Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

Beilstein J. Org. Chem. 2020, 16, 1991–2006, doi:10.3762/bjoc.16.166

• with their complex structure, a number of total syntheses have been reported. This review will compare the synthetic strategies reported through the end of 2019. Keywords: antiproliferative; polyketide natural products; tetrahydropyrans; total synthesis; Introduction The spliceostatins/thailanstatins

Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• the regiochemistry for terminal alkynes, affording the products substituted at the β-position. This regiochemistry switch might be regarded as the Holy Grail in Pauson–Khand chemistry. The synthetic potential of this methodology was demonstrated by the formal total synthesis of α-cuparenone [74][75

• intermediate in the total synthesis of α-cuparenone. Effect of the olefin partner in the regioselectivity of the PKR with trifluoromethyl alkynes [79]. Intermolecular PKR of trifluoromethylalkynes with 2-norbornene reported by the group of Konno [54]. Intermolecular PKR of diarylalkynes with 2-norbornene

Heterogeneous photocatalysis in flow chemical reactors

• Christopher G. Thomson,
• Ai-Lan Lee and
• Filipe Vilela

Beilstein J. Org. Chem. 2020, 16, 1495–1549, doi:10.3762/bjoc.16.125

An overview on disulfide-catalyzed and -cocatalyzed photoreactions

• Yeersen Patehebieke

Beilstein J. Org. Chem. 2020, 16, 1418–1435, doi:10.3762/bjoc.16.118

• applications in total synthesis, medium- and large-ring syntheses, and conjugate diene isomerization processes. In 2006, Crimmins successfully used this isomerization method in the syntheses of ophirin B and astrogorgin (Scheme 25) [31]. In the reaction, the intermediate 70 reacts with

• presence of PhSSPh, the new isomer 73 could also be converted to the desired (E,E)-isomer 71. In the total synthesis of the macrocyclic antibiotic antitumor agent (+)-hitachimycin, Smith used a disulfide-catalyzed isomerization [32] to synthesize the intermediate 75 with an E-configuration, which was

• disulfide-catalyzed enantioselective synthesis of ophirin B. Disulfide-catalyzed isomerization in the total synthesis of (+)-hitachimycin. Disulfide-catalyzed isomerization in the synthesis of (−)-gloeosporone. Acknowledgements I thank Prof. Xiao Wang (Nanjing University) for helpful discussions. Funding I

Recent synthesis of thietanes

• Jiaxi Xu

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

• intermediate for the total synthesis of sesquiterpene thioalkaloids (Scheme 3). Spiro[3.3]heptane derivatives were recently used as the surrogates of piperazines, piperidines, morpholines, and thiomorpholines, which display pharmacological activities [35]. 1,6-Thiazaspiro[3.3]heptane (24) was synthesized for

• starting material was converted into bis(hydroxymethyl)quinolizidinone 56. After mesylation and the double displacement with sodium sulfide, spirothietane-quinolizidine 57 was obtained as a key intermediate. It was further applied in the total synthesis of four different natural products of Nuphar

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

• this reaction, in most cases providing the products with a high enantioselectivity and a moderate yield. An exception was found with diisopropylzinc, for which only 56% ee could be obtained. The methodology was also successfully applied to the total synthesis of the natural alkaloid (R)-coniine

• , and future developments in substrate and organometallics scope can be expected. Copper-catalysed ACA of organometallics to piperidones. A) addition of organozinc reagents; B) addition of organoaluminium reagent in the total synthesis of (+)-myrtine; C) addition of Grignard reagents. Copper-catalysed

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

• group total synthesis of (–)-oxycodone. Biomimetic syntheses of rhodonoids A, B, E, and F. α-Photooxygenation of chiral aldehydes. Asymmetric photooxidation of indanone β-keto esters by singlet oxygen using PTC as a chiral inducer, and the related mechanism. Asymmetric photooxidation of both β-keto

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

• metathesis in tandem with a diene cross-metathesis as the crucial steps were reported by Lee in the total synthesis of (−)-amphidinolide E (3) (Scheme 6) [70]. It is noteworthy that the second-generation Grubbs catalyst was quite active and stereoselective for both the enyne and cross-metathesis steps

• complexity, by essentially using a Ru-catalyzed alkene–alkyne (Ru-AA) coupling reaction and a macrolactonization step (Scheme 8). In this carefully designed total synthesis, after applying a Marshall coupling reaction aimed at installing a propargyl group into the initial acetylene component, an enyne

• -metal-catalyzed transformations were needed to achieve the total synthesis of des-epoxy-amphidinolide N, including a palladium asymmetric allylic alkylation (Pd-AAA), a Mukaiyama aldol reaction (with Sn), and a Krische allylation (with Ir) [72]. As special feature of this procedure, an Evans aldol

