Efficient solid-phase synthesis and structural characterization of segetalins A–H, J and K

• Liangyu Liu,
• Wanqiu Lu,
• Quanping Guo and
• Zhaoqing Xu

Beilstein J. Org. Chem. 2025, 21, 2612–2617, doi:10.3762/bjoc.21.202

• , successful macrocyclization was achieved by employing benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) as the coupling reagent in DMF at a concentration of 10−3 M. After cleavage from the resin and global side-chain deprotection, the crude cyclic peptides were purified by preparative

• reagent for the challenging head-to-tail macrocyclization step under moderate dilution (10−3 M). This protocol afforded the target cyclic peptides in practical isolated yields (45–70%) and high purity. Comprehensive structural characterization by HRESIMS, NMR, and HPLC confirmed the identity and high

Enantioselective desymmetrization strategy of prochiral 1,3-diols in natural product synthesis

• Lihua Wei,
• Rui Yang,
• Zhifeng Shi and
• Zhiqiang Ma

Beilstein J. Org. Chem. 2025, 21, 1932–1963, doi:10.3762/bjoc.21.151

• two steps. Macrocyclization of 147, followed by glycosylation with 135, gave compound 148, which was converted into azithromycin (149) upon desilylation. This desymmetrization strategy was also employed in the synthesis of (−)-dysiherbaine reported by Kang and co-workers in 2012 (Scheme 21) [61

Chiral phosphoric acid-catalyzed asymmetric synthesis of helically chiral, planarly chiral and inherently chiral molecules

• Wei Liu and
• Xiaoyu Yang

Beilstein J. Org. Chem. 2025, 21, 1864–1889, doi:10.3762/bjoc.21.145

• directly used as a planarly chiral primary amine catalyst in the asymmetric electrophilic amination reaction of aldehyde 34, which yielded the α-amination product 35 with high enantioselectivity. In 2022, our group disclosed an enantioselective macrocyclization protocol for the asymmetric synthesis of

• planarly chiral paracyclophanes [39]. Commenced with a macrocyclization precursor 36 featuring both a hydroxy group and an allenamide moiety, the CPA-catalyzed asymmetric intramolecular addition led to the successful construction of planarly chiral macrocycles 37 (Scheme 10). This method demonstrated broad

• , resulting in kinetic resolution with an exceptional performance. In 2025, Zhou and co-workers disclosed the asymmetric synthesis of planarly chiral macrocycles via CPA-catalyzed atroposelective macrocyclization [42]. The authors devised and prepared a series of indole-based hydroxy-substituted carboxylic

3,3'-Linked BINOL macrocycles: optimized synthesis of crown ethers featuring one or two BINOL units

• Somayyeh Kheirjou,
• Jan Riebe,
• Maike Thiele,
• Christoph Wölper and
• Jochen Niemeyer

Beilstein J. Org. Chem. 2025, 21, 1719–1729, doi:10.3762/bjoc.21.134

• ]. However, under the same coupling conditions (Pd2(dba)3, P(o-Tol)3, n-Bu4N+OH−, toluene/H2O, 90 °C), the reaction of diiodide 1 with bisboronic acids 75/6/7/8 gave only low yields of the desired macrocycles Me-M1 (7/32/22/21% for Me-M15/6/7/8). Thus, the macrocyclization via two-fold Suzuki coupling was

• were slightly increased (40% for H-M18, 53% for iPr-M18). As a general trend, we observed that the pentaethylene glycol linker seems to be too short to result in efficient macrocyclization (both in Suzuki and Williamson reactions), while the longer linkers give moderate to good yields of the desired

• . Yields for the macrocyclization step depended strongly on ring size and substitution pattern and ranged from 11–74%. Second, we could use Me/H/iPr-2 as starting materials for bis-BINOL macrocycles. Attachment of ethylene glycol chains with suitable leaving groups (tosylate or chloride), followed by

Selective monoformylation of naphthalene-fused propellanes for methylene-alternating copolymers

