Recent advances in photocatalyzed reactions using well-defined copper(I) complexes

• Mingbing Zhong,
• Xavier Pannecoucke,
• Philippe Jubault and
• Thomas Poisson

Beilstein J. Org. Chem. 2020, 16, 451–481, doi:10.3762/bjoc.16.42

• subsequently adds to the alkene. The resulting C-centered radical is oxidized by the Cu(II) complex, regenerating the Cu(I) catalyst, and the formed carbocation is trapped by the halide. Worth to mention is that very recently, Reiser and Engl demonstrated the possible use of [Cu(dmp)2Cl]Cl as an efficient

• )]/[Cu(I)]*/[Cu(II)] species and the reduction of the Zhdankin reagent by the copper catalyst to form an azidyl radical, which then reacted with the olefin. The resulting benzyl radical could then be oxidized, probably by the catalyst in the +II oxidation state, to generate a benzylic carbocation and the

• radical was oxidized to the corresponding carbocation, regenerating the photocatalyst in the ground state. The benzylic carbocation was finally trapped with MeOH, which was used as the solvent to form the trifluoromethyl methoxylated product. In the same publication, Dilman and co-workers reported the

Photophysics and photochemistry of NIR absorbers derived from cyanines: key to new technologies based on chemistry 4.0

• Bernd Strehmel,
• Christian Schmitz,
• Ceren Kütahya,
• Yulian Pang,
• Anke Drewitz and
• Heinz Mustroph

Beilstein J. Org. Chem. 2020, 16, 415–444, doi:10.3762/bjoc.16.40

• ]. Aziridines tolerate nucleophiles because chain growth requests the ammonium ion [93][94][95][96]. On the other hand, chain propagation includes the carbocation in the case of oxiranes and oxetanes [92]. More of interest can be seen absorbers, which do not follow such reaction routes. Scheme 7 depicts a

[1,3]/[1,4]-Sulfur atom migration in β-hydroxyalkylphosphine sulfides

• Katarzyna Włodarczyk,
• Piotr Borowski and
• Marek Stankevič

Beilstein J. Org. Chem. 2020, 16, 88–105, doi:10.3762/bjoc.16.11

• being hydroxy group removal followed by intramolecular formation of a sulfur–carbon bond. The second step seemed to be slow, and the intermediate carbocation could be trapped in the form of an alkenylphosphine sulfide. The comparison of the reactivity of the same substrate under two different reaction

• OH group, facilitated proton transfer from the γ- to β-carbon atom via a process similar to the elimination/electrophilic addition to alkenes pathway. The computational results discussed above showed that the crucial point for sulfur atom migration was the formation of a tertiary carbocation at the β

Understanding the role of active site residues in CotB2 catalysis using a cluster model

• Keren Raz,
• Ronja Driller,
• Thomas Brück,
• Bernhard Loll and
• Dan T. Major

Beilstein J. Org. Chem. 2020, 16, 50–59, doi:10.3762/bjoc.16.7

• ]. Theoretical quantum mechanical (QM) investigations on the chemistry of terpenes in the gas phase have provided a detailed understanding of the carbocation mechanisms underlying terpene synthase function [25][26][27]. Further, we have used multiscale modeling tools to study the effects of the enzyme

• , Hong and Tantillo [38] and Sato and co-workers [39] investigated the CotB2 mechanism using QM tools. According to Meguro and co-workers [41], the cyclization process commences with the dissociation of the pyrophosphate leaving group of GGPP, forming an allylic carbocation, and two subsequent

• by a sequential decreasing pattern (Figure 1). The inspection of the gas phase profile revealed important information regarding the inherent reactivity [27] of the carbocation species. As the reaction proceeded, π-bonds transformed into σ-bonds, explaining the steady downhill progress of the energy

Terpenes

• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2019, 15, 2966–2967, doi:10.3762/bjoc.15.292

• generate a highly reactive cationic intermediate that can be subject to a cascade reaction through typical carbocation chemistry, including cyclisation reactions, hydride migrations and Wagner–Meerwein rearrangements [1][2]. The cascade is usually terminated by deprotonation or attack of water. The

Bacterial terpene biosynthesis: challenges and opportunities for pathway engineering

