Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

• epimerisation to obtain diastereoenriched spirocycles, utilising t-BuOK/t-BuOH for the anti-diastereomer 163 and LDA/PivOH at −78 °C for the syn-diastereomer 162 (dr >10:1 in both protocols). Mechanistic and computational studies suggested the following series of steps: excitation of 159 via energy transfer

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

• , resulting in the C2-dearomatized naphthalenone products 41a–d with high efficiency (Scheme 41). In addition, electron-rich phenols or nonfunctionalized 2-naphthols could also be used as nucleophiles, providing the desired chiral spirocycles 43a–e and 44a–e in good yields with excellent ee values (Scheme 42

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

• well as a wide range of nucleophiles provides access to a structural diversity of medically relevant 2-oxoazetidine-3-carboxylic acid amides and esters. Keywords: β-lactams; diazotetramic acids; nucleophiles; spirocycles; thermolysis; Wolff rearrangement; Introduction The importance of the β-lactam

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

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

• perspective, the incorporation of a spiro fragment significantly impacts the properties of the drug candidate. Introducing a spirocyclic moiety often leads to increased potency and selectivity, as observed in comparisons between spirocycles and their non-spiro counterparts. Furthermore, several examples

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 1256–1269, doi:10.3762/bjoc.20.108

• . Similarly to products 35, relatively low yields were observed for reactions of methoxy-substituted 3-halochromones. The two-step one-pot reaction of N-unsubstituted ketoamide 33a with 3-halochromones 29a and 31a afforded spirocycles 36a,b, albeit, in only moderate yields (Scheme 20) [41]. The formation of

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

• alcohols, followed by base-promoted cyclization to afford the target spirocyclic compounds in good to high yields. Keywords: diazoarylidene succinimides; intramolecular cyclization; rhodium(II) carbene O–H insertion; spirocycles; Introduction Spirocyclic motifs have emerged as auspicious frameworks for

A novel spirocyclic scaffold accessed via tandem Claisen rearrangement/intramolecular oxa-Michael addition

• Anastasia Vepreva,
• Alexander Yanovich,
• Dmitry Dar’in,
• Grigory Kantin,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1649–1655, doi:10.3762/bjoc.18.177

• arylidene succinimides; intramolecular oxa-Michael addition; rhodium(II) carbene O–H insertion; spirocycles; Introduction Spirocycles undoubtedly occupy a special place in drug design [1] and, in general, spirocyclic compounds intended for the interrogation of biological targets have been associated with

• higher success rates [2] in discovering new cases of affinity towards a three-dimensional protein molecule [3]. Spirocycles of all sorts are omnipresent in the natural product realm [4]. Among the approved medicines the following spirocyclic molecules are notable: spironolactone for heart disease and

• hypertention [5], buspirone for anxiety disorders [6], cevimeline for dry mouth and dry eye syndrome [7], fluspirilene for schizophrenia [8] and ilbesartan for hypertention and diabetic nephropathy [9], to mention a few (Figure 1). Hence the development of novel synthetic methods to construct spirocycles [10

Accelerating fragment-based library generation by coupling high-performance photoreactors with benchtop analysis

• Quentin Lefebvre,
• Christophe Salomé and
• Thomas C. Fessard

Beilstein J. Org. Chem. 2020, 16, 982–988, doi:10.3762/bjoc.16.87

• preliminary quality control (QC) could be performed using a benchtop 60 MHz NMR machine (Figure 3). Structural information was obtained to corroborate mass spectrometry data, an important information when dealing with strained bicycles or spirocycles, which could be prone to skeletal rearrangement. If

Combination of multicomponent KA² and Pauson–Khand reactions: short synthesis of spirocyclic pyrrolocyclopentenones

• Riccardo Innocenti,
• Elena Lenci,
• Gloria Menchi and
• Andrea Trabocchi

Beilstein J. Org. Chem. 2020, 16, 200–211, doi:10.3762/bjoc.16.23

• in numerous natural products [7][8][9], a wide array of spirocyclic compounds are being studied in drug discovery and their chemical space have been systematically charted and characterized recently by Bajorath and co-workers (Figure 1) [10]. This study revealed that spirocycles are found only in few

Experimental and computational electrochemistry of quinazolinespirohexadienone molecular switches – differential electrochromic vs photochromic behavior

• Eric W. Webb,
• Jonathan P. Moerdyk,
• Kyndra B. Sluiter,
• Benjamin J. Pollock,
• Amy L. Speelman,
• Eugene J. Lynch,
• William F. Polik and
• Jason G. Gillmore

