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

The biomimetic synthesis of balsaminone A and ellagic acid via oxidative dimerization

• Sharna-kay Daley and
• Nadale Downer-Riley

Beilstein J. Org. Chem. 2020, 16, 2026–2031, doi:10.3762/bjoc.16.169

• ]. There are many important applications of oxidative dimerization reactions, one of which is the direct synthesis of natural product scaffolds [1][7][16][17][18]. Examples of this application include the biomimetic synthesis of the bioactive natural products bismurrayaquinone A (1) [16], parvistemin A (2

• be achieved in 57% yield over 5 steps. The synthesis of ellagic acid (5) on the other hand featured an o-chloranil-mediated dimerization of methyl gallate (15), which yielded the natural product in 48% yield over 5 steps, as reported by Tsuboi et al. (Scheme 3) [23]. Results and Discussion Biomimetic

• the biomimetic synthesis of the natural product as shown in Scheme 5. Synthesis of ellagic acid With the synthesis of balsaminone A (4) accomplished, the direct biomimetic synthesis of ellagic acid (5) was targeted. While the synthesis of ellagic acid (5) has been achieved in 48% yield over four steps

A complementary approach to conjugated N-acyliminium formation through photoredox-catalyzed intermolecular radical addition to allenamides and allencarbamates

• Olusesan K. Koleoso,
• Matthew Turner,
• Felix Plasser and
• Marc C. Kimber

Beilstein J. Org. Chem. 2020, 16, 1983–1990, doi:10.3762/bjoc.16.165

• innovative transformations, including cycloadditions [5][6][7][8][9], intramolecular cyclizations and intermolecular addition reactions [10][11][12][13][14][15][16][17][18], as well as the use of the allenamide building block in natural product synthesis [1]. Addition reactions of allenamides, which can also

Et₃N/DMSO-supported one-pot synthesis of highly fluorescent β-carboline-linked benzothiophenones via sulfur insertion and estimation of the photophysical properties

• Dharmender Singh,
• Vipin Kumar and
• Virender Singh

Beilstein J. Org. Chem. 2020, 16, 1740–1753, doi:10.3762/bjoc.16.146

• ] which were attributed to the presence of an electrophilic as well as a nucleophilic functionality in this natural product [1]. Encouraged by the applications of β-carboline and benzothiophene motifs in medicinal and materials chemistry, it was envisaged to construct a β-carboline-based novel molecular

Recent synthesis of thietanes

• Jiaxi Xu

Beilstein J. Org. Chem. 2020, 16, 1357–1410, doi:10.3762/bjoc.16.116

A cyclopeptide and three oligomycin-class polyketides produced by an underexplored actinomycete of the genus Pseudosporangium

• Shun Saito,
• Kota Atsumi,
• Tao Zhou,
• Keisuke Fukaya,
• Daisuke Urabe,
• Naoya Oku,
• Md. Rokon Ul Karim,
• Hisayuki Komaki and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2020, 16, 1100–1110, doi:10.3762/bjoc.16.97

• , which was chosen with the aid of a database survey on the history of chemical studies and the presence of biosynthetic genes. The same approach is also applicable to other natural product resources and should help discover metabolites with higher degree of novelty, provided that support from

Copper-catalysed alkylation of heterocyclic acceptors with organometallic reagents

• Yafei Guo and
• Syuzanna R. Harutyunyan

Beilstein J. Org. Chem. 2020, 16, 1006–1021, doi:10.3762/bjoc.16.90

• the total synthesis of the natural product (+)-myrtine with 14% overall yield (Scheme 1B) [17]. For this application, the highest yield (73%) and enantioselectivity (96% ee) were obtained using the chiral ligand L3 and a copper salt as the catalyst. Despite the fact that examples of high yield and

• quinolone scope revealed that substrates bearing Me, Br, CF3, ether, amide, and ester substituents, respectively, were also tolerated successfully. In addition, the catalytic system was applied to the synthesis of the natural product (+)-angustureine with an excellent outcome (92% yield, 97% ee) (Scheme 6A

Fabclavine diversity in Xenorhabdus bacteria

• Sebastian L. Wenski,
• Harun Cimen,
• Natalie Berghaus,
• Sebastian W. Fuchs,
• Selcuk Hazir and
• Helge B. Bode

Beilstein J. Org. Chem. 2020, 16, 956–965, doi:10.3762/bjoc.16.84

• via conjugation, with Escherichia coli as a donor strain, followed by homologous recombination as described previously [14][22]. This led to a formal ‘knock out’ of the BGC and no production of the respective natural product without induction, whereas induced mutants showed mostly an overproduction of

• the respective natural product [14]. Initially, the non-induced promoter-exchange mutant was compared with the induced mutant and the wild type to identify signals, related to possible biosynthesis products of the fcl BGCs using the known structure of 1 as a reference [20]. To confirm these signals as

Recent applications of porphyrins as photocatalysts in organic synthesis: batch and continuous flow approaches

• Rodrigo Costa e Silva,
• Luely Oliveira da Silva,
• Aloisio de Andrade Bartolomeu,
• Timothy John Brocksom and
• Kleber Thiago de Oliveira

Beilstein J. Org. Chem. 2020, 16, 917–955, doi:10.3762/bjoc.16.83

• garden under sunlight irradiation; notably, ascaridole is an effective anthelmintic natural drug obtained in this protocol from another readily available natural product α-terpinene. Several other approaches have been described in both synthesis and derivatizations of ascaridole. However, the Meunier

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

• Valerian Dragutan,
• Ileana Dragutan,
• Albert Demonceau and
• Lionel Delaude

Beilstein J. Org. Chem. 2020, 16, 738–755, doi:10.3762/bjoc.16.68

•  11). This innovative methodology allowed the installation of the vicinal exo‐methylene branches characteristic for the cytotoxic marine natural product amphidinolide V as well as the determination of its absolute configuration. It further enabled the synthesis of a set of diastereomers and analogs of