The phenyl vinyl ether–methanol complex: a model system for quantum chemistry benchmarking

• Dominic Bernhard,
• Fabian Dietrich,
• Mariyam Fatima,
• Cristóbal Pérez,
• Hannes C. Gottschalk,
• Axel Wuttke,
• Ricardo A. Mata,
• Martin A. Suhm,
• Melanie Schnell and
• Markus Gerhards

Beilstein J. Org. Chem. 2018, 14, 1642–1654, doi:10.3762/bjoc.14.140

• -docking motifs via the phenyl and vinyl moieties, with an additional less populated OH∙∙∙P(phenyl)-bound isomer detected only by microwave spectroscopy. The correct prediction of the energetic order of the isomers using quantum-chemical calculations turns out to be challenging and succeeds with a

• and the respective role of different intermolecular forces such as electrostatic, dispersion and induction forces is needed. Thus, experimental examination as well as the precise prediction of a preferred molecular docking site for different molecules is of crucial importance. Despite the remarkable

• prediction, LCCSD(T0)-F12/CBS[T:Q] calculations were carried out on top of the DFT-optimized geometries. The results are presented in Table 1, with and without zero-point vibrational energy (ZPVE) corrections. The coupled cluster results show a clear energetic preference for the OH–O and OH–O’ isomers

Phosphoramidite building blocks with protected nitroxides for the synthesis of spin-labeled DNA and RNA

• Timo Weinrich,
• Eva A. Jaumann,
• Ute M. Scheffer,
• Thomas F. Prisner and
• Michael W. Göbel

Beilstein J. Org. Chem. 2018, 14, 1563–1569, doi:10.3762/bjoc.14.133

• of the duplex while DNA 18mers 23c and 25c should also form the monomeric hairpin structures. This prediction can be verified by native gel electrophoresis (Supporting Information File 1, Figure S19). Electrophoresis also shows the 12mer RNA 26c to form mainly duplexes while high amounts of monomers

Steric “attraction”: not by dispersion alone

• Ganna Gryn’ova and
• Clémence Corminboeuf

Beilstein J. Org. Chem. 2018, 14, 1482–1490, doi:10.3762/bjoc.14.125

• recognized in aliphatic systems compared to London dispersion, and are therefore likely to have implications for the development of force fields and methods for crystal structure prediction. Keywords: charge penetration; dispersion; hydrocarbon; non-covalent interactions; steric attraction; Introduction In

• ) and other methods for the modeling and crystal structure prediction of hydrocarbons. In the case of π-conjugated complexes or assemblies, neglecting ECpen would flatten the potential energy surface dramatically. As shown in Figure 5, the penetration energy contribution strongly discriminates even

[3 + 2]-Cycloaddition reaction of sydnones with alkynes

• Veronika Hladíková,
• Jiří Váňa and
• Jiří Hanusek

Beilstein J. Org. Chem. 2018, 14, 1317–1348, doi:10.3762/bjoc.14.113

• (εHOMO = −8.6 eV and εLUMO = 0.3 eV) and predicted that the εLUMO for structurally related sydnones containing an electron-withdrawing –COO– motif should be even much lower suggesting a LUMO-controlled reaction (type III). Such a prediction seems to be correct for reaction of 4-(substituted phenyl

Are dispersion corrections accurate outside equilibrium? A case study on benzene

• Tim Gould,
• Erin R. Johnson and
• Sherif Abdulkader Tawfik

Beilstein J. Org. Chem. 2018, 14, 1181–1191, doi:10.3762/bjoc.14.99

• a dispersion correction. The latest variants of these approaches have been highly successful in predicting key properties of a wide range of molecules and materials, such as binding energies and molecular/material structures [4][5][15]. Methods are increasingly converging towards accurate prediction

• in prediction of the relative energies of the various local minima, U0(T), U0(P) and U0(SP), for the T, parallel (P) and slipped-parallel (SP) configurations, respectively. We thus show the energy differences, ΔU(P/SP) = U0(P/SP) − U0(T), between the local minima for the parallel and slipped-parallel

Local energy decomposition analysis of hydrogen-bonded dimers within a domain-based pair natural orbital coupled cluster study

