Strong Anomeric Effect Research Articles

Evidence for stereoelectronic effects in the N-C-N group of 8,10,12-triaza-1-azoniatetracyclo[8.3.1.1(8,12).0(2,7)]pentadecane 4-nitrophenolate 4-nitrophenol monosolvate from the protonation of aminal (2R,7R)-1,8,10,12-tetraazatetracyclo[8.3.1.1(8,12).0(2,7)]pentadecane: X-ray and natural bond orbital analysis.

The title molecular salt, C11H21N4(+)·C6H4NO3(-)·C6H5NO3, (II), crystallizes with two independent three-component aggregates in the asymmetric unit. In the cations, the cyclohexane rings fused to the cage azaadamantane systems both adopt a chair conformation. In the crystal structure, the aggregates are connected by C-H···O hydrogen bonds, forming a supramolecular unit enclosing an R4(4)(24) ring motif. These units are linked via C-H···O and C-H···N hydrogen bonds, forming a three-dimensional network. Even hydrogen-bond formation to one of the N atoms is enough to induce structural stereoelectronic effects in the normal donor→acceptor direction. The C-N bond distances provide structural evidence for a strong anomeric effect. The structure also displays O-H···O and N-H···O hydrogen bonding. Geometric optimization and natural bond orbital (NBO) analysis of (II) were undertaken by utilizing DFT/B3LYP with the 6-31+G(d,p) basis set. NBO second-order perturbation theory calculations indicate donor-acceptor interactions between nitrogen lone pairs and the antibonding orbital of the C-C and C-N bonds for the protonated polyamine, in agreement with the occurrence of bond-length and bond-angle changes within the aminal cage structure.

Studies of the Structure, Amidicity, and Reactivity of N-Chlorohydroxamic Esters and N-Chloro-β,β-dialkylhydrazides: Anomeric Amides with Low Resonance Energies

Density functional calculations have been carried out to determine the properties of the title anomeric amides. At the B3LYP/6-31G(d) level, N-chloro-N-methoxyacetamide 8a is computed to be strongly pyramidal at nitrogen with a long amide bond that is untwisted. N-Chloro-N-dimethylaminoacetamide 9a is completely planar, but its amide bond is still much longer than that in N,N-dimethylacetamide 4. This is a steric, rather than a resonance, effect. COSNAR and a trans-amidation method calculate low resonance energies for both model amides, which is attributed to the combined electronegativity of the heteroatoms at the amide nitrogen and the strong anomeric effect when there is a chlorine substituent on nitrogen. When M06 and ωB97X-D dispersion-corrected density functional methods are used with the expanded 6-311++G(d,p) basis set, the resonance energies of 8a (–34 kJ mol–1) and 9a (–49 kJ mol–1) are in line with the gross electronegativity of the substituent atoms. Unlike other anomeric amides, 8a and 9a are not predicted to undergo HERON reactivity.

Peracetylated alpha-D-glucopyranosyl fluoride and peracetylated alpha-maltosyl fluoride.

The X-ray analyses of 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl fluoride, C(14)H(19)FO(9), (I), and the corresponding maltose derivative 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl-(1-->4)-2,3,6-tri-O-acetyl-alpha-D-glucopyranosyl fluoride, C(26)H(35)FO(17), (II), are reported. These add to the series of published alpha-glycosyl halide structures; those of the peracetylated alpha-glucosyl chloride [James & Hall (1969). Acta Cryst. A25, S196] and bromide [Takai, Watanabe, Hayashi & Watanabe (1976). Bull. Fac. Eng. Hokkaido Univ. 79, 101-109] have been reported already. In our structures, which have been determined at 140 K, the glycopyranosyl ring appears in a regular (4)C(1) chair conformation with all the substituents, except for the anomeric fluoride (which adopts an axial orientation), in equatorial positions. The observed bond lengths are consistent with a strong anomeric effect, viz. the C1-O5 (carbohydrate numbering) bond lengths are 1.381 (2) and 1.381 (3) A in (I) and (II), respectively, both significantly shorter than the C5-O5 bond lengths, viz. 1.448 (2) A in (I) and 1.444 (3) A in (II).

