Conformational Transmission Effect Research Articles

The regio- and stereo-selective reduction of steroidal 4-en-3-ones using Na2S2O4/NaHCO3 and CuCl/NaBH4

This paper describes the regio- and stereoselective reduction of △4-3-keto moiety in certain steroids using Na2S2O4/NaHCO3 and CuCl/NaBH4, respectively. Using either one of the two reduction agents in the reaction, the 17-substituents in the D ring were observed to have clearly influenced the stereoselective reduction of 4-ene in the A ring by the so-called conformational transmission effect. Na2S2O4/NaHCO3 regioselectively reduced CC at 4-position of 17-substituted-androst-4-en-3-one derivatives to 5α-H-3-one as the main isomer. And as an extended application, Epiandrosterone (11) was further synthesized from androst-4-en-3,17-dione (AD) via four steps. The total yield from this was about 45%. In the presence of CuCl/NaBH4, △4-3-keto conjugated reduction of 17-spirocyclic ethylene ketal protected androst-4-en-3-one derivatives mainly produced 3α-hydroxy-5β-H isomers, at a yield around 81%. Considering the scaffold configuration of 3α-hydroxy-5β-H moiety coincided with that of bile acid analogs, this selective reduction could also be used as an alternative method for the synthetic study of bile acids using AD and its derivatives, which are from the microorganism degradation of natural sterols, as the potential materials. Meanwhile, configurations of the reductive compounds 5b, 6b, 9, 10 and 17e were identified by X-ray diffraction.

Assessment of competing 2′«5′ versus 3′«5′ stackings in solution structure of branched-RNA by 1H- &31 P-NMR spectroscopy

Preparation of five novel phosphorylated derivatives of adenosine, i.e. adenosine 2′,3′-bis(ethylphosphate) (11), adenosine 2′,3′-bis(phosphate (13), adenosine 2′,3′,5′-tris(ethylphosphate (15), adenosine 2′,5′-bis(ethylphospahte) (17), and adenosine 3′,5′-bis(ethylphospahte) (19) is reported. These compounds, along with methyl β-D-ribofuranosyl-bis-2′,3′-ethylphosphate (9), were used as reference systems for 31P and1H-NMR conformational studies on the branched RNA structures 20 – 30. Compounds 11, 13, 15, 17, and 19 preserve the essential structural elements of the branch point adenosine, while the intramolecular base stacking interactions are removed. The 31P-NMR chemical shifts of 20 – 30, referenced against 9, 11, 13, or 15, show a pattern that is generally consistent with our previous results from variable temperture 31P-NMR experiments. The data indicate that the contribution of g,g around the P-O3′ (ζ) and P-05′ (α) boonds is significantly greater for the 2′-phosphate group than for the 3′-phosphate grooup. These results point towards preferential 2′→5′ rather than 3′→5′ base stacked structures in all of these synthetic models of the lariat. This is especially the case for the branched trimer 20 and the pentamer 27 which are part of a naturally occurring lariat structure. Note that the strongest 2′ →5′ stacking is however found in the unnatural trimers 22 and 23 in which the 2′-linked residue is a pyrimidine nucleotide. Compounds 11, 13, and 15 were also used to calibrate the 1H-NMR oligomerization shifts of the H2 protons of the branch-point adenosine. These data show a consistency with the results from variable temperature 1H-NMR experiments, as well as with the results of31P-NMR experiments. The results obtained with the series of compounds 20 (2′p5′G3′p5′U), 26a (UA2′p5′G3'o5′U, 27 (A2′p5′GU3′p5′UC), 28 (CUA2′p5′GU3′p5′UC), 29 (CUA2′p5′GUG3′p5′UCA), and 30 (CCUA2′p5′GUG3′p5′UCA) are of special interest since these structures are constituents of the naturally occurring lariat in the excised intron in Group II splicing of bl 1 of Yeast mitochondria. Qualitatively, the present 1H- and 31P-NMR data on 26a, 27, 28, 29, and 30 show 2′→5′ base stacking of an intermediate strength; 2′→5′ base stacking is substantially stronger for trimer 20 and pentamer 27. This difference is ascribed to the 5′-conformational transmission effect owing to the presence of at least one nucleotide upstream of the branch-point. 5′-Conformational transmission appears to weaken the 2′→5′ stacking at the expense of some 3′→5′ stacking. The experimental data on the conformation of 20 (A2′p5′g3′p5′U) (31 P and 1H chemical shifts, vicinal 1H-1H, 1H-31P, and 13C-31P coupling constants) formed the basis for a series of AMBER molecular mechanics calculations. These molecular modelling studies allowed us to conclude that g,g, conformation in the 2′-phosphate group is primarily g-(ζ),g- (α). This is found to be the only conformation that gives 2′→5′ base stacking as evident in the temperature dependent chemical shift and in the oligomerization shift studies. Modelling studies furthermore showed two energetically possible ζ and α torsions for the 3′-phosphate group (g−(ζ),g−(α) and g−(ζ),???(α)). The present use of reference compounds 9, 11, 13, 15, 17, and 19 has led to a refined and partially revised concept for the conformational description of oligomeric branched RNAs.

