Copper-catalyzed yne-allylic substitutions: concept and recent developments

• Shuang Yang and
• Xinqiang Fang

Beilstein J. Org. Chem. 2024, 20, 2739–2775, doi:10.3762/bjoc.20.232

• as Meldrum’s acid and 1,3-dimethylbarbituric acid were used as the nucleophiles, the yne-allylic substitution products underwent further intramolecular cyclizations to give the spiro-cyclic products in high yields (Scheme 31, 30a–f). The generation of products likely begins with an α-attack on the

• vinyl allenylidene species. A series of differently substituted spiro-cyclic products can be obtained with high yields, regio- and stereoselectivities (Scheme 32, 30a–x). Preliminary mechanistic studies indicated that the reaction first undergoes a substitution at the α-position of yne-allylic ester

Synthesis of spiroindolenines through a one-pot multistep process mediated by visible light

• Francesco Gambuti,
• Jacopo Pizzorno,
• Chiara Lambruschini,
• Renata Riva and
• Lisa Moni

Beilstein J. Org. Chem. 2024, 20, 2722–2731, doi:10.3762/bjoc.20.230

• Francesco Gambuti Jacopo Pizzorno Chiara Lambruschini Renata Riva Lisa Moni Department of Chemistry and Industrial Chemistry, University of Genoa, Via Dodecaneso 31, 1646 Genova, Italy 10.3762/bjoc.20.230 Abstract Spiro-heterocyclic indolenines are privileged scaffolds widely present in numerous

• indole alkaloids. Here, we develop a novel approach for the one-pot multistep synthesis of different spiro[indole-isoquinolines]. The protocol proposed involves the visible light mediated oxidation of N-aryl tertiary amines using bromochloroform with the generation of a reactive iminium species, which

• aromatic substitution giving the final spiro-indolenine. The scope of the process has been investigated with respect to all three components. Simple operations, mild conditions, and good yields make this strategy a convenient and sustainable way to obtain novel spiro-indolenine derivatives. Keywords

Base-promoted cascade recyclization of allomaltol derivatives containing an amide fragment into substituted 3-(1-hydroxyethylidene)tetronic acids

• Andrey N. Komogortsev,
• Constantine V. Milyutin and
• Boris V. Lichitsky

Beilstein J. Org. Chem. 2024, 20, 2585–2591, doi:10.3762/bjoc.20.217

• deprotonates to the anion B under action of DBU. Subsequent intramolecular cyclization at the double bond of pyranone fragment leads to the formation of spiro compound C. Next, opening of the dihydropyranone ring results in pyrrolidin-2-one D which further transformed to the salt of 3-acyltetronic acid E

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• practical potential of the methodology was illustrated by constructing the medicinal chemistry-relevant highly fused spiro compound 140 featuring 5 stereocentres (3 quaternary) in 99% ee and 76% overall yield from achiral 136 and racemic 137 in just 2 steps. Selected substrates were converted to the

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

Beilstein J. Org. Chem. 2024, 20, 2171–2207, doi:10.3762/bjoc.20.187

Diastereoselective synthesis of highly substituted cyclohexanones and tetrahydrochromene-4-ones via conjugate addition of curcumins to arylidenemalonates

• Deepa Nair,
• Abhishek Tiwari,
• Banamali Laha and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2024, 20, 2016–2023, doi:10.3762/bjoc.20.177

• cascade triple-Michael (Michael/Michael/oxa-Michael) reaction between curcumins and isatylidene malononitriles, giving spiro-oxindoles in excellent yields and diastereoselectivities [36]. Sahu et al. introduced a one-pot multicomponent reaction of curcumin, arylaldehyde and 2-aminobenzothiazole to

• -arylidene-1,3-indandiones was reported by Zhang and co-workers using quinine as a catalyst, giving multicyclic spiro-1,3-indandiones in moderate yields with enantioselectivities as well as diastereoselectivities [39]. However, to the best of our knowledge, arylidenemalonates have not been employed as

Access to 2-oxoazetidine-3-carboxylic acid derivatives via thermal microwave-assisted Wolff rearrangement of 3-diazotetramic acids in the presence of nucleophiles