• Eric J. N. Helfrich,
• Geng-Min Lin,
• Christopher A. Voigt and
• Jon Clardy

Beilstein J. Org. Chem. 2019, 15, 2889–2906, doi:10.3762/bjoc.15.283

• a linear polyene with branching methyl groups that form the core hydrocarbon structure in a single enzyme-catalyzed step [9]. The enzyme, which is called terpene cyclase, holds the linear methyl-branched polyene in a defined conformation that initiates a series of carbocation-driven cyclizations and

• the leaving pyrophosphate group and the nucleophilic alkenes in proximity to initiate the C–C-bond forming, carbocation-mediated cascade reactions [10]. The hydrophobic binding pocket stabilizes the reaction intermediates and tames the propagation of carbocations through cation–π and other

• electrostatic interactions [54]. Moreover, TCs also assist intramolecular atom transfer and rearrangements including hydride or proton transfer and carbon shifts [10]. Eventually, the carbocation is quenched by deprotonation (E1-like) or nucleophilic attack (SN1-like) of water [45]. In contrast to

Iodine-mediated hydration of alkynes on keto-functionalized scaffolds: mechanistic insight and the regiospecific hydration of internal alkynes

• Zachary Lee,
• Brandon R. Jones,
• Nyochembeng Nkengbeza,
• Michael Phillips,
• Kayla Valentine,
• Alexis Stewart,
• Brandon Sellers,
• Nicholas Shuber and
• Karelle S. Aiken

Beilstein J. Org. Chem. 2019, 15, 2747–2752, doi:10.3762/bjoc.15.265

• , asymmetric, internal alkynes capped by alkyl groups typically yield two ketone products, as the incorporation of the new oxo group can occur at either carbon atom of the triple bond. In fact, unless the substrate contains a carbocation-stabilizing group, such as a phenyl unit, hydration of asymmetric

Unexpected one-pot formation of the 1H-6a,8a-epiminotricyclopenta[a,c,e][8]annulene system from cyclopentanone, ammonia and dimethyl fumarate. Synthesis of highly strained polycyclic nitroxide and EPR study

• Sergey A. Dobrynin,
• Igor A. Kirilyuk,
• Yuri V. Gatilov,
• Andrey A. Kuzhelev,
• Olesya A. Krumkacheva,
• Matvey V. Fedin,
• Michael K. Bowman and
• Elena G. Bagryanskaya

Beilstein J. Org. Chem. 2019, 15, 2664–2670, doi:10.3762/bjoc.15.259

• in hydride abstraction with the formation of carbocation 9 and subsequent cyclization to the bicyclic alkoxyamine 10. The resulting isoxazolidine ring is then opened with m-CPBA in the usual way, retaining the configuration of the asymmetric center at 3aC-OH [13] (Scheme 4). The steric strain in

Acid-catalyzed rearrangements in arenes: interconversions in the quaterphenyl series

• Sarah L. Skraba-Joiner,
• Carter J. Holt and
• Richard P. Johnson

Beilstein J. Org. Chem. 2019, 15, 2655–2663, doi:10.3762/bjoc.15.258

• . This supports thermodynamic control based on carbocation energies. Keywords: arenium ion; carbocation; density functional theory; microwave reaction; rearrangement; superacid; Introduction Carbocations are enigmatic reactive intermediates of enduring importance in chemistry. No other reactive species

• displays such a complex and fascinating collection of molecular rearrangements. Building on a long history, new synthetic applications [1][2] and explanations of carbocation reaction mechanisms [3][4][5][6] continue to be discovered. Chemistry in superacid solutions has played a major role in this field [7

• extend the temperature range, we developed a more reliable method for studying higher temperature carbocation rearrangements. In our method, we use 1 M (ca. 20% by volume) trifluoromethanesulfonic acid (TfOH) as catalyst with dichloroethane as our preferred solvent. Most importantly, reactions are

Nanangenines: drimane sesquiterpenoids as the dominant metabolite cohort of a novel Australian fungus, Aspergillus nanangensis

• Heather J. Lacey,
• Cameron L. M. Gilchrist,
• Andrew Crombie,
• John A. Kalaitzis,
• Daniel Vuong,
• Peter J. Rutledge,
• Peter Turner,
• John I. Pitt,
• Ernest Lacey,
• Yit-Heng Chooi and
• Andrew M. Piggott

Beilstein J. Org. Chem. 2019, 15, 2631–2643, doi:10.3762/bjoc.15.256

• -type sesquiterpenoids from farnesyl diphosphate is proposed to proceed via the protonation-initiated mechanism (class II terpene synthases) [24], which is distinct from the ionisation-initiated mechanism (class I) terpene synthases, where a carbocation is generated by the release of a diphosphate group

