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

• on a decagram scale in five steps from (+)-limonene oxide (13), involving epoxide manipulation, oxidative cleavage, and intramolecular aldol condensation. Similarly, the right-half fragment, allyl chloride 16, was synthesized from limonene in five steps. Site-selective hydrogenation, oxidative

• cleavage, and intramolecular cyclization provided 15, followed by functional group manipulation to yield 16. The two segments 14 and 16 were assembled by Nozaki–Hiyama–Kishi (NHK) coupling while controlling the regio- and diastereoselectivities to afford intermediate 17 [25]. Site-selective hydroboration

• synthesis of the bis-THIQ alkaloid family, Oguri and Oikawa utilized the NRPS module SfmC to construct a highly functionalized scaffold from amino acid derivatives (Scheme 10) [102]. The total synthesis of 5 from original biosynthetic intermediate 93 requires regioselective amide bond cleavage to remove the

Ring opening of photogenerated azetidinols as a strategy for the synthesis of aminodioxolanes

• Henning Maag,
• Daniel J. Lemcke and
• Johannes M. Wahl

Beilstein J. Org. Chem. 2024, 20, 1671–1676, doi:10.3762/bjoc.20.148

• % yield along with 14% acetophenone (6) as the major side product (Table 1, entry 1). Acetophenone (6) is thought to be generated by a Norrish type II cleavage of biradical 2a. Changes at the aromatic core, as demonstrated by acetonaphthone 1b, resulted in low conversions (Table 1, entry 2). When

• extending the reaction time to reach full conversion, significant amounts of Norrish type II cleavage were obtained and product 3b was isolated in only 16% yield. This substrate was therefore abandoned. Interestingly, ethyl (1c) and benzyl (1d) substitution was detrimental to the cyclization, indicated by

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

• in bacterial natural products. Crocagin biosynthesis starts with formation of the central ring structure, followed by cleavage of the core peptide by peptidase CgnD. The final steps involve N-methylation by CgnL and carbamoylation by CgnI. It is unclear which modification is installed first. CgnL is

• were first identified in 1994, but their BGC was not identified until 2013 [89][90]. The biosynthesis of ustiloxin starts with the UstA precursor, which contains a 16-fold repeat of the Tyr-Ala-Ile-Gly core. Following the cleavage of the precursor into tetrapeptides, the tetrapeptides are cyclised via

• binding domain (CBD) at the N-terminus and an rSAM domain at the C-terminus (Figure 9) [119]. In addition to its different enzyme structure, a distinct mechanism of methylation than the classical SN2 mechanism is employed. Reductive cleavage of SAM generates a 5'-deoxyadenosyl (dAdo) radical, which

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

• agarases to be encoded which belonged to the GH-50 agarase family. The enzymes were named AgaA50, AgaB50, and AgaC50. Biochemical characterization of these three enzymes revealed that AgaA50 and AgaC50 generated neoagarobiose products implying cleavage within the agarose polymer (endolytic hydrolysis). 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

• transformation (Figure 3B). Collectively, our experimental observations are in agreement with the proposed mechanistic picture detailed in Figure 3C. The anodically generated Ce(IV) carboxylates are able to undergo homolytic cleavage of the Ce–O bond upon light irradiation. The resulting carboxyl radical would

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

• predominant product (see 18i and 18j). In total, 13 groups could be attached to the different triazenylpyrazoles, yielding 18 products (see Table 1). In analogy to reported procedures for cleavage of polymer-bound triazenes [23], we attempted to develop the first protocol for synthesizing pyrazolyl azides 19

• , presumably due to the increased stability of isomer 18 towards acids. This corresponds with the results for the previously reported triazene cleavage to diazonium intermediates and subsequent cyclization to triazine derivatives [3]. In the next step, the obtained pyrazolyl azides were reacted with different

• via copper-catalyzed cross-coupling [29] with an electron-rich aryl substituent was exemplarily conducted to further expand the scope of possible products (see Scheme S2, Supporting Information File 1). We also investigated the scope and limitations of a one-pot reaction for the triazene cleavage and

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

• photocatalytic and electrochemical deoxygenation of acids and alcohols has attracted significant attention as the strategic cleavage of the C–O bond is quite challenging and opens up new possibilities for constructing useful compounds [12][13][14]. The use of photogenerated carbon-centered radicals, such as acyl

• and alkyl radicals, has shown great promise in the synthesis and functionalization of various organic molecules [15][16]. These carbon radicals can be generated in several ways. The first and most straightforward method is the homolytic cleavage of labile C–heteroatom bonds, especially alkyl halides

• and acyl radicals and maintaining a high degree of selectivity with respect to the desired outcome are key obstacles to the growth of alkyl and acyl radical chemistry. With this in mind, the emergence of new chemical transformations involving radicals generated via C–O bond cleavage by visible light

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

• 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

Transition-metal-catalyst-free electroreductive alkene hydroarylation with aryl halides under visible-light irradiation

