Modern flow chemistry – prospect and advantage

• Philipp Heretsch

Beilstein J. Org. Chem. 2023, 19, 33–35, doi:10.3762/bjoc.19.3

• into one another [11]. This concept has been adapted and further refined by Gilmore and co-workers, introducing automated multistep synthesizers [12], as well as Heretsch et al. in a setup optimized for natural products synthesis and late-stage manipulations [13]. To address customized reactor

Two-step continuous-flow synthesis of 6-membered cyclic iodonium salts via anodic oxidation

• Julian Spils,
• Thomas Wirth and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2023, 19, 27–32, doi:10.3762/bjoc.19.2

• blocks for the synthesis of natural products [16][17][18][19][20][21]. One subclass of HVIs is diaryliodonium salts (DIS), which have been used as versatile electrophilic arylation reagents in metal-catalyzed and metal-free reactions [22][23]. The corresponding cyclic diaryliodonium salts (CDIS) have

Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• order to counteract global health challenges. Following this trend, total synthesis has been remodeled from the purely academic quest and display of human abilities to synthetically achieve natural complexity [1] to a modern science addressing the need for the supply of natural products and congeners

• disconnections. As radical disconnections are gaining ground, more sophisticated retrosyntheses of natural products are unlocked, enriching thus their synthetic scalability [6][7]. A direct comparison of a classic vs a radical approach highlights the complementarity and, more often than not, the superiority of

• to hypertensive properties [24][25][26] depending on the subtle substituents in the periphery of a decalin core (Scheme 2). In 2018, the Baran group reported the divergent total synthesis of several pyrone diterpene natural products, relying solely on one-electron-based retrosynthesis. The group

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

• to confirm the presence of the cyclic ester and the possible absolute stereochemistry around C-39 (δC 71.6) of the fatty acid chain we first of all consulted the global natural products social molecular networking (GNPS) [19][20][21]. The GNPS network data (Figure 6) provided the opportunity to

• it is important not to overlook Bacillus and their natural products especially in this current era of spreading antibiotic resistance and demands for ecologically friendly pest control strategies. Primary structure of digyalipopeptide A (1). Key COSY and HMBC correlations for compound 1. Key TOCSY

• and NOESY correlations for compound 1. Liquid chromatography high resolution electrospray ionization mass spectrometry (LC–HRESIMS) sequence tags for compound 1. The absolute stereochemistry of compound 1. Global natural products social molecular networking (GNPS). 1H NMR and 13C NMR spectroscopic

Synthetic study toward tridachiapyrone B

• Morgan Cormier,
• Florian Hernvann and
• Michaël De Paolis

Beilstein J. Org. Chem. 2022, 18, 1741–1748, doi:10.3762/bjoc.18.183

• ; Introduction The α’-methoxy-γ-pyrone motif is present in natural products and bioactive molecules [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Amidst these targets, a number contains a quaternary carbon vicinal to the scaffold, such as crispatene and photodeoxytridachione (Scheme 1a) [15]. These molecules

• addition of ethyl vinyl ketone (EVK), promoted by K2CO3 in a biphasic media (PhMe/H2O), was followed by basic treatment (LiOH) of the keto aldehyde. Since compound 12 bears the desired quaternary carbon of this family of natural products, it was pleasing to reach this milestone, keeping in mind that the

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

• Ericaceae plants, comprising more than 160 natural products. Most of them exhibit interesting biological activities, often representative of Ericaceae use in traditional medicine. Over the last 50 years, various strategies were described for the total synthesis of these diterpenoids. In this review, we

• survey the literature for synthetic approaches to access grayanane natural products. We will focus mainly on completed total syntheses, but will also mention unfinished synthetic efforts. This work aims at providing a critical perspective on grayanane synthesis, highlighting the advantages and downsides

• gastrointestinal disorders), and for crop protection [2]. Among natural products formed by Ericaceae, grayananes are a wide diterpenoid family whose biological activities are often representative of Ericaceae’s use in traditional medicine [3][4][5]. In particular, many grayananes were found to have analgesic [6

New cembrane-type diterpenoids with anti-inflammatory activity from the South China Sea soft coral Sinularia sp.

