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

• Suzuki–Miyaura coupling with boronic ester 53 and O-acetylation furnished 54. The dienophile component, morachalcone A (44), was synthesized from phenol 55 in four steps including O-prenylation and subsequent Claisen rearrangement, aldol condensation with 56, and deprotection. The key chemo-enzymatic

• this problem, the research group designed synthetic substrate analogs (96, 101) that mimic the biosynthetic intermediate 88 (Scheme 10A). By replacing an amide linkage in 88 with an ester linkage, the fatty acid side chain could be removed under mild conditions after enzymatic construction of the

• pentacyclic secondary amine 97 bearing the ester linker in the C1 side chain in one pot. After removal of SfmC by precipitation and centrifugation, the reaction mixture containing secondary amine 97 was subjected to the reductive amination using 2-picoline borane as a hydride source, yielding tertiary amine

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

• ]. Further O-MTs can be classified based on a common acceptor group of modification, namely C-terminal carboxy-MTs and peptide/protein ʟ-aspartyl O-MTs (PAMTs). C-terminal carboxymethyltransferases Carboxy-MTs catalyse the formation of a methyl ester by methylating the oxygen atom within the hydroxy group of

• enzyme engineering and rational design [73][74]. Lentzea kentuckyensis sp. produces lassomycin (Figure 4), a lasso peptide, with a methyl ester at the C-terminus. The las cluster encodes LasF, which is predicted to function as an O-MT. Since no other putative MT is encoded in the las cluster, LasF is

• proposed to methylate lassomycin [77]. PAMTs – peptide/protein ʟ-aspartyl O-methyltransferases PAMTs share a conserved C-terminal domain, substantial sequence homology, and a common enzymatic activity. They catalyse the conversion between aspartate and isoaspartate with aspartyl-O-methyl ester and

Polymer degrading marine Microbulbifer bacteria: an un(der)utilized source of chemical and biocatalytic novelty

• Weimao Zhong and
• Vinayak Agarwal

Beilstein J. Org. Chem. 2024, 20, 1635–1651, doi:10.3762/bjoc.20.146

• . Their structures differ from common parabens by the presence of an acetamide group ortho to the phenolic hydroxy group [14]. They exhibited weak activity against E. coli and methicillin-sensitive Staphylococcus aureus (MSSA). The three analogues 15–17 (Figure 6) with different ester chain lengths were

• synthesized and tested for antimicrobial activity. However, no clear trend was found between the ester length and bioactivity. In addition to the paraben derivatives, three known nucleosides, 4´,5´-didehydro-5´-deoxyinosine (18), 2´-O-methyladenosine (19), and 5´-methylthioinosine (20) were also identified

Supramolecular assemblies of amphiphilic donor–acceptor Stenhouse adducts as macroscopic soft scaffolds

• Ka-Lung Hung,
• Leong-Hung Cheung,
• Yikun Ren,
• Ming-Hin Chau,
• Yan-Yi Lam,
• Takashi Kajitani and
• Franco King-Chi Leung

Beilstein J. Org. Chem. 2024, 20, 1590–1603, doi:10.3762/bjoc.20.142

• nitrogen atmosphere, followed by reduction of the indole motif in compound 1n to indoline in 2n. The ester group in compound 2n was deprotected under basic conditions to give compound 3n (Scheme 2). DAn with different chain lengths of the alkyl linker were synthesized through an aza-Piancatalli

Electrocatalytic hydrogenation of cyanoarenes, nitroarenes, quinolines, and pyridines under mild conditions with a proton-exchange membrane reactor

• Koichi Mitsudo,
• Atsushi Osaki,
• Haruka Inoue,
• Eisuke Sato,
• Naoki Shida,
• Mahito Atobe and
• Seiji Suga

Beilstein J. Org. Chem. 2024, 20, 1560–1571, doi:10.3762/bjoc.20.139

• yields (7a–e, 7g, and 7h), except for 6f which contained a methyl group at the 4-position. The reaction of 2,3-dimethylquinoline (6i) gave the desired product 7i (cis/trans = 3:1) in 77% yield. Substrates bearing acetyl (6k), ester (6l), and amide (6m) groups were tolerated under these conditions and

