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

• a single hydroxylation step of β-carotene (6), but it requires two hydroxylation steps in plants [84]. In the crocin biosynthetic pathways, lycopene (5), β-carotene (6), and zeaxanthin (7) are cleaved by different CCDs to form crocetin dialdehyde (8). CsCCD2 from C. sativus could break the 7,8 and 7

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• hydroxylation and epoxidation using three P450s (TylI, JuvD and MycCI) involved in the biosynthesis of several different macrolides, eight additional macrolides were achieved from 50, including juvenimicin B1, M-4365 G2, and juvenimicin A3. In the light of this approach, the following bioactive assay

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

• molecular species withdraws a hydrogen atom, and the generated radical induces various reactions such as hydroxylation, unsaturation, epoxidation, halogenation, endoperoxidation, and C–C bond reconstruction, leading to the formation of diverse chemical structures [22][26][27][28][29][30][31]. Structure

Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

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

Transition-metal-catalyzed C–H bond activation as a sustainable strategy for the synthesis of fluorinated molecules: an overview

• Louis Monsigny,
• Floriane Doche and
• Tatiana Besset

Beilstein J. Org. Chem. 2023, 19, 448–473, doi:10.3762/bjoc.19.35

• moiety (OCH2CF3), an important fluorinated group found in several bioactive compounds such as flecanide [154][155] and lansoprazole [156], as flagship molecules. Although the transition-metal-catalyzed hydroxylation and alkoxylation have been studied especially under palladium catalysis [157][158], the

Combretastatins D series and analogues: from isolation, synthetic challenges and biological activities

• Jorge de Lima Neto and
• Paulo Henrique Menezes

Beilstein J. Org. Chem. 2023, 19, 399–427, doi:10.3762/bjoc.19.31

• pathway was proposed by Ponnapalli and co-workers [14] and was initially based on the conversion of phenylalanine into tyrosine by phenylalanine hydroxylase and m-tyrosine via radical hydroxylation (Scheme 2). Subsequent deamination of tyrosine, with concomitant hydroxylation/deamination of m-tyrosine

Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• conceptualized by Renata’s group to access various oxidized members of pyrone meroterpenoids. The divergent plan of Renata’s group depended on the development of a highly chemoselective, chemoenzymatic 3-hydroxylation of sclareolide (29) and (−)-sclareol (43, Scheme 3 and Scheme 4). The group began by conducting

• –Giese coupling, followed by reductive cleavage of the lactone moiety with LiI. Enzymatic hydroxylation by the BM3 MERO1 variant worked equally well to provide the 3-hydroxylated product 46. Photochemical radical decarboxylation of the formed mercaptopyridine derivative and radical capture by iodoform

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

• active oxidative agent. Asymmetric quaternary ammonium phase-transfer catalysts proved to be effective in the asymmetric nucleophilic epoxidation of electron-poor alkenes by hydroperoxides [70] and the asymmetric hydroxylation of enolizable carbonyl compounds employing O2 or H2O2 as terminal oxidants [71

• ][72]. A recent achievement of the enantioselective hydroxylation of α‑aryl-δ-lactams by O2 is shown in Scheme 5 [73] as an example of such organocatalyzed reaction type. Triethyl phosphite is added to reduce a hydroperoxide, which is initially formed by the enolate oxidation with O2. In summary

• –H2O2 system the adducts of H2O2 and ketones (perhydrates) can also be active oxidative species [51]. Dioxiranes formed from ketones and hydroperoxides are electrophilic oxygen transferring agents used in epoxidation (including asymmetric variants) [131][132], CH-hydroxylation, and other oxidation

Cytochrome P450 monooxygenase-mediated tailoring of triterpenoids and steroids in plants

• Karan Malhotra and
• Jakob Franke

Beilstein J. Org. Chem. 2022, 18, 1289–1310, doi:10.3762/bjoc.18.135

• that performs hydroxylation and epoxidation reactions of the β-amyrin (6) scaffold to produce 12,13β-epoxy-16β-hydroxy-β-amyrin [1][99]. Thus, CYP51H10 is an example of a neofunctionalised CYP recruited from primary sterol metabolism. Two members of the CYP87D subfamily decorate the tetracyclic

• rare C24 and C25 hydroxylation [100]. Based on feeding assays in yeast it was found that CYP87D18 catalyses a two-step sequential C11 oxidation of cucurbitadienol (4) to 11-hydroxycucurbitadienol and 11-oxo-cucurbitadienol [101]. CYP87D18 also catalysed C11 hydroxylation of trans-24,25

