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

• -enzymatic synthesis, featuring the late-stage enzymatic oxidation of chemically synthesized intricate scaffolds are attracting increasing attention. A collaboration between Stoltz and Arnold led to the pioneering accomplishment in the total synthesis of nigelladine A by exploiting P450 enzymes engineered

• through directed evolution [11]. P450 catalysis during the oxidation phase enabled the total synthesis of mitrephorone A [12], chevalone A [13], polysin [14], excolide B [15], and gedunin [16]. Fe(II)/2OG-dependent dioxygenases, such as FtmOx1, were employed as versatile catalysts in the synthesis of 13

• hydroxy group of the aglycon. Cotylenin exhibits promising anticancer activity, and its diterpene aglycon, cotylenol (1), was isolated from the filamentous fungi such as Phomopsis amygdali and Cladosporium sp. 501-7W (Scheme 2A) [20][21][22]. Brassicicenes, differing in oxidation levels from 1, have been

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

• iodanes (NHIs) as suitable reagents for the mild oxidation of activated alcohols. Two different protocols, both involving activation by chloride additives, were used to synthesize benzylic ketones and aldehydes without overoxidation in up to 97% yield. Based on MS experiments an activated hydroxy(chloro

• )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

• oxidants in combination with transition-metal catalysts. Metal-free methods employ chlorodimethylsulfonium compounds as the reactive species and have gained great popularity under the name Swern oxidation or the Corey–Kim oxidation [11]. Hypervalent iodine compounds have also been studied and are well

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

• generated in situ simply by mixing PIFA with a Lewis acid, in this case AlCl3. The importance of this protocol arises from the oxidation of an AlCl3-based chlorine atom, which is an available and cheap reagent. Then it is used as an electrophile source in the chlorination process with an umpolung reactivity

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

• the relative stability of primary, secondary and tertiary benzylic radicals and cations. As a result, the presence of benzylic C(sp3)–H bonds in bioactive molecules can be problematic as they are particularly labile to enzymatic oxidation [16], and hence, their functionalisation has become a strategy

• 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

• benzylic fluorination method that employed unprotected amino acids as radical precursors, Figure 12 [50]. Oxidation of glycine by Ag(II) promotes decarboxylation and results in the α-amino radical, which performs a HAT on the benzylic substrate to furnish the benzylic radical. This subsequently undergoes

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

• . Keywords: azidation; nitration; organocatalysis; oxidation; quaternary ammonium iodides; Introduction Organic compounds containing an azide functionality are highly valuable synthesis targets that offer considerable potential for various applications and further manipulations [1][2][3][4][5][6][7][8][9

• the presence of a catalytic amount of tetrabutylammonium iodide (TBAI). Control experiments support a mechanistic scenario proceeding via in situ formation of a catalytically competent quaternary ammonium hypoiodite first. This higher oxidation state species then facilitates the α-iodination of the

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

• by anodic oxidation and visible light irradiation of the Ce species in a sequential fashion [38][39][40][41][42][43][44][45]. Therefore, the anodic electrode potential for this process could be substantially reduced. In doing so, a low working potential at the anode offers the opportunity for

• invention of cooperative catalysis with electrochemical transition metal catalysis, which generally has mild oxidation potential for the generation of persistent radicals in the form of nucleophile-bound metal complexes. We and other groups have successfully applied this reaction design to enantioselective

• , experiments using stoichiometric Cu(II) and Ce(IV) indicated that the radical decarboxylative cyanation reaction can only occur under light irradiation. In contrast, reaction with Ce(III) exhibited nearly no reactivity, demonstrating the crucial roles of anodic oxidation and light irradiation to the

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

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

• simplified form, focuses on the base-induced disproportionation of two molecules of a non-enolizable aromatic and/or aliphatic aldehyde (without an α-hydrogen atom). These aldehydes undergo in the presence of concentrated alkali or other strong bases, a simultaneous oxidation and reduction sequence of two