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

• yields, with the authors proposing that HFIP aided in stabilising the electrochemically generated benzylic radical cation intermediates. Secondary and tertiary benzylic substrates bearing halogen, ester, protected amine and alkyl functional groups tolerated the reaction conditions well. The authors

• showed they were able to scale-up and selectively fluorinate the ibuprofen methyl ester at the methylene group to produce over 2 g of product 12. The utility of the benzyl fluoride products as strategic intermediates for benzylation of electron-rich arenes was demonstrated by the authors (Figure 41B

Towards an asymmetric β-selective addition of azlactones to allenoates

• Behzad Nasiri,
• Ghaffar Pasdar,
• Paul Zebrowski,
• Katharina Röser,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1504–1509, doi:10.3762/bjoc.20.134

• investigated the generality of this protocol. As outlined in Scheme 2, differently substituted allenoates were reasonably well tolerated (see products 5a–d), albeit some erosion in enantioselectivity was observed when using a tert-butyl ester containing allenoate (product 5d). Various α-arylmethyl-substituted

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

• size of the alkyl side chain at the alpha position of arylacetic acids (9–16). These features offer great opportunities for the introduction of a wide range of functional groups, including bromide (9), boron (12), ether (13), nitrile (14), ester (15), and alkene (16) moieties, which are versatile

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

Hypervalent iodine-catalyzed amide and alkene coupling enabled by lithium salt activation

• Akanksha Chhikara,
• Fan Wu,
• Navdeep Kaur,
• Prabagar Baskaran,
• Alex M. Nguyen,
• Zhichang Yin,
• Anthony H. Pham and
• Wei Li

Beilstein J. Org. Chem. 2024, 20, 1405–1411, doi:10.3762/bjoc.20.122

• , ester, and phthalimide proceeded smoothly with good yields and excellent regioselectivities to access the oxazoline products as single regioisomers (Figure 3, products 18–22). The o-bromo-substituted styrene also afforded the corresponding product 23. Furthermore, 1,1-di-substituted α-methylstyrene and

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

• benzylic residues differed depending on the benzylic residue's functional groups and the pyrazole substitution pattern. For starting materials 15a and 15d, an excess of product 17 was usually observed. With the ester-functionalized triazene 15c and m-substituted benzylic reagents, regioisomer 18 was the

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

• % enantioselectivity. They employed a double asymmetric induction with (+)/(−)-menthol (12), and CuX2 bis(oxazoline) catalyst where the corresponding chiral mandelate ester 13 was obtained in 81% yield and high selectivity (90% de) (Scheme 6). The proposed mechanism of the reaction is depicted below. Hong et al

• modern modifications using mild and sustainable reagents, solvents, advanced instrumental techniques, and catalysts in both intramolecular and intermolecular versions of the reaction have made the Cannizzaro reaction an important tool for the synthesis of diverse molecules containing alcohol, acid, ester

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

• )], regenerating the [Ir(III)] catalyst and completing the catalytic cycle. Overman and co-workers [50] used tert-alkyl N-phthalimidoyl oxalates to produce alkyl radicals that were further reacted with various Michael acceptors (Scheme 13). The photocatalyst Ru(bpy)32+ and Hantzsch ester were essential for the

• excitation of [Ir(III)] to activated *[Ir(III)], which is then reduced by Hantzsch ester to form [Ir(II)]. After SET, the resultant [Ir(II)] species reduces N-alkoxyphthalimide to produce the N-alkoxyphthalimide radical anion. The Hantzsch ester radical cation further protonates this anion, promoting

• the production of an alkyl radical. After that, this alkyl radical reacts with allyl and alkenyl sulfones in an addition–elimination cycle to produce the required product and a benzenesulfonyl radical. The benzenesulfonyl radical abstracts a hydrogen radical from the Hantzsch ester radical to form

Synthesis of indano[60]fullerene thioketone and its application in organic solar cells

• Yong-Chang Zhai,
• Shimon Oiwa,
• Shinobu Aoyagi,
• Shohei Ohno,
• Tsubasa Mikie,
• Jun-Zhuo Wang,
• Hirofumi Amada,
• Koki Yamanaka,
• Kazuhira Miwa,
• Naoyuki Imai,
• Takeshi Igarashi,
• Itaru Osaka and
• Yutaka Matsuo

