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

• pikromycin and the aglycones in this family, 10-deoxymethynolide (24) and norbonolide (25), using asymmetric aldol reaction, Yamaguchi esterification, and ring-closing metathesis as key steps [65][66]. Nevertheless, the inherent complexity of these natural products demands high step counts, leading to low

• , they established a preparative-scale approach toward the pikromycins family and their aglycones in 2013 [70]. The preparation of activated pentaketides (37) using asymmetric α-alkylation and cross metathesis as key reactions reduced the step counts from 14 to 11 steps. Replacing the extender unit from

• epoxidation with enzymatic macrocyclization in 2020 as shown in Scheme 8 [85]. According to their previous report [86], the production of fragments 61 was initiated by Evans’ asymmetric aldol and alcohol protection to generate 57. Six-step route transformations, including cross metathesis, afforded aldehyde

A laterally-fused N-heterocyclic carbene framework from polysubstituted aminoimidazo[5,1-b]oxazol-6-ium salts

• Andrew D. Gillie,
• Matthew G. Wakeling,
• Bethan L. Greene,
• Louise Male and
• Paul W. Davies

Beilstein J. Org. Chem. 2024, 20, 621–627, doi:10.3762/bjoc.20.54

• -aminoimidazo[5,1-b]oxazol-6-ium motif, followed by salt metathesis using KPF6 leading to the clean hexafluorophosphate salt 9a in 67% yield after recrystallisation [4]. This two-step assembly of the 3-aminoimidazo[5,1-b]oxazol-6-ium motif was also applied to ynamide 1b affording the PMP-substituted salt 9b in

(E,Z)-1,1,1,4,4,4-Hexafluorobut-2-enes: hydrofluoroolefins halogenation/dehydrohalogenation cascade to reach new fluorinated allene

• Nataliia V. Kirij,
• Andrey A. Filatov,
• Yurii L. Yagupolskii,
• Sheng Peng and
• Lee Sprague

Beilstein J. Org. Chem. 2024, 20, 452–459, doi:10.3762/bjoc.20.40

• significantly. One of the new and budding directions in recent years is the stereoselective olefin metathesis processes based on catalysis by complexes of molybdenum, tungsten and ruthenium [3][4][5]. The first publications have recently appeared that molybdenum complexes can catalyze cross-metathesis of butene

• 1b. Wherein various alkyl and aryl olefins, including those that contain Lewis basic esters, carbamates and amines or α-branched moieties, may be used in efficient and exceptionally Z-selective cross-metathesis reactions [6][7][8]. A few years ago, some publications devoted to the cleavage of the C–F

Radical chemistry in polymer science: an overview and recent advances

• Zixiao Wang,
• Feichen Cui,
• Yang Sui and
• Jiajun Yan

Beilstein J. Org. Chem. 2023, 19, 1580–1603, doi:10.3762/bjoc.19.116

• mechanism (cf. section 3.2) [86]. 2.3 Metal-free ring opening metathesis polymerization (MF-ROMP) ROMP is a powerful and broadly applicable technique for synthesizing polymers. Traditional ROMP systems are initiated by transition-metal complexes and Ru-based alkylidene complexes, which are also known as

Pyridine C(sp²)–H bond functionalization under transition-metal and rare earth metal catalysis

• Haritha Sindhe,
• Malladi Mounika Reddy,
• Karthikeyan Rajkumar,
• Akshay Kamble,
• Amardeep Singh,
• Anand Kumar and
• Satyasheel Sharma

Beilstein J. Org. Chem. 2023, 19, 820–863, doi:10.3762/bjoc.19.62

• involves the formation of (dibenzylamido)yttrium complex 28 by the reaction of yttrium complex 26 with HNBn2. Then σ-bond metathesis between the Y–N bond of 28 and the ortho-C–H bond of pyridine gives η2-pyridyl species 29 which on imine insertion produces species 30. Subsequent protonation then provides

• to furnish the transient complex 81 which undergoes σ-bond metathesis to give the product 77 and regenerating 78 (Scheme 16b). While speaking regarding the alkenylation, the geometrical isomerism, i.e., the stereoselectivity between the cis- and trans-alkenylation, has not been considered so far

Strategies in the synthesis of dibenzo[b,f]heteropines

• David I. H. Maier,
• Barend C. B. Bezuidenhoudt and
• Charlene Marais

Beilstein J. Org. Chem. 2023, 19, 700–718, doi:10.3762/bjoc.19.51

• moderate to good yield (35–82%). 3.5 Ring-closing metathesis Olefin metathesis is a metal-catalysed reaction wherein carbon–carbon double bonds are cleaved and formed through an intermediate cyclometallacarbene 114, thus allowing for transalkylidenation and the formation of mixed alkenes 115 (Scheme 24

