Conformational flexibility in open chain molecules: chiral and achiral alkanes

Conformational partition functions of chiral and achiral alkanes have been computed by using a continuum approach (instead of rotational isomeric state approximations). The accessible conformational space per bond depends upon the structure of the compound and is only in the range of 5–13% of the maximum accessible range. In order to partly overcome the intrinsic ambiguity of the term “conformational flexibility”, the distinction between number flexibility (a measure of the number of accessible energy minima) and space flexibility (a measure of the total allotted space) is proposed. Further, the conformational versatility of each bond of a molecule is evaluated in terms of the a priori probability density function of that bond, and it is shown that the use of this function permits a comparison of the relative conformational flexibilities of the individual bonds, which is particularly useful for molecules having more than two rotation angles (where the conventional energy maps cannot be used). Optical rotations are calculated for a series of chiral alkanes by combining the continuum approach for conformational analysis and a recent optical activity calculation scheme. Contributions of single bonds to the molar optical rotation are evaluated and discussed. The influence of temperature upon conformational and chiral properties is evaluated.     

Efficient and flexible synthesis of chiral gamma- and delta-lactones

An efficient and highly flexible synthesis for chiral gamma- and delta-lactones with high enantiomeric purity is described (>99% ee and 57-87% overall yield). The protocol involves alkylation of chiral 1,2-oxiranes with terminally unsaturated Grignard reagents. Subsequent oxidative degradation (OsO(4)-Oxone) of the terminal double bond from chiral alk-1-en-5-ols and alk-1-en-6-ols affords 4- or 5-hydroxy acids and gamma- and delta-lactones after acidic workup. The flexibility and efficiency of the protocol is illustrated by the synthesis of several alkanolides and alkenolides, hydroxy fatty acids and dihydroisocoumarins.     

Palladium-catalyzed asymmetric synthesis of axially chiral molecules

The asymmetric synthesis of chiral 3-alkylidene bicyclo[3.3.0]octane and 4-substituted 1-alkylidene cyclohexane systems has been carried out (in up to 40% ee) by the palladium-catalyzed reaction of allylic acetates with sodium dimethyl malonate or morpholine.     

Conformational preferences of chiral molecules: free jet rotational spectrum of 1-phenyl-1-propanol

The rotational spectra of normal and O-d species of the two most stable conformers of chiral 1-phenyl-1-propanol, obtained by free jet millimetre-wave absorption spectroscopy reveal that both conformers are stabilized by a O-H[dot dot dot]pi interaction, and have the Calpha-Cbeta-bond oriented nearly perpendicular to the plane of the benzene ring. The methyl group is trans with respect to the phenyl group for the most stable conformer (T), while it is gauche with respect to the phenyl group and entgegen with respect to the hydroxyl group for the second most stable conformer (GE). The energy difference (E(GE)-E(T)) was estimated to be 50(50) cm(-1) from relative intensity measurements.     

Relevance of torsional effects to the conformational equilibria of 1,5-diaza-cis-decalins: a theoretical and experimental study

1,5-Diaza-cis-decalin populates two conformations in which the nitrogen atoms are either gauche (N-in) or anti (N-out) to one another. The equilibrium mixture of the two conformers depends on the substituents at the nitrogen atom, as well as the reaction conditions. Ab initio (HF/6-31G, B3LYP/6-31+G) and molecular mechanics (Amber) calculations have been performed to examine the possible role of stereoelectronics and steric effects in controlling the equilibrium of substituted 1,5-diaza-cis-decalins. In the present study, N,N'-diethyl- and N,N'-bistrifluoroethyl-1,5-diaza-cis-decalins have been synthesized, and the equilibrium mixtures have been measured using 1H and 13C NMR experiments. Steric effects appear to control the equilibria between the two conformational isomers of 1,5-diaza-cis-decalin while torsional effects appear to dominate the equilibria for the N,N'-dialkyl derivatives.     

Structure-driven design and synthesis of chiral dioxocyclam derivatives

Based on an analysis of previously reported structures and a potential geometry fit with substrates, a new family of chiral dioxocyclam derivatives have been designed. The synthesis of those ligands was accomplished starting from l-proline and α-d-amino acids (converted to β-amino acids) with a key step of macrocyclization reaction of amino esters. All ligands were converted into neutral copper(II) complexes (amide groups underwent deprotonation of upon treatment of ligands with copper(II) acetate). The complexes exhibit the desired shape of their active surfaces, as proved by X-ray analysis.     