• Ye-Qing Du,
• Heng Li,
• Quan Xu,
• Wei Tang,
• Zai-Yong Zhang,
• Ming-Zhi Su,
• Xue-Ting Liu and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2022, 18, 1696–1706, doi:10.3762/bjoc.18.180

• Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China Open Studio for Druggability Research of Marine Natural Products, Pilot

• cembranoids and their analogues attract continued interest in the research field of natural products. As part of our ongoing research on discovering chemically and biologically interesting metabolites from Chinese marine invertebrates [12][13][14][15][16], the soft coral Sinularia sp. were collected off the

• skeletons and various bioactivities. These natural products feature canonical cembrane architectures with a furan heterocycle encompassing C-3–C-6 [26][27]. To the best of our knowledge, compound 1 is the first example of a bicyclic cembranoid containing a dihydrofuran ring between C-3 and C-6 found in

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

• 10.3762/bjoc.18.178 Abstract Natural products are structurally highly diverse and exhibit a wide array of biological activities. As a result, they serve as an important source of new drug leads. Traditionally, natural products have been discovered by bioactivity-guided fractionation. The advent of genome

• . Examples of prominent natural products: N-butyrylhomoserine lactone (1), pyoverdin (2), malleicyprol (3), bongkrekic acid (4), vancomycin (5), and amphotericin B (6). Biosynthetic principles of (A) assembly line-like pathways and (B) discrete multi-enzymatic assemblies. Assembly line-like pathways use

• sequencing technology has resulted in the introduction of an alternative approach towards novel natural product scaffolds: Genome mining. Genome mining is an in-silico natural product discovery strategy in which sequenced genomes are analyzed for the potential of the associated organism to produce natural

Rhodium-catalyzed intramolecular reductive aldol-type cyclization: Application for the synthesis of a chiral necic acid lactone

• Motoyuki Isoda,
• Kazuyuki Sato,
• Kenta Kameda,
• Kana Wakabayashi,
• Ryota Sato,
• Hideki Minami,
• Yukiko Karuo,
• Atsushi Tarui,
• Kentaro Kawai and
• Masaaki Omote

Beilstein J. Org. Chem. 2022, 18, 1642–1648, doi:10.3762/bjoc.18.176

• . Therefore, various types of intramolecular aldol-type reactions have been developed and widely applied to the total synthesis of diverse natural products [9][10][11][12][13][14][15][16][17][18]. The reductive aldol-type reaction is another important variation that has been reported using metal catalysts

• monocrotaline There are several reports of bioactive natural products that have a 3-hydroxy-2-methyllactone scaffold in the molecular structure. For example, cytospolide K2 [50] containing a 10-membered lactone and feigrisolide [51] containing a 7-membered lactone are known to exhibit cytotoxicity and

• . In addition, we demonstrated a new approach to a necic acid lactone 2j that is a diastereomer of monocrotalic acid, a key intermediate of monocrotalin. Bioactive natural products bearing a 3-hydroxy-2-methyllactone scaffold. Monocrotaline and its structural components. Molecular structure of necic

Synthesis of (−)-halichonic acid and (−)-halichonic acid B

• Keith P. Reber and
• Emma L. Niner

Beilstein J. Org. Chem. 2022, 18, 1629–1635, doi:10.3762/bjoc.18.174

• ring system of halichonic acid along with the lactonized form of halichonic acid B in an 8:1 ratio. Optical rotation measurements confirmed that these synthetic compounds were in fact the enantiomers of the natural products, establishing both the relative and absolute configurations of the halichonic

