem. 2024, 20, 497–503, doi:10.3762/bjoc.20.44

• , anticancer, antitumor, antiinflammatory, antihyperglycemic, antiapoptotic, immunosuppressant, and antioxidant compounds [1][2][3]. According to natural product screening since the 1920s, about 30,000 compounds derived from microbial sources have been reported [4]. Over 10,000 compounds are produced by

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

• synthetase A (GrsA) in the gramicidin S-producer Aneurinibacillus migulanus ATCC 9999, providing an alternative scaffold to develop novel A-domain inhibitors. Keywords: adenylation domain inhibitor; gramicidin S synthetase; natural product; nonribosomal peptide; nonribosomal peptide synthetase

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• of chemoselectivity can benefit from the multitude of mechanisms for their activation. Particularly, the use of RAEs in natural product total synthesis enables the assembly of strategic C–C bonds through radical coupling reactions that can draw from a wide range of reaction conditions (Scheme 37

Synthesis of π-conjugated polycyclic compounds by late-stage extrusion of chalcogen fragments

• Aissam Okba,
• Pablo Simón Marqués,
• Kyohei Matsuo,
• Naoki Aratani,
• Hiroko Yamada,
• Gwénaël Rapenne and
• Claire Kammerer

Beilstein J. Org. Chem. 2024, 20, 287–305, doi:10.3762/bjoc.20.30

• [65]. Synthesis of dinaphthooxepine bisimide 33 and conversion into PBI 6f by O-extrusion triggered by electron injection [66]. Top: Early example of 6-membered ring contraction with concomitant S-extrusion leading to dinaphthothiophene [69]. Bottom: Photoactivated S-extrusion occurring in natural

• product thiarubrine A [70]. Examples of S-extrusion from annelated 1,2-dithiins under photoactivation (top) or thermal activation (bottom) [71][72]. Synthesis of dibenzo[1,4]dithiapentalene upon photoextrusion of SO2 [78]. Extrusion of SO in naphthotrithiin-2-oxides for the synthesis of 2,5

Identification of the p-coumaric acid biosynthetic gene cluster in Kutzneria albida: insights into the diazotization-dependent deamination pathway

• Seiji Kawai,
• Akito Yamada,
• Yohei Katsuyama and
• Yasuo Ohnishi

Beilstein J. Org. Chem. 2024, 20, 1–11, doi:10.3762/bjoc.20.1

• natural product, we performed heterologous expression of the cma cluster. Plasmids named pHKO4-cmaI-D and pTYM3a-cmaG (Figure 2A) were introduced into S. albus by conjugation, resulting in S. albus-cma [20]. S. albus-cma possesses all the cma genes, except for the genes encoding a transporter (cmaF) and a

• product produced by K. albida [30]. Although rare actinomycetes have been expected to be a source of novel natural products, reports of natural product isolation from rare actinomycetes are limited because of the difficulty in cultivation and genetic manipulation. This study demonstrates that heterologous

• diazo group-containing compounds through directed evolution. Finally, this study is important because of the success of genome mining for BGCs in a rare actinomycete, K. albida. Although 47 BGCs were indicated in the K. albida genome by the antiSMASH analysis, only aculeximycin was reported as a natural

Trifluoromethylated hydrazones and acylhydrazones as potent nitrogen-containing fluorinated building blocks

• Zhang Dongxu

Beilstein J. Org. Chem. 2023, 19, 1741–1754, doi:10.3762/bjoc.19.127

• more in-depth applications of fluoromethylated hydrazones and acylhydrazones to synthesize natural product analogues and fluorinated drugs is highly desirable. These methods should encourage the introduction of these difluoromethylated nitrogen-containing building blocks in future bioactives discovery

Decarboxylative 1,3-dipolar cycloaddition of amino acids for the synthesis of heterocyclic compounds

• Xiaofeng Zhang,
• Xiaoming Ma and
• Wei Zhang

Beilstein J. Org. Chem. 2023, 19, 1677–1693, doi:10.3762/bjoc.19.123

• -stabilized azomethine ylide; Introduction The 1,3-dipolar cycloaddition of azomethine ylides (AMYs) [1][2][3][4][5][6] is a powerful method for the synthesis of bioactive pyrrolidine-containing compounds and natural product analogs [7][8][9][10][11][12][13][14][15]. AMYs generated from the reaction of

