Skeletal rearrangement of 6,8-dioxabicyclo[3.2.1]octan-4-ols promoted by thionyl chloride or Appel conditions

• Martyn Jevric,
• Julian Klepp,
• Johannes Puschnig,
• Oscar Lamb,
• Christopher J. Sumby and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2024, 20, 823–829, doi:10.3762/bjoc.20.74

• the observed retention of configuration, showing that substantial interactions between the oxygens of the ring and centres on the larger bridge are possible [32]. The specificity of the rearrangement also eliminates the possibility of an intermediate secondary C4 carbocation, and requires a concerted

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

Beilstein J. Org. Chem. 2024, 20, 787–814, doi:10.3762/bjoc.20.72

• the alkene in the first step, providing a carbocation that subsequently reacts with a chloride anion to yield the Markovnikov product. While this ionic mechanism is commonly illustrated in textbooks by showing “naked” cations as intermediates, several recent studies suggest a molecular concerted or

• ) [78]. Another advantage of the MH HAT process is that the α-C–H bond in the corresponding radical is comparatively stable, whereas a carbocation has superacidic α-C–H bonds with a pKa of ≈ −17 [79]. Therefore, polar hydrochlorination reactions are in competition with elimination reactions which is not

Genome mining of labdane-related diterpenoids: Discovery of the two-enzyme pathway leading to (−)-sandaracopimaradiene in the fungus Arthrinium sacchari

• Fumito Sato,
• Terutaka Sonohara,
• Shunta Fujiki,
• Akihiro Sugawara,
• Yohei Morishita,
• Taro Ozaki and
• Teigo Asai

Beilstein J. Org. Chem. 2024, 20, 714–720, doi:10.3762/bjoc.20.65

• complexity. TCs are generally classified into two main classes, class I and class II. Class I TCs initiate the cyclization by heterolytic cleavage of substrates to generate a diphosphate anion and an allylic carbocation, and class II enzymes start cyclization by protonating a double bond or an epoxide

SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes

• Julien Borrel and
• Jerome Waser

Beilstein J. Org. Chem. 2024, 20, 701–713, doi:10.3762/bjoc.20.64

• , further oxidation would generate the corresponding carbocation, which upon reaction with a nucleophilic alkyne would form the product (Scheme 1B, reaction 3). Based on precedence in the literature, this method should allow to transfer efficiently both aryl- and alkyl-substituted alkynes [41][42][43][44

• ]. On the other hand, the nature of the alkene might be limited as it would strongly influence the oxidation potential of the carbon radical and the stability of the resulting carbocation. Recently, we reported the first successful application of an RPC strategy for the azido-alkynylation of styrenes

• since it is known to be reduced by photocatalysts such as Cu(dap)2Cl [17]. This perfectly fits a catalytic cycle involving the reduction of Ts-ABZ (3) followed by oxidation of the carbon radical to form a carbocation and regenerate the ground state catalyst. Styrene (1a) was used as model substrate

Tandem Hock and Friedel–Crafts reactions allowing an expedient synthesis of a cyclolignan-type scaffold

• Viktoria A. Ikonnikova,
• Cristina Cheibas,
• Oscar Gayraud,
• Alexandra E. Bosnidou,
• Nicolas Casaretto,
• Gilles Frison and
• Bastien Nay

Beilstein J. Org. Chem. 2024, 20, 162–169, doi:10.3762/bjoc.20.15

• oxocarbenium 7 and 7’ which exists as a stabilized form including an intramolecular stabilizing interaction between the carbocation and the ester carbonyl group. However, in close agreement with Hess and Baldwin’s values found for the rearrangement of cis-1,3-pentadiene [24], this transition state was high in

Unraveling the role of prenyl side-chain interactions in stabilizing the secondary carbocation in the biosynthesis of variexenol B

• Moe Nakano,
• Rintaro Gemma and
• Hajime Sato

Beilstein J. Org. Chem. 2023, 19, 1503–1510, doi:10.3762/bjoc.19.107

• cyclization reactions involve a number of carbocation intermediates. In some cases, these carbocations are stabilized by through-space interactions with π orbitals. Several terpene/terpenoids, such as sativene, santalene, bergamotene, ophiobolin and mangicol, possess prenyl side chains that do not participate

• possibility of through-space interactions with prenyl side chains using DFT calculations. Our calculations show that (i) the unstable secondary carbocation is stabilized by the cation–π interaction from prenyl side chains, thereby lowering the activation energy, (ii) the four-membered ring formation is

