4C1 Conformation Research Articles

Synthesis of Flake-shaped [3]Cyclo-4,6-dibenzofuranylene

The cyclic trimer of dibenzofuran linked at the 4,6-positions, named [3]cyclo-4,6-dibenzofuranylene, was synthesized by Ni(0)-mediated reductive coupling of 4,6-dibromodibenzofuran. DFT calculation indicated that the flake-shaped C2 symmetric structure is the most stable conformer and the propeller-shaped D3 symmetric structure is the minor conformer with a higher energy (+19.1 kcal mol−1). The calculated inversion energy of the C2 conformer through a Cs symmetric transition state was +4.1 kcal mol−1, showing rapid fluctuation, which is consistent with the observation of only one set of 1H NMR signals of dibenzofuran of [3]cyclo-4,6-dibenzofuranylene.

Conformational analysis of some 4′-substituted 2-(phenylselanyl)- 2-(methoxy)- acetophenones

A conformational study of some 4′-substituited 2-(phenylselanyl)-2-(methoxy)-acetophenones (OMe 1, H 2, and Cl 3) was performed using IR carbonyl stretching band analysis supported by NBO and PCM calculations at the B3LYP/6-31 + G (d,p) level for 1–3 and using X-ray diffraction for 1 and 2. The computational results indicated the existence of three stable conformers for the series (c2, c3, and c1 in order of decreasing stability), whose relative abundance changes with solvent permittivity. The experimental trend observed for the components of the triplet carbonyl band in all solvents matches well with computational results and thus allows for their assignment to distinct conformers. The relative population of the c1 conformer increases in more polar solvents, becoming the most stable conformer in the highest permittivity solvent, acetonitrile, as indicated by IR spectra and PCM calculations. These findings are related to the quasi parallel geometry assumed by the Cδ+ = Oδ− and Cδ+-Oδ- dipoles, which favour stronger solvation. NBO analysis shows that the sum of the energies (ΣE) of the relevant orbital interactions stabilizes the c3 conformer of 1–3 slightly, likely due to the minor contribution of the LPO5→σ*C3Se10 interaction. However, only the c1 conformer is significantly destabilized by the Oδ−(1)CO … Oδ−(5)OMe short contact electrostatic repulsion, which is also responsible for its highest νCO frequency. In addition, the LPO5→ σ*C2C3 orbital interaction accounts for the lowest νCO frequency of c3 conformer. X-ray single crystal analysis of compounds 1 and 2 indicates that in the solid state they assume the least stable c1 conformation found in the gas phase. Molecules of these compounds are stabilized in the crystal through a series of CH⋯O and CH … π intermolecular interactions.

The influence of solvent on conformational properties of peptides with Aib residue\u2014a DFT study

The conformational propensities of the Aib residue on the example of two model peptides Ac-Aib-NHMe (1) and Ac-Aib-NMe2 (2), were studied by B3LYP and M06-2X functionals, in the gas phase and in the polar solvents. To verify the reliability of selected functionals, we also performed MP2 calculations for the tested molecules in vacuum. Polarizable continuum models (PCM and SMD) were used to estimate the solvent effect. Ramachandran maps were calculated to find all energy minima. Noncovalent intramolecular interactions due to hydrogen-bonds and dipole attractions between carbonyl groups are responsible for the relative stabilities of the conformers. In order to verify the theoretical results, the available conformations of similar X-ray structures from the Cambridge Crystallographic Data Center (CCDC) were analyzed. The results of the calculations show that both derivatives with the Aib residue in the gas phase prefer structures stabilized by intramolecular N–H⋯O hydrogen bonds, i.e., C5 and C7 conformations, while polar solvent promotes helical conformation with φ, ψ values equal to +/−60°, +/−40°. In addition, in the case of molecule 2, the helical conformation is the only one available in the polar environment. This result is fully consistent with the X-ray data.Graphical abstractEffect of solvent on the Ramachandran maps of the model peptides with Aib residue