• a competing Cannizzaro reaction during the electrochemical oxidation of furfural [60]. On the other hand, 5-hydroxymethyl-2-furancarboxylic acid (HMFCA) and dihydroxymethylfuran (DHMF), obtained via the Cannizzaro disproportionation of 5-(hydroxymethyl)furfural, were electrochemically oxidized to

• where other methods of oxidation or reduction might be challenging or impractical. The present discussion focuses on some recent synthetic advances and their application in biologically active compounds. Lewis acid-catalyzed intramolecular Cannizzaro reaction Wang et al. [73] depicted a highly

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

• . Appropriate selection of the phosphine reagent was the key to success in the process. Due to the lower oxidation potential, electron-rich PMe2Ph preferentially transferred a single electron to the excited state of the photocatalyst rather than the alkene, which was essential for obtaining the desired product

• catalyst is first excited and then transfers one electron to the thiocarbamate moiety to form a thiocarbamate radical anion, with change in oxidation state from III to IV. Next, the sacrificial electron donor Hünig base successfully converts [Ir(IV)] to [Ir(III)], with concurrent formation of an amine

• mechanism involves C–O bond activation of tertiary oxalates. It requires [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 and NiCl2⋅DME along with dtbbpy ligand. The reaction commences with single-electron oxidation of cesium oxalate initiated by *[Ir(III)] photocatalyst. This transfer leads to the elimination of two CO2

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

• when the C6–C7 alkene of 2 was oxidized by mCPBA oxidation, resulting in formation of the gersemianol derivative 8 [7]. Inspired by the reactivity of the trans-eunicellane skeleton, we conducted a series of chemical transformations to convert 2 into trans/trans-6/6/6 bicyclic skeletons with various

Oxidative hydrolysis of aliphatic bromoalkenes: scope study and reactivity insights

• Amol P. Jadhav and
• Claude Y. Legault

Beilstein J. Org. Chem. 2024, 20, 1286–1291, doi:10.3762/bjoc.20.111

• metals, inspired by Nature's metalloproteins. However, using toxic and expensive metals is not always practical, making alternative oxidative methodologies more appealing. Enter hypervalent iodine reagents – a leading metal-free choice for oxidation reactions. These robust and low-toxicity reagents have

• transformations, cementing their position as a go-to option for organic chemists. Based on our continued interest in iodine(III)-mediated chemistry, we have explored numerous strategies in oxidative transformations such as direct α-tosyloxylation of ketones [12][13][14], and the oxidation of enol esters [15][16

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 1256–1269, doi:10.3762/bjoc.20.108

• alcohol and oxidation of the latter resulted in formation of the final product. The reason for the change of the regioselectivity of cyclization, as compared to the formation of products 36, remains unclear at present. The reaction of 3-halochromones with 3H-indole-2-thiones (thiooxindoles) 38a–c afforded

Synthesis and optical properties of bis- and tris-alkynyl-2-trifluoromethylquinolines

• Stefan Jopp,
• Franziska Spruner von Mertz,
• Peter Ehlers,
• Alexander Villinger and
• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 1246–1255, doi:10.3762/bjoc.20.107

• methyl groups and are known to protect from metabolic oxidation [16]. Fluorine-containing arenes are metabolically more stable as compared to non-fluorinated arenes and they show a higher lipophilicity. Known synthetic approaches towards 2-trifluoromethylquinolines include the cyclisation of anilines

Competing electrophilic substitution and oxidative polymerization of arylamines with selenium dioxide

• Vishnu Selladurai and
• Selvakumar Karuthapandi

Beilstein J. Org. Chem. 2024, 20, 1221–1235, doi:10.3762/bjoc.20.105

• polymerization, and solvent oxidation. For aniline and o-anisidine, predominant oxidative polymerization occurred, leading to the formation of the respective polyaniline polymers as major products. For methyl anthranilate, the oxidative polymerization was suppressed due to the delocalization of amine lone pair

• calculations suggest that the highest occupied molecular orbital of methyl anthranilate was deeply buried, which suppressed the oxidative polymerization pathway. Due to solvent oxidation, oxamide formation was also noticed to a considerable extent. This study provides that utmost care must be exercised while