Beilstein J. Org. Chem. 2019, 15, 2473–2485, doi:10.3762/bjoc.15.240

• calculations of bond lengths, bond orders, and molecular orbitals allow the rationalization of this differential photochromic vs electrochromic behavior of the QSHDs. Keywords: cyclic voltammetry; density functional theory; heterocycles; molecular switches; photochromic photooxidants; spirocycles

Domino ring-opening–ring-closing enyne metathesis vs enyne metathesis of norbornene derivatives with alkynyl side chains. Construction of condensed polycarbocycles

• Ritabrata Datta and
• Subrata Ghosh

Beilstein J. Org. Chem. 2018, 14, 2708–2714, doi:10.3762/bjoc.14.248

• ][28][29][30][31][32][33] for the synthesis of a variety of complex ring systems such as condensed, bridged and spirocycles difficult to obtain otherwise. On the contrary, the domino process involving a ring-opening metathesis (ROM) followed by a ring-closing enyne metathesis (RCEYM) [34][35][36][37

Synergistic approach to polycycles through Suzuki–Miyaura cross coupling and metathesis as key steps

• Sambasivarao Kotha,
• Milind Meshram and
• Chandravathi Chakkapalli

Beilstein J. Org. Chem. 2018, 14, 2468–2481, doi:10.3762/bjoc.14.223

• with Suzuki–Miyaura cross coupling in combination with metathesis (or vice-versa). Several cyclophanes, polycycles, macrocycles, spirocycles, stilbenes, biaryls, and heterocycles have been synthesized by employing a combination of Suzuki cross-coupling and metathesis. Various popular reactions such as

• ][20][21][22], oligomers [23][24], polycyclic ethers [25], heterocycles [26], nonbenzenoid aromatics [27], and spirocycles [28][29]) by decreasing the number of steps. Different metathesis catalysts used in this study are shown in Figure 1. Review Annulation Grela and co-workers [30] demonstrated a

• the ring-closure product 25 (84%). Finally, CAN oxidation gave the desired tetracyclic compound 26 in 84% yield (Scheme 3). Spirocycles In another event, an efficient approach to spirocyclopentane derivatives has been described, where the combination of RCM and SM coupling was employed [34]. In this

Construction of highly enantioenriched spirocyclopentaneoxindoles containing four consecutive stereocenters via thiourea-catalyzed asymmetric Michael–Henry cascade reactions

• Yonglei Du,
• Jian Li,
• Kerong Chen,
• Chenglin Wu,
• Yu Zhou and
• Hong Liu

Beilstein J. Org. Chem. 2017, 13, 1342–1349, doi:10.3762/bjoc.13.131

• attention because of its high efficiency in constructing functionalized spirocyclopentaneoxindoles. However, lower temperatures are required (−30 °C) [50]. Therefore, it is highly desirable to develop novel and efficient methods to access directly various spirocycles. In our continuous endeavor to develop

Recent applications of ring-rearrangement metathesis in organic synthesis

• Sambasivarao Kotha,
• Milind Meshram,
• Priti Khedkar,
• Shaibal Banerjee and
• Deepak Deodhar

Beilstein J. Org. Chem. 2015, 11, 1833–1864, doi:10.3762/bjoc.11.199

• with the RCM product 78 in 71% (Scheme 15). Burnell and co-workers [20] have demonstrated the RRM of unsaturated spirocycles with two alkenyl chains by employing catalyst 2 to generate a unsaturated spiro-fused tricyclic system. In this context, the compounds 80 and 81 were subjected to RRM with

• the cyclohexene systems. RRM of cyclopentene system 74. RRM approach to compound 79. RRM approach to spirocycles. RRM approach to bicyclic dihydropyrans. RCM–ROM–RCM cascade using non strained alkenyl heterocycles. First ROM–RCM–ROM–RCM cascade for the synthesis of trisaccharide 97. RRM of cyclohexene

Spiro annulation of cage polycycles via Grignard reaction and ring-closing metathesis as key steps

• Sambasivarao Kotha,
• Mohammad Saifuddin,
• Rashid Ali and
• Gaddamedi Sreevani

Beilstein J. Org. Chem. 2015, 11, 1367–1372, doi:10.3762/bjoc.11.147

• ) reaction as a key step is described. The structures of three new cage compounds 7, 12 and 18 were confirmed by single crystal X-ray diffraction studies. Keywords: cage molecules; Diels–Alder reaction; Grignard reaction; ring-closing metathesis; spirocycles; Introduction Design and synthesis of