Simulated Raman spectra of four tetraphenylbutadiene polymorphs

AbstractWe report a combined experimental and theoretical investigation on the Raman spectra of the polymorphs α, β, γ, and δ of 1,1,4,4‐tetraphenyl‐1,3‐butadiene (TPB), in the region of the intramolecular modes. The interpretation of the polarized spectra is supported by ab‐initio calculations for the isolated molecules and by lattice dynamics calculations for the crystals. The calculations reproduce the peculiar, and surprisingly large, differences among the spectra of the various polymorphs. The phenyl groups of 1,1,4,4‐tetraphenyl‐1,3‐butadiene may arrange themselves around the butadiene skeleton in 2 stable conformers, which have either inversion (Ci) or 2‐fold (C2) symmetry and therefore exhibit intramolecular vibrations with quite different Raman selection rules and spectra. The compound forms 4 crystalline polymorphs (α, β, γ, and δ) with different combinations of Ci and C2 conformers, and correspondingly different intramolecular spectra. The theoretical calculations provide a quantitative analysis of the various spectra.

1,3-syn-Diaxial Repulsion of Typical Protecting Groups Used in Carbohydrate Chemistry in 3-O-Substituted Derivatives of Isopropyl d-Idopyranosides.

The strength of 1,3-syn-diaxial repulsion was evaluated for main types of protecting groups (alkyl, silyl, and acyl) usually used in carbohydrate chemistry. As molecular probes for this study, derivatives of isopropyl 2-O-benzyl-4,6-O-benzylidene-α-d-idopyranoside bearing allyl, acetyl, and tert-butyldiphenylsilyl (TBDPS) protecting groups at O-3 were prepared from p-methoxyphenyl d-galactopyranoside. The equilibrium between OS2 and 4C1 conformations in these compounds was investigated using 3JH,H and 3JC,H coupling constants that were determined from 1D 1H NMR and 2D J-resolved HMBC spectra in various solvents. The analysis of the corresponding coupling constants calculated using DFT/B3LYP/pcJ-1 approximation applied to conformations optimized at DFT/B3LYP/6-311++G** level supported the investigation. Proportions of conformers in the equilibrium revealed the highest repulsion between the 3-allyloxy group and the isopropoxy aglycon and its dependence on the solvent polarity. Differences in the conformational behavior of 3-O-allyl and 3-O-acetyl-α-d-idopyranoside derivatives complied with the notion that higher electron density on O-3 increased 1,3-syn-diaxial repulsion. 3-O-TBDPS derivative existed mainly in 4C1 conformation. The attenuation of the 1,3-syn-diaxial repulsive interaction indicates that TBDPS has stereoelectronic properties that may have significance in context of fixing unnatural pyranoside conformation with the help of silyl groups but have been disregarded until now.

Conformational Analysis of the Mannosidase Inhibitor Kifunensine: A Quantum Mechanical and Structural Approach.

The varied yet family-specific conformational pathways used by individual glycoside hydrolases (GHs) offer a tantalising prospect for the design of tightly binding and specific enzyme inhibitors. A cardinal example of a GH-family-specific inhibitor, and one that finds widespread practical use, is the natural product kifunensine, which is a low-nanomolar inhibitor that is selective for GH family 47 inverting α-mannosidases. Here we show, through quantum-mechanical approaches, that kifunensine is restrained to a "ring-flipped" 1 C4 conformation with another accessible, but higher-energy, region around the 1,4 B conformation. The conformations of kifunensine in complex with a range of GH47 enzymes-including an atomic-level resolution (1 Å) structure of kifunensine with Caulobacter sp. CkGH47 reported herein and with GH family 38 and 92 α-mannosidases-were mapped onto the kifunensine free-energy landscape. These studies revealed that kifunensine has the ability to mimic the product state of GH47 enzymes but cannot mimic any conformational states relevant to the reaction coordinate of mannosidases from other families.

