Kinetics of enzyme-catalysed desymmetrisation of prochiral substrates: product enantiomeric excess is not always constant

• Peter J. Halling

Beilstein J. Org. Chem. 2021, 17, 873–884, doi:10.3762/bjoc.17.73

• prochiral diol esters. The enzyme reacts enantiospecifically with the ester to release a chiral product, leaving the acyl group attached to the active site. In a second stage the achiral acyl group undergoes hydrolysis by water. In the desymmetrisation of diols (and diacids, below) kinetic amplification can

Valorisation of plastic waste via metal-catalysed depolymerisation

• Francesca Liguori,
• Carmen Moreno-Marrodán and
• Pierluigi Barbaro

Beilstein J. Org. Chem. 2021, 17, 589–621, doi:10.3762/bjoc.17.53

• 3), whilst a high surface area around 150 m2⋅g−1 was proposed to increase the number of exposed sites [214]. Zn@TiNT afforded BHET in 87% yield at 196 °C reaction temperature. TiNT have received significant general interest in heterogeneous catalysis because of the better active-site-accessibility

Synthetic strategies of phosphonodepsipeptides

• Jiaxi Xu

Beilstein J. Org. Chem. 2021, 17, 461–484, doi:10.3762/bjoc.17.41

• derivatives 85 were obtained. The phosphonate moiety in these analogues represented an important new lead in the development of folylpolyglutamate synthetase inhibitors (Scheme 14) [29]. γ-Phosphonodepsipeptides were also designed and synthesized as potent inhibitors and active site probes of γ-glutamyl

• the macrocyclic phosphonodepsipeptide backbone closely approximated that of the lead inhibitor and showed the low-energy conformation accommodated in the active site of penicillopepsin without significant distortion (Scheme 34) [54]. Synthesis of γ-phosphonodepsipeptides The acyloxyalkyl esters 194

Vicinal difluorination as a C=C surrogate: an analog of piperine with enhanced solubility, photostability, and acetylcholinesterase inhibitory activity

• Yuvixza Lizarme-Salas,
• Alexandra Daryl Ariawan,
• Ranjala Ratnayake,
• Hendrik Luesch,
• Angela Finch and
• Luke Hunter

Beilstein J. Org. Chem. 2020, 16, 2663–2670, doi:10.3762/bjoc.16.216

• relative activities of 1 vs 2 in the AChE vs BACE-1 assays. One possibility is that analog 2 is induced to adopt the “correct” conformation when binding to both targets (i.e., 2f, Figure 2), and this structure fits well within the AChE active site but poorly within the BACE-1 active site, perhaps due to

• unfavourable interactions of the fluorine substituents of 2 with BACE-1 active site residues. A second possibility is that 2 adopts an “incorrect” conformation upon binding to both targets (e.g., 2a, Figure 2), and this novel molecular shape is readily accommodated by AChE [35] but not by BACE-1, perhaps due

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

Access to highly substituted oxazoles by the reaction of α-azidochalcone with potassium thiocyanate

• Mysore Bhyrappa Harisha,
• Pandi Dhanalakshmi,
• Rajendran Suresh,
• Raju Ranjith Kumar and
• Shanmugam Muthusubramanian

Beilstein J. Org. Chem. 2020, 16, 2108–2118, doi:10.3762/bjoc.16.178

• short time frame. The current method involves a broad substrate scope, excellent functional group tolerance and leaves the active site for further synthetic transformation. The overall strategy allows the generation of new C–N and C–O bonds in one-pot. Experimental General considerations: The melting

Automated high-content imaging for cellular uptake, from the Schmuck cation to the latest cyclic oligochalcogenides

• Rémi Martinent,
• Javier López-Andarias,
• Dimitri Moreau,
• Yangyang Cheng,
• Naomi Sakai and
• Stefan Matile

Beilstein J. Org. Chem. 2020, 16, 2007–2016, doi:10.3762/bjoc.16.167

• react with carboxylate in the active site to produce an ester, and thus covalently attach the transporter to the fusion protein (Figure 6b). The subsequently added reporter 26 passively diffuses into the cells and labels all free HaloTags. The fluorescence signal from the HaloTag reporter 26 is then

