Synthesis and Conformation of Fluorinated β‐Peptidic Compounds

Experimental and theoretical data indicate that, for α‐fluoroamides, the F? C? C(O)? N(H) moiety adopts an antiperiplanar conformation. In addition, a gauche conformation is favoured between the vicinal C? F and C? N(CO) bonds in N‐β‐fluoroethylamides. This study details the synthesis of a series of fluorinated β‐peptides ( 1 – 8 ) designed to use these stereoelectronic effects to control the conformation of β‐peptide bonds. X‐ray crystal structures of these compounds revealed the expected conformations: with fluorine β to a nitrogen adopting a gauche conformation, and fluorine α to a C?O group adopting an antiperiplanar conformation. Thus, the strategic placement of fluorine can control the conformation of a β‐peptide bond, with the possibility of directing the secondary structures of β‐peptides.     

The Gauche Effect in XCH2CH2X Revisited

We have quantum chemically investigated the rotational isomerism of 1,2-dihaloethanes XCH₂CH₂X (X = F, Cl, Br, I) at ZORA-BP86-D3(BJ)/QZ4P. Our Kohn-Sham molecular orbital (KS-MO) analyses reveal that hyperconjugative orbital interactions favor the gauche conformation in all cases (X = F−I), not only for X = F as in the current model of this so-called gauche effect. We show that, instead, it is the interplay of hyperconjugation with Pauli repulsion between lone-pair-type orbitals on the halogen substituents that constitutes the causal mechanism for the gauche effect. Thus, only in the case of the relatively small fluorine atoms, steric Pauli repulsion is too weak to overrule the gauche preference of the hyperconjugative orbital interactions. For the larger halogens, X⋅⋅⋅X steric Pauli repulsion becomes sufficiently destabilizing to shift the energetic preference from gauche to anti, despite the opposite preference of hyperconjugation.     

Effect of Anchimeric Assistance in the Reaction of Triphenylphosphine with α,β‐Unsaturated Carboxylic Acids

Quaternization of triphenylphosphine with maleic and cis‐aconitic acids is strongly accelerated by participation of the cis‐carboxyl group in stabilization of the phosphonium zwitterion intermediate by intramolecular hydrogen bonding, in spite of steric hindrance by the acid's reaction center. A similar effect for trans‐isomeric acids is not observed, which can be rationalized on the basis of spatial structures of the generated zwitterions, implying an electrostatic interaction between the phosphonium center and carbonyl oxygen atom. The effect of anchimeric assistance decreases when the intramolecular hydrogen bonding disfavors attack of the phosphine on the sterically less hindered carbon atom of the C=C bond, as observed for cis‐aconitic acid.     

The Crystal Structure of (2 R, 7 S, 10 R)-2,10-diamino-5,5,7-trimethyl-4,8-diazaundecanenickel (II) perchlorate

The structure of the title compound, a tricyclic Ni(II) tetra-amine complex has been determined from analysis of photographic X-ray data. The crystal system is orthorhombic, space group P2₁2₁2₁, with unit cell dimensions a = 9.802, b = 8.998, c = 24.378 Å. The Ni atom is square planar coordinated. The six-membered chelate ring has a chair conformation. One of the five-membered chelate rings has a distorted gauche (λ) conformation with the methyl substituent in an equatorial position, the other has an unsymmetrical gauche (δ) conformation with the methyl substituent axial.     

Determination of the Influence of Side‐Chain Conformation on Glycosylation Selectivity using Conformationally Restricted Donors

The synthesis of a series of conformationally locked mannopyranosyl thioglycosides in which the C6?O6 bond adopts either the gauche,gauche, gauche,trans, or trans,gauche conformation is described, and their influence on glycosylation stereoselectivity investigated. Two 4,6‐O‐benzylidene‐protected mannosyl thioglycosides carrying axial or equatorial methyl groups at the 6‐position were also synthesized and the selectivity of their glycosylation reactions studied to enable a distinction to be made between steric and stereoelectronic effects. The presence of an axial methoxy group at C6 in the bicyclic donor results in a decreased preference for formation of the β‐mannoside, whereas an axial methyl group has little effect on selectivity. The result is rationalized in terms of through‐space stabilization of a transient intermediate oxocarbenium ion by the axial methoxy group resulting in a higher degree of S_N1‐like character in the glycosylation reaction. Comparisons are made with literature examples and exceptions are discussed in terms of pervading steric effects layered on top of the basic stereoelectronic effect.     