Eculizumab-C5 complexes express a C5a neoepitope in vivo: Consequences for interpretation of patient complement analyses

The complement system has obtained renewed clinical focus due to increasing number of patients treated with eculizumab, a monoclonal antibody inhibiting cleavage of C5 into C5a and C5b. The FDA approved indications are paroxysmal nocturnal haemoglobinuria and atypical haemolytic uremic syndrome, but many other diseases are candidates for complement inhibition. It has been postulated that eculizumab does not inhibit C5a formation in vivo, in contrast to what would be expected since it blocks C5 cleavage. We recently revealed that this finding was due to a false positive reaction in a C5a assay. In the present study, we identified expression of a neoepitope which was exposed on C5 after binding to eculizumab in vivo. By size exclusion chromatography of patient serum obtained before and after infusion of eculizumab, we document that the neoepitope was exposed in the fractions containing the eculizumab-C5 complexes, being positive in this actual C5a assay and negative in others. Furthermore, we confirmed that it was the eculizumab-C5 complexes that were detected in the C5a assay by adding an anti-IgG4 antibody as detection antibody. Competitive inhibition by anti-C5 antibodies localized the epitope to the C5a moiety of C5. Finally, acidification of C5, known to alter C5 conformation, induced a neoepitope reacting identical to the one we explored, in the C5a assays. These data are important for interpretation of complement analyses in patients treated with eculizumab.

Conformational studies of N-(α-d-glucofuranurono-6,3-lactone)- and N-(methyl β-d-glucopyranuronate)-p-nitroanilines

N-(α-d-Glucofuranurono-6,3-lactone)-p-nitroaniline and N-(methyl β-d-glucopyranuronate)-p-nitroaniline were obtained as crystalline solids. The single-crystal X-ray diffraction, NMR data and DFT calculations for N-(α-d-glucofuranurono-6,3-lactone)-p-nitroaniline indicate that this N-furanoside adopts a 3T2/3E-like conformation in the crystal lattice, solution and gas phase. Thus, the structure of recorded for N-furanoside 1H NMR spectrum is indicative of the 3T2/3E region of the pseudorotational itinerary for furanose derivatives with α-d-gluco, β-L-ido and α-d-xylo configurations. Moreover, it is concluded that the 1T2/E2/3T2/3E region of the pseudorotational itinerary for furanose derivatives with d-gluco, L-ido and d-xylo configurations should be characterised by the lack of coupling between H2 and H3 protons, irrespective of the anomeric configuration. Such a lack of vicinal coupling is characteristic for some of the trans-oriented furanose ring protons. The single-crystal X-ray diffraction and NMR data for N-(methyl β-d-glucopyranuronate)-p-nitroaniline indicate that this N-glucuronide adopts the 4C1 conformation, both in the crystal lattice and solution. The occurrence of anomeric effects in the presented N-glycosides is discussed. The crystal structure analysis of both N-glycosides gives evidence that the amine group in p-nitroaniline is planar due to the nitrogen sp2 hybridisation.

Exhaustive rotamer search of the 4C1 conformation of α- and β-d-galactopyranose

An exhaustive search approach was used to establish all possible rotamers of α- and β-d-galactopyranose using DFT at the B3LYP/6-311+G** and M06-2X/6-311+G** levels, both in vacuum calculations, and including two variants of continuum solvent models as PCM and SMD to simulate water solutions. Free energies were also calculated. MM3 was used as the starting point for calculations, using a dielectric constant of 1.5 for vacuum modeling, and 80 for water solution modeling. For the vacuum calculations, out of the theoretically possible 729 rotamers, only about a hundred rendered stable minima, highly stabilized by hydrogen bonding and scattered in a ca. 14 kcal/mol span. The rotamer with a clockwise arrangement of hydrogen bonds was the most stable for the α-anomer, whereas that with a counterclockwise arrangement was the most stable for the β-anomer. Free energy calculations, and especially solvent modeling, tend to flatten the potential energy surface. With PCM, the total range of energies was reduced to 9–10 kcal/mol (α-anomer) or 7–8 kcal/mol (β-anomer). These figures fall to 4.5–6 kcal/mol using SMD. At the same time, the total number of possible rotamers increases dramatically to about 300 with PCM, and to 400 with SMD. Both models show a divergent behavior: PCM tends to underestimate the effect of solvent, thus rendering as the most stable many common rotamers with vacuum calculations, and giving underestimations of populations of β-anomers and gt rotamers in the equilibrium. On the other hand, SMD gives a better estimation of the solvent effect, yielding correct populations of gt rotamers, but more β-anomers than expected by the experimental values. The best agreement is observed when the functional M06-2X is combined with SMD. Both DFT models show minimal geometrical differences between the optimized conformers.