• ) [66]. Variations of this reaction include alkyne metathesis [67] and carbonyl metathesis [68]. Ring-closing metathesis (RCM) gave access to a series of dibenzo[b,f]heteropines, as reported by Matsuda and Sato [31] (Scheme 25). The authors synthesised a series of Si-, Sn-, Ge- and B-tethered dienes 118

• –Grubbs catalyst) catalysed ring-closing metathesis gave dibenzo[b,f]heteropines 122 in excellent yields (>80%). Unfortunately, the metathesis reaction required elevated temperatures (>100 °C) and dilute solutions to reduce unwanted self-metathesis competing with RCM. While excellent yields for

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

• applied for the synthesis of seven to fourteen-membered phostam, phostone, and phostine derivatives. 1.1 Synthesis via C–C bond formation Most medium and large phostams, phostones, and phostines were prepared via C–C bond formation, especially via ring-closing metathesis (RCM). 1.1.1 Synthesis via C–C

• bond formation through RCM reaction: Ring-closing metathesis (RCM) is an efficient strategy for the construction of common to large cyclic compounds via the formation of a C=C bond [26], which can be further reduced to a C–C bond. To prepare phostam-derived antitumor agents, ethyl N-allyl-N-(but-3-en-1

• -azaphosphocin-1(4H)-yl)acetate (4), respectively, in the presence of the Grubbs first generation catalyst via ring closing metathesis. The products 3 and 4 were further transformed to antitumor agents 5, 6, 9 and 10 through aminolysis with O-TMS hydroxylamine or hydrogenolysis followed by aminolysis with O-TMS

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• difunctionalization of π-systems is a power tool for the facile synthesis of complex boronate-containing compounds [42]. Generally, these reactions proceed through the generation of a Cu–boryl species via σ-bond metathesis, followed by migratory insertion with a π-system. The subsequent alkyl–Cu intermediate is

• 88%. The authors proposed the reaction begins with the generation of the tert-butoxide Cu salt which undergoes σ-bond metathesis with B2Pin2 generating the Cu–boryl species 59 (Scheme 9). Side-on coordination on the exo face of the bicyclic alkene followed by migratory insertion generates the alkyl

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

• the authors consisted in the ring closure through a metathesis reaction using the Grubbs catalyst [52][53]. The required compound 99 was prepared by converting compound 16 into the styrene 98 via a Wittig reaction followed by a transesterification to yield the desired allylic ester. Several reaction

• conditions for the metathesis using the 1st generation Grubbs catalyst were attempted without success, but when 2nd generation catalyst was used, the dimerization product 100 was observed (Scheme 20). Despite the yield for macrolide formation, Cousin proposed alternatives for the formal synthesis of 2

Group 13 exchange and transborylation in catalysis

• Dominic R. Willcox and
• Stephen P. Thomas

Beilstein J. Org. Chem. 2023, 19, 325–348, doi:10.3762/bjoc.19.28

• transfer one or more groups from one group 13 element to another, through σ-bond metathesis; where boron is both of the group 13 elements, this is termed transborylation. These redox-neutral processes are increasingly being used to render traditionally stoichiometric group 13-mediated processes catalytic

• by σ-bond metathesis, a redox neutral process (Scheme 1). Stoichiometric group 13 exchange reactions are key to the synthesis of group 13 reagents including in organoboron chemistry [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28], and more recently with aluminium [29][30][31

• [58]. The alkyne 1 and dialkylborane reacted to give an alkenylborane 2. Transborylation with HBpin gave the alkenyl boronic ester 3 and regenerated the catalyst, HBR2. Isotopic labelling (H10Bpin) confirmed B–C(sp2)/B–H transborylation proceeded by σ-bond metathesis, and not ligand exchange. Using

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

• construction of the 8-membered ring from an appropriate cyclopentane precursor. The proposed strategies include metathesis, Nozaki–Hiyama–Kishi (NHK) cyclization, Pd-mediated cyclization, radical cyclization, Pauson–Khand reaction, Lewis acid-promoted cyclization, rearrangement, cycloaddition and biocatalysis

• precursor. The proposed strategies include metathesis, Nozaki–Hiyama–Kishi (NHK) cyclization, Pd-mediated cyclization, radical cyclization (including SmI2), Pauson–Khand reaction, Lewis acid-promoted cyclization, rearrangement, cycloaddition, and biocatalysis. In particular, the purpose will focus on the

