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

• several positions and also form 6–14 residue cyclic peptides [37][38]. It should be noted that TycC TE was more sensitive to the amino acid changes near the site of ring closure. The alkyne-containing analogs were conjugated to a variety of azido sugars via copper(I)-catalyzed cycloaddition to obtain the

Synthesis of π-conjugated polycyclic compounds by late-stage extrusion of chalcogen fragments

• Aissam Okba,
• Pablo Simón Marqués,
• Kyohei Matsuo,
• Naoki Aratani,
• Hiroko Yamada,
• Gwénaël Rapenne and
• Claire Kammerer

Beilstein J. Org. Chem. 2024, 20, 287–305, doi:10.3762/bjoc.20.30

• synthesis and a final closure of the 7-membered ring by C–C bond formation. This is in sharp contrast with the widely adopted strategy relying on the late-stage insertion of the sulfur atom with concomitant ring closure, using either electrophilic or nucleophilic sulfur reagents. By way of example, thiepine

• naphthyl substituents carrying each an alkyne moiety on the ortho position. Ring expansion of both thiophene units in 19 was then triggered by platinum catalysis to generate the corresponding thiopyrans, and finally the bromine atoms located on the latter rings were exploited for the ring closure of the

Perspectives on push–pull chromophores derived from click-type [2 + 2] cycloaddition–retroelectrocyclization reactions of electron-rich alkynes and electron-deficient alkenes

• Michio Yamada

Beilstein J. Org. Chem. 2024, 20, 125–154, doi:10.3762/bjoc.20.13

• -tetracyano-p-quinodimethane (TCNQ), results in the formation of a zwitterionic intermediate, wherein the negative charge evolves into a stabilized carbanion (dicyanomethide anion). Subsequently, the ring closure of the zwitterionic intermediate generates the corresponding cyclobutene intermediate. Finally

Synthesis of N-acyl carbazoles, phenoxazines and acridines from cyclic diaryliodonium salts

• Nils Clamor,
• Mattis Damrath,
• Thomas J. Kuczmera,
• Daniel Duvinage and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2024, 20, 12–16, doi:10.3762/bjoc.20.2

• followed by a ring-closure starting from 2,2'-diiodo-1,1'-biphenyls [15][16][17]. Related one-pot procedures are also described (Scheme 1b) [18][19]. Such 2,2´-dihalobiphenyls are established starting materials for synthesizing a variety of heterocycles. Usually, their utilization leads to the production

Thienothiophene-based organic light-emitting diode: synthesis, photophysical properties and application

• Recep Isci and
• Turan Ozturk

Beilstein J. Org. Chem. 2023, 19, 1849–1857, doi:10.3762/bjoc.19.137

• synthesis commenced with the treatment of 3-bromothiophene (1) with n-butyllithium at −78 °C, followed by the addition of elemental sulfur and subsequent reaction with 2-bromo-1-(4-methoxyphenyl)ethanone to produce compound 2 in 83% yield. The following ring-closure reaction was conducted in the presence of

Synthesis and biological evaluation of Argemone mexicana-inspired antimicrobials

• Jessica Villegas,
• Bryce C. Ball,
• Katelyn M. Shouse,
• Caleb W. VanArragon,
• Ashley N. Wasserman,
• Hannah E. Bhakta,
• Allen G. Oliver,
• Danielle A. Orozco-Nunnelly and
• Jeffrey M. Pruet

Beilstein J. Org. Chem. 2023, 19, 1511–1524, doi:10.3762/bjoc.19.108

• of two substituted arylboronic acids, followed by N-methylation, and final ring-closure via Bischler–Napieralski conditions [45][47][48]. These steps provided chelerythrine variants C1–C4, with structural variability stemming from the initial substituted tetralone (R1/R2) and/or the arylboronic acid

Clauson–Kaas pyrrole synthesis using diverse catalysts: a transition from conventional to greener approach

• Dileep Kumar Singh and
• Rajesh Kumar

Beilstein J. Org. Chem. 2023, 19, 928–955, doi:10.3762/bjoc.19.71

• removal of methanol, produces intermediate E. In the next steps, the ring closure of intermediate E due to the lone pair of nitrogen gives F, which after the elimination of methanol and water in subsequent steps provides intermediate H. Finally, an aromatic N-substituted pyrrole 3 is produced by basic

Photoredox catalysis enabling decarboxylative radical cyclization of γ,γ-dimethylallyltryptophan (DMAT) derivatives: formal synthesis of 6,7-secoagroclavine