Vibrational analysis of dibenzo-18-crown-6. Effect of dispersion correction on the calculated vibrational spectra

We report for the first time a detailed vibrational analysis of dibenzo-18-crown-6, db18c6. The experimental IR and Raman spectra of db18c6 were measured. The assignment of the fundamental vibrational frequencies of db18c6 was aided by using scaled quantum mechanical force fields calculated at the B3LYP/6-311G** and CAM-B3LYP/6-311G** levels. Comparison between the experimental and calculated spectra of some of the important conformations of db18c6 led to the conclusion that db18c6 in the solid phase exists in a C2 conformation that is similar to that predicted by X-ray, for also the solid phase. The effect of inclusion of the atom pair-wise dispersion correction to the B3LYP method, known as the B3LYP-D3 method, on the calculated IR and Raman spectra of db18c6 at the B3LYP level was also investigated. It was concluded that the effect of inclusion of the dispersion correction on the calculated vibrational frequencies and intensities is negligible.

Studies on the 6-homologation of β-D-idopyranosides

β-D-Idopyranosides are interesting sugars because of their unusual conformational flexibility in the pyranosyl ring, and also their β-1,2-cis-anomeric configuration. Here we report our studies of the regioselective opening of 4,6-O-benzylidene-protected β-D-idopyranosides under reducing conditions, and the subsequent 6-homologation via Swern oxidation and Wittig olefination to afford a 6,7-dideoxy-β-D-ido-hept-6-enopyranoside. This olefination product was found to adopt predominantly 1C4 conformation in solution by NMR experiments, which places the vinyl group at a more sterically hindered axial position and creates difficulty in subsequent hydroborations.

Insight into the Mechanism of Thermal Stability of α-Diimine Nickel Complex in Catalyzing Ethylene Polymerization

The union of experimental and computational methods can accelerate the development of polymerization catalysts for industrial applications. Herein, we report complementary experimental and computational studies of the thermal stability of α-diimine nickel complexes by using thermally stable Cat. 1 and a typical Brookhart catalyst (B-Cat) as models. Experimentally, we found that many more nickel atoms could be activated for Cat. 1 at elevated temperature during the ethylene polymerization process compared to those for B-Cat. Computationally, first-principle calculations showed that the decomposition energies of Cat. 1 were found to be higher than those of B-Cat, contributing to the activation observed for Cat. 1. We found that the presence of ethydene evidently affected the conformation of C1–N1–Ni–N2–C2 five-membered ring (where the nickel center is located) of Cat. 1, turning the envelope conformation (B-Cat) into a half-chair conformation (Cat. 1). According to calculations, the decomposition energy of ...

Computational Design of Experiment Unveils the Conformational Reaction Coordinate of GH125 α-Mannosidases.