• arylselenium compounds [26][27][28]. Noteworthy examples are the use of SeO2 as selenium source in aromatic electrophilic substitution reactions [27][28][29]. Selenium dioxide is a well-known oxidizing agent for the allylic oxidation and oxidation of α-CH bonds located adjacent to electron-withdrawing groups

Cofactor-independent C–C bond cleavage reactions catalyzed by the AlpJ family of oxygenases in atypical angucycline biosynthesis

• Jinmin Gao,
• Liyuan Li,
• Shijie Shen,
• Guomin Ai,
• Bin Wang,
• Fang Guo,
• Tongjian Yang,
• Hui Han,
• Zhengren Xu,
• Guohui Pan and
• Keqiang Fan

Beilstein J. Org. Chem. 2024, 20, 1198–1206, doi:10.3762/bjoc.20.102

• scaffolds (Scheme 1) [1][2][8][9][10][11][12][13][14]. Noteworthy is the prerequisite for FADH2/FMNH2, provided by E. coli Fre or flavin reductases in corresponding biosynthetic pathways, to facilitate these oxidation reactions. Experimental data support that 1 was firstly oxidized to a lactone intermediate

• 2 via Baeyer–Villiger oxidation, followed by hydrolysis to yield another crucial aldehyde/acid intermediate 3 [11][15]. Commencing from 3, diverse ring rearrangement reactions can occur, leading to the formation of distinct products. In the AlpJ-catalyzed reaction, compound 3 undergoes ring

• resemblance of AlpJ-family oxygenases to cofactor-independent anthrone oxygenases rather than to the conventional FADH2-dependent counterparts, we aimed to investigate the potential for catalyzing oxidation reactions in a cofactor-independent manner. For cofactor-independent oxygenases such as TcmH and ActVA

Two-fold addition reaction of silylene to C₆₀: structural and electronic properties of a bis-adduct

• Masahiro Kako,
• Masato Kai,
• Masanori Yasui,
• Michio Yamada,
• Yutaka Maeda and
• Takeshi Akasaka

Beilstein J. Org. Chem. 2024, 20, 1179–1188, doi:10.3762/bjoc.20.100

• of 1 with the HOMO of 2a should be considered. Electrochemical measurements of 3 Cyclic voltammetry (CV) and differential pulse voltammetry (DPV) measurements were conducted to evaluate the electronic effects of the silylene addends in 3 (Figure 9). The oxidation processes of 3 were shown to be

• irreversible, probably because of the removal of silylene addends, whereas the electrochemically reversible behavior was observed for the reduction waves. Table 2 presents the redox potentials of 3 obtained by DPV with those of C60 and 2, as reference compounds. Both the reduction (Ered) and the oxidation (Eox

Bismuth(III) triflate: an economical and environmentally friendly catalyst for the Nazarov reaction

• Manoel T. Rodrigues Jr.,
• Aline S. B. de Oliveira,
• Ralph C. Gomes,
• Amanda Soares Hirata,
• Lucas A. Zeoly,
• Hugo Santos,
• João Arantes,
• Catarina Sofia Mateus Reis-Silva,
• João Agostinho Machado-Neto,
• Leticia Veras Costa-Lotufo and
• Fernando Coelho

Beilstein J. Org. Chem. 2024, 20, 1167–1178, doi:10.3762/bjoc.20.99

• synthesis has been reported for several transformations, such as epoxide opening [56], ketal formation and deprotection [57][58], Mannich reaction [59], intramolecular Sakurai cyclization [60], alcohol oxidation [61], aromatic hydrocarbon nitration [62], imine allylation [63], Knoevenagel condensation [64

• according to well-established protocols [71][72][73][74]. The β-ketoesters were obtained employing a sequence of two reactions, the formation of the benzylic alcohol derivative, through a Reformatsky reaction using In(0), followed by a pyridinium chlorochromate (PCC) oxidation, giving the β-ketoesters 7a–g

Light on the sustainable preparation of aryl-cored dibromides

• Fabrizio Roncaglia,
• Alberto Ughetti,
• Nicola Porcelli,
• Biagio Anderlini,
• Andrea Severini and
• Luca Rigamonti