Hybrid macrocycle formation and spiro annulation on cis-syn-cis-tricyclo[6.3.0.0^2,6]undeca-3,11-dione and its congeners via ring-closing metathesis

• Sambasivarao Kotha,
• Ajay Kumar Chinnam and
• Rashid Ali

Beilstein J. Org. Chem. 2015, 11, 1123–1128, doi:10.3762/bjoc.11.126

• recurring motif in bioactive molecules. Consequently, assembling architecturally complex spirocycles is of great relevance to the diversity-oriented synthesis of biologically active spirocycles. In this context, new synthetic methods to generate multiple spirocenters in a simple manner remain a challenging

• -spirocycles via RCM. List of bis-spirocycles assembled by RCM. Supporting Information Supporting Information File 303: Experimental and analytical data. Supporting Information File 304: NMR spectra. Acknowledgements AKC and RA acknowledge the University Grant Commission, New Delhi for the award of research

One-pot three-component synthesis and photophysical characteristics of novel triene merocyanines

• Christian Muschelknautz,
• Robin Visse,
• Jan Nordmann and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2014, 10, 599–612, doi:10.3762/bjoc.10.51

• convergent strategies paved the way to luminescent push–pull dienes 1–4 with conformationally flexible and fixed acceptor units (Figure 1) [30][31][32], pyrazoles [33][34], benzodiazepines [35], furans and pyrroles [36][37] by consecutive multicomponent reactions and to highly emissive spirocycles [38][39

Development of an additive-controlled, SmI₂-mediated stereoselective sequence: Telescoped spirocyclisation, lactone reduction and Peterson elimination

• Brice Sautier,
• Karl D. Collins and
• David J. Procter

Beilstein J. Org. Chem. 2013, 9, 1443–1447, doi:10.3762/bjoc.9.163

• spirocycles 2 in good yields and as single diastereoisomers with only small amounts of saturated ketolactone byproducts (cf. 4b) observed. No byproducts arising from reaction of the additional functional groups present were formed (Scheme 3). Of particular note, keto-lactone 1f bearing an ester-containing

• side chain gave the expected spirocycle 2f, albeit with low conversion (unoptimized). As expected, no products arising from the reduction of the ester were observed [40][41][42]. Telescoped spirocyclisation/lactone reduction Although the reduction of the spirocycles 2 proceeds smoothly with SmI2−H2O

Anionic cascade reactions. One-pot assembly of (Z)-chloro-exo-methylenetetrahydrofurans from β-hydroxyketones

• István E. Markó and
• Florian T. Schevenels

Beilstein J. Org. Chem. 2013, 9, 1319–1325, doi:10.3762/bjoc.9.148

• -methylenetetrahydrofurans. Formation of dioxanes. Formation of a new spirocyclic dimer. Mechanism leading to dioxanes and spirocycles. (S,S)-syn and (S,R)-syn approaches. Formation of a bridged dimer and a triene. Mechanism leading to bridged and dienic dimers. Preparation of (Z)-chloro-exo-methylenetetrahydrofurans

Stereoselective, nitro-Mannich/lactamisation cascades for the direct synthesis of heavily decorated 5-nitropiperidin-2-ones and related heterocycles

• Pavol Jakubec,
• Dane M. Cockfield,
• Madeleine Helliwell,
• James Raftery and
• Darren J. Dixon

Beilstein J. Org. Chem. 2012, 8, 567–578, doi:10.3762/bjoc.8.64

• –c to LiAlH4 in THF followed by quenching and treatment with HCOOH, spirocycles 11a–c were obtained in good yields. The chemoselectivity of the reduction was unambiguously confirmed by single-crystal X-ray diffraction studies of 11c. Furthermore, the use of an excess of DIBAL at room temperature

When gold can do what iodine cannot do: A critical comparison

• Sara Hummel and
• Stefan F. Kirsch

Beilstein J. Org. Chem. 2011, 7, 847–859, doi:10.3762/bjoc.7.97

• with AuCl3 at 38 °C in CH2Cl2. With alkyl substituents on the alkyne, the same reaction led to low yields of products and decomposition. Significantly, the reaction also proceeds with cyclic carbonyl compounds with seven- and eight-membered rings to give six- and seven-membered spirocycles