Asymmetric desymmetrization of meso-diols by C₂-symmetric chiral 4-pyrrolidinopyridines

• Hartmut Schedel,
• Keizo Kan,
• Yoshihiro Ueda,
• Kenji Mishiro,
• Keisuke Yoshida,
• Takumi Furuta and
• Takeo Kawabata

Beilstein J. Org. Chem. 2012, 8, 1778–1787, doi:10.3762/bjoc.8.203

• responsible for the asymmetric acylation. The most stable conformer A of the acylpyridinium ion was generated by a molecular modeling search (AMBER* force field with the GB/SA solvation model for chloroform using MacroModel V 9.0 (50,000 steps MCMM)) and shown in Figure 2a and Figure 2b. Since the amide

Synthesis and evaluation of new guanidine-thiourea organocatalyst for the nitro-Michael reaction: Theoretical studies on mechanism and enantioselectivity

• Tatyana E. Shubina,
• Matthias Freund,
• Sebastian Schenker,
• Timothy Clark and
• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2012, 8, 1485–1498, doi:10.3762/bjoc.8.168

• the further optimization at the B3PW91/6–31G(d) level. Conformer 7a is the only one with two hydrogen bonds between a nitrogen atom in the guanidine moiety and hydrogen atoms from the thiourea fragment. While inclusion of the solvent effect (DFT-PCM) gives a preference of 3.1 kcal·mol−1 for 7b over 7a

The preferred conformation of erythro- and threo-1,2-difluorocyclododecanes

• Yi Wang,
• Peer Kirsch,
• Tomas Lebl,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2012, 8, 1271–1278, doi:10.3762/bjoc.8.143

• a transition state. This may arise as a result of desolvation for this isomer. Computational study In order to explore conformer energies further, a theoretical study MP2/6-311+G(2d,p)//B3LYP/6-311+G(2d,p)+ZPE) [16] was carried out to assess relative ground-state energies of candidate conformers

• conformer III, the lowest in energy. For the threo stereoisomer 5b, four conformers, IV–VII were considered. Conformers IV and V, which have two and one endo fluorine, respectively, are highest in energy. In particular, conformer IV with two endo fluorines has a ground-state energy of 6.65 kcal·mol−1, the

• highest of all of those examined, illustrating the additive and negative impact of placing fluorines into endo orientations. Conformers VI and VII are lower in energy. It was anticipated at the outset that conformer VI may be the most favoured for the threo isomer; however, this does not appear to be the

Conformational analysis, stereoelectronic interactions and NMR properties of 2-fluorobicyclo[2.2.1]heptan-7-ols

• Fátima M. P. de Rezende,
• Marilua A. Moreira,
• Rodrigo A. Cormanich and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2012, 8, 1227–1232, doi:10.3762/bjoc.8.137

• ) in steps of 10° at the HF/6-31g(d,p) level, using the Gaussian09 package of programs [13]. Each minimum was subsequently optimized at the MP2/aug-cc-pVDZ level, and the respective energies are given in Table 1, which shows that the conformer of 5 with the hydroxy hydrogen directed toward the fluorine

• hydroxy group do not exhibit such an interaction and are highly stable [6][8]. This can be either due to other attractive interactions present in the referred conformer or prevalent repulsive interactions (e.g., between fluorine and oxygen lone pairs) in the other conformer(s). In the present study

• , comparison of 5 with three diastereoisomers (6–8) gives insight into the role of F∙∙∙HO intramolecular HB for the conformer stabilization, since the simple observation that the conformational energy in 5 is ca. 2.9 kcal mol−1 does not warrant that F∙∙∙HO intramolecular HB is the dominating, or even an

Synthesis of a library of tricyclic azepinoisoindolinones

• Bettina Miller,
• Shuli Mao,
• Kara M. George Rosenker,
• Joshua G. Pierce and
• Peter Wipf

Beilstein J. Org. Chem. 2012, 8, 1091–1097, doi:10.3762/bjoc.8.120

• steric bulk of the adamantyl group: molecular mechanics calculations indicate that the aminolysis of 5 to regioisomer 10 proceeds with minimal isomerization of the seven-membered ring geometry in the lowest-energy product conformer, whereas the formation of 9 requires a substantial ring flip [41

Toward unidirectional switches: 2-(2-Hydroxyphenyl)pyridine and 2-(2-methoxyphenyl)pyridine derivatives as pH-triggered pivots