• Ivan Lyutin,
• Vasilisa Krivovicheva,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 1894–1899, doi:10.3762/bjoc.20.164

• -generated ketene, previously described using carbocyclic diazodiketones [35] were also unsuccessful. Of the diazotetramic acids, only the spiro adamantane derivative 1m was not able to form the desired β-lactam. These reactions gave complex mixtures of unidentified products. The benzyl esters 3k and 3n were

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

Chiral bifunctional sulfide-catalyzed enantioselective bromolactonizations of α- and β-substituted 5-hexenoic acids

• Sao Sumida,
• Ken Okuno,
• Taiki Mori,
• Yasuaki Furuya and
• Seiji Shirakawa

Beilstein J. Org. Chem. 2024, 20, 1794–1799, doi:10.3762/bjoc.20.158

• enantioselectivity. The reactions of α,α-dialkyl-5-hexenoic acids 2e and 2f gave the corresponding bromolactonization products 3e and 3f with moderate enantioselectivities. The present catalytic method could also be applied to the asymmetric synthesis of spirolactones [37][38][39]. For example, α-spiro-δ-lactone

• -hexenoic acids 2, β-substituted substrates 2j–n were submitted to the present catalytic system. As a result of these asymmetric reactions, β,β-dialkyl-δ-valerolactones 3j–k and β-spiro-δ-lactones 3l–n were obtained in good levels of enantioselectivity. The reaction of 2-allylbenzoic acid 2o as a related

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• , spanning the period from 2000 to 2023, for the preparation of spiro heterocyclic steroids. The compounds surveyed encompass four-, five-, six-, and seven-membered heterocycles appended to various positions of steroidal backbones, with spirocycles containing oxygen, nitrogen, and sulfur atoms being

• predominant. The outlined synthetic procedures emphasize the pivotal steps for constructing the heterocycles, often accompanied by a detailed account of the overall synthesis pathway. The review encompasses innovative compounds, including bis-steroids linked by a spiro heterocycle and steroids conjugated to

• the future design of more potent and selective drugs. Keywords: biological activity; drug development; heterocycle; spiro steroid; synthetic transformations; Introduction Small-ring heterocycles constitute valuable scaffolds in medicinal chemistry for generating biologically active derivatives

Synthetic applications of the Cannizzaro reaction

• Bhaskar Chatterjee,
• Dhananjoy Mondal and
• Smritilekha Bera

Beilstein J. Org. Chem. 2024, 20, 1376–1395, doi:10.3762/bjoc.20.120

• -Cannizzaro reaction in the construction of the spiro-β-lactone ring while targeting the spiro-β-lactone-γ-lactam ring of oxazolomycin and lazollamycin [88]. Proceeding towards the requisite fragment they envisaged a series of crucial diastereoselective transformations arriving at the precursor 69 to the

• Cannizzaro reaction commencing from 68. The primary hydroxymethyl functionality in 69 was oxidized to the corresponding aldehyde 70, which was subsequently treated with 37% aqueous formaldehyde and NaOH, to result in a mixture of the gem-hydroxymethyl derivative 72 and the carbamate 71 which led to the spiro

• intramolecular Cannizzaro reaction. Spiro-β-lactone-γ-lactam part of oxazolomycins via aldol crossed-Cannizzaro reaction. Synthesis of indole alkaloids via aldol crossed-Cannizzaro reaction. Aldol and crossed-Cannizzaro reaction towards the synthesis of ertuliflozin. Synthesis of cyclooctadieneones using a

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

• proposing a reasonable cyclization mechanism [5]. Spiroviolene (1, Figure 1) was identified by Dickschat and co-workers as a nascent cyclization product of spiroviolene synthase (SvS), the coding gene of which was cloned from Streptomyces violens NRRL ISP-5597 [6]. Its unique spiro-fused linear triquinane

Entry to new spiroheterocycles via tandem Rh(II)-catalyzed O–H insertion/base-promoted cyclization involving diazoarylidene succinimides

• Alexander Yanovich,
• Anastasia Vepreva,
• Ksenia Malkova,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 561–569, doi:10.3762/bjoc.20.48