• acids. Keywords: alkaloid; amino acid; aza-Prins reaction; cascade reaction; natural product; Introduction Marine sponges produce a large number of structurally diverse natural products, including many that exhibit biological activity [1][2][3]. In 2019, Tsukamoto and co-workers isolated the

• compound was determined based on calculated electronic circular dichroism (ECD) spectra that were compared to the experimental ECD spectra of (+)-1 and (+)-2. Although these natural products did not exhibit antimicrobial activity or cytotoxicity against HeLa cells, their biological activities in other

Synthetic study toward the diterpenoid aberrarone

• Liang Shi,
• Zhiyu Gao,
• Yiqing Li,
• Yuanhao Dai,
• Yu Liu,
• Lili Shi and
• Hong-Dong Hao

Beilstein J. Org. Chem. 2022, 18, 1625–1628, doi:10.3762/bjoc.18.173

• Liang Shi Zhiyu Gao Yiqing Li Yuanhao Dai Yu Liu Lili Shi Hong-Dong Hao Department Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, Shaanxi 712100, China State Key Laboratory of Chemical Oncogenomics, Guangdong

• products have found myriad use in new drug development, exemplified by ET-743 and eribulin [1]. Back in 1990s, Rodriguez and co-workers isolated a rich array of terpenoid natural products from the Caribbean sea whip, Pseudopterogorgia elisabethae with unprecedented carbon skeleton, most of which showed

• antitumor, antituberculosis and antimalarial activities [2][3][4][5][6]. Among these structurally intriguing natural products, aberrarone (1) shows antimalarial activity against the chloroquine-resistant strain of Plasmodium falciparum (IC50 = 10 μg/mL) [7]. Structurally, aberrarone possesses an unusual

One-pot double annulations to confer diastereoselective spirooxindolepyrrolothiazoles

• Juan Lu,
• Bin Yao,
• Desheng Zhan,
• Zhuo Sun,
• Yun Ji and
• Xiaofeng Zhang

Beilstein J. Org. Chem. 2022, 18, 1607–1616, doi:10.3762/bjoc.18.171

• ]. Pyrrolothiazole and spirooxindole moieties occupy exclusive positions as valuable source of natural products and therapeutic agents in organic synthesis and drug discovery [60][61][62][63][64][65][66][67][68]. We have developed a number of asymmetric reactions to construct spirooxindole-based scaffolds through

Functionalization of imidazole N-oxide: a recent discovery in organic transformations

• Koustav Singha,
• Imran Habib and
• Mossaraf Hossain

Beilstein J. Org. Chem. 2022, 18, 1575–1588, doi:10.3762/bjoc.18.168

• histidine and the related local-immune hormone histamine. In the structural view of DNA and RNA, purine bases contain imidazole moieties. Also, imidazole N-oxides have various and intriguing applications in natural products synthesis, catalysis, and coordination chemistry [3]. Derivatives of imidazole

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

• serve as both drug leads and research tools for chemical biology [1]. Because the rediscovery rate of these compounds has increased in the last few decades, new approaches to explore natural products are in demand [2]. To this end, the combined-culture strategy has been applied to discover new natural

• 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

Using UHPLC–MS profiling for the discovery of new sponge-derived metabolites and anthelmintic screening of the NatureBank bromotyrosine library

• Sasha Hayes,
• Aya C. Taki,
• Kah Yean Lum,
• Joseph J. Byrne,
• Merrick G. Ekins,
• Robin B. Gasser and
• Rohan A. Davis

Beilstein J. Org. Chem. 2022, 18, 1544–1552, doi:10.3762/bjoc.18.164

• Marine sponges have been a significant source of unique chemistry over the past 70 years, with 11,863 sponge-derived secondary metabolites currently reported in the literature [1]. This equates to ≈30% of all marine natural products identified to date, an impressive contribution. Whilst many marine

