Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

• Pratibha Sharma,
• Raakhi Gupta and
• Raj K. Bansal

Beilstein J. Org. Chem. 2021, 17, 2585–2610, doi:10.3762/bjoc.17.173

• as an important synthetic strategy for the preparation of a large variety of β-amino carbonyl and similar motifs which are present in many bioactive natural products [8][9], antibiotics [10][11][12] and chiral auxiliaries [13][14][15]. However, the reaction of many nitrogen-nucleophiles, such as

α-Ketol and α-iminol rearrangements in synthetic organic and biosynthetic reactions

• Scott Benz and
• Andrew S. Murkin

Beilstein J. Org. Chem. 2021, 17, 2570–2584, doi:10.3762/bjoc.17.172

• , tandem reactions, and the total synthesis and biosynthesis of natural products. This review explores the use of α-ketol rearrangements in these contexts over the past two decades. Keywords: acyloin rearrangement; asymmetric synthesis; iminol rearrangement; ketol rearrangement; tandem reactions

• 1,4-dioxane with a single drop of water. α-Ketol rearrangements implemented in total syntheses Although rare, α-ketol rearrangements have been included in the total syntheses of some natural products with high success. In the first total synthesis of periconianone A (31), an α-ketol rearrangement was

• episilvestrol (35), natural products with potent anticancer properties. The step prior to the rearrangement involved a photoinduced [3 + 2] cycloaddition between hydroxyflavone 36 and methyl cinnamate (37), resulting in the bicyclic α-ketol 38 as a mixture of diastereomers (Ph and CO2Me groups trans) (Figure 9

Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones

• Robin Klintworth,
• Garreth L. Morgans,
• Stefania M. Scalzullo,
• Charles B. de Koning,
• Willem A. L. van Otterlo and
• Joseph P. Michael

Beilstein J. Org. Chem. 2021, 17, 2543–2552, doi:10.3762/bjoc.17.170

• ; tetrahydroindolizines; Introduction Partially or fully saturated variants of the pyrrolizine nucleus 1 are widely occurring motifs in natural products. The hexahydropyrrolizine (pyrrolizidine) system, for example, forms the nucleus of literally hundreds of alkaloids, many of which have gained notoriety owing to their

• nonsteroidal anti-inflammatory drug [6], and licofelone (7) [9][10], a promising co-drug for anticancer combination chemotherapy [7]. Related 5,6,7,8-tetrahydroindolizines such as CMV423 (8) [11], a lead compound for treating infections by human cytomegalovirus, and the natural products polygonatine A (9) [12

• enaminones, and further investigations are warranted. Finally, in view of our interest in the synthesis of natural products possessing fully substituted pyrrole rings (e.g., the lamellarin alkaloids [50][51][52][70]), we also demonstrated that dihydropyrrolizines such as 19a could easily be functionalized on

Synthesis of new substituted 7,12-dihydro-6,12-methanodibenzo[c,f]azocine-5-carboxylic acids containing a tetracyclic tetrahydroisoquinoline core structure

• Agnieszka Grajewska,
• Maria Chrzanowska and
• Wiktoria Adamska

Beilstein J. Org. Chem. 2021, 17, 2511–2519, doi:10.3762/bjoc.17.168

• ; cyclization; multicomponent reactions; synthetic methods; tetrahydroisoquinoline; Introduction The tetrahydroisoquinoline moiety is the key structure in large number of natural and synthetic biologically important molecules. Among them, isoquinoline alkaloids constitute a large family of natural products

Direct C(sp³)–H allylation of 2-alkylpyridines with Morita–Baylis–Hillman carbonates via a tandem nucleophilic substitution/aza-Cope rearrangement

• Siyu Wang,
• Lianyou Zheng,
• Shutao Wang,
• Shulin Ning,
• Zhuoqi Zhang and
• Jinbao Xiang

Beilstein J. Org. Chem. 2021, 17, 2505–2510, doi:10.3762/bjoc.17.167

• ; Morita–Baylis–Hillman carbonates; Introduction Pyridines are among the most important heterocyclic structural moieties in many biologically active natural products, pharmaceuticals, and agrochemicals [1][2][3]. Therefore, the development of efficient strategies for functionalized pyridine derivatives

Recent advances in the tandem annulation of 1,3-enynes to functionalized pyridine and pyrrole derivatives

• Yi Liu,
• Puying Luo,
• Yang Fu,
• Tianxin Hao,
• Xuan Liu,
• Qiuping Ding and
• Yiyuan Peng

Beilstein J. Org. Chem. 2021, 17, 2462–2476, doi:10.3762/bjoc.17.163

• in many natural products, pharmaceuticals, and bioactive molecules. For instance, some pyridine derivatives have been used for therapy of HIV, cancer, inflammation, microbial infection and so on [1][2][3][4][5]. In addition, it is also an important synthetic unit, which is frequently used as catalyst

