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

• catalytic strategy provided direct access to a range of chiral spiropyrazolones in good to high yields, displaying moderate to excellent enantiomeric excess (Scheme 47, 47a–l). The method represents a novel approach for the synthesis of enantioenriched spirocyclic compounds with structural complexity

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

• by the higher reactivity of benzyl bromide and the lower conformational mobility of the side chain with the ortho-phenylene link. As a result, new spirocyclic compounds 5 were obtained in high (5a,b) or moderate (5c) yields. With some other bromo-substituted OH substrates, we obtained O–H insertion

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

• . The resulting spirocyclic compounds are formed with a clear preference to the syn diastereomer over anti which can be rationalized by conformational analysis of the Claisen rearrangement precursors to their formation. Examples of approved spirocyclic drugs. (a) Earlier reported Rh(II)-catalyzed

Synthesis of bis-spirocyclic derivatives of 3-azabicyclo[3.1.0]hexane via cyclopropene cycloadditions to the stable azomethine ylide derived from Ruhemann's purple

• Alexander S. Filatov,
• Olesya V. Khoroshilova,
• Anna G. Larina,
• Vitali M. Boitsov and
• Alexander V. Stepakov

Beilstein J. Org. Chem. 2022, 18, 769–780, doi:10.3762/bjoc.18.77

• developing an approach to the synthesis of bis-spiro[3-azabicyclo[3.1.0]hexanes] (compounds containing spiro units at the 2,4-positions of the 3-azabicyclo[3.1.0]hexane moiety) that are a hitherto unknown class of spirocyclic compounds. When considering a synthetic approach to obtaining such compounds, we

Bifurcated synthesis of methylene-lactone- and methylene-lactam-fused spirolactams via electrophilic amide allylation of γ-phenylthio-functionalized γ-lactams

• Tetsuya Sengoku,
• Koki Makino,
• Ayumi Iijima,
• Toshiyasu Inuzuka and
• Hidemi Yoda

Beilstein J. Org. Chem. 2020, 16, 2769–2775, doi:10.3762/bjoc.16.227

• spirocyclic compounds through nucleophilic amide allylation, and (c) syntheses of spirocyclic compounds through electrophilic amide allylation. Syntheses of N-phenyl and N-alkyl-substituted spirolactams (two-step yields from 3). Screening of reaction conditions for electrophilic amide allylation. Supporting

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

• potential of the arylated product and promote oxidative decomposition. Several spirocyclic compounds with larger ring sizes could be coupled to 3-bromopyridine to give products 4c, 4d, 5a and 5b, provided that steric hindrance was not too high (see 5c). Surprisingly, oxetanes appear to be incompatible with

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

• conformational entropy penalty upon binding to a protein target, and the approach of constraining the ligand conformation with a ring is widely used in drug design [2]. Accordingly, with increasing interest for sp3-rich molecules, spirocyclic compounds are being considered valuable as molecular platforms for the

• 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

• fully exploited so far, some contributions on the diversity-oriented synthesis of spirocyclic compounds have appeared in the literature recently, also employing multicomponent approaches to give the spirocyclic adduct after a cyclization step [34][35][36]. We recently focused our interest to the

Sigmatropic rearrangements of cyclopropenylcarbinol derivatives. Access to diversely substituted alkylidenecyclopropanes

• Guillaume Ernouf,
• Jean-Louis Brayer,
• Christophe Meyer and
• Janine Cossy

Beilstein J. Org. Chem. 2019, 15, 333–350, doi:10.3762/bjoc.15.29

• produced in excellent yield (94%). More sterically hindered substituents were tolerated at C3, as illustrated with the isolation of the spirocyclic compounds 58j (60%) and 58k (77%), and alkylidenecyclopropane 58l possessing a fully substituted three-membered ring was also formed in excellent yield (96

Synthesis of spirocyclic scaffolds using hypervalent iodine reagents

• Fateh V. Singh,
• Priyanka B. Kole,
• Saeesh R. Mangaonkar and
• Samata E. Shetgaonkar

Beilstein J. Org. Chem. 2018, 14, 1778–1805, doi:10.3762/bjoc.14.152

• stereoselective synthesis. Additionally, the applications of these reagents in natural product synthesis are also covered. Keywords: hypervalent iodine reagents; iodoarenes; natural products; oxidative cyclization; spirocyclic compounds; Review 1. Introduction The chemistry of spirocyclic compounds is a well

• [17]. There are several ways available in literature for the synthesis of spirocyclic compounds but most of them are associated either with transition metals or hypervalent iodine reagents [1][2][3]. Hypervalent iodine reagents provide various functional group transformation opportunities in organic

• ortho- or para-position can be used as starting material for the synthesis of ortho- and para-spirocyclic compounds in the presence of iodine(III)-based electrophiles (Scheme 1). Phenolic oxygen of compound 7 attacks to the iodine of 8 to form intermediate 9. Furthermore, on nucleophilic attack of the

A survey of chiral hypervalent iodine reagents in asymmetric synthesis

• Soumen Ghosh,
• Suman Pradhan and
• Indranil Chatterjee

Beilstein J. Org. Chem. 2018, 14, 1244–1262, doi:10.3762/bjoc.14.107

• enantioselective oxidative dearomatization of phenolic derivatives 25 (spirolactonization) which is known as Kita oxidation to yield spirocyclic compounds 26 with good enantioselectivity [32]. The indication of an associative mechanism was also confirmed due to an increased enantioselectivity observed in polar