Enantioselective Aziridination of Cyclic Enals Facilitated by the Fluorine‐Iminium Ion Gauche Effect

The enantioselective, organocatalytic aziridination of small, medium and macro‐cyclic enals is reported using (S)‐2‐(fluorodiphenyl methyl)‐pyrrolidine. Central to the reaction design is the reversible formation of a β‐fluoroiminium ion intermediate, which is pre‐organised on account of the fluorine‐iminium ion gauche effect. This conformational effect positions the fluorine substituent synclinal‐endo to the electropositive nitrogen centre thus benefiting from favourable stereoelectronic and electrostatic interactions (σ_C?H→σ_C?F*; F^δ?…?N⁺). Consequently, one of the shielding groups on the fluorine‐bearing carbon atom is positioned above the π‐system, forming the basis of an enantioinduction strategy. Treatment of this intermediate with a “nitrene” source furnished a series of novel, optically active aziridines (e.r. up to 99.5:0.5). Further derivatisation of the product aziridines gives facile access to various amino acid derivatives, including β‐fluoroamino acids. Crystallographic analyses of both the aziridines and their derivatives are disclosed.     

Theoretical and X-ray Crystallographic Evidence of a Fluorine-Imine Gauche Effect: An Addendum to Dunathan's Stereoelectronic Hypothesis

The preference of β‐fluoroimines to adopt a gauche conformation has been studied by single‐crystal X‐ray diffraction analysis and DFT methods. Empirical and theoretical evidence for a preferential gauche arrangement around the NCCF torsion angle (?) is presented ((E)‐2‐fluoro‐N‐(4‐nitrobenzylidene)ethanamine: ?_NCCF=70.0°). In the context of this study, the analysis of a pyridoxal‐derived β‐fluoroaldimine was performed, a species that is implicated in the inhibition of pyridoxal phosphate (PLP)‐dependent enzymes by β‐fluoroamine derivatives. The gauche preference of the internal aldimine (=NCH₂CH₂F) that can be rationalized by stereoelectronic arguments does not hold for the corresponding external system (N?CHCH₂F) (E_min when ?_NCCF=120°). Moreover, the C? F bond is lengthened by more than 0.02 Å at ?_NCCF=±90°, when it is exactly antiperiplanar to the conjugated imine. This activation of the C? F σ bond by an adjacent π system constitutes an addendum to Dunathan’s stereoelectronic hypothesis.     

Analyse Conformationnelle par RMN du Proton des Oxo-2 Oxathiazannes-1,2,3 (Sulfinamates Cycliques) Diversement Substitués en 3, 4 et 6

In this study, carried out with 16 compounds, the chair form with an axial S?O group (CA) is found, in the absence of C-4, C-5 and C-6 substituents, to be the most stable (ΔG>8,4 kJ mole^?1), as previously reported for analogous cyclic sulfites. When methyl or tert-butyl substituents are present on the 4 and 6 carbon atoms, the conformation of the ring depends on their respective orientation towards the S?O group, and on the nature of the substituent of the nitrogen atom. For the trans isomers, the conformation remains anancomeric chair (CA) except when important gauche interactions exist: thus the strong Me/tBu gauche interaction in the 3-tert-butyl-4-t-methyl-2-r-oxo-1,2,3-oxathiazan induces a twist form with a 3,6-axis and an axial S?O group (CNA). When the 4- or 6-substituent is cis, the conformation of the sulfinamate may be either a chair form with an axial S?O group (CA), if the 4-substituent is a methyl, (even with a tert-butyl group in the 3-position which would be in the axial orientation) or a twist form with a 1,4-axis and an axial S?O group (COA) if the 4-substituent is a tert-butyl. Unlike cyclic sulfites, the equatorial SO chair form (CE) and the twist forms with a 2,3-axis and an isoclinal S?O group (CS, CS′) are rarely involved.     