• Christina Tepper and
• Gebhard Haberhauer

Beilstein J. Org. Chem. 2012, 8, 977–985, doi:10.3762/bjoc.8.110

• repulsive interaction between the free electron pairs of the nitrogen and the oxygen atoms, should be the more stable one (Scheme 1). A protonation of the nitrogen inverts the relative energies of the two conformers. Due to the internal hydrogen bridge the conformer of 4 having a dihedral angle of 0° is the

• . Unfortunately, there is no hint toward a preference for the M conformer of 13 in solution: For example, in the 1H NMR spectrum of 13 signals for only one conformer were found, even at lower temperatures, which means that the diastereomers are rapidly interconverting and the ratio between them cannot be

On the bromination of the dihydroazulene/vinylheptafulvene photo-/thermoswitch

• Virginia Mazzanti,
• Martina Cacciarini,
• Søren L. Broman,
• Christian R. Parker,
• Magnus Schau-Magnussen,
• Andrew D. Bond and
• Mogens B. Nielsen

Beilstein J. Org. Chem. 2012, 8, 958–966, doi:10.3762/bjoc.8.108

• ; photoswitch; vinylheptafulvene; Introduction 1,8a-Dihydroazulene-1,1-dicarbonitrile (DHA, 1) is a yellow photochromic compound, which undergoes a light-induced 10-electron retro-electrocyclization to a red-colored vinylheptafulvene (VHF) (Scheme 1) [1][2][3]. The VHF compound is formed as the s-cis conformer

• , which, however, is in equilibrium with the more stable s-trans conformer. The s-cis VHF undergoes a thermally induced cyclization to regenerate the original DHA. The significant structural difference between the DHA and VHF forms, as reflected in their different colors and hence electronic properties

An easy α-glycosylation methodology for the synthesis and stereochemistry of mycoplasma α-glycolipid antigens

• Yoshihiro Nishida,
• Yuko Shingu,
• Yuan Mengfei,
• Kazuo Fukuda,
• Hirofumi Dohi,
• Sachie Matsuda and
• Kazuhiro Matsuda

Beilstein J. Org. Chem. 2012, 8, 629–639, doi:10.3762/bjoc.8.70

• + gt + tg = 1. In this equation, a perfect staggering (Φ1 and Φ2 = +60, −60 or 180 degree) is assumed for every conformer. Figure 3 summarizes the results for a series of 3-substituted 1,2-di-O-palmitoyl-sn-glycerols, which involve tripalmitin (Figure 3, entry 1), DPPC (1,2-di-O

• symmetric lipid, the asymmetric phospholipid (DPPC) favors the gt-conformer more strongly around the tail lipid moiety along the sn-1,2 position, while disfavoring the tg-conformer, in the ratio of gt (59%), gg (34%) and tg (7%). The head phosphate moiety along the sn-2,3 position adopts the three

• conformation. Here, it should be mentioned that the conformer distribution coincides between I-a (Figure 3, entry 5) and DPPC (Figure 3, entry 2) at the head moiety [gt (33%), gg (34%) and tg (33%)]. The above analysis was carried out also for the stereoisomer I-b and the related glycolipids (Figure 4, entries

Fifty years of oxacalix[3]arenes: A review

• Kevin Cottet,
• Paula M. Marcos and
• Peter J. Cragg

Beilstein J. Org. Chem. 2012, 8, 201–226, doi:10.3762/bjoc.8.22

• , the presence of a hydrogen-bond motif in the cone conformer makes it the more stable form. In 1985, Gutsche investigated the conformational flexibility of parent calix[n]arenes (n = 4–8) and oxacalixarenes by temperature-dependent 1H NMR [5]. The through-the-annulus rotation barrier for oxacalix[3

• inversion in CDCl3 was <38 kJ mol−1, in contrast with 66 kJ mol−1 for the calix[4]arene analogue. To freeze the oxacalix[3]arene conformer, through-the-annulus rotation must be prevented. This can be achieved by the introduction of sufficiently large groups on the lower rim of the macrocycle. Upper-rim

• conformation only. When the reaction was performed in the presence of t-BuOK a 1:4 mixture of cone and partial-cone was obtained and even with Cs2CO3 the cone conformer could be detected. It seems that K+ and Cs+ favourably interact with the three phenolic oxygen atoms placed on the same side, whereas Na

The interplay of configuration and conformation in helical perylenequinones: Insights from chirality induction in liquid crystals and calculations

• Elisa Frezza,
• Silvia Pieraccini,
• Stefania Mazzini,
• Alberta Ferrarini and
• Gian Piero Spada

Beilstein J. Org. Chem. 2012, 8, 155–163, doi:10.3762/bjoc.8.16

• instance, g+ t is a conformer with one chain in the gauche+ and the other in the trans state. The conformers with side chains in different states are two-fold degenerate: g+ t (= t g+), g+ g− (= g− g+) and g− t (= t g−). For the conformational study, we used DFT calculations in vacuum as implemented in the