• completed through bridging from the exomethylene group, and (iii) the annulation from the exomethylene group proceeds in a barrier-free manner. Keywords: biosynthesis; carbocation; cation–π interaction; DFT; terpene; Introduction Terpene/terpenoids are most abundant natural products in nature, more than

N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• conversion of 1-I to 2-II was confirmed by mechanistic studies due to the stability of the benzyl carbocation, followed by 6-endo-dig cyclization. In this method, toxic transition metal catalysts, oxidants, or bases are not used, which made it economically and environmentally reliable. In 2023, Gao et al

Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

• Hui Yu and
• Feng Xu

Beilstein J. Org. Chem. 2023, 19, 1259–1288, doi:10.3762/bjoc.19.94

• ) process, the carbocation intermediate B is generated, which is attacked by a nucleophile to afford the target product. Further, C–H bonds in the ortho-position of a heteroatom are activated through a SET pathway generating a radical cation C, which is easily deprotonated by an oxidant to generate a

• carbocation D. Finally, the nucleophile attacks the carbocation D, to obtain the final coupled product. The deprotonation of the nucleophile occurs before or after the attack on the carbocation intermediate, depending on the acidity of the nucleophile. In 2008, Li et al. reported that Fe2(CO)9 as a catalyst

Radical ligand transfer: a general strategy for radical functionalization

• David T. Nemoto Jr,
• Kang-Jie Bian,
• Shih-Chieh Kao and
• Julian G. West

Beilstein J. Org. Chem. 2023, 19, 1225–1233, doi:10.3762/bjoc.19.90

• elimination-like pathway to afford unsaturated C–C bonds in the presence of copper(II) sulfate, presumably via competitive RPC to the carbocation followed by E1 olefination. Kochi also demonstrated that RLT can be combined with other radical generation strategies to enable new, non-biomimetic reactions to be

• (XAT) from the alkyl halide reagent and further oxidation of the transient radical to a carbocation by radical polar crossover (RPC), providing two mechanistic pathways to form the ATRA products [32]. While powerful, this approach is inherently incompatible with introducing alternative functionality

• proposed to follow one of two pathways: formation of a carbocation through RPC followed by nucleophilic attack or direct RLT from a redox-active metal complex. Preliminary evidence for a radical decarboxylation/RLT cascade was reported in 1965, when Kochi demonstrated decarboxylative chlorination of

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

• the corresponding carbocation 4+ while simultaneously generating S32−. Subsequent deprotonation of 4+ yields the C–H arylated product 4 while SET between S4•− and S32− regenerates the catalytically active polysulfide species S42− and S3•− and closes both catalytic cycles. Showing high versatility, the

Synthesis of tetrahydrofuro[3,2-c]pyridines via Pictet–Spengler reaction

• Elena Y. Mendogralo and
• Maxim G. Uchuskin

Beilstein J. Org. Chem. 2023, 19, 991–997, doi:10.3762/bjoc.19.74

• /ipso-cyclization/Michael-type Friedel–Crafts alkylation (Scheme 1b) [14][15][16]. Unfortunately, approaches including the intramolecular alkylation of 3-substituted furans are underinvestigated as these substrates are usually hard to reach and the resulting benzyl carbocation is often prone to undergo

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

• proposed by Wang [55] (Scheme 2b), 2,5-dimethoxytetrahydrofuran (2) is first protonated with acetic acid, followed by ring opening to form carbocation B. In the following step, primary amine 1 nucleophilically attacks carbocation B to produce intermediate C, which, after proton rearrangement and the

Asymmetric tandem conjugate addition and reaction with carbocations on acylimidazole Michael acceptors

• Brigita Mudráková,
• Renata Marcia de Figueiredo,
• Jean-Marc Campagne and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 881–888, doi:10.3762/bjoc.19.65

• obtained by other conjugate addition reactions. Keywords: acylimidazole; asymmetric catalysis; carbocation; conjugate addition; enolate; Introduction Asymmetric metal-catalyzed conjugate additions provide access to numerous chiral scaffolds. This type of C–C bond formation efficiently enables the

Bromination of endo-7-norbornene derivatives revisited: failure of a computational NMR method in elucidating the configuration of an organic structure

