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

• , introduce hydroxy groups at C8 and C16 to produce FD-8β,16-diol (7), and BscE-catalyzed O-methylation generates the putative intermediate 8. The subsequent oxidative allylic rearrangement (8→9), catalyzed by the nonheme iron(II) and 2-oxoglutarate (Fe(II)/2OG)-dependent dioxygenase BscD, was a key step

• toward developing a chemo-enzymatic synthetic process. Presumably, the reactive iron(IV)-oxo species in dioxygenase BscD abstracts an allylic hydrogen at C1 and generates intermediate A. Subsequent α-face-selective hydroxylation of the resulting allylic radical at the C3 position would yield brassicicene

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

• directing group strategies, this approach opens the door to fluorinating a wider range of benzylic substrates. Metal catalysed In 2013, Lectka and co-workers reported an iron(II)-catalysed benzylic fluorination with Selectfluor (Figure 11) [49]. The authors were able to use an inexpensive iron source to

• intramolecular fluorine-atom-transfer (FAT) from an N-fluorinated amide to a pendant carbon-based radical formed from an iron catalyst (Figure 15) [55][56]. This concept of fluorine transfer through a 6-membered transition state was shown to work efficiently from primary, as well as secondary, benzylic radicals

• the loadings of K2S2O8 and Selectfluor, selectivity for the mono- (conditions A) or difluorination (conditions B) products could be achieved. Building on their previous iron-catalysed work, Figure 11, Lectka and co-workers reported in 2014 the use of triethylborane as a radical chain initiator for C

Photoswitchable glycoligands targeting Pseudomonas aeruginosa LecA

• Yu Fan,
• Ahmed El Rhaz,
• Stéphane Maisonneuve,
• Emilie Gillon,
• Maha Fatthalla,
• Franck Le Bideau,
• Guillaume Laurent,
• Samir Messaoudi,
• Anne Imberty and
• Juan Xie

Beilstein J. Org. Chem. 2024, 20, 1486–1496, doi:10.3762/bjoc.20.132

• increasingly limited for treatment of infections. PA has been classified as a priority 1 pathogen by the WHO [2][3]. Various approaches to treating PA, in addition to traditional antibiotics, have been developed including inhibition of quorum sensing, biofilm formation, iron chelation, and interfering with

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

• (entries 1–7, Table 1). Similarly to what was observed by Yu and co-workers for the intramolecular cyclization of alkynyl aldehyde acetals [28][29], it was found that the use of FeCl3 provided the better result in terms of overall yield (entry 3, Table 1). Moreover, the choice of iron(III) seemed to have

• content of the reaction environment during the time. Then, to explain the related formation of 5 and 6, we hypothesized a plausible reaction mechanism in which iron is involved in two concomitant catalytic cycles (Scheme 4). Initially, FeCl3 forms an acid–base complex with one of the alkoxy groups of 4

• suitably N-3-functionalized (thio)hydantoins 4a–r. aDCM was utilized as solvent with isothiocyanates 3a–f, while bEtOH was utilized with isocyanates 3g,h. Substrate scope of the iron(III)-catalyzed synthesis of functionalized heterocyclic N,O-aminals 5a–r and hemiaminals 6a–p. Proposed mechanism for 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

• . developed an asymmetric iron catalyst with the aim of expanding the platform of metal catalysis. Catalysts 14 and 15 proved to be effective in the transformation of glyoxal monohydrates 1a and alcohol 2, to deliver mandelate esters 3a in good yields and enantioselectivities via an enantioselective

Rhodium-catalyzed homo-coupling reaction of aryl Grignard reagents and its application for the synthesis of an integrin inhibitor

• Kazuyuki Sato,
• Satoki Teranishi,
• Atsushi Sakaue,
• Yukiko Karuo,
• Atsushi Tarui,
• Kentaro Kawai,
• Hiroyuki Takeda,
• Tatsuo Kinashi and
• Masaaki Omote