• intermediate [42][43]. Members of the CYP93E subfamily are restricted to legumes and are involved in the biosynthesis of triterpenoid saponins. So far, nine CYP93E members were identified from different legume species [37][40]. All of these perform C24 hydroxylation of β-amyrin (6) to form 24-hydroxy-β-amyrin

Vicinal ketoesters – key intermediates in the total synthesis of natural products

• Marc Paul Beller and
• Ulrich Koert

Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129

• species to the α-ketoester 15 (Scheme 3) [6]. The ketoester 15 was synthesized by a chiral pool approach starting from (+)-3-carene derived cycloheptenone 13 [7][8] and aldehyde 12 (accessible from (R)-Roche ester [9]) via the γ-lactone 14. The ketoester moiety was established by an enolate hydroxylation

New azodyrecins identified by a genome mining-directed reactivity-based screening

• Atina Rizkiya Choirunnisa,
• Kuga Arima,
• Yo Abe,
• Noritaka Kagaya,
• Kei Kudo,
• Hikaru Suenaga,
• Junko Hashimoto,
• Manabu Fujie,
• Noriyuki Satoh,
• Kazuo Shin-ya,
• Kenichi Matsuda and
• Toshiyuki Wakimoto

Beilstein J. Org. Chem. 2022, 18, 1017–1025, doi:10.3762/bjoc.18.102

• distinct mechanism is employed in the biosynthesis of valanimycin, an aliphatic azoxy natural product. This involves the N-hydroxylation of isobutylamine, mediated by the flavin-dependent monooxygenase VlmH [15][16][17], and the following formation of O-(ʟ-seryl)-isobutylhydroxylamine by the tRNA-utilizing

Anti-inflammatory aromadendrane- and cadinane-type sesquiterpenoids from the South China Sea sponge Acanthella cavernosa

• Shou-Mao Shen,
• Qing Yang,
• Yi Zang,
• Jia Li,
• Xueting Liu and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2022, 18, 916–925, doi:10.3762/bjoc.18.91

• characterized the function of a P450 enzyme CYP76AH1 which was responsible for the formation of the aromatic ring of ferruginol in the biosynthesis pathway of tanshinones [34]. Hence, we proposed that the oxidation occurred on L to furnish the aromatic ring of calamenene (M) [29], followed by the hydroxylation

Structural basis for endoperoxide-forming oxygenases

• Takahiro Mori and
• Ikuro Abe

Beilstein J. Org. Chem. 2022, 18, 707–721, doi:10.3762/bjoc.18.71

• highly reactive Fe(IV)=O species and a succinate byproduct. This Fe(IV)=O abstracts a hydrogen atom from an aliphatic C–H bond of the substrate to generate a radical intermediate. When the enzyme catalyzes the hydroxylation reaction, the radical reacts with the Fe(III)-OH species to form a hydroxylated

• bridge and a C3' radical. Finally, the hydroxylation at C3' by the Fe(III)-OH species yields fumigatonoid A (path 2). At the stage of intermediate 3 in path 1, HAT from an active site residue or reductant to the C3' radical in intermediate 3 generates intermediate 4. Then, the hydroxylation at C3' forms

• enzymatically incorporated into fumigatonoid A, in which the oxygen atoms of the endoperoxide are derived from the O2 molecule and the C3' hydroxy group most likely originates from the solvent water. Although the oxygen atom in the hydroxylation reaction is usually from molecular oxygen, the oxygen atom in the

Four bioactive new steroids from the soft coral Lobophytum pauciflorum collected in South China Sea

• Di Zhang,
• Zhe Wang,
• Xiao Han,
• Xiao-Lei Li,
• Zhong-Yu Lu,
• Bei-Bei Dou,
• Wen-Ze Zhang,
• Xu-Li Tang,
• Ping-Lin Li and
• Guo-Qiang Li

Beilstein J. Org. Chem. 2022, 18, 374–380, doi:10.3762/bjoc.18.42

• in 2, which was in agreement with the 13C NMR spectrum and the molecular mass. The hydroxylation at C-5 was deduced from the HMBC correlations (Figure 2) from H3-19/H-4 to C-5. Moreover, the HMBC correlations found from H-4 to C-5/C-6, H-7 to C-6, and H3-18/H3-21 to C-17 confirmed the location of a

Tenacibactins K–M, cytotoxic siderophores from a coral-associated gliding bacterium of the genus Tenacibaculum