2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl azide

The CuI-catalysed 1,3-dipolar cyclo­addition of an azide and a terminal alkyne is becoming an increasingly popular tool for synthetic chemists. This is the most representative of the so-called `click reactions' and it is used to generate 1,4-di­substituted triazoles in high yield. During studies on such cyclo­addition reactions, a reduced reactivity of an α-glucosyl azide with respect to the corresponding β-anomer was observed. With the aim of understanding this phenomenon, the structure of the title compound, C14H19N3O9, has been determined at 140 K. The glucopyranosyl ring appears in a regular 4C1 chair conformation with all the substituents in equatorial positions, except for the anomeric azide group, which adopts an axial orientation. The observed bond lengths are consistent with a strong anomeric effect, which is reflected in a change in dipolar character and hence reduced reactivity of the α-glucosyl azide.

DFT calculations of the anomeric and exo-anomeric effect of the hydroperoxy and peroxy groups

DFT calculations were carried out on axially and equatorially oriented 2-hydroperoxy and 2-peroxy tetrahydropyran, cyclohexyl hydroperoxide, hydroperoxides of 2,3-unsaturated hexapyranoses, and hydroperoxides of OMe and OBn substituted derivatives of 2-deoxy-glucopyranose and 2-deoxy-galactopyranose to investigate the anomeric and exo-anomeric effects of these groups. The structure and energy of the conformers were calculated at the B3LYP/6-311++G ∗∗ level. Calculations showed that the peroxy anion group exhibits a strong anomeric effect, comparable in magnitude to the methoxy group, and that the anomeric effect of the hydroperoxy group is similar to the hydroxyl group. These results revealed that hydroperoxy and peroxy anion groups display an exo-anomeric effect, but the orientation around the C1–O1 bond is also affected by hydrogen bonding and electrostatic interactions.

Contribution of the anomeric effect to the solution and crystal structure of [1 S,2 S,6 S,7 S]-1,6-diaza-4,9-dioxa-2,7-dimethoxycarbonylbicyclo[4.4.1]undecane, a condensation product of l-serine methyl ester with formaldehyde

The reaction of l-serine methyl ester hydrochloride ( 1) with paraformaldehyde ( 2) in dichloromethane in the presence of triethylamine afforded a novel compound: [1 S,2 S,6 S,7 S]-1,6-diaza-4,9-dioxa-2,7-dimethoxycarbonylbicyclo[4.4.1]undecane ( 4) as a 2:3 adduct of 1 with 2. 1H and 13C NMR spectroscopy were unable to discriminate between two possible symmetrical structures. The latter was unambiguously proved by X-ray crystallography. The crystal structure established: (i) the existence of two identical seven-membered rings each containing a NCO grouping; (ii) the existence of a long COCNCNCOC sequence in which each nitrogen belongs simultaneously to a NCO (oxazolidine) and to a NCN (aminal) motifs; (iii) the existence of a chair-like conformation for both seven-membered rings; (iv) the antiperiplanar geometry of pNCO and consequently the manifestation of a strong anomeric effect in both NCO groupings, whereas anomeric effect was virtually absent in the NCN sequence, as corroborated by bond distances and bond angles. Chemical shifts, coupling constants and NOE effects confirm that the conformational features of 4 are preserved in solution.

The conformational analysis of 3-hydroxytetrahydro-1,3-oxazines by NMR spectroscopy

The stereochemistry of the preferred conformers of several 3-hydroxytetrahydro-1,3-oxazines has been established by NMR spectroscopy. Strong anomeric effect stabilises the conformation having equatorial orientation of the lone pair on nitrogen. Nitrogen inversion process was found to be the rate limiting process in the conformational equilibria.