AgNTf₂-catalyzed formal [3 + 2] cycloaddition of ynamides with unprotected isoxazol-5-amines: efficient access to functionalized 5-amino-1H-pyrrole-3-carboxamide derivatives

• Ziping Cao,
• Jiekun Zhu,
• Li Liu,
• Yuanling Pang,
• Laijin Tian,
• Xuejun Sun and
• Xin Meng

Beilstein J. Org. Chem. 2019, 15, 2623–2630, doi:10.3762/bjoc.15.255

• derivatives can be obtained in up to 99% yield. The reaction mechanism might involve the generation of an unusual α-imino silver carbene intermediate (or a silver-stabilized carbocation) and subsequent cyclization/isomerization to build the significant pyrrole-3-carboxamide motif. The reaction features the

• O- and N-nucleophilic sites, respectively. In addition, silver-stabilized carbocation intermediate I generated from intermediate C might be another possible process to form E, although it was rarely mentioned due to weak Ag–C bond (Scheme 6). It should be also mentioned that a direct

• high efficiency. The reaction conditions involve the use of catalytic AgNTf2 with DCE as the solvent at 80 °C, without needing to exclude moisture or air. The presumed reaction mechanism might involve the generation of an unusual α-imino silver carbene species (or a silver-stabilized carbocation) and

Synthetic terpenoids in the world of fragrances: Iso E Super^® is the showcase

• Alexey Stepanyuk and
• Andreas Kirschning

Beilstein J. Org. Chem. 2019, 15, 2590–2602, doi:10.3762/bjoc.15.252

• additional cyclisation through compound rac-53 (Scheme 9). This is initiated by the acid employed in the second step of the synthesis. Thus, the ketone is protonated and the highly electrophilic carbon atom reacts with the alkene moiety. The resulting tertiary carbocation undergoes a 1,2-methyl shift to

Current understanding and biotechnological application of the bacterial diterpene synthase CotB2

• Ronja Driller,
• Daniel Garbe,
• Norbert Mehlmer,
• Monika Fuchs,
• Keren Raz,
• Dan Thomas Major,
• Thomas Brück and
• Bernhard Loll

Beilstein J. Org. Chem. 2019, 15, 2355–2368, doi:10.3762/bjoc.15.228

• ) [12] to the acyclic terpene synthase substrate geranylgeranyl diphosphate 3 (GGDP) [1][13][14][15][16]. Following initial substrate binding and folding in a product-like conformation, the cyclization reaction can be subdivided into three steps: (1) generation of a reactive allyl carbocation as a

• result of heterolytic cleavage of the pyrophosphate–hydrocarbon bond or protonation of a double bond, (2) propagation of the carbocation along the forming terpene skeleton as a result of ring formations, hydride and/or methyl shifts, de- and reprotonation of intermediates, the creation of a terminal

• carbocation (3) and finally the quenching of the carbocation by a base or water [16][17]. TPSs can be divided into two distinct classes, which are distinguished by their substrate activation mechanism. Whereas ionization of an isoprenoid diphosphate is caused by hydrolysis of the pyrophosphate by a trinuclear

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

• Xiaowei Li,
• Xiaolin Shi,
• Xiangqian Li and
• Dayong Shi

Beilstein J. Org. Chem. 2019, 15, 2213–2270, doi:10.3762/bjoc.15.218

• , mild reaction conditions (room temperature) and excellent functional group tolerance. In this instance, the copper catalyst may only promote the generation of the tert-butoxyl radical from TBHP. The oxidation of the intermediate A with t-BuOOH produces a carbocation B, followed by an oxidative

Harnessing enzyme plasticity for the synthesis of oxygenated sesquiterpenoids

• Melodi Demiray,
• David J. Miller and
• Rudolf K. Allemann

Beilstein J. Org. Chem. 2019, 15, 2184–2190, doi:10.3762/bjoc.15.215

• closure to form the bisabolyl cation (6). A [1,3]-hydride shift to form carbocation 7 and 1,10-ring closure yield the amorphyl cation (8). Finally, deprotonation generates amorpha-4,11-diene (3) [8][9]. Several sesquiterpene synthases including ADS accept FDP analogues containing a variety of heteroatoms

Genome mining in Trichoderma viride J1-030: discovery and identification of novel sesquiterpene synthase and its products