Solution structure of pentameric and heptameric branched-RNA modelling the lariat structure of group II or nuclear m-RNA introns studied by one- and two-dimensional nmr spectroscopy at 500 mhz

A detailed 500 MHz 1H NMR study of the branched RNA systems 3 (pentamer) and 4 (heptamer) is reported. The conformational properties of 3 and 4 were compared with those of the previously studied smaller branched RNAs 1 (trimer) and 2 (tetramer). Compounds 1 – 3 are structural constituents of 4, which corresponds to the sequence at the branch site of Group II intron b11 from yeast mitochondria. The present data provide further substantiation to our previous preliminary conclusion that trimer 1 and pentamer 3 show very similar conformational features, which are remarkably distinct from tetramer 2 and heptamer 4. It is found that the absence of a nucleotide unit at the 5′-site of the branch point (A) leads to a conformation at the branch point which is characterized by C2′-endo (S) ribose, syn orientation of the A-base, and A2′ → 5′G base stacking. This conformation is encountered for trimer 1, and -to a larger extent- also for pentamer 3. The introduction of a mono- or dinucleotide unit at the 5′-site of the branch point introduces a marked conformational transition at the branchpoint, in such a way that the conformation becomes C3′-endo (N) ribose, anti orientation of the base, and disruption of A2′ → 5′G base stacking. This conformation is found for tetramer 2 and heptamer 4. The structural differences between 1,3 and 2,4 are highly reminiscent of the 5′-conformational transmission effect for a series of linear trimer and tetramer RNA molecules. We therefore propose that the 5′-conformational model is also of great interest with respect to our understanding of the structural preferences of branched RNAs. However, our chemical shift vs. temperature profiles and NOE data on 3 and 4 show several additional conformational features. We propose a model for the secondary structure of pentamer 3, which entails peculiar backfolding of the 3′-linked chain in such a way that stacking is achieved between the remote bases C+2 (in the 3′-linked chain), and branch point A. Also, our NOE data on heptamer 4 led to the suggestion that a stack exists between the bases U+2 (in the 2′-linked chain), and U-1 (upstream of A). All our experimental observations on 3 and 4 were integrated into preliminary structural models, shown in Figure 10. It was impossible, however, to obtain strong support for these models from NOE data, since virtually no interresidual NOE crosspeaks appeared in our 2D NOESY spectra. Only in the case of 4, we could observe four weak interresidual NOEs at mixing times of 300, 500 and 900 ms in the aromatic spectral region, provided that a sample temperature of 292 K was used; elevation of the sample temperature to 303 K rendered these NOEs invisible.

Conformational transmission in pentacoordinated phosphorus systems, modelling the activated state of cyclic AMP

The proposed activated state of cyclic adenosine 3′,5′-monophosphate (cAMP) is modelled by two nucleoside cyclic 3 ′,5 ′ Pv-TBP compounds 3 and 4. The reason for the design of compound 3, in which a probe fragment (OCH2CH2OCH3 group) is linked to phosphorus, was reflected in a conformational transmission effect, which occurs when the probe is located in the axis of a Pv-TBP. This means that the six-membered 3′5′-dioxaphosphorinane ring predominantly remains in a diequatorial (e,e) orientation. In the absence of conformational transmission, as in compound 4, the 3′,5′-dioxaphosphorinane ring favors an equatorial-axial (e,a) orientation. From this we conclude that the occurrence of conformational transmission can stabilize the (e,e) orientation of the 3′,5′-ring. This can be of relevance to the activation of protein kinase by cAMP. In order to obtain more structural information from 3 and 4, we performed MNDO calculations on the models 8–10. These calculations revealed that the (e,e) orientation of the 3′,5′-ring is destabilized by 3–4 kcal/mol compared to the (e,a) orientation. For the (e,a) geometry, the 3′,5′-ring adopts a twist conformation, whereas the (e,e) orientated 3′,5′-ring shows a half-chair geometry.

