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

• its nucleophilicity and improving its orientation. Furthermore, Ser105 formed a strong hydrogen bond also with benzaldehyde, making it a better electron acceptor. Interestingly, also the imine intermediate showed strong interaction with Thr40 and Ser105 residues, so becoming a good electrophile for

• (IPT)-mediated intramolecular oxidative annulation and a hydroxylamine-induced ring cleavage of intermediate 48. With this one-pot sequential procedure they synthesized 49 in yields up to 95% (Scheme 19). The subsequent GBB-3CR led to the unique 1H-imidazo[1,2-a]imidazole core 50 with 4 distinct

• provide the ammonium 77. The intermediate 77 underwent Steven rearrangement to give a bridged polyheterocycle 78 in 28% yield. Unlike the previous examples, Jeong et al. [60] developed a cascade reaction by installing the additional ring prior to the GBB reaction (Scheme 26). The bifunctional 2-(2

Oxidative fluorination with Selectfluor: A convenient procedure for preparing hypervalent iodine(V) fluorides

• Samuel M. G. Dearman,
• Xiang Li,
• Yang Li,
• Kuldip Singh and
• Alison M. Stuart

Beilstein J. Org. Chem. 2024, 20, 1785–1793, doi:10.3762/bjoc.20.157

• ] reacted a perfluorinated iodine(III) compound with XeF2 and postulated the formation of a (perfluoroalkyl)iodine(V) difluoride intermediate which underwent a reductive elimination to afford perfluorinated products (Scheme 2C). In 2019 Togni reported a safer route to a range of acyclic iodine(V) fluorides

Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles

• Javier Gómez-Ayuso,
• Pablo Pertejo,
• Tomás Hermosilla,
• Israel Carreira-Barral,
• Roberto Quesada and
• María García-Valverde

Beilstein J. Org. Chem. 2024, 20, 1758–1766, doi:10.3762/bjoc.20.154

• different competitive reactions triggered by it, such as the interrupted Ugi reaction resulting from the competitive addition over the nitrilium intermediate [9][10] or the split-Ugi reaction arising from a competitive O,N-acyl transference on the imidate intermediate, through a remote Mumm rearrangement

• reactions seem to take place through conjugated additions on the enol tautomer of the Ugi adduct. Indeed, the enolate intermediate would explain the stereochemical results, controlled by the configuration in the hemiaminal intermediate and not by the chiral information on the amine, unlike in the case of

Synthesis of polycyclic aromatic quinones by continuous flow electrochemical oxidation: anodic methoxylation of polycyclic aromatic phenols (PAPs)

• Hiwot M. Tiruye,
• Solon Economopoulos and
• Kåre B. Jørgensen

Beilstein J. Org. Chem. 2024, 20, 1746–1757, doi:10.3762/bjoc.20.153

• dimers, which indicates a radical intermediate [36]. Swenton and co-workers [37] established evidence for the phenoxonium ion (Scheme 1), and were further able to divert the reaction into forming ortho-oxidation due to steric hindrance (Scheme 2). Cyclic voltammetry studies of the oxidation of 2-naphthol

• multiple products were formed. The lability of the acetals prompted us to submit the crude intermediate directly to hydrolysis without prior isolation (Table 4). As mentioned above, having an aqueous reaction mixture in the electrochemical oxidation will give reduced yields. The overall yield of 9b from 6b

• chrysenols nor phenanthrols, suggesting a chemically irreversible reaction of the radical cation intermediate with the ensuing product no longer being electrochemically active within the potential window of the CV scans. However, a reduction peak was observed for compound 1b (see Figure S2 in Supporting

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• of these compounds against various diseases. Review Spiro steroids with four-membered heterocycles Spirooxetane steroids In 2003 Wüst et al. reported the synthesis of the oxetan-3-one derivative 2 in an overall yield of 4.2% from hydrocortisone, in six steps. A key intermediate for oxetan-3-one 2 was

• protecting group yielded the corresponding hydroxyalkynyl derivative 4. Subsequent Lindlar reduction resulted in the (Z)-alkene and a chemoselective tosylation of the primary alcohol led to the formation of tosylate 5. This intermediate underwent a stereospecific 4-exo cyclization upon exposure to iodine