• following criteria: position/stage of the key cyclooctane ring formation in the synthesis plan, the selectivity, and the opportunity for late-stage functionalization. Review 1 Metathesis: ring-closing metathesis and related methods The metathesis reaction, first discovered by serendipity in the 1950s, has

Catalytic aza-Nazarov cyclization reactions to access α-methylene-γ-lactam heterocycles

• Bilge Banu Yagci,
• Selin Ezgi Donmez,
• Onur Şahin and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2023, 19, 66–77, doi:10.3762/bjoc.19.6

• chlorides 6 initially gives N-acyliminium salts 8, which are activated upon treatment with AgOTf resulting in an anion metathesis of Cl− with OTf−. This activation is proposed to facilitate the desired aza-Nazarov reaction to afford the cyclized intermediate 9, which is stabilized by the trimethylsilyl (TMS

Inline purification in continuous flow synthesis – opportunities and challenges

• Jorge García-Lacuna and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 1720–1740, doi:10.3762/bjoc.18.182

• purifications can be an easier and more effective alternative. An efficient method to homogeneously scavenge a ruthenium complex used in a metathesis reaction was described by Grela and co-workers on a 60 g scale [89]. The use of heterogeneous scavenger columns in flow mode is sometimes criticized. If the final

• produced as byproduct in the metathesis reaction. Some subsequent publications include the Pd-complex removal after a Suzuki coupling [126], a Heck catalyst retention with reverse boiling-point-order solvent exchange [127], and a membrane for recovery of the photocatalyst TBADT (tetrabutylammonium

B–N/B–H Transborylation: borane-catalysed nitrile hydroboration

• Filip Meger,
• Alexander C. W. Kwok,
• Franziska Gilch,
• Dominic R. Willcox,
• Alex J. Hendy,
• Kieran Nicholson,
• Andrew D. Bage,
• Thomas Langer,
• Thomas A. Hunt and
• Stephen P. Thomas

Beilstein J. Org. Chem. 2022, 18, 1332–1337, doi:10.3762/bjoc.18.138

• transborylation (a σ-bond metathesis turnover method) has been used for borane-catalysed reductions of N-heteroarenes [28][29], and the borane-catalysed cyanation of enones [30]. Applying B–N/B–H transborylation to the hydroboration of nitriles would enable the development of a borane-catalysed hydroboration of

Ionic multiresonant thermally activated delayed fluorescence emitters for light emitting electrochemical cells

• Merve Karaman,
• Abhishek Kumar Gupta,
• Subeesh Madayanad Suresh,
• Tomas Matulaitis,
• Lorenzo Mardegan,
• Daniel Tordera,
• Henk J. Bolink,
• Sen Wu,
• Stuart Warriner,
• Ifor D. Samuel and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2022, 18, 1311–1321, doi:10.3762/bjoc.18.136

• -dibromobutane in moderate yield, followed by a second alkylation step with 1-methylimidazole in very good yield. DiKTa-OBuIm was isolated as its hexafluorophosphate salt following anion metathesis with NH4PF6. DiKTa-DPA-OBuIm was obtained also in three steps at 35% overall yield from compound 4 using a similar

Vicinal ketoesters – key intermediates in the total synthesis of natural products

• Marc Paul Beller and
• Ulrich Koert

Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129

• ]. The α-ketoester 41 was accessible from amide 38, which in turn was obtained from allylic alcohol 37. Oxidation and Horner–Wadsworth–Emmons reaction with phosphonate 39 delivered the silyl enol ether 40, which was deprotected and cyclized via a Grubbs metathesis to α-ketoester 41. Subsequent

Synthetic strategies for the preparation of γ-phostams: 1,2-azaphospholidine 2-oxides and 1,2-azaphospholine 2-oxides

• Jiaxi Xu

Beilstein J. Org. Chem. 2022, 18, 889–915, doi:10.3762/bjoc.18.90

• -oxides 56a in 23% and 93 in 63% yields, respectively, showing the limited scope of the synthetic method (Scheme 17) [39]. Ring-closing metathesis (RCM) is an efficient strategy for the construction of cyclic compounds via the formation of a C=C bond [40][41], which can be reduced to the C–C bond. 2

Synthesis of odorants in flow and their applications in perfumery

• Merlin Kleoff,
• Paul Kiler and
• Philipp Heretsch

Beilstein J. Org. Chem. 2022, 18, 754–768, doi:10.3762/bjoc.18.76

• -closing metathesis [3][4]. It is well described that metathesis reactions can be significantly accelerated in flow, as the boiling point of the solvent employed can be exceeded using back pressure regulators (BPRs) and formed gases (e.g., ethylene) can be easily removed employing tube-in-tube reactors [11