• ., Saint Petersburg 191036, Russian Federation Department of Medicinal Chemistry, Institute of Chemistry, Saint Petersburg State University, 26 Universitetskiy pr., Peterhof 198504, Russian Federation 10.3762/bjoc.20.48 Abstract A facile approach to novel medicinally relevant spiro heterocyclic scaffolds

• (namely furan-2(5H)-ones, tetrahydrofurans and pyrans spiro-conjugated with the succinimide ring) has been developed. The protocol consists of Rh(II)-catalyzed insertion of heterocyclic carbenes derived from diazoarylidene succinimides (DAS) into the O–H bond of propiolic/allenic acids or brominated

• synthesis of spiro-annulated pyrrolidine-2,5-diones by catalyzed spirocyclizations involving aldehydes [11], tetrahydrofuran [12][13], and in the O–H insertion/Claisen rearrangement/intramolecular oxa-Michael addition cascade [14] (Scheme 1). Herein, we report our findings obtained, while investigating the

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

• alkaloids containing an unprecedented spiro[bicyclo[2.2.2]octane-diketopiperazine] skeleton, chevalinulins A and B, and the first cytochalasin homodimer containing a thioether bridge, verruculoid A, were identified from deep-sea cold seeps-derived fungi and were described to have potent proangiogenic and

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

Synthesis of spiropyridazine-benzosultams by the [4 + 2] annulation reaction of 3-substituted benzoisothiazole 1,1-dioxides with 1,2-diaza-1,3-dienes

• Wenqing Hao,
• Long Wang,
• Jinlei Zhang,
• Dawei Teng and
• Guorui Cao

Beilstein J. Org. Chem. 2024, 20, 280–286, doi:10.3762/bjoc.20.29

• ] annulation reaction; 1,2-diaza-1,3-dienes; spiro-benzosultams; 3-substituted benzoisothiazole 1,1-dioxides; Introduction Spirobenzosultams have various biological activities [1][2][3] such as antiviral, anticancer, antimicrobial, antimalarial, and antileukemia, and are widely used in the pharmaceutical

• ketimines as suitable three-carbon synthons in [3 + 2] and [3 + 3] annulations [11][12][13][14][15]. However, methods using N-sulfonyl ketimines as dienophiles in [4 + 2] annulation reactions to afford biologically important spiro compounds are still limited to date [16]. 1,2-Diaza-1,3-dienes [17][18][19

Perspectives on push–pull chromophores derived from click-type [2 + 2] cycloaddition–retroelectrocyclization reactions of electron-rich alkynes and electron-deficient alkenes

• Michio Yamada

Beilstein J. Org. Chem. 2024, 20, 125–154, doi:10.3762/bjoc.20.13

• adduct leads to the formation of a spiro compound [89][90][91][92][93][94]. Ester-substituted, electron-deficient alkenes have also been employed in [2 + 2] CA–RE reactions involving electron-rich alkynes. Alkenes featuring either one or two ester substitutions exclusively catalyze [2 + 2] CA–RE

Construction of diazepine-containing spiroindolines via annulation reaction of α-halogenated N-acylhydrazones and isatin-derived MBH carbonates

• Xing Liu,
• Wenjing Shi,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2023, 19, 1923–1932, doi:10.3762/bjoc.19.143

• . Additionally, the similar reaction with α-halogenated N-tosylhydrazones also afforded N-tosyl-substituted spiro[indoline-3,5'-[1,2]diazepine] in satisfactory yields. This protocol provides a convenient approach for the assembly of diverse highly functionalized spiro[indoline-3,5'-[1,2]diazepines] and also

• efficient synthesis of spiro[azepine-4,3'-indoline] derivatives via the [4 + 3] cycloaddition reaction of bromo-substituted isatin-derived MBH adducts and N-(o-chloromethyl)arylamides. In this efficient protocol, the reactive allylic phosphonium ylides and aza-o-quinone methides were generated in situ and

• satisfactory yields and with good diastereoselectivity (reaction 3, Scheme 1) [57]. Very recently, we found that the base-catalyzed [4 + 3] cycloaddition reaction of isatin-derived MBH carbonates with various α,β-unsaturated N-arylaldimines affords spiro[indoline-3,5'-pyrrolo[3,4-b]azepine] derivatives