• Kosuke Yamamoto,
• Kazuhisa Arita,
• Masami Kuriyama and
• Osamu Onomura

Beilstein J. Org. Chem. 2024, 20, 1327–1333, doi:10.3762/bjoc.20.116

• a methoxy group were transformed into the products in good yields (3la–na). 4-(Trifluoromethoxy)iodobenzene also well participated in this reaction, affording 3oa in 65% yield. Aryl iodides having fluoro and chloro substituents underwent selective C–I bond cleavage to provide monoalkylated products

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

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

• -dicarboxylate (3) with 2,3-unsubstituted parent chromone (9a) afforded benzocoumarine 17 in 56% yield (Scheme 3) [32]. The formation of the product can be explained by 1,4-addition of 3 to the chromone to give intermediate A and ring cleavage to give intermediate B. Subsequent Knoevenagel reaction by attack of

• crude form for the next step. Treatment of the latter with triethylamine in methanol resulted in ring-cleavage to give intermediate E. Subsequent base-mediated Knoevenagel reaction with extrusion of water gave intermediate F which underwent lactonization and resulted in the formation of the final

• ) [32]. The formation of the products can be explained by Michael reaction (1,4-addition) of 3 to the chromone and ring cleavage to give intermediate G. Subsequent Knoevenagel reaction by attack of the methylene carbon to the aldehyde resulted in the formation of the final products. The regioselective

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

• cleavage and rearrangement reactions, which are catalyzed by AlpJ-family oxygenases, including AlpJ, JadG, and GilOII. Prior investigations established the essential requirement for FADH2/FMNH2 as cofactors when utilizing the quinone intermediate dehydrorabelomycin as a substrate. In this study, we unveil

• a previously unrecognized facet of these enzymes as cofactor-independent oxygenases when employing the hydroquinone intermediate CR1 as a substrate. The enzymes autonomously drive oxidative ring cleavage and rearrangement reactions of CR1, yielding products identical to those observed in cofactor

• distinctive subset of compounds, including jadomycin, gilvocarcin, kinamycin, fluostatin, and lomaiviticin, arises from typical angucycline intermediates via oxidative C–C bond cleavage and subsequent ring rearrangement reactions. These atypical angucyclines exhibit intriguing chemical structures and various

Stability trends in carbocation intermediates stemming from germacrene A and hedycaryol

• Naziha Tarannam,
• Prashant Kumar Gupta,
• Shani Zev and
• Dan Thomas Major

Beilstein J. Org. Chem. 2024, 20, 1189–1197, doi:10.3762/bjoc.20.101

• (GPP, FPP, GGPP) undergo highly complex cyclisation cascades forming terpenes and terpenoids that often have great structural complexity. For class I terpene synthases this multistep process is initiated by a heterolytic C–O bond cleavage, separating the diphosphate and isoprenoid ion pairs [3][4]. The

Synthesis of 1,4-azaphosphinine nucleosides and evaluation as inhibitors of human cytidine deaminase and APOBEC3A

• Maksim V. Kvach,
• Stefan Harjes,
• Harikrishnan M. Kurup,
• Geoffrey B. Jameson,
• Elena Harjes and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2024, 20, 1088–1098, doi:10.3762/bjoc.20.96

• ]. Scheme 1 shows the synthesis of the target nucleobases. N-Boc-vinylamine (3) was synthesised from commercially available N-vinylformamide (1) as a stable source of vinylamine by treatment of 1 with Boc2O in THF in the presence of a catalytic amount of DMAP, followed by cleavage of the formyl moiety under

• the basic medium required to remove the toluoyl groups in the next step. This unfortunate instability of nucleoside 19 in basic medium repelled us from the idea of introducing the charge-neutral compound Vb into DNA because basic conditions are used for DNA cleavage and deprotection. To obtain Vb for

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

• . Useful alkenyl functional groups can also be obtained by means of elimination processes, if proper alkyl side chains are present. Additional opportunities offered by C(sp3)–Hal bonds arise from the ease of their homolytic cleavage, leading to the formation of reactive carbon-centred radicals. C(sp2)–Hal

• ] resulting in easier recyclability. Light irradiation often significantly influences the selectivity of halogenation processes. Photolytic cleavage of molecular halogens gives rise to radicals that are known to favour benzylic functionalisation [17]. Conversely, the same molecular halogens exhibit prominent

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

• 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

(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

• -workers reported a method for the selective bridge bromination of BCPs, giving access to brominated 1,2-BCP (±)-16 (Scheme 2) [33]. By exploiting the homolytic cleavage of the C–Br bond using in situ-generated silyl radicals, they were then able to harness the installed bromide functionality in

• substituted ortho-benzene. Stephenson and co-workers accessed 1,2-BCHeps 79a–c by insertion of alkenes into BCPs 78, and proposed the 1,2-BCHeps as isosteres of ortho-benzenes (Scheme 7A) [46]. The reaction proceeded via homolytic cleavage of a C–C bond adjacent to the imine functionality and stepwise alkene