Synthesis, docking study and biological evaluation of ᴅ-fructofuranosyl and ᴅ-tagatofuranosyl sulfones as potential inhibitors of the mycobacterial galactan synthesis targeting the galactofuranosyltransferase GlfT2

• Marek Baráth,
• Jana Jakubčinová,
• Zuzana Konyariková,
• Stanislav Kozmon,
• Katarína Mikušová and
• Maroš Bella

Beilstein J. Org. Chem. 2020, 16, 1853–1862, doi:10.3762/bjoc.16.152

• synthesized. We performed docking studies of these compounds into the active site of GlfT2 by computational chemistry methods. Although the docking study showed good binding affinities of the prepared compounds towards the GlfT2 active site, their biological evaluation revealed a very poor effect on the

• substrate of mycobacterial galactofuranosyltransferase GlfT2 in the transition state, we evaluated these compounds by computational methods, as well as in an enzyme assay for the possible inhibition of the mycobacterial galactan biosynthesis. Our data show that despite favorable docking scores to the active

• site of GlfT2, none of these compounds serve as efficient inhibitors of the enzymes involved in the mycobacterial galactan biosynthesis. Keywords: GlfT2; molecular modeling; mycobacterium tuberculosis; synthesis; transition state inhibitors; Introduction Tuberculosis (TB) is one of the most prevalent

The charge-assisted hydrogen-bonded organic framework (CAHOF) self-assembled from the conjugated acid of tetrakis(4-aminophenyl)methane and 2,6-naphthalenedisulfonate as a new class of recyclable Brønsted acid catalysts

• Svetlana A. Kuznetsova,
• Alexander S. Gak,
• Yulia V. Nelyubina,
• Vladimir A. Larionov,
• Han Li,
• Michael North,
• Vladimir P. Zhereb,
• Alexander F. Smol'yakov,
• Artem O. Dmitrienko,
• Michael G. Medvedev,
• Igor S. Gerasimov,
• Ashot S. Saghyan and
• Yuri N. Belokon

Beilstein J. Org. Chem. 2020, 16, 1124–1134, doi:10.3762/bjoc.16.99

• ][31], gas separation and absorption [28][29], enzyme encapsulation [36], and even asymmetric synthesis (albeit with a framework that contained a transition metal ion) [37]. However, for the HOF and CAHOF catalysts to have a similar appeal to other regular active site distribution materials, such as

Copper catalysis with redox-active ligands

• Agnideep Das,
• Yufeng Ren,
• Cheriehan Hessin and
• Marine Desage-El Murr

Beilstein J. Org. Chem. 2020, 16, 858–870, doi:10.3762/bjoc.16.77

• metalloenzymatic active site was not characterized in detail, it might bear some resemblance to the original biological active site. Building on their previously discussed phenol oxidation methodology (Scheme 5 and Scheme 6), Lumb and co-workers have targeted subsequent C–N bond formation to access oxindoles [34

Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition

• Sivaraman Balasubramaniam,
• Sajith Vijayan,
• Liam V. Goldman,
• Xavier A. May,
• Kyra Dodson,
• Sweta Adhikari,
• Fatima Rivas,
• Davita L. Watkins and
• Shana V. Stoddard

Beilstein J. Org. Chem. 2020, 16, 628–637, doi:10.3762/bjoc.16.59

• that of panobinostat [12]. In developing such analogues, the hydroxamate tails and indole capping moiety were maintained as both are essential to binding at the active site of HDAC2 and HDAC8. Results suggested that TOI1, TOI2, and TOI4 [12] would be inhibitors exhibiting similar potency as that of

• the HDAC8 receptor. (a) Overlay of all compounds investigated in this study in the HDAC8 active site: panobinostat (green), TOI1 (purple), TOI2 (yellow) and TOI4 (grey); (b) TOI3-rev (pink) docking pose in active site; (c) TOI4 (grey) docking pose in the active site. General building blocks for the

Synthesis and herbicidal activities of aryloxyacetic acid derivatives as HPPD inhibitors

• Man-Man Wang,
• Hao Huang,
• Lei Shu,
• Jian-Min Liu,
• Jian-Qiu Zhang,
• Yi-Le Yan and
• Da-Yong Zhang