Heteroorganic betaines

The structures of three silicon-containing organophosphorus betaines containing the⁺P−C−Si−S⁻ fragment were established by X-ray diffraction study. Due to the attractive electrostatic interaction between the anionic and cationic centers, the main chain adopts agauche conformation, whereas this chain in theS-ethyl derivative of the phosphonic salt [Ph₃P⁺−CMe₂−SiMe₂SEt]Br⁻ adopts atrans conformation. The changes in the geometric parameters of betaines depending on the substituents at the phosphorus, carbon, and silicon atoms were analyzed. The P−S bond can in principle be formed, resulting in the closure of the four-membered ring provided that additional steric hindrances at the silicon atom occur.     

Janus Face All-cis 1,2,4,5-tetrakis(trifluoromethyl)- and All-cis 1,2,3,4,5,6-hexakis(trifluoromethyl)- Cyclohexanes

We report the synthesis of all-cis 1,2,4,5-tetrakis (trifluoromethyl)- and all-cis 1,2,3,4,5,6-hexakis (trifluoromethyl)- cyclohexanes by direct hydrogenation of precursor tetrakis- or hexakis- (trifluoromethyl)benzenes. The resultant cyclohexanes have a stereochemistry such that all the CF₃ groups are on the same face of the cyclohexyl ring. All-cis 1,2,3,4,5,6-hexakis(trifluoromethyl)cyclohexane is the most sterically demanding of the all-cis hexakis substituted cyclohexanes prepared to date, with a barrier (ΔG) to ring inversion calculated at 27 kcal mol⁻¹. The X-ray structure of all-cis 1,2,3,4,5,6-hexakis(trifluoromethyl)cyclohexane displays a flattened chair conformation and the electrostatic profile of this compound reveals a large diffuse negative density on the fluorine face and a focused positive density on the hydrogen face. The electropositive hydrogen face can co-ordinate chloride (K≈10³) and to a lesser extent fluoride and iodide ions. Dehydrofluorination promoted decomposition occurs with fluoride ion acting as a base.     

Equilibres conformationnels de dérivés de sucres à insaturation terminale

The conformation in solution of several unsatured sugars of the general type XHC?CH—glycosyl has been studied by NMR. In the trans series, the population of the sterically permitted gauche conformer increases with the M-ability of X. In the cis series, the population of the trans conformer increases with the space requirements of X. These phenomena are discussed.     

Co‐crystals of 3‐deoxy‐3‐fluoro‐α‐d‐glucopyranose and 3‐deoxy‐3‐fluoro‐β‐d‐glucopyranose

3‐Deoxy‐3‐fluoro‐d ‐glucopyranose crystallizes from acetone to give a unit cell containing two crystallographically independent molecules. One of these molecules (at site A) is structurally homogeneous and corresponds to 3‐deoxy‐3‐fluoro‐β‐d ‐glucopyranose, C₆H₁₁FO₅, (I). The second molecule (at site B) is structurally heterogeneous and corresponds to a mixture of (I) and 3‐deoxy‐3‐fluoro‐α‐d ‐glucopyranose, (II); treatment of the diffraction data using partial‐occupancy oxygen at the anomeric center gave a high‐quality packing model with an occupancy ratio of 0.84:0.16 for (II):(I) at site B. The mixture of α‐ and β‐anomers at site B appears to be accommodated in the lattice because hydrogen‐bonding partners are present to hydrogen bond to the anomeric OH group in either an axial or equatorial orientation. Cremer–Pople analysis of (I) and (II) shows the pyranosyl ring of (II) to be slightly more distorted than that of (I) [θ_(I) = 3.85 (15)° and θ_(II) = 6.35 (16)°], but the general direction of distortion is similar in both structures [ϕ_(I) = 67 (2)° (B_C1,C4) and ϕ_(II) = 26.0 (15)° (^C3TB_C1); B = boat conformation and TB = twist‐boat conformation]. The exocyclic hydroxymethyl (–CH₂OH) conformation is gg (gauche–gauche) (H5 anti to O6) in both (I) and (II). Structural comparisons of (I) and (II) to related unsubstituted, deoxy and fluorine‐substituted monosaccharides show that the gluco ring can assume a wide range of distorted chair structures in the crystalline state depending on ring substitution patterns.     