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

• diaryliodonium salts in a cascade cyclization, the cyclization features a copper-catalyzed activation strategy involving the cleavage of the C–I bond and esterification. The resulting cascade of selective arylation/intramolecular cyclization facilitated the synthesis of 3,4-benzocoumarin derivatives. The

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

• -cleavage reactions and rearrangements when modified at the 4-position [15][16][17]. Baillargeon and Reddy first reported rearrangements of 6,8-dioxabicyclo[3.2.1]octane derivatives promoted by diethylaminosulfur trifluoride (DAST) [18], and later Karban and co-workers reported a migration of oxygen from

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

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

• the higher-substituted carbon atom to furnish intermediate species C. The irreversibility of the hydride addition and the regioselectivity thereof were supported by a deuterium labelling study with PhSiD3. The next steps involve homolytic cleavage of the cobalt–carbon bond to yield a carbon-centered

Synthesis and characterization of water-soluble C₆₀–peptide conjugates

• Yue Ma,
• Lorenzo Persi and
• Yoko Yamakoshi

Beilstein J. Org. Chem. 2024, 20, 777–786, doi:10.3762/bjoc.20.71

• acid-substituted C60 derivative 3 and the peptides on resin 2a–c were performed by SPPS to provide the C60–oligopeptides on resin 4a–c (Figure 1a). Subsequently, the last step of the reaction – the cleavage of the C60–peptide conjugate from the resin and the simultaneous deprotection of the amino acid

• the C60–peptide conjugates on resin 4a–c from 2a–c. The C60–oligopeptides 5a–c were obtained by cleavage from resin and simultaneous deprotection of the PGs on the amino acid side chains through the addition of by the addition of a mixture of TFA and TIPS in water. The most soluble conjugate, C60

• was subjected to SPPS with the peptides on trityl resin (i.e., 2a–c) to provide 4a–c. By simultaneous deprotection of peptide side chains and cleavage from resin, C60–oligo-Lys (5a), C60–oligo-Glu (5b), and C60–oligo-Arg (5c) were obtained. Reagents and conditions: i) 20% piperidine, rt, 2 × 10 min

Methodology for awakening the potential secondary metabolic capacity in actinomycetes

• Shun Saito and
• Midori A. Arai

Beilstein J. Org. Chem. 2024, 20, 753–766, doi:10.3762/bjoc.20.69

• et al. applied a fluorescence-based DNA cleavage assay coupled with HiTES to Streptomyces clavuligerus and identified the steroid 11α-hydroxyprogesterone (14) as an effective elicitor and characterized 10 cryptic enediyne-derived natural products, designated clavulynes A (15) and B–J with unusual

Research progress on the pharmacological activity, biosynthetic pathways, and biosynthesis of crocins

• Zhongwei Hua,
• Nan Liu and
• Xiaohui Yan

Beilstein J. Org. Chem. 2024, 20, 741–752, doi:10.3762/bjoc.20.68

• , etc. For example, during the harvest of C. sativus, a high drying temperature leads to the cleavage of the glycosidic bonds [20][21][22]. Crocins are stable in alkaline and neutral solutions but are labile under acidic solutions. Crocins can be detected in the flowers, fruits, stigmas, leaves, and

• retinopathy [70][71][72][73][74][75][76][77][78][79][80]. Biosynthesis The biosynthetic pathways of crocins have recently been studied extensively. Crocin biosynthesis can be divided into three stages: 1) biosynthesis of lycopene (5) from simple carbon resources, 2) cleavage of lycopene (5), β-carotene (6

• ), or zeaxanthin (7) by a carotenoid cleavage dioxygenase (CCD) to form crocetin aldehyde (8) and, after oxidation, 1, and 3) glycosylation of 1 to generate crocins (Figure 3). Since the biosynthetic pathways of 5 in plants and microorganisms have been elucidated and reviewed, we will only elaborate the

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

Palladium-catalyzed three-component radical-polar crossover carboamination of 1,3-dienes or allenes with diazo esters and amines

• Geng-Xin Liu,
• Xiao-Ting Jie,
• Ge-Jun Niu,
• Li-Sheng Yang,
• Xing-Lin Li,
• Jian Luo and
• Wen-Hao Hu

Beilstein J. Org. Chem. 2024, 20, 661–671, doi:10.3762/bjoc.20.59

• , hydride shift process, and photoinduced homolytic cleavage of the C–Pd bond, furnishing hybrid α-ester alkylpalladium radical I. In path b, upon irradiation with blue light, photoexcited Pd(0)Ln* reduces ethyl diazoacetate (1a) to Pd-radical species I by a proton-coupled electron transfer (PCET) process

Entry to new spiroheterocycles via tandem Rh(II)-catalyzed O–H insertion/base-promoted cyclization involving diazoarylidene succinimides

• Alexander Yanovich,
• Anastasia Vepreva,
• Ksenia Malkova,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 561–569, doi:10.3762/bjoc.20.48

• attack of the oxygen atom of the ester group on the benzyl bromide residue prevails, with the cleavage of the arylidene succinimide fragment involved in further non-selective processes. The causes of the failed cyclizations in the last two cases can be summarized as follows. The intermediates obtained