• Yasuhiro Igarashi,
• Yiwei Ge,
• Tao Zhou,
• Amit Raj Sharma,
• Enjuro Harunari,
• Naoya Oku and
• Agus Trianto

Beilstein J. Org. Chem. 2022, 18, 110–119, doi:10.3762/bjoc.18.12

• in 1. Among the five amide bonds, amide protons were present at N21 and N32, thereby leaving N15, N26, and N37 as the hydroxylation sites. This assignment was supported by the 13C NMR chemical shifts. Within each cadaverine moiety, the 13C chemical shifts for the methylenes adjacent to the N

• conducted [24] (Figure 4). In the negative ion mode, a precursor ion m/z 654 underwent sequential eliminations at every hydroxamate C–N bond, giving rise to ketene-terminated product ions at m/z 621 and 421, which supported the position of hydroxylation at N37 and N26 and chain lengths of each cadaverine

• produced by both Gram-positive and -negative bacteria and have a linear or macrocyclic backbone [23][30] composed of alternately arranged cadaverine or putrescine and succinic acid modules with N-hydroxylation at every other amide bond. Modifications of these core structures include internal hydroxylation

Efficient and regioselective synthesis of dihydroxy-substituted 2-aminocyclooctane-1-carboxylic acid and its bicyclic derivatives

• İlknur Polat,
• Selçuk Eşsiz,
• Uğur Bozkaya and
• Emine Salamci

Beilstein J. Org. Chem. 2022, 18, 77–85, doi:10.3762/bjoc.18.7

• diol 5 as a single isomer in 91% yield. We assume that the trans selectivity of hydroxylation in ester 4 is due to the steric effect of the presence of the bulky Boc group. The structure of 5 was determined with the help of 1D (1H and 13C) and 2D (COSY and HMQC) NMR spectra. The diagonal peak at 4.10

Unsaturated fatty acids and a prenylated tryptophan derivative from a rare actinomycete of the genus Couchioplanes

• Shun Saito,
• Kanji Indo,
• Naoya Oku,
• Hisayuki Komaki,
• Masashi Kawasaki and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2021, 17, 2939–2949, doi:10.3762/bjoc.17.203

• hydroxylation on the same carbon. This was supported by COSY correlations establishing the connectivity from H-5 to H-8, and completely the same HMBC and NOESY correlations for the remaining part to those observed for 1 and 2 (Figure 2). To address the absolute configuration, 4 was esterified with TMS

Recent advances in the tandem annulation of 1,3-enynes to functionalized pyridine and pyrrole derivatives

• Yi Liu,
• Puying Luo,
• Yang Fu,
• Tianxin Hao,
• Xuan Liu,
• Qiuping Ding and
• Yiyuan Peng

Beilstein J. Org. Chem. 2021, 17, 2462–2476, doi:10.3762/bjoc.17.163

• structural motifs to provide the functionalized pyridine and pyrrole derivatives. The functionalization reactions cover iodination, bromination, trifluoromethylation, azidation, carbonylation, arylation, alkylation, selenylation, sulfenylation, amidation, esterification, and hydroxylation. We also briefly

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• biologically active molecules (22 and 23) (Scheme 9A) [92]. Interestingly, the same conditions could be used for benzene hydroxylation to obtain phenol but were ineffective with benzene rings bearing either electron-donating or electron-withdrawing substituents. Notably, the catalyst could be reused five times

• reaction suggested it goes through a radical pathway. Similar to the oxidation of alkanes to give alcohols and carbonyl compounds, vanadium complexes have been reported to mediate the hydroxylation of arenes, including the obtaining of phenol from benzene. However, most mechanistic studies provided

• has a further effect improvement, however, it is even more challenging. In front of this, White and co-workers (2020) adopted a strategy consisting of an initial hydroxylation of the C(sp3)–H bonds adjacent to N- or O-heteroatoms followed by a methylation step (Scheme 19B and C) [137]. The

Designed whole-cell-catalysis-assisted synthesis of 9,11-secosterols

• Marek Kõllo,
• Marje Kasari,
• Villu Kasari,
• Tõnis Pehk,
• Ivar Järving,
• Margus Lopp,
• Arvi Jõers and
• Tõnis Kanger

Beilstein J. Org. Chem. 2021, 17, 581–588, doi:10.3762/bjoc.17.52

• chemistry and synthetic biology. Stereo- and regioselective hydroxylation at C9 (steroid numbering) is carried out using whole-cell biocatalysis, followed by the chemical cleavage of the C–C bond of the vicinal diol. The two-step method features mild reaction conditions and completely excludes the use of

