Conformation analysis

Herein, we describe the use of thioglycosides as glycosidase inhibitors by employing novel modifications at the reducing end of these glycomimetics. The inhibitors display a basic galactopyranosyl unit (1→4)‐bonded to a 3‐deoxy‐4‐thiopentopyranose moiety. The molecular basis of the observed inhibition has been studied by using a combination of NMR spectroscopy and molecular modeling techniques. It is demonstrated that these molecules are not recognized by Escherichia coli β‐galactosidase in their ground‐state conformation, with a conformational selection process taking place. In fact, the observed conformational distortion depends on the chemical nature of the compounds and results from the rotation around the glycosidic linkage (variation of Φ or Ψ) or from the deformation of the six‐membered ring of the pentopyranose. The bound conformations of the ligand are adapted in the enzymatic pocket with a variety of hydrogen‐bond, van der Waals, and stacking interactions.

The 2‐(prop‐2‐yn‐1‐yloxy)naphthalene (compound I) and 1‐nitro‐2‐(prop‐2‐yn‐1‐yloxy)benzene (compound II) were prepared in excellent yields by the reaction of propargyl bromide with 2‐naphthol and 2‐nitrophenol, respectively. Structural and conformational properties of both compounds have been analyzed using a combined approach including single‐crystal X‐ray diffraction and quantum chemical calculations. Two forms are found to be stable and nearly isoenergetic conformers, depending on the mutual orientation of the C≡C triple bond and the O–C single bond of the prop‐2‐yn‐1‐yloxy group. The gauche conformation is the most stable form for the vacuum isolated species, with the anti conformation higher in energy by 1.00 and 1.89 kcal/mol computed at the M06‐2X/6‐311++G(d,p) level of approximation, for I and II, respectively. The gauche form is observed in the crystal of I but the nearly planar anti conformation is adopted in the crystalline phase of compound II. The occurrence of C–H⋅⋅⋅π ...

Herein, we have investigated the effect of an endocyclic group (forming the N-CC -F fragment) on the conformational preferences of 2-fluorocyclohexanone analogs. A combined approach of nuclear magnetic resonance and density functional theory calculations was employed to assess the conformational equilibrium in several media. In turn, natural bond orbital analysis and the conformational behavior of other 2halocyclohexanone analogs were used to get more insights about the intramolecular interactions governing the conformer

The structural features of MUC1-like glycopeptides bearing the Tn antigen (a-O-GalNAc-Ser/Thr) in complex with an anti MUC-1 antibody are reported at atomic resolution. Fort he a-O-GalNAc-Ser derivative,t he glycosidic linkage adopts ah igh-energy conformation, barely populated in the free state.This unusual structure (also observed in an aS -GalNAc-Cys mimic) is stabilized by hydrogen bonds between the peptidic fragment and the sugar.T he selection of ap articular peptide structure by the antibody is thus propagated to the carbohydrate through carbohydrate/peptide contacts,w hich force ac hange in the orientation of the sugar moiety.T his seems to be unfeasible in the a-O-GalNAc-Thr glycopeptide owingtothe more limited flexibility of the side chain imposed by the methyl group.O ur data demonstrate the non-equivalence of Ser and Thr O-glycosylation points in molecular recognition processes.T hese features providei nsight into the occurrence in nature of the APDTRP epitope for anti-MUC1 antibodies.

A cyclic CCK8 analogue, cyclo 29,34 [Dpr 29 ,Lys 34 ]-CCK8 (Dpr L-2,3diaminopropionic acid), has been designed on the basis of the NMR structure of the bimolecular complex between the N-terminal fragment of the CCK A receptor and its natural ligand CCK8. The conformational features of cyclo 29,34 [Dpr 29 ,Lys 34 ]-CCK8 have been determined by NMR spectroscopy in aqueous solution and in water containing DPC-d 38 micelles (DPC dodecylphosphocholine). The structure of the cyclic peptide in aqueous solution is found to be in a relaxed conformation, with the backbone and Dpr29 side chain atoms making a planar ring and the N-terminal tripeptide extending approximately along the plane of this ring. In DPC/ water, the cyclic peptide adopts a ™boat-shaped∫ conformation, which is more compact than that found in aqueous solution. The cyclic constraint between the Dpr29 side chain and the CCK8 carboxyl terminus (Lys34) introduces a restriction in the backbone conformational freedom. However, the interaction of cyclo 29,34-[Dpr 29 ,Lys 34 ]-CCK8 with the micelles still plays an important role in the stabilisation of the bioactive conformation. A careful comparison of the NMR structure of the cyclic peptide in a DPC micelle aqueous solution with the structure of the rationally designed model underlines that the turn-like conformation in the Trp30 ± Met31 region is preserved, such that the Trp30 and Met31 side chains can adopt the proper spatial orientation to interact with the CCK A receptor. The binding properties of cyclo 29,34 [Dpr 29 ,Lys 34 ]-CCK8 to the N-terminal receptor fragment have been investigated by fluorescence spectroscopy in a micellar environment. Estimates of the apparent dissociation constant, K d , were in the range of 70 ± 150 nM, with a mean value of 120 AE 27 nM. Preliminary nuclear medicine studies on cell lines transfected with the CCK A receptor indicate that the sulfated-Tyr derivative of cyclo 29,34 [Dpr 29 ,Lys 34 ]-CCK8 displaces the natural ligand with an IC 50 value of 15 mM.