• sodium hydride, yielding moderate yields (ranging from 23% to 68%). The cyclization initially formed the non-isolated intermediate i, which was oxidized by molecular oxygen from air, introducing the hydroxy group at the α-position of the cyano group. The protocol utilised mild conditions and short

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

• well as their analogs, is outlined with an emphasis on comparing these chemo-enzymatic syntheses with the corresponding natural biosynthetic pathways. Keywords: chemo-enzymatic synthesis; late-stage modification; reactive biosynthetic intermediate; regio- and stereoselective (macro)cyclization; total

• , introduce hydroxy groups at C8 and C16 to produce FD-8β,16-diol (7), and BscE-catalyzed O-methylation generates the putative intermediate 8. The subsequent oxidative allylic rearrangement (8→9), catalyzed by the nonheme iron(II) and 2-oxoglutarate (Fe(II)/2OG)-dependent dioxygenase BscD, was a key step

• toward developing a chemo-enzymatic synthetic process. Presumably, the reactive iron(IV)-oxo species in dioxygenase BscD abstracts an allylic hydrogen at C1 and generates intermediate A. Subsequent α-face-selective hydroxylation of the resulting allylic radical at the C3 position would yield brassicicene

Oxidation of benzylic alcohols to carbonyls using N-heterocyclic stabilized λ³-iodanes

• Thomas J. Kuczmera,
• Pim Puylaert and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2024, 20, 1677–1683, doi:10.3762/bjoc.20.149

• )iodane is proposed as the reactive intermediate. Keywords: alcohol oxidation; hypervalent iodine; N-heterocycles; Introduction The oxidation of alcohols to aldehydes and ketones is an essential transformation in organic chemistry [1][2]. Generating aldehydes is particularly challenging as they are

• experiment no formation of an alkoxyiodane was observed, indicating that the formation of this ligand-exchanged intermediate is slower than the dehydrogenation. As a consequence, we attempted to accelerate the ligand exchange through the addition of a Lewis acid and the performance of the NHIs was compared

• was investigated, potentially leading to the formation of a hydroxy(chloro)iodane intermediate. This intermediate either liberates hypochlorous acid as the terminal oxidant or undergoes a direct ligand exchange with the alcohol, followed by oxidative elimination to form the aldehyde. Thus, these

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry

• Maria-Paula Schröder,
• Isabel P.-M. Pfeiffer and
• Silja Mordhorst

Beilstein J. Org. Chem. 2024, 20, 1652–1670, doi:10.3762/bjoc.20.147

• -inflammatory, antidiabetic, antihypertensive, and anti-parkinsonian [7][8]. This diverse profile makes RiPPs particularly valuable for various therapeutic and medicinal applications. Generally, peptide natural products are promising drug development candidates due to their intermediate molecular weight, which

• intermediate is then reduced with H2 [37]. When synthesising via a reductive ring opening, typically, an N-Fmoc-protected amino acid is condensed with formaldehyde in the presence of p-toluic acid in refluxing toluene to yield the 5-oxazolidinone. Reductive ring opening can be achieved by using an excess of

• of ʟ-aspartate, resulting in an ʟ-aspartyl-O-methyl ester. The ʟ-succinimide intermediate that is formed is non-enzymatically hydrolysed to the final isoaspartate. Experimental proof demonstrated that OlvSA operates without the need for leader peptide recognition; instead, it relies on an already

Divergent role of PIDA and PIFA in the AlX₃ (X = Cl, Br) halogenation of 2-naphthol: a mechanistic study

• Kevin A. Juárez-Ornelas,
• Manuel Solís-Hernández,
• Pedro Navarro-Santos,
• J. Oscar C. Jiménez-Halla and
• César R. Solorio-Alvarado

Beilstein J. Org. Chem. 2024, 20, 1580–1589, doi:10.3762/bjoc.20.141

• an equilibrium of Cl–I(Ph)–OTFA–AlCl3 and [Cl–I(Ph)][OTFA–AlCl3], rather than PhICl2 being the active species. On the other hand, bromination using PIDA and AlBr3 was more efficient, wherein the intermediate Br–I(Ph)–OAc–AlBr3 was formed as active brominating species. Similarly, PhIBr2 was higher in