A DFT study on the origin of the fluorine gauche effect in substituted fluoroethanes

DFT derived conformational energy profiles of a series of β-substituted α-fluoroethanes (F-CH₂CH₂-X) have been explored where the substituent X was varied as NH₃⁺, OCOH, NCO, NO₂, NHCHO, F, N₃, CHNH, NCS, CHCCH₂, CH₃, CHCH₂, NC, CN, CHO, and CCH. Comparisons were correlated relative to 1,2-difluoroethane, a compound which exhibits a well known gauche preference. Only four of the compounds displayed an anti preference, with the large majority preferring a gauche conformation. In particular the influence of steric and electrostatic attraction/repulsion between the fluorine atom and the X-substituent was explored by evaluating rotational energy profiles for all compounds and separately NBO correlations were evaluated to assess the contribution of hyperconjugation to the minimised gauche and anti conformers. In the event the gauche preference for 1,2-difluoroethane was shown to have an origin due largely to σ(C-H)→σ*(C-F) hyperconjugative interactions, whereas the conformational preference for the remaining structures is rationalised by hyperconjugative as well as steric and electrostatic contributions. The anti preferred compounds 13, 14 and 16 possessed triple bonds and the preference arose due to fluorine/p-orbital repulsion.     

α-Fluoro decalones as chiral epoxidation catalysts: fluorine effect

Three rigid monofluorinated trans-decalones 4a, 5e, and 6e (90% ee) have been synthesized from commercially available (−)-(R)-methyl naphthalenone (90% ee). Their structures have been fully characterized (NMR, X-ray): ketones 4a and 5e are Me,F-disubstituted α to the carbonyl with the fluorine axial and equatorial, respectively, while ketone 6e is F-monosubstituted α to the carbonyl with the fluorine equatorial. The use of these ketones as chiral catalysts for the epoxidation of trans-olefins (such as stilbene, β-methylstyrene and p-methoxy cinnamate) through the formation of dioxiranes shows (i) that dioxiranes with an equatorial fluorine α to the dioxirane ring are less reactive and provide lower ee’s than dioxiranes with an axial fluorine and having the same chirality and (ii) that an axial methyl α to the dioxirane ring is significantly less efficient than a fluorine. The results corroborate Armstrong and Houk’s theoretical model and our first hypothesis to rationalize the inverted enantioselectivities observed using α-fluorinated cyclohexanones having the same chirality, i.e.: rapid ring inversion (Curtin–Hammett principle) allows the dioxirane conformation to have the fluorine axial (even if less populated than the other) to contribute significantly to the epoxidation reaction.     

Designing Fluorinated Cinchona Alkaloids for Enantioselective Catalysis: Controlling Internal Rotation by a Fluorine‐Ammonium Ion gauche Effect (φNCCF)

The C9 position of cinchona alkaloids functions as a molecular hinge, with internal rotations around the C8? C9 (τ₁) and C9? C4′ (τ₂) bonds giving rise to four low energy conformers ( 1 ; anti‐closed, anti‐open, syn‐closed, and syn‐open). By substituting the C9 carbinol centre by a configurationally defined fluorine substituent, a fluorine‐ammonium ion gauche effect (σ_C?H→σ_C?F*; F^δ????N⁺) encodes for two out of the four possible conformers ( 2 ). This constitutes a partial solution to the long‐standing problem of governing internal rotations in cinchonium‐based catalysts relying solely on a fluorine conformational effect.     