Herein, we describe the use of thioglycosides as glycosidase inhibitors by employing novel modifications at the reducing end of these glycomimetics. The inhibitors display a basic galactopyranosyl unit (1→4)‐bonded to a 3‐deoxy‐4‐thiopentopyranose moiety. The molecular basis of the observed inhibition has been studied by using a combination of NMR spectroscopy and molecular modeling techniques. It is demonstrated that these molecules are not recognized by Escherichia coli β‐galactosidase in their ground‐state conformation, with a conformational selection process taking place. In fact, the observed conformational distortion depends on the chemical nature of the compounds and results from the rotation around the glycosidic linkage (variation of Φ or Ψ) or from the deformation of the six‐membered ring of the pentopyranose. The bound conformations of the ligand are adapted in the enzymatic pocket with a variety of hydrogen‐bond, van der Waals, and stacking interactions.

Desiccation or extreme water loss leads to protein denaturation, aggregation, and degradation and impairs membrane lipid fluidity, resulting in loss of membrane integrity at the cellular level. The induction of late embryogenesis abundant proteins (LEAPs) is considered an essential component of desiccation tolerance strategy in so-called resurrection plants. This heterogeneous group of hydrophilic, non-globular proteins is characterized by a high structural plasticity that allows them to adopt a random conformation in aqueous solutions that transforms into α-helices during dehydration [1]. Therefore, LEAPs can interact with various ligands and partners, including ion sequestration and stabilization of membranes and enzymes during freezing or drying [2]. All identified LEAPs (164) were clustered into six subfamilies based on difference in sequence domains. The classification summary can be found on Figure 1. Further protein analysis is shown on Figures 2-6. We have built homology models using Protein Data Bank structure information. Homology models show variation in LEAPs secondary and tertiary structures with 30% on average primary sequence similarity between subfamilies. We found that LEAPs adopt diverse helix-bundle topologies, with an exception of LEA_2 which adopts alphabeta-fold type and is related to membrane, lipid interaction. LEA_4 and SMP may adopt structure which resembles a-synuclein. The information obtained from the representative structural models is key to understanding the function of LEAPs and the regulation of their intrinsic structural disorder-to-order transition during desiccation. This will pave the way for the identification of LEAPs endogenous partners and their targets in the cell and provide further insights into the protective mechanisms of desiccation tolerance.

Indirect spin-spin NMR 1 H-1 H coupling constants of newly synthesized furanose monosaccharide derivatives were interpreted on the basis of ab initio modeling. Epoxy, epithio, and epimino groups were inserted into the sugars and significantly limited their conformational flexibility, which was confirmed by a systematic conformer analysis. Because of the restriction, the performance of the computations and the dependence of the coupling constants on the geometry could be estimated more easily. Conventional Karplus equations are not optimized for this class of compounds and cannot be used for reliable interpretation of the NMR spectra. Fully analytical B3LYP/IGLOII computations of the coupling constants were performed including all the four important magnetic terms (SD, DSO, PSO, FC) in the Hamiltonian. Good agreement of the calculated and the experimental coupling constants was achieved, and computed structural parameters are consistent with available X-ray data. The influence of the different functional groups on the spin-spin coupling constants was discussed.

