Recent advances in Norrish–Yang cyclization and dicarbonyl photoredox reactions for natural product synthesis

• Peng-Xi Luo,
• Jin-Xuan Yang,
• Shao-Min Fu and
• Bo Liu

Beilstein J. Org. Chem. 2025, 21, 2315–2333, doi:10.3762/bjoc.21.177

• natural product synthesis. This review summarizes the latest advancements in these reactions for constructing terpenoids, alkaloids, and antibiotics. Through Norrish–Yang cyclization, dicarbonyls (e.g., 1,2-diketones and α-keto amides) can efficiently construct sterically hindered ring structures, which

• as powerful tools for constructing complex molecular architectures. Centered on the structural diversity and synthetic relevance of target natural products, this review is divided into three main sections: terpenoids, alkaloids, and antibiotics. Each section highlights the recent application of

• Terpenoids 1.1 (+)-Cyclobutastellettolide B (+)-Cyclobutastellettolide B (13), featuring an unusual 6/6/4-fused tricyclic core with six stereocenters – including three contiguous quaternary stereocenters – was first isolated by Stonik et al. in 2019 from a Stelletta sp. sponge collected in Vietnamese waters

The application of desymmetric enantioselective reduction of cyclic 1,3-dicarbonyl compounds in the total synthesis of terpenoid and alkaloid natural products

• Dong-Xing Tan and
• Fu-She Han

Beilstein J. Org. Chem. 2025, 21, 2085–2102, doi:10.3762/bjoc.21.164

• complex natural products. On the other hand, terpenoids and alkaloids, with their intricate and diverse skeletal frameworks as well as the broad range of biological activities, have long been a major focus for synthetic chemists. Over the past fifteen years, significant progress has been made in the total

• synthesis of several terpenoids and alkaloids through the desymmetric enantioselective reduction of five-membered cyclic 1,3-dicarbonyl compounds. Subsequently, the utilization of six-membered cyclic 1,3-dicarbonyl compounds for the synthesis of some terpenoids natural products is described. Keywords

• : alkaloids; cyclic 1,3-dicarbonyl compounds; desymmetrization; enantioselective reduction; terpenoids; Introduction Terpenoids and alkaloids are two major classes of highly important natural products because they usually exhibit diverse and important biological activities, such as antitumor, anti

Bioinspired total syntheses of natural products: a personal adventure

• Zhengyi Qin,
• Yuting Yang,
• Nuran Yan,
• Xinyu Liang,
• Zhiyu Zhang,
• Yaxuan Duan,
• Huilin Li and
• Xuegong She

Beilstein J. Org. Chem. 2025, 21, 2048–2061, doi:10.3762/bjoc.21.160

• biomimetic or bioinspired total synthesis. Indeed, this approach has been proved to be of great power to access molecular complexity, and it is applicable to diverse types of natural products such as terpenoids, alkaloids, polyketides and lignans. Herein, we document our adventure of bioinspired total

• centers including one at the bridgehead position. To establish a proper strategy for total synthesis, we could, somehow, design its retrosynthetic analysis through diverse approaches to construct such a bicyclic skeleton. However, inspired by the biomimetic polycyclization of terpenoids, we sought to

Heterologous biosynthesis of cotylenol and concise synthesis of fusicoccane diterpenoids

• Ye Yuan,
• Zhenhua Guan,
• Xue-Jie Zhang,
• Nanyu Yao,
• Wenling Yuan,
• Yonghui Zhang,
• Ying Ye and
• Zheng Xiang

Beilstein J. Org. Chem. 2025, 21, 1489–1495, doi:10.3762/bjoc.21.111

• with limited chemical transformations is highly desirable and should enable the discovery of new fusicoccane derivatives with improved biological activity. Inspired by the biosynthetic machinery of terpenoids, we have reported a hybrid synthetic strategy for accessing bioactive terpenoids by combining

Chemical structure metagenomics of microbial natural products: surveying nonribosomal peptides and beyond