• , respectively). Then, the tetracoordinate TFAO–AlCl2 salt is released, giving rise to intermediate I-1–Cl (ΔG = −25.2 kcal/mol), which contains the key Cl–I(III) bond, in a formal TFAO/Cl ligand exchange. The Cl–I bond length is 2.46 Å, with the halogen atom sharing the hypervalent iodine bond in the equatorial

• nonaromatic intermediate I-4–Cl (ΔG = −23.1 kcal/mol). Next, aromatization assisted by TFAO–AlCl2 via TS2–Cl (ΔG‡ = 11.1 kcal/mol) and hydrogen transfer from the nonaromatic intermediate to TFAO–AlCl2 are observed. In TS2–Cl, the energy barrier must be overcome to give rise to the 1-chloro-2-naphthol adduct

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• for the efficient monofluorination of 4- and 2-alkylpyridines (Figure 4 – conditions [A]) [36]. The transformation relied on the polarisation of the heterobenzylic C–H bond, via the intermediate formation of an N-sulphonylpyridinium salt, to promote deprotonation. Following a polar mechanism with

• palladacycle intermediate, defining the stereochemical outcome. Subsequent oxidation to the Pd(IV)–F species, which triggered reductive elimination, afforded the fluorinated product. The non-innocent behaviour of the isobutyrylnitrile co-solvent aided in stabilising the palladacycle through occupying the

• functional groups on the aromatic ring and adjacent to the benzylic position. Mechanistic investigations suggested an initial electron transfer to generate a radical cation en route to the intermediate benzylic radical, rather than a HAT process, however, the authors did not distinguish between a stepwise

Primary amine-catalyzed enantioselective 1,4-Michael addition reaction of pyrazolin-5-ones to α,β-unsaturated ketones

• Pooja Goyal,
• Akhil K. Dubey,
• Raghunath Chowdhury and
• Amey Wadawale

Beilstein J. Org. Chem. 2024, 20, 1518–1526, doi:10.3762/bjoc.20.136

• assembly) activates the pyrazol-5-one 2a through hydrogen bonding and forms the corresponding enol. Simultaneously, the enol form of the pyrazol-5-one attacks the Re-face of the α,β-unsaturated ketone 1b to provide the intermediate 5 (Scheme 5), which after hydrolysis leads to product ent-3ba'. In situ

Tetrabutylammonium iodide-catalyzed oxidative α-azidation of β-ketocarbonyl compounds using sodium azide

• Christopher Mairhofer,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1510–1517, doi:10.3762/bjoc.20.135

• first, which then facilitates the α-iodination of 1a (hereby either the formed benzoate or the hypoiodite itself may serve as a base). Intermediate 3 then undergoes a phase-transfer-catalyzed nucleophilic substitution with NaN3 thus delivering the final product 2a. With optimized conditions and a

• observed intermediate formation of the α-iodinated β-ketoester 3 as well (vide supra), which suggests an analogous mechanistic scenario as for the azidation (compare with Scheme 3). However, it should also be stated that the α-nitro products 10 were found to be not too stable, undergoing some unspecific

Electrophotochemical metal-catalyzed synthesis of alkylnitriles from simple aliphatic carboxylic acids

• Yukang Wang,
• Yan Yao and
• Niankai Fu

Beilstein J. Org. Chem. 2024, 20, 1497–1503, doi:10.3762/bjoc.20.133

• system [48]. To probe the radical intermediate in the reaction, a radical rearrangement experiment with cyclopropane-derived acid 31 was subjected to the standard conditions, leading to the expected ring opening, alkene-containing nitrile product 32 in 62% isolated yield (Figure 3A). Moreover

Photoswitchable glycoligands targeting Pseudomonas aeruginosa LecA

• Yu Fan,
• Ahmed El Rhaz,
• Stéphane Maisonneuve,
• Emilie Gillon,
• Maha Fatthalla,
• Franck Le Bideau,
• Guillaume Laurent,
• Samir Messaoudi,
• Anne Imberty and
• Juan Xie

