On drug discovery against infectious diseases and academic medicinal chemistry contributions

• Yves L. Janin

Beilstein J. Org. Chem. 2022, 18, 1355–1378, doi:10.3762/bjoc.18.141

• human pharmacology. Moreover, preparing fully artificial β-lactam analogues is also an active research field since, for instance aztreonam (61), is produced by total synthesis [304][305]. Amongst other issues, the main concern in this domain remains the design of compounds capable of resisting the

Enantioselective total synthesis of putative dihydrorosefuran, a monoterpene with an unique 2,5-dihydrofuran structure

• Irene Torres-García,
• Josefa L. López-Martínez,
• Rocío López-Domene,
• Manuel Muñoz-Dorado,
• Ignacio Rodríguez-García and
• Miriam Álvarez-Corral

Beilstein J. Org. Chem. 2022, 18, 1264–1269, doi:10.3762/bjoc.18.132

• decided to perform its total synthesis. Results and Discussion Our synthetic strategy is based on two metal-mediated steps (Scheme 1). In this way, we thought that the 2,5-dihydrofuran structural motif that is found in the target molecule 1 could be prepared through a Ag(I)-induced intramolecular addition

• rosiridol (Table 1), a substance that has been isolated from other natural sources [18][19], whose structure was also confirmed by total synthesis some years ago [20]. Comparison of NMR data (Table 1) confirmed the initial suspicion. We are still intrigued about the real structure of the natural product

• cyclization is a simple and efficient strategy for the preparation of the 2,5-dihydrofuran moiety present in many natural products. In fact, we have achieved the total synthesis of the 2,5-dihydrofuran structure 1. After systematic data analysis of our prepared compound and those in the literature, it can be

Vicinal ketoesters – key intermediates in the total synthesis of natural products

• Marc Paul Beller and
• Ulrich Koert

Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129

• intermediates in the total synthesis of natural products utilizing their electrophilic keto group as reactive site. Suitable key reactions are, e.g., aldol additions, carbonyl ene reactions, Mannich reactions, and additions of organometallic reagents. The vicinal arrangement of carbonyl groups allows the

• stabilization of reactive conformations by chelation or dipole control. Keywords: aldol addition; ketoesters; natural products; total synthesis; Introduction Vicinal ketoesters contain a carbonyl group adjacent to an ester group. One keto group results in α-ketoesters 1 and two vicinal keto groups lead to α,β

• as key intermediates for the total synthesis of natural products [1]. Thus, the high electrophilicity of the central carbonyl group in α,β-diketoesters 2 allows the formation of stable hydrates 5. In case of an enolizable position enolization (2→6) is facilitated. The chemistry of vicinal

Synthesis of protected precursors of chitin oligosaccharides by electrochemical polyglycosylation of thioglycosides

• Md Azadur Rahman,
• Kana Kuroda,
• Hirofumi Endo,
• Norihiko Sasaki,
• Tomoaki Hamada,
• Hiraku Sakai and
• Toshiki Nokami

Beilstein J. Org. Chem. 2022, 18, 1133–1139, doi:10.3762/bjoc.18.117

• blocks can reduce the number of steps in the total synthesis. However, it requires manipulation of the anomeric leaving groups and deprotection of the protected hydroxy group at the 4-position prior to glycosylation. Although automated electrochemical assembly, which is a one-pot iterative synthesis of

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

• dynamics of the active site during the enzyme reaction. Conclusion Endoperoxide compounds have recently attracted keen attention as a source of new drug leads, due to their unique structures and remarkable biological activities. To date, the total synthesis of endoperoxide-containing natural products and

Regioselectivity of the S_EAr-based cyclizations and S_EAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

• Jonali Das and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2022, 18, 293–302, doi:10.3762/bjoc.18.33

• stereochemistry in the Ir-catalyzed allylic substitution reactions. In 2016, Billingsley and co-workers disclosed the total synthesis of (−)-indolactam V (6), a nanomolar agonist of protein kinase C (Scheme 3) [12]. The authors applied an intramolecular SEAr reaction of 4-substituted indole derivative to

• construct a 3,4-fused tricyclic indole in a late stage of their total synthesis. Specifically, Michael-type addition of compound 4 took place regio- and diastereoselectively at the indole C3 position, furnishing tricyclic compound 5 (77%) which was then elaborated into the target natural product 6 in two