• imparted superior reactivity compared to Ishihara’s system without the need of achiral alcohols as an additive. Profitable results were obtained regarding the oxidative cyclization of phenolic derivatives 36 to spirocyclic compounds 37. Chiral hypervalent iodine reagents having binaphthyl backbones were

1H-Imidazol-4(5H)-ones and thiazol-4(5H)-ones as emerging pronucleophiles in asymmetric catalysis

• Antonia Mielgo and
• Claudio Palomo

Beilstein J. Org. Chem. 2016, 12, 918–936, doi:10.3762/bjoc.12.90

• two other examples (Scheme 7b), however, rhodanines of type 45 have been employed to produce spirocyclic compounds. The first case is an enamine/Michael tandem reaction to unsaturated enones [81] (Scheme 7b,1) and the second one is the Diels–Alder reaction with 2,4-dienals which occurs via trienamine

The Shono-type electroorganic oxidation of unfunctionalised amides. Carbon–carbon bond formation via electrogenerated N-acyliminium ions

• Alan M. Jones and
• Craig E. Banks

Beilstein J. Org. Chem. 2014, 10, 3056–3072, doi:10.3762/bjoc.10.323

• popularity with an elegant synthesis of the natural product, kingianin A, recently published by the Moses group, albeit not through a Shono or non-Kolbe mechanism [75]. The Shono-type electrooxidation has been used to prepare spirocyclic compounds using a double silyl electroauxiliary approach (Scheme 13

• ]. Preparation of dienes using the Shono oxidation [23]. Combination of an electroauxiliary mediated anodic oxidation and RCM to afford spirocyclic compounds [76]. Total synthesis of (+)-myrtine (66) using an electrochemical approach [78]. Total synthesis of (−)-A58365A (70) and (±)-A58365B (71) [79]. Anodic

Chiral phosphines in nucleophilic organocatalysis

• Yumei Xiao,
• Zhanhu Sun,
• Hongchao Guo and
• Ohyun Kwon

Beilstein J. Org. Chem. 2014, 10, 2089–2121, doi:10.3762/bjoc.10.218

• spirocyclic compounds containing two neighboring quaternary and tertiary stereocenters in modest to excellent yields (up to 97%) and high enantioselectivities (up to 95% ee). Subsequently, the Fu group applied this approach to the [3 + 2] annulation of allenes with 1,1-disubstituted olefins to synthesize

• ] annulations of 4-substituted 2,6-diarylidenecyclohexanones with allenoates occurred with high diastereo- and enantioselectivity, providing spirocyclic compounds in satisfactory yields with up to 92% ee (Scheme 6) [39]. Using the catalyst B2, Jørgensen and co-workers developed a sequential annulation

• a series of spirocyclic compounds – promising drug precursors – in good yields and with modest enantioselectivities (Scheme 20) [51]. Generally, it is difficult to control an enantioselective annulation when using an acyclic chiral phosphine lacking additional functionality. This example is one of

The regioselective synthesis of spirooxindolo pyrrolidines and pyrrolizidines via three-component reactions of acrylamides and aroylacrylic acids with isatins and α-amino acids

• Tatyana L. Pavlovskaya,
• Fedor G. Yaremenko,
• Victoria V. Lipson,
• Svetlana V. Shishkina,
• Oleg V. Shishkin,
• Vladimir I. Musatov and
• Alexander S. Karpenko

Beilstein J. Org. Chem. 2014, 10, 117–126, doi:10.3762/bjoc.10.8

• indolones. Keywords: acrylamides; aroylacrylic acids; azomethine ylide; cyclative rearrangement; cycloaddition; multicomponent; spirooxindoles; Introduction The design of new spirocyclic compounds is intriguing due to their unique non-planar structure and great potential for binding to biomolecules due to

Asymmetric allylic alkylation of Morita–Baylis–Hillman carbonates with α-fluoro-β-keto esters

• Lin Yan,
• Zhiqiang Han,
• Bo Zhu,
• Caiyun Yang,
• Choon-Hong Tan and
• Zhiyong Jiang

Beilstein J. Org. Chem. 2013, 9, 1853–1857, doi:10.3762/bjoc.9.216

• various chiral C- [7][8][9][10][11][12][13][14][15][16][17][18][19], N- [20][21][22][23][24][25], O- [26][27][28][29][30], P- [31][32][33] and S-allylic [34] and spirocyclic compounds [35][36][37]. Several protocols have been established to introduce fluorine atoms in AAA of MBH adducts. For example, to

Synthesis of 5-oxyquinoline derivatives for reversal of multidrug resistance

• Torsten Dittrich,
• Nils Hanekop,
• Nacera Infed,
• Lutz Schmitt and
• Manfred Braun

Beilstein J. Org. Chem. 2012, 8, 1700–1704, doi:10.3762/bjoc.8.193

• purification in the coupling reaction with epoxide (R)-16. The spirocyclic compounds 6c–13c were obtained by standard acid-catalyzed reaction with the corresponding diols for the formation of acetals 6c–12c and propanedithiol for 13c, starting from N-acetyl-4-piperidone. Basic hydrolysis was found to be