• Alessio Regni,
• Francesca Bartoccini and
• Giovanni Piersanti

Beilstein J. Org. Chem. 2023, 19, 918–927, doi:10.3762/bjoc.19.70

• no desired cyclized product was observed, an interesting aspect of this reaction was the access of an attractive, unusual, and highly functionalized 3,4-fused eight-membered tricyclic indole, whose ring closure would not have been possible or at least very difficult in the ground state [87][88][89

• the importance of steric effects [99]. Indeed, while the addition of the nucleophilic α-amino radical to the α-styrenyl position affords the 6-membered ring (kinetic product via intramolecular 6-exo-trig ring closure) [100] the resulting radical is unstabilized, the 7-membered ring (obtained via

• intramolecular 7-endo-trig ring closure) may well be the thermodynamic product based on the more stabilized benzylic radical that is produced [101]. As largely reported in the literature [102][103], radicals generated next to alcohols do not normally undergo β-elimination to give alkene/carbon–carbon double-bond

First synthesis of acylated nitrocyclopropanes

• Kento Iwai,
• Rikiya Kamidate,
• Khimiya Wada,
• Haruyasu Asahara and
• Nagatoshi Nishiwaki

Beilstein J. Org. Chem. 2023, 19, 892–900, doi:10.3762/bjoc.19.67

• bulkier. The obtained nitrocyclopropane was transformed into furan upon treatment with tin(II) chloride via a ring-opening/ring-closure process. Keywords: acetoxyiodine; conjugate addition; dihydrofuran; nitroalkene; nitrocyclopropane; Introduction 3-Arylated 2-nitrocyclopropane-1,1-dicarbonylic acid

• ) halogenation, and 3) ring closure (Scheme 2). β-Nitrostyrene 2 serves as an appropriate acceptor for conjugate addition by diethyl malonate (3a) to afford adduct 4a, in which the methine group flanked by two carbonyl groups is readily halogenated, and the subsequent intramolecular nucleophilic substitution by

• substituent may prevent the attack of other reagents and suppress the decomposition of the nitrocyclopropane framework. The chemical transformation of cyclopropane 1e was investigated. When a solution of 1e and tin(II) chloride in benzene was heated at 100 °C for 14 h, successive ring-opening/ring-closure

Eschenmoser coupling reactions starting from primary thioamides. When do they work and when not?

• Lukáš Marek,
• Jiří Váňa,
• Jan Svoboda and
• Jiří Hanusek

Beilstein J. Org. Chem. 2023, 19, 808–819, doi:10.3762/bjoc.19.61

• (Scheme 6). This means that the cleavage of the amide group that evolves aniline (pKa = 4.6) occurred smoothly after the initial thiazole ring closure (through 12a’ in Scheme 6). The addition of a thiophile (trimethyl phosphite) does not turn the reaction toward ECR and only decreases the yield of 13

• thiirane ring. Since direct measurements of acidity at carbon (pKaC) and the rate of ring closure is impossible, we calculated the energies of important reaction species on the potential energy surface for imidothioates derived from α-thioiminium salts 6a, 10a, 12a, and 15 at the B3LYP-D3/6-311+G(d,p

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

• the incorporation of a diverse scope of heteroatoms (e.g., O, N, S, P, B and Si) and may give access to a range of dibenzo[b,f]heteropines 1 using common intermediates [30][31]. Therefore, this section will be broadly organised by reaction type responsible for ring closure. Review 1 Industrial route

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

• with the bicyclic substrate to produce 123. A 5-exo-trig ring closure of 123 produces 124 followed by a rapid protodemetalation with water releasing the final indane product 119a and regenerating the active Rh(I) species. The authors proposed that the origin of the diastereoselectivity is due to

• after dissociation. Alternatively, 205 can undergo a ring closure followed by a subsequent C–P-bond cleavage causing a ring opening resulting in 207. Intramolecular SN2’ and elimination of the phosphine oxide generates the final product 202e which the authors propose is stereoselective due to

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

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

• variecolin synthesis Following Kagan’s work, Molander’s group thoroughly investigated the potential of SmI2-mediated intramolecular ring closure. Among the approaches they studied, the Barbier-type cyclization rapidly gained popularity for five-to-eight-membered ring formation. Based on a reductive addition

• of an alkyl halide to a carbonyl group, implementation of the Barbier-type ring closure relied thus on the preliminary introduction of both aldehyde and alkyl halide functional groups on a suitable substrate. The mechanism was first thought to involve the coupling of an alkyl radical and a ketyl

• ketyl addition, one would have to wait almost two decades before employing it again in eight-membered ring closure. Among the diterpenes and sesterterpenes featuring a cyclooctane framework, (+)-pleuromutilin (1) was recently targeted by Reisman’s group through an elegant approach involving a SmI2

Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• Bu3SnH in the presence of AIBN as initiator provided the tetracyclic core of dysideanones. The late introduction of an ethoxy group completed the total synthesis of dysideanone B (75) and “dysideanone F” (76). Ring closure to the dysiherbol scaffold was a much more challenging task as the classic

Total synthesis of grayanane natural products

• Nicolas Fay,
• Rémi Blieck,
• Cyrille Kouklovsky and
• Aurélien de la Torre

Beilstein J. Org. Chem. 2022, 18, 1707–1719, doi:10.3762/bjoc.18.181

• -membered ring closure through a SmI2-promoted pinacol coupling. This reaction had been previously described by the same group and proved to be highly effective [23]. For rings A, C and D, other SmI2-promoted steps were employed, giving respectively the cyclopentane A ring moiety and the bicyclo[3.2.1

• with a yield of 26%. The secondary alcohol was protected as a MOM ether and the allylic silyl ether was converted to an enone. A selective oxidative cleavage, only affecting the monosubstituted alkene, led to the formation of 31, which underwent a key SmI2-promoted seven-membered ring closure, giving a

• . This first total synthesis of principinol D, in 19 steps as the longest linear sequence, is asymmetric even though a separation of the mixture of diastereomers resulting from fragment coupling is necessary. The SmI2-mediated reductive ring-closure of the 7-membered ring is among the most remarkable

A new route for the synthesis of 1-deazaguanine and 1-deazahypoxanthine

• Raphael Bereiter,
• Marco Oberlechner and
• Ronald Micura

Beilstein J. Org. Chem. 2022, 18, 1617–1624, doi:10.3762/bjoc.18.172

• synthesis of 1-deazaguanine and 1-deazahypoxanthine. Previously published routes toward these compounds focused on ring closure of the imidazole part of the purine system after the pyrimidine core had been functionalized, however, the drawback of this approach is the passage of rather hazardous/explosive

One-pot synthesis of 2-arylated and 2-alkylated benzoxazoles and benzimidazoles based on triphenylbismuth dichloride-promoted desulfurization of thioamides

• Arisu Koyanagi,
• Yuki Murata,
• Shiori Hayakawa,
• Mio Matsumura and
• Shuji Yasuike

Beilstein J. Org. Chem. 2022, 18, 1479–1487, doi:10.3762/bjoc.18.155

• constructing azoles with an amine functional group at the 2-position, such as benzoxazole or benzoimidazole, but are unsuitable for the syntheses of 2-arylated or 2-alkylated benzoxazoles and benzimidazoles. In fact, only two reports cover the subject. Jackson et al. carried out the intramolecular ring-closure

• . performed the dehydrosulfurization of thioamides and thioureas that provided nitriles and cyanamides [35]. Using bismuth compounds as desulfurization reagents for synthesizing heteroazoles, this paper presents the syntheses of 2-aryl- and 2-alkylbenzoxazoles through the ring-closure reaction of 2

• initially focused on identifying the optimal experimental conditions for the synthesis of 2-phenylbenzoxazole (8a) using 2-aminophenol (1a) with benzothioamides 2–5 in the presence of organobismuth or organoantimony compounds 6 or 7. The results, including those for the screening of suitable ring-closure

Cytochrome P450 monooxygenase-mediated tailoring of triterpenoids and steroids in plants

• Karan Malhotra and
• Jakob Franke

Beilstein J. Org. Chem. 2022, 18, 1289–1310, doi:10.3762/bjoc.18.135

• oxidative ring closure, leading to a hemiketal bridge between C16 and C22. Following these initial hydroxylations, CYPs from multiple families catalyse end-of-chain hydroxylation at C27 which is followed by spontaneous spiroketalisation to form diosgenin (13). The CYP pairs PpCYP90G4-PpCYP94D108 in P

Understanding the competing pathways leading to hydropyrene and isoelisabethatriene

• Shani Zev,
• Marion Ringel,
• Ronja Driller,
• Bernhard Loll,
• Thomas Brück and
• Dan T. Major

Beilstein J. Org. Chem. 2022, 18, 972–978, doi:10.3762/bjoc.18.97

• yields cation B’, which is more stable than A’ by −15.7 kcal/mol. A subsequent 1,3-hydride transfer results in an allyl cation (C’, −32.1 kcal/mol relative to A’), with a barrier of 5.4 kcal/mol. Cation C’ collapses into D’ via a barrierless 1,6-ring closure (ΔGr of −35.9 kcal/mol relative to A’). D’ can