• Ahmet Altun,
• Frank Neese and
• Giovanni Bistoni

Beilstein J. Org. Chem. 2018, 14, 919–929, doi:10.3762/bjoc.14.79

• literature is 2.912 ± 0.005 Å [68]. The re(O···O) distance calculated in this work at the RI-MP2/aug-cc-pVTZ level (2.908 Å) is very close to the CCSD(T) prediction. The effect of excitations beyond CCSD(T) has been shown to be negligible by means of CCSDTQ calculations [69]. For the HF dimer, the re(F···F

Terahertz spectroscopy of 2,4,6-trinitrotoluene molecular solids from first principles

• Ido Azuri,
• Anna Hirsch,
• Anthony M. Reilly,
• Alexandre Tkatchenko,
• Shai Kendler,
• Oded Hod and
• Leeor Kronik

Beilstein J. Org. Chem. 2018, 14, 381–388, doi:10.3762/bjoc.14.26

• former dominating below ca. 1.5 THz. We also find that intramolecular contributions primarily involve the nitro and methyl groups. Finally, we present a prediction for the terahertz spectrum of 1,3,5-trinitrobenzene, showing that a modest chemical change leads to a markedly different terahertz spectrum

• many-body dispersion terms for this system, allowing us to present a prediction for the terahertz spectrum of 1,3,5-TNB and showing that a modest chemical modification may result in a markedly different terahertz spectrum. Structures of: (a) orthorhombic TNT, (b) monoclinic TNT, (c) orthorhombic TNB

A permutation approach to the assignment of the configuration to diastereomeric tetrads by comparison of experimental and ab initio calculated differences in NMR data

• Przemysław J. Boratyński

Beilstein J. Org. Chem. 2017, 13, 2478–2485, doi:10.3762/bjoc.13.245

• configuration, while any swapped configuration should obtain an adequately lower score. The score gap between the best permutation and a second runner-up conveys the confidence in the assignment. The entire process begins with DFT prediction of isotropic shieldings by one of the established literature

Are boat transition states likely to occur in Cope rearrangements? A DFT study of the biogenesis of germacranes

• José Enrique Barquera-Lozada and
• Gabriel Cuevas

Beilstein J. Org. Chem. 2017, 13, 1969–1976, doi:10.3762/bjoc.13.192

• considered when a prediction of the configuration of an elemane is determined before a Cope rearrangement. Finally, we studied the role the γ-lactone ring plays in the transformation of germacranes into elemanes. Takeda et al. carried out a series of experiments, which proved that γ-lactone rings prevent the

Biomimetic molecular design tools that learn, evolve, and adapt

• David A Winkler

Beilstein J. Org. Chem. 2017, 13, 1288–1302, doi:10.3762/bjoc.13.125

• parameters, often by trial and error. It has been shown that Bayesian statistics can be used to find the optimal values of α and β to generate models with the best prediction performance. Detailed discussion is beyond the scope of this paper but are available elsewhere [21][22][23]. Deep learning Very

• targets [25]. Table 1 summarizes the prediction performance of deep neural networks (DNN) and (shallow) Bayesian regularized neural networks (BNN) for very large sets of organic drug-like molecules screened against fifteen protein targets [25]. Good predictions have low RMS errors (RMSE) or standard error

• of prediction (SEP) values. Table 1 clearly shows that, on average deep and shallow neural networks have broadly similar prediction performance. Conspicuously, the very significant advantages of regularized machine learning methods can be further enhanced when processes to identify the most important

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

• ) and outlet of the reactor [44]. In such cases, reaction engineering models are useful for the prediction of the temperature profile inside the reactor and to investigate if any hot spot is occurring inside the reactor. Reizman and Jensen demonstrated the use of the automated platform for estimating

How and why kinetics, thermodynamics, and chemistry induce the logic of biological evolution

• Addy Pross and
• Robert Pascal

Beilstein J. Org. Chem. 2017, 13, 665–674, doi:10.3762/bjoc.13.66

• particular path followed during the process. These complex systems can reach bifurcation points from which the system can evolve along different paths [10] rendering any prediction of evolutionary paths impossible. Evolutionary possibilities invariably depend on earlier choices. Additionally, the boundaries

Biosynthetic origin of butyrolactol A, an antifungal polyketide produced by a marine-derived Streptomyces

• Enjuro Harunari,
• Hisayuki Komaki and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2017, 13, 441–450, doi:10.3762/bjoc.13.47