Conformational analysis of enzyme-catalyzed mannoside hydrolysis has revealed two predominant conformational itineraries through B2,5 or 3H4 transition-state (TS) conformations. A prominent unassigned catalytic itinerary is that of exo-1,6-α-mannosidases belonging to CAZy family 125. A published complex of Clostridium perfringens GH125 enzyme with a nonhydrolyzable 1,6-α-thiomannoside substrate mimic bound across the active site revealed an undistorted 4C1 conformation and provided no insight into the catalytic pathway of this enzyme. We show through a purely computational approach (QM/MM metadynamics) that sulfur-for-oxygen substitution in the glycosidic linkage fundamentally alters the energetically accessible conformational space of a thiomannoside when bound within the GH125 active site. Modeling of the conformational free energy landscape (FEL) of a thioglycoside strongly favors a mechanistically uninformative 4C1 conformation within the GH125 enzyme active site, but the FEL of corresponding O-glycoside substrate reveals a preference for a Michaelis complex in an OS2 conformation (consistent with catalysis through a B2,5 TS). This prediction was tested experimentally by determination of the 3D X-ray structure of the pseudo-Michaelis complex of an inactive (D220N) variant of C. perfringens GH125 enzyme in complex with 1,6-α-mannobiose. This complex revealed unambiguous distortion of the -1 subsite mannoside to an OS2 conformation, matching that predicted by theory and supporting an OS2 → B2,5 → 1S5 conformational itinerary for GH125 α-mannosidases. This work highlights the power of the QM/MM approach and identified shortcomings in the use of nonhydrolyzable substrate analogues for conformational analysis of enzyme-bound species.

The role of amino acid side chains in stabilizing dipeptides: the laser ablation Fourier transform microwave spectrum of Ac-Val-NH2.

The steric effects imposed by the isopropyl group of valine in the conformational stabilization of the capped dipeptide N-acetyl-l-valinamide (Ac-Val-NH2) have been studied by laser ablation molecular beam Fourier transform microwave (LA-MB-FTMW) spectroscopy. The rotational and quadrupole coupling constants of the two 14N nuclei determined in this work show that this dipeptide exists as a mixture of C7 and C5 conformers in the supersonic expansion. The conformers are stabilized by a C[double bond, length as m-dash]OH-N intramolecular hydrogen bond closing a seven- or a five-membered ring, respectively. The observation of both conformers is in good agreement with previous results on the related dipeptides containing different residues, confirming that the polarity/non-polarity of the side chains of the amino acid is responsible for the conformational locking/unlocking. The voluminous isopropyl group is not able to prevent the less stable C5 conformer from forming but it destabilizes the C[double bond, length as m-dash]OH-N interaction.

Conformational structures of the tetrahydrofuran cation determined using one-photon mass-analyzed threshold ionization spectroscopy.

One-photon vacuum ultraviolet mass-analyzed threshold ionization (VUV-MATI) spectroscopy was used to characterize the essential conformations of tetrahydrofuran (THF) and thus determine the stereochemistry of the furanose ring constituting the backbones of DNA and RNA. Since the VUV-MATI spectrum of THF exactly corresponds to the vibrational spectrum of the gas-phase THF cation, the above cation was detected using time-of-flight mass spectrometry featuring the delayed pulsed-field ionization of the target in high Rydberg states by scanning the wavelength of the VUV pulse across the region of the vibrational spectrum. The position of the 0-0 band in the recorded VUV-MATI spectrum was extrapolated to the zero-field limit, allowing the adiabatic ionization energy of THF to be accurately estimated to be 9.4256 ± 0.0004 eV. The above ionization was assigned to a transition between C2-symmetric neutral (S0) and cationic (D0) ground states. The potential energy surfaces associated with molecular pseudorotation in the above states were constructed at the B3LYP/aug-cc-pVDZ level, being in good agreement with experimental observations. The twisted (C2-symmetric) and bent (CS-symmetric) conformers of the S0 state were predicted to be separated by a small interconversion barrier, whereas the D0 state exclusively existed in the C2 conformation. Based on the above, the peaks in the MATI spectrum were successfully assigned based on the Franck-Condon factors and vibrational frequencies calculated by varying the geometrical parameters of the C2 conformation, which determines the precise molecular structure of the THF cation.