Beilstein J. Org. Chem. 2024, 20, 1486–1496, doi:10.3762/bjoc.20.132

• formation of the 1,2-anhydro sugar through intramolecular attack of the 2-hydroxy group of the DMC-activated β-intermediate, followed by dihydroxyazobenzene attacking the anomeric center in an SN2 manner, or by direct nucleophilic SN2 attack on the DMC-activated α-intermediate, to produce the corresponding

Bioinformatic prediction of the stereoselectivity of modular polyketide synthase: an update of the sequence motifs in ketoreductase domain

• Changjun Xiang,
• Shunyu Yao,
• Ruoyu Wang and
• Lihan Zhang

Beilstein J. Org. Chem. 2024, 20, 1476–1485, doi:10.3762/bjoc.20.131

• obscured by the following dehydration by the DH domain. It is widely believed that an α,β-trans (E) double bond is generated from a ᴅ-β-hydroxy intermediate produced by a B-type KR, whereas a cis (Z) double bond is from an ʟ-β-hydroxy intermediate generated by an A-type KR via syn elimination [21]. However

• -hydroxyacyl intermediate produced by B-type KR, and a cis (Z) double bond is formed from the ʟ-β-hydroxyacyl intermediate [5]. However, only 5 out of 42 KRs associated with Z-type DHs contain the conserved W (7) motif found in A-type KRs. Additionally, some KRs associated with Z-type DHs possessed the LDD (2

• formed during post-PKS modification [22][34]. To gain a better understanding of the stereoselectivity of KRs in γ- and δ-modules, we focused on KRs associated with an inactive DH domain (DH0) that still produce a β-hydroxy intermediate. These KRs are phylogenetically mixed together with those in γ- and δ

Synthesis of 2-benzyl N-substituted anilines via imine condensation–isoaromatization of (E)-2-arylidene-3-cyclohexenones and primary amines

• Lu Li,
• Na Li,
• Xiao-Tian Mo,
• Ming-Wei Yuan,
• Lin Jiang and
• Ming-Long Yuan

Beilstein J. Org. Chem. 2024, 20, 1468–1475, doi:10.3762/bjoc.20.130

• speculate that the solvation effect might be beneficial for stabilizing the condensation intermediate I and avoiding further unwanted conversions, e.g., nucleophilic attack of excessive benzylamine to the intermediate I. The following examination on solvents demonstrated that using ether solvents as the

Synthesis of 4-functionalized pyrazoles via oxidative thio- or selenocyanation mediated by PhICl₂ and NH₄SCN/KSeCN

• Jialiang Wu,
• Haofeng Shi,
• Xuemin Li,
• Jiaxin He,
• Chen Zhang,
• Fengxia Sun and
• Yunfei Du

Beilstein J. Org. Chem. 2024, 20, 1453–1461, doi:10.3762/bjoc.20.128

• presented a method for the C–H thiocyanation of pyrazoles by using a sustainable catalyst of graphite-phase carbon nitride (g-C3N4) under visible light irradiation (Scheme 1c) [2]. Furthermore, Yao harnessed an electrochemical approach to form the electrophilic SCN+ intermediate, which reacted with

• to give (SeCN)2 [60]. Then, one selenium atom of (SeCN)2 nucleophilically attacks the iodine center in PhICl2 to generate intermediate A, which was further transformed into intermediate B by release of one molecule of iodobenzene. Next, the nucleophilic attack of chloride anion to the bivalent

• selenium center of intermediate B resulted in the formation of two molecules of Cl–SeCN. Subsequently, Cl–SeCN undergoes an electrophilic addition reaction with pyrazole 1 to give intermediate C, which, after deprotonative rearomatization affords the 4-selenocyanated pyrazole 3. Conclusion In conclusion

Rapid construction of tricyclic tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine via isocyanide-based multicomponent reaction

• Xiu-Yu Chen,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2024, 20, 1436–1443, doi:10.3762/bjoc.20.126

• polycyclic compounds. At first, the nucleophilic addition of alkyl isocyanide to dialkyl but-2-ynedioate afforded the expected Huisgen’s 1,4-dipolar intermediate A. Secondly, the sequential addition of the Huisgen’s 1,4-dipole A to the second molecular dialkyl but-2-ynedioate resulted in a 1,5-dipolar