Beilstein J. Org. Chem. 2024, 20, 1270–1277, doi:10.3762/bjoc.20.109

• derivatives with an emphasis on tuning solubility and energy levels. Meanwhile, less attention has been devoted to improving the thermal stability of fullerene derivatives. One well-known example is [6,6]-phenyl-C61-butyric acid methyl ester (PCBM), which is recognized for its excellent solubility in solution

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

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

• to the chromone and ring cleavage to give intermediate I. Subsequent Knoevenagel reaction by attack of the methylene carbon to the carbonyl group adjacent to the ester group resulted in the formation of the final products. The regioselective cyclization can be explained by the higher electrophilicity

• of the carbonyl group adjacent to the ester, due to the electron-withdrawing effect of the latter. The yields were generally good to very good and no trend was observed depending on the structure of the chromones. 1,3-Diphenylacetone Similarly, reaction of 1,3-diphenylacetone (4) with 11a,d afforded

• observed under these conditions, because the electron-withdrawing character of the additional ester group which destabilizes formation of a cation at the neighboring position. The yields were in most cases moderate (42–54%). Two products were obtained in higher yields (71 and 80%). However, no clear trend

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

• . It crystallized in a triclinic crystal system in the space group P−1. It was structurally similar to the other oxamides 3 and 9. It showed an intramolecular hydrogen bonding between the NH and the carbonyl group of the methoxy ester. A layer-by-layer packing was observed in the crystal structure

• (Figure S37, Supporting Information File 1). The dipolar characteristics of the ester group appeared to assist the molecular layer-by-layer stacking seen in the crystal packing. The molecular structure of the quinone derivative 10 is shown in Figure 4. It crystallized in a monoclinic crystal system in the

Manganese-catalyzed C–C and C–N bond formation with alcohols via borrowing hydrogen or hydrogen auto-transfer

• Mohd Farhan Ansari,
• Atul Kumar Maurya,
• Abhishek Kumar and
• Saravanakumar Elangovan

Beilstein J. Org. Chem. 2024, 20, 1111–1166, doi:10.3762/bjoc.20.98

• )phosphine ligand (PN3P) (Mn3) and studied N-methylation reactions in the presence of t-BuOK (20 mol %) at 120 °C for 24 h in toluene [36]. This catalytic system tolerated various functional groups, including nitro, ester, amide, and ketones and gave moderate to good yields (42–98%) of the mono-N-methylated

• moderate-to-high yields with aliphatic and aromatic alcohols (Scheme 18). In addition, this protocol allowed for the synthesis of indole through an intramolecular reaction and a resveratrol-derived amine. However, this catalytic method did not tolerate some functional groups such as nitro, ester, and

• heterocyclic alcohols were tested and showed good functional group tolerances. However, ester and nitrile-substituted ketones were not alkylated with this protocol. The proposed mechanism showed that the Mn(CO)5Br reacted with ligand L3 to generate the active complex Mn-L3-I in the presence of a base. The

Novel analogues of a nonnucleoside SARS-CoV-2 RdRp inhibitor as potential antivirotics

• Luca Julianna Tóth,
• Kateřina Krejčová,
• Milan Dejmek,
• Eva Žilecká,
• Blanka Klepetářová,
• Lenka Poštová Slavětínská,
• Evžen Bouřa and
• Radim Nencka

Beilstein J. Org. Chem. 2024, 20, 1029–1036, doi:10.3762/bjoc.20.91

• suitably decorated benzoxazole derivative 12a. The benzoxazole core showed increased sensitivity towards a basic environment, resulting in the ring-opened side product 13 through saponification of the ester function of compound 12a. The identification of this side product proved to be challenging due to

• insufficient evidence provided even by meticulous NMR analysis and eventually had to be confirmed by X-ray crystallography (Figure S1, Supporting Information File 1). Changing the ester function from an ethyl to an allyl group enabled a very mild cleavage using a Pd-mediated reaction with triethylsilane [28