Stereochemical and electronic interaction studies of 4′-substituted 2-(phenylselanyl)-2-(ethylsulfinyl)-acetophenones

Infrared carbonyl band analysis, supported by B3LYP/6-31 + G(d,p) and single-point PCM calculations, natural bond orbital (NBO) analysis and X-ray diffraction (XRD) were carried out for the diastereoisomers of a selection of 4′-substituted 2-(phenylselanyl)-2-(ethylsulfinyl)-acetophenones bearing the substituents NO21a, Br 2a, H 3a, Me 4a and OMe 5a for the CRSR/CSSS enantiomeric pair and Br 2b and Me 4b for the CRSS/CSSR pair. The theoretical data indicated the existence of three stable conformations for the CRSR series and two for the CRSS series. For both series, the single-point PCM calculations showed that the relative abundance of the less stable conformers in the gas phase progressively increases as the dielectric constant of the media increases. For compounds 1a–5a, the balance between the electrostatic and orbital interactions controls the calculated stability, as well as the νCO frequency order. Conversely, the more stable conformer in the 2b and 4b compounds is mainly stabilised by the additional orbital interactions LP(S) → σ*C-Se, LPO(S-O) → σ*C-H(CH2Me) and LPO(S-O) → σ*C-H(o-PhSe). The XRD analysis indicates that the major component of 3a (CRSR) matches the geometry of the intermediate stable c2 conformer. Similarly, the solid-state structure of 2b (CRSS) corresponds to the less stable c2 conformer. The molecules in the solid are linked in centrosymmetrical pairs through π … π interactions between Se-bound phenyl rings, along with phenyl-CH…O (carbonyl and sulphinyl) interactions.

Radical-Mediated C-H Functionalization: A Strategy for Access to Modified Cyclodextrins.

A simple and efficient radical C-H functionalization to access modified cyclodextrins (CDs) has been developed. The well-defined conformation of glycosidic and aglyconic bonds in α-, β-, and γ-CDs favors the intramolecular 1,8-hydrogen atom transfer (HAT) promoted by the 6I-O-yl radical, which abstracts regioselectively the hydrogen at C5II of the contiguous pyranose. The C5II-radical evolves by a polar crossover mechanism to a stable 1,3,5-trioxocane ring between two adjacent glucoses or alternatively triggers the inversion of one α-d-glucose into a 5-C-acetoxy-β-l-idose unit possessing a 1C4 conformation. The 6I,IV- and 6I,III-diols of α- and β-CDs behave similarly to the monoalcohols, forming mostly compounds originating from two 1,8-HAT consecutive processes. In the case of 6I,II-diols the proximity of the two 6-O-yl radicals in adjacent sugar units allows the formation of unique lactone rings within the CD framework via a 1,8-HAT-β-scission tandem mechanism. X-ray diffraction carried out on the crystalline 1,4-bis(trioxocane)-α-CD derivative shows a severe distortion toward a narrower elliptical shape for the primary face.

Structure and bonding of 2,2,2-trichloroethylacetate: An experimental gas phase and computational study

AbstractThe structural and conformational properties of 2,2,2-trichloroethylacetate, H3CCO2CH2CCl3, have been determined in the gas phase using gas electron diffraction (GED). The experimental measurements were complemented by MP2 and DFT quantum-chemical calculations. Two conformers separated by a shallow rotational barrier have been identified, one ofC1(syn-gauche) and the other ofCssymmetry (syn-anti). All calculations indicate thatsyn-gaucheis preferred in terms of enthalpy, whereassyn-antiseems to be slightly more stable regarding Gibbs free energy. In the gas-phase structure determination, dynamic models based on different potential energy surface scans were used. The one from dispersion-corrected density functional theory, predicting a preference ofsyn-gaucheby 1.7kJmol−1, was found to describe the experimental data best. One- and two-conformer models had to be rejected due to correlations and unrealistically large amplitudes. Experimentally determined structural parameters are in good agreement with both, quantum-chemical calculations as well as GED data for related compounds. Interacting quantum atoms (IQA) analyses revealed that interplay between the carbonyl group and the hydrogen as well as chlorine atoms of the trichloroethyl group accounts for most of the stabilisation of theC1conformer. With intramolecular symmetry-adapted perturbation theory (I-SAPT) analyses it was possible to further elucidate the nature of dominant interactions in the two conformers. Herein, preference ofsyn-gauchecan for the most part be attributed to electrostatic and to some extent to induction and dispersion interplays. In contrast this conformer is severely destabilised through steric repulsion. These results were supported by NBO analyses.