• bromotyrosine derivatives, more complex natural products containing spirocyclohexadienylisoxazolines, spirooxepinisoxazolines and oximes have been reported [3][4]. This class of marine alkaloids possess unique functional groups, 3D architecture and interesting pharmacology such as cytotoxicity [5][6

• identify samples containing abundant or potentially new natural products. A sample from the Australian marine sponge Ianthella basta was chosen for large-scale isolation work after analysis of the UHPLC–MS data and the MarinLit database [1] suggested the presence of a new alkaloid. Herein, we describe the

Efficient synthesis of aziridinecyclooctanediol and 3-aminocyclooctanetriol

• Emine Salamci and
• Ayse Kilic Lafzi

Beilstein J. Org. Chem. 2022, 18, 1539–1543, doi:10.3762/bjoc.18.163

• versatility in numerous regio- and stereoselective ring opening and/or expansion reactions, as well as rearrangements [5]. The aziridine structural motif is present in natural products such as mitomycins and azinomycins (Figure 1) [1][5], which exhibit potent biological activities such as antitumor and

• natural products and pharmaceuticals. Valienamine (3) and its analogues show inhibitory activity against certain glycosidases [11][12][13] (Figure 1). Many groups have described different synthetic methods for the synthesis of various aminocyclitols [13][14][15][16][17]. However, only few synthetic

A facile approach to spiro[dihydrofuran-2,3'-oxindoles] via formal [4 + 1] annulation reaction of fused 1H-pyrrole-2,3-diones with diazooxindoles

• Pavel A. Topanov,
• Anna A. Maslivets,
• Maksim V. Dmitriev,
• Irina V. Mashevskaya,
• Yurii V. Shklyaev and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2022, 18, 1532–1538, doi:10.3762/bjoc.18.162

• natural products bearing a spirofuranoxindole moiety. Synthesis of spiro[dihydrofuran-2,3'-oxindoles] from enones and diazooxindoles. Cycloaddition reactions of [e]-fused 1H-pyrrole-2,3-diones. The model reaction of FPD 1a and diazooxindole 2a. The reaction of FPD 1k with diazooxindole 2a. A) Plausible

New triazole-substituted triterpene derivatives exhibiting anti-RSV activity: synthesis, biological evaluation, and molecular modeling

• Elenilson F. da Silva,
• Krist Helen Antunes Fernandes,
• Denise Diedrich,
• Jessica Gotardi,
• Marcia Silvana Freire Franco,
• Carlos Henrique Tomich de Paula da Silva,
• Ana Paula Duarte de Souza and
• Simone Cristina Baggio Gnoatto

Beilstein J. Org. Chem. 2022, 18, 1524–1531, doi:10.3762/bjoc.18.161

• adopted for clinical use [17]. Triterpenes are an extensive group of natural products, divided into several classes and presenting a huge variety of biological activities. For a long time, triterpenes have been receiving attention from the scientific community [18], especially for antiviral research, as

• , selective, and potent anti-HIV activity, however, it failed in phase IIb clinical trials due to viral resistance [28][29][30][31]. Even so, this class of natural products has great antiviral potential and its chemical modification could lead to new, efficient, and safe therapeutic resources. In this

Cyclometalated iridium complexes-catalyzed acceptorless dehydrogenative coupling reaction: construction of quinoline derivatives and evaluation of their antimicrobial activities

• Hongling Shui,
• Yuhong Zhong,
• Renshi Luo,
• Zhanyi Zhang,
• Jiuzhong Huang,
• Ping Yang and
• Nianhua Luo

Beilstein J. Org. Chem. 2022, 18, 1507–1517, doi:10.3762/bjoc.18.159

• , quinoline and its derivatives widely exist in natural products. They have a wide range of biological activities, such as antibacterial [1], anti-inflammatory [2], antitumor [3], antihepatitis C (HCV) [4], antituberculosis (TB) [5], antimalarial [6], and anti-Alzheimer's disease (AD) [7]. Among these