• Xiang Sun,
• You-Sheng Cai,
• Yujie Yuan,
• Guangkai Bian,
• Ziling Ye,
• Zixin Deng and
• Tiangang Liu

Beilstein J. Org. Chem. 2019, 15, 2052–2058, doi:10.3762/bjoc.15.202

• invertebrates [1][2]. More than 80,000 terpenoids have been identified and characterised [3][4][5]. These diverse and complex natural products are mostly derived from carbocation cyclisation with linear C5 isoprene precursors, which are catalysed by terpene synthases (TPSs) [6]. TPSs can be classified into

• three types based on their amino acid sequence. Type I TPSs are metal-dependent enzymes that initiate cyclisation by the elimination of diphosphate groups from precursors and carbocation formation, and type II TPSs initiate the catalytic process by the protonation of an olefinic double bond [7]. The

Analysis of sesquiterpene hydrocarbons in grape berry exocarp (Vitis vinifera L.) using in vivo-labeling and comprehensive two-dimensional gas chromatography–mass spectrometry (GC×GC–MS)

• Philipp P. Könen and
• Matthias Wüst

Beilstein J. Org. Chem. 2019, 15, 1945–1961, doi:10.3762/bjoc.15.190

• abstracted, resulting in d8-α-cubebene [M]+• with m/z = 212 as highly labeled isotopologue (Figure 4, lower mass spectrum). Biosynthesis of sesquiterpene hydrocarbons via (R)-(+)-germacrene D Lodewyk, Gutta and Tantillo postulated an α-ylangene-forming carbocation cascade based on computer calculations [34

• ]. Tantillo and co-workers showed that germacrene D does not have to be involved in the formation of α-ylangene due to carbocation energetics. However, according to our results the formation of this tricyclic sesquiterpene hydrocarbon and its isomer β-ylangene occurs via the intermediate (R)-(+)-germacrene D

Inherent atomic mobility changes in carbocation intermediates during the sesterterpene cyclization cascade

• Hajime Sato,
• Takaaki Mitsuhashi,
• Mami Yamazaki,
• Ikuro Abe and
• Masanobu Uchiyama

Beilstein J. Org. Chem. 2019, 15, 1890–1897, doi:10.3762/bjoc.15.184

• 351-0198, Japan Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan 10.3762/bjoc.15.184 Abstract We previously showed that the regio- and stereoselectivity in terpene-forming reactions are determined by the conformations of the carbocation

• the first detailed analysis of the inherent atomic mobility in carbocation intermediates during sesterterpene biosynthesis. We identified two methyl groups as the least mobile of all the carbons of the carbocation intermediates in the first half of the cyclization cascade. Our analysis suggests that

• these two methyl groups are critical for the preorganization of GFPP in the biosynthetic pathways leading to sesterfisherol and quiannulatene. Keywords: biosynthesis; carbocation; DFT; substrate recognition; terpene cyclase; Introduction Terpene synthases are thought to have four main roles: (i

The cyclopropylcarbinyl route to γ-silyl carbocations

• Xavier Creary

Beilstein J. Org. Chem. 2019, 15, 1769–1780, doi:10.3762/bjoc.15.170

• solvolysis chemistry of mesylate and triflate derivatives of trans-1-hydroxymethyl-2-trimethylsilylcyclopropane and 1-substituted analogs can be quite different since these substrates do not generally lead to 3-trimethylsilylcyclobutyl cations. Keywords: bicyclobutane; carbocation; cyclopropylcarbinyl

• contributed heavily to the development of carbocation chemistry. This article will deal with three types of carbocations that have been of intense and fundamental interest over the years, i.e., cyclopropylcarbinyl cations, electron-deficient cations, and silyl substituted carbocations. A brief overview of

• will deal with is the so-called “electron-deficient” carbocation, i.e., carbocations 9 (Figure 1) substituted with electron-withdrawing groups E [21]. Many studies have shown that such cations can indeed be generated and that they can derive stabilization by a variety of mechanisms. Chief among these

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

Transient and intermediate carbocations in ruthenium tetroxide oxidation of saturated rings

• Manuel Pedrón,
• Laura Legnani,
• Maria-Assunta Chiacchio,
• Pierluigi Caramella,
• Tomás Tejero and
• Pedro Merino