The geometry of the intermolecular hydrogen bonds in 3a, 9a, and 9c is reported in Table 6. The configuration of the nitrogen atom N(2) adapts both to optimize the local conformation and the hydrogen bonding network. In 3a, the N-H•••O bond makes infinite chains of molecules parallel to the a axis (see below for a figure of the crystal packings). In the crystal of compound 9c, the molecules are stacked along the c axis direction forming linear supermolecular structures connected by N-H•••O hydrogen bonds. Similar hydrogen bonding systems, connecting

The conformational equilibria of the low-energy conformers of isomaltose have been studied in different solvents. The structure of each individual conformer was refined from the 18 distinct low-energy regions determined from potential energy function. Molecular geometry optimization was carried out using the quantum chemical method of perturbative configuration interaction with localized orbitals or PCILO and yielded to 15 distinct minima. Carbon-proton vicinal coupling constants J C. H have been calculated based on the finite perturbation theory formulation with the intermediate neglect of differential overlap for these minima. For evaluation of the influence of the environment on the conformational structure of isomaltose, the population of the low-energy conformers was estimated in four solvents by a method in which the total energy is divided into the energy of the isolated molecule and the solvation energy. The calculated abundances of conformers depend strongly on the solvents. Based on the determined abundance of conformers, thermodynamically averaged torsion angles and coupling constants 3Jc H describing the "average" conformation about glycosidic linkage have been calculated. Results obtained are compared with available experimental data from solution and solid state.

The glycopyran-6-O-yl radical promoted hydrogen atom transfer reaction (HAT) between the two pyranose units of α-D-Manp-(1‹4)-α-D-Glcp and α-D-Manp-(1‹4a)-4a-carba-α-D-Glcp disaccharides provides supporting chemical evidence for the conformational differences between O-and C-glycosyl compounds. In the O-disaccharide the 6-alkoxyl radical, generated under oxidative or reductive conditions, abstracts exclusively the hydrogen at C-5' via a completely regioselective 1,8-HAT reaction. This may be attributable to the conformational restriction of the glycosidic and aglyconic bonds [a]

Constrained peptidomimetic scaffolds are of considerable interest for the design of therapeutically useful analogues of bioactive peptides. We present the single-step cyclization of (S)- or (R)-α-hydroxy-β(2)- or α-substituted-α-hydroxy-β(2, 2)-amino acids already incorporated within oligopeptides to 5-aminomethyl-oxazolidine-2,4-dione (Amo) rings. These scaffolds can be regarded as unprecedented β(2)- or β(2, 2)-homo-Freidinger lactam analogues, and can be equipped with a proteinogenic side chain at each residue. In a biomimetic environment, Amo rings act as inducers of extended, semi-bent or folded geometries, depending on the relative stereochemistry and the presence of α-substituents.

The hierarchical self-assembling of complex molecular systems is dictated by the chemical and structural information stored in their components. This information can be expressed through an adaptive process that determines the structurally fittest assembly under given environmental conditions. We have set up complex disulphide-based dynamic covalent libraries of chemically and topologically diverse pseudopeptidic compounds. We show how the reaction evolves from very complex mixtures at short reaction times to the formation of a major compound almost exclusively, under the establishing of intramolecular noncovalent interactions. Our experiments demonstrate that the systems evolve through error-check and error-correction processes. The nature of these interactions, the importance of the folding and the effects of the environment are also discussed.

A family of linear, carbohydrate-derived oligo(amidetriazole)s has been designed and synthesized. These molecules possess a regular distribution of triazole rings (from one to four) linking the carbohydrate units to give dimer to pentamer derivatives. Their binding to halide anions was qualitatively analyzed by means of NMR spectroscopy and mass spectrometry. All the compounds were able to bind chloride anions, with a stoichiometry that depended on the chain length. The dimer and trimer gave 2:1 host:chloride ratio, while the tetramer and pentamer gave 1:1 complexes. The secondary structure of the oligo(amide-triazole)s was studied using NMR spectroscopy and circular dichroism. These studies showed that the larger host molecules (tetramer and pentamer) adopted a stabilized U-turn and were able to bind just one chloride anion. Only the pentamer displayed a helical conformation, which was slightly distorted in the presence of chloride salts. Interestingly, chloride binding involves not only the triazole-CH but also H atoms from the carbohydrate moieties. These compounds could be applied for chloride sensing by ESI-MS.

