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The anomeric effect in the phosphodiester backbone of nucleic acids is a stereoelectronic effect that has conventionally been linked to interactions between lone pairs on the O(ester) atoms and P-O(ester) antibonding orbitals. The present study demonstrates that the anomeric effect in the phosphodiester backbone is significantly more complex than portrayed by this description. The presence of multiple lone pairs and antibonding orbitals around the phosphorus atom leads to additional contributions to the anomeric effect, especially involving the anionic oxygen lone pairs. On the basis of the structural changes and Natural Bond Orbital analysis it is shown that a complex balance between stereoelectronic effects involving both the ester and anionic oxygen lone pairs governs the conformational properties of the phosphodiester backbone. The N3'-phosphoramidate DNA backbone differs from the phosphodiester backbone due to the N3'-H moiety having only a single lone pair instead of the two lone pairs present on the O3' atom substituted. The present study uses N3'-phosphoramidate as a control to understand the changes in stereoelectronic effects as a result of changes in the structure and conformation. Two previously uncharacterized properties of the N3'-phosphoramidate backbone are also observed and explained through the complex balance of the postulated electronic delocalizations. The first observation is that the N3'-H moiety in N3'-phosphoramidate is a flexible moiety that can change the orientation of its hydrogen through inversion without a significant energetic penalty in both the gas phase and the aqueous phase. The second observation is that the stabilization of the C3'-endo conformation in N3'-phosphoramidate is primarily due to aqueous solvation rather than intrinsic gas-phase effects involving the reduced electronegativity of the 3'-substituent.

The fluorescence quenching of two azoalkanes, the weak acceptor 2,3-diazabicyclo[2.2.2]oct-2-ene and its less reactive derivative 4-methyl-1-isopropyl-2,3-diazabicyclo[2.2.2]oct-2-ene, by a series of aliphatic amine donors was examined by time-resolved spectroscopy in benzene. The fluorescence quenching rate constants ranged from 0.13 × 107 to 25 × 107 M-1 s-1, while the activation energies were found to be 1.3 and 3.0 kcal mol-1 for the best (N-ethyldicyclohexylamine) and the poorest (N,N-diisopropyl-3-pentylamine) donor. The oxidation potentials of the amines and the reduction potentials of the azoalkanes were measured. Deviations from the expected dependence of the quenching rate constants on the energetics of electron transfer were observed. Steric effects on the kinetics of quenching, namely a reduction by up to a factor of 50, became significant for amines with three secondary alkyl substituents, triisopropylamine, and N,N-diisopropyl-3-pentylamine, while a stereoelectronic effect was found for 1,4-...

The catalytic asymmetric intermolecular Stetter reaction of heterocyclic aldehydes and nitroalkenes has been developed. We have identified a strong stereoelectronic effect on catalyst structure when a fluorine substituent is placed in the backbone. X-ray structure analysis provides evidence that hyperconjugative effects are responsible for a change in conformation in the azolium precatalyst. This new N-heterocyclic carbene precursor bearing fluorine substitution in the backbone results in significantly improved enantioselectivities across a range of substrates.

A systematic study of C-H insertion reactions with variously substituted and conformationally constrained substrates was carried out. High selectivity in the insertion between two competing C-H bonds caused by a strong stereoelectronic effect of an oxygen substituent was achieved. This regioselective C-H insertion reaction was employed as a platform to develop a concise asymmetric synthesis of platensimycin.

The conformational behavior of different aza-C-glycosides synthesized as glycosidase inhibitors has been studied using a combination of NMR spectroscopy (J and NOE data) and time-averaged restrained molecular dynamics calculations. The obtained results show that the population distribution of conformers around their pseudoglycosidic linkages is mainly controlled by 1,3-syn-diaxial interactions. Electrostatic effects slightly modulate the conformational equilibrium. This result is in contrast with that observed for O-glycosides. For these natural compounds, the conformational behavior around the glycosidic linkage Φ is mainly governed by the exo-anomeric effect. Experimentally based energy values for both the 1,3-syn-diaxial interactions and the stereoelectronic effect have been deduced. Finally, the inhibitory activity of these compounds has been tested again a variety of glycosidase enzymes.

Synthesis of the title compound 2 was accomplished in a multistep sequence starting from hypophosphorous acid. In strong base, the bicyclic phosphinate 2 hydrolyzes 2 orders of magnitude faster than the bicyclic phosphate OP(OCH2)3CCH3 (1a) and the acceleration is entirely enthalpic. This rate enhancement is attributed to the greater ease with which 2 achieves the five-coordinate transition state. The molecular structure of 2, determined by X-ray means, compared with that of 1a reveals no evidence of strain within either bicyclic framework. The observed acceleration does not support the contribution of a stereoelectronic effect in the hydrolysis of six-membered ring phosphates.