Beilstein J. Org. Chem. 2020, 16, 233–247, doi:10.3762/bjoc.16.25

• -dicarbonyl bidentate chelation with the active center metal, and 2) through favorable sandwich π–π stacking interactions between aromatic rings and the Phe360, Phe403 residues of the active site. Thus, 1,3-dicarbonyl and aromatic moieties are indispensable pharmacophores for potent HPPD-inhibiting compounds

• revealed the bioactive binding site positions of potential inhibitors within the targets active site. We modeled the interactions of I12 and II4 (C) with AtHPPD (PDB ID: 1TFZ). The structure of AtHPPD was taken from the PDB data bank. All molecular modeling studies were carried out as previously reported

• [10][19][32][33][34]. The results show that two main interactions exist between I12 and the AtHPPD active site (Figure 4), as was observed for mesotrione; the 1,3-dicarbonyl unit is chelated to the iron ion, and the aromatic ring moiety formed π–π interactions with Phe403 and Phe360. Electron

Understanding the role of active site residues in CotB2 catalysis using a cluster model

• Keren Raz,
• Ronja Driller,
• Thomas Brück,
• Bernhard Loll and
• Dan T. Major

Beilstein J. Org. Chem. 2020, 16, 50–59, doi:10.3762/bjoc.16.7

• active site cluster model. The results revealed the significant effect of the active site residues on the relative electronic energy of the intermediates and transition state structures with respect to gas phase data. A detailed understanding of the role of the enzyme environment on the CotB2 reaction

• cascade can provide important information towards a biosynthetic strategy for cyclooctatin and the biomanufacturing of related terpene structures. Keywords: active site; CotB2 cyclase; diterpene; mechanism; quantum mechanics; Introduction Enzymes catalyze numerous complex biochemical reactions in

• relevant, i.e., that have a ligand bound in a reactive configuration and have a fully closed active site. Recently, a crystal structure of the CotB2 enzyme that met these criteria was published [42]. In the current work, we describe the crucial role of the amino acids in the active site on the reaction

Synthesis of C-glycosyl phosphonate derivatives of 4-amino-4-deoxy-α-ʟ-arabinose

• Lukáš Kerner and
• Paul Kosma

Beilstein J. Org. Chem. 2020, 16, 9–14, doi:10.3762/bjoc.16.2

• have frequently been exploited as potential inhibitors for glycosyl transferases since the carbon–phosphorus bond is not hydrolyzed in the active site of glycosyl transferases [10][11][12][13]. Herein, we report on the synthesis of α-anomeric C-arabinosyl methylphosphonate ester derivatives as model

Bacterial terpene biosynthesis: challenges and opportunities for pathway engineering

• Eric J. N. Helfrich,
• Geng-Min Lin,
• Christopher A. Voigt and
• Jon Clardy

Beilstein J. Org. Chem. 2019, 15, 2889–2906, doi:10.3762/bjoc.15.283

• . Indeed, besides the influence on kinetic properties by changing the conserved motifs, many bacterial TCs are able to produce novel skeletons through mutations of other active-site residues. This could result in either the arrest of catalytic intermediates or the creation of new trajectories to quench the

• cationic species. For instance, remodeling the hydrophobic pocket of the active site by single-point mutation, epi-isozizaene (33) synthase was engineered to produce various linear, monocyclic, bicyclic, and tricyclic terpene skeletons (Figure 9b) [119][120][121]. Another prominent example is cyclooctat-9

• -en-7-ol (23, Figure 7a) synthase, for which the active-site residues responsible for cationic intermediate stabilization were identified through analysis of the crystal structure [122] and structural modeling [123]. Mutations of the identified residues were shown to alter product profiles and yielded

Synthetic terpenoids in the world of fragrances: Iso E Super^® is the showcase

• Alexey Stepanyuk and
• Andreas Kirschning

Beilstein J. Org. Chem. 2019, 15, 2590–2602, doi:10.3762/bjoc.15.252

• -protein receptors consisting of seven intermembrane domains [28]. The quaternary structure including the membrane set up the active site. Approximately 370 different G-type proteins are known, that are linked with the odour perception. Because molecules can bind to an array of olfactory receptors

Current understanding and biotechnological application of the bacterial diterpene synthase CotB2