• butterfly” by Falk and co-workers [37]. The two geometries, as obtained for the g+ g+ conformer of 1, are shown in Figure 3. Table 1 reports the twist angles χ1 [C(1)–C(12b)–C(12a)–C(12)] and χ2 [C(6)–C(6a)–C(6b)–C(7)], which characterize the helical shape of the core of 1 and 2. Not surprisingly, in view

• considered in our systematic analysis of the effects of side-chain conformations. Very similar structures were obtained by geometry optimization at the B3LYP/6-31g(d,p) and at the M06-2X/6-31+g(d,p) level; the latter are shown in Figure 4. On the contrary, the conformer energies were found to depend strongly

Computational evidence for intramolecular hydrogen bonding and nonbonding X···O interactions in 2'-haloflavonols

• Tânia A. O. Fonseca,
• Matheus P. Freitas,
• Rodrigo A. Cormanich,
• Teodorico C. Ramalho,
• Cláudio F. Tormena and
• Roberto Rittner

Beilstein J. Org. Chem. 2012, 8, 112–117, doi:10.3762/bjoc.8.12

• 10.3762/bjoc.8.12 Abstract The conformational isomerism and stereoelectronic interactions present in 2'-haloflavonols were computationally analyzed. On the basis of the quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis, the conformer stabilities of 2'-haloflavonols were

• carbonyl oxygen (conformer A), establishing an intramolecular HB as the stabilizing interaction of this conformation, in agreement with the crystal structure of 2'-methoxyflavonol [19] and with the bioactive conformation of fisetin [20] and quercetin [21]. Moreover, a weak (H)O···H–C HB also takes place in

• and a nonbonding F…O interaction. The formation of the nonbonding F…O interaction in conformer A, having fluorine as electron acceptor, is supposed to be due to the partial negative atomic charge on the ether oxygen and a less negative atomic charge on the fluorine atom (the QTAIM atomic charges are

Binding of group 15 and group 16 oxides by a concave host containing an isophthalamide unit

• Jens Eckelmann,
• Vittorio Saggiomo,
• Svenja Fischmann and
• Ulrich Lüning

Beilstein J. Org. Chem. 2012, 8, 11–17, doi:10.3762/bjoc.8.2

• anion transport. Rotation along the amide–aryl bonds leads to syn/anti, syn/syn and anti/anti conformers (syn and anti defined with respect to the relative orientation of the NH atoms), and only the syn/syn conformer of an isophthalamide is capable of simultaneously binding an anion by both NH groups

(How) does 1,3,5-triethylbenzene scaffolding work? Analyzing the abilities of 1,3,5-triethylbenzene- and 1,3,5-trimethylbenzene-based scaffolds to preorganize the binding elements of supramolecular hosts and to improve binding of targets

• Xing Wang and
• Fraser Hof

Beilstein J. Org. Chem. 2012, 8, 1–10, doi:10.3762/bjoc.8.1

• were studied and reported here. The results of the calculation in the gas phase were in good agreement with the values reported by Mislow (Table 4). The ududud conformer adopted the most stable conformation and the energy level of this conformation was 4.3 kcal/mol lower than the second most stable

• conformer, namely uddudd. One can expect a significant effect of the nature of the recognition elements on conformational energies. Many recognition elements that vary in shape, functionality, charge, and chirality have been reported. We picked pyrazole-derived hosts 4 (used for cation binding) [17] and

• calculations. The conformers ududud and uddudd, are almost of the same energy and the next two most stable conformers, ududdd and udduud, lie only 0.3 and 0.4 kcal/mol above the ududud conformer. When the solvent condition is changed to water the trend of the results is much closer to those of hexaethylbenzene

Structural conditions required for the bridge lithiation and substitution of a basic calix[4]arene

• Conrad Fischer,
• Wilhelm Seichter and
• Edwin Weber

Beilstein J. Org. Chem. 2011, 7, 1602–1608, doi:10.3762/bjoc.7.188

• methine proton. In contrast, after addition of the fixatives to a CDCl3 solution of 14, a more complex signal pattern indicates the presence of at least two fixed conformations. One can be related to the expected resonances of the cone conformer, while the resonances of the second species fit best to a

• , transferring the 1,2-alternate to the cone conformer, is impossible, since it would ultimately lead to an axial orientation of the COOH group, which is strictly avoided for steric reasons [4][10]. Crystal structure of compound 12 Crystallization of the mixed calixarene ether 12 from ethanol yielded colourless