• Demet Demirci Gültekin,
• Arif Daştan,
• Yavuz Taşkesenligil,
• Cavit Kazaz,
• Yunus Zorlu and
• Metin Balci

Beilstein J. Org. Chem. 2023, 19, 764–770, doi:10.3762/bjoc.19.56

• , and assigned our product the structure (1R,2S,3R,4S,7r)-2,3,7-tribromobicyclo[2.2.1]heptane. To fit their revised structure, they proposed an alternative mechanism featuring a skeletal rearrangement without the intermediacy of a carbocation. Herein, we are not only confirming the structure originally

• bromonium ion 10, which is sterically feasable. However, after the backside attack by the bromide in 10, the resulting tribromo compound 3 undergoes an unprecedented skeletal rearrangement without a carbocation intermediate to give compound 7, their proposed alternative structure to 6. Wagner–Meerwein

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

• authors postulated an intramolecular electrophilic substitution via a carbocation intermediate 42 (Scheme 9). Elliott et al. [47] investigated several methods to synthesise substituted dibenzo[b,f]azepines, which included the ring expansion of N-arylindoles 41 to synthesise 43 and the rearrangements of 9

Photocatalytic sequential C–H functionalization expediting acetoxymalonylation of imidazo heterocycles

• Deepak Singh,
• Shyamal Pramanik and
• Soumitra Maity

Beilstein J. Org. Chem. 2023, 19, 666–673, doi:10.3762/bjoc.19.48

• ∙+ then oxidizes the resulting radical II to carbocation III which rearomatizes by losing a proton to generate the intermediate IV and closing the first catalytic cycle. Meanwhile, the bromide ions in the medium undergo anion exchange with the Zn(OAc)2 to release free acetate ions, along with the

• conversion into ZnBr2 (confirmed by HRMS). These in situ-generated free acetate ions function as a base, deprotonating carbocation III to produce the intermediate IV and AcOH. The first step of cycle-2 involves the oxidation of the excited photocatalyst by aerial oxygen to generate superoxide anion and PC

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

1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures

• Bram Ryckaert,
• Ellen Demeyere,
• Frederick Degroote,
• Hilde Janssens and
• Johan M. Winne

Beilstein J. Org. Chem. 2023, 19, 115–132, doi:10.3762/bjoc.19.12

• suppress homodimerization, via a stepwise (3 + 2) cycloaddition of the initially generated cumyl cation across the olefin in amylene. Our group became intrigued by the potential of dihydrodithiins to act as carbocation-stabilizing groups, as these would represent a synthetic equivalent of ‘naked’ allyl

• over (3 + 2) cycloaddition pathways, leading us to investigate the use of the 1,4-dithiane-fused allyl alcohol 90 (and its derived carbocation) in purposeful (3 + 2) cycloadditions. In our studies of the cycloaddition reactivity of dihydrodithiinmethanol 90 [103], we found that single-trans-locked

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

• N-acyliminium ion 28, the aza-Nazarov cyclization of which would provide the final product 30 through the intermediacy of 29 (Scheme 6). According to our hypothesis, the carbocation of intermediate 29 would be stabilized by the β-silicon effect similar to intermediate 9 (vide supra). Unfortunately

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

• cyclization based on a bridgehead tertiary carbocation intermediate forging the B ring; iii) redox manipulations and a 1,2-migration as final steps. The synthesis started from (S)-ketone 44 which was prepared via asymmetric CBS reduction of diketone 26 (Scheme 7). Firstly, this (S)-ketone 44 was transformed

• diastereoselectivity in 58% on a 3 g scale. Subsequently, vinyl halide 48 was converted to diene 50 by Suzuki coupling with potassium vinyltrifluoroborate (49) in 90% yield (Scheme 8). The C7–C8 bond formation from a bridgehead carbocation was a real challenge to close the 7-membered ring. To achieve this, the

• secondary alcohol was oxidized by DMP, the tertiary alcohol was triflated, 4-phenylpyridine was added and the mixture was heated at 80 °C for 14 h. The intermediate carbocation was trapped by the terminal olefin, generating a dienone 51 after deprotonation at the relatively acidic position C2. A singlet

Navigating and expanding the roadmap of natural product genome mining tools

• Friederike Biermann,
• Sebastian L. Wenski and
• Eric J. N. Helfrich

Beilstein J. Org. Chem. 2022, 18, 1656–1671, doi:10.3762/bjoc.18.178

• , terpene cyclases generate the oftentimes multicyclic, hydrocarbon scaffold via a carbocation-mediated cascade reaction [30]. Terpene cyclases are obligatory components of canonical terpene pathways and are used to identify terpene BGCs (Figure 3B) [30][31]. RiPPs, on the other hand, lack genes that are