• intermediate B. Thirdly, the intramolecular coupling of the positive charge and the negative charge in intermediate B resulted in the formation of polysubstituted 5-(alkylimino)cyclopenta-1,3-diene intermediate C, which has been described in several papers about the reaction of alkyl isocyanides and electron

• -deficient alkynes [59][60][61][62][63]. The in situ generated cyclic intermediate C has a resonance hybrid C’. Then, the further nucleophilic addition of the electron-rich enamino unit to 5-(alkylimino)cyclopenta-1,3-diene intermediate C gave intermediate D. At last, the coupling of the iminium cation with

Synthesis of cyclic β-1,6-oligosaccharides from glucosamine monomers by electrochemical polyglycosylation

• Md Azadur Rahman,
• Hirofumi Endo,
• Takashi Yamamoto,
• Shoma Okushiba,
• Norihiko Sasaki and
• Toshiki Nokami

Beilstein J. Org. Chem. 2024, 20, 1421–1427, doi:10.3762/bjoc.20.124

• product of monomer 6. The proposed mechanism is shown in Scheme 2. Anodic oxidation of thioglycoside 6 generated radical cation 11, which was converted to glycosyl triflate 12. 1,6-Anhydrosugar 7 was produced via 4C1-to-1C4 conformational change of the pyran ring to generate cation intermediate 13

• disaccharide 21α, which did not afford the cyclic disaccharide, should have been produced as an intermediate of 19a. The influence of the functional group in position C-2 on the formation of the cyclic products is summarized in Scheme 5. Notably, the C-2 position is the most influential because it is the

• intramolecular glycosylation of the disaccharide intermediate afforded cyclic disaccharide 16 exclusively (Scheme 5b). Only the C-2 azido group afforded cyclic trisaccharide 19, which contained both α- and β-glycosidic linkages (Scheme 5c). Therefore, the synthesis of a cyclic trisaccharide with only β

Challenge N- versus O-six-membered annulation: FeCl₃-catalyzed synthesis of heterocyclic N,O-aminals

• Giacomo Mari,
• Lucia De Crescentini,
• Gianfranco Favi,
• Fabio Mantellini,
• Diego Olivieri and
• Stefania Santeusanio

Beilstein J. Org. Chem. 2024, 20, 1412–1420, doi:10.3762/bjoc.20.123

• ), whose sequential acylation process by iso(thio)cyanates 3a–h gives rise to the asymmetric (thio)urea derivatives (intermediate II). The spontaneous nucleophilic attack of the (thio)amide nitrogen on the terminal methyl ester function at C-4 of the starting azo-ene system provides a regioselective

• -hydrazino form [17][24][25], we conceived the idea of reversing the reactivity of 4a–r in the six-membered cyclization process (N- vs O-annulation) through the generation of an electrophilic oxocarbenium [26][27] cation intermediate from the acetal residue at N-3 of the (thio)hydantoin core. To pursue our

• providing intermediate A. The latter, by loss of a trichloro(alkoxy)ferrate(III) anion, generates a strong electrophile such as the oxocarbenium cation intermediate B. The released trichloro(alkoxy)ferrate(III) splits into FeCl3, which enters the catalytic cycle, and a free alkoxide, which acts as a base

Synthesis of substituted triazole–pyrazole hybrids using triazenylpyrazole precursors

• Simone Gräßle,
• Laura Holzhauer,
• Nicolai Wippert,
• Olaf Fuhr,
• Martin Nieger,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2024, 20, 1396–1404, doi:10.3762/bjoc.20.121

• 21gd could be isolated in quantitative yield with this technique, avoiding additional purification steps for the azide intermediate without any losses in product formation. The developed procedure was exemplarily transferred to solid-phase synthesis. In quantitative yields, 5-methyl-1H-pyrazol-3-amine

• (14b) was immobilized on benzylamine resin 22 (Scheme 5). For this purpose, a diazonium intermediate was generated from the pyrazoloamine with BF3∙Et2O and isoamyl nitrite accordingly to the liquid phase synthesis of 15b. The subsequent functionalization of resin 23 to the phenyl-substituted derivative