Beilstein J. Org. Chem. 2024, 20, 1341–1347, doi:10.3762/bjoc.20.118

• . Therefore, alternative procedures for homo-coupling reactions using other transition-metal catalysts such as palladium, nickel, manganese, and iron have been developed [5][6][7][8][9][10][11][12][13]. In recent years, transition-metal-free coupling reactions have also been developed for environmentally

Synthesis and physical properties of tunable aryl alkyl ionic liquids based on 1-aryl-4,5-dimethylimidazolium cations

• Stefan Fritsch and
• Thomas Strassner

Beilstein J. Org. Chem. 2024, 20, 1278–1285, doi:10.3762/bjoc.20.110

• formation of N-oxides, which were then reduced using iron powder. The imidazoles were synthesized in a one-pot procedure on a scale of up to 400 mmol. Quaternization of the imidazoles using bromoalkanes with different chain lengths provided the bromide salts 10–36. Conversion to the NTf2 ionic liquids 37–63

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

• considerably inexpensive, eco-friendly and more abundant in the Earth’s crust. According to this viewpoint, manganese is biocompatible and less expensive than noble metals. Also, it is the third most abundant transition metal, behind titanium and iron. After the independent pioneering works of Beller [16] and

(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

• ester 136g. The latter could then be oxidised to the corresponding alcohols 137f–g. The bridgehead iodine substituent could also be harnessed in iron-catalysed Kumada coupling reactions to furnish a larger number of arene-substituted 1,5-BCHeps 138. Anderson and co-workers also reported access to

Activity assays of NnlA homologs suggest the natural product N-nitroglycine is degraded by diverse bacteria

• Kara A. Strickland,
• Brenda Martinez Rodriguez,
• Ashley A. Holland,
• Shelby Wagner,
• Michelle Luna-Alva,
• David E. Graham and
• Jonathan D. Caranto

Beilstein J. Org. Chem. 2024, 20, 830–840, doi:10.3762/bjoc.20.75

• experimental samples resulted from NNG degradation activity by the recombinantly expressed NnlA homologs. We conclude from these results that all five of the selected NnlA homologs exhibit NNG degradation activity. NnlA homologs exhibit similar heme and iron occupancy as Vs NnlA To better compare the NnlA

• nm/A280 nm ratio for each homolog was greater than 1.0, consistent with high occupancy of heme incorporation in the proteins. Iron analyses of each of the homologs were consistent with this conclusion; the heme iron concentrations per protein were consistent with stoichiometric or nearly

• , likely acting as its proximal ligand. As described above, the H73A Vs NnlA variant lacked NNG degradation activity and had reduced iron content [21]. The AlphaFold model also predicts a distal pocket composed of Tyr99, Ala101, Ile109, Val111, and Gln127. These amino acids are conserved in an alignment of

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

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

• interest as the starting materials are inexpensive bulk chemicals and the reactions can be carried out under air without any particular precautions. Radical hydrochlorination reactions Cobalt and iron-promoted radical hydrochlorination reactions are part of the large family of metal hydride hydrogen atom

• DHB as a hydride donor and thus give the fully reduced product 142. However, when both DHB and TosCl were present, the reaction of the radical with TosCl was significantly faster leading to 143 in 92% yield. In 2012, Boger demonstrated the efficiency of iron(III) catalysts for the hydrochlorination of

• activated alkenes [86]. Subjecting citronellol (122) to the optimized reaction conditions resulted in the formation of chloride 133 with a yield of 62% (Scheme 25). It is worth noting that the iron-catalyzed procedure tolerates free alcohols, a distinction from Carreira's protocol [80]. In 2014, the Thomas

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

• secondary metabolites with chelating activity, which enables the actinomycetes to acquire that metal (Figure 3c). Béchet and Blondeau reported that Streptomyces aureofaciens ATCC 10762 produces substantial amounts of tetracycline (23) only when the defined medium is deprived of iron [62]. Although not a

• orsellinic acid, lecanoric acid, and the compounds F-9775A and F-9775B. Lee et al. discovered that secondary metabolism in Streptomyces coelicolor A3(2) M145 is activated by iron competition during co-culture with Myxococcus xanthus [110]. Co-culture promotes the production of the siderophore myxochelin in M