• ], and thus avoiding the use of base, leading to the desired intermediate 14 in good yield. Compound 14 was then coupled with ʟ-tyrosine methyl ester followed by deprotection of the amino acid carboxyl group by LiOH⋅H2O. As in the previous base-mediated saponification, here we also received a product of

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

• 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

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

• carbon monoxide insertion, and Suzuki–Miyaura coupling reaction, from 2-gem-dibromovinylaniline [12]. In the presence of Pd(PPh3)4 (5 mol %) as catalyst, 5 equivalents of base (K2CO3), an aryl- or heteroarylboronic ester (1.1 equivalents), CO (12 bar), in dioxane at 100 °C after 16 h the indole

• carried out using 2 mol % of PdI2, 20 mol % of KI and 40 bar of a 4:1 mixture of CO–air, in methanol or ethanol in the presence of an ortho-ester (1:3 mixture) as solvent to prevent hydrolysis of the substrate. After 15 hours at 80 °C the indoles derivatives were isolated in good yields (Scheme 4). Two

• synthesis of a set of 12 desired products. These included an ethyl ester and a carboxylic acid, and were all obtained in good yields of up to 99% (Scheme 45). Conclusion We have summarized the importance of carbon monoxide as C1 building block to promote different kinds of transformations to synthesize and

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

• -containing electron-withdrawing groups such as methyl ester and ketone did not show much of an effect in the outcome of the reaction, providing compounds 4bd and 4be in high yields and good er. On the other hand, product 4bq was obtained in a higher yield but with a lower er. The p-halogen-containing

Direct synthesis of acyl fluorides from carboxylic acids using benzothiazolium reagents

• Lilian M. Maas,
• Alex Haswell,
• Rory Hughes and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2024, 20, 921–930, doi:10.3762/bjoc.20.82

• , replacing the benzylamine coupling partner with phenylalanine methyl ester provided dipeptide 5t in 67% yield (Scheme 3b). With the scope of the deoxyfluorination process established, our attention turned to an investigation of the reaction mechanism (Scheme 4). As demonstrated in our previous work

(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

• 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

• rearrangement, amine (±)-27 was then accessible in one additional step. Formation of redox active ester (±)-28 from acid (±)-26 allowed photochemical Minisci reaction to 1,2-BCH (±)-29 and borylation to boronic ester (±)-30. Synthesis of phenol isostere (±)-31 was possible through oxidation of boronic ester

• homologation and hydrolysis led to aldehyde (±)-46 which could then be oxidised to acid (±)-47 using a Pinnick oxidation. BCH 42b also led to ester (±)-48 via a Horner–Wadsworth–Emmons reaction followed by hydrogenation of the formed alkene. 1,2-BCH 44 could be turned into amine (±)-49 by oxime formation and

Ortho-ester-substituted diaryliodonium salts enabled regioselective arylocyclization of naphthols toward 3,4-benzocoumarins

• Ke Jiang,
• Cheng Pan,
• Limin Wang,
• Hao-Yang Wang and
• Jianwei Han

Beilstein J. Org. Chem. 2024, 20, 841–851, doi:10.3762/bjoc.20.76

• salts is an efficient tool for the construction of two or more chemical bonds in a one-pot process. Ortho-functionalized diaryliodonium salts have showcased distinct reactivity in the exploration of benzocyclization or arylocyclization. With this strategy of ortho-ester-substituted diaryliodonium salts

• [31][32][33]. Building on our great interest in ortho-functionalized diaryliodonium salts and their dual activation capabilities, we sought to incorporate carboxylic ester groups into the structures of ortho-substituted diaryliodonium salts to explore their properties and reactivity. Our previous

• investigations demonstrated the ability of diaryliodonium salts for selective mono-arylation of 2-naphthols [34]. In this context, we embark on a strategy to modify the neighbouring position of the diaryliodonium salt with an ester group, presenting a novel copper-catalysed regioselective arylocyclization of

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

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

• solution of HCl, even in the presence of secondary alcohol and ester functionalities (Scheme 5B) [45]. An application in the synthesis of Δ9-tetrahydrocannabutol, the butyl homologue of Δ9-tetrahydrocannabinol (Δ9-THC), is outlined in Scheme 5C [46]. In this case, ZnCl2 was employed as a catalyst, but