• or annulation of: (A) substituted arenes/heteroarenes and (B) 3,5-unsubstituted, 4-substituted indoles. Indole C3 regioselective intramolecular alkylation of indolyl allyl carbonates. Indole C3 regioselective Michael-type cyclization in the total synthesis of (−)-indolactam V. Synthesis of azepino

Iridium-catalyzed hydroacylation reactions of C1-substituted oxabenzonorbornadienes with salicylaldehyde: an experimental and computational study

• Angel Ho,
• Austin Pounder,
• Krish Valluru,
• Leanne D. Chen and
• William Tam

Beilstein J. Org. Chem. 2022, 18, 251–261, doi:10.3762/bjoc.18.30

• intermediates have found use in the total synthesis of (+)-norchelidonine (an isoquinoline alkaloid) [55], sertraline (an antidepressant) [56], and arnottin I (an anti-inflammatory) [57]. Although OBD 1 has been shown to undergo many different modes of reactivity in both a stereo- and enantioselective manner

Synthesis and late stage modifications of Cyl derivatives

• Phil Servatius and
• Uli Kazmaier

Beilstein J. Org. Chem. 2022, 18, 174–181, doi:10.3762/bjoc.18.19

• . Supporting Information Supporting Information File 16: Detailed synthetic procedures, characterization of all molecules and copies of NMR spectra. Acknowledgements This article is part of the PhD thesis of Phil Servatius “Total synthesis of natural HDAC inhibitors and derivatives thereof”, Saarland

The enzyme mechanism of patchoulol synthase

• Houchao Xu,
• Bernd Goldfuss,
• Gregor Schnakenburg and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2022, 18, 13–24, doi:10.3762/bjoc.18.2

• (ca. 40%) [1][2]. Pure patchoulol is a crystalline material that has first been described by Gal in 1869 [3]. Its planar structure was initially described as that of compound 1 (Figure 1) by Treibs [4], and later reassigned to structure 2 based on a total synthesis from camphor by Büchi [5]. Because

• CAS number 21698-41-9 is even assigned the opposite absolute configuration as expected from these biosynthetic considerations. After a recent correction [22] of its initially reported relative configuration [23] that was shown to be erroneous by total synthesis [24], we now address the problem of the

First total synthesis of hoshinoamide A

• Haipin Zhou,
• Zihan Rui,
• Yiming Yang,
• Shengtao Xu,
• Yutian Shao and
• Long Liu

Beilstein J. Org. Chem. 2021, 17, 2924–2931, doi:10.3762/bjoc.17.201

• -sensitive Plasmodium falciparum. Herein, we describe the first total synthesis of hoshinoamide A by the combination of liquid-phase and solid-phase peptide synthesis. Liquid-phase synthesis is to improve the coupling yield of ʟ-Val3 and N-Me-ᴅ-Phe2. Connecting other amino acids efficiency and convergence is

• achieved by solid-state synthesis. Our synthetic strategy could synthesize the target peptide in high yield with good purity Keywords: antimalarial; highly methylated polypeptides; hoshinoamides; total synthesis; Introduction Malaria is an insect-borne infectious disease caused by parasites of the genus

• cytotoxicity compared to hoshinoamide B. Herein, we report the initial progress on the total synthesis of hoshinomaide A. The key challenges for the total synthesis of hoshinoamide A are the coupling of highly methylated amino acids and the purification of hydrophobic peptides. Results and Discussion As shown

Total synthesis of the O-antigen repeating unit of Providencia stuartii O49 serotype through linear and one-pot assemblies

• Tanmoy Halder and
• Somnath Yadav

Beilstein J. Org. Chem. 2021, 17, 2915–2921, doi:10.3762/bjoc.17.199

• , we herein report the total synthesis of a trisaccharide repeating unit of the O-antigen polysaccharide of the P. stuartii O49 serotype containing the →6)-β-ᴅ-Galp-(1→3)-β-ᴅ-GalpNAc(1→4)-α-ᴅ-Galp(1→ linkage. The synthesis of the trisaccharide repeating unit was carried out first by a linear strategy

• synthesis of the O-antigens, that of Providencia rustigianii O34 was reported by Mukhopadhyay et al. in 2013 [34]. Chheda and co-worker, in 2015, reported the total synthesis of the pentasaccharide repeating unit of the O-specific polysaccharide of Providencia alcalifaciens O28 [35]. In 2017, Kulkarni and