A kinetic study of the alkaline hydrolysis of four‐coordinated phosphorus (PIV) compounds. Impact of conformational transmission in the transiently formed five‐coordinated (PV‐TBP) intermediates on reaction rate and product distribution

AbstractIt can be shown that alkaline hydrolysis of four‐coordinated phosphorus (PIV) compounds is substantially accelerated if the trigonal‐bipyramidal (TBP) five‐coordinated phosphorus (PV) intermediate in the reaction can exhibit conformational transmission. With the compounds 5a‐c, it was shown that this acceleration is an entropy effect. Pseudorotation in the PV‐TBP intermediate is facilitated if conformational transmission occurs, and therefore the entropy loss during build‐up of the PV‐TBP is reduced. This evidently results in a lower free energy of activation for the reaction. For the phosphate triester systems 6a and 6b, it was also found that the occurrence of conformational transmission speeds up the hydrolysis reaction, although the effect is less pronounced than for compounds 5a‐c. The cyclopentylmethoxy group (6a) and the tetrahydrofurfuryloxy group (6b) show slight preferences for equatorial and axial positioning in the transient PV‐TBP, respectively. This study shows for the first time that reaction rate and product selectivity of hydrolyses of phosphate esters can be determined in part by the conformational transmission effect.

ChemInform Abstract: Pseudorotation in Pentacoordinated Phosphorus Compounds. The Influence of the Conformational Transmission Effect on the Barriers to Pseudorotation in Cyclic Alkoxyphosphoranes

Abstract(1H and 31P NMR data as well as variable‐temp.

Acceleration of the pseudorotation rates in pentacoordinated phosphorus compounds. Conformational transmission versus hexacoordinated zwitterionic intermediates

A variable-temperature 13C NMR study, accompanied by a high-resolution 1H NMR conformational analysis study, on a series of monocyclic oxyphosphoranes is reported. The selected compounds enabled us to study the acceleration of the rates of intramolecular ligand reorganization on pentacoordinated phosphorus. It allowed us to determine whether the enhancement of the reorganization rates was brought about by accelerated pseudorotation due to the conformational transmission effect or by the involvement of hexacoordinated zwitterionic phosphorus intermediates. The results of the study further substantiate the findings that the involvement of such hexacoordinated intermediates is of no importance in the type of oxyphosphoranes studied.

Pseudorotation in pentacoordinated phosphorus compounds. The influence of the conformational transmission effect on the barriers to pseudorotation in cyclic alkoxyphosphoranes

A variable-temp. 13C NMR study on a series of monocyclic oxyphosphoranes I (R1 = H, Me; R2 = Me, Ph; R3 = Me, OEt; R4 = Me, cyclopentylmethyl, etc.) is used to examine the influence of the conformational transmission effect on the barriers to pseudorotation in pentacoordinated P compds. The pseudorotation rates of monocyclic oxyphosphoranes exhibiting the conformational transmission effect is 2-4 times faster as compared to their counterparts in which the effect is absent. The conformational change in the basal ligands of the intermediate square planar structures, due to the conformational transmission effect, is responsible for the lowering of the activation barriers by 2-3 kJ mol-1.

Application of the conformational transmission effect for the assignment of diastereotopic proton resonances

AbstractA new method is presented for the assignment of the NMR resonances of the diastereotopic protons in tetrahydrofur‐furyl and pyrrolidinylmethyl groups, based on the conformational transmission effect This effect describes the conformational changes produced by an increase of coordination from four to five of a phosphorus, silicon or germanium atom attached to the tetrahydrofurfuryl or pyrrolidinylmethyl moieties. The 1H NMR conformational analysis of these cyclic four‐ and five‐coordinated compounds yields two possible results, based on two assignments of the diastereotopic proton resonances. Comparison with the conformations of the analogous four‐ and five‐coordinated systems with acyclic 2‐methoxyethyl and dimethylaminoethyl groups (which lack diastereotopic protons) directly shows which assignment is correct, since a similar conformational transmission occurs in both the cyclic and the acyclic compounds.