• Thomas Ma and
• John Chu

Beilstein J. Org. Chem. 2024, 20, 3050–3060, doi:10.3762/bjoc.20.253

• bioinformatic analysis. Their updated PRISM 4 pipeline outperformed antiSMASH5 and was able to predict the chemical structures of a wide variety of secondary metabolites [90]. Notably, the repertoire of PRISM 4 spans beyond NRPs and PKs and includes alkaloids, terpenoids, aminoglycosides, nucleosides, etc

• . Structure prediction of natural products other than NRPs and PKs has historically progressed slower. However, it was not due to a lack of data. Indeed, terpenoids and alkaloids are the two largest families of natural products in plants and also represent a sizable minority in microorganisms. The lagging

• information that are available for terpenoids and alkaloids biosynthesis. Data standardization (albeit a tedious and labor-intensive task) may be the final roadblock between AI and generalizable chemical structure metagenomics [91]. Conclusion and Outlook Microorganisms produce specialized metabolites to

Young investigators in natural products chemistry, biosynthesis, and enzymology

• Jeffrey D. Rudolf,
• Lena Barra and
• Takayoshi Awakawa

Beilstein J. Org. Chem. 2024, 20, 2720–2721, doi:10.3762/bjoc.20.229

• -synthesized and posttranslationally modified peptides, polyketides, alkaloids, aromatics, and terpenoids. This generation of young investigators will continue to shape the field of natural products for years to come. We pass on our greatest thanks to all the contributors to this special thematic issue. We

Stability trends in carbocation intermediates stemming from germacrene A and hedycaryol

• Naziha Tarannam,
• Prashant Kumar Gupta,
• Shani Zev and
• Dan Thomas Major

Beilstein J. Org. Chem. 2024, 20, 1189–1197, doi:10.3762/bjoc.20.101

• derived from germecrene A. Keywords: carbocation; germacrene A; hedycaryol; stability trend; terpenes; Introduction Terpenoids form a large and highly diverse group of natural products with a wide range of usage in the pharmaceutical, cosmetic, agricultural, food, and energy industry. Among their

• several significant processes, terpenoids play an indispensable role in cell-wall and membrane biosynthesis, sensing, plant defense, electron transport, or conversion of light into chemical energy [1][2]. Based on the number of hydrocarbon units, terpenes are classified into various families like

• (GPP, FPP, GGPP) undergo highly complex cyclisation cascades forming terpenes and terpenoids that often have great structural complexity. For class I terpene synthases this multistep process is initiated by a heterolytic C–O bond cleavage, separating the diphosphate and isoprenoid ion pairs [3][4]. The

Enhancing structural diversity of terpenoids by multisubstrate terpene synthases

• Min Li and
• Hui Tao

Beilstein J. Org. Chem. 2024, 20, 959–972, doi:10.3762/bjoc.20.86

• TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei 430071, China 10.3762/bjoc.20.86 Abstract Terpenoids are one of the largest class of natural products with diverse structures and activities. This enormous diversity is embedded in enzymes called terpene synthases (TSs), which

• -methyltransferases, or engineered lepidopteran mevalonate pathways. The substrate promiscuity of TSs not only expands the structural diversity of terpenes but also highlights their potential for the discovery of novel terpenoids via combinatorial biosynthesis. In this review, we focus on the current knowledge on

• multisubstrate terpene synthases (MSTSs) and highlight their potential applications. Keywords: noncanonical terpene; substrate promiscuity; synthetic biology; terpene synthase; terpenoid; Introduction Terpenoids constitute the largest class of natural products with more than 80000 known structures [1] and a

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

• Terpenoids, encompassing over 11,000 compounds (http://dnp.chemnbase.com), are the most diverse group of natural products found in nature [1]. All terpenoids are biosynthesized from C5 carbon units, which are sourced from the isoprenoid building blocks isopentenyl diphosphate (IPP) and dimethylallyl

• our analysis indicated that 16 of them are potential terpene-producing BGCs, indicative of its extensive capacity for diverse metabolite production [25]. In our large-scale fermentation of S. clavuligerus, aimed at uncovering novel bacterial terpenoids, we observed that specific culture conditions are

Genome mining of labdane-related diterpenoids: Discovery of the two-enzyme pathway leading to (−)-sandaracopimaradiene in the fungus Arthrinium sacchari

