Synthesis of electrophile-tethered preQ₁ analogs for covalent attachment to preQ₁ RNA

• Laurin Flemmich and
• Ronald Micura

Beilstein J. Org. Chem. 2025, 21, 483–489, doi:10.3762/bjoc.21.35

• were required to obtain the corresponding mesylate 3b. Similar to 11, compound 12 was isolated as its trifluoroacetate salt. Selective Boc protection of the aliphatic amine gave 13, which was selectively O-mesylated to give compound 14. Compound 14 was found to slowly undergo intramolecular cyclization

Electrochemical synthesis of cyclic biaryl λ³-bromanes from 2,2’-dibromobiphenyls

• Andrejs Savkins and
• Igors Sokolovs

Beilstein J. Org. Chem. 2025, 21, 451–457, doi:10.3762/bjoc.21.32

• approach would conceptually differ from previously reported anodic syntheses of cyclic diaryl iodonium compounds, where an electrochemically generated acyclic iodine(III) intermediate undergoes an intramolecular SEAr-type reaction to form the cyclic product [19][20]. Herein, we report on the development of

• Br(II) followed by subsequent deprotonation to generate radical B. A following disproportionation of radical B would lead to the formation of Br(III) species C (anodic oxidation cannot be fully excluded), which undergoes intramolecular SNAr-type substitution to form cyclic λ3-bromane 1a and

New tandem Ugi/intramolecular Diels–Alder reaction based on vinylfuran and 1,3-butadienylfuran derivatives

• Yuriy I. Horak,
• Roman Z. Lytvyn,
• Andrii R. Vakhula,
• Yuriy V. Homza,
• Nazariy T. Pokhodylo and
• Mykola D. Obushak

Beilstein J. Org. Chem. 2025, 21, 444–450, doi:10.3762/bjoc.21.31

• reaction and Diels–Alder [4 + 2] cycloaddition based on vinylfuran and 1,3-butadienylfuran derivatives was designed and studied. It was found that in the case of 3-(furan-2-yl)acrylaldehyde, a one-pot Ugi reaction and intramolecular Diels–Alder vinylarene (IMDAV) reaction leads to the formation of the

• yields. The studied tandem Ugi and intramolecular Diels–Alder reactions allow high substituent variation in the named isoindoles. Keywords: 1,3-butadienylfuran; furo[2,3-f]isoindole; intramolecular Diels–Alder reaction; isoindole; one-pot; Ugi reaction; vinylfuran; Introduction Energy-saving and

• construction [27][28]. For instance, the intramolecular Diels–Alder reactions of vinylarenes (IMDAV) strategy [29][30] has been used to synthesize annulated isoindoles, including thieno[2,3-f]isoindoles [31][32] and furo[2,3-f]isoindoles [33][34], from thienyl- or furylallylamines and unsaturated acid

The effect of neighbouring group participation and possible long range remote group participation in O-glycosylation

• Rituparna Das and
• Balaram Mukhopadhyay

Beilstein J. Org. Chem. 2025, 21, 369–406, doi:10.3762/bjoc.21.27

• , Scheme 18) gave product 108 with higher 1,2-cis selectivity. In protocol A, the tosylamide forms an intramolecular hydrogen bonding with the benzylic oxygen forming a quasi-bicyclic intermediate acting as a 1,2-trans directing protecting group. Thus, following subsequent formation of the oxocarbenium ion

• disturbs the intramolecular hydrogen bonding, as in 107 thereby generating a non-participating form as an intermediate. Thus, the acceptor easily attacks from the α-face of the sugar ring, and thereby, leading to the product with higher 1,2-cis stereoselectivity (87:13). A similar bimodal protocol was also

Synthesis, structure, ionochromic and cytotoxic properties of new 2-(indolin-2-yl)-1,3-tropolones

• Yurii A. Sayapin,
• Eugeny A. Gusakov,
• Inna O. Tupaeva,
• Alexander D. Dubonosov,
• Igor V. Dorogan,
• Valery V. Tkachev,
• Anna S. Goncharova,
• Gennady V. Shilov,
• Natalia S. Kuznetsova,
• Svetlana Y. Filippova,
• Tatyana A. Krasnikova,
• Yanis A. Boumber,
• Alexey Y. Maksimov,
• Sergey M. Aldoshin and
• Vladimir I. Minkin