Functions of enzyme domains in 2-methylisoborneol biosynthesis and enzymatic synthesis of non-natural analogs

• Binbin Gu,
• Lin-Fu Liang and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 1452–1459, doi:10.3762/bjoc.19.104

• ; isotopes; substrate analogs; terpenes; Introduction The musty odorant 2-methylisoborneol (1, Scheme 1) has first been obtained through synthesis from camphor [1] and has subsequently been discovered as a natural product in streptomycetes [2][3]. The volatile compound was later also found in various other

Radical ligand transfer: a general strategy for radical functionalization

• David T. Nemoto Jr,
• Kang-Jie Bian,
• Shih-Chieh Kao and
• Julian G. West

Beilstein J. Org. Chem. 2023, 19, 1225–1233, doi:10.3762/bjoc.19.90

• intermediate. RLT to this radical from another azide ligand leads to a diazidated product. The overall scope of both reports suggests that the diazidation of simple to complex drugs/natural product-derived alkene substrates is readily achievable, including highly substituted and cyclic aliphatic alkenes

Aromatic C–H bond functionalization through organocatalyzed asymmetric intermolecular aza-Friedel–Crafts reaction: a recent update

• Anup Biswas

Beilstein J. Org. Chem. 2023, 19, 956–981, doi:10.3762/bjoc.19.72

• -substituted indoles which effectively attacked the electrophile through the C2 position. The reaction was even compatible with pyrroles (Scheme 7a). The utility of this methodology was successfully demonstrated by the synthesis of product 23a, the key intermediate of natural product (+)-trigonoliimine (Scheme

Clauson–Kaas pyrrole synthesis using diverse catalysts: a transition from conventional to greener approach

• Dileep Kumar Singh and
• Rajesh Kumar

Beilstein J. Org. Chem. 2023, 19, 928–955, doi:10.3762/bjoc.19.71

• . This methodology has been applied to diverse areas of chemistry, including natural product synthesis [45][46], medicinal chemistry [47][48], polymer chemistry [49][50] and porphyrin chemistry [51][52][53]. In recent years, green chemistry has become a widely used method for organic synthesis in order

• demonstrated the synthesis of polygonatine, an alkaloid natural product, using this protocol. (2) Reactions under solvent-free conditions In recent years, interest in organic reactions that do not use toxic organic solvents has increased due to environmental considerations. Ramesh et al. [71] in 2012 reported

• a mechanism for this protocol as shown in Scheme 38b. Conclusion The synthesis of pyrrole derivatives has piqued the interest of many synthetic researchers as they offer promising applications in pharmaceutical, polymer, and natural product chemistry. The introduction of a pyrrole moiety into a

Intermediates and shunt products of massiliachelin biosynthesis in Massilia sp. NR 4-1

• Till Steinmetz,
• Blaise Kimbadi Lombe and
• Markus Nett

Beilstein J. Org. Chem. 2023, 19, 909–917, doi:10.3762/bjoc.19.69

• order to scavenge iron from the environment. An example is the thiazoline-containing natural product massiliachelin, which is produced by Massilia sp. NR 4-1 under iron-deficient conditions. Based on experimental evidence and genome analysis, it was suspected that this bacterium synthesizes further iron

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• oxanorbornenes; however, the latter two substrates did not undergo dehydrogenation, generating cis-selective annulated coumarins (10b and 10d). In 2006, the same group applied this methodology for the total synthesis of arnottin I (10h), a coumarin-type natural product isolated from the bark of the Xanthoxylum

Total synthesis: an enabling science

• Bastien Nay

Beilstein J. Org. Chem. 2023, 19, 474–476, doi:10.3762/bjoc.19.36

• synthetic methodology developments and to natural product isolation or biosynthesis. Thus, thematic issues dealing with total synthesis in the Beilstein Journal of Organic Chemistry have naturally been published in these fields, such as "Transition-metal and organocatalysis in natural product synthesis

• the success of total synthesis and can be a source of new discoveries. Indeed, as a science allowing the preparation of useful functional compounds, it is strongly connected to biological and medicinal studies, while the development of natural-product-based tools for chemical biology often requires