Conformational assignments and a nitrogen inversion process in some 3-acyloxy-1,3-oxazinanes by NMR and X-ray analysis

The stereochemistry of the preferred conformers of several 3-acyloxy-1,3-oxazinanes has been established by NMR spectroscopy. A strong anomeric effect stabilizes the conformation having an equatorial orientation of the lone pair on nitrogen. A nitrogen inversion process was found to be the rate-limiting process in the conformational equilibria. The range of ΔG ‡ values was found to be 60–71 kJ mol–1. Solid state structures as determined by X-ray diffraction confirm the findings of the NMR study.

Catalytic Asymmetric Epoxidation of Aldehydes. Optimization, Mechanism, and Discovery of Stereoelectronic Control Involving a Combination of Anomeric and Cieplak Effects in Sulfur Ylide Epoxidations with Chiral 1,3-Oxathianes

A range of 1,3-oxathianes based on camphorsulfonic acid have been prepared and tested in the catalytic asymmetric epoxidation of carbonyl compounds. It was found that the 1,3-oxathiane derived from acetaldehyde 5b gave the highest yield and enantioselectivity in the epoxidation process. The enantioselectivity was independent of the solvent and metal catalyst used (although yields were dependent on both). The optimum conditions were applied to a range of aldehydes, and good enantioselectivities and diastereoselectivities were observed. The origin of the enantioselectivity was probed, and in particular the role of the oxygen of the 1,3-oxathiane was investigated. Thus, the sulfur and carbon analogues of the camphorsulfonic acid based 1,3-oxathiane (derived from formaldehyde) were prepared (i.e., 1,3-dithiane and thiane analogues). With this series of analogues the steric effects are minimized so that the electronic effects can be investigated. The series of compounds was reacted in the catalytic cycle with benzaldehyde and gave stilbene oxides with 44% ee (sulfur analogue), 41% ee (1,3-oxathiane), and 20% ee (carbon analogue). Thus, it was concluded that the oxygen of the 1,3-oxathiane exerted a significant electronic effect in controlling the face selectivity of the ylide reactions. This electronic effect was a result of combined anomeric (higher with the sulfur analogue, not present with the carbon analogue) and Cieplak effects. A strong anomeric effect was observed in the X-ray structures of one of the 1,3-oxathianes, and an even greater one was observed in the corresponding sulfoxide (this was used as an electronic analogue of the ylide). The face selectivity of the ylide was believed to be complete in reactions with 5b. The minor enantiomer resulted from reaction of the minor conformer of the ylide, reacting again with high face selectivity. This was proven by using a more substituted diazo compound, which was expected to give much less of the minor conformer. Indeed, reaction with mesityldiazomethane gave the corresponding epoxide in essentially enantiomerically pure form.

Consequences of Replacing the DNA 3‘-Oxygen by an Amino Group: High-Resolution Crystal Structure of a Fully Modified N3‘ → P5‘ Phosphoramidate DNA Dodecamer Duplex