The structural features of MUC1-like glycopeptides bearing the Tn antigen (a-O-GalNAc-Ser/Thr) in complex with an anti MUC-1 antibody are reported at atomic resolution. Fort he a-O-GalNAc-Ser derivative,t he glycosidic linkage adopts ah igh-energy conformation, barely populated in the free state.This unusual structure (also observed in an aS -GalNAc-Cys mimic) is stabilized by hydrogen bonds between the peptidic fragment and the sugar.T he selection of ap articular peptide structure by the antibody is thus propagated to the carbohydrate through carbohydrate/peptide contacts,w hich force ac hange in the orientation of the sugar moiety.T his seems to be unfeasible in the a-O-GalNAc-Thr glycopeptide owingtothe more limited flexibility of the side chain imposed by the methyl group.O ur data demonstrate the non-equivalence of Ser and Thr O-glycosylation points in molecular recognition processes.T hese features providei nsight into the occurrence in nature of the APDTRP epitope for anti-MUC1 antibodies.

The structural features of MUC1-like glycopeptides bearing the Tn antigen (a-O-GalNAc-Ser/Thr) in complex with an anti MUC-1 antibody are reported at atomic resolution. Fort he a-O-GalNAc-Ser derivative,t he glycosidic linkage adopts ah igh-energy conformation, barely populated in the free state.This unusual structure (also observed in an aS -GalNAc-Cys mimic) is stabilized by hydrogen bonds between the peptidic fragment and the sugar.T he selection of ap articular peptide structure by the antibody is thus propagated to the carbohydrate through carbohydrate/peptide contacts,w hich force ac hange in the orientation of the sugar moiety.T his seems to be unfeasible in the a-O-GalNAc-Thr glycopeptide owingtothe more limited flexibility of the side chain imposed by the methyl group.O ur data demonstrate the non-equivalence of Ser and Thr O-glycosylation points in molecular recognition processes.T hese features providei nsight into the occurrence in nature of the APDTRP epitope for anti-MUC1 antibodies.

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The hierarchical self-assembling of complex molecular systems is dictated by the chemical and structural information stored in their components. This information can be expressed through an adaptive process that determines the structurally fittest assembly under given environmental conditions. We have set up complex disulphide-based dynamic covalent libraries of chemically and topologically diverse pseudopeptidic compounds. We show how the reaction evolves from very complex mixtures at short reaction times to the formation of a major compound almost exclusively, under the establishing of intramolecular noncovalent interactions. Our experiments demonstrate that the systems evolve through error-check and error-correction processes. The nature of these interactions, the importance of the folding and the effects of the environment are also discussed.

Conformational flexibility around the ester and ether linkages in S-0-cinnamoyl+Larabinofuranose (1) and 5-0-KS)-1-phenethyl]-cY-L-arabinofuranose (2), models for lignincarbohydrate complexes, has been investigated by molecular orbital PCILO calculations. The structures of individual minima were refined by minimising the energy by adjusting geometrical parameters from the distinct low-energy regions in two-dimensional maps. The calculations show that the ester and ether linkages in lignin-carbohydrate complex models display a large amount of conformational freedom. This involves a rapid equilibrium between the various pseudorotamers of the furanose ring, rotamers of the exocyclic group, and rotation around the ester and ether linkages. The calculations reveal the strong influence of solvent on the conformer populations and that this effect is more pronounced in the ether linkage. The results for aqueous solution predict that (a) the North-and South-type pseudorotamers of the cy-L-arabinofuranose ring are present in equilibrium in approximately equal amounts in the ester 1, whereas the North-type pseudorotamers prevail in the ether 2; (b) the gt conformation is more populated in both compounds; and (c) the antiperiplanar orientation is dominant in both the ester and ether. The present results give some insight into the conformational flexibility that both molecules display, shed light on the possible arrangement of hydrophilic and hydrophobic parts of lignin-carbohydrate compIexes, and provide the basis for the generation of more accurate models for further studies of lignin-carbohydrate complexes.

The geometry of the intermolecular hydrogen bonds in 3a, 9a, and 9c is reported in Table 6. The configuration of the nitrogen atom N(2) adapts both to optimize the local conformation and the hydrogen bonding network. In 3a, the N-H•••O bond makes infinite chains of molecules parallel to the a axis (see below for a figure of the crystal packings). In the crystal of compound 9c, the molecules are stacked along the c axis direction forming linear supermolecular structures connected by N-H•••O hydrogen bonds. Similar hydrogen bonding systems, connecting

Indirect spin-spin NMR 1 H-1 H coupling constants of newly synthesized furanose monosaccharide derivatives were interpreted on the basis of ab initio modeling. Epoxy, epithio, and epimino groups were inserted into the sugars and significantly limited their conformational flexibility, which was confirmed by a systematic conformer analysis. Because of the restriction, the performance of the computations and the dependence of the coupling constants on the geometry could be estimated more easily. Conventional Karplus equations are not optimized for this class of compounds and cannot be used for reliable interpretation of the NMR spectra. Fully analytical B3LYP/IGLOII computations of the coupling constants were performed including all the four important magnetic terms (SD, DSO, PSO, FC) in the Hamiltonian. Good agreement of the calculated and the experimental coupling constants was achieved, and computed structural parameters are consistent with available X-ray data. The influence of the different functional groups on the spin-spin coupling constants was discussed.

