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

Isolation and biosynthesis of daturamycins from Streptomyces sp. KIB-H1544

• Yin Chen,
• Jinqiu Ren,
• Ruimin Yang,
• Jie Li,
• Sheng-Xiong Huang and
• Yijun Yan

Beilstein J. Org. Chem. 2022, 18, 1009–1016, doi:10.3762/bjoc.18.101

• DatA, which catalyzes the Claisen–Dieckmann condensation of phenylpyruvic acid (7) to generate the key intermediate polyporic acid (8). Finally, we proposed a biosynthetic pathway for daturamycins. Results and Discussion Daturamycin A (1), a yellow powder, possessed a molecular formula of C19H16O5 with

Introducing a new 7-ring fused diindenone-dithieno[3,2-b:2',3'-d]thiophene unit as a promising component for organic semiconductor materials

• Valentin H. K. Fell,
• Joseph Cameron,
• Alexander L. Kanibolotsky,
• Eman J. Hussien and
• Peter J. Skabara

Beilstein J. Org. Chem. 2022, 18, 944–955, doi:10.3762/bjoc.18.94

• previously by other groups [38][39], however, we here use a different protocol. Intermediates 25 or 26 were reacted in Suzuki–Miyaura couplings [36] with commercially available methyl 5-bromo-2-iodobenzoate [40], to obtain the key intermediate dimethyl 6,6’-(dithieno[3,2-b:2’,3’-d]thiophene-2,6-diyl)bis(3

• , 21.5 h, 79% [35]. Ring closure of key intermediate 27 to achieve 29: a) Methyl 5-bromo-2-iodobenzoate, Aliquat 336®, Pd(PPh3)4, K2CO3, THF/H2O, 70 °C, 40 h, 28% [40][41]; b) polyphosphoric acid [16], 100 °C, 4.5 h, then 130 °C, overnight, 0%; c) sulfuric acid, 115 °C, 6 h, 0% [42]; d) LiOH, THF, H2O

Synthesis of novel alkynyl imidazopyridinyl selenides: copper-catalyzed tandem selenation of selenium with 2-arylimidazo[1,2-a]pyridines and terminal alkynes

• Mio Matsumura,
• Kaho Tsukada,
• Kiwa Sugimoto,
• Yuki Murata and
• Shuji Yasuike

Beilstein J. Org. Chem. 2022, 18, 863–871, doi:10.3762/bjoc.18.87

• phenylacetylene (3a) was used as a model reaction to determine a suitable base and an equivalent number of reagents (Table 1). The key intermediate 2a was prepared in situ from 1a (0.5 mmol) and Se powder (0.5 mmol) in the presence of 10 mol % of CuI and 1,10-phenanthroline at 130 °C in DMSO under aerobic

Copper-catalyzed multicomponent reactions for the efficient synthesis of diverse spirotetrahydrocarbazoles

• Shao-Cong Zhan,
• Ren-Jie Fang,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 796–808, doi:10.3762/bjoc.18.80

• 3-substituted indole, which undergoes dehydration to form the key intermediate indole-based ortho-quinodimethanes (o-QDMs, A). In the meantime, the cyclic 1,3-diones and aromatic aldehyde undergo Knoevenagel condensation to afford the different kinds of dienophiles. Subsequently, the Diels–Alder

New synthesis of a late-stage tetracyclic key intermediate of lumateperone

• Mátyás Milen,
• Bálint Nyulasi,
• Tamás Nagy,
• Gyula Simig and
• Balázs Volk

Beilstein J. Org. Chem. 2022, 18, 653–659, doi:10.3762/bjoc.18.66

• these efforts, a novel synthesis of the late-stage tetracyclic key intermediate of lumateperone starting from the commercially available quinoxaline is described. The tetracyclic skeleton was constructed by the reaction of 1-trifluoroacetyl-4-aminoquinoxaline with ethyl 4-oxopiperidine-1-carboxylate in

• a Fischer indole synthesis. The inexpensive starting material, the efficient synthetic steps, and the avoidance of the borane-based reduction step provide a reasonable potential for scalability. Keywords: drug substance; indole synthesis; key intermediate; protecting group; telescoping

• ] for the resolution of compound (±)-10, a direct intermediate of lumateperone, easily available from (±)-9a, we aimed to elaborate a new, practical synthesis of the latter. First, we envisaged a new synthetic route to the racemic key intermediate (±)-9a, significantly shorter than those described

Synthesis of sulfur karrikin bioisosteres as potential neuroprotectives

• Martin Pošta,
• Václav Zima,
• Lenka Poštová Slavětínská,
• Marika Matoušová and
• Petr Beier

Beilstein J. Org. Chem. 2022, 18, 549–554, doi:10.3762/bjoc.18.57

• Goddard-Borger [24] for the preparation of 2 using the Xavier’s procedure [33] towards 5-thiopyranose-fused butenolides and the reaction pathway is outlined in Scheme 5. The synthesis of the key intermediate butenolide 23 was accomplished starting from easily available ᴅ-xylose, following a published

Menadione: a platform and a target to valuable compounds synthesis

• Acácio S. de Souza,
• Ruan Carlos B. Ribeiro,
• Dora C. S. Costa,
• Fernanda P. Pauli,
• David R. Pinho,
• Matheus G. de Moraes,
• Fernando de C. da Silva,
• Luana da S. M. Forezi and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 381–419, doi:10.3762/bjoc.18.43