Beilstein J. Org. Chem. 2025, 21, 358–368, doi:10.3762/bjoc.21.26

• reactions of 2-methylquinolines with 3,5-di-(tert-butyl)-1,2-benzoquinone [1] and benzophenones with o-chloranil [15]. The norcaradiene derivatives 5, formed in the next step by the intramolecular cyclization reaction of 4, undergo thermal isomerization into 2,3-dihydrotropolones 6. The formation of 2

• increase in the intramolecular hydrogen bond length NH···O of the (NH) isomers and a decrease in the magnitude of hydrogen bond N···HO of the (OH) forms (Figure 1). On the other hand, the position of the benzoannelated fragment does not significantly affect the structural and energetic parameters of the

• the previously obtained 2-(indolin-2-yl)-1,3-tropolone)). The angle between the planes C(2)C(3)C(6)C(7) and (3)C(4)C(5)C(6) is equal to 27.6° (34°). In compound 7b, as in 2-(indolin-2-yl)-1,3-tropolone, an intramolecular hydrogen bond N(1)–H(1)···O(2) was realized with parameters: distances N–H = 0.86

Red light excitation: illuminating photocatalysis in a new spectrum

• Lucas Fortier,
• Corentin Lefebvre and
• Norbert Hoffmann

Beilstein J. Org. Chem. 2025, 21, 296–326, doi:10.3762/bjoc.21.22

• formed. This reaction only occurs close to the photocatalyst or sensitizer fixed at the intracellular target, for example at tubulin. An intramolecular Diels–Alder reaction followed by nitrogen extrusion

Synthesis and characterizations of highly luminescent 5-isopropoxybenzo[rst]pentaphene

• Islam S. Marae,
• Jingyun Tan,
• Rengo Yoshioka,
• Zakaria Ziadi,
• Eugene Khaskin,
• Serhii Vasylevskyi,
• Ryota Kabe,
• Xiushang Xu and
• Akimitsu Narita

Beilstein J. Org. Chem. 2025, 21, 270–276, doi:10.3762/bjoc.21.19

• (13%). BPP-dione, when compared to the parent BPP, also displayed improved absorption and emission from the first excited singlet (S1) state with a PLQY of 62% and an intramolecular charge-transfer character. The rod-like nano- to microcrystals as well as longer wires of these BPPs were also revealed

• by scanning electron microscopy. The intriguing optical properties of BPP and its derivatives may lead to their application as fluorophores. Keywords: benzo[rst]pentaphene; intramolecular charge transfer; nanocrystals; photoluminescence; polycyclic aromatic hydrocarbon; Introduction Polycyclic

• , in comparison with parent BPP 2. Notably, both BPP-OiPr 3 and BPP-dione 4 displayed enhanced PLQYs while a significant solvent-polarity dependence of the emission was observed only for the latter, suggesting the photoinduced intramolecular charge-transfer character of 4. Moreover, BPPs 2–4 formed

Visible-light-promoted radical cyclisation of unactivated alkenes in benzimidazoles: synthesis of difluoromethyl- and aryldifluoromethyl-substituted polycyclic imidazoles

• Yujun Pang,
• Jinglan Yan,
• Nawaf Al-Maharik,
• Qian Zhang,
• Zeguo Fang and
• Dong Li

Beilstein J. Org. Chem. 2025, 21, 234–241, doi:10.3762/bjoc.21.15

• abstraction to yield the hydrodifluoromethylation product. Building upon this work, we hypothesized that if the newly formed alkyl radical could undergo intramolecular cyclization with an aromatic ring, instead of hydrogen abstraction, it could enable the construction of polycyclic structures. Thus, as part

• intermediate D via intramolecular radical cyclization. A single-electron-transfer (SET) process then occurred between the radical B and the radical D, resulting in the generation of cationic intermediate E, difluoroacetate anion and PhI. Finally, the product 3a was obtained after the deprotonation by