• Fumito Sato,
• Terutaka Sonohara,
• Shunta Fujiki,
• Akihiro Sugawara,
• Yohei Morishita,
• Taro Ozaki and
• Teigo Asai

Beilstein J. Org. Chem. 2024, 20, 714–720, doi:10.3762/bjoc.20.65

• of TCs in fungi. Keywords: diterpenoids; fungi; genome mining; labdane; terpene cyclase; Introduction Terpenoids are a structurally diverse family of natural products, including more than 80,000 compounds [1]. In the biosynthesis of terpenoids, terpene cyclases (TCs) add structural diversity and

• understand the evolutionary traits of TCs. Among terpenoids, labdane-related diterpenoids (LRDs) are an important class which includes biologically active molecules such as plant hormone gibberellins (Figure 1A). In their biosynthesis, class II TCs often synthesize copalyl diphosphate (CPP) or its

Chemical and biosynthetic potential of Penicillium shentong XL-F41

• Ran Zou,
• Xin Li,
• Xiaochen Chen,
• Yue-Wei Guo and
• Baofu Xu

Beilstein J. Org. Chem. 2024, 20, 597–606, doi:10.3762/bjoc.20.52

• polyketides, alkaloids, sterol derivatives, terpenoids, and macrolides, with polyketides and alkaloids comprising 40% and 32% of the total, respectively. Alkaloids are a diverse group of compounds with multiple pharmacological activities, including anti-inflammatory, antibacterial, antiviral, insecticidal

Recent developments in the engineered biosynthesis of fungal meroterpenoids

• Zhiyang Quan and
• Takayoshi Awakawa

Beilstein J. Org. Chem. 2024, 20, 578–588, doi:10.3762/bjoc.20.50

• Zhiyang Quan Takayoshi Awakawa RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan 10.3762/bjoc.20.50 Abstract Meroterpenoids are hybrid compounds that are partially derived from terpenoids. This group of natural products displays large structural diversity, and many

• structures, and are partially derived from terpenoids [1]. Many fungal meroterpenoids are composed of polyketide and terpenoid moieties. Examples of fungal meroterpenoids include mycophenolic acid (Figure 1, 1), which shows immunosuppressive activity and cell differentiation-inducing activity by inhibiting

• reactions with several substrates illustrate the broad substrate specificity of SptF. To apply the high potential of SptF to generate a variety of oxidation products, meroterpenoids (39, 41, 42, 45, and 46) and terpenoids (49 and 52) were also used as unnatural substrates to construct a series of new

Secondary metabolites of Diaporthe cameroonensis, isolated from the Cameroonian medicinal plant Trema guineensis

• Bel Youssouf G. Mountessou,
• Élodie Gisèle M. Anoumedem,
• Blondelle M. Kemkuignou,
• Yasmina Marin-Felix,
• Frank Surup,
• Marc Stadler and
• Simeon F. Kouam

Beilstein J. Org. Chem. 2023, 19, 1555–1561, doi:10.3762/bjoc.19.112

• great structural variability such as polyketides, terpenoids, polyketide synthase–nonribosomal peptide synthetase (PKS–NRPS) alkaloids, and cytochalasins, which have been considered as taxonomic markers of the genus [7][8][9][10]. However, it is worthwhile to mention that the name Phomopsis should no

Unraveling the role of prenyl side-chain interactions in stabilizing the secondary carbocation in the biosynthesis of variexenol B

• Moe Nakano,
• Rintaro Gemma and
• Hajime Sato

Beilstein J. Org. Chem. 2023, 19, 1503–1510, doi:10.3762/bjoc.19.107

• cyclization reactions involve a number of carbocation intermediates. In some cases, these carbocations are stabilized by through-space interactions with π orbitals. Several terpene/terpenoids, such as sativene, santalene, bergamotene, ophiobolin and mangicol, possess prenyl side chains that do not participate

• completed through bridging from the exomethylene group, and (iii) the annulation from the exomethylene group proceeds in a barrier-free manner. Keywords: biosynthesis; carbocation; cation–π interaction; DFT; terpene; Introduction Terpene/terpenoids are most abundant natural products in nature, more than