Synthesis and structural and photoswitchable properties of novel chiral host molecules: axis chiral 2,2'-dihydroxy-1,1'-binaphthyl-appended stiff-stilbene

Novel photoswitchable chiral hosts having an axis chiral 2,2'-dihydroxy-1,1'-binaphthyl (BINOL)-appended stiff-stilbene, trans-(R,R)- and -(S,S)-1, were synthesized by palladium-catalyzed Suzuki-Miyaura coupling and low-valence titanium-catalyzed McMurry coupling as key steps, and they were fully characterized by various NMR spectral techniques. The enantiomers of trans-1 showed almost complete mirror images in the CD spectra, where two split Cotton effects (exciton coupling) were observed in the beta-transitions of the naphthyl chromophore at 222 and 235 nm, but no Cotton effect was observed in the stiff-stilbene chromophore at 365 nm. The structures of (R)-10 and trans-(R,R)-1 were confirmed by X-ray structural analysis. The optimized structure of cis-1 by MO calculations has a wide chiral cavity of 7-8 A in diameter, whereas trans-1 cannot form an intramolecular cavity based on the X-ray data. Irradiation of (R,R)-trans-1 with black light (lambda = 365 nm) in CH3CN or benzene at 23 degrees C led to the conversion to the corresponding cis-isomer, as was monitored by 1H NMR, UV-vis, and CD spectra. At the photostationary state, the cis-1/trans-1 ratio was 86/14 in benzene or 75/25 in CH3CN. On the other hand, irradiation of the cis-1/trans-1 (75/25) mixture in CH3CN with an ultra-high-pressure Hg lamp at 23 degrees C (lambda = 410 nm) led to the photostationary state, where the cis-1/trans-1 ratio was estimated to be 9/91 on the basis of the 1H NMR spectra. The cis-trans and trans-cis interconversions could be repeated 10 times without decomposition of the C=C double bond. Thus, a new type of photoswitchable molecule has been developed, and trans-1 and cis-1 were quite durable under irradiation conditions. The guest binding properties of the BINOL moieties of trans- and cis-(R,R)-1 with F-, Cl-, and H2PO4- were examined by 1H NMR titration in CDCl3. Similar interaction with F- and Cl- was observed in trans-1 (host/guest = 1/1, Kassoc = (1.0 +/- 0.13) x 103 for F- and (4.6 +/- 0.72) x 102 M-1 for Cl-) and cis-1 (host/guest = 1/1, Kassoc = (1.0 +/- 0.13) x 103 for F- and (5.9 +/- 0.69) x 10 M-1 for Cl-), but H2PO4- interacted differently: the cis-isomer formed the 1/1 complex (Kassoc = (9.38 +/- 2.67) x 10 M-1), whereas multistep equilibrium was expected for the trans-isomer.     

Novel chiral lipoxygenase substrates: design and synthesis. Part 2

A series of novel lipoxygenase substrates carrying a spacing modifier with a non-ionic hydroxyl terminus have been synthesized in an enantioselective fashion. One of the methylene hydrogens (flanked by the cis,cis-pentadienyl moiety) is replaced by alkyl, aryl and hydroxyl groups. The key steps in the synthesis involved enzymatic transesterification of 1,3-propanediol derivatives and two consecutive cis-selective Wittig olefinations.     

Design and synthesis of novel chiral spiro ionic liquids

[reaction: see text] Novel chiral imidazolium salts have been synthesized as examples of chiral ionic liquids with a spiro skeleton. Effects of N-substituents and counteranions on the melting point of spiro imidazolium salts and their chiral discrimination abilities are described.     

Stereoselective synthesis of chiral 3,4,5-trisubstituted 1,5-dihydropyrrol-2-ones from azadienes

A new access to enantiopure 3-phthalimido-4-amino-5-(1-hydroxyalkyl) 1,5-dihydropyrrol-2-ones has been developed from 1,3-azadienes. Stereoselective Lewis acid catalyzed addition of a cyano group to an azadiene, followed by intramolecular ring closure, in a four-step one-pot synthesis, results in the formation of γ-lactams in satisfactory yields.     

Conformational analysis of nucleic acid molecules with flexible furanose rings in dihedral angle space

The computational algorithm that works in the coordinate space of dihedral angles (i.e., bond lengths and bond angles are kept fixed and only rotatable dihedral angles are treated as independent variables) is extended to deal with the pseudorotational m otion of furanose rings by introducing a variable of pseudorotation. Then, this algorithm is applied to a distance geometry calculation that generates three-dimensional (3D) structures that are consistent with given constraints of interatomic distances. This method efficiently generates 3D structures of an RNA hairpin loop which satisfy a set of experimental NMR data. © 1996 by John Wiley & Sons, Inc.     

Conformational control of enolate geometry: a short synthesis of germacrene-D

A synthesis of (±)-germacrene-D is reported that employs a site- and stereoselective enolization of a conformationally biased ten-membered ring ketone.     

A novel chiral sulfonium yilde: highly enantioselective synthesis of vinylcyclopropanes

A newly designed chiral sulfonium allylide, generated in situ from the corresponding sulfonium salt in the presence of KOBu(t), reacted with alpha,beta-unsaturated esters, ketones, amides, and nitriles to afford trans-2-silylvinyl-trans-3-substituted cyclopropyl esters, ketones, amides, and nitriles with outstanding diastereoselectivity and excellent enantioselectivity in good to high yields. A mechanistic rationale is proposed.     