Asymmetric synthesis of a stereopentade fragment toward latrunculins

• Benjamin Joyeux,
• Antoine Gamet,
• Nicolas Casaretto and
• Bastien Nay

Beilstein J. Org. Chem. 2023, 19, 428–433, doi:10.3762/bjoc.19.32

• demonstrated thanks to the synthesis of analogues, which hardly superseded the natural product properties, highlighting the importance of the macrocycle and of the lactol ring for this biological activity (3 is inactive) [6][7]. Considering the structural features of these toxins and their valuable biological

• partner (8) for the aldol reaction brings the thiazolidinone heterocycle of the natural product. It was synthesized in four steps from ʟ-cysteine ester derivative 16, first reacting with carbonyldiimidazole (CDI) to afford thiazolidinone 17 in 85% yield (Scheme 2). The nitrogen atom was protected with a

• latrunculins. Structure of latrunculins (the red dots show the natural product stereopentade). General strategy for latrunculin cycle disconnections (left), previous works towards linear precursor 4 (A), and our alternative disconnection of 7 through the aldol reaction (B). Synthesis of fragment 15 from (+)-β

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

• ) was different from the value reported for the natural product ([α]D −100, c 0.015, CHCl3) [16] and hypothesized that the configuration of the natural compound would be 3S,4R, different from that reported in the Pettit previous work. Couladouros and co-workers based the synthetic design of

Synthesis, α-mannosidase inhibition studies and molecular modeling of 1,4-imino-ᴅ-lyxitols and their C-5-altered N-arylalkyl derivatives

• Martin Kalník,
• Sergej Šesták,
• Juraj Kóňa,
• Maroš Bella and
• Monika Poláková

Beilstein J. Org. Chem. 2023, 19, 282–293, doi:10.3762/bjoc.19.24

• successful [25][26][27]. The only exception is the latest study by Cheng et al. who reported breakthrough findings in the development of highly potent and selective human GMII inhibitors. A combination of natural product-inspired combinatorial chemistry and computation-guided synthesis provided a nanomolar

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

• Langemann reported an efficient and short total synthesis of the natural product dactylol (72) (Scheme 12) [37]. The main originality of this work was the use of the Schrock molybdenum carbene catalyst 73 for the ring-closing metathesis reaction. The metathesis precursor 70 was obtained in 4 steps from

• -8-6-5] tetracyclic all-carbon system with 10 stereogenic centers (Scheme 15). This natural product was isolated from two Gentianella plant species, namely G. nitida and G. alborosea used in Peruvian traditional medicine. The first report of its synthesis was given in 2014 by Hog and co-workers [46

• unit. The final steps of this synthesis involved alcohol deprotection, double bond hydrogenation and oxidation, and allowed the total synthesis of (−)-nitidasin (93) in 27 steps. Naupliolide (97) was first isolated from the aerial parts of Nauplius graveolens in 2006. This tetracyclic natural product

An accelerated Rauhut–Currier dimerization enabled the synthesis of (±)-incarvilleatone and anticancer studies

• Tharun K. Kotammagari,
• Sweta Misra,
• Sayantan Paul,
• Sunita Kunte,
• Rajesh G. Gonnade,
• Manas K. Santra and
• Asish K. Bhattacharya

Beilstein J. Org. Chem. 2023, 19, 204–211, doi:10.3762/bjoc.19.19

• (±)-rengyolone (3). Despite of these syntheses, the synthesis of the dimeric natural product (±)-incarvilleatone (1), whose monomeric unit (±)-rengyolone (3) was connected by accelerated intermolecular Rauhut–Currier (RC) reaction was not reported in literature. Herein, we present the total synthesis of

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

• through Wagner–Meerwein rearrangement to I2c and deprotonation, but also this compound is not known as a natural product. This hydrocarbon has been obtained by partial hydrogenation of (+)-α-vetispirene (49) in a small scale reaction using PtO2 hydrate in CHCl3 as a catalyst (Scheme 12F). The amounts of

• through 1,2-hydride shift to L3a and deprotonation (Scheme 16A). However, this compound itself is not known as a natural product, but has been obtained together with γ-gurjunene (64) from guai-11-en-5-ol (63), a natural product isolated from gurjun wood oil, by elimination (Scheme 16D) [131]. Conclusion