The conformation of several 2'-deoxy-a-~-ribofuranoside and 2'-deoxy-P-~-ribofuranoside derivatives in solution were studied by 'H NMR at 300 MHz, using vicinal coupling constants and chemical shifts obtained as a probe. The conformation of the five-membered sugar ring of these derivatives in solution is quantitatively described in terms of the concept of pseudorotation. It appeared that, in D20 solution, methyl 2'deoxy-P-~-ribofuranoside (lb) is engaged in an equilibrium between two conformational species. The geometry of the N-type conformer can be described as an intermediate between :T and 2E (P = 335', 0, = 45'), whereas that of the S-type conformer can be denoted as a 4E conformation (P = 234', a, , , = 42'). It is shown that the conformation of the sugar ring of l b is quite different from the geometry of the N-type conformer usually observed for P-nucleosides(tides). This observation demonstrates the dominant influence of the substituent at CI, on the conformation of the five-membered ring. A comparison of the pseudorotational parameters of the N-type conformation of the p-nitrobenzoylated derivative of l b (2b) in solution with those observed in the solid state shows that the former ( P ( N ) = 340', 0,(N) = 45') differs significantly from the latter (P(N) = 291.7', @,,,(N) = 33.7'). This discrepancy is attributed to crystal-packing forces in the solid-state structure. The conformational features of methyl 2'-deoxy-cu-~-ribofuranoside (la) (in D 2 0 solution) as deduced from 'H NMR indicate that in this compound an S-type conformation of the five-membered sugar ring is strongly favored. The geometry of the latter conformation is best described as an I E form (P = 132', 0, = 40'). Our analyses of 'H NMR data are complemented by a molecular mechanics study of compounds la and lb. It is shown that the geometric features of la and l b are very well reproduced by MM-2 force field calculations. However, the calculated relative energies of the distinct conformers in these compounds are contradicted by the conformational populations determined experimentally by NMR. Notwithstanding, the application of Allinger's MM-2 provided a better insight into the experimental results. The results of the present study on the conformational properties of la and lb can be interpreted in terms of the well-known gauche and anomeric effects: The N-type conformer of l b can be explained by an anomeric stabilization of the sugar ring, whereas, in contrast, the S-type conformer of l b is stabilized by the Occurrence of a predominant gauche effect. Furthermore, it is suggested that, in the S-type conformer of compound la, both the anomeric and the gauche effects are operative. The 'H NMR spectra for la and l b permitted an evaluation of the relative populations of the three conformers around the exocyclic C,-C5, bond. Our data indicate that for the N-type pucker the gauche' rotamer might be forbidden. Double-helical complexes formed from so-called "base-deleted" oligonucleotides4 form convenient models for the investigation of the recognition mechanism of apurinic or apyrimidinic (AP) sites5 in nucleic acids by repairing proteins. The interaction between the protein and the AP site is likely to be influenced by the conformationzl features of the base-deleted sugar residue 2'deoxy-D-ribofuranose.6 Therefore, the study of the solution conformations of this sugar residue will bring about basic knowledge necessary for understanding the complex behavior of the specific binding of the AP site to the enzyme AP-endonuclease. By application of 'H NMR techniques to the basedeleted sugar, the preferred solution conformations can be derived.',* However, the N M R investigation of an aqueous solution of 2'-deoxy-~ribofuranose is hampered by the fact that the hemiacetal function of the sugar is configurationally unstable. This difficulty, originating from mutarotation in water, complicates a detailed conformational analysis. In recent studies of base-deleted D oligonucleotides, the problem has been circumvented by designing sugar analogues that are stable in aqueous solution: 1',2'-dideoxy-~-ribofuranose~ and 1'-(2'-deoxy-~-~-ribofuranosyl) ~y a n i d e . ~ Our approach to solving this problem is to prevent the