Streamlined modular synthesis of saframycin substructure via copper-catalyzed three-component assembly and gold-promoted 6-endo cyclization

• Asahi Kanno,
• Ryo Tanifuji,
• Satoshi Yoshida,
• Sota Sato,
• Saori Maki-Yonekura,
• Kiyofumi Takaba,
• Jungmin Kang,
• Kensuke Tono,
• Koji Yonekura and
• Hiroki Oguri

Beilstein J. Org. Chem. 2025, 21, 226–233, doi:10.3762/bjoc.21.14

• coupling of alkyne 8, THIQ segment 9, and benzaldehyde would enable convergent assembly of the building blocks to produce 10 [43][44][45][46]. Removal of the cyclic acetal in 10 followed by Strecker-type conversion leading to an α-amino nitrile would enable tandem intramolecular cyclization with phenol to

• form 2,3-diaminobenzofuran 11. The subsequent gold(I)-mediated intramolecular 6-endo hydroamination of 11 would construct the left THIQ ring to furnish the substructure 14 of saframycin A (1) [47][48][49][50][51]. To selectively promote the desired 6-endo cyclization (11 → 12) over the competing 5-exo

• transformations: copper(I)-catalyzed regiocontrolled three-component assembly of alkyne 8, THIQ segment 9, and benzaldehyde to yield 10, followed by tandem Strecker reaction and intramolecular cyclization to form 2,3-diaminobenzofuran 11. Subsequent gold(I)-mediated 6-endo hydroamination of 11 leads to the

Heteroannulations of cyanoacetamide-based MCR scaffolds utilizing formamide

• Marios Zingiridis,
• Danae Papachristodoulou,
• Despoina Menegaki,
• Konstantinos G. Froudas and
• Constantinos G. Neochoritis

Beilstein J. Org. Chem. 2025, 21, 217–225, doi:10.3762/bjoc.21.13

• the desired thienopyrimidones 5a–e, quinolinopyrimidones 6a–e and indolopyrimidones 7a–e, respectively, as reported in the literature [42][44]. In accordance with the reported mechanism, after the initial formylation of the amino group at position 2, an intramolecular nucleophilic attack by the NH

Dioxazolones as electrophilic amide sources in copper-catalyzed and -mediated transformations

• Seungmin Lee,
• Minsuk Kim,
• Hyewon Han and
• Jongwoo Son

Beilstein J. Org. Chem. 2025, 21, 200–216, doi:10.3762/bjoc.21.12

• enantioselectivity. Furthermore, a lactam containing a quaternary carbon center (2g) was prepared. However, a lower enantioselectivity was observed for product 2h due to the similar steric environment of the two alkyl substituents. As shown in Figure 1, a catalytic cycle was proposed for the intramolecular C–H

• ) nitrenoid intermediate INT-7. Subsequent nitrene insertion, protodemetalation, and intramolecular cyclization furnish the desired 1,2,4-triazole. 1.3 Three-component formation of N-acyl amidines In 2019, N-acyl amidines were prepared from dioxazolones using a copper catalyst with terminal alkynes and

Hydrogen-bonded macrocycle-mediated dimerization for orthogonal supramolecular polymerization

• Wentao Yu,
• Zhiyao Yang,
• Chengkan Yu,
• Xiaowei Li and
• Lihua Yuan

Beilstein J. Org. Chem. 2025, 21, 179–188, doi:10.3762/bjoc.21.10

• aromatic amide macrocycles [36][37][38][39][40][41][42], a class of cyclic compounds comprising a number of aromatic residues with consecutive intramolecular hydrogen bonds and amide linkages, stand out as versatile host molecules as their cavity size, peripheral side chains, and recognition sites are

Recent advances in electrochemical copper catalysis for modern organic synthesis

• Yemin Kim and
• Won Jun Jang

Beilstein J. Org. Chem. 2025, 21, 155–178, doi:10.3762/bjoc.21.9

• elimination, produces C–H alkynylated arene 10, which then forms the final product 3 through intramolecular cyclization. Finally, the Cu(I) complex 9 produced via reductive elimination is reoxidized at the anode to regenerate the Cu(II) complex 4, completing the catalytic cycle. Yao and Shi developed the