Beilstein J. Org. Chem. 2024, 20, 1076–1087, doi:10.3762/bjoc.20.95

• -cored halides can be broadened by converting C–Hal functions into different functional groups. For example, aldehyde and amine functionalities can be readily derived from C(sp3)–Hal functions through hydrolysis–oxidation [13] or substitution [14], respectively. This is of significant interest in the

• ) greater electrophilicity of the halo compound due to better leaving group ability of the halide ion, (iii) reduced toxicity, presumably due to faster hydrolysis [18], and (iv) easier oxidation of the halide to molecular halogen (E0 = 1.087 V (SHE) for Br2/Br−; E0 = 1.358 V (SHE) for Cl2/Cl−) [19

Structure–property relationships in dicyanopyrazinoquinoxalines and their hydrogen-bonding-capable dihydropyrazinoquinoxalinedione derivatives

• Tural N. Akhmedov,
• Ajeet Kumar,
• Daken J. Starkenburg,
• Kyle J. Chesney,
• Khalil A. Abboud,
• Novruz G. Akhmedov,
• Jiangeng Xue and
• Ronald K. Castellano

Beilstein J. Org. Chem. 2024, 20, 1037–1052, doi:10.3762/bjoc.20.92

• slight excess of diamines to sequester released HCl proved to be pivotal in achieving better yields. Oxidation with two equivalents of DDQ provided the comparator DCPQs 1a and 2a in 89% and 87% yield, respectively. The synthesis of DCPQ 3a was attempted rigorously under different conditions using

• to access 7a as depicted in Scheme 3. The synthetic strategy first involved the access of dihydropyrazine precursor 10 which then underwent oxidation in the final step. Next, 7e was easily converted to (Z,E)-bis-oxime derivative 7d in satisfactory yield. The oxime stereochemistry shown is presumably

• (7c) in moderate yield. The condensation of 7c with 13 in the presence of 1,4-dioxane yielded poorly soluble 10. Unfortunately, several oxidation attempts to access target 7a failed presumably due to the insolubility of 10 even in high polarity solvents, listed in Table S3 (Supporting Information File

Auxiliary strategy for the general and practical synthesis of diaryliodonium(III) salts with diverse organocarboxylate counterions

• Naoki Miyamoto,
• Daichi Koseki,
• Kohei Sumida,
• Elghareeb E. Elboray,
• Naoko Takenaga,
• Ravi Kumar and
• Toshifumi Dohi

Beilstein J. Org. Chem. 2024, 20, 1020–1028, doi:10.3762/bjoc.20.90

• reported [18][19] (Scheme 1). The importance of the trimethoxyphenyl (TMP) group as an auxiliary (dummy) ligand on the iodonium salt has prompted researchers to synthesize aryl(TMP)iodonium(III) trifluoroacetates via oxidation of iodoarene with m-chloroperbenzoic acid (mCPBA) in the presence of

• prepared through the oxidation of iodoarenes with NaBO3·4H2O [34], AcOOH [35], mCPBA [36], and NaClO·5H2O [37] in the presence of acetic acid. The reaction of (diacetoxyiodo)arenes bearing electron-donating (methyl (1b), methoxy (1c), and phenyl (1d)) and electron-withdrawing (methyl ester (1e), nitro (1f

• ) carboxylate 7aj carrying a fluorescent-labeling group in 93% yield. Iodosoarenes 5b–f can be easily obtained by treating (dichloroiodo)arenes [41] or (diacetoxyiodo)arenes [42] with sodium hydroxide, by oxidation of iodoarenes with NaClO·5H2O [43], or by electrolysis [44]. The reaction scope of iodosoarenes

Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• by the oxidation of the catalyst. The reaction proceeded with dppp and 1,10-phenantroline (12 mol % each) under 6 bar of CO at 80 °C in DMF for 22–96 hours depending on the substrate. After the required reaction time, seven carbazolones were isolated with good yields of up to 89% (Scheme 12). In 2005

• reactions were catalyzed through Pd(dba)2, dppp, 1,10-phenantroline under 6 bar of CO at 120 °C in DMF and the products were obtained within 48–96 hours. All products were isolated with good yields except the pyranindole because it decomposed; it could only be isolated after complete oxidation in air. The