Potential Energy Surface-Based Automatic Deduction of Conformational Transition Networks and Its Application on Quantum Mechanical Landscapes of d-Glucose Conformers.

This paper describes our approach that is built upon the potential energy surface (PES)-based conformational analysis. This approach automatically deduces a conformational transition network, called a conformational reaction route map (r-map), by using the Scaled Hypersphere Search of the Anharmonic Downward Distortion Following method (SHS-ADDF). The PES-based conformational search has been achieved by using large ADDF, which makes it possible to trace only low transition state (TS) barriers while restraining bond lengths and structures with high free energy. It automatically performs sampling the minima and TS structures by simply taking into account the mathematical feature of PES without requiring any a priori specification of variable internal coordinates. An obtained r-map is composed of equilibrium (EQ) conformers connected by reaction routes via TS conformers, where all of the reaction routes are already confirmed during the process of the deduction using the intrinsic reaction coordinate (IRC) method. The postcalculation analysis of the deduced r-map is interactively carried out using the RMapViewer software we have developed. This paper presents computational details of the PES-based conformational analysis and its application to d-glucose. The calculations have been performed for an isolated glucose molecule in the gas phase at the RHF/6-31G level. The obtained conformational r-map for α-d-glucose is composed of 201 EQ and 435 TS conformers and that for β-d-glucose is composed of 202 EQ and 371 TS conformers. For the postcalculation analysis of the conformational r-maps by using the RMapViewer software program we have found multiple minimum energy paths (MEPs) between global minima of 1C4 and 4C1 chair conformations. The analysis using RMapViewer allows us to confirm the thermodynamic and kinetic predominance of 4C1 conformations; that is, the potential energy of the global minimum of 4C1 is lower than that of 1C4 (thermodynamic predominance) and that the highest energy of those of all the TS structures along a route from 4C1 to 1C4 is lower than that of 1C4 to 4C1 (kinetic predominance).

Synthesis, PASS-Predication and in Vitro Antimicrobial Activity of Benzyl 4-O-benzoyl-α-l-rhamnopyranoside Derivatives.

Benzyl α-l-rhamnopyranoside 4, obtained by both conventional and microwave assisted glycosidation techniques, was subjected to 2,3-O-isopropylidene protection to yield compound 5 which on benzoylation and subsequent deprotection of isopropylidene group gave the desired 4-O-benzoylrhamnopyranoside 7 in reasonable yield. Di-O-acetyl derivative of benzoate 7 was prepared to get newer rhamnopyranoside. The structure activity relationship (SAR) of the designed compounds was performed along with the prediction of activity spectra for substances (PASS) training set. Experimental studies based on antimicrobial activities verified the predictions obtained by the PASS software. Protected rhamnopyranosides 5 and 6 exhibited slight distortion from regular 1C4 conformation, probably due to the fusion of pyranose and isopropylidene ring. Synthesized rhamnopyranosides 4–8 were employed as test chemicals for in vitro antimicrobial evaluation against eight human pathogenic bacteria and two fungi. Antimicrobial and SAR study showed that the rhamnopyranosides were prone against fungal organisms as compared to that of the bacterial pathogens. Interestingly, PASS prediction of the rhamnopyranoside derivatives 4–8 were 0.49 < Pa < 0.60 (where Pa is probability ‘to be active’) as antibacterial and 0.65 < Pa < 0.73 as antifungal activities, which showed significant agreement with experimental data, suggesting rhamnopyranoside derivatives 4–8 were more active against pathogenic fungi as compared to human pathogenic bacteria thus, there is a more than 50% chance that the rhamnopyranoside derivative structures 4–8 have not been reported with antimicrobial activity, making it a possible valuable lead compound.