• (KR) of the racemic ketimine ester, providing the same chiral product 35 with recovered enantioenriched starting material. Additionally, when a 1-naphthyl ester was used instead of a methyl ester at −10 °C, 1,4-addition followed by intramolecular tandem annulation generated the corresponding chiral

• electrochemical oxidation. In contrast, the naphthyl-substituted Schiff base generated the corresponding enantioenriched product 36 through 1,4-addition followed by intramolecular annulation. When 2,6-disubstituted hydroquinone was used as the starting material, 1,6-addition occurred due to steric hindrance

Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• corresponding saturated compounds. Subsequent nucleophilic addition of the cyclic vinyl ether to the iminium salt generates an intermediate XXI susceptible of intramolecular electrophilic attack to give a tricyclic structure XXII. The final deprotonation provides the desired product 24. The multicomponent

• reaction between the anhydride and the amine suggested the subsequent reaction with the ketone to give an imine intermediate XXIV. This latter can undergo intramolecular nucleophilic attack affording the quinazolinone derivative 26 (Scheme 20) [37]. Polysubstituted pyrroles 27 were obtained in a cascade

• , which favors the approach of the reaction centers. It is again a metal coordination that activates the C–C double bond towards an intramolecular reaction to give the tetrahydropyrazole XXX via formation of a C–N bond. The final oxidation in air gives the 4,5-dihydropyrazole 31. Cu(OTf)2 is also capable

Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

• activation, atroposelective aza-Michael addition, and intramolecular aldol reaction to form the cationic intermediate Int-6. Release of the catalyst C2, reduction with NaBH4, and dehydration with acetic acid leads to the desired product 6. Recently, an organocatalytic atroposelective intramolecular (4 + 2

• intermediate Int-9. As the assumed rate-determining step the intramolecular nucleophilic addition takes place, followed by further cyclization and finally, release of the organocatalyst to form the axially chiral product 9. Various aryl-substituted indolines 9 were obtained in good yields and high enantiomeric

• yields and enantiomeric purities. The reaction was initiated by the formation of acylazolium intermediate Int-24 that underwent a 1,6-addition with the enol form of the carbonyl substrate to give Int-25. Cyclization was realized via an intramolecular aldol reaction to Int-26 (Scheme 15). Ye and co

Synthesis, characterization, and photophysical properties of novel 9‑phenyl-9-phosphafluorene oxide derivatives

• Shuxian Qiu,
• Duan Dong,
• Jiahui Li,
• Huiting Wen,
• Jinpeng Li,
• Yu Yang,
• Shengxian Zhai and
• Xingyuan Gao

Beilstein J. Org. Chem. 2024, 20, 3299–3305, doi:10.3762/bjoc.20.274

• recent years, and they are mostly based on purely organic electron donor−electron acceptor (D−A) or D−A−D systems with significant intramolecular charge transfer interactions for frontier molecular orbital separation [28][29][30]. Due to the electron-accepting properties, PhFlOP can clearly act as an

• * transitions associated with the conjugated system, while the band at around 340 nm is attributed to intramolecular charge transfer processes. The low-energy absorption bands of 7-t-Bu (λmax = 345 nm, Table 2) and 7-Cz-2 (λmax = 342 nm) are slightly redshifted compared to 7-H (λmax = 338 nm), and larger

• redshifts are observed for 7-Ph-1 (λmax = 354 nm) and 7-Ph-2 (λmax = 366 nm). In contrast to 7-H, 7-Br (λmax = 327 nm) and 7-Cz-1 (λmax = 316 nm) show a blueshift. With a stronger electron-donating ability than 7-Cz-1, 7-Cz-2 shows a lower energy level for the absorption band stemming from intramolecular

Synthesis of acenaphthylene-fused heteroarenes and polyoxygenated benzo[j]fluoranthenes via a Pd-catalyzed Suzuki–Miyaura/C–H arylation cascade

• Merve Yence,
• Dilgam Ahmadli,
• Damla Surmeli,
• Umut Mert Karacaoğlu,
• Sujit Pal and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2024, 20, 3290–3298, doi:10.3762/bjoc.20.273