• . xanthus, which enhances the iron-scavenging capacity of M. xanthus and places S. coelicolor A3(2) M145 under iron starvation conditions. This chemical interaction activates the actinorhodin (8) biosynthetic gene cluster in S. coelicolor A3(2) M145. Onaka’s group reported that co-cultivation of

New variochelins from soil-isolated Variovorax sp. H002

• Jabal Rahmat Haedar,
• Aya Yoshimura and
• Toshiyuki Wakimoto

Beilstein J. Org. Chem. 2024, 20, 692–700, doi:10.3762/bjoc.20.63

• iron cycle within the rhizosphere. This study focused on exploring the natural products of the soil-isolated Variovorax sp. H002, leading to the isolation of variochelins A–E (1–5), a series of lipohexapeptide siderophores. NMR and MS/MS analyses revealed that these siderophores share a common core

• structure – a linear hexapeptide with β-hydroxyaspartate and hydroxamate functional groups, serving in iron-binding coordination. Three new variochelins C–E (3–5) were characterized by varied fatty acyl groups at their N-termini; notably, 4 and 5 represent the first variochelins with N-terminal unsaturated

• : antimicrobial activity; siderophore; variochelin; Variovorax; Introduction Almost all organisms require iron as a crucial cofactor of enzymes essential for their physiological functions, encompassing primary and secondary metabolisms [1]. However, in an aerobic environment, iron predominantly exists in the

Recent developments in the engineered biosynthesis of fungal meroterpenoids

• Zhiyang Quan and
• Takayoshi Awakawa

Beilstein J. Org. Chem. 2024, 20, 578–588, doi:10.3762/bjoc.20.50

• the αKG-dependent dioxygenase have been analyzed in detail due to its relatively small molecular weight and the low costs of its cofactors: αKG, ascorbic acid, and iron ions. The αKG reacts with iron and molecular oxygen to form the highly reactive Fe(IV)=O via oxidative decarboxylation. This active

Synthesis and biological profile of 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines, a novel class of acyl-ACP thioesterase inhibitors

• Jens Frackenpohl,
• David M. Barber,
• Guido Bojack,
• Birgit Bollenbach-Wahl,
• Ralf Braun,
• Rahel Getachew,
• Sabine Hohmann,
• Kwang-Yoon Ko,
• Karoline Kurowski,
• Bernd Laber,
• Rebecca L. Mattison,
• Thomas Müller,
• Anna M. Reingruber,
• Dirk Schmutzler and
• Andrea Svejda

Beilstein J. Org. Chem. 2024, 20, 540–551, doi:10.3762/bjoc.20.46

• quantities of the most active compounds for advanced biological testing. Pleasingly, our four-step approach using a potassium O-ethyl dithiocarbonate-mediated formation of thio intermediates 11a–c (thiol–thione tautomers) with subsequent sulfur removal using iron powder in acetic acid [19] proceeded smoothly

• , 1H), 7.19–7.15 (m, 1H). The thiol–thione tautomer 11b (14.55 g, 42.64 mmol, 1.0 equiv) was dissolved in acetic acid (200 mL), and iron powder (35.71 g, 639.61 mmol, 15 equiv) was carefully added in portions. The resulting reaction mixture was stirred at 100 °C for 10 h. After full conversion

• (indicated by LC–MS), the reaction mixture was cooled to 60 °C, and the iron powder was filtered off. The remaining solution was diluted with water, and the resulting precipitate was filtered, washed with water, and dried under reduced pressure. The remaining crude residue was redissolved in DCM, then water

Green and sustainable approaches for the Friedel–Crafts reaction between aldehydes and indoles

• Periklis X. Kolagkis,
• Eirini M. Galathri and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2024, 20, 379–426, doi:10.3762/bjoc.20.36

• -proline on the surface of the magnetic nanoparticle via iminium formation as seen in Scheme 18, allowing the indole to attack the formed double bond and initiate the Michael-type mechanism [107]. In an effort to replace the widespread use of nano-iron oxides, which present issues, such as aggregation, and

