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

• from the above work from the Gademann group, Kalmode et al. incorporated the same synthetic strategy into their total synthesis of racemic periconianone A [12]. Interestingly, these authors not only tested the natural product for neural anti-inflammatory activity but also the two immediate synthetic

• reduction in conjugation. Another example of a tandem α-ketol rearrangement was used in the total synthesis of delitschiapyrone A (49), a cytotoxic natural product with previously demonstrated efficacy against several cancer cell lines. The final steps of the synthesis include a Diels–Alder reaction between

• continued development in these areas can be expected in the coming years. It is becoming apparent that nature also utilizes these rearrangements in natural product biosynthesis, and one might expect to see an increase in the discovery of enzymes governing these reactions. Generalized α-ketol or α-iminol

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

• -spectrum biological functions which include antifungal [9][10][11] and antibacterial activities [12][13][14]. Natural product scaffolds isolated from species of this genus have contributed immensely as leads to drug discovery and development [15]. For instance, clofazimine [16], the antimycobacterial agent

• used for the treatment of leprosy and inflammation was inspired by the natural product phenazine [17][18]. Also, pseudomononic acid (mupirocin) isolated from Pseudomonas fluorescens by Fuller and co-workers in 1971 was discovered to possess novel antibacterial activities against 310 clinical isolates

• methanolic extract from a small-scale culture of Pseudomonas sp. UIAU-6B in modified SGG medium indicated the presence of some interesting peaks with molecular ions which gave no hits when they were searched in natural product databases (Antibase). At the same time, the 1H NMR fingerprints suggested the

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

• . The Hg(OTf)2-catalyzed isomerization of the double bond in compound 205 yielded thermodynamically favorable isomer 206 as a major product [123]. In 2010, Ravindar et al. developed the total synthesis of the steroidal natural product hippuristanol (211) starting from 11-ketotigogenin 208 (Scheme 63

Synthesis of phenanthridines via a novel photochemically-mediated cyclization and application to the synthesis of triphaeridine

• Songeziwe Ntsimango,
• Kennedy J. Ngwira,
• Moira L. Bode and
• Charles B. de Koning

Beilstein J. Org. Chem. 2021, 17, 2340–2347, doi:10.3762/bjoc.17.152

• the synthesis of the simple phenanthridine natural product trisphaeridine (3). Results and Discussion To investigate the scope and limitations of the reaction we initially opted to prepare a number of biaryl substrates possessing one aromatic electron accepting ring possessing a variety of methoxy

• was demonstrated to be useful for the synthesis of the natural product trisphaeridine (3) [17]. Exposure of 1-bromo-2,4,5-trimethoxybenzene (19) to Suzuki–Miyaura coupling reaction conditions with boronic acid 20 resulted in the formation of aldehyde 21 (Scheme 5). Treatment of 21 with hydroxylamine

• proceeding by means of the initial generation of an iminyl radical that cyclizes onto the electron-rich aromatic ring or through the formation of a radical cation on the electron-rich benzene ring. Finally, the methodology has successfully been applied to synthesizing the natural product trisphaeridine

A visible-light-induced, metal-free bis-arylation of 2,5-dichlorobenzoquinone

• Pieterjan Winant and
• Wim Dehaen

Beilstein J. Org. Chem. 2021, 17, 2315–2320, doi:10.3762/bjoc.17.149

• synthesizing betulinan A, a natural product isolated from Lenzites betulina [2], in two steps starting from commercially available starting materials. Analogs of the natural product 5a, such as 5b can also readily be prepared from the corresponding diarylquinone 3a (Scheme 2). Conclusion In summary, we have

• product. The reactive aryldiazonium salt is synthesized in situ, minimizing risks and enabling scale-up. The chlorine substituents on the quinone were successfully functionalized as part of the synthesis of natural product betulinan A, proving that this work may further facilitate the synthesis of new

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

• long-acting vitamin K antagonist (Figure 1) [8]. This scaffold has also been reported as anti-Alzheimer’s disease [9], such as the natural product decursinol, isolated from Angelica gigas [10]. In this sense, our research group has synthesized and evaluated a library of coumarin derivatives as

• multicomponent reaction (IMCR) [31]. The enantioenriched hemiacetals 5 were obtained using the Jørgensen catalyst 7 as previously described by Rueping et al. [32]. This approach enables the rapid assembly of complex natural product hybrids 6 including up to four different molecular fragments, such as