• %). This cascade involves an initial Suzuki–Miyaura cross-coupling reaction between 1,8-dihalonaphthalenes and heteroarylboronic acids or esters, followed by an intramolecular C–H arylation under the same conditions to yield the final heterocyclic fluoranthene analogues. The method was further employed to

• )-catalyzed [2 + 2 + 2] cycloaddition reactions with 1,8-dialkynylnaphthalenes to access azafluoranthenes and 2-pyridone-fused naphthalenes [27]. In 2017, we reported a Pd-catalyzed cascade reaction that involves a sequential Suzuki–Miyaura cross-coupling and a subsequent intramolecular C–H arylation between

• boronic esters of 1,8-DHN have recently been investigated and reported by Krempner and co-workers [51]. To our delight, the Suzuki–Miyaura coupling/intramolecular C–H arylation sequence between 12 and boronic ester 17d proceeded smoothly affording product 15a in 84% yield. The results summarized in Table

Efficient synthesis of fluorinated triphenylenes with enhanced arene–perfluoroarene interactions in columnar mesophases

• Yang Chen,
• Jiao He,
• Hang Lin,
• Hai-Feng Wang,
• Ping Hu,
• Bi-Qin Wang,
• Ke-Qing Zhao and
• Bertrand Donnio

Beilstein J. Org. Chem. 2024, 20, 3263–3273, doi:10.3762/bjoc.20.270

• molecular density of 1.688 g cm−3. In more details, the crystal structure reveals two short intramolecular F···H hydrogen contacts in the triphenylene core part with lengths of 2.047 Å and 2.114 Å, respectively (see Figure S33 in Supporting Information File 1). The triphenylene part of the molecule is

Intramolecular C–H arylation of pyridine derivatives with a palladium catalyst for the synthesis of multiply fused heteroaromatic compounds

• Yuki Nakanishi,
• Shoichi Sugita,
• Kentaro Okano and
• Atsunori Mori

Beilstein J. Org. Chem. 2024, 20, 3256–3262, doi:10.3762/bjoc.20.269

• % yield, respectively. The related reaction is also carried out with amides of non-pyridine derivatives terephthal- and benzamides to afford multiply fused heterocyclic compounds in 81% and 89% yields, respectively. Keywords: intramolecular C–H arylation; multiply fused heterocycles; palladium acetate

• efficiencies in atom economy [3][4]. The extension of the reaction to an intramolecular version represents a viable approach for the construction of several fused-ring skeletons [5]. Such ring structures containing heterocyclic rings would be of crucial importance because heterocycle-fused ring structures [6

• fused structure toward a phenanthroline diamide (Phen-2,9-diamide) [23] can be achieved by employing a palladium-catalyzed intramolecular C–H arylation [24][25][26][27][28]. One of the thus obtained products exhibited a remarkable extraction performance for a lanthanide ion, in which a metal-specific

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• hydrogen bonding with the protonated tertiary amine. Then, a Michael addition of malononitrile to the azadiene takes place to obtain exclusively the (S)-intermediate A. Subsequently an intramolecular nucleophilic addition of the nitrile leads to the intermediate B, which undergoes tautomerization to

• -derived azadiene by H-bonding. This dual activation promotes a stereoselective addition of 3-chlorooxindole to the azadiene leading to intermediate A. The latter is also activated by the chiral guanidine and undergoes an intramolecular nucleophilic substitution which delivers the product 19b with the

• the bifunctional squaramide enables a stereoselective Michael addition of the azlactone to the azadiene forming intermediate A which transforms into intermediate B, which then undergoes an intramolecular cyclization to give the desired product 20. In 2020, Ni, Song and co-workers described a

Synthesis of extended fluorinated tripeptides based on the tetrahydropyridazine scaffold

• Thierry Milcent,
• Pascal Retailleau,
• Benoit Crousse and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2024, 20, 3174–3181, doi:10.3762/bjoc.20.262

• intramolecular Michael addition. Preliminary conformational studies on tripeptides including this scaffold in the central position show an extended conformation in solution (NMR) and in the solid state (X-ray). Keywords: fluoroalkyl groups; heterocycles; hydrazino acids; peptides; tetrahydropyridazines