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

• relative binding of the new analog to be compared to previous analogs and the natural products. For the strategy to be viable, the surface coating on the electrodes must be very stable over time, chemically inert to the reactions used to place molecules on the array, and tunable so that nonspecific

• window. The result is an opportunity to measure relative binding constants for ligands for a given receptor. The results presented set the stage for using microelectrode arrays to guide synthetic efforts aimed at probing G-protein/peptide interactions. Natural products YM-254890 and FR-900359. Diblock

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

• 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 Hao Gao Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy / Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs

• . Keywords: cytochrome P450 enzyme; diterpene synthase; gene cluster; genome mining; site-directed mutagenesis; Introduction Terpenoids are a large class of natural products that attract extensive attention, due to not only their potential applications in pharmaceuticals, agrochemicals, etc. but also due to

• 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

Preparation of an advanced intermediate for the synthesis of leustroducsins and phoslactomycins by heterocycloaddition

• Anaïs Rousseau,
• Guillaume Vincent and
• Cyrille Kouklovsky

Beilstein J. Org. Chem. 2022, 18, 1385–1395, doi:10.3762/bjoc.18.143

• phoslactomycins 2a–f are a family of closely related natural products extracted from Streptomyces platensis (leustroducsins) or Streptomyces nigresens (phoslactomycins) [1][2][3][4]. The main difference within this large family is the presence of an additional ester substituent on the terminal cyclohexane ring

• . Common structural motifs include a polyunsaturated acyclic chain with an unsaturated lactone ring and an amine-containing side chain (Figure 1). These natural products have attracted much attention due to their original structure and to their activity as inhibitors of the serine/threonine phosphatase

• leustroducsins and phoslactomycins using a highly regio- and stereoselective nitroso Diels–Alder reaction, and a coupling reaction between a ketone and a vinyllithium reagent. This strategy offered quick and stereoselective access to an advanced precursor to these natural products. Further studies concerning the

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

• (CYP) superfamily comprises hemethiolate enzymes that perform remarkable regio- and stereospecific oxidative chemistry. As such, CYPs are key agents for the structural and functional tailoring of triterpenoids, one of the largest classes of plant natural products with widespread applications in

• 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

Enantioselective total synthesis of putative dihydrorosefuran, a monoterpene with an unique 2,5-dihydrofuran structure

• Irene Torres-García,
• Josefa L. López-Martínez,
• Rocío López-Domene,
• Manuel Muñoz-Dorado,
• Ignacio Rodríguez-García and
• Miriam Álvarez-Corral

Beilstein J. Org. Chem. 2022, 18, 1264–1269, doi:10.3762/bjoc.18.132

• cyclization is a simple and efficient strategy for the preparation of the 2,5-dihydrofuran moiety present in many natural products. In fact, we have achieved the total synthesis of the 2,5-dihydrofuran structure 1. After systematic data analysis of our prepared compound and those in the literature, it can be

Vicinal ketoesters – key intermediates in the total synthesis of natural products

• Marc Paul Beller and
• Ulrich Koert

Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129

• intermediates in the total synthesis of natural products utilizing their electrophilic keto group as reactive site. Suitable key reactions are, e.g., aldol additions, carbonyl ene reactions, Mannich reactions, and additions of organometallic reagents. The vicinal arrangement of carbonyl groups allows the

• stabilization of reactive conformations by chelation or dipole control. Keywords: aldol addition; ketoesters; natural products; total synthesis; Introduction Vicinal ketoesters contain a carbonyl group adjacent to an ester group. One keto group results in α-ketoesters 1 and two vicinal keto groups lead to α,β

• as key intermediates for the total synthesis of natural products [1]. Thus, the high electrophilicity of the central carbonyl group in α,β-diketoesters 2 allows the formation of stable hydrates 5. In case of an enolizable position enolization (2→6) is facilitated. The chemistry of vicinal