(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• -cubanes (Scheme 9B) [51]. Partial deprotection of diester 88 led to acid 89 as a key intermediate and in situ activation of the acid as the hypervalent iodine complex enabled a photoredox decarboxylative amination to 1,2-cubane 90. Alternatively, conversion of the acid moiety of 89 to redox active esters

Confirmation of the stereochemistry of spiroviolene

• Yao Kong,
• Yuanning Liu,
• Kaibiao Wang,
• Tao Wang,
• Chen Wang,
• Ben Ai,
• Hongli Jia,
• Guohui Pan,
• Min Yin and
• Zhengren Xu

Beilstein J. Org. Chem. 2024, 20, 852–858, doi:10.3762/bjoc.20.77

• synthetic intermediate of 2 to spiroviolene. By taking advantage of the DFT transition state analysis of the hydroboration reaction of a key intermediate, as well as NOE correlation analysis of the resultant product, Snyder and co-workers have reassigned the right structure of spiroviolene to 1. However

Pseudallenes A and B, new sulfur-containing ovalicin sesquiterpenoid derivatives with antimicrobial activity from the deep-sea cold seep sediment-derived fungus Pseudallescheria boydii CS-793

• Zhen Ying,
• Xiao-Ming Li,
• Sui-Qun Yang,
• Hong-Lei Li,
• Xin Li,
• Bin-Gui Wang and
• Ling-Hong Meng

Beilstein J. Org. Chem. 2024, 20, 470–478, doi:10.3762/bjoc.20.42

• pathway, the bergamotene sesquiterpenoid (I) is presumed to be a key intermediate cyclized from farnesyl diphosphate (FPP) via nerolidyl diphosphate (NPP) followed by a bisabolyl cation [14]. Subsequent oxidation (bishydroxylation) catalyzed by some oxygenase such as P450 would afford the key intermediate

Metal-catalyzed coupling/carbonylative cyclizations for accessing dibenzodiazepinones: an expedient route to clozapine and other drugs

• Amina Moutayakine and
• Anthony J. Burke

Beilstein J. Org. Chem. 2024, 20, 193–204, doi:10.3762/bjoc.20.19

• diverse dibenzodiazepinones via a copper-catalyzed C–N bond coupling between 2-halobenzoates and o-phenylenediamines leading to a key intermediate that undergoes an intramolecular N-acylation to afford the corresponding dibenzodiazepinone structure in high yields (Scheme 1b) [14]. Another innovative

Unprecedented synthesis of a 14-membered hexaazamacrocycle

• Anastasia A. Fesenko and
• Anatoly D. Shutalev

Beilstein J. Org. Chem. 2023, 19, 1728–1740, doi:10.3762/bjoc.19.126

• EtOH, and NaOH in water (Scheme 1). The key intermediate of the macrocycle preparation, imidate 4, was synthesized using the reported procedure [43] by refluxing a solution of aminopyrazole 3 in triethyl orthoformate. First, we studied the reaction of imidate 4 with hydrazine hydrate in EtOH under

• )) for the N2H4-promoted transformation of pyrazolopyrimidine (E)-8 into macrocycle 5 in MeOH solution. Free energies in kcal/mol at 298 K and 1 atm. Synthesis of the key intermediate of the macrocycle preparation, 3-[(ethoxymethylene)amino]-1-methyl-1H-pyrazole-4-carbonitrile (4). Synthesis of

Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

• shown in Figure 14. 2-Methylbut-3-en-2-ol (14.1) was used as substrate and the next steps were almost comparable to those reported in Figure 13. The key intermediate 14.4 was isolated after a three-step sequence and used to prepare 14.5. 1.3 Analogues of PAF with modification at the sn-2 position The

• 22.10. However, the last step features the lower yield (54%) of this 8-step synthesis. In 1994, Bittman et al. reported an alternative strategy to introduce the phosphocholine moiety by the preparation of a cyclic phosphite as a key intermediate [119]. This one-pot three-step sequence starts with the

• alcohol with iodoethane and the transformation of the t-Bu ether in acetyl ester following the method of Ganem and Small [141], produced, after saponification, the key intermediate 31.6. In 1993, Pinchuk reported a stereocontrolled synthesis of both enantiomers of analogues of edelfosine featuring a C18:1

Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

• Hui Yu and
• Feng Xu

Beilstein J. Org. Chem. 2023, 19, 1259–1288, doi:10.3762/bjoc.19.94

• oxidative alkylation of cyclic benzyl ethers with malonates or ketones. Oxygen is used as a terminal oxidant at atmospheric pressure. The key intermediate of this oxidative coupling reaction is benzyl alcohol intermediate C (Scheme 4) [52]. The generation of N–O radicals from NHPI in the presence of oxygen