• the synthesis of five- or six-membered cyclic compounds [54]. Various efficient synthetic methods have been developed for the synthesis of halogenated pyrroles, which are widely presented in many pharmacologically active natural products, bioactive molecules, and organic building blocks. Based on the

• standard conditions could inhibit the formation of target product. In contrast, the compound TEMPO–N3 was detected by GC–MS analysis. Based on the radical trapping experiment and previous reports, the reaction may undergo a radical process. 2-Carbonylpyrrole is a key subunit of many bioactive natural

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

Strategies for the synthesis of brevipolides

• Yudhi D. Kurniawan and
• A'liyatur Rosyidah

Beilstein J. Org. Chem. 2021, 17, 2399–2416, doi:10.3762/bjoc.17.157

• assay against the cell proliferation of the human hormone-refractory prostate cancer cell line (PC-3). Mohapatra’s strategy to brevipolide H (8) As part of the interest in synthesizing biologically active cyclopropane-containing natural products, Mohapatra and co-workers in 2015 started their attempt to

• [4]. These compounds demonstrated cytotoxicity against various human cancer cells. Additionally, the research group led by Pereda-Miranda later isolated more members of brevipolide (1–15) from the same plant during 2013–2017 and further confirmed the cytotoxic activity of these natural products [1

• Poit., i.e., the brevipolides A–O, parallel with their appealing biological activity, in addition to the fact that they were produced in a small quantity from nature, make these natural products highly relevant when considering total synthesis. Since the first attempt to prepare brevipolide H by

Isolation and characterization of new phenolic siderophores with antimicrobial properties from Pseudomonas sp. UIAU-6B

• Emmanuel T. Oluwabusola,
• Olusoji O. Adebisi,
• Fernando Reyes,
• Kojo S. Acquah,
• Mercedes De La Cruz,
• Larry L. Mweetwa,
• Joy E. Rajakulendran,
• Digby F. Warner,
• Deng Hai,
• Rainer Ebel and
• Marcel Jaspars

Beilstein J. Org. Chem. 2021, 17, 2390–2398, doi:10.3762/bjoc.17.156

• ]. One way out of this is an extensive search for novel bioactive natural products from microbial sources [2][3]. There is focus on the genus Pseudomonas for scientific research due to its widespread distribution in water, soil, and extreme habitats, including the exceptional ability to colonize the

• rhizosphere of host plants, serving as a microbial biocontrol [4][5]. This genus, belonging to the Gram-negative proteobacteria is diverse in nature and possesses unique environmental adaptability which shows in their versatile metabolism [6][7][8]. They are prolific producers of natural products with broad

• . faecium VanA15167 at the highest concentration (64 µg/mL) tested (see Supporting Information File 1). Conclusion In summary, we have isolated seven natural products, including five new phenolic siderophores (1–5) that have not been reported in the literature and their biosynthetic pathways were proposed

Advances in mercury(II)-salt-mediated cyclization reactions of unsaturated bonds

• Sumana Mandal,
• Raju D. Chaudhari and
• Goutam Biswas

Beilstein J. Org. Chem. 2021, 17, 2348–2376, doi:10.3762/bjoc.17.153

• cyclization reactions that are performed with Hg(II) salts. These salts are also successfully applied in stoichiometric or catalytic amounts to form complex cyclic structures and natural products. Keywords: carbocyclic; catalyzed; cyclization; heterocyclic; mercury(II) salts; Introduction The use of

• total syntheses of many natural products [34]. Despite its wide application in ring formation reactions, only a few review articles on Hg(II)-salt-mediated cyclization reactions are available in the literature [35]. This review describes the intramolecular cyclization of unsaturated compounds in the

• heterocycles, namely benzofurans, benzothiophenes, isocoumarins, chromones, benzopyrans, 1,2-dihydronaphthaIenes, coumarins, and coumestan including some physiologically active heterocyclic natural products like flavones [84]. In the presence of Hg(OAc)2 in acetic acid, simple cyclization of ortho-substituted

Phenolic constituents from twigs of Aleurites fordii and their biological activities

• Kyoung Jin Park,
• Won Se Suh,
• Da Hye Yoon,
• Chung Sub Kim,
• Sun Yeou Kim and
• Kang Ro Lee

Beilstein J. Org. Chem. 2021, 17, 2329–2339, doi:10.3762/bjoc.17.151

• Kyoung Jin Park Won Se Suh Da Hye Yoon Chung Sub Kim Sun Yeou Kim Kang Ro Lee Natural Products Laboratory, School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea Laboratory of Pharmacognosy, College of Pharmacy, Gachon University, Incheon, 21936, Republic of Korea Department