• toxic oxidants. Keywords: chemoenzymatic synthesis; cortisol; hydroxylation; secosterol; whole-cell catalysis; Introduction Developments in the chemistry of steroids have stimulated extensive research interest in the exploration of new synthetic methods since the 1960s. Advances in synthetic biology

• approach to 9,11-secosterols is depicted in the retrosynthetic analysis in Scheme 1. There are two key steps in obtaining the skeleton of the secosterol. The first is (di)hydroxylation at C9 (C11), and the second is C9–C11-bond cleavage, which can be carried out by a well-developed chemical oxidation of

Biochemistry of fluoroprolines: the prospect of making fluorine a bioelement

• Vladimir Kubyshkin,
• Rebecca Davis and
• Nediljko Budisa

Beilstein J. Org. Chem. 2021, 17, 439–460, doi:10.3762/bjoc.17.40

• the “proline world” [25]. Pioneering experiments on the substitution of proline by fluorinated proline analogues in proteins date back to the 1960s [26][27][28]. These experiments were predominantly conducted to address the role of proline residue hydroxylation in collagen. The conformational rigidity

• modifications of proline residues are sparse. The most common among them is hydroxylation at position 4 by molecular oxygen, which is mediated by prolyl-4-hydroxylase [34]. This process has a remarkable relevance in the stabilization of collagen in higher organisms [35]. The experimental expression of the

Synthesis of legonmycins A and B, C(7a)-hydroxylated bacterial pyrrolizidines

• Wilfred J. M. Lewis,
• David M. Shaw and
• Jeremy Robertson

Beilstein J. Org. Chem. 2021, 17, 334–342, doi:10.3762/bjoc.17.31

• Baeyer–Villiger-type ring expansion, hydrolysis and decarboxylation, cyclization and dehydration, and finally hydroxylation at C(7a). Just one month later, Bode reported the identification of an unknown gene cluster in the symbiotic bacterium Xenorhabdus stockiae [23]. Cloning and expression of this

• might be thought to be theoretically possible [18][19], via a late-stage addition to an intact pyrrolizidine core. The molecules are isolated as their racemates and, by analogy to the clazamycins, even if the LgnC-mediated hydroxylation is fully stereoselective, the C(7a) center is expected to be

• legonmycins A and B, expecting to facilitate the C(7a) hydroxylation by exploiting the tendency to C(1–7a) enolization. Since Snider was unsuccessful in adapting his route to encompass the synthesis of jenamidines B and C [15], a successful route to the legonmycins would establish conditions for the synthesis

¹⁹F NMR as a tool in chemical biology

• Diana Gimenez,
• Aoife Phelan,
• Cormac D. Murphy and
• Steven L. Cobb

Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

• biosynthesis through hBBOX-catalysed GBBNF hydroxylation, both in vitro and in cell lysates [43]. Moreover, by using a competitive substrate for the enzyme, inhibition experiments could be directly employed to determine the IC50 values in the basis of fluoride release, and the extent of GBBNF turnover

Bifurcated synthesis of methylene-lactone- and methylene-lactam-fused spirolactams via electrophilic amide allylation of γ-phenylthio-functionalized γ-lactams

• Tetsuya Sengoku,
• Koki Makino,
• Ayumi Iijima,
• Toshiyasu Inuzuka and
• Hidemi Yoda

Beilstein J. Org. Chem. 2020, 16, 2769–2775, doi:10.3762/bjoc.16.227

• the construction of the spiro skeleton of 4 and 5. For this purpose, we initially attempted to transform 3b to 5a through the reaction sequence consisting of copper-mediated hydroxylation and acid-mediated lactonization based on our previous reports [10][11][14][21]. Substitution of the phenylthio

• initially treated the hydroxylactam prepared through CuBr-mediated hydroxylation of 3b with di-tert-butyl dicarbonate (Boc2O) in the presence of N,N-dimethyl-4-aminopyridine (DMAP), but a mixture of structurally unidentified products was formed. Meanwhile, when the reaction was carried out with 2.0

• transposed reaction sequence, N-Boc protection followed by hydroxylation (Scheme 2). N-Boc amides were readily obtained by treatment of 3b–o with Boc2O and DMAP, which were successively subjected to hydroxylation in the presence of CuBr. Expectedly, the desired lactonization occurred spontaneously under the