Asymmetric synthesis and antiviral activity of novel chiral amino-pyrimidine derivatives

By using a chiral cinchona alkaloid-squaramide catalyst, a series of both enantiomers of novel amino-pyrimidine derivatives can be obtained in an enantioselective three-component one-pot Mannich reaction with high yields and excellent enantioselectivities. In addition, these chiral derivatives were found to exhibit higher antiviral activities against tobacco mosaic virus (TMV) in vivo than the commercial agent ningnanmycin. In particular, chiral compounds (R)-4b and (R)-4e showed excellent antiviral activity against TMV at a concentration of 500?μg/mL, with a curative activity of 56.8% and 55.2%, respectively, a protection activity of 69.1% and 67.1%, respectively, and an inactivation activity of 91.5% and 94.3%, respectively. These values are superior to those of the agent ningnanmycin (which has curative, protective, and inactivation activities of 52.9%, 62.8%, and 90.4%, respectively). The antiviral mechanisms and enhanced antiviral activities of these chiral derivatives are interesting subjects for future investigation.     

Conformational control of flexible molecular tweezers by intramolecular CH/π interaction

The synthesis of new flexible molecular tweezers based on 3,4,8,10,11,13-hexahydro-1H,6H-2,5,9,12-tetraoxa-benzo[1,2:4,5]dicyclooctene bearing two naphthalenes is presented. Intramolecular CH/π interaction between the alkyl ring and the two terminal naphthalenes controls the conformation to give a self-quenched cleft form.     

Enantiodiscrimination in deuterium NMR spectra of flexible chiral molecules with average axial symmetry dissolved in chiral liquid crystals: the case of tridioxyethylenetriphenylene

Flexible chiral molecules undergoing fast interconversion (on the NMR time scale) between different conformational enantiomers may yield "average" axial species with enantiotopically related sites. Contrary to the situation observed for rigid axial molecules, signals from these enantiotopic sites in NMR spectra recorded in chiral liquid-crystalline solvents can be resolved. In the present work, we studied the deuterium NMR spectra of tridioxyethylenetriphenylene (compound 4) statistically deuterated to 10% in the flexible side chains and dissolved in chiral and achiral lyotropic liquid crystals based on poly(gamma-benzylglutamate). The fast chair-chair flipping of the side chains in 4 on average renders the molecule axially symmetric ( D 3 h ) with pairs of enantiotopic ethylene deuterons. These deuterons exhibit unusually large enantiodiscrimination. To explain this observation, we first describe how the average symmetry of flexible molecules can be derived from the symmetry of the "frozen" conformers and the nature of the averaging process. The procedure is then applied to 4 and used to analyze the NMR results. It is shown that the large enantiodiscrimination in the present case reflects a large difference in the orientational ordering of the conformational enantiomers participating in the interconversion processes as well as a large geometrical factor due to the special shape of the dioxyethylene side groups. (1)H and (13)C NMR spectra of 4 in the same lyotropic liquid crystalline solvent are analyzed to determine its ordering characteristics. Several related cases are also discussed.     

Molecular design of flexible liquid crystal oligomers stabilising the chiral frustrated phases

ABSTRACT

Chirality induces structural frustration in liquid crystal systems, producing various kinds of chiral frustrated phases, for example, twist grain boundary (TGB) phases, blue phases (BPs) and dark conglomerate (DC) phases. Almost all molecules exhibiting these frustrated phases have a rigid shape. Especially, a bent–core unit is regarded as a key structure for BPs and DC phases. This paper describes that some flexible liquid crystal oligomers being far from a rigid bent–core molecule stabilise these phases. The LC oligomers have a supermolecular structure in which mesogenic units are connected via flexible spacers. By designing intermolecular interactions, they can exhibit various molecular packing structures in the liquid-crystalline phases as follows: chiral dimers inducing TGB phases, U-shaped and T-shaped oligomers stabilising BPs and achiral liquid crystal trimers exhibiting DC phases. I discuss how the designed liquid crystal oligomers produce the chiral frustrated phases.     

Conformational analysis of 1,3-benzenediol dibenzoate as a model of banana-shaped molecules forming chiral smectic phases

Banana-shaped molecules, e.g. 1,3-phenylene bis[4-(4-n-alkoxyphenyliminomethyl)benzoates] and 1,3-phenylene bis[4-(4-n-alkylphenyliminomethyl)benzoates], form ferroelectric and chiral smectic phases without a chiral carbon. ¹³C NMR measurement suggested that 1,3-benzenediol dibenzoate (BD) moiety assumes asymmetrically twisted conformation which may be ascribed to the chirality of the phases. In this study, conformational analysis was carried out for BD by using the density functional theory (DFT) calculation. The results indicated that the asymmetrical twist conformation of the BD moiety is most stable.