Synthesis of enantiomerically enriched (R)-¹³C-labelled 2-aminoisobutyric acid (Aib) by conformational memory in the alkylation of a derivative of L-alanine

• Stephen P. Fletcher,
• Jordi Solà,
• Dean Holt,
• Robert A. Brown and
• Jonathan Clayden

Beilstein J. Org. Chem. 2011, 7, 1304–1309, doi:10.3762/bjoc.7.152

• less hindered conformer of 3. Alkylated 5 was freed from its protecting group and the naphthamide “aide-mémoire” by heating to reflux in 47% hydrobromic acid, followed by esterification with methanol and thionyl chloride, which returned the labelled Aib as its methyl ester hydrochloride salt 6* in 93

NMR studies of anion-induced conformational changes in diindolylureas and diindolylthioureas

• Damjan Makuc,
• Jennifer R. Hiscock,
• Mark E. Light,
• Philip A. Gale and
• Janez Plavec

Beilstein J. Org. Chem. 2011, 7, 1205–1214, doi:10.3762/bjoc.7.140

• mechanics calculations. NOE experiments showed that the anti–anti conformer along the C7–N7α bonds was predominant in DMSO-d6 solution in the absence of anions. Anion-induced changes in the 1H and 15N chemical shifts confirm the weak binding of chloride anions with negligible conformational changes. Strong

• along the C7–N7α bonds and the syn–syn conformer was preferred for anion–receptor complexes. The conformational changes upon anion binding are in good agreement with energetic preferences established by ab initio calculations. Keywords: anion recognition; conformation analysis; host–guest systems; NMR

• major, energetically preferred, conformers are likely to be observed (Figure 3). The syn–syn conformer, where NH protons form a convergent hydrogen-bonding array, is expected to be adopted in the presence of bound anionic guests, based on the previous solid-state studies. On the other hand, this

Toward an integrated route to the vernonia allenes and related sesquiterpenoids

• Da Xu,
• Michael A. Drahl and
• Lawrence J. Williams

Beilstein J. Org. Chem. 2011, 7, 937–943, doi:10.3762/bjoc.7.104

• -decalin system. Low energy conformers were identified for these species [59]. The lowest energy conformer gave the greatest torsion angles (~175°) for both the alcohol V and the alkoxide VI, and these approach 180°. For comparison purposes, the cis-hydrindane derivative in entry 3 was also studied [38

Intraannular photoreactions in pseudo-geminally substituted [2.2]paracyclophanes

• Henning Hopf,
• Vitaly Raev and
• Peter G. Jones

Beilstein J. Org. Chem. 2011, 7, 658–667, doi:10.3762/bjoc.7.78

• -conformation, which has been shown to be present as a conformer in the solid state by X-ray structural analysis does not photocyclize to 8. Moreover, syn,syn-7 is evidently too sterically hindered (by repulsion of the relevant hydrogen atoms as shown in Scheme 3) to be part of the conformational equilibrium

Accuracy in determining interproton distances using Nuclear Overhauser Effect data from a flexible molecule

• Catharine R. Jones,
• Craig P. Butts and
• Jeremy N. Harvey

Beilstein J. Org. Chem. 2011, 7, 145–150, doi:10.3762/bjoc.7.20

• multi-conformer, flexible small molecules was investigated with the model compound 4-propylaniline. The low accuracy assumed for semi-quantitative NOE distance restraints is typically taken to suggest that large numbers of constraints need to be used in the dynamical analysis of flexible molecules, and

• obtained in a rigid organic molecule, it seems sensible to examine whether this approach can be extended more generally to multi-conformational systems with similar accuracy. Further, it is likely that the accurate interproton distance-assessments from NOE will allow accurate modelling of conformer

• ensemble-averaging of the observed NOEs for each corresponding interproton distance in each contributing conformer. One approach to analysing such ensemble-averaged NOEs is to assume the molecule will occupy a number of distinct low-energy conformations with particular populations in solution. The ensemble

Synthesis of Ru alkylidene complexes

• Renat Kadyrov and
• Anna Rosiak

Beilstein J. Org. Chem. 2011, 7, 104–110, doi:10.3762/bjoc.7.14

• with the resonances of the residual protons H5 (8.12, d, J = 8.2 Hz), H6 (7.50, t, J = 7.0 Hz) and H7/H8 (7.67-7.75, m). Strong NOE enhancement of H1 upon saturation of the carbene proton at 19.75 ppm (see Figure 2) is consistent with preferred conformer 1g in which the naphthyl moiety is directed away