Synthesis of (−)-halichonic acid and (−)-halichonic acid B

• Keith P. Reber and
• Emma L. Niner

Beilstein J. Org. Chem. 2022, 18, 1629–1635, doi:10.3762/bjoc.18.174

• envisioned for this carbocation (e.g., a nucleophilic attack of formic acid to give a formate ester), only alkene formation was observed in this system. Interestingly, the deprotonation step is completely regioselective, giving the more highly substituted endocyclic trisubstituted alkene found in 8 as

• the resulting tertiary carbocation to occupy equatorial positions (14), establishing the observed trans-relationship between these groups while simultaneously setting two new stereogenic centers. As before, one can envision several different fates for the tertiary carbocation present in 14. Although

• methyl group now occupies a pseudo-axial position, and the cyclohexenyl ring system occupies a pseudo-equatorial position. In this case, the aza-Prins reaction forms trans-fused lactone 10 via an analogous intramolecular nucleophilic attack of the ethyl ester on the intermediate tertiary carbocation 15

Characterization of a new fusicoccane-type diterpene synthase and an associated P450 enzyme

• Jia-Hua Huang,
• Jian-Ming Lv,
• Liang-Yan Xiao,
• Qian Xu,
• Fu-Long Lin,
• Gao-Qian Wang,
• Guo-Dong Chen,
• Sheng-Ying Qin,
• Dan Hu and
• Hao Gao

Beilstein J. Org. Chem. 2022, 18, 1396–1402, doi:10.3762/bjoc.18.144

• stereogenic centers at C2, C6, C10, and C14 introduced during the two cyclization steps, FC-type diterpene synthases (DTSs) could be divided into 16 subtypes [20]. Furthermore, considering the modes of potential carbocation rearrangement and final carbocation quenching, there might be more FC-type DTSs in

• ], MgMS [20], CotB2 [19], and CpCS [21] have been deciphered. All these enzymes undergo a common C1,11–C10,14-bicyclization to form a C15 carbocation, but differ a lot at the following C2,6 cyclization (Scheme 1B). CotB2 and CpCS trigger the C2,6 cyclization via a distant hydride shift, whereas PaFS

Facile and diastereoselective arylation of the privileged 1,4-dihydroisoquinolin-3(2H)-one scaffold

• Dmitry Dar’in,
• Grigory Kantin,
• Alexander Bunev and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2022, 18, 1070–1078, doi:10.3762/bjoc.18.109

• 16 was obtained and its structure was confirmed by single-crystal X-ray analysis. Presumably, the formation of ester 16 can be justified by the trapping of the carbocation intermediate 17 (vide infra) by the formamide carbonyl oxygen atom followed by hydrolysis of the iminium moiety (Scheme 4

• ). Mechanistically, the arylation of diazo substrates 10 likely proceeds via the protonation of the diazo moiety and elimination of a nitrogen molecule, whereby carbocation 17 is generated. The latter can either be deprotonated to give byproduct 15 or be intercepted by an arene molecule in SEAr fashion to give

• arylation product 9. The trans-diastereoselectivity in the latter process is reasonably justified by the approach of the arene molecule to carbocation 17 from the sterically less hindered side (Scheme 5). Compounds 9 have a pronounced three-dimensional character which makes this novel chemotype a promising

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

• kinetic control; Introduction Terpenes constitute a ubiquitous class of natural molecules that are synthesized by terpene synthases (TPS). TPS generate a plethora of terpenes employing rich carbocation chemistry from a very limited number of substrates, known as geranyl pyrophosphate (GPP), farnesyl

• pyrophosphate (FPP), and geranylgeranyl pyrophosphate (GGPP), to produce mono-, sesqui-, and diterpenes, respectively. The formation of terpenes relies on an assortment of carbocation steps like cyclization, methyl migrations, rearrangements, proton or hydride transfers, hydroxylations, and epoxidations. TPS

• ). We studied the inherent chemistry of the reaction leading to HP and IE using gas-phase calculations. This provided the free energy of distinct carbocation intermediates and transition states along the proposed reaction path leading to products in the gas phase. The gas phase is a natural choice as a