Synthesis of O⁶-alkylated preQ₁ derivatives

• Laurin Flemmich,
• Sarah Moreno and
• Ronald Micura

Beilstein J. Org. Chem. 2021, 17, 2295–2301, doi:10.3762/bjoc.17.147

• natural occurrence of methylated prequeuosine bases stems from a recent study that demonstrated that m6preQ0 is produced by Streptomyces [17]. Moreover, the natural products huimycin [18] and dapiramicin contain m6preQ0 as core with their 2-NH2 group linked to a 2'-acetamido-2'-deoxy-ß-ᴅ-glucopyranosyl

• queuosine (Q), the natural products dapiramicin A and huimycin, as well as intermediates of queuosine biosynthesis (preQ1 and preQ0), and the major synthetic targets of this study, m6preQ0 (1) and m6preQ1 (2) (grey box). Synthesis of compound 1 (m6preQ0) by cyclocondensation using a 4-methoxypyrimidine

Base-free enantioselective S_N2 alkylation of 2-oxindoles via bifunctional phase-transfer catalysis

• Mili Litvajova,
• Emiliano Sorrentino,
• Brendan Twamley and
• Stephen J. Connon

Beilstein J. Org. Chem. 2021, 17, 2287–2294, doi:10.3762/bjoc.17.146

• synthesis of a potent CRTH2 receptor antagonist. Keywords: alkylation; base-free; cinchona alkaloids; CRTH2 antagonist; hydrogen-bonding; oxindole; phase-transfer catalysis; Introduction The 2-oxindole scaffold is an important motif present in a myriad of natural products. Among 2-oxidole derivatives, 3,3

Nomimicins B–D, new tetronate-class polyketides from a marine-derived actinomycete of the genus Actinomadura

• Zhiwei Zhang,
• Tao Zhou,
• Taehui Yang,
• Keisuke Fukaya,
• Enjuro Harunari,
• Shun Saito,
• Katsuhisa Yamada,
• Chiaki Imada,
• Daisuke Urabe and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2021, 17, 2194–2202, doi:10.3762/bjoc.17.141

• similar to those for the tetronic acid bearing an exo-methylene substituent in known natural products [16][17][18]. Secondly, the UV spectrum of 3, showing absorption maxima at 243 and 302 nm, was matched well with that for ecteinamycin, which possesses the exo-methylene-substituted tetronic acid moiety

Enantioenriched α-substituted glutamates/pyroglutamates via enantioselective cyclopropenimine-catalyzed Michael addition of amino ester imines

• Zara M. Seibel,
• Jeffrey S. Bandar and
• Tristan H. Lambert

Beilstein J. Org. Chem. 2021, 17, 2077–2084, doi:10.3762/bjoc.17.134

• synthetic building blocks and as a common substructure in a number of biologically active molecules [1][2][3][4][5]. In addition, the lactamized derivatives of these compounds, pyroglutamates, occur in a number of well-known biologically active natural products including dysibetaine [6][7][8][9][10][11][12

• and several natural products with pyroglutamate substructures. Effect of the aryl substituent on reaction efficiency and selectivity. Proposed transition state model. Optimization of the cyclopropenimine-catalyzed addition of alanine imine 1 to methyl acrylate. Substrate scope of amino ester imine

A study on selective transformation of norbornadiene into fluorinated cyclopentane-fused isoxazolines

• Zsanett Benke,
• Attila M. Remete and
• Loránd Kiss

Beilstein J. Org. Chem. 2021, 17, 2051–2066, doi:10.3762/bjoc.17.132

• of natural products (especially macrocycles) [12], alkaloids [13], amino acids and functionalized biomolecules such as peptides [14][15][16][17][18][19][20] or various drugs [21]. Due to the ring strain, bicyclic systems and derivatives, such as norbornadiene derivatives can easily be converted

Asymmetric organocatalyzed synthesis of coumarin derivatives

• Natália M. Moreira,
• Lorena S. R. Martelli and
• Arlene G. Corrêa

Beilstein J. Org. Chem. 2021, 17, 1952–1980, doi:10.3762/bjoc.17.128

• starting material in the asymmetric organocatalyzed reaction, the Enders group described the use of (S)-proline as catalyst in an intramolecular aldol reaction, enabling a new strategy to obtain coumarin natural products [34]. As for example, the total synthesis of (+)-smyrindiol (17), a linear