Stereoelectronic effects have been identified as contributing factors to the conformational stability of collagen-mimetic peptide sequences. To assess the relevance of these factors within other protein structural contexts, three polypeptide sequences were prepared in which the sequences were derived from the canonical repeat unit (Val-Pro-Gly-Val-Gly) of the protein material elastin. These elastin-mimetic polypeptides, elastin-1, elastin-2, and elastin-3, incorporate (2S)-proline, (2S,4S)-4-fluoroproline, and (2S,4R)-4-fluoroproline, respectively, at the second position of the elastin repeat. Calorimetric and spectroscopic investigations of these three polypeptides indicate that the incorporation of the substituted proline residues had a dramatic effect upon the self-assembly of the corresponding elastin peptide. The presence of (2S,4R)-4-fluoroproline in elastin-3 lowered the temperature of the phase transition and increased the type II beta-turn population with respect to the parent polypeptide, while the presence of (2S,4S)-4-fluoroproline in elastin-2 had the opposite effect. These results suggest that stereoelectronic effects could either enhance or hinder the self-assembly of elastin-mimetic polypeptides, depending on the influence of the proline analogue on the energetics of the beta-turn conformation that develops within the pentapeptide structural repeats above the phase transition. Density functional theory (DFT) was employed to model three possible turn types (betaI-, betaII-, and inverse gamma-turns) derived from model peptide segments (MeCO-Xaa-Gly-NHMe) (Xaa = Pro, 4S-F-Pro, or 4R-F-Pro) corresponding to the turn-forming residues of the elastin repeat unit (Val-Pro-Gly-Val-Gly). The results of the these calculations suggested a similar outcome to the experimental data for the elastin-mimetic polypeptides, in that type II beta-turn structures were stabilized for peptide segments containing (2S,4R)-fluoroproline and destabilized for segments containing (2S,4S)-fluoroproline relative to the canonical proline residue.

A polypeptide chain can adopt many conformations. Yet, the sequence of its amino acid residues directs folding to a particular native state.1 The loss of conformational entropy associated with folding destabilizes the native state. This destabilization is overcome by the hydrophobic effect, hydrogen bonds, other noncovalent interactions, and disulfide bonds.2 We have identified another force that can contribute to the conformational stability of a protein. The structure and reactivity of an organic molecule can rely on the stereochemistry of its electron pairs, bonded or nonbonded.3 Such stereoelectronic effects, which arise from the mixing of an electron pair with the antibonding σ* of an adjacent polar bond (C-X, where X ) N or O), endow nucleic acids and carbohydrates with conformational stability.4 For example, the multiple gauche effects (X-C-C-X) arising from a 2′ oxygen distinguish RNA‚RNA and RNA‚DNA duplexes from DNA‚DNA duplexes.5 The anomeric effect (X-C-X) enhances the stability of the R anomer of glycosides.6 Here, we demonstrate for the first time that a stereoelectronic effect is critical for the conformational stability of a protein. Collagen is the most abundant protein in animals.7 For example, collagen comprises one-third of the protein in humans and threefourths of the weight of human skin. The polypeptide chains of collagen are composed of approximately 300 repeats of the sequence XaaYaaGly, where Xaa is often an L-proline (Pro) residue and Yaa is often a 4(R)-hydroxy-L-proline (Hyp) residue. These chains are wound in tight triple helices, which are organized into fibrils of great tensile strength. Pro and Hyp comprise nearly one-fourth of the residues in common types of collagen.8 This prevalence of tertiary amides has dichotomous consequences for conformational stability. Pro and Hyp residues are constrained by their pyrrolidine rings, and this rigidity stabilizes triple-helical collagen.9 Yet, the trans and cis conformations of the peptide bonds to Pro and Hyp residues are of nearly equal free energy, which destabilizes collagen because all peptide bonds in triple-helical collagen are in the trans conformation (Figure 1).10 The 4(R)-hydroxyl group of the prevalent Hyp residues increases dramatically the conformational stability of collagen.11 We had shown previously that this increase arises from inductive effects.12 Can a stereoelectronic effect influence Ktrans/cis? To answer this question, we synthesized residue mimics of the form AcYaaOMe, where Yaa is Pro, Hyp, 4(S)-hydroxy-L-proline (hyp), 4(R)-fluoroL-proline (Flp), or 4(S)-fluoro-L-proline (flp).13 We chose Flp and flp because fluorine is small and electronegative and forms only weak hydrogen bonds when bound to carbon.14,15 We chose a methyl ester rather than an amide to prevent γ-turn formation, as had been observed in AcProNHMe.16 We find that the electronegativity and stereochemistry of the 4-substituent in the Yaa mimics has a significant effect on Ktrans/cis (Table 1). Compared to a flp residue, a Pro residue is twice as likely and a Flp residue is 3 times as likely to have a trans peptide bond. Does the value of Ktrans/cis have an impact on collagen stability? To answer this question, we synthesized (ProYaaGly)7 strands containing Flp or flp residues in the Yaa position.19 These strands are diastereomeric, differing only in the stereochemistry at Cγ of the Yaa residues. We found that a (ProFlpGly)7 triple helix has a Tm of 45 °C.20 In contrast, a (ProflpGly)7 triple helix has a Tm of

Le phosphite de triethyle reagit avec le benzenesulfenate d'ethyle ou le peroxyde d'ethyle pour donner le pentaethoxyphosphorane. Par contre, le methyl-1 trioxa-3,5,8 phospha-4 bicyclo [2.2.2] octane (I) ne reagit pas avec ces electrophiles pour donner le phosphorane bicyclique attendu (II). La faible reactivite du phosphite I est due a une barriere cinetique plutot que thermodynamique car le phosphorane II est forme a partir d'un melange equimolaire de P(OEt) 5 et de tris(hydroxymethyl)-1,1,1 ethane

Etude de la reaction d'alkylimines du phenyl-2 propanal avec des organometalliques allyliques