• Ronja Driller,
• Daniel Garbe,
• Norbert Mehlmer,
• Monika Fuchs,
• Keren Raz,
• Dan Thomas Major,
• Thomas Brück and
• Bernhard Loll

Beilstein J. Org. Chem. 2019, 15, 2355–2368, doi:10.3762/bjoc.15.228

• segments and additional five short α-helices (α1 to α5; (Figure 2A and B)). CotB2 resembles the classical α-helical fold of TPSs [18] with significant differences in its primary sequence compared to other TPSs. The core α-helices surround a large, deep cleft, which forms the active site (Figure 2A and B

• active site. Moreover, the two missing Mg2+ ions prevent helix D, accommodating the Asp-rich motif, from shifting towards the active site (Figure 3). Consequently, the active site remains partially open and the C-terminus cannot fold over the active site, making a proper substrate positioning and

• , such as FGGDP, have been used for the crystallization of other TPSs and have been shown to stick to the active site without undergoing cyclization, trapping the enzyme in a closed state [52][53]. Comparing the overall structure of CotB2wt·Mg2+3·F-Dola to the open conformation of CotB2 reveals major

Harnessing enzyme plasticity for the synthesis of oxygenated sesquiterpenoids

• Melodi Demiray,
• David J. Miller and
• Rudolf K. Allemann

Beilstein J. Org. Chem. 2019, 15, 2184–2190, doi:10.3762/bjoc.15.215

• properties and are used to treat epilepsy [27][28]. This array of important compounds shows the potential of generating novel sesquiterpenoids with desirable bio-properties. ADS is a high fidelity sesquiterpene synthase that produces almost exclusively a single product. Its active site plasticity

• bisabolyl cation and the amorphane skeleton. Rather the active site conformations of 11 and cation 22 appear to enable a 1,11-cyclisation to 23. A subsequent [1,3]-hydride shift to cation 24 and deprotonation from C15 lead to 8-methoxy-γ-humulene (20, Scheme 3A). Alternatively, the nucleophilic 8-methoxy

Inherent atomic mobility changes in carbocation intermediates during the sesterterpene cyclization cascade

• Hajime Sato,
• Takaaki Mitsuhashi,
• Mami Yamazaki,
• Ikuro Abe and
• Masanobu Uchiyama

Beilstein J. Org. Chem. 2019, 15, 1890–1897, doi:10.3762/bjoc.15.184

• terpene cyclase active site [3][5][6]. Although many terpene cyclases are known [6][7][8][9][10], it is still challenging to identify the precise initial conformation of the oligoprenyl diphosphate substrate in the active site, even by X-ray crystal structure determination. This is because the substrate

• can sometimes bind to the active site in an unreactive conformation [11]. Recently, Siegel and Tantillo reported an innovative method for predicting the docking mode of carbocation intermediates in terpene cyclase [12][13], based on QM calculation and computational docking with the Rosetta protein

Molecular basis for the plasticity of aromatic prenyltransferases in hapalindole biosynthesis

• Takayoshi Awakawa and
• Ikuro Abe

Beilstein J. Org. Chem. 2019, 15, 1545–1551, doi:10.3762/bjoc.15.157

• distance from C-1 of GSPP to C-3 of 1 (Figure 4B, c: 4.6 Å) became closer than that to C-2 of 1 (Figure 4B, d: 5.4 Å). Importantly, an additional Mg2+ ion (Figure 3C, Mg-2) appeared in the active site close to the isonitrile of 1, stabilized by the hydrogen bonding with D172, T173, G208, and E209 (Figure

•  4B). The AmbP1 E209A and E209L mutants completely lost their activities, implying that E209 plays an important role in forming the catalytic cavity as well as binding the Mg2+ ion. The active site structure depicted by the surface mode indicated that E209 is important to form the wall of the cavity

• PTases that utilize a Mg2+ ion to reorganise the active site cavity to control the regiospecificity of the prenylation reaction. X-ray crystal structure analysis of AmbP3 The crystal structures of AmbP3 complexed with DMSPP/hapalindole U (HU structure) and A (HA structure) were each solved at 2.00 Å [14

Synthesis and biological evaluation of truncated derivatives of abyssomicin C as antibacterial agents

• Leticia Monjas,
• Peter Fodran,
• Johanna Kollback,
• Carlo Cassani,
• Thomas Olsson,
• Maja Genheden,
• D. G. Joakim Larsson and
• Carl-Johan Wallentin