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution

• Ryan M. Alam and
• John J. Keating

Beilstein J. Org. Chem. 2021, 17, 1939–1951, doi:10.3762/bjoc.17.127

•  4, entries 3 and 4) provides further support for the important role that tight ion pair formation plays in directing N-alkylation of the indazole scaffold. Examples of indazole natural products (1 and 2) and synthetic biologically active indazole derivatives (3–8). Observation of a 1H–13C

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• amiodarone (93, antiarrhythmic activity) (Scheme 32A) [166]. The method consists of a tandem, regioselective Fe(III)-catalyzed C–H halogenation, followed by an Fe or Cu-catalyzed O-arylation to access the benzo[b]furan derivatives in high yields. Several natural products and pharmacologically active targets

Natural products in the predatory defence of the filamentous fungal pathogen Aspergillus fumigatus

• Jana M. Boysen,
• Nauman Saeed and
• Falk Hillmann

Beilstein J. Org. Chem. 2021, 17, 1814–1827, doi:10.3762/bjoc.17.124

• . fumigatus as an example because of its high medical importance and its diverse profile of secondary metabolites which seems to fulfil dual roles: targeting innate immune cells during virulence and protect from environmental predators in natural habitats. Review Natural products of Aspergillus fumigatus The

Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• strategy, is regarded as a crucial tactic in the area of natural products, drug discovery, and medicinal chemistry [7][8][9][10][11][12] as it confers an invaluable synthetic opportunity for the facile diversification of biologically active complex molecules at the late stage. In recent years, much effort

• derivatives of complex biologically active compounds and natural products were evaluated in the late-stage benzylic C–H amination process using MnIII(ClPc) (18) and iminoiodinane. For example, the amination of FKGK11 (17a), a potent inhibitor of iPLA2, proceeded smoothly in a moderate yield. Notably

• install the free NH functionality. These findings highlight the convenience of manganese catalysis for the late-stage benzylic C–H amination of sophisticated bioactive molecules and natural products. The proposed mechanism of the Mn-catalyzed benzylic amination is shown in Figure 6. Initially

A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• employing a variety of amino esters and a wide range of (hetero)aromatic and alkyl ketones. Natural products, such as 5α-cholestan-3-one and dihydrotestosterone, were also tolerated, affording a new strategy to modify biologically active compounds. Amino acids, such as tyrosine, ʟ-Phe-ʟ-Phe, glutamic acid

Copper-mediated oxidative C−H/N−H activations with alkynes by removable hydrazides

• Feng Xiong,
• Bo Li,
• Chenrui Yang,
• Liang Zou,
• Wenbo Ma,
• Linghui Gu,
• Ruhuai Mei and
• Lutz Ackermann

Beilstein J. Org. Chem. 2021, 17, 1591–1599, doi:10.3762/bjoc.17.113

• , cyanations, aminations, nitrations, oxygenations, thiolations, halogenations, and phosphorylations, among others, were accomplished [14][15][16][17][18][19]. The 3-methyleneisoindolin-1-one moiety represents a key structure motif in natural products [20][21][22][23] or important pharmacophores [24]. In this

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• Thiago S. Silva Fernando Coelho Laboratory of Synthesis of Natural Products and Drugs, Department of Organic Chemistry, Chemistry Institute, University of Campinas, PO Box 6154 - 13083-970, Campinas – SP, Brazil 10.3762/bjoc.17.112 Abstract Olefin double-bond functionalization has been

• yield, and a nature-inspired bicycle 47 was synthetized via two sequential 6-exo-trig cyclizations, giving a preview of the potential use of MHAT methodologies in the synthesis of complex natural products via radical polyene cyclization [78]. Although relevant, the MHAT hydroalkylation methodology

• methanol and gentle heating was necessary to optimize the formation of 75 from 74. As is usual in these Mukaiyama-like reaction conditions, the developed hydromethylation tolerated an array of functional groups and the late-stage functionalization of complex natural products (75e–g). Deuterated and other

A straightforward conversion of 1,4-quinones into polycyclic pyrazoles via [3 + 2]-cycloaddition with fluorinated nitrile imines

• Greta Utecht-Jarzyńska,
• Karolina Nagła,
• Grzegorz Mlostoń,
• Heinz Heimgartner,
• Marcin Palusiak and
• Marcin Jasiński

Beilstein J. Org. Chem. 2021, 17, 1509–1517, doi:10.3762/bjoc.17.108

• , 1379, 1267, 1170, 1118, 1070, 1029, 954, 850, 816, 712 cm−1; ESIMS (m/z): 365.4 (100, [M + H]+); Anal. calcd for C19H19F3N2O2: C, 62.63; H, 5.26; N, 7.69; found: C, 62.76; H, 5.39; N, 7.95. Structures of exemplary benzo- and heteroaromatic fused 1,4-quinone drugs and natural products. X-ray structure