DETERMINATION OF THE NATURE OF THE CONFORMATIONAL TRANSMISSION EFFECT IN PENTACOORDINATED PHOSPHORUS COMPOUNDS

Abstract A high resolution 1HNMR study of several 4- and 5-coordinated (TBP) phosphorus compounds enabled us to determine the nature of the conformational transmission effect, which describes the influence of the phosphorus coordination on the molecular conformation. Of great use was the accurate determination of the J POMe coupling constant, with which the pseudorotational equilibrium around the pentacoordinated phosphorus can be described. It was determined that conformational transmission is purely electrostatic in origin, due to a larger charge density in the axis of the TBP structure. These findings were corroborated with quantumchemical calculations.

Conformational transmission in silatranes. Confirmation of the pentacoordinated structure in solution

AbstractA 300‐MHz 1H‐NMR conformational analysis study of a set of pentacoordinated silicon compounds (silatranes) and their tetracoordinated counterparts is presented. The solution conformation of the silatranes shows a close resemblance to known X‐ray structures, although the silatrane conformation was found to depend upon the solvent polarity. Comparison of the conformation of a 2‐methoxyethoxy fragment in the tetra‐ and pentacoordinated systems showed the existence of conformational transmission, similar to that known for phosphorus compounds. Enhanced electrostatic repulsion between the vicinal oxygens in the 2‐methyoxyethoxy fragment produces a trans conformation around the CC bond in the pentacoordinated silatranes. The conformational transmission effect is smaller in silatranes than in phosphorus compounds, due to a relatively weak fifth bond.

Steroid structure and function--IX. Molecular conformation and receptor binding of isomeric analogs of D-homo-estradiol.

Abstract The fact that rac - d -homo-8α-estra-1,3,5(10)-triene-3,17a-diol (DH8α) has a higher affinity for the estrogen receptor in rabbit uterus than rac - d -homo-estra-1,3,5(10)-triene-3,17a-diol (DH8β) may be due to differences in hydrogen bonding potential of the C(3) hydroxyl due to conformational transmission effects. The crystal structure determinations of DH8α and DH8β reported here unambiguously establish the relative configurations of the two structures and show that the difference in the binding affinity is not due to a change in O(3)–O(17) distance. The greater affinity of DH8α, estradiol, and diethylstilbestrol (DES) may be linked to an enhanced potential to act as hydrogen bond acceptors as well as donors in the active site. Crystallographic evidence suggests that the weaker binding DH8β and estrone act as donors only. Quantum calculations suggest that the energy of a sequential pair of hydrogen bonds is not merely additive (≅6 Kcal/mol) but may be as much as 9 Kcal/mol. These results support the hypothesis that there is a highly specific association between the A-rings and the binding site of the estrogen receptor protein involving O(3) as a hydrogen bond donor and acceptor and that the receptor accommodates greater variability in the d -ring region.

Long-range Substituent Effects in Morphine-type Agonists and Antagonists: A Possible Explanation for some Opiate Anomalies

Anomalous variations in the pKa values of variously substituted morphine-type agonists and antagonists are interpreted as a reflection of long-range substituent effects operating in these molecules. Based on the operation of long-range effects, a mechanism is proposed by which substitution into the N-normorphine portion of morphine-type agonists and antagonists changes the activity of the parent molecule. Thus, a remote substituent would distort the whole molecule via a conformational transmission effect and thereby (a) change the fit between the opiate and its receptor; (b) change the electron density distribution throughout the molecule and, therefore, at the nitrogen; (c) modify the directionality of the lone-electron pair on the nitrogen; and (d) affect the pKa of the drug. The operation of long-range effects as proposed here could account for some of the anomalous changes in opiate activity effected by substitution into the parent molecule.

Steroidal analogues of unnatural configuration. Part 12. RingAreactions of 9-methyl-5β,9β,10α- and 9-methyl-5α,9β,10α-estran-3-ones: conformational analysis and X-ray crystallography of products

Bromination of 17β-acetoxy-9-methyl-5β- and 17β-acetoxy-9-methyl-5α,9β,10α-estran-3-one, obtained through stereoselective reductions of the olefinic bond of the corresponding testosterone analogue, leads to complex mixtures of α-bromo-ketones. In both cases, bromination at C(2) is favoured, and the distributions of positional isomers are rationalised in terms of conformational transmission effects. It is shown that the respective epimeric pairs are readily interconverted. The crystal structures of 17β-acetoxy-9-methyl-5α,9β,10α-estran-3-one (3b) and its 2α- and 2β-bromo-derivatives (11) and (12) have been determined by X-ray analysis. Ring A of (3b) and (11) suffers slight deformation from a chair conformation, whereas that of (12) adopts a twist-boat conformation in response to the severe steric interaction between the 2β-bromo- and 9β-methyl groups. The solid-state conformations of the three compounds clarify anomalies in their spectroscopic properties.