• metal-triggered oxidation of the ether substrate to obtain the corresponding radical or oxonium ion as the key intermediate to obtain the final coupling product. Subsequently, some novel Co-catalyzed coupling mechanisms have been proposed. In 2016, Lu et al. reported that the Co/TBHP catalyst oxidation

Selective construction of dispiro[indoline-3,2'-quinoline-3',3''-indoline] and dispiro[indoline-3,2'-pyrrole-3',3''-indoline] via three-component reaction

• Ziying Xiao,
• Fengshun Xu,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2023, 19, 1234–1242, doi:10.3762/bjoc.19.91

• ), in which the in situ-generated adduct of thiophenol and 3-phenacylideneoxindole was believed to be the key intermediate [53][54][55]. Inspired by these elegant synthetic protocols and in continuation of our aim to develop convenient reactions for the synthesis of diverse spiro compounds [56][57][58

Unravelling a trichloroacetic acid-catalyzed cascade access to benzo[f]chromeno[2,3-h]quinoxalinoporphyrins

• Chandra Sekhar Tekuri,
• Pargat Singh and
• Mahendra Nath

Beilstein J. Org. Chem. 2023, 19, 1216–1224, doi:10.3762/bjoc.19.89

• with 2-hydroxynaphthalene-1,4-dione, aromatic aldehydes and dimedone in the presence of 20 mol % trichloroacetic acid in chloroform at 65 °C. Interestingly, a sequential approach for constructing copper(II) benzo[f]chromeno[2,3-h]quinoxalinoporphyrin 3 was also followed by capturing a key intermediate

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

• beyond the frontier orbitals of the neutral photocatalyst and thus, higher redox potentials. However, the identity of the key intermediate has remained a matter of debate [40][70][71]. Full elucidations of the mechanism toward confirming the key(/main) active catalyst species and possible deactivation

• transfer. Second-order kinetics analyses revealed that rapid charge recombination (e.g., kCR (PC1•−) = 2.6 × 108 M−1 s−1) is a significant deactivation pathway in the generation of the key intermediate. This deactivation by back electron transfer taking place in the Marcus-inverted region of electron

Aromatic C–H bond functionalization through organocatalyzed asymmetric intermolecular aza-Friedel–Crafts reaction: a recent update

• Anup Biswas

Beilstein J. Org. Chem. 2023, 19, 956–981, doi:10.3762/bjoc.19.72

• -substituted indoles which effectively attacked the electrophile through the C2 position. The reaction was even compatible with pyrroles (Scheme 7a). The utility of this methodology was successfully demonstrated by the synthesis of product 23a, the key intermediate of natural product (+)-trigonoliimine (Scheme

• was shown by synthesizing 110, a key intermediate of (R)-bifonazole (Scheme 25b) [55]. Thioureas and squaramides In 2018, Yang, Deng and co-workers developed an aza-Friedel–Crafts aminoalkylation of 4- and 5-hydroxyindoles 111. As electron-demanding component, N-Boc pyrazolinone ketimines 100 were

Photoredox catalysis enabling decarboxylative radical cyclization of γ,γ-dimethylallyltryptophan (DMAT) derivatives: formal synthesis of 6,7-secoagroclavine

• Alessio Regni,
• Francesca Bartoccini and
• Giovanni Piersanti

Beilstein J. Org. Chem. 2023, 19, 918–927, doi:10.3762/bjoc.19.70

• ][79][80][81][82][83][84][85]. To test this concept, we turned our attention to the synthesis of key intermediate 5 (Scheme 1). The synthesis began with protection of the indole nitrogen of the known compound 1, which is readily available from commercially available 4-bromoindole in one step [62

• ]. Regioselective palladium-catalyzed prenylation of 2 with prenylboronic acid pinacol ester and subsequent hydrolysis with LiOH provided the linear prenylated acid 4 in good yield. Coupling acid 4 with N-hydroxyphthalimide using DCC and a catalytic amount of DMAP afforded the key intermediate 5 in 59% yield. With

• functionalized 3,4-fused tricyclic indoles with medium-sized rings (seven and eight), which have been largely neglected in previous studies, can be synthesized by this new protocol. Notably, the reaction has been successfully applied in the formal synthesis of (±)-6,7-secoagroclavine, a key intermediate for a

Pyridine C(sp²)–H bond functionalization under transition-metal and rare earth metal catalysis