Beilstein J. Org. Chem. 2019, 15, 1468–1474, doi:10.3762/bjoc.15.147

• cysteine residue in the immediate proximity to the active site and the enone moiety of AbC. The PABA pathway is essential in bacteria but absent in humans, making AbC a promising compound for further development towards an antibiotic drug candidate. Because of its intriguing structure and antibacterial

• docking of known and proposed ligands. The crystal structure contains a tryptophan molecule in the active site. Restrained molecular dynamics [20][21] was employed to position the active site cysteine (Cys-263) in a position that would allow covalent binding of the ligands in the active site. The

• , which suggests a suitable level of structural truncation of compound 2. Further docking studies, using covalent docking, also showed that both atrop-O-benzyl-desmethyl-abyssomicin C and 2 can bind to the active site cysteine via a Michael addition to the α,β-unsaturated ketone, still maintaining the

Mechanistic investigations on multiproduct β-himachalene synthase from Cryptosporangium arvum

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2019, 15, 1008–1019, doi:10.3762/bjoc.15.99

• enantiomerically pure form (ee values were varying between 64% and 88%, as judged by integration), which may point to different possible binding and folding modes within the TS’s active site for GPP involving both enantiomers of linalyl diphosphate (LPP, Scheme 1) and the terpinyl cation (A). Other TSs producing

• or multiple compounds, are terpene synthases (TSs). These enzymes are able to guide complex cascade reactions from structurally simple oligoprenyl diphosphates to often complex, polycyclic products [4][5][6] circumventing the low selectivity observed for carbocationic reactions by a defined active

• -site architecture. Although these enzymes are mostly highlighted for their great product selectivity, TSs producing only one compound are by far not the general case. Mostly, the main product is accompanied by several side products. Prominent examples are the TS identified from the plant Medicago

Stereochemical investigations on the biosynthesis of achiral (Z)-γ-bisabolene in Cryptosporangium arvum

• Jan Rinkel and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2019, 15, 789–794, doi:10.3762/bjoc.15.75

• of the C-2,C-3-double bond by the enzyme’s active site (e.g., on top of it, Figure 4A). This migration of OPP to C-3 results in a reorganisation of the resulting structure to a cisoid conformation for the follow up 1,6-ring closure. To explain the astonishing selectivity between the two NPP

• enantiomers by BbS, different NPP conformations inside the chiral environment of the active site in BbS have to be assumed (Figure 4B + 4C). The architecture of the active site may stay the same in both cases, so a fixed OPP moiety with binding by the trinuclear Mg2+ cluster and a comparable folding of the

• isoprenoid chain in both cases is reasonable. Therefore, the two smallest substituents at the stereocentre formally change their places for the two enantiomers of NPP, representing a minor structural change of the substrate that can be tolerated in the active site. While the binding of (R)-NPP leads to a

Synthesis of polydicyclopentadiene using the Cp₂TiCl₂/Et₂AlCl catalytic system and thin-layer oxidation of the polymer in air

• Zhargolma B. Bazarova,
• Ludmila S. Soroka,
• Alex A. Lyapkov,
• Мekhman S. Yusubov and
• Francis Verpoort

Beilstein J. Org. Chem. 2019, 15, 733–745, doi:10.3762/bjoc.15.69

• bond from the norbornene ring of dicyclopentadiene in the double bond reaction, as a result of the rearrangement of the active site, structures of both exo- and endo-polydicyclopentadiene (A and B, see Scheme 2) can be formed [1][10]. At the same time, with participation in the reaction of the

Synthesis and SAR of the antistaphylococcal natural product nematophin from Xenorhabdus nematophila

• Frank Wesche,
• Hélène Adihou,
• Thomas A. Wichelhaus and
• Helge B. Bode

Beilstein J. Org. Chem. 2019, 15, 535–541, doi:10.3762/bjoc.15.47

• described as a potent inhibitor of various proteases, in particular trypsin and thrombin [17][18][19]. Hereby, the α-keto amide covalently binds to the serine oxygen in the active site under formation of a stable tetrahedral hemiketal. Furthermore, substitution of the indole hydrogen by alkyl, aryl or