Molecular conformation and protein binding affinity of progestins

Analysis of X-ray data concerning 277 estranes, androstanes, and pregnanes and comparison with progesterone receptor binding data have prompted the following observations. In general: 1. The flexibility of natural steroid hormones permits them to take up conformations optimal for binding to sites on proteins that vary in individual structural requirements. 2. When substituents strain the fused ring system, the strain will be delocalized and often transmitted to the most flexible point of the molecule, thus giving rise to conformational transmission effects. Consequently, substituents will generally stabilize a specific conformation, limiting protein interaction and enhancing a specific hormone response. 3. Hydrogen bond patterns in crystals can be used to predict points of active site attachment. 4. Distortions resulting from crystal packing forms are insignificant. Progestin receptor binding affinity: 5. Complementarity of fit is not specific on the alpha and beta faces of the B, C, and D rings. 6. The delta4-3-one composition is the only consistently required element. 7. Five of the eight highest-affinity binders have inverted A rings. Others may be easily converted to it. 8. The inverted A ring is proposed as the optimal conformation and primary factor controlling binding. 9. An A ring binding pattern is apparent in other steroidal hormones. 10. The D-ring region is open to contribute to conformational change in the receptor or genome interaction.

Conformational preference of ringAin 3-oxo-Δ5,10-steroids: X-ray crystal structure analysis of 17α-ethynyl-17β-hydroxyestr-5(10)-en-3-one (norethynodrel)

The crystal structure and solid-state conformations of the title compound (5) have been established by X-ray analysis. Crystals are orthorhombic, space group P212121, with a= 21.593(13), b= 22.075(13), c= 7.015(8)Å, Z= 8. The structure was solved by direct methods and refined by least-squares calculations to R 0.046 over 2 572 statistically significant reflections from diffractometer measurements. The A rings in the two crystallographically independent molecules approximate to envelope conformations in which C(2) is displaced to the α-side in one and to the β-side in the other. Stabilization of the higher energy C(2)β-side envelope form is a consequence of the intramolecular hydrogen bonding arrangement in the crystal. The B ring shapes also differ slightly owing to conformational transmission effects.

Reactions of Δ7-steroids. Part III. Conformational transmission effects in the methylation of 5β-cholest-7-en-3-one

Methylation of 5β-cholest-7-en-3-one yields 2β-methyl-5β-cholest-7-en-3-one and 2,2-dimethyl-5β-cholest-7-en-3-one. The structure of the former was proven by its conversion into the known 2β-methyl-5β-cholestan-3-one; the structure of the latter was established from the mass spectrum of its ethylene acetal. Use is made of Bucourt's rules of dihedral angle changes in describing the conformational transmission effects which may account for methylation at C-2 rather than at C-4.

Conformational transmission. Part II. The effect of a 7,8-double bond on the enol acetylation properties of 3-oxo-5β-steroids

The enol acetylation of 5β-cholest-7-en-3-one with isopropenyl acetate–sulphuric acid (kinetic control) yields a mixture of 5β-cholesta-2,7-dien-3-ol acetate and 5β-cholesta-3,7-dien-3-ol acetate. Treatment with perchloric acid–acetic anhydride altered the proportions of this mixture to the equilibrium ratio of 90·5 : 9·5. Thus the conformational transmission effect of the 7,8-double bond reverses the usual direction of enolisation by a factor equivalent to 3·0 kcal./mole.

Conformation of non-aromatic ring compounds—XXIV : On the geometry of the perhydrophenanthrene skeleton in some steroids

A quantitative description of the conformation of the A,B,C,-moiety of eight steroids in terms of valency and torsional angles is given. The geometrical details of the molecules from X-ray structure determinations are compared with those obtained from theoretical considerations on appropriately substituted cyclohexane and cyclohexene rings. It is shown that the use of such building material leads to a qualitative agreement. A number of interactions present in a steroid, but not in a cyclohexane unit, prevents a quantitative agreement. The steroid skeleton (all trans) has a somewhat bent overall shape. The occurrence of conformational transmission effects is discussed and a number of rules concerning the torsional angles around junctions given.