• requires large amounts of capping agents to combat, Pratihar and his research group offered the alternative of iron oxalates for the nanocatalysis of BIMs, which, after thermal decomposition form Fe(ox)-Fe3O4 oxides [108]. Metal oxalates in general are more stable nanoparticles than their oxide

• clamps were formed, which led to a more complex recovery of the catalyst as firstly the water needed to be removed by decantation and next acetone was added so that the BIMs were dissolved and the nanoparticles could be retrieved with the use of a tiny magnet. All in all, while the iron oxalates

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• decarboxylative cross-coupling (DCC) of NHPI esters with organometallic reagents, resembling classic Kumada, Negishi, and Suzuki couplings, has been enabled by nickel (Ni), cobalt (Co), iron (Fe), and copper (Cu) catalysts [84][85][86][87][88][89][90][91] (Scheme 23A). The typical mechanism begins by

Photochromic derivatives of indigo: historical overview of development, challenges and applications

• Gökhan Kaplan,
• Zeynel Seferoğlu and
• Daria V. Berdnikova

Beilstein J. Org. Chem. 2024, 20, 228–242, doi:10.3762/bjoc.20.23

• using heme-containing oxygenases (cytochrome P450 monooxygenases, styrene/indole monooxygenases, flavin-containing monooxygenases, Baeyer–Villiger monooxygenases, etc.) or non-heme iron oxygenases (naphthalene dioxygenases, multicomponent phenol hydroxylases) [5][6][7][8]. The synthetic approaches

Selectivity control towards CO versus H₂ for photo-driven CO₂ reduction with a novel Co(II) catalyst

• Lisa-Lou Gracia,
• Philip Henkel,
• Olaf Fuhr and
• Claudia Bizzarri

Beilstein J. Org. Chem. 2023, 19, 1766–1775, doi:10.3762/bjoc.19.129

• ]. Among the most employed earth-abundant metal-based PS, Cu(I) complexes have the first place, not only in artificial photosynthesis, but also in a large variety of photo(redox)catalyses [12][13][14][15][16][17]. On the other hand, several complexes based on 3d transition metals, like manganese [18], iron

Tying a knot between crown ethers and porphyrins

• Maksym Matviyishyn and
• Bartosz Szyszko

Beilstein J. Org. Chem. 2023, 19, 1630–1650, doi:10.3762/bjoc.19.120

• of coordination compounds of copper(II), iron(II/III), manganese(II), nickel(II), and cobalt(II) with 9-Zn and 9-Cu was demonstrated. The emission quenching was rationalised considering the binding of the transition metal within the crown ether cavity. No quenching was observed upon the addition of

• iron(II) and manganese(II) complexes with similar compositions. Interestingly, by-products incorporating the [2 + 2] macrocycles were isolated from the reaction mixtures targeting 16-Fe, 18a-Fe and 16-Mn, 18a-Mn (Figure 13) [67]. The helical geometry of [16-M]2 was attributed to the inherent

• flexibility of macrocyclic ligands, as demonstrated by X-ray molecular structures. The helicates consisted of two metal centres, namely cobalt, manganese, or iron, each coordinated by two nitrogens and oxygen donors of the ligand. The metal centres adopted distorted octahedral geometries with slight

Synthesis of 7-azabicyclo[4.3.1]decane ring systems from tricarbonyl(tropone)iron via intramolecular Heck reactions

• Aaron H. Shoemaker,
• Elizabeth A. Foker,
• Elena P. Uttaro,
• Sarah K. Beitel and
• Daniel R. Griffith

Beilstein J. Org. Chem. 2023, 19, 1615–1619, doi:10.3762/bjoc.19.118

• accessed from tropone (via its η4-diene complex with Fe(CO)3) in a short sequence of steps: 1) nucleophilic amine addition and subsequent Boc-protection, 2) photochemical demetallation of the iron complex, and 3) an intramolecular Heck reaction. Minor modifications to the protocol enabled access to the