Conformational flexibility around the ester and ether linkages in S-0-cinnamoyl+Larabinofuranose (1) and 5-0-KS)-1-phenethyl]-cY-L-arabinofuranose (2), models for lignincarbohydrate complexes, has been investigated by molecular orbital PCILO calculations. The structures of individual minima were refined by minimising the energy by adjusting geometrical parameters from the distinct low-energy regions in two-dimensional maps. The calculations show that the ester and ether linkages in lignin-carbohydrate complex models display a large amount of conformational freedom. This involves a rapid equilibrium between the various pseudorotamers of the furanose ring, rotamers of the exocyclic group, and rotation around the ester and ether linkages. The calculations reveal the strong influence of solvent on the conformer populations and that this effect is more pronounced in the ether linkage. The results for aqueous solution predict that (a) the North-and South-type pseudorotamers of the cy-L-arabinofuranose ring are present in equilibrium in approximately equal amounts in the ester 1, whereas the North-type pseudorotamers prevail in the ether 2; (b) the gt conformation is more populated in both compounds; and (c) the antiperiplanar orientation is dominant in both the ester and ether. The present results give some insight into the conformational flexibility that both molecules display, shed light on the possible arrangement of hydrophilic and hydrophobic parts of lignin-carbohydrate compIexes, and provide the basis for the generation of more accurate models for further studies of lignin-carbohydrate complexes.

A conformational study on di-and trisubstituted y-butyrolactones has been performed using molecular mechanics (MM) calculations and analysis of coupling constants through an empirically generalized Karplus equation. Our results corroborate the existence of only two envelope conformations for every compound. Calculated coupling constants reproduce experimental values with a global root-mean-square (rms) deviation of 0.93 Hz. The y-lactone system possesses great importance in natural product chemistry. The existence of several metabolites having as constitutional unit the y-butyrolactone 0022-3263/86/1951-3946$01.50/0 ring 1, such as eldanolide, 2, litsenolides 3, and antimycinones 4, has generated an enormous interest on the synthesis and configurational assignments of variously

The absolute configurations of (s)-timolol hemihydrate and (S')-timolol O,Odiacetyl-(R,R)-tartaric acid monoester were determined by single crystal X-ray diffraction. An NMR analysis based on the temperature dependence of vicinal coupling constants was carried out to characterize the conformational behaviour of the S,R,Rand R,R,R-forms in solution. The same conformation as in crystalline state was also found in solution, although with a rather low preference over some other conformations. Results of theoretical calculations using MNDO and AMBER force field methods are reported. An infinite chain of hydrogen bonds, along with other favourable inter-and intramolecular forces that are present in the crystal framework of the (s)timolol-(RR)-te but not possible for (R)-timolol-(R,R)-tartrate, explain the astonishingly dominating crystallization of the S,R,R-form, Racemic timolol is accordingly easily resolved.

The absolute configurations of (s)-timolol hemihydrate and (S')-timolol O,Odiacetyl-(R,R)-tartaric acid monoester were determined by single crystal X-ray diffraction. An NMR analysis based on the temperature dependence of vicinal coupling constants was carried out to characterize the conformational behaviour of the S,R,Rand R,R,R-forms in solution. The same conformation as in crystalline state was also found in solution, although with a rather low preference over some other conformations. Results of theoretical calculations using MNDO and AMBER force field methods are reported. An infinite chain of hydrogen bonds, along with other favourable inter-and intramolecular forces that are present in the crystal framework of the (s)timolol-(RR)-te but not possible for (R)-timolol-(R,R)-tartrate, explain the astonishingly dominating crystallization of the S,R,R-form, Racemic timolol is accordingly easily resolved.

PCILO calculation on the conformation of the 16, 17, 18, 19, 28, 29 hexahydrorifamycin S points to an ansa chain conformation of the C(12)-C(28) fragment from the alternatives given by a previous 'H NMR spectroscopic study. The energetically favoured conformation of the C(19)-N fragment has also been determined.