Decarboxylative 1,3-dipolar cycloaddition of amino acids for the synthesis of heterocyclic compounds

• Xiaofeng Zhang,
• Xiaoming Ma and
• Wei Zhang

Beilstein J. Org. Chem. 2023, 19, 1677–1693, doi:10.3762/bjoc.19.123

•  6) [75]. One-pot double annulations for the synthesis of tetrahydropyrrolothiazoles The unique tetrahydropyrrolothiazole and spiro[indole-tetrahydropyrrolothiazole] scaffolds are found in bioactive compounds such as those shown in Figure 7 [76][77]. Using cysteine as a key reactant, we developed a

• olefinic oxindoles to replace maleimides, the reactions gave spiro[indoline-tetrahydropyrrolothiazole] products 30 in 55–70% with greater than 4:1 dr [76]. The reaction mechanism suggests that the reaction of cysteine with arylaldehydes gives N,S-acetals 27 which convert to AMYs 28 after decarboxlyation

Sulfur-containing spiroketals from Breynia disticha and evaluations of their anti-inflammatory effect

• Ken-ichi Nakashima,
• Naohito Abe,
• Masayoshi Oyama,
• Hiroko Murata and
• Makoto Inoue

Beilstein J. Org. Chem. 2023, 19, 1604–1614, doi:10.3762/bjoc.19.117

•  1) exhibited signals corresponding to a spiro-carbon at δC 100.6 (C-9) and a ketone carbon at δC 213.3 (C-8). The HMBC correlations of H-10β/C-8, C-9, C-11, C-12; H-11/C-9, C-13; H2-13/C-9; H-16/C-7, C-8; and H3-18/C-11, C-12, C-13 and the connectivity confirmed by DQF-COSY indicated that 3 also

Synthesis of 5-arylidenerhodanines in L-proline-based deep eutectic solvent

• Stéphanie Hesse

Beilstein J. Org. Chem. 2023, 19, 1537–1544, doi:10.3762/bjoc.19.110

• compounds and allow, for example, the formation of rhodanine-fused spiro[pyrrolidine-2,3′-oxindoles] D having antidiabetic activity [6]. Thiazolidinediones and thiazolidinones were found to be potent moieties of a series of furan-2-ylmethylenethiazolidinediones E that were studied as selective ATP

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

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

• Scheme 1) [12]. In the presence of piperidine, the reaction in methanol at room temperature did not yield the product (Table 1, entry 1). However, the reaction in methanol at elevated temperature gave the expected spiro compound 3a in 51% and 48% yields, respectively (Table 1, entries 2 and 3). The

• -oxoindolin-3-ylidene)acetate with 5-chloro and 5-fluoro substituent gave the spiro compounds 3a–k in satisfactory yields. However, the dimedone adducts of ethyl 2-(2-oxoindolin-3-ylidene)acetate itself and its derivatives with 5-methyl group gave the products 3l and 3m in moderate yields. The chemical

Synthesis of medium and large phostams, phostones, and phostines

• Jiaxi Xu

Beilstein J. Org. Chem. 2023, 19, 687–699, doi:10.3762/bjoc.19.50

• dialkyl 3-aryl-2-phenyl/alkoxy-3-hydrobenzo[f][1,2]oxaphosphepin-5(4H)-one-4,4-dicarboxylate 2-oxides 84 in good yields with excellent diastereoselectivities accompanied by alkyl 5'-alkoxy-2-phenyl/alkoxy-4-oxo-3'-aryl-2,3'-dihydro-4H-2λ5-spiro[benzo[d][1,3,2]dioxaphosphinine-2,2'-[1,2]oxaphosphole]-4

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• step which yields the α-propargyl-β-hydroxyketones 201 in good yields and excellent diastereo- and enantiopurities. Soon after, the Lautens group has further extended their methodology to the synthesis of spirooxirane derivatives 203 by implementing a spiro-cyclization step following the aldol reaction

• (Scheme 51B) [94]. Giving only a single diastereomer with good enantioselectivity using a Rh/bicyclo[2.2.2]octane-2,5-diene (bod) complex, a broad variety of spiro compounds were isolated in good to excellent yields. The authors have also shown that this skeleton provides a great opportunity to prepare