• related 2-azabicyclo[4.4.1]undecane system, albeit in lower yield. Keywords: alkaloids; azabicycles; Heck reaction; iron complex; tropone; Introduction Azapolycycles are embedded within numerous biologically active alkaloids [1] and pharmaceuticals [2]. As such, novel approaches to the synthesis of

• these scaffolds, even though they are found within a number of biologically active alkaloids. We recently demonstrated that the readily available, bench-stable tricarbonyl(tropone)iron complex [4] (1, Scheme 1) could serve as a precursor to the previously unreported 2-azatricyclo[4.3.2.04,9]undecane

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

• sulfide moieties 11 was performed by Fu et al. (Scheme 6) [47]. Iron(III) chloride was used as a catalyst for this coupling reaction without the need of any ligand and additive. Screening for other metal salts, such as Cu(OAc)2, Pd(OAc)2, AgOAc or CuI was not successful, although FeS·7H2O, FeS, Fe2(SO4)3

• of unactivated arenes. Iron- or boron-catalyzed C–H arylthiation of substituted phenols. Iron-catalyzed azidoalkylthiation of alkenes. Plausible mechanism for iron-catalyzed azidoalkylthiation of alkenes. BF3·Et2O‑mediated electrophilic cyclization of aryl alkynoates. Tentative mechanism for BF3·Et2O

• . Co-catalyzed C2-sulfenylation and C2,C3-disulfenylation of indole derivatives. Plausible catalytic cycle for Co-catalyzed C2-sulfenylation and C2,C3-disulfenylation of indoles. C–H thioarylation of electron-rich arenes by iron(III) triflimide catalysis. Difunctionalization of alkynyl bromides with

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

• , and the cleavage of the C(sp3)–H bond in the ether substrates which produces α-alkyl radicals is the rate-determining step. Fe-catalyzed reactions Iron is a transition metal with abundant reserves, low price, and non-toxicity, which shows many characteristics in catalytic processes, such as the

• properties of transition metals and Lewis acids [69][70][71][72]. These advantages make iron salts attractive catalysts or reagents in chemical transformations and are considered ideal materials for developing catalysts [73]. Fe-catalyzed CDC reactions have achieved remarkable achievements in recent years

• directing groups could be used as coupling partners. The ligand acts as an activator of the catalyst to promote the reaction, and the iron-bound anion plays a crucial role in catalysis. This reaction might occur via a radical pathway, with the iron catalyst playing a significant role in electron transfer

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

• alkyl C–H bond to a high valent iron oxo species, resulting in formation of iron hydroxo and alkyl radical intermediates [15]. Subsequent RLT of the hydroxo ligand to the alkyl radical produces a hydroxylated product, allowing for metabolism and excretion of previously diverse bioactive compounds

• behavior of P450 oxygenases encouraged early work on site-selective C–H functionalization [20]. Throughout their studies, it was found that manganese could perform the same HAT and RLT steps as iron at heme active sites. Groves developed the manganese tetramesitylporphine catalyst V (Scheme 2), which was

• the power of RLT to install a variety of medicinally relevant groups, largely mirroring the selectivity of CYP450s. Intriguingly, studies by Groves have revealed earth abundant iron and manganese to be particularly privileged for this application of RLT, a major advantage for sustainable method

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

• and Epred = −2.10 V vs SCE for CF3Br) [93]. As a further application of conPET to atom transfer processes, the Wärnmark group recently disclosed an alternative protocol for the ATRA reaction of perfluoroalkyl iodides using the iron-based NHC complex [FeIII(btz)3](PF6)3 (btz = (3,3’-dimethyl-1,1’-bis(p

• -tolyl)-4,4’-bis(1,2,3-triazol-5-ylidene))) as the first example of an earth-abundant transition metal complex capable of accumulating two photon energies via consecutive 2LMCT and 3MLCT excitations in an overall conPET mechanism [94]. Since iron-based photocatalysts generally suffer notoriously short

• of iron CT states (in the nanosecond domain) enabled by the relatively longer lifetimes of e.g. Fe–NHC complexes [97][98][99][100]. In particular, the Wärnmark group reported two sets of conditions with and without Et3N as a sacrificial electron donor, to achieve reductive and oxidative quenching