As part of the quest for antisense compounds with relative to DNA and RNA improved nuclease-resistance and favorable RNA hybridization properties, a large variety of oligonucleotide analogues has been generated in recent years. Among these, the oligonucleotide N3‘ → P5‘ phosphoramidate DNA (3‘-NP DNA), an analogue with the 3‘-oxygen in the nucleic acid sugar−phosphodiester backbone replaced by an amino group, displays several unique features. Self-pairing of 3‘-NP DNA single strands is significantly favored thermodynamically over self-pairing of both DNA and RNA (Gryaznov, S. M.; et al. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 5798−5802). CD measurements in solution have shown that the duplex conformation of 3‘-NP DNA is very similar to the RNA A-form. Moreover, 3‘-NP DNA can form stable triplexes with double-stranded DNA under conditions where native DNA fails to do so. Recently, it was shown that all-phosphoramidate DNA analogues of HIV-1 RRE and TAR RNA specifically bind to the RNA-binding Rev- and Tat-related peptides (Rigl, C. T.; et al. Biochemistry 1997, 36, 650−659). We have determined the X-ray crystal structure of the all-modified 3‘-NP DNA duplex [5‘-d(CnpGnpCnpGnpAnpAnpTnpTnpCnpGnpCnpG)]2 at 2-Å resolution. Whereas the Dickerson−Drew type phosphodiester DNA 5‘-d(CGCGAATTCGCG) adopts a B-form duplex in the crystal as well as in solution, the 3‘-NP DNA duplex with identical sequence displays an A-RNA conformation in the crystal. Combined with the earlier CD results in solution, our observation provides convincing evidence that the A-conformation with 3‘-NP DNA is modification- and not sequence-induced. The crystal structure reveals a dramatically improved hydration of the phosphoramidate DNA relative to DNA due to the presence of the amino group in its sugar−phosphate backbone. Compared with A-DNA and A-RNA, the 3‘-NP DNA duplex geometry appears more uniform, with backbone torsion angles of individual nucleotides displaying only minor variations. This is consistent with an observed repetitive pattern of coordination by either chloride anions or water molecules to the 3‘-amino groups in the crystal, suggesting a strong anomeric effect between the 3‘-nitrogen lone electron pair and the σ* orbital of the P−O5‘ bond. Our crystal structure can qualitatively explain the exceptional thermodynamic stability of 3‘-NP DNA, and helps to rationalize previously ill understood findings, such as the surprising fact that DNA with NH substituted for O5‘ fails to pair with either DNA or RNA. The crystal structure also establishes 3‘-NP DNA as the quintessential RNA mimetic, in terms of overall duplex structure, rigidity, and level of hydration.

Nitrogen inversion and N–O bond rotation in some hydroxylamine and isoxazolidine derivatives

A series of trisubstituted hydroxylamine derivatives, both cyclic and acyclic, has been prepared. The energy barriers in these hydroxylamines are found to be dominated either by nitrogen inversion or N–O bond rotation depending on the nature of the substituents attached to the nitrogen. In several series of compounds, having XC6H4CH2 substituents attached to nitrogen, Hammett free energy correlations are obtained with positive ρ values, indicating increased electron density at the transition state for the inversion process. Isoxazolidines with C(5) ethoxy substituents demonstrate a strong anomeric effect.

NMR study of the anomeric effect and nitrogen inversion in some isoxazolidines

A series of isoxazolidines with various alkyl substituents at N and an ethoxy group at C(5) have been synthesised and their NMR spectra recorded over a range of temperatures. The NMR spectra at low temperature indicate the presence of two isomers due to slow nitrogen inversion. The nitrogen inversion barriers are determined using complete band shape analysis and are found to be in the range 59.3–65.6 kJ mol −1. The strong anomeric effect exerted by the C(5) ethoxy group locks the substituent in the pseudoaxial orientation. The cis isomers are found to be more stable than the trans isomers.

The anomeric effect in thio derivatives of benzocycloheptene

The conformational properties of six thio derivatives of benzocycloheptene were studied by 1H and 13C high-field NMR spectroscopy in solution at low temperature. Both parent compounds 2 and 6, with sulfur at positions 3 and 1, respectively, were found to exist in the chair conformation. The 2-substituted derivatives of 2 (3: Y = OCH3 and 4: Y = Cl) revealed the presence of the Ca form only. In contrast, the 2-substituted derivatives of 6 (7: Y = OCH3 and 8: Y = Cl), with sulfur at position 1, showed mixtures of three conformers, namely Ca:Ce:TB (Ca = axial chair, Ce = equatorial chair, and TB = twist-boat), whose populations in CHF2Cl were, respectively, 93:5:2 and 85:12:3. The predominance of the Ca form in both series argues in favour of a strong anomeric effect in spite of the large departure from coplanarity (~35°) in the:—S—C—Y fragment of both 7 and 8. This noncoplanarity appears to weaken only slightly the n–σ* overlap characteristic of the endo-anomeric effect, contrary to earlier observations for the:—O—C—Y fragment in 5. The differences between the effects of O and S are discussed.