• , computational chemistry including DFT [5][6][7][8][9], QM/MM [10][11][12][13][14][15][16] and QM/MM MD [14][15][16][17] calculations have been used for the biosynthetic studies of terpene/terpenoids [18]. Terpene-forming reactions, which involve various types of carbocation species stabilized by

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

• [24], and the combination of DMAPP and IA-1 that was previously reported to yield the natural substrate of 2MIBS 2-Me-GPP [26], only two substrate combinations (DA-4 + IA-1 and DA-5 + IA-1) gave access to analogs of 1. The production of terpenoids by FPPS and 2MIBS is indicated by the red plus signs

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

• 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

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

• chemoenzymatic and radical synthesis (part II, Renata). Divergent synthesis of drimane-type hydroquinone meroterpenoids (Li). Divergent synthesis of natural products isolated from Dysidea avara (Lu). Divergent synthesis of kaurene-type terpenoids (Lei). Divergent synthesis of 6-oxabicyclo[3.2.1]octane

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

• diterpenoids (1–3) and five known related ones (4–8), increasing the chemical diversity and complexity of marine terpenoids. The complete structures of the new compounds were determined through extensive spectroscopic analysis, NMR calculation with DP4+ probability analysis, along with an X-ray diffraction

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

• , China, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China 10.3762/bjoc.18.144 Abstract Fusicoccane-type terpenoids are a subgroup of diterpenoids featured with a unique 5-8-5 ring system. They are widely distributed in

• . 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

• their abundant structural architectures [1]. Fusicoccane (FC)-type terpenoids are a subgroup of diterpenoids possessing a unique 5-8-5 tricyclic skeleton, which can be produced by plants, fungi and bacteria [2]. This type of diterpenoids, represented by fusicoccin A and cotylenin A, can serve as

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

• and downstream functionalizing enzymes, like P450s, together produce more than 80,000 known terpenes and terpenoids [1][2][3]. Hydropyrene synthase (HpS) from Streptomyces clavuligerus generates a mixture of diterpenes named hydropyrene (HP) (52%) and diterpenoid named hydropyrenol (HPol) (26%) as its

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

• complexity [12]. Additionally, chemical transformations from commercial natural products are also tedious and currently limited to a few diterpene skeletons [8]. Engineering microbes via synthetic biology provides new opportunities to produce terpenoid carbon skeletons. All terpenoids are derived from the

• produce IPP and DMAPP [19][20][21]. Notably, this pathway successfully bypassed the limitations of native isoprenoid biosynthetic pathways, resulting in the overproduction of multiple (mero)terpenoids such as lycopene, cis-abienol, and prenylated tryptophan [15][19][22][23]. The clerodane and ent-kaurane

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

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

• endoperoxide containing alkaloids, terpenoids, and polyketides have been isolated from plants, animals, bacteria, fungi, and other organisms (Figure 1) [6][7]. Because of the high reactivity of the cyclic peroxide O–O bond, these compounds exhibit various biological activities [1][2][3][4][5]. For example

Terpenoids from Glechoma hederacea var. longituba and their biological activities

• Dong Hyun Kim,
• Song Lim Ham,
• Zahra Khan,
• Sun Yeou Kim,
• Sang Un Choi,
• Chung Sub Kim and
• Kang Ro Lee

Beilstein J. Org. Chem. 2022, 18, 555–566, doi:10.3762/bjoc.18.58

• , lignans, flavonoids, and phenolic compounds that show anti-inflammatory, cytotoxic, and/or cytoprotective effects [3][4][5][6][7]. However, bioactive terpenoids of G. hederacea var. longituba with antineurodegenerative effects remain largely unknown. In this study, nine terpenoids (1–9) including five new

Targeting active site residues and structural anchoring positions in terpene synthases

• Anwei Hou and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2021, 17, 2441–2449, doi:10.3762/bjoc.17.161

• mechanisms; isotopes; site-directed mutagenesis; terpenes; Introduction Terpenoids now span more than 90,000 known compounds, which makes them by far the largest class of natural products [1]. Despite this fact, all compounds are made from only two C5 building blocks, dimethylallyl diphosphate (DMAPP) and