• resonances of both isomers 1e and 1e’. Saturation of the carbene proton at 18.9 ppm led to strong NOE enhancement of the singlet at 7.68 ppm (Figure 3) and allowed the assignment of this signal to the H3 proton of the thienyl moiety and was consistent with the s-trans isomer 1e being the preferred conformer

• (see Scheme 5). The EXSY effect made it possible to assign the signal at 8.80 ppm to H3’ of the minor s-cis conformer. Enhancement of the signal at 6.99 ppm (Figure 4) by saturation of the signal at 8.07 ppm and EXSY inversion of the resonance at 7.79 ppm allowed the assignment of the signals for H5

Intramolecular hydroxycarbene C–H-insertion: The curious case of (o-methoxyphenyl)hydroxycarbene

• Dennis Gerbig,
• David Ley,
• Hans Peter Reisenauer and
• Peter R. Schreiner

Beilstein J. Org. Chem. 2010, 6, 1061–1069, doi:10.3762/bjoc.6.121

• thermodynamic preference for either 7 or 8. The thermal barrier for the reaction of 5 via conformer 5i leading to 8 is lower (18 kcal mol–1, via TS3) than that leading to 7 (27 kcal mol–1, via TS1). These results help rationalize the observed reactivity under HVFP conditions. The thermal barrier for the

• +•). Attempted generation of 12 and the actual pyrolysis product 11. Unanticipated reaction of 6 upon heating in xylenes. Potential energy hypersurface of (o-methoxyphenyl)hydroxycarbene (5) (not drawn to scale; ZPVE included); legend: 5c: carbene, cis conformation; 5t: carbene, trans conformation; 5i: conformer

Catalysis: transition-state molecular recognition?

• Ian H. Williams

Beilstein J. Org. Chem. 2010, 6, 1026–1034, doi:10.3762/bjoc.6.117

• course of 30 ps trajectories, even in the presence of propionate and propionic acid moieties to mimic Glu78 and Glu172 [23]. In contrast, analogous MD simulations for the 4C1 conformer of the reactant complex of phenyl β-xylobioside with BCX showed spontaneous transformation to the 2,5B conformer (Figure

• , revealed a decrease in free energy of activation of about 40 kJ mol−1 due to the presence of the single OY atom in BCX (Figure 6). Fluctuations in the hydrogen-bond distances HY…Oring (red) and HY…Onuc (blue) to the boat conformer of RC, TS and glycosyl-enzyme COV intermediate in the active site of BCX, as

• reorganisation of the electrostatic environment to go from RC to TS than is needed in aqueous solution, thereby achieving selective stabilisation of TS. The boat conformer of a xyloside substrate is favoured over the chair in the active site of BCX owing to a hydrogen bond from Tyr69 to Oring of xylose, but

Synthesis and crystallographic analysis of meso-2,3-difluoro-1,4-butanediol and meso-1,4-dibenzyloxy-2,3-difluorobutane

• Bruno Linclau,
• Leo Leung,
• Jean Nonnenmacher and
• Graham Tizzard

Beilstein J. Org. Chem. 2010, 6, No. 62, doi:10.3762/bjoc.6.62

• disparity in the amounts of each conformer present gives rise to the disorder observed in the crystal structure. The vicinal difluoro group adopts an anti conformation with the F–C–C–F dihedral angle exactly 180°, which manifests itself in the crystallographic inversion centre. Nevertheless, each benzyloxy

The C–F bond as a conformational tool in organic and biological chemistry

• Luke Hunter

Beilstein J. Org. Chem. 2010, 6, No. 38, doi:10.3762/bjoc.6.38

• in these systems. Hyperconjugation effects Consider the well-studied molecule 1,2-difluoroethane (11, Figure 1c). There are two possible staggered conformers, with the fluorine atoms either gauche or anti. NMR and molecular modelling studies have shown that the gauche conformer is lower in energy

• , which is perhaps a surprising result since the fluorine atoms might reasonably be expected to repel each other. What effect overrides the difluoro repulsion and stabilises the gauche conformer? There is a vacant low-energy σ* antibonding orbital associated with each C–F bond (Figure 1c). In the gauche

• conformer of 11, both σ*CF orbitals are aligned with adjacent C–H bonds, which can donate electron density into the σ*CF orbitals in a process known as hyperconjugation [1][2]. Feeding electron density into an antibonding orbital in this way is equivalent to partially breaking the bond, so when

Molecular recognition of organic ammonium ions in solution using synthetic receptors

• Andreas Späth and
• Burkhard König

Beilstein J. Org. Chem. 2010, 6, No. 32, doi:10.3762/bjoc.6.32