• ]. Therefore, Roberge, Fogg, and co-workers investigated the advantages of continuously stirred tank reactors (CSTR) and tube reactors in comparison to the corresponding batch reaction for the ring-closing metathesis of diene 58, producing macrocyclic olefin 60 (Scheme 14) [52]. Although, macrocycle 60 is not

• 20 min at 80 °C using 1 mol % of catalyst 59 [52]. Due to the fact that ethylene formed in the ring-closing metathesis can result in the formation of unstable ruthenium methylidene species, causing degeneration of the metathesis catalyst, the continuous removal of ethylene from the reaction mixture

BINOL as a chiral element in mechanically interlocked molecules

• Matthias Krajnc and
• Jochen Niemeyer

Beilstein J. Org. Chem. 2022, 18, 508–523, doi:10.3762/bjoc.18.53

• equivalents of the acyclic precursor (S)-46 were preorganized by a Ca template and catenation was achieved by two-fold ring closing metathesis. This reaction yielded catenane (S,S)-47 (14% yield, see Figure 12) together with the non-interlocked macrocycle (S,S)-48 (22% yield, for the structure see Figure 13

A resorcin[4]arene hexameric capsule as a supramolecular catalyst in elimination and isomerization reactions

• Tommaso Lorenzetto,
• Fabrizio Fabris and
• Alessandro Scarso

Beilstein J. Org. Chem. 2022, 18, 337–349, doi:10.3762/bjoc.18.38

• synthesis of sesquiterpene natural product derivatives [38][39] and the carbonyl olefin metathesis leading to 2,5-dihydropyrroles [40]. Herein we present our investigation on the ability of the hexameric capsule 16 to act as a supramolecular self-assembled organocatalyst for a series of unimolecular

Synthesis and late stage modifications of Cyl derivatives

• Phil Servatius and
• Uli Kazmaier

Beilstein J. Org. Chem. 2022, 18, 174–181, doi:10.3762/bjoc.18.19

• compound, we decided to use the Cyl-1 amino acid backbone and introduce a double unsaturated side chain (Scheme 1). In principle, selective modifications at the two different double bonds (internal and terminal) should be possible. Ring-closing metathesis (RCM) should generate an allylglycine unit, which

• the removal of metathesis catalysts is the formation of Ru-DMSO complexes, which do not eluate from a silica column [56]. This allowed us to remove at least the Ru contamination, but we were unable to subject 12 to further modifications such as cross metathesis or thiol-ene click reactions due to poor

Earth-abundant 3d transition metals on the rise in catalysis

• Nikolaos Kaplaneris and
• Lutz Ackermann

Beilstein J. Org. Chem. 2022, 18, 86–88, doi:10.3762/bjoc.18.8

• syntheses, crop protection or medicinal chemistry. Particularly, cross-coupling reactions [1], as well as alkene and alkyne metathesis [2][3], have considerably changed the art of molecular synthesis, with a major impact on neighboring disciplines, such as molecular biology or materials sciences. Despite of

Peptide stapling by late-stage Suzuki–Miyaura cross-coupling

• Hendrik Gruß,
• Rebecca C. Feiner,
• Ridhiwan Mseya,
• David C. Schröder,
• Michał Jewgiński,
• Kristian M. Müller,
• Rafał Latajka,
• Antoine Marion and
• Norbert Sewald

Beilstein J. Org. Chem. 2022, 18, 1–12, doi:10.3762/bjoc.18.1

• stapling and the most prominent methodology was developed by the groups of Grubbs and Verdine using ring-closing metathesis (RCM) [4][5][6]. The optimised protocol for these so-called hydrocarbon-stapled peptides uses α-methyl-, α-alkenylglycines in a distance of i, i + 3/i + 4 for one helix turn or i, i

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

Recent advances in the tandem annulation of 1,3-enynes to functionalized pyridine and pyrrole derivatives

• Yi Liu,
• Puying Luo,
• Yang Fu,
• Tianxin Hao,
• Xuan Liu,
• Qiuping Ding and
• Yiyuan Peng

Beilstein J. Org. Chem. 2021, 17, 2462–2476, doi:10.3762/bjoc.17.163

• -hydrogen shift and σ-bond metathesis with hydrosilane to give the silylated pyrrole product 63 and the LCuH catalyst 57. In addition, the intermediate 58 might go through isomerization to form imine intermediate 64, which undergoes intramolecular cyclization to provide the minor regioisomer 67 (inner cycle