• , tolerates electron-donating and -withdrawing groups and maintains its performance in gram scale (Scheme 36). Page et al. developed a total synthesis of the natural product (+)-scuteflorin A (119), being the key step an asymmetric epoxidation of xanthyletin (115) employing biphenylazepinium 120 as PTC

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

• present in the natural product bismurrayafoline E (36) [105], an alkaloid found in the leaves of Murraya koeniggi (Scheme 13D) [106]. The oxidative formation of carbon–carbon bonds mediated by vanadium has been reported as a method for the aminomethylation of arenes and heteroarenes. The so far described

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

• Jana M. Boysen Nauman Saeed Falk Hillmann Junior Research Group Evolution of Microbial Interactions, Leibniz-Institute for Natural Product Research and Infection Biology – Hans Knöll Institute (HKI), Beutenbergstr. 11a, 07745 Jena, Germany Institute of Microbiology, Friedrich Schiller University

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

• , a natural product scaffold, was transformed into glycosylated tryptophan 31f. It is noteworthy that this manganese(I)-catalyzed glycoconjugation method avoids racemization. Furthermore, manganese-catalyzed allylative linchpin C–H glycosylation was investigated using structurally sophisticated

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

• reactions an ideal platform for the synthesis of molecules with increased molecular complexity. Keywords: hydroalkylation; hydrogen atom transfer; quaternary carbon center; radical addition; unactivated olefins; Introduction Natural product structures remain some of the main sources of inspiration for the

Synthesis of 1-indolyl-3,5,8-substituted γ-carbolines: one-pot solvent-free protocol and biological evaluation

• Premansh Dudhe,
• Mena Asha Krishnan,
• Kratika Yadav,
• Diptendu Roy,
• Krishnan Venkatasubbaiah,
• Biswarup Pathak and
• Venkatesh Chelvam

Beilstein J. Org. Chem. 2021, 17, 1453–1463, doi:10.3762/bjoc.17.101

• purification reduce the efforts in the synthesis of complex molecular architectures. Therefore, cascade reactions are essential in synthetic organic chemistry, even with moderate yields [26]. Recently, such reactions have claimed their much deserving place in drug design and natural product synthesis [27]. In

Icilio Guareschi and his amazing “1897 reaction”

• Gian Cesare Tron,
• Alberto Minassi,
• Giovanni Sorba,
• Mara Fausone and
• Giovanni Appendino

Beilstein J. Org. Chem. 2021, 17, 1335–1351, doi:10.3762/bjoc.17.93

• industrialized total synthesis of a nontrivial natural product. The original experimental protocol was recently improved by replacing the inorganic base (KOH, NaOH) with the amidine base diazobicycloundecane (DBU) as well as ethanol with n-propanol [49]. The type-III Guareschi reaction is a three-component

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

• , an immunoactivating natural product (substrate 37) [97][98]. In 2015, the diastereoselective synthesis of (E,S)-3-hydroxy-7-tritylthio-4-heptenoic acid 43, a key component of cyclodepsipeptide histone deacetylase (HDAC) inhibitors, was achieved in flow (Scheme 4) [99]. Acetyloxazolidinone 41 was used

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• single diastereoisomer [126]. The diastereoselectivity of the addition was controlled in this case by both the α-siloxyl group and the chiral sulfinamide moiety. Interestingly, the utility of this approach was also demonstrated by the synthesis of (+)-febrifugine (133), a natural product isolated from

Synthesis of 10-O-aryl-substituted berberine derivatives by Chan–Evans–Lam coupling and investigation of their DNA-binding properties

• Peter Jonas Wickhorst,
• Mathilda Blachnik,
• Denisa Lagumdzija and
• Heiko Ihmels

Beilstein J. Org. Chem. 2021, 17, 991–1000, doi:10.3762/bjoc.17.81

• of this family, berberine (1a) is a natural product and may be isolated from different plants such as berberis vulgaris, hydrastis canadensis or coptidis rhizome [2]. Particularly, the latter is established in traditional Chinese medicine as source for anti-inflammatory extracts [2]. Berberine has