• to an active site base, as has been observed in other cases, like taxadiene synthase [26]. Second, the chemical changes occurring up to intermediates C and C’ in both routes are similar and diverge in the transformation of C→D and C’→D’. Here, we suggest that the ring closure in the IE pathway (C’→D

Introducing a new 7-ring fused diindenone-dithieno[3,2-b:2',3'-d]thiophene unit as a promising component for organic semiconductor materials

• Valentin H. K. Fell,
• Joseph Cameron,
• Alexander L. Kanibolotsky,
• Eman J. Hussien and
• Peter J. Skabara

Beilstein J. Org. Chem. 2022, 18, 944–955, doi:10.3762/bjoc.18.94

• Information File 1. According to the literature [41], Aliquat 336® can be added to Suzuki–Miyaura reactions. Here, this did not improve the yield, but decreased its fluctuation from batch to batch. After sufficient amounts of intermediate 27 were isolated, attempts for ring-closure were made. Initial attempts

• the ring closure proceeded on one side of the molecule. It was assumed that this species precipitated, preventing further reaction. We thus turned to a ‘hot’ Friedel–Crafts acylation, in which the reaction mixture was refluxed after the addition of oxalyl chloride, followed by removal of the volatiles

• . Since the ring-closure with a ‘hot’ Friedel–Crafts acylation [43] led to an insoluble material, we wanted to synthesise a soluble derivative by attaching 4-(2-ethylhexyl)-2-methylthiophene groups. This was done by reacting intermediate 27 with compound 32, which was prepared as shown in Scheme 3. In a

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

• pumped through a tube reactor in which a smaller tube consisting of semipermeable Teflon AF2400 is placed. To the inner tube, vacuum is applied removing efficiently the ethylene that is formed in the reaction. Using a low concentration of the substrate to facilitate ring-closure and employing a moderate

Synthesis of sulfur karrikin bioisosteres as potential neuroprotectives

• Martin Pošta,
• Václav Zima,
• Lenka Poštová Slavětínská,
• Marika Matoušová and
• Petr Beier

Beilstein J. Org. Chem. 2022, 18, 549–554, doi:10.3762/bjoc.18.57

• ] exhibited excellent activity. No targeted synthesis of 8 exists; it was isolated in low yield as a side-product in the synthesis of KAR1 (1) [21]. In this reaction sequence, thiopyranthione 6b is the side-product in the pyranthione 6a synthesis and both analogues were progressed to the final furan ring

• closure (Scheme 1). A plausible mechanism for the cyclization of compounds 7 is the Darzens reaction to episulfide, followed by Barton–Kellogg-type reaction with triphenylphosphine and elimination of triphenylphosphine sulfide. Compound 8 showed lower germination activity than KAR1 [22], but achieved IC50

Regioselectivity of the S_EAr-based cyclizations and S_EAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

• Jonali Das and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2022, 18, 293–302, doi:10.3762/bjoc.18.33

• approaches toward such compounds have been developed. Among these, cyclization and annulation of 3,5-unsubstituted, 4-substituted indoles involving an electrophilic aromatic substitution (SEAr) as the ring closure are particularly attractive, because they avoid the use of 3,4- or 4,5-difunctionalized indoles

• as starting materials. However, since 3,5-unsubstituted, 4-substituted indoles have two potential ring-closure sites (indole C3 and C5 positions), such reactions in principle can furnish either or both of the indole 3,4- and 4,5-fused ring systems. This Commentary will briefly highlight the issue by

• ring-closure step have been routinely employed for the construction of diverse arene- and heteroarene-fused rings (Scheme 1A) [1][2][3]. In most of these approaches, the new CAr–C bond is formed ortho to the tether/directing functionality on an aromatic or a heteroaromatic ring, as the geometrical

Synthesis of novel [1,2,4]triazolo[1,5-b][1,2,4,5]tetrazines and investigation of their fungistatic activity

• Anna V. Korotina,
• Svetlana G. Tolshchina,
• Rashida I. Ishmetova,
• Natalya P. Evstigneeva,
• Natalya A. Gerasimova,
• Natalya V. Zilberberg,
• Nikolay V. Kungurov,
• Gennady L. Rusinov,
• Oleg N. Chupakhin and
• Valery N. Charushin

Beilstein J. Org. Chem. 2022, 18, 243–250, doi:10.3762/bjoc.18.29

• occur followed by ring-opening and ring closure (Scheme 4). It has been found that triazolo[1,5-b][1,2,4,5]tetrazines 3 do not enter the characteristic for isomeric [4,3-b]-annulated derivative reactions with malonic ester, leading to expansion of the tetrazine ring and the formation of