Recent advances in Cu-catalyzed C(sp³)–Si and C(sp³)–B bond formation

• Balaram S. Takale,
• Ruchita R. Thakore,
• Elham Etemadi-Davan and
• Bruce H. Lipshutz

Beilstein J. Org. Chem. 2020, 16, 691–737, doi:10.3762/bjoc.16.67

• either an anthryl or naphthyl group, the use of which led to moderate to good enantioselectivities in most cases. An application of this method is shown for the total synthesis of the natural product (+)-blastmycinone (Scheme 24). As a follow up to this work, the same authors successfully accomplished

• . Interestingly, this protocol was applied to the total synthesis of (R)-oxiracetam (142), a drug used for the treatment of Alzheimer’s disease [61]. In a similar way, a ligand-free, intramolecular silylarylation of unsaturated amides 143 could be performed, albeit following a radical pathway leading to cyclic

Towards the total synthesis of chondrochloren A: synthesis of the (Z)-enamide fragment

• Jan Geldsetzer and
• Markus Kalesse

Beilstein J. Org. Chem. 2020, 16, 670–673, doi:10.3762/bjoc.16.64

Absolute configurations of talaromycones A and B, α-diversonolic ester, and aspergillusone B from endophytic Talaromyces sp. ECN211

• Ken-ichi Nakashima,
• Junko Tomida,
• Takao Hirai,
• Yoshiaki Kawamura and
• Makoto Inoue

Beilstein J. Org. Chem. 2020, 16, 290–296, doi:10.3762/bjoc.16.28

• were presented. Furthermore, Nicolaou and Li introduced a means by which the absolute configuration can be determined from the total synthesis of α-diversonolic ester (3) [5]. However, to the best of our knowledge, data that enabled the determination of the absolute configuration has not been published

• esters [3], and globosuxanthone B [4], among others. Diversonolic esters were firstly reported by Holker from cultures of Talaromyces diversus, anamorph Penicillium diversum [3]; however, the originally proposed structures of the diversonolic esters were revised after 25 years, following their total

• synthesis [5]. Furthermore, the compound with the originally proposed structure of β-diversonolic ester had already been isolated as blennolide C from the fungus Blennoria sp. prior to structural revision [2]. Consequently, the structures and spectroscopic data of the diversonolic esters and blennolide C

Recent developments in photoredox-catalyzed remote ortho and para C–H bond functionalizations

• Rafia Siddiqui and
• Rashid Ali

Beilstein J. Org. Chem. 2020, 16, 248–280, doi:10.3762/bjoc.16.26

• compounds, including bioactive natural and nonnatural products, but also due to its impact on the discovery of pharmaceutical candidates and the total synthesis of intricate natural products. On the other hand, more recently, the field of photoredox catalysis has become an indispensable and unparalleled

Copper-catalyzed enantioselective conjugate addition of organometallic reagents to challenging Michael acceptors

• Delphine Pichon,
• Jennifer Morvan,
• Christophe Crévisy and
• Marc Mauduit

Beilstein J. Org. Chem. 2020, 16, 212–232, doi:10.3762/bjoc.16.24

• products. Second, in order to be attractive for the total synthesis of relevant molecules, the involved EWG should preferably allow readily applicable and practicable postfunctionalizations [10]. Among the plethora of studied Michael acceptors, α,β-unsaturated aldehydes, thioesters, acylimidazoles, N

• , or trialkylaluminium reagents toward those challenging substrates and their fruitful application in the total synthesis of natural products. Review Enantioselective conjugate addition to challenging Michael acceptors Copper-catalyzed ECA to α,β-unsaturated aldehydes Nowadays, β-substituted enals

• ratios were obtained (51:49 to 97:3). Of note, chiral phosphines were also screened, but without any improvement of selectivity. Furthermore, this methodology was then efficiently applied to the total synthesis of several bisabolane sesquiterpenes, which exhibited anticancer and antimicrobial activities

Rapid, two-pot procedure for the synthesis of dihydropyridinones; total synthesis of aza-goniothalamin

• Thomas J. Cogswell,
• Craig S. Donald and
• Rodolfo Marquez

Beilstein J. Org. Chem. 2020, 16, 135–139, doi:10.3762/bjoc.16.15

• , three component coupling. Optimized conditions for the synthesis of diene 5. Ring-closing metathesis reaction of diene 5 to yield dihydropyridone 7 [20][21][22][23]. Total synthesis of aza-goniothalamin 1. Supporting Information Supporting Information File 218: Experimental, characterization data and

Convenient synthesis of the pentasaccharide repeating unit corresponding to the cell wall O-antigen of Escherichia albertii O4