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

• , and pharmaceutical agents. These structural motifs are frequently used as synthons and as key intermediates for natural product synthesis. Therefore, the development of stereoselective synthetic methods for the substituted THP subunit has long been the area of fundamental research in organic chemistry

• underwent Prins-type cyclization in the presence of BF3·OEt2 as well as SnBr4 to deliver the desired 37 and 40, respectively, without loss of optical purity (Scheme 9) [34][35]. This strategy was successfully utilized for the synthesis of the natural product (−)-centrolobine [33] and for the stereoselective

• -trisubstituted tetrahydropyran 97 through Prins cyclization, as shown in Scheme 21. Similarly, an SnCl4-catalyzed Prins reaction was reported for the synthesis of 4-chlorotetrahydropyran 100. This intermediate was further utilized for the synthesis of the natural product centrolobine, as shown in Scheme 22 [56

Deoxygenative C2-heteroarylation of quinoline N-oxides: facile access to α-triazolylquinolines

• Geetanjali S. Sontakke,
• Rahul K. Shukla and
• Chandra M. R. Volla

Beilstein J. Org. Chem. 2021, 17, 485–493, doi:10.3762/bjoc.17.42

• transformation for late-stage modification of complex natural products was explored, and as shown in Scheme 4, the protocol was tested with various natural-product-derived triazoles. Novel C2-triazolyl products 4a–c were synthesized in good yield of 61–70% from triazoles derived from thymol, cholesterol and

Synthesis of legonmycins A and B, C(7a)-hydroxylated bacterial pyrrolizidines

• Wilfred J. M. Lewis,
• David M. Shaw and
• Jeremy Robertson

Beilstein J. Org. Chem. 2021, 17, 334–342, doi:10.3762/bjoc.17.31

• , delivering the natural product in 56% yield (corrected for the presence of ≈10 wt % toluene) on a ≈2.0 mmol scale. The repetition of the process, using isocaproyl chloride instead of isovaleryl chloride, afforded legonmycin B in moderate yield from ≈0.5 mmol of intermediate 17. In a larger-scale reaction

Total synthesis of decarboxyaltenusin

• Lucas Warmuth,
• Aaron Weiß,
• Marco Reinhardt,
• Anna Meschkov,
• Ute Schepers and
• Joachim Podlech

Beilstein J. Org. Chem. 2021, 17, 224–228, doi:10.3762/bjoc.17.22

• . [3][5][6], and from the endophytic fungus Botryosphaeria dothidea in Melia azedarach [7] it turned out to be a widely occurring natural product. It shows marked DPPH radical scavenging activities with determined IC50 values of 18.7 ± 0.2 μM [7] and 148 ± 3 μM [2], respectively, and displays

• been used in a 1.2-fold excess) turned out to be very laborious. Moreover, the subsequent deprotection to the natural product 1 could not be achieved sufficiently: After treatment of 10a with tetrabutylammonium fluoride (TBAF), the signals of 1 could be detected in a 1H NMR spectrum of the crude

• pressure (Scheme 4). The product 1 could now be purified by a simple chromatography on silica gel and was obtained in 88% yield. NMR spectroscopic data of the natural product had been published by Wang et al. [2] and by Xiao et al. [7] (Table 1). A comparison of the 13C NMR data of the now synthesized

Recent progress in the synthesis of homotropane alkaloids adaline, euphococcinine and N-methyleuphococcinine

• Dimas J. P. Lima,
• Antonio E. G. Santana,
• Michael A. Birkett and
• Ricardo S. Porto

Beilstein J. Org. Chem. 2021, 17, 28–41, doi:10.3762/bjoc.17.4

• identical to that of the natural product [28]. The specific rotation [α]D of +5.7 was also compatible with that found in the literature {lit. [α]D +6 (c 2.0, MeOH), [19]}. Finally, the synthetic sample obtained by the authors when treated with (S)–Mosher's acid chloride was converted entirely to a Mosher

• NMR, 13C NMR, MS) were identical to those of the natural product, and the specific rotation [α]D28 −11.4 (c 0.7, CHCl3) comparable to that found in the literature {[α]D20 −13 (CHCl3), [17]}. Yu synthesis – 2009 Yu et al. prepared (−)-adaline (1) and the nonnatural enantiomer (−)-euphococcinine (2) in