• Haritha Sindhe,
• Malladi Mounika Reddy,
• Karthikeyan Rajkumar,
• Akshay Kamble,
• Amardeep Singh,
• Anand Kumar and
• Satyasheel Sharma

Beilstein J. Org. Chem. 2023, 19, 820–863, doi:10.3762/bjoc.19.62

Sulfate radical anion-induced benzylic oxidation of N-(arylsulfonyl)benzylamines to N-arylsulfonylimines

• Joydev K. Laha,
• Pankaj Gupta and
• Amitava Hazra

Beilstein J. Org. Chem. 2023, 19, 771–777, doi:10.3762/bjoc.19.57

• persulfate (K2S2O8) as the exclusive reagent [14]. The mechanistic study revealed that an initial oxidation to an iminium ion could be the key intermediate in the intramolecular cyclization step. In sharp contrast, when N-aryl(benzyl)amines that do not have an ortho-substituted nucleophile in aniline ring

Photocatalytic sequential C–H functionalization expediting acetoxymalonylation of imidazo heterocycles

• Deepak Singh,
• Shyamal Pramanik and
• Soumitra Maity

Beilstein J. Org. Chem. 2023, 19, 666–673, doi:10.3762/bjoc.19.48

• isolated, further confirming the involvement of a malonyl radical generated by the cleavage of the C–Br bond of 2a [28]. Next, an attempt was made to identify the key intermediate of the reaction (Scheme 3B). When compound 5 was subjected to the acetylation reaction individually with Zn(OAc)2 and AcOH

Combretastatins D series and analogues: from isolation, synthetic challenges and biological activities

• Jorge de Lima Neto and
• Paulo Henrique Menezes

Beilstein J. Org. Chem. 2023, 19, 399–427, doi:10.3762/bjoc.19.31

• seco-acid 36. Using this approach, the authors were able to achieve the formal synthesis of 2 reaching a key intermediate in 34% overall yield after 9 steps (Scheme 16). Cousin and co-workers [50] innovated by using the Chan–Lam coupling [23][24][25] for the diaryl ether formation and applying an

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

• % yield [17][18]. This key intermediate was then converted into ketone 19 in 11 steps leading to the desired dicyclopenta[a,d]cyclooctane structure 21 [19]. As explained by the authors, the RCM reaction was not as easy as expected and extensive work was necessary to accomplished the construction of this

• additional functionalization steps the key intermediate 128. This compound constituted the substrate for the Pd-promoted intramolecular cyclization. In this case, an enol triflate was used instead of an alkenyl halide which required the presence of an electron-rich phosphine, a lower temperature (50 °C

NaI/PPh₃-catalyzed visible-light-mediated decarboxylative radical cascade cyclization of N-arylacrylamides for the efficient synthesis of quaternary oxindoles

• Dan Liu,
• Yue Zhao and
• Frederic W. Patureau

Beilstein J. Org. Chem. 2023, 19, 57–65, doi:10.3762/bjoc.19.5

• replacing the methyl with a phenyl group at the N-arylacrylamide core significantly affected the reaction efficiency from 72% to 34% yield (3pa). Satisfyingly, substrate 1q could successfully undergo decarboxylative cascade cyclization to afford 3qa with 70% yield, which is used as a key intermediate in the

Total synthesis of grayanane natural products

• Nicolas Fay,
• Rémi Blieck,
• Cyrille Kouklovsky and
• Aurélien de la Torre

Beilstein J. Org. Chem. 2022, 18, 1707–1719, doi:10.3762/bjoc.18.181

• ). This intermediate was then allylated, the ester group selectively reduced with Zn(TMP)2 and LiBH3NMe2 and the resulting primary alcohol was protected as a TBS ether, providing intermediate 23 as a single diastereomer. This key intermediate 23 was then submitted to a Ni-catalyzed α-vinylation and direct

• authors showed that a key intermediate could be obtained enantioselectively (93% ee) by a combination of a chiral catalyst and chiral auxiliary, although requiring extra steps for auxiliary installation and cleavage. Scheme 12 summarizes the last 3 synthetic strategies for grayanane synthesis. Each group

Rhodium-catalyzed intramolecular reductive aldol-type cyclization: Application for the synthesis of a chiral necic acid lactone

• Motoyuki Isoda,
• Kazuyuki Sato,
• Kenta Kameda,
• Kana Wakabayashi,
• Ryota Sato,
• Hideki Minami,
• Yukiko Karuo,
• Atsushi Tarui,
• Kentaro Kawai and
• Masaaki Omote