• Tapasi Manna,
• Arin Gucchait and
• Anup Kumar Misra

Beilstein J. Org. Chem. 2020, 16, 106–110, doi:10.3762/bjoc.16.12

• fragments with adequate purity. In this direction, the total synthesis of the pentasaccharide repeating unit corresponding to the cell wall O-antigenic polysaccharide of the E. albertii O4 strain using a sequential glycosylation strategy is presented herein (Figure 1). Results and Discussion The synthesis

Pigmentosins from Gibellula sp. as antibiofilm agents and a new glycosylated asperfuran from Cordyceps javanica

• Soleiman E. Helaly,
• Wilawan Kuephadungphan,
• Patima Phainuphong,
• Mahmoud A. A. Ibrahim,
• Kanoksri Tasanathai,
• Suchada Mongkolsamrit,
• Janet Jennifer Luangsa-ard,
• Souwalak Phongpaichit,
• Vatcharin Rukachaisirikul and
• Marc Stadler

Beilstein J. Org. Chem. 2019, 15, 2968–2981, doi:10.3762/bjoc.15.293

• ], invertebrate-pathogenic [38], and marine-derived [39] fungi, or even obtained by total synthesis [40][41][42], with diverse biological activities [40][41][43][44][45]. Nevertheless, the new compound, glycoasperfuran (3), was devoid of activity in all antimicrobial assays in spite of the fact that the

Terpenes

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2019, 15, 2966–2967, doi:10.3762/bjoc.15.292

• elucidation, total synthesis, biosynthetic studies, bioactivity and functionalisation for mode of action studies, and other applications of terpenes, e.g. as fragrances. I thank all colleagues who have participated in this issue for their contributions and the whole Beilstein team for the professional support

Chemical synthesis of tripeptide thioesters for the biotechnological incorporation into the myxobacterial secondary metabolite argyrin via mutasynthesis

• David C. B. Siebert,
• Roman Sommer,
• Domen Pogorevc,
• Michael Hoffmann,
• Silke C. Wenzel,
• Rolf Müller and
• Alexander Titz

Beilstein J. Org. Chem. 2019, 15, 2922–2929, doi:10.3762/bjoc.15.286

• Saarbrücken, Germany 10.3762/bjoc.15.286 Abstract The argyrins are secondary metabolites from myxobacteria with antibiotic activity against Pseudomonas aeruginosa. Studying their structure–activity relationship is hampered by the complexity of the chemical total synthesis. Mutasynthesis is a promising

• , cytotoxicity and antibiotic activity, the selectivity profile of this class of compounds should be considered for optimization of future antibacterials. The first total synthesis was reported by Ley and co-workers [14] for argyrin B in 18 linear steps, followed by an alternative strategy towards argyrin F (6

• ) by the Kalesse group [15]. In 2011, Wu et al. reduced the length to 14 linear steps for the total synthesis of argyrins A and E [16]. Finally, Chen et al. described a synthesis yielding several derivatives of argyrin A with modification of the 4’-methoxytryptophan residue [17]. Changing the 4

Bacterial terpene biosynthesis: challenges and opportunities for pathway engineering

• Eric J. N. Helfrich,
• Geng-Min Lin,
• Christopher A. Voigt and
• Jon Clardy

Beilstein J. Org. Chem. 2019, 15, 2889–2906, doi:10.3762/bjoc.15.283

• significantly (Figure 8) [98]. Despite difficulties in engineering terpene biosynthesis, total synthesis of complex terpenoids does not appear to be a viable alternative. Traditionally, complex terpenes are synthesized from small and cheap chiral terpenes as starting material in (linear) multistep syntheses [99

• functionalization of nonactivated carbon atoms is one of the remaining challenges in organic synthesis [100][112][113]. Despite the progress made in total synthesis of terpenoids and the introduction of the two-phase mimicry of terpene biosynthesis during biomimetic syntheses, it has become obvious that total

• synthesis is currently not an efficient alternative to either the biotechnological production of terpenoids or the biosynthetic expansion of terpene chemical space [100][113]. Engineering terpene biosynthetic features to produce novel, non-natural terpenoids Terpene cyclases Most bacterial TCs produce one

A review of asymmetric synthetic organic electrochemistry and electrocatalysis: concepts, applications, recent developments and future directions

• Munmun Ghosh,
• Valmik S. Shinde and
• Magnus Rueping

Beilstein J. Org. Chem. 2019, 15, 2710–2746, doi:10.3762/bjoc.15.264

• in the synthesis of different complex and biologically relevant compounds as well as natural products. In 2008, Pilli and Santos developed an innovative method for the enantioselective total synthesis of the local anesthetic drug ropivacaine (197c) and its analogues levobupivacaine (197b) and