Enhancing structural diversity of terpenoids by multisubstrate terpene synthases

• Min Li and
• Hui Tao

Beilstein J. Org. Chem. 2024, 20, 959–972, doi:10.3762/bjoc.20.86

• at low titers [61]. To increase C16 terpene titers, a later study redirected the 3-ketovaleryl-CoA formation step from the previous thiolase-dependent LMVA pathway to a β-oxidation LMVA pathway, and combined it with a promiscuous phosphatase, NudB, to produce C6- and C7-isoprenol. Notably, the final

Innovative synthesis of drug-like molecules using tetrazole as core building blocks

• Jingyao Li,
• Ajay L. Chandgude,
• Qiang Zheng and
• Alexander Dömling

Beilstein J. Org. Chem. 2024, 20, 950–958, doi:10.3762/bjoc.20.85

• of tetrazole building blocks which provides the handle of alcohol functionality and further oxidation serves as an oxo component in subsequent MCRs (Figure 1d). The synthesis of oxo-tetrazoles was targeted because of the prevalence of the aldehyde substrate in MCRs and their use in medicinal

• chemistry literature. Results and Discussion First, we planned to provide a number of orthogonally protected tetrazole carbaldehyde building blocks. This should be accomplished by synthesizing the hydroxymethyl precursors by a Passerini-tetrazole synthesis, followed by oxidation to the aldehyde (Figure 1d

• Passerini-tetrazole product. Then, the Swern oxidation [22][23][24], which is widely exploited and has a wide tolerance of functional groups, was used to convert the tetrazole containing alcohols to aldehydes, in particular for derivatives bearing convertible isocyanides. Most building blocks were well

Enantioselective synthesis of β-aryl-γ-lactam derivatives via Heck–Matsuda desymmetrization of N-protected 2,5-dihydro-1H-pyrroles

• Arnaldo G. de Oliveira Jr.,
• Martí F. Wang,
• Rafaela C. Carmona,
• Danilo M. Lustosa,
• Sergei A. Gorbatov and
• Carlos R. D. Correia

Beilstein J. Org. Chem. 2024, 20, 940–949, doi:10.3762/bjoc.20.84

• followed by a sequential Jones oxidation. The overall method displays a broad scope and good enantioselectivity, favoring the (R) enantiomer. The applicability of the protocol is highlighted by the efficient enantioselective syntheses of the selective phosphodiesterase-4-inhibitor rolipram and the

• Heck adducts (methyl N,O-acetals) were efficiently converted into several arylated γ-lactams by a simple oxidation procedure (Jones oxidation). To demonstrate the applicability of the strategy, two of the chiral aryl-lactams were further derivatized to provide the selective phosphodiesterase-4

• presence of a methoxy group after the Heck–Matsuda reaction indicates methanolysis after arylation. Given the importance of the lactam rings, we envisioned a sequential Jones oxidation protocol without isolation of the methyl N,O-acetal products to obtain the corresponding lactams 4. As observed in

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• , deiodination at the bridgehead position, and nucleophilic substitution at the alkyl chloride. From 1,2-BCP (±)-4, a variety of 1,2-BCPs were prepared through basic chemical transformations (Scheme 1B) [26]. Selective deprotection gave access to free alcohol-containing 1,2-BCPs (±)-5 and (±)-8. Oxidation and

• esterification of alcohol (±)-5 gave redox active ester (±)-6, which was itself shown to be a suitable substrate for nickel-catalysed decarboxylative cross coupling reactions to aryl-substituted BCPs (±)-7. Oxidation of alcohol (±)-8 gave acid (±)-9 which yielded amine (±)-10 after a Curtius rearrangement

• -workers also reported the modification of these 1,2-BCHs to increase the number of derivatives accessible using this approach (Scheme 3B) [38]. Transformation of the naphthyl ketone moiety of BCH (±)-25d by Baeyer–Villiger oxidation followed by hydrolysis gave carboxylic acid (±)-26. Through Curtius