• Kenichi Kato,
• Tatsuki Hiroi,
• Seina Okada,
• Shunsuke Ohtani and
• Tomoki Ogoshi

Beilstein J. Org. Chem. 2025, 21, 1183–1191, doi:10.3762/bjoc.21.95

• well with the observed reactivities and selectivity. Attempted macrocyclization leading to linear polymers Formyl groups have diverse reactivities and enable facile condensation, dynamic covalent chemistry, and so on. In this work, we tried the synthesis of cyclic oligomers composed of naphthalene

Synthetic approach to borrelidin fragments: focus on key intermediates

• Yudhi Dwi Kurniawan,
• Zetryana Puteri Tachrim,
• Teni Ernawati,
• Faris Hermawan,
• Ima Nurasiyah and
• Muhammad Alfin Sulmantara

Beilstein J. Org. Chem. 2025, 21, 1135–1160, doi:10.3762/bjoc.21.91

• construct the C11–C15 fragment of borrelidin and macrocyclization using a model compound based on metathesis reaction Two years earlier, in 2006, Iqbal and co-workers developed a strategy for synthesizing the C11–C15 fragment of borrelidin [34]. Additionally, they conducted a synthetic study to achieve the

• macrocyclization using a model system, employing a ring-closing metathesis reaction. As shown in Scheme 23, ylide 152, derived from triphenylphosphine and chloroacetonitrile, was treated with bromine in the presence of sodium hexamethyldisilazide to afford compound 153 in 72% yield. Reaction of this intermediate

• )-configurations, respectively. The macrocyclization study of borrelidin was subsequently carried out using model compounds 155a and 155b (Scheme 24). Heating compound 155a in dichloromethane for 18 hours in the presence of 5 mol % Grubbs’ second generation catalyst yielded coupling product 156a and unreacted

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

Discovery of antimicrobial peptides clostrisin and cellulosin from Clostridium: insights into their structures, co-localized biosynthetic gene clusters, and antibiotic activity

• Moisés Alejandro Alejo Hernandez,
• Katia Pamela Villavicencio Sánchez,
• Rosendo Sánchez Morales,
• Karla Georgina Hernández-Magro Gil,
• David Silverio Moreno-Gutiérrez,
• Eddie Guillermo Sanchez-Rueda,
• Yanet Teresa-Cruz,
• Brian Choi,
• Armando Hernández Garcia,
• Alba Romero-Rodríguez,
• Oscar Juárez,
• Siseth Martínez-Caballero,
• Mario Figueroa and
• Corina-Diana Ceapă

Beilstein J. Org. Chem. 2024, 20, 1800–1816, doi:10.3762/bjoc.20.159

• Tables S6–S9). These experiments provided crucial insights into the cellulosin lanthipeptide structure. High-confidence conclusions from the MS2 experiment on the fragment with 6 net dehydrations highlighted the linearity of N1–V29. They identified T27 as Dhb, revealing macrocyclization of C30–C39 and

• suggesting Dhb and Dha residues at T31 and S35, respectively, with potential macrocyclization of S42 forming a lanthionine bridge. Additionally, medium-confidence observations hinted at macrocyclization of C64 (Figure 4 and Supporting Information File 1, Figure S2 associated with ion lists in Tables S6–S9

• ). Furthermore, analysis of the MS2 experiment post-iodoacetamide reaction indicated the absence of free cysteines between C30 and C39, supported by alkylated y35 and y24 ions, implying macrocyclization, and proposed the presence of three macrocycles between G41 and the C-terminus (Figure S3 in Supporting

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• the chemo-enzymatic approach for synthesizing this family of natural products [57]. Regioselective macrocyclization: tylactone and juvenimicins In the chemical synthesis of macrolides, macrolactone construction most generally involves the generation of activated esters from the corresponding

• ]. In the field of chemo-enzymatic total synthesis utilizing polyketide synthase (PKS)-related macrocyclization enzymes, Xiang and co-workers recently reported the total synthesis of cylindrocyclophanes [64]. The cyanobacterial non-canonical enzyme CylK, discovered and characterized by Balskus and co

• ][75][76][77]. In the proposed biosynthesis of 4 as illustrated in Scheme 7, five units of the type I polyketide synthase (PKS), TylGI–GV, comprising eight modules catalyze the polyketide chain extension reactions and a macrocyclization (Scheme 7) [78]. Initially, the acyltransferase (AT) domain of

Mining raw plant transcriptomic data for new cyclopeptide alkaloids

• Draco Kriger,
• Michael A. Pasquale,
• Brigitte G. Ampolini and
• Jonathan R. Chekan

Beilstein J. Org. Chem. 2024, 20, 1548–1559, doi:10.3762/bjoc.20.138

• ), 4.42 (m, 1H), 3.05 (m, 1H), 2.85 (d, J = 13.5 Hz, 1H), 2.74 (dd, J = 4.0 Hz, J = 10.0 Hz, 1H), 2.59 (t, J = 12.5 Hz, 1H), 2.33 (m, 1H), 2.16 (m, 1H), 1.97 (s, 1H), 1.95 (m, 1H), 1.79 (m, 1H), 1.68 (m, 2H), 1.15 (d, J = 7.0 Hz, 1H), 0.926 (d, J = 7.0 Hz, 1H) Ceanothine B macrocyclization between Tyr-3

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• , and their hybrids, thioesterase (TE) domains play a significant role in late-stage macrocyclization. These domains can accept mimics of native substrates in vitro and exhibit potential for use in total synthesis. This review summarizes the recent advances of TE domains in the chemoenzymatic synthesis

• requires effective and economical preparation methods [5]. In the synthesis of these natural products and their analogs, macrocyclization through linear precursors, the key step in the general routes, was typically accomplished via conventional chemical methodologies [6][7], keeps presenting an obstacle

• . Developing more efficient and diverse macrocyclization strategies is urgently needed to overcome issues such as insufficient regioselectivity, intermolecular oligomerization, the overuse of protective groups, and other drawbacks [8]. In the biosynthetic logic, these natural products are produced by the large

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

• , whereas the corresponding spirocycle in kadsulignan E was formed under Ir photocatalysis. In addition, photoinduced Pd catalysis was applied in the key macrocyclization

Active-metal template clipping synthesis of novel [2]rotaxanes

• Cătălin C. Anghel,
• Teodor A. Cucuiet,
• Niculina D. Hădade and
• Ion Grosu

Beilstein J. Org. Chem. 2023, 19, 1776–1784, doi:10.3762/bjoc.19.130

• molecule which catalyzes the macrocyclization reaction around the axle (Figure 1b). Results and Discussion In order to access the target [2]rotaxanes we made use of the CuAAC reaction, performed in the presence of a copper(I) N-heterocyclic carbene, a very stable and efficient class of catalysts used in

• ]rotaxanes using both a [1 + 1] macrocyclization clipping reaction to obtain R1 and an intramolecular macrocyclization to access R2 (Scheme 2). In both cases formation of the [2]rotaxanes was observed by HRESI(+)-MS (Figure 3, top). Thus, the HRESI(+)-MS spectrum of R1 showed two characteristic peaks at m/z

• Information File 1). However, only [2]rotaxane R2 could be isolated as pure compound in 3% yield, after several purification operations by column chromatography. The improved results obtained in the intramolecular macrocyclization for the clipping reaction as compared to the [1 + 1] strategy are in line with

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

• obtained instead [40]. Since this type of macrocycle self-assembly seems to be very promising, we decided to reproduce the Dolzhenko’s procedure, then study the macrocyclization in detail, and extend this approach to the synthesis of other polyunsaturated 1,2,4,8,9,11-hexaazamacrocycles. Herein, we report

• ]hexaazacyclotetradecine-4,12-diamine (5) under various conditions. Mechanistic aspects of the macrocyclization are also discussed. Some features of the structure and reactivity of the obtained macrocycle are outlined. Results and Discussion The readily available 3-amino-1-methyl-1H-pyrazole-4-carbonitrile (3) was used as

• calculations was proposed. It involves nucleophilic attack of hydrazine on the C2 carbon of the pyrimidine ring followed by cleavage of the C2–N3 bond, dimerization of the bis-amidrazone formed, and macrocyclization of the dimer. The DFT calculations also showed that the hydrazine-promoted transformation of

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

• intramolecular Wittig reaction to promote the macrocyclization in the formal synthesis of compound 2. Initially, the authors synthesized the fragment 14 from the starting aldehyde 80 by using a Wittig reaction followed by hydrogenation using ammonium formate (Scheme 17). Concomitantly, 4-formylphenylboronic acid

• macrocyclization using SO3·pyridine [68] gave the corresponding thioether 151, which was oxidized to the cyclic sulfone 152 using m-CPBA. Extrusion of SO2 by FVP followed by demethylation of the formed macrolide furnished the compound 154 which can be converted in combretastatin D-1 (1) by known methodologies [43

Supramolecular approaches to mediate chemical reactivity

• Pablo Ballester,
• Qi-Qiang Wang and
• Carmine Gaeta

Beilstein J. Org. Chem. 2022, 18, 1463–1465, doi:10.3762/bjoc.18.152

• -substrate catalyzed the macrocyclization with pyrrole. Interestingly, only 5 mol % of catalyst loadings were necessary in order to promote the condensation processes, and calix[4]pyrrole derivatives were obtained in moderate to high yields. Mild reaction conditions were employed, thus highlighting the

Synthesis of meso-pyrrole-substituted corroles by condensation of 1,9-diformyldipyrromethanes with pyrrole

• Baris Temelli and
• Pinar Kapci

Beilstein J. Org. Chem. 2022, 18, 1403–1409, doi:10.3762/bjoc.18.145

• macrocyclization reaction of 1,9-diformyl-5-phenyl dipyrromethane (1a) with tris(2-pyrrolyl)methane was investigated by changing the reaction conditions in the presence of various acids such as acetic acid, hydrochloric acid and p-toluenesulfonic acid (Scheme 3). Among these reactions, the reaction in acetic acid

Bioinspired tetraamino-bisthiourea chiral macrocycles in catalyzing decarboxylative Mannich reactions

• Hao Guo,
• Yu-Fei Ao,
• De-Xian Wang and
• Qi-Qiang Wang

Beilstein J. Org. Chem. 2022, 18, 486–496, doi:10.3762/bjoc.18.51

• % yields. It is worth noting that common dilute conditions for macrocyclization reactions was not required here. Due to the very high efficiency, gram-scale preparation of the chiral macrocycles was readily achieved (see Supporting Information File 1). To enrich the diversity of the macrocyclic scaffolds

Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• , demonstrating significant bioorthogonality in manganese(I) catalysis. The robustness of the method bears significance for further synthetic applications, such as “Click” chemistry or N-functionalization. Moreover, as shown in Scheme 9B, the manganese(I) catalysis regime enabled peptide macrocyclization (see 25f

• cyclic peptide motif (Scheme 11). Dipeptide substrate 26f decorated with a Morita–Baylis–Hillman carbonate underwent the intramolecular C–H allylation process to yield cyclic peptide 28f under dilute reaction conditions. This macrocyclization strategy introduces an exocyclic olefin motif onto the cyclic

• , late-stage intramolecular C–H macrocyclization was also investigated (Scheme 15). To avoid unwanted intermolecular oligomerization, the reaction was performed at a high dilution, furnishing either C- or N-terminus-alkenylated products with excellent chemoselectivity. In this macrocyclization, cyclic

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

• Sakurai macrocyclization/dimerization strategy to produce 150 in the presence of TMSOTf, as shown in Scheme 35 [70]. Hoye and Hu utilized camphor sulfonic acid (CSA) to construct a cis-2,6-disubstituted tetrahydropyran 153 via an intramolecular Sakurai cyclization reaction between the enal 151 and an

Design and synthesis of a bis-macrocyclic host and guests as building blocks for small molecular knots

• Elizabeth A. Margolis,
• Rebecca J. Keyes,
• Stephen D. Lockey IV and
• Edward E. Fenlon

Beilstein J. Org. Chem. 2020, 16, 2314–2321, doi:10.3762/bjoc.16.192

• spectrum showed the loss of the ethyl ester peaks (Scheme 4). Bis-macrocyclization of 15 under high-dilution using Shiina’s mixed-anhydride method [29] afforded host 1 in 28% yield. As with the analogous first-generation knot-precursor bis-macrocycle [15], host 1 was formed as a mixture of meta- and ortho

• )amine. Better yielding route to core diester 13. aLigand = tris(2-benzimidazolylmethyl)amine. Saponification of 13 and bis-macrocyclization to form host 1. Synthesis of 23 backbone-atom bis(ammonium) guest 2. Synthesis of 25 backbone-atom bis(pyridinium) guest 3. Supporting Information Supporting

Design, synthesis and application of carbazole macrocycles in anion sensors

• Alo Rüütel,
• Ville Yrjänä,
• Sandip A. Kadam,
• Indrek Saar,
• Mihkel Ilisson,
• Astrid Darnell,
• Kristjan Haav,
• Tõiv Haljasorg,
• Lauri Toom,
• Johan Bobacka and
• Ivo Leito

Beilstein J. Org. Chem. 2020, 16, 1901–1914, doi:10.3762/bjoc.16.157

• transducer). Results and Discussion Design We aimed to investigate the effects of ring size on the binding of carboxylates and the biscarbazolylurea moiety was selected. The studied receptors are shown in Figure 3. In order to achieve macrocyclization, we decided to use linear aliphatic dicarboxylic acid

Five-component, one-pot synthesis of an electroactive rotaxane comprising a bisferrocene macrocycle

• Natalie Lagesse,
• Luca Pisciottani,
• Maxime Douarre,
• Pascale Godard,
• Brice Kauffmann,
• Vicente Martí-Centelles and
• Nathan D. McClenaghan

Beilstein J. Org. Chem. 2020, 16, 1564–1571, doi:10.3762/bjoc.16.128

• high yields. This methodology consisted of a 4-component macrocyclization reaction, templated by the thread to obtain the corresponding interlocked molecule (Figure 1a) [4][5]. This class of macrocycle has proved extremely versatile, having given rise to a wealth of functional architectures [6][7][8][9

• also arranging the molecule in an appropriate reactive position favouring the intramolecular macrocyclization reaction (Figure 3b) [19]. Despite the theoretically favourable preorganization, the observed experimental templating effect was modest as the macrocyclization yield was only ≈29% of impure

• 1 and macrocycle 2. Most stable conformers obtained by Monte Carlo conformational search using model compounds. (a) Model macrocyclization reaction intermediate in the absence of a template; (b) model macrocyclization reaction intermediate in the presence of a template. 1H NMR spectrum (300 MHz) of

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

• Valerian Dragutan,
• Ileana Dragutan,
• Albert Demonceau and
• Lionel Delaude

Beilstein J. Org. Chem. 2020, 16, 738–755, doi:10.3762/bjoc.16.68

• total synthesis of amphidinolides [73][74][75], Fürstner et al. applied both ring-closing alkyne metathesis and intramolecular enyne metathesis with ethylene in a sequential mode for the synthesis of amphidinolide V (7) [75]. As a special merit of this original protocol, the macrocyclization of the

Light-controllable dithienylethene-modified cyclic peptides: photoswitching the in vivo toxicity in zebrafish embryos

• Sergii Afonin,
• Oleg Babii,
• Aline Reuter,
• Volker Middel,
• Masanari Takamiya,
• Uwe Strähle,
• Igor V. Komarov and
• Anne S. Ulrich

Beilstein J. Org. Chem. 2020, 16, 39–49, doi:10.3762/bjoc.16.6

• plasma stability in vivo, limited understanding of their mechanisms of action, and high in vivo toxicity. The former two drawbacks are being adequately resolved [9] (e.g., by modifying the peptide backbone [10], macrocyclization [11], or by use of unnatural amino acids [12]), and mechanistic