• respective ditellurides, a disulfide and a diselenide (Scheme 27). Recently, Ribeiro and co-workers used menadione as a nucleophile for the synthesis of 3-chloromethylated menadione 84, a key intermediate used to prepare selenium-menadione conjugates 86 [128]. In this work, compound 84 was prepared through

Anomeric 1,2,3-triazole-linked sialic acid derivatives show selective inhibition towards a bacterial neuraminidase over a trypanosome trans-sialidase

• Peterson de Andrade,
• Sanaz Ahmadipour and
• Robert A. Field

Beilstein J. Org. Chem. 2022, 18, 208–216, doi:10.3762/bjoc.18.24

• 13C NMR experiment, where the α-anomer is a doublet and the β-anomer is a singlet [28]. The key intermediate 1 was further used in CuAAC reaction [29][30][31][32] with eleven (hetero)aromatic and non-aromatic terminal alkynes readily available in our lab [23]. Although CuAAC is reputedly tolerant of a

• 3a–h via copper-catalysed azide–alkyne cycloaddition (CuAAC) from the key intermediate 1 (B). TcTS and neuraminidase hydrolase activity (A) as well as TcTS transferase activity (B) in the presence of an acceptor substrate. TcTS and neuraminidase inhibition by 1,2,3-triazole-linked sialic acid

Ready access to 7,8-dihydroindolo[2,3-d][1]benzazepine-6(5H)-one scaffold and analogues via early-stage Fischer ring-closure reaction

• Irina Kuznetcova,
• Felix Bacher,
• Daniel Vegh,
• Hsiang-Yu Chuang and
• Vladimir B. Arion

Beilstein J. Org. Chem. 2022, 18, 143–151, doi:10.3762/bjoc.18.15

• as the key intermediate. The third pathway (c) was centered around a ring-closure reaction via lactam-bond formation from a precursor that contains a carboxylic ester in position 2 and an o-aniline moiety in position 3 of the indole ring by Fischer indole synthesis from methyl 4-(2-nitrophenyl)-3

A photochemical C=C cleavage process: toward access to backbone N-formyl peptides

• Haopei Wang and
• Zachary T. Ball

Beilstein J. Org. Chem. 2021, 17, 2932–2938, doi:10.3762/bjoc.17.202

• give amide 12 with a half-life (t1/2) of 6.4 h. The observation of N-formyl products can be rationalized with a bifurcating mechanism (Figure 5). Following photoactivation, H-atom abstraction and nucleophilic addition of water would produce the key intermediate B. Such hemi-aminal compounds would be

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

• synthesized in high efficiency. After systematic screening of the coupling reagents in liquid phase, the key intermediate tripeptide 7 was obtained in high yield. The solid-phase synthesis improves the entire efficiency of the synthetic route. This strategy could be applied to the stereoselective synthesis of

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

• the expected high syn diol diastereoselectivity (Scheme 1). The obtained anti,syn-(hydroxyamino)alkenol 4 will be then subjected to reductive cleavage of the N–O bond. Next, a key intermediate epoxide 5 with the desired syn (threo) configuration between the hydroxy group and the epoxide oxygen could

Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

• Umesh P. Aher,
• Dhananjai Srivastava,
• Girij P. Singh and
• Jayashree B. S

Beilstein J. Org. Chem. 2021, 17, 2680–2715, doi:10.3762/bjoc.17.182

• undesired isomers. Over the past three decades, several research groups have been working on devising novel methods for installing glycosidic linkages during the synthesis of modified nucleosides. For 1,3-oxathiolane nucleosides, to achieve β-selective glycosylation, a certain key intermediate was employed

• . Reaction of 24 with pyridinium dichromate (PDC) in DMF solvent afforded the acid derivative 25. This derivative was converted to the key intermediate 20 by oxidative decarboxylation [33]. Han et al. [43] developed a method for the novel oxathiolane intermediate 2-(tert-butyldiphenylsilyloxy)methyl-5

• recrystallized to obtain the enantiomerically pure ʟ-menthyl ester 35a (Scheme 8). Milton et al. [47] synthesized the key intermediate 38 by two synthetic routes. The first route involves a reaction of bromoacetaldehyde diethyl acetal (36) with a xanthate ester, followed by treatment of ethylenediamine, which

N-Sulfinylpyrrolidine-containing ureas and thioureas as bifunctional organocatalysts

• Viera Poláčková,
• Dominika Krištofíková,
• Boglárka Némethová,
• Renata Górová,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2021, 17, 2629–2641, doi:10.3762/bjoc.17.176

• which the key intermediate, pyrrolidine derivative 2, can be obtained in three steps according to the literature procedure [32]. Using this method, we obtained the product 2 in a yield comparable (56% overall yield) to that described in the literature. However, the difficult chromatographic separation

Synthesis of new substituted 7,12-dihydro-6,12-methanodibenzo[c,f]azocine-5-carboxylic acids containing a tetracyclic tetrahydroisoquinoline core structure

• Agnieszka Grajewska,
• Maria Chrzanowska and
• Wiktoria Adamska

Beilstein J. Org. Chem. 2021, 17, 2511–2519, doi:10.3762/bjoc.17.168

• -tetrahydroisoquinoline derivative TA-073 using substituted N-acyl aminoacetal as the key intermediate which, depending on the reaction conditions, could be transformed either into TA-073 or the appropriate double cyclized product, isopavine or pavine (not shown) (Scheme 6). Inspired by these results, we next