Synthetic applications of the Cannizzaro reaction

• Bhaskar Chatterjee,
• Dhananjoy Mondal and
• Smritilekha Bera

Beilstein J. Org. Chem. 2024, 20, 1376–1395, doi:10.3762/bjoc.20.120

• of a hydride ion from a tetracoordinated intermediate (B), which is formed upon hydroxide addition to the aldehyde (A). The primary pathway of the reaction entails the rate-determining step of hydride ion transfer via either a linear or bent transition state (C) to a second molecule of aldehyde

• . The Cannizzaro reaction also finds extensive industrial use in synthesizing pentaerythritol, a crucial intermediate in manufacturing of alkyd resins and plasticizers [55]. The crossed-Cannizzaro reaction contributes to polyol production for polyester resin synthesis. In the field of fragrance and

• and the intermediate aldehyde reacts with the hydroxide under the Cannizzaro conditions to give the desired product (Scheme 13). The mechanistic pathway for the transformation is represented in Figure 4. Desymmetrization via intramolecular Cannizzaro reaction Vida et al. reported the intramolecular

Generation of alkyl and acyl radicals by visible-light photoredox catalysis: direct activation of C–O bonds in organic transformations

• Mithu Roy,
• Bitan Sardar,
• Itu Mallick and
• Dipankar Srimani

Beilstein J. Org. Chem. 2024, 20, 1348–1375, doi:10.3762/bjoc.20.119

• benzoate. This benzoate then reacts with the triphenylphosphine radical cation, resulting in the formation of the phosphoranyl radical intermediate, which undergoes β-scission, leading to the formation of a benzoyl radical, accompanied by the liberation of a triphenylphosphine oxide molecule. After this

• , the addition of the benzoyl radical to azobenzene results in the generation of a nitrogen-centered radical. This radical is then subjected to reduction by the reduced photocatalyst, producing the nitrogen-centered anion intermediate. Ultimately, the protonation of this anion gives rise to the desired

• molecules and results in a tertiary alkyl radical, which eventually reacts with an alkyne to yield a vinyl radical 35. Later, the addition of Ni(0) and ligand to the vinyl radical 35 gives the intermediate 36. This intermediate undergoes oxidative addition with aryl bromide to produce Ni(III) species 37. A

Synthesis of 1,2,3-triazoles containing an allomaltol moiety from substituted pyrano[2,3-d]isoxazolones via base-promoted Boulton–Katritzky rearrangement

• Constantine V. Milyutin,
• Andrey N. Komogortsev and
• Boris V. Lichitsky

Beilstein J. Org. Chem. 2024, 20, 1334–1340, doi:10.3762/bjoc.20.117

• , intramolecular recyclization accompanied by opening of the isoxazole ring and formation of the N–N bond leads to intermediate B. Finally, target 1,2,3-triazole 4 is produced via acidification of anion B. Next, we tried to expand the presented rearrangement to hydrazones derived from aliphatic hydrazines (MeNHNH2

• recyclization is depicted at Scheme 8. Initially, hydrazine molecule is added to double bond of the pyranone ring leading to zwitter-ion A. Further, cleavage of dihydropyranone fragment results in intermediate B. Next, enehydrazine C is formed from compound B through migration of a proton. Then, intramolecular

Computation-guided scaffold exploration of 2E,6E-1,10-trans/cis-eunicellanes

• Zining Li,
• Sana Jindani,
• Volga Kojasoy,
• Teresa Ortega,
• Erin M. Marshall,
• Khalil A. Abboud,
• Sandra Loesgen,
• Dean J. Tantillo and
• Jeffrey D. Rudolf

Beilstein J. Org. Chem. 2024, 20, 1320–1326, doi:10.3762/bjoc.20.115

• energies of the neutral products. In the cyclization of 2, protonation at C6, results in a C7 tertiary cationic intermediate (A2+) where C2 is only 1.65 Å away from C7 (Figure 2B); this structure can be viewed as protonated 5 or 6 with a strongly hyperconjugated C2–C7 bond [21]. Reducing this

• energy profile is seen for protonation-induced cyclization of 1, although the 6/6/6-tricyclic C3 tertiary cation is 7.1 kcal mol−1 higher in energy than its preceding intermediate (Figure 2C). A lower energy conformer of 1 exists, but we have been unable to find the corresponding cation A1b+, which