Beilstein J. Org. Chem. 2019, 15, 1552–1562, doi:10.3762/bjoc.15.158

• carbocation. In the case of pyrrolidines, the carbocation is completely stabilized as an energy minimum in the form of an iminium ion and the reaction takes place in two steps. Keywords: alkanes; carbocations; DFT; oxidations; ruthenium tetroxide; Introduction Ruthenium-catalyzed oxidations [1][2] and, in

• , with P1, P2 and P3, respectively. A close inspection of the IRCs revealed a shoulder characteristic of a transient carbocation [23] which is more pronounced following the sequence R1 < R2 < R3. The preliminary analysis of the evolution of bonds along those IRCs further confirmed a high asynchronicity

• are broken and formed in two separate events, only a topological analysis of the ELF will provide the exact moment in which those events take place and provide evidences of the formation of a transient carbocation. The ELF analysis [39][40][72][73] allows calculation of the so-called basins of

Superelectrophilic carbocations: preparation and reactions of a substrate with six ionizable groups

• Sean H. Kennedy,
• Makafui Gasonoo and
• Douglas A. Klumpp

Beilstein J. Org. Chem. 2019, 15, 1515–1520, doi:10.3762/bjoc.15.153

• electrophiles based on the triarylmethyl cation scaffold (3–5, Scheme 1) [11][12]. These systems utilized pyridyl rings to produce increasing amounts of positive charge adjacent to the carbocation center. Both theoretical calculations and experimental results indicated that the carbocation center undergoes a

• studies of tri-, tetra-, and pentacationic systems [11][12]. This product, 10, is the result of charge migration involving the carbocation center and the phenyl group (vide infra). When compound 9 is treated with only superacid, the bis(pyrido[1,2-a]indole) 11 is formed as the major product. Likewise, the

• explained by mechanisms involving highly ionized intermediates. It is proposed that compound 9 initially reacts in excess superacid to give the tetracationic species 12 (Scheme 4). Protonation of the hydroxy groups leads to immediate ionization and formation of the carbocation centers. For related

Enantioselective Diels–Alder reaction of anthracene by chiral tritylium catalysis

• Qichao Zhang,
• Jian Lv and
• Sanzhong Luo

Beilstein J. Org. Chem. 2019, 15, 1304–1312, doi:10.3762/bjoc.15.129

• of a highly active carbocation Lewis acid catalyst. The stereocontrol potential of the chiral tritylium ion pair was demonstrated by its application in an enantioselective Diels–Alder reaction of anthracene. Keywords: anthracene; carbocation catalysis; Diels–Alder reaction; Fe(III)-based phosphate

• anion; tritylium salt; Introduction Carbocation Lewis acid catalysis has grown significantly over the last two decades [1][2][3][4][5][6][7][8][9][10][11][12][13]. The development of asymmetric carbocation catalysts has been long pursued but remains a challenging task. One strategy is to design and

• , the enantioselectivity was low in most cases. In addition, the synthetic efforts to access these chiral cations were generally non-trivial which limited their further development. Recently, we developed a chiral ion-pair strategy for asymmetric carbocation catalysis, with chiral trityl phosphate as

Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

• Edorta Martínez de Marigorta,
• Jesús M. de Los Santos,
• Ana M. Ochoa de Retana,
• Javier Vicario and
• Francisco Palacios

Beilstein J. Org. Chem. 2019, 15, 1065–1085, doi:10.3762/bjoc.15.104

• , that rearranges to afford cationic isoindolinone moiety 95. Then, benzene derivative 86 would react by a Friedel–Crafts type reaction to form diaryl γ-lactam 88. When ketone 89 is used instead of arene 86, the enol form would act as nucleophile and upon reaction with carbocation 95, compounds 90 could

• be isolated. Finally, cyclopropyl ketone 91 would first rearrange by copper catalysis and the so-obtained furane derivative 96 would add to the carbocation in 95, followed by Friedel–Crafts cyclization, thus generating the polycyclic isoindolinones 92 in a formal hetero [4 + 2] cycloaddition process

Stereochemical investigations on the biosynthesis of achiral (Z)-γ-bisabolene in Cryptosporangium arvum

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2019, 15, 789–794, doi:10.3762/bjoc.15.75

• ; carbocation chemistry; enzyme mechanisms; nerolidyl diphosphate; terpenes; Introduction Given the enormous impact of chirality within biomolecules for all forms of life, it is fascinating to see how nature is able to maintain and reproduce stereochemical information. This concept largely involves the