Beilstein J. Org. Chem. 2022, 18, 1642–1648, doi:10.3762/bjoc.18.176

• . In addition, we demonstrated a new approach to a necic acid lactone 2j that is a diastereomer of monocrotalic acid, a key intermediate of monocrotalin. Bioactive natural products bearing a 3-hydroxy-2-methyllactone scaffold. Monocrotaline and its structural components. Molecular structure of necic

Synthetic study toward the diterpenoid aberrarone

• Liang Shi,
• Zhiyu Gao,
• Yiqing Li,
• Yuanhao Dai,
• Yu Liu,
• Lili Shi and
• Hong-Dong Hao

Beilstein J. Org. Chem. 2022, 18, 1625–1628, doi:10.3762/bjoc.18.173

• was further confirmed through X-ray crystallographic analysis. With the key intermediate 10 in hand, we were in a position to test the planned two-step transformation including the palladium-catalyzed reductive cross coupling with HCO2H followed by Pd/C-catalyzed hydrogenation. To our surprise, the

• natural product aberrarone from the key intermediate cyclopentenone 8 is currently underway, and will be reported in due course. Selected representative natural products with 6-5-5 tricyclic skeleton. Retrosynthetic analysis of aberrarone (1). Synthetic study toward aberrarone (1). Supporting Information

Formal total synthesis of macarpine via a Au(I)-catalyzed 6-endo-dig cycloisomerization strategy

• Jiayue Fu,
• Bingbing Li,
• Zefang Zhou,
• Maosheng Cheng,
• Lu Yang and
• Yongxiang Liu

Beilstein J. Org. Chem. 2022, 18, 1589–1595, doi:10.3762/bjoc.18.169

• total synthesis of macarpine [12] is proposed via a Au(I)-catalyzed cycloisomerization reaction. Retrosynthetically, the target molecule macarpine (1) could be disconnected into naphthol 12 (Scheme 3), a key intermediate reported by Ishikawa in the total synthesis of macarpine. This intermediate could

• ) in tetrahydrofuran (THF), resulting in the formation of naphthol 12 [12][13], a key intermediate in the previous total synthesis of macarpine (1) reported by Ishikawa (Scheme 6). To simplify the synthetic procedure, a more straightforward strategy was proposed by using alkynyl ketone 9 [27][28][29

Simple synthesis of multi-halogenated alkenes from 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane)

• Yukiko Karuo,
• Atsushi Tarui,
• Kazuyuki Sato,
• Kentaro Kawai and
• Masaaki Omote

Beilstein J. Org. Chem. 2022, 18, 1567–1574, doi:10.3762/bjoc.18.167

• mechanism shown in Scheme 2 [15][26]. In the reaction medium, 3 is deprotonated by KOH to generate phenoxide ion 4, which acts as a base and as a nucleophile. Removal of an acidic hydrogen from halothane provides 5, which is a key intermediate in the reaction. Intermediate 5 is sufficiently electrophilic to

Cytochrome P450 monooxygenase-mediated tailoring of triterpenoids and steroids in plants

• Karan Malhotra and
• Jakob Franke

Beilstein J. Org. Chem. 2022, 18, 1289–1310, doi:10.3762/bjoc.18.135

• compound 0. This nucleophilic and basic intermediate is prone to dehydration (step 6), leading to the strongly electrophilic and oxidising key intermediate G, which is commonly known as compound I (cpd I). Although there has been a lot of debate regarding the exact structure and electronic properties of

• foenum-graecum; Pp: Paris polyphylla; Dz: Dioscorea zingiberensis) [35][66]. B) Formation of the defence compound ellarinacin (15) in bread wheat [26]. Stereochemistry of ellarinacin (15) is shown as published. C) Biosynthesis of the key intermediate melianol (21) in the pathway to the limonoid limonin

A one-pot electrochemical synthesis of 2-aminothiazoles from active methylene ketones and thioureas mediated by NH₄I

• Shang-Feng Yang,
• Pei Li,
• Zi-Lin Fang,
• Sen Liang,
• Hong-Yu Tian,
• Bao-Guo Sun,
• Kun Xu and
• Cheng-Chu Zeng

Beilstein J. Org. Chem. 2022, 18, 1249–1255, doi:10.3762/bjoc.18.130

• ) should be a key intermediate for this tandem reaction. On the basis of the above mechanistic studies and the previous works on iodide-mediated electrochemical transformation [37][38][39][40], a possible mechanism for this electrochemical reaction was proposed (Scheme 5). It is well known that amino acid