• co-worker accomplished the total synthesis of a O-polysaccharide of Providencia alcalifaciens O22 via a one pot assembly of the oligosaccharide unit [36]. Recently in 2020 Werz and co-workers completed the total synthesis of a tri-, hexa-, and heptasaccharide of the O-polysaccharide of Providencia

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

• , the reactivity and applicability outperformed the racemic variant. Application of this methodology was applied towards the total synthesis of maraviroc, an anti-HIV drug, which was synthesized in 5 steps starting from styrene (115a) and CBr4 (20a). Carboamination In 2017, the Bao group investigated

Highly stereocontrolled total synthesis of racemic codonopsinol B through isoxazolidine-4,5-diol vinylation

• Lukáš Ďurina,
• Anna Ďurinová,
• František Trejtnar,
• Ľuboš Janotka,
• Lucia Messingerová,
• Jana Doháňošová,
• Ján Moncol and
• Róbert Fischer

Beilstein J. Org. Chem. 2021, 17, 2781–2786, doi:10.3762/bjoc.17.188

• were inactive towards the examined α-glucosidases. The enantiomer of 2 was the only one that still exhibited inhibitory activity against yeast α-glucosidase [2]. To our knowledge, the sole total synthesis of (−)-codonopsinol B and similar hydroxylated pyrrolidines to date was reported in the above

Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds

• Alemayehu Gashaw Woldegiorgis and
• Xufeng Lin

Beilstein J. Org. Chem. 2021, 17, 2729–2764, doi:10.3762/bjoc.17.185

• considerable attention in recent years due to their wide application in the total synthesis of axially chiral natural products, functional materials, bioactive compounds, privileged chiral ligands, and have further potential applications in asymmetric catalysis and drug discovery. Accordingly, considerable

The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet–Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids

• Marco Keller,
• Karl Sauvageot-Witzku,
• Franz Geisslinger,
• Nicole Urban,
• Michael Schaefer,
• Karin Bartel and
• Franz Bracher

Beilstein J. Org. Chem. 2021, 17, 2716–2725, doi:10.3762/bjoc.17.183

• relationships in this chemotype. Keywords: acyl Pictet–Spengler reaction; alkaloids; antiproliferative activity; benzyltetrahydroisoquinolines; ion channels; protective group; total synthesis; Introduction The benzylisoquinoline alkaloids are a large and diverse class of plant secondary metabolites including

• by lithium alanate reduction [18][19]. In a novel total synthesis of the racemic alkaloid N-methylcoclaurine (1) performed in this course we also used the ethoxycarbonyl group successfully for protection of two phenolic groups at two different rings during the N-acyl-Pictet–Spengler reaction [15

Synthesis of highly substituted fluorenones via metal-free TBHP-promoted oxidative cyclization of 2-(aminomethyl)biphenyls. Application to the total synthesis of nobilone

• Ilya A. P. Jourjine,
• Lukas Zeisel,
• Jürgen Krauß and
• Franz Bracher

Beilstein J. Org. Chem. 2021, 17, 2668–2679, doi:10.3762/bjoc.17.181

• groups for phenols) and was further utilized in the first total synthesis of the natural product nobilone. Keywords: cross-dehydrogenative coupling; cyclization; fluorenones; nobilone; total synthesis; Introduction Fluorenones are an important class of aromatic natural products, and since the

• activated derivatives (intramolecular Friedel–Crafts acylation) [29][30][31] found wide application here. In a different approach, a total synthesis of dengibsin (1a) was accomplished by Wang and Snieckus in 15 steps by means of a directed remote metalation [32], using a benzamide residue as the directing

• -radical reagents [62]. An extremely poor yield was further obtained with methylenedioxy substrate 15p. Our application of this new protocol to the first total synthesis of the natural product nobilone (1d) is depicted in Scheme 7. The commercially available phenol 16 was TBS-protected to give compound 17

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

• tertiary amine-thiourea catalyst (cat. 82). This cascade reaction afforded aza-Michael adducts in 77–92% yields with high ee (up to 90%) (Table 19) [55]. Du et al. developed an enantioselective catalytic tandem aminolysis/aza-Michael addition for the asymmetric total synthesis of two natural Apocynaceae