All-carbon [3 + 2] cycloaddition in natural product synthesis

• Zhuo Wang and
• Junyang Liu

Beilstein J. Org. Chem. 2020, 16, 3015–3031, doi:10.3762/bjoc.16.251

• -carbon quaternary centers in a single step and has been demonstrated in the synthesis of complex natural products. In this review, we present the development of all-carbon [3 + 2] cycloadditions and illustrate their application in natural product synthesis reported in the last decade covering 2011–2020

• (inclusive). Keywords: all-carbon; cyclization; [3 + 2] cycloaddition; natural product synthesis; stereocenters; Introduction The highly-substituted, stereo-congested, five-membered carbocycle containing contiguous stereocenters is one of the most common structural features in many structurally complicated

• as the phosphine-catalyzed [3 + 2] cycloaddition [17], platinum-catalyzed [3 + 2] cycloaddition [18], and Rhodium-catalyzed [3 + 2] cycloaddition [12], were invented and have been extensively used in natural product synthesis in the last decade. Many reviews focusing the method development of the all

Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives

• Jonas Becher,
• Daria V. Berdnikova,
• Heiko Ihmels and
• Christopher Stremmel

Beilstein J. Org. Chem. 2020, 16, 2795–2806, doi:10.3762/bjoc.16.230

• successfully developed as G4-DNA ligands [17], the natural product berberine (1a) has attracted special attention. Berberine (1a) is an isoquinoline alkaloid with an exceptionally wide range of biological activities [23][24]. It has been shown that berberine (1a) and its derivatives act, for example, as anti

3-Acetoxy-fatty acid isoprenyl esters from androconia of the ithomiine butterfly Ithomia salapia

• Florian Mann,
• Daiane Szczerbowski,
• Lisa de Silva,
• Melanie McClure,
• Marianne Elias and
• Stefan Schulz

Beilstein J. Org. Chem. 2020, 16, 2776–2787, doi:10.3762/bjoc.16.228

• -enoate (12) was performed to verify the structural proposal and to determine the absolute configuration of the natural product (Scheme 4). The commercially available epoxide (S)-22 served as chiral starting material. 1,9-Nonanediol (19) was monobrominated and oxidized with IBX to yield 9-bromononanal (20

Vicinal difluorination as a C=C surrogate: an analog of piperine with enhanced solubility, photostability, and acetylcholinesterase inhibitory activity

• Yuvixza Lizarme-Salas,
• Alexandra Daryl Ariawan,
• Ranjala Ratnayake,
• Hendrik Luesch,
• Angela Finch and
• Luke Hunter

Beilstein J. Org. Chem. 2020, 16, 2663–2670, doi:10.3762/bjoc.16.216

• ), University of Florida, Gainesville FL 32610, United States School of Medical Sciences, University of New South Wales (UNSW), Sydney NSW 2052, Australia 10.3762/bjoc.16.216 Abstract Piperine, a natural product derived from peppercorns, has a variety of biological activities that make it an attractive lead

• for E-alkenes in medicinal chemistry. Keywords: Alzheimer's disease; bioisostere; conformational analysis; gauche effect; stereoselective synthesis; Introduction Piperine (1, Figure 1) is a well-known natural product that is derived from peppercorns [1][2][3]. Many biological studies of 1 have been

• motif is sometimes but not always an effective surrogate for E-alkenes suggests that this bioisosteric switch could be exploited more widely in medicinal chemistry as a means of increasing the selectivity of a lead compound towards its desired target. The natural product piperine (1) is the inspiration

A proposed sustainability index for synthesis plans based on input provenance and output fate: application to academic and industrial synthesis plans for vanillin as a case study

• John Andraos

Beilstein J. Org. Chem. 2020, 16, 2346–2362, doi:10.3762/bjoc.16.196

• ][28][29][30]; five plans involved chemical synthesis from wood-derived starting materials (lignosulfonic acid liquor or sawdust) [31][32][33][34][35][36][37]; seven plans involved chemical synthesis from either fossil-fuel or natural product-derived starting materials (guaiacol, eugenol, isoeugenol

• ] and other cellulosic biomass feedstocks, respectively. Isoeugenol and eugenol were chosen to originate from the natural product clover oil since 80% by weight of this essential oil is eugenol [48], and isoeugenol is directly obtained from eugenol by base-catalyzed isomerization. (5) Oxygen from air