• ,anti. Then, hydrazones 3 were reacted with zinc and methyl 2-(bromomethyl)acrylate (4). This aza-Barbier reaction was performed in a biphasic medium (THF/aqueous solution of saturated NH4Cl) to avoid the formation of the α-methylene-γ-lactam obtained by intramolecular cyclization of the zinc amide on

• on an intramolecular Michael addition carried out in DMF and catalyzed by 10% of potassium carbonate. As previously observed [37], under these conditions, the 5-endo-trig cyclization was selective and the lactam resulting from the 5-exo-trig cyclization was not observed. Furthermore, in the case of

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• a multicomponent reaction to obtain SIRT2 inhibitors (Scheme 12). The authors suggest a Knoevenagel condensation approach between isatin derivatives and ethyl cyanoacetate, followed by a Michael addition with C–H activated carbonyl compounds and intramolecular cyclization [50]. They synthesized 45

• intramolecular SNAr reactions. Ugi-4CR/deprotection/cyclization (UDC) strategy: In the UDC approach a protected amine and an electrophilic functional group like esters or ketones are used. Convertible isocyanides can also be employed. Once the Ugi reaction is completed, the protecting group is removed, and the

• eliminated through microwave-assisted treatment under acidic conditions, resulting in the intramolecular cyclization of the amine onto the ketone derived from glyoxaldehyde (Scheme 14). Vézina-Dawod and co-workers [60] introduced a strategy, which consists of two reactions, for synthesizing highly

Hypervalent iodine-mediated intramolecular alkene halocyclisation

• Charu Bansal,
• Oliver Ruggles,
• Albert C. Rowett and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 3113–3133, doi:10.3762/bjoc.20.258

• , the intramolecular HVI-mediated halocyclisation of alkenes using carbon, oxygen, nitrogen or sulfur nucleophiles. Herein, we describe the examples reported in the literature, which are organised by the different halogens involved and the internal nucleophiles. Keywords: cyclisation; halogenation

• ; heterocycles; hypervalent iodine; oxidation; Introduction Halogenated carbocyclic and heterocyclic compounds are present in many active pharmaceutical ingredients [1][2]. The intramolecular halocyclisation of alkenes mediated by HVI(III) reagents allow access to a range of halogenated cyclic scaffolds in a

• firstly through the coordination of an alkene by the HVI reagent, which activates it toward intramolecular attack by an internal nucleophile. Following this, substitution of the iodane(III) can occur from the nucleophilic halide in solution to reveal the halo-cyclised product (Figure 2). In this review

Synthesis of the 1,5-disubstituted tetrazole-methanesulfonylindole hybrid system via high-order multicomponent reaction

• Cesia M. Aguilar-Morales,
• América A. Frías-López,
• Nadia V. Emilio-Velázquez,
• Alejandro Islas-Jácome,
• Angelica Judith Granados-López,
• Jorge Gustavo Araujo-Huitrado,
• Yamilé López-Hernández,
• Hiram Hernández-López,
• Luis Chacón-García,
• Jesús Adrián López and
• Carlos J. Cortés-García

Beilstein J. Org. Chem. 2024, 20, 3077–3084, doi:10.3762/bjoc.20.256

• , an intramolecular cyclization takes place, facilitated by CuI. This step involves a 5-endo-dig cyclization, where the negatively nitrogen atom of the sulfonamide 25 attacks intramolecularly to yield the intermediate 26. The final product is formed when iodide is regenerated as CuI, allowing it to re

Chemical structure metagenomics of microbial natural products: surveying nonribosomal peptides and beyond

• Thomas Ma and
• John Chu

Beilstein J. Org. Chem. 2024, 20, 3050–3060, doi:10.3762/bjoc.20.253

• megaenzyme machinery. Water can act as the nucleophile during the offloading step, which amounts to hydrolysis and results in a linear peptide. On the other hand, a cyclic peptide forms when an intramolecular functional group acts as the nucleophile in this step. Regardless of the resulting topology, the NRP