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

• reactions through mid-2002 have been thoroughly discussed in a past review by Paquette [1]. The current review expands on that work by providing an updated account from mid-2002 through early 2021, including the following recently developed applications: asymmetric synthesis, total synthesis, tandem

• 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

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

• brevipolide H (8) Two years after the successful synthesis of ent-brevipolide H (ent-8), in 2016, Hou and co-workers reported the first total synthesis of natural brevipolide H (8) [15]. The retrosynthesis was initiated by disconnection of the cinnamate ester bond to give intermediate 79. The 5,6-dihydro-α

• (13) Sabitha and Raju demonstrated the first total synthesis of brevipolide M (13) in 2017 [17]. In the retrosynthesis, compound 93 is hypothesized from the Mitsunobu inversion at the C6’ stereocenter with (E)-p-methoxycinnamic acid (17) and ring-closing metathesis of tetrahydrofuran 93 (Scheme 11

• , Sabitha and Raju reported another approach to synthesize brevipolide M (13) which was shorter and more efficient than the former strategy [18]. Furthermore, this improved strategy was applied to achieve the first total synthesis of brevipolide N (14) by utilizing a different acid counterpart in the late

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

• presence of stoichiometric/catalytic amounts of Hg(II) salts. The classification of this review is based on the following topics. Cyclization reactions involving the stoichiometric amount of Hg(II) salts. Cyclization reactions involving the catalytic amount of Hg(II) salts. Total synthesis involving Hg(II

• insertion and then oxidation (Scheme 54). This methodology was later successfully utilized for the total synthesis of raloxifene and benzo[b]thiophene derivatives [115]. Cyclization involving allenes (>C=C=C<) Hg(II) triflate salts had also been successfully employed for the arylallene 181 cyclization by

• 186 in an efficient and selective manner. It was also shown that from enantiopure allenyl derivatives, the desired pure cyclized product was generated by utilizing the above reaction conditions (Scheme 57) [118]. Mercury(II)-salt-mediated cyclization in total synthesis Apart from previously described

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

• the SN2 alkylation of methylene ester-substituted 2-oxindole 4 [31]. The utility of this methodology has been demonstrated through the total synthesis of (−)-debromoflustramine B (Scheme 1B). In an attempt to devise variants of this reaction of greater versatility and synthetic utility; we sought to

Progress and challenges in the synthesis of sequence controlled polysaccharides

• Giulio Fittolani,
• Theodore Tyrikos-Ergas,
• Denisa Vargová,
• Manishkumar A. Chaube and
• Martina Delbianco

Beilstein J. Org. Chem. 2021, 17, 1981–2025, doi:10.3762/bjoc.17.129

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

• , 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

• cascade reaction. Total synthesis of (+)-smyrindiol (17). Michael addition of 4-hydroxycoumarin (1) to enones 2 through a bifunctional modified binaphthyl organocatalyst 18. Michael addition of ketones 20 to 3-aroylcoumarins 19 using a cinchona alkaloid-derived primary amine catalyst 22. Enantioselective

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

• increasing the overall yield. The resulting eight-step synthesis could be scaled to produce more than 100 kg of compound 41 [109]. Based on what was presented so far, vanadium catalysis is mainly applied as one of the steps involved in a total synthesis that usually leads to the formation of a valuable

• White’s oxidation method as the final step in the first total synthesis of gracilioether F (75) [157], a natural polyketide with an unusual tricyclic core and five contiguous stereocenters, part of the family of gracilioethers 71–74 (Scheme 26A) extracted from the marine sponge Plakinastrella mamillaris

• anilines afforded α-aminoalkyl radicals that could be coupled with a wide range of electrophilic partners to afford the products in moderate to good yields. The new reaction was also used in the first step of the total synthesis of a caspase-3 inhibitor (90), and mechanistic investigations showed that O2

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

• strategy in total synthesis can be found [82][83][84][85][86][87][88][89][90]. The reaction’s mild conditions and high chemoselectivity allowed its use even in advanced steps in a total synthesis route when diverse functional groups were present in the intermediates. Two representative examples of the

• potential of this strategy in total synthesis routes are the work by Liu [83] for the synthesis of hispidanin A (55, Scheme 23A) and the synthesis of (−)-nodulisporic acid C (58) described by Pronin [84] (Scheme 23B). In both studies, cascade reactions involving the putative enolate ion formed after the