• conclusion is consistent with our previous bioinformatic prediction that suggested the presence of genes necessary for the supply of hydroxymalonyl-ACP adjacent to the PKS gene cluster of the butyrolactol biosynthesis. The results obtained in this study provide useful information for further biosynthetic

Self-optimisation and model-based design of experiments for developing a C–H activation flow process

• Alexander Echtermeyer,
• Yehia Amar,
• Jacek Zakrzewski and
• Alexei Lapkin

Beilstein J. Org. Chem. 2017, 13, 150–163, doi:10.3762/bjoc.13.18

• a weak influence of k1,ref and Ea,1 on the model output, i.e., this cannot be estimated with precision. However, this was not necessary, as the parameters do not change the model prediction. Therefore, also the very large 95% confidence interval can be explained. For all other parameters, the

• experiments were conducted, four for each of the two parameter types (shown in Supporting Information File 1). Despite the remaining uncertainty in some of the parameters, indicated by the large 95% confidence intervals, the quality of model prediction was considered to be good-enough for the purpose of in

• convergence, since it is exploring the reaction space to develop a better statistical model. The physical experiments performed thereafter confirmed prediction of the successfully attained target values. Hence, only the successful predicted experimental conditions Xopt were tested in real experiments, which

A new class of organogelators based on triphenylmethyl derivatives of primary alcohols: hydrophobic interactions alone can mediate gelation

• Wangkhem P. Singh and
• Rajkumar S. Singh

Beilstein J. Org. Chem. 2017, 13, 138–149, doi:10.3762/bjoc.13.17

• prediction of the gel forming ability of a given molecule is still a formidable challenge, if not altogether impossible [7][8]. Often, the discovery of new gelators relies on an empirical approach wherein structural components capable of forming non-covalent interactions are incorporated into different

Synthesis of spiro[isoindole-1,5’-isoxazolidin]-3(2H)-ones as potential inhibitors of the MDM2-p53 interaction

• Salvatore V. Giofrè,
• Santa Cirmi,
• Raffaella Mancuso,
• Francesco Nicolò,
• Giuseppe Lanza,
• Laura Legnani,
• Agata Campisi,
• Maria A. Chiacchio,
• Michele Navarra,
• Bartolo Gabriele and
• Roberto Romeo

Beilstein J. Org. Chem. 2016, 12, 2793–2807, doi:10.3762/bjoc.12.278

• -isoxazolidin isoindolinone scaffold in the receptor/ligand complex was difficult because of the open and lipophilic nature of the p53 binding site on MDM2. Therefore, prediction of the possible binding mode was based on two energy types, i.e., the lowest binding energy of the largest cluster and the

Computational methods in drug discovery

• Sumudu P. Leelananda and
• Steffen Lindert

Beilstein J. Org. Chem. 2016, 12, 2694–2718, doi:10.3762/bjoc.12.267

• methods are discussed. Advances in virtual high-throughput screening, protein structure prediction methods, protein–ligand docking, pharmacophore modeling and QSAR techniques are reviewed. Keywords: ADME; computer-aided drug design; docking; free energy; high-throughput screening; LBDD; lead optimization

• structure prediction tools that are routinely used in structure-based drug discovery, widely used docking algorithms, scoring functions, virtual high-throughput screening, lead optimization and methods of assessment of ADME properties of drugs. Review Structure-based drug discovery (SBDD) If the three

• where the target structure is not possible to be determined by experimental methods, computational methods become useful. Determining structures from sequences using computational methods is a powerful tool that can bridge the sequence–structure gap. Importance of protein structure prediction methods

A new paradigm for designing ring construction strategies for green organic synthesis: implications for the discovery of multicomponent reactions to build molecules containing a single ring

• John Andraos

Beilstein J. Org. Chem. 2016, 12, 2420–2442, doi:10.3762/bjoc.12.236

• verify the prediction is therefore gratifying and demonstrates that the method is indeed a useful tool in discovering new ways to assemble known rings. Following from the preceding discussion about synthesizing odd-membered rings, the Glorius, Shen, and Stonehouse examples involve redox chemistries in

Methylenelactide: vinyl polymerization and spatial reactivity effects

• Judita Britner and
• Helmut Ritter

Beilstein J. Org. Chem. 2016, 12, 2378–2389, doi:10.3762/bjoc.12.232

• -diphenyl-2-picrylhydrazyl radical (DPPH) the spontaneous radical formation could also be observed by the naked eye. Furthermore, the copolymerization parameters of MLA with styrene and MMA were obtained and the Q and e values calculated. The latter allows the prediction of the copolymerization process with