The effect of ring-oxygen protonation on the structure and conformational properties of a model deoxyaldofuranose, 2-deoxy-D-glycero-tetrofuranose 2, has been examined with the use of NMR spectroscopy and ab initio molecular orbital calculations conducted at the HF/6-31G* level of theory. The computational method was validated by comparing the conformational behavior of 2 derived from PSEUROT treatment of 3 J HH values measured in 2 (2 H 2 O solvent) with that predicted from the theoretical calculations. Coupling data indicate that 2 favors S forms in solution (∼89% 4 T 3 , ∼11% E 2), while MO data indicated more comparable populations of the same or very similar N and S forms. Protonation of 2 at the ring oxygen (O4), yielding 1, gave two distinct protonated forms which differed in the orientation of the proton about O4. Both forms showed substantial changes in ring structure and conformation compared to 2. Protonated forms almost exclusively prefer S forms (E 3), and energy barriers for N/S interconversion were found to be considerably higher than those for 2, leading to the conclusion that 1 is more conformationally constrained than 2. Bond lengths in the vicinity of O4 changed significantly upon conversion of 2 to 1; for example, the C1-O4 bond length increases by ∼14%, the C1-H1 and C1-O1 bond lengths decrease by 1-5%, and the C4-O4 bond length increases by ∼5%. These results indicate that O4 protonation predisposes 2 toward ring opening by inducing specific structural and conformational modifications, thus providing a more concise explanation of the role of acid catalysis in furanose anomerization (i.e., 1 resembles the transition state of the acid-catalyzed anomerization reaction more than 2). The molecular orbital data obtained in this investigation also provide evidence for a new structural factor (a 1,3-effect involving oxygen lone-pair orbitals) that influences bond lengths in carbohydrates.

The best average values for C-C bond lengths and C-C-C bond angles were calculated for fragments in which the C-C bond was at least one C-C bond distant from heavy atom substituents by using the results of searches of the Cambridge Structural Database. The values found, 1.51 .& and 113" for a C-C-CH, fragment, and 1.52 A and 114" for a fragment inside a carbon chain, differ significantly from the values commonly used in theoretical calculations which are generally based on a limited set of crystallographic data or on the diamond structure. To test the sensitivity of quantum-chemical energy calculation methods to different input geometries, the PCILO method was taken as an example and checked for reproducibility of experimental conformational energy for the n-butane molecule. Energy minimization with respect to the C-C bond length and the C-C-C bond angle led to values of 1.49 A and 115", respectively. For this geometry the gauche conformation was found to be preferred by 1.4 kJ mol" over the trans conformation. This result is inconsistent with experimental data and indicates that the proper choice of geometrical parametrization is of the greatest importance in energy calculations.

The NMR spectra of a number of 2,4-disubstituted 1,3-dioxolanes have been recorded and the proton chemical shifts and coupling constants derived from complete spectral analysis. Vicinal coupling constants were found to be dependent on the substituent at C-4 and this effect is more pronounced for J(trans) of the C -4 4 -5 fragment. These coupling constants also indicate a homogeneous behgviour within a series with either a cis or trans configuration, although the cis behaviour differs from that of trans isomers. This has been interpreted in terms of definite ring conformations in substituted derivatives, while the unsubstituted 1,3-dioxolane undergoes free pesudorotation. Calculadons of coupling constants were performed by semi-empirical MO methods, both for unsubstituted 1,3-dioxolane and for C-4 substituted derivatives in a large number of conformations, in order to compare calculated and experimental values; the correct order of $(cis) and J(trans) for 1,3-dioxolane is obtained only by employing energies from ab-initio MO calculations averaged over the pseudorotation circuit. For the C-4 substituted compounds calculated coupling constants were employed in a 'trial and error' process for the identification of the preferred conformations of these compounds; a set of two torsional angles for each compound was derived which allows a tentative description of the geometry of each molecule. A criticism of these geometries is given according to the evidence available on the structure of substituted 1,3-dioxolanes.

We report here a method to perform the conformational analysis of ®ve-membered rings. This method is based on the Cremer and Pople description and it has been implemented in the GenMol software. After testing our method on a series of ®vemembered rings, we used it to study the behavior of pyrrolidine-N-oxy radicals. These calculations allowed us to calculate ESR b-hyper®ne coupling constants (b-hfcc) and to compare them with experimental ones. This approach can be used to assist the design of new nitroxide targets with desired properties. q

A theoretical conformational analysis of dimethoxymethane, 2-methoxytetrahydropyran, cellobiose, and maltose has been performed. The validity of several commonly used classical approaches to conformational energy, assuming non-bonded interactions, torsional terms, and the exo-anomeric contribution, and the MM2CARB method (a modified version of the MM2 force-field program using the Jeffrey-Taylor parameters) was tested against available experimental data or previous quantum-chemical calculations. The MM2CARB method correctly reproduces the energies and the variations in bond lengths and bond angles for conformers of dimethoxymethane and 2-methoxytetrahydropyran.

