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

Synthesis of novel sulfide-based cyclic peptidomimetic analogues to solonamides

• José Brango-Vanegas,
• Luan A. Martinho,
• Lucinda J. Bessa,
• Andreanne G. Vasconcelos,
• Alexandra Plácido,
• Alex L. Pereira,
• José R. S. A. Leite and
• Angelo H. L. Machado

Beilstein J. Org. Chem. 2019, 15, 2544–2551, doi:10.3762/bjoc.15.247

• reported for solonamides. Keywords: antivirulence drug; bacteria; macrocyclization; pathoblocker; quorum quenching; Introduction The cyclodepsipeptides called solonamides A and B are natural molecules extracted from the marine bacterium Photobacterium halotolerans [1][2] (Figure 1). They are able to

• cysteine sulfhydryl side chain to electrophilic Cβ of an O-acetylated Morita–Baylis–Hillman (MBH) adduct residue (Scheme 1). Despite reports describing the use of amino acid residues with nucleophilic side chains to prompt the macrocyclization of peptides and their mimetics, to the best of our knowledge

• , this is the first report on the participation of MBH residues as electrophilic sites to allow an SN2’-based macrocyclization of peptidomimetics [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. Two of these new compounds were able to interfere with the hemolytic activity of S. aureus, and

1,2,3-Triazolium macrocycles in supramolecular chemistry

• Mastaneh Safarnejad Shad,
• Pulikkal Veettil Santhini and
• Wim Dehaen

Beilstein J. Org. Chem. 2019, 15, 2142–2155, doi:10.3762/bjoc.15.211

• macroring. A second strategy is the macrocyclization of an acyclic precursor containing pre-functionalized triazole by other ring closure methods such as Grubbs metathesis [25] and amidation reactions. The macrocyclization is normally followed by N-alkylation (often methylation) leading to the synthesis of

• developed for the synthesis of bile acid-based macrocycles, using macrolactamization, ring-closing metathesis and Ugi-multicomponent macrocyclization. Developing more efficacious and economical methods for the construction of these macrocycles is still in demand due to the disadvantages of the

Bambusuril analogs based on alternating glycoluril and xylylene units

• Tomáš Lízal and
• Vladimír Šindelář

Beilstein J. Org. Chem. 2019, 15, 1268–1274, doi:10.3762/bjoc.15.124

• structure of glycoluril features methine protons on its convex face which can either point to the same or the opposite direction within the macrocycle. Both isomers 1a and 1b were present in the crude product also due to the irreversible nature of the macrocyclization reaction. This is in contrast with the

• to achieve separation of these isomers. Therefore, our attention turned to macrocycle 1, which was the major product of the macrocyclization reaction. The separation of diastereomers 1a and 1b was achieved by preparative HPLC using a reversed-phase column and acetonitrile/water gradient elution. The

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• and complexity-generating processes [2][3] have proven success in peptide ligation [4] and macrocyclization [5][6], protein glycoconjugation [7], lipidation of peptides [8] and glycosides [9], and carbohydrate modification [10]. A special class of lipidic biomolecules are the steroids, which can be

• the steroidal nucleus, the assembly of nitrogen-heterocycles fused to the steroid-ring system, the steroid conjugation and macrocyclization, all relying on MCRs. 2 Modification of the steroidal nucleus and the side chain 2.1 Isocyanide-based MCRs 2.1.1 Steroids as carbonyl component: One of the first

• have been included in previous reviews [12][13] this section will cover those reports from 2009 on, with emphasis on multicomponent macrocyclization approaches leading to steroidal cages. The first report of a MCR-derived steroidal macrocycles was described by Wessjohann et al. in 2005 as part of a

Molecular recognition using tetralactam macrocycles with parallel aromatic sidewalls

• Dong-Hao Li and
• Bradley D. Smith

Beilstein J. Org. Chem. 2019, 15, 1086–1095, doi:10.3762/bjoc.15.105

• (i.e., 27+·Cl−). Not only was 27+·Cl− a high affinity guest for tetralactam B, it was also an effective template for the macrocyclization reaction that produced tetralactam B. 3.5. Oligosaccharides The advantages of the amphiphilic cavity are also highlighted by the work of the Davis group who have

Synthesis of (macro)heterocycles by consecutive/repetitive isocyanide-based multicomponent reactions

• Angélica de Fátima S. Barreto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2019, 15, 906–930, doi:10.3762/bjoc.15.88

• followed by formation of an acyclic depsipeptoid via Passerini reaction between acid 96, isocyanide 98 and aldehydes 97. Trifluoroacetic acid (TFA) allowed deprotection of the amine/acid groups. In the last step, a macrocyclization reaction via an intramolecular Ugi reaction provided the achievement of the

• chimeric peptoid macrocycles containing steroid moieties [37]. The process was based on designing a 4-fold Ugi-4CR macrocyclization by using the steroidal diisocyanide 107 with diacid 108 or diamine 109 (Scheme 21). According to the authors, this was the first report of repetitive multicomponent reactions

• . In the approach, one of the building blocks taking part in the first Ugi-MiB must contain a protected, Ugi-reactive functional group to be subsequently activated for the next macrocyclization. In this way, after the first double Ugi reaction between diamine 130, diisocyanide 116, paraformaldehyde and

Solid-phase synthesis of biaryl bicyclic peptides containing a 3-aryltyrosine or a 4-arylphenylalanine moiety

• Iteng Ng-Choi,
• Àngel Oliveras,
• Lidia Feliu and
• Marta Planas

Beilstein J. Org. Chem. 2019, 15, 761–768, doi:10.3762/bjoc.15.72

• protein–protein interactions [1][2][3][4][5][6][7][8][9]. These advantageous attributes rise from the rigidity of their conformational structure and from the low susceptibility to protease degradation of the cyclic backbone. There is a wide range of methods for the macrocyclization of linear peptides [1

• -terminal groups of the peptide and their putative target. This method has been used for the macrocyclization of peptides through, for example, copper-catalyzed azide–alkyne cycloadditions [14], ring-closing olefin metathesis [13] or the formation of an aryl–aryl bond between the side chain of two aromatic

• –Miyaura reaction of 10 was carried out using the same conditions for the macrocyclization of resin 7. Mass spectrometry analysis of the crude reaction mixture from cleavage of an aliquot of the resulting 11 revealed the formation of the expected biaryl cyclic peptide 12 in 21% HPLC purity. Selective Boc

Selectivity in multiple multicomponent reactions: types and synthetic applications

• Ouldouz Ghashghaei,
• Francesca Seghetti and
• Rodolfo Lavilla

Beilstein J. Org. Chem. 2019, 15, 521–534, doi:10.3762/bjoc.15.46

• multicomponent macrocyclization strategy [18][20] (Scheme 4) constitutes a breakthrough in the field, providing a powerful synthetic tool to systematically design and prepare a variety of structures. The implementation of this approach goes beyond simple macrocycles, and was exploited to deliver macromulticycles

• 4CR-macrocyclization efficiently afforded the final target (Scheme 14). Furthermore, additional sequential versions of multiple MCRs have been employed to construct natural products. For instance, Ugi reported the synthesis of a 6-aminopenicillanic acid derivative using two different MCRs [33][52]. As

• transformations lead to well-defined macromolecules. An interesting case is found in systems where the reaction conditions and the preorganization of some inputs leads to selective macrocyclization, affording extremely complex MCR adducts in just one step. Rationalization of these processes allows programmed

Design of indole- and MCR-based macrocycles as p53-MDM2 antagonists

• Constantinos G. Neochoritis,
• Maryam Kazemi Miraki,
• Eman M. M. Abdelraheem,
• Ewa Surmiak,
• Tryfon Zarganes-Tzitzikas,
• Beata Łabuzek,
• Tad A. Holak and
• Alexander Dömling

Beilstein J. Org. Chem. 2019, 15, 513–520, doi:10.3762/bjoc.15.45

• synthesis was accomplished by a rapid, one-pot synthesis of indole-based macrocycles based on Ugi macrocyclization. The reaction of 12 different α,ω-amino acids and different indole-3-carboxaldehyde derivatives afforded a unique library of macrocycles otherwise difficult to access. Screening of the library

• ]. Herein, an indole-based macrocycle synthesis is reported in a one-pot fashion based on Ugi macrocyclization with readily available α,ω-amino acids. Moreover, in continuation of our efforts in the design and synthesis of macrocycles targeting the p53–MDM2 interaction demonstrating the potential of these

• indole-based macrocycles, a subset of them was screened searching for MDM2 inhibitors. Compared to our previous indole-based macrocycles 1 following a different strategy (employing a classical Ugi-4C as the key reaction) [23], this one-pot Ugi macrocyclization leading to macrocycles 2 offers speed (one

First synthesis of cryptands with sucrose scaffold

• Patrycja Sokołowska,
• Michał Kowalski and
• Sławomir Jarosz

Beilstein J. Org. Chem. 2019, 15, 210–217, doi:10.3762/bjoc.15.20

• ’,4,4’-penta-O-benzylsucrose and 1’,2,3,3’,4,4’-hexa-O-benzylsucrose. Keywords: cryptands; macrocyclization; sucrose; Introduction The design and synthesis of macrocyclic receptors is one of the main challenges of supramolecular chemistry [1][2]. These artificial systems exhibit interesting properties