Conformational Analysis of Fluorinated Pyrrolidines Using 19F–1H Scalar Couplings and Heteronuclear NOEs

A series of 3‐fluoropyrrolidines have been studied to investigate the influence of the stereoelectronic fluorine gauche effect on ring conformations in the solid state by single‐crystal X‐ray analysis and in solution phase by NMR spectroscopy. As part of these studies 1D ¹⁹F–¹H heteronuclear NOE (HOESY) experiments have been optimised for applications to small molecules and are described in detail. These have been employed to estimate ¹⁹F–¹H internuclear distances and were combined with vicinal ³J(F,H) and ³J(H,H) scalar coupling constants to analyse the ring conformations. Where possible the derived solution‐phase structural data have been compared with those of the crystalline state. The results demonstrate the influence of the gauche effect in stabilising C^γ‐exo conformations of the fluorinated pyrrolidines. It was further shown that when steric interactions were also present, this conformational bias was diminished and the contribution of the alternative C^γ‐endo conformation was seen to increase in solution at lower sample temperatures.     

Weak C—H...Cl—Pd interactions toward conformational polymorphism in trans‐dichloridobis(triphenylphosphane)palladium(II)

A new triclinic polymorph of the title compound, [PdCl₂(C₁₈H₁₅P)₂], has two independent molecules in the unit cell, with the Pd atoms located on inversion centres. One molecule has an eclipsed conformation, whereas the second molecule adopts a gauche conformation. The molecules with a gauche conformation are involved in weak intermolecular C—H...Cl—Pd interactions with symmetry‐related molecules. It is suggested that C—H...Cl—Pd interactions are mainly responsible for the existence of conformational differences, which contribute to the polymorph formation. In the crystal, there are layers of eclipsed and gauche molecules separated by normal van der Waals interactions.     

CP/MAS 13C NMR analyses of hydrogen bonding and the chain conformation in the crystalline and noncrystalline regions for poly(vinyl alcohol) films

The chain conformation and hydrogen bonding in the crystalline and noncrystalline regions have been characterized for atactic poly(vinyl alcohol) (PVA) films prepared under different conditions by CP/MAS ¹³C NMR analyses developed recently. The CH resonance lines of the crystalline and noncrystalline components split in different ways, depending significantly on casting solvents and annealing. These lines are found to be successfully resolved into 3–7 constituent lines by the least‐squares curve fitting. In this analysis, nine lines with different chemical shifts are prepared as elementary lines for the curve fitting by assuming the upfield shifts due to the γ‐gauche effect and the downfield shifts due to the formation of the intramolecular hydrogen bonds. The integrated intensities of the constituent lines thus obtained are also interpreted in terms of statistical calculations, assuming the random distribution of the trans and gauche conformations along PVA chains and the statistical distribution of the intramolecular and intermolecular hydrogen bonds between appropriate adjacent OH groups. On the basis of probabilities f_t and f_a for the trans conformation and the intramolecular hydrogen bond obtained through these analyses, the effects of casting solvents and annealing are discussed for both crystalline and noncrystalline components. © 2000 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 38: 1–9, 2000     

Computational study of the fluorination effect on nitrogen–boron bond

The Lewis acid‐base H_3?nF_nN–BF_mH_3?m (n = 0–3; m = 0–3) system was examined using the density functional theory calculations. The N? B bond strength can be adjusted stepwise by increasing the number of substituted fluorine atoms. The main finding of this work is the bond distances of the complexes do not correlate directly with the bond strengths. Some rationalization of this interesting observation was provided by the fluorine substitution effect on the HOMO‐LUMO gap, hybridization of bonding orbitals and electrostatic interaction. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2008     

[N,N′‐Bis­(salicyl­idene)‐1,2‐di­phenyl‐(RS,SR)‐1,2‐ethane­di­amin­ato]­nickel(II)

In crystals of the title compound, [Ni(C₂₈H₂₂N₂O₂)], the coordination geometry around the Ni atom is square planar with a slight tetrahedral distortion. The five‐membered N,N′‐chelate ring adopts a distorted gauche conformation with the two phenyl groups in axial and equatorial orientations.