Evidence for an iterative module in chain elongation on the azalomycin polyketide synthase

• Hui Hong,
• Yuhui Sun,
• Yongjun Zhou,
• Emily Stephens,
• Markiyan Samborskyy and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2016, 12, 2164–2172, doi:10.3762/bjoc.12.206

• in a cis-AT PKS is well-precedented [45][46][47]. The bioinformatic prediction of the configuration at each of the seven asymmetric centres was also in accord with the configuration of authentic ebelactone confirmed by total synthesis [48] (Scheme 1). The essentially complete congruence between

• prediction and the known ebelactone structure means, unless the clone sequenced here under the reference number ATCC 31860 is different from that previously analysed under this same ATCC number [37], that the previous proposal of iteration may have been based on mis-assembly of the DNA sequence due to the

• optional mono- or dimethylation of azalomycin at the guanidino group, and the attachment of a malonyl sidechain at either C-23 or C-25 (Figure 1). No methyltransferase or discrete malonyltransferase is encoded within the respective BGCs. Comparison of the bioinformatic prediction for either marginolactone

Stereo- and regioselectivity of the hetero-Diels–Alder reaction of nitroso derivatives with conjugated dienes

• Lucie Brulíková,
• Aidan Harrison,
• Marvin J. Miller and
• Jan Hlaváč

Beilstein J. Org. Chem. 2016, 12, 1949–1980, doi:10.3762/bjoc.12.184

• -lactams 63 (Scheme 16) [95], which is in accordance with the general prediction. The exclusive regioselectivity of this reaction is due to steric effects. Similar conclusions result from the reaction of 1,3-butadienes 65 with various nitroso heterodienophiles 66, giving proximal isomer 67 (Scheme 17) [85

Rearrangements of organic peroxides and related processes

• Ivan A. Yaremenko,
• Vera A. Vil’,
• Dmitry V. Demchuk and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2016, 12, 1647–1748, doi:10.3762/bjoc.12.162

The EIMS fragmentation mechanisms of the sesquiterpenes corvol ethers A and B, epi-cubebol and isodauc-8-en-11-ol

• Patrick Rabe and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 1380–1394, doi:10.3762/bjoc.12.132

• , contain several methyl groups, and possibly one or more olefinic double bonds, an alcohol or ether function. Their much higher structural complexity compared to, e.g., FAMEs and monoterpenes renders a prediction of the fragmentation behaviour of unknown compounds in mass spectrometry and consequently the

Modular synthesis of the pyrimidine core of the manzacidins by divergent Tsuji–Trost coupling

• Sebastian Bretzke,
• Stephan Scheeff,
• Felicitas Vollmeyer,
• Friederike Eberhagen,
• Frank Rominger and
• Dirk Menche

Beilstein J. Org. Chem. 2016, 12, 1111–1121, doi:10.3762/bjoc.12.107

• dimer in the crystal lattice, which is stabilized by two hydrogen bonds between the urea oxygen atoms and the tosyl-protected nitrogens. This also unambiguously confirms the absolute configuration of 39 and corroborates our prediction of the asymmetric adduct 31. We then attempted the installation of

Is conformation a fundamental descriptor in QSAR? A case for halogenated anesthetics

• Maria C. Guimarães,
• Mariene H. Duarte,
• Josué M. Silla and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2016, 12, 760–768, doi:10.3762/bjoc.12.76

• stable minima (ruled by intramolecular interactions) do not necessarily coincide with the bioconformation (ruled by enzyme induced fit). Consequently, a QSAR model based on two-dimensional chemical structures was built and exhibited satisfactory modeling/prediction capability and interpretability, then

• structure indeed encodes biochemical properties and that MIA descriptors can be useful to anticipating pMAC of prospective congeneric drug-like candidates. MIA-QSAR and 3D-QSAR have already been compared to each other in a variety of studies and the prediction results are similar [10][24][25][26], but the

• available in the Dragon software. Thus, a major goal in QSAR is to determine and interpret the chemical motifs/properties responsible for the observed biological effects. We have checked that even the simple log P model yields good prediction ability upon selection of test set compounds using the Kennard