Syntheses of Amino‐dideoxyallose and Amino‐deoxyribose Derivatives Using Acylnitroso Dienophiles

AbstractThe dimethyl acetals 4 of (E)‐2,4‐pentadienal and of (E,E)‐ and (E,Z)‐2,4‐hexadienals undergo regio‐ and stereospecific cycloaddition reactions with in‐situ‐generated acylnitroso dienophiles 5a and 5b, leading thereby to the corresponding dihydrooxazines 7a–d and 8c–d. cis‐Glycolization of these latter adducts stereospecifically gave the dihydro derivatives 9a–d and 10d which, after sequential hydrogenolysis, deacetalization, and instant cyclization, led to the aminodeoxyribose derivatives 17a, 17f, and 18, and to the amino‐dideoxyallose compounds 17c and 17h. These piperidino‐deoxysugar derivatives exhibit a strong anomeric effect, i.e. OHC(1) is always axial, which is explained in terms of a nN(π)‐σ*(COH) orbital compression, as compared to the less pronounced one in the more classical pyranose series.

Conformational preference of the s=O group.3. Continued evidence for a very strong s-s=o anomeric interaction from the nmr spectroscopic study of 44,5,5-tetramethyl-1,2-dithiane 1-oxide

The 1H and 13C NMR behavior of the title compound ( 4 ) was studied in order to determine the conformational preference of the S=O group in this heterocycle. The NMR spectra were assigned by a combination of homo- and heteronuclear double irradiation, as well as nuclear Overhauser enhancement experiments. From the results of variable temperature, solvent effects and shift reagent experiments, it is concluded that the axial conformer dominates the equilibrium to such an extent that no contribution of the equatorial isomer is recorded. This result suggest that ΔG° ( 4 -ax 4 -eq)⩾ 1.7 kcal mol , and because the axial conformer suffers from a syn -diaxial Me/S=O interaction, a ΔG° ⩾ 3.0 kcal mol for the conformational equilibrium in the parent 1,2-dithiane mono-S-oxide ( 1 ) can be extrapolated. Some discussion of the possible mechanism responsible for such strong anomeric effect is presented.

ChemInform Abstract: ANOMERIC EFFECT IN SULFUR HETEROCYCLES CARRYING SULFUR SUBSTITUENTS

AbstractEs werden mit 1H‐NMR‐spektroskopischen Methoden die Konformation von 1,3,5‐ Trithianen wie z.B. 2‐Phenylthio‐ und 2,4‐Bis(phenylthio)‐l ,3,5‐trithian sowie im letzteren Falle auch das cis‐trans‐Gleichgewicht untersucht.

Anomeric Effect in Sulfur Heterocycles Carrying Sulfur Substituents

Abstract Conformational analysis of 1,3,5-trithiane derivatives with sulfur-substituents was carried out with the aid of PMR spectra at various temperatures. 2-Phenylthio-1,3,5-trithiane exhibited the strong anomeric effect whereas 2-phenylthiothiane the moderate. This enhanced anomeric effect in trithiane derivatives was attributed to both the stabilization of the axial form and the destabilization of the equatorial form. cis-2,4-Bis(phenylthio)-1,3,5-trithiane was found to possess a diaxial conformation to a fair extent in support of the presence of the strong anomeric effect. Equilibration between cis and trans forms of 2,4-bis(phenylthio)-1,3,5-trithiane was carried out to show that the trans form was more stable than the cis. The barrier to inversion of trans-2,4-bis(phenylthio)-1,3,5-trithiane was obtained as ca. 11 kcal/mol.