• -cyclodextrin as the cocatalyst provide 196 in a good yield and excellent stereoselectivity (Scheme 61). In 2011, Hurvois and his group reported a stereoselective electrochemical total synthesis of the tetrahydroisoquinoline alkaloid (−)-crispine A (200) and its natural enantiomer [108]. The initial steps

Safe and highly efficient adaptation of potentially explosive azide chemistry involved in the synthesis of Tamiflu using continuous-flow technology

• Cloudius R. Sagandira and
• Paul Watts

Beilstein J. Org. Chem. 2019, 15, 2577–2589, doi:10.3762/bjoc.15.251

• continuous-flow technology. The two steps involving azide chemistry in flow are reported herein (Scheme 2), with the vision of further integrating the other steps towards continuous-flow total synthesis of this drug. To this effect, we have already reported continuous flow shikimic acid (3) esterification

Chemical synthesis of the pentasaccharide repeating unit of the O-specific polysaccharide from Escherichia coli O132 in the form of its 2-aminoethyl glycoside

• Debasish Pal and
• Balaram Mukhopadhyay

Beilstein J. Org. Chem. 2019, 15, 2563–2568, doi:10.3762/bjoc.15.249

• glycoside; diarrhea; galactofuranose; O-specific polysaccharide; total synthesis; Introduction O-Polysaccharides are the most complex molecular systems present in the bacterial cell wall owing to the presence of various sugar residues connected through diverse glycosidic linkages. These complex structures

• and Galf. In this communication we report on the total synthesis of this pentasaccharide repeating unit of the O-specific polysaccharide in the form of its 2-aminoethyl glycoside (Figure 1) through a [3 + 2] converging strategy. The building blocks were prepared by suitable protecting group

• reducing end of the target pentasaccharide that will allow further conjugation using the terminal amine without affecting the glycosidic stereochemistry. Further retrosynthetic analysis of the target pentasaccharide 1 revealed that a [3 + 2] strategy will be the most suitable one for the total synthesis of

Functionalization of 4-bromobenzo[c][2,7]naphthyridine via regioselective direct ring metalation. A novel approach to analogues of pyridoacridine alkaloids

• Benedikt C. Melzer,
• Alois Plodek and
• Franz Bracher

Beilstein J. Org. Chem. 2019, 15, 2304–2310, doi:10.3762/bjoc.15.222

• biosyntheses of known alkaloids, a “pyridoacridine family tree” which is claimed to be useful for designing total synthesis, but also for predicting yet undiscovered alkaloids from this chemotype [6]. Only two tricyclic benzo[c][2,7]naphthyridine alkaloids, perlolidine (6; from rye grass, Lolium perenne) [7

• , phenolates), acyl anions (generated by umpolung of aldehydes with imidazolium salts) and by palladium-catalyzed cross-coupling reactions (Suzuki, Stille) [10]. A related Stille cross coupling of a benzo[c][2,7]naphthyridine bearing a triflate group at C-5 gave an intermediate for the total synthesis of

• of the 4-bromo residue (cross-coupling reactions, nucleophilic substitutions) should open the opportunity to generate a broad variety of 4,5-disubstituted benzo[c][2,7]naphthyridines as building blocks for natural products total synthesis (Figure 2D). Results and Discussion For the envisaged direct

Synthesis of acremines A, B and F and studies on the bisacremines

• Nils Winter and
• Dirk Trauner

Beilstein J. Org. Chem. 2019, 15, 2271–2276, doi:10.3762/bjoc.15.219

• isolated from fungi of the genus Acremonium. Here, we present the asymmetric total synthesis of acremine F which hinges on a modestly enantioselective dihydroxylation and a subsequent kinetic resolution via a highly selective asymmetric reduction. Chemoselective oxidation of acremine F gave access to

• acremines A and B. The dimerization of acremine F to bisacremine E was investigated but could not be achieved, shedding light on the formation of the acremine dimers in nature. Keywords: meroterpenoid; natural product; selective oxidation; total synthesis; Introduction Endophytic fungi grow in a symbiotic

• transformation requires enzymatic catalysis in nature. Selected members of the acremine family [3][4][5]. Retrosynthetic analysis of acremine F (5). Total synthesis of acremine F (5). Synthesis of acremines A and B through selective oxidation of acremine F. Proposed biomimetic dimerization of 5. Attempted

An overview of the cycloaddition chemistry of fulvenes and emerging applications

• Ellen Swan,
• Kirsten Platts and
• Anton Blencowe

Beilstein J. Org. Chem. 2019, 15, 2113–2132, doi:10.3762/bjoc.15.209

• al. developed a programmable enantioselective one-pot synthesis of molecules with eight stereocentres greatly improving the efficiency of natural product synthesis [83]. Each of these natural products are biologically active, hence their total synthesis will allow further characterisation of their