The conformational behaviour of methyl B-D-and methyl cw+arabinofuranosides have been assessed through computations performed with the molecular mechanics program MM3 using the flexible residue method. Energies for various envelope and twist conformers were calculated as a function of the puckering parameters Q and 4. The gauche-gauche, gauche-trans, and trans-gauche orientations of the primary hydroxyl groups at C-5 were accounted for. Our calculations provide some insight into extensive conformational flexibility that both molecules display and shed light on the possible pathways for conformational interconversions. Both molecules display very characteristic conformational behaviour. The conformations of methyl /3-D-arabinofuranoside, which have been determined by single-crystal X-ray diffraction studies, are distributed in two fairly deep low-energy wells. These conformations are no more than 1.5 kcal/mol above the respective energy minima. In

The van der Waals surface envelope was calculated for molecules with О-X-О segment (where X is a tetrahedral centre) as a function of the torsional angles of X-О bonds. Merely small differences were found between the surface and the volume of energetically stable conformers. The conforma tional variation of the surface was not substantially affected by an inclusion of lone electron pairs in the calculation. The implications of torsional variation of molecular surface on the microthermodynamical surface and on the Gibbs energy of solvation in Sinanoglu's solvophobic theory have been discussed. The limitations have been pointed out for the use of molecular surface as the sole criterion of the extent of solute solvation.

Cl), C,,H,O,,, M, = 376.4, is trthorhombic, space group P2,2,2, with a = 10.3028(10), b = 11.1875(3), c = 15.748403) A, V= 1815.2(4) k, DC = 1.377 gcmp3, ~(CuKcu) = 9.5 cm-' and 2 = 4. The structure was refined to R = 0.033 and R, = 0.045 for 1984 observed reflections. Crystalline 1 has a dimeric cyclic acetal-hemiacetal structure, formed by self aldol condensation of two monomers. The absolute configuration at the condensation centers, C-5 and C-5', were assigned as 5R and 5S, respectively. In the dimer 1, the xylofuranose rings adopt different conformations, one is a twist 3T4, whereas the second is an envelope E4 slightly distorted towards the 3T4 conformation; their fused 1,2-0-isopropylidene rings adopt 0m2E and o-2Tc_6 conformations, respectively. The J,3-dioxane ring has a distorted chair conformation with puckering parameters Q = 0.516 A, 4 = 90.9, and f3 = 11.0". The molecules are linked in the crystal through intermolecular hydrogen-bonding interactions that involve the two hydroxyl groups, OH-3 and OH-5', and the isopropylidene ring oxygen atoms, O-2 and O-l', as donor and acceptor, respectively.

The semiempirical PCILO method has been used to study stereochemistry of the intramolecular hydrogen bond O-H...0 in 2-methoxyphenol (guaiacol) and 2-methoxy-6-fonmyl phenol (o-vanillin). According to my calculations, the hydrogen bond in guaiacol is weak and has energy of 2.7 kJ/mole and forms a planar five membered ring. The hydrogen bond fonmed by carbonyl oxygen of the formyl gTOUp in o-vanillin is more stable and fonms a nonplanar six membered ring with an angle of rotation of the -CHO group out-of-the-plane of the benzene ring equal to 15O. The energy of this hydrogen bond is 6.07 kJ/mole. +FOT PaTt VII see Tef. L81 l ++Present address:

The 2-methylaminotetrahydropyran was used as a model to study conformational properties of the N-glycosidic linkage in glycosylamines. Relaxed two-dimensional conformational (phi, psi) maps in 20 solvents were calculated by a method in which the total energy is divided into the energy of the isolated molecule and the solvation energy. Molecular geometry optimization has been carried out for each conformer using the quantum chemical method PCILO. The calculated variations of the geometry are consistent with the results obtained by the statistical analysis of available experimental data retrieved from the Cambridge Structural Database. The calculated abundances of conformers show that the polarity of the solvent has little effect on the anomeric ratio, and the form having the methylamino group equatorial is favored in all considered solvents.

The three-dimensional conformational space available to cc-~-(1 + 6)-linked glycans is reported. The isoenergy conformational maps were prepared by defining three rotatable bonds between rigid glucopyranose residues. The calculation of internal energy considered van der Waals, torsional, and hydrogen-bond factors. The results of the analysis may be used to predict properties of (1 3 6)-a-D-homoglycans having either an axial or equatorial hydroxyl group at C-4. The theoretical isoenergymaps are in good agreement with experimental data from crystal structures of oligosaccharides having the same linkage. The results are discussed in terms of the biological role of polysaccharides containing the a-~-(1 + 6) linkage. *Dedicated to Professor Dexter French on the occasion of his 60th birthday; his contributions to the chemistry and biochemistry of starch have opened the "Pandora's box" of the native granule. tPresent address: