Ring Junction Research Articles

Influence of 2-methyl substitution on the geometry and complexing ability of sparteine: Packing of chiral vs. racemic building blocks

2-Methylsparteine ( 1) and its complexes with ZnL 2 of the general formula [(C 16H 28N 2)ZnL 2] [L = CN − ( 2), Br − ( 3), CH 3COO − ( 4), C 4 H 5 O 2 - ( 5)] have been prepared and the 1:1 (metal:alkaloid) stoichiometry was confirmed by elemental analysis. The complexes have been characterised by IR and NMR spectroscopy. Crystal structures are reported for racemic compounds 1, 2 and 3, and compared with the structures of chiral (–)-sparteine analogues. For the sake of comparison, synthesis and crystal structure of 1:1 (–)-sparteine complex with Zn(CN) 2 ( 6) is also reported. The crystal structures of 2, 3 and 6 reveal the zinc center four coordinated by two nitrogen atoms from the alkaloid and two halides or cyanide groups in the form of distorted tetrahedral. Comparison with the crystal structure of 1 reveals that coordination to metal center in 2 and 3 brings about an inversion at the N16 nitrogen and consequent change in configuration at the ring junction from trans to cis, accompanied by a change in the C-ring conformation from boat to chair. The racemic crystals of 2 and 3 display only moderate packing similarity, but 3 exhibits very similar supramolecular architecture to that of the previously reported chiral C 16H 28N 2ZnCl 2, albeit in space groups P 1 ¯ and P2 1, respectively. Packing of 2-methylsparteine ZnL 2 metal complexes in racemic crystals is more efficient and diverse than in chiral crystals of the analogous (–)-sparteine and α-sparteine complexes which, in turn, tend to form an isomorphic series.

Altering Hydrophilic and Hydrophobic Region via O–H···O and C–H···O Hydrogen Bonds and van der Waals Forces in Solagenin 6-O-(β-d-quinovopyranoside) Methanol Solvate Monohydrate

The title compound, C33H52O8·CH3OH·H2O, isolated from Solanum torvum, consisted of a solagenin 6-O-(β-d-quinovopyranoside) molecule, a methanol solvate and a hydrate. The six-membered rings A, B, C, F and G have chair conformations. The five-membered ring D adopts a half-chair conformation and the ring E adopts an envelope conformation. The A/B, B/C and C/D ring junctions are trans, whereas the D/E junction is cis. The molecular packing appeared to be established by alternation of a hydrophilic region involving methanol molecules, water molecules and the β-d-quinovopyranoside of the steroid nucleus via the classic O–H···O hydrogen bonds and a hydrophobic region consisted by the other part of the steroid nucleus via weak C–H···O hydrogen bonds and van der Waals forces. The molecular packing of the title compound appeared to be established by alternation of a hydrophilic region involving methanol molecules, water molecules and the β-d-quinovopyranoside of the steroid nucleus via the classic O–H···O hydrogen bonds and a hydrophobic region consisted by the other part of the steroid nucleus via weak C–H···O hydrogen bonds and van der Waals forces.

(±)-1-{8′-(tert-Butyldiphenylsilyloxymethyl)-1′,7′-dioxaspiro[5.5]undecan-2′-yl}uridine

The crystal structure of the title compound, C30H38N2O5Si, has been investigated to establish the relative stereochemistry at the spiro ring junction and the two anomeric centres. Each of the O atoms in the tetra­hydro­pyran rings adopts an axial position on the neighbouring ring. This bis­-diaxial conformation is adopted, thus gaining maximum stablization from the anomeric effect. The silyl-protected hydroxy­methyl and uracil substituents adopt equatorial positions on their associated tetra­hydro­pyran rings, thereby minimizing unfavourable steric inter­actions. The dimeric (2′R*,6′R*,8′R*)- and (2′S*,6′S*,8′S*)-uridine units are connected to each other across crystallographic inversion centres via inter­molecular N—H⋯O hydrogen bonds.

Switching Antibody Specificity through Minimal Mutation

Antibody 1E9, which was elicited with a hexachloronorbornene derivative and catalyzes the Diels–Alder reaction between tetrachlorothiophene dioxide and N-ethylmaleimide with high efficiency, was successfully reengineered to bind a range of structurally diverse steroids with nanomolar affinities. Remarkably, two mutations (LeuH47Trp/ArgH100Trp) out of 36 total sequence differences suffice to switch the selectivity of 1E9 to that of the progesterone-binding antibody DB3. In contrast to the double mutant, which tightly binds multiple steroids with differently configured A–B ring junctions, the individual LeuH47Trp and ArgH100Trp single mutants both exhibit significantly greater specificity than DB3, preferentially binding 5α-pregnan-3β-ol-20-one (Kd≈5 nM) over other steroids. These findings illustrate how easily differently shaped binding pockets can be created through subtle changes to the same primordial germ line template.

ASYMMETRIC SYNTHESIS OF THE ABCD RING SYSTEM OF DAPHNILACTONE B VIA A TANDEM, DOUBLE INTRAMOLECULAR, [4+2]/[3+2] CYCLOADDITION STRATEGY.

An asymmetric synthesis of the ABCD ring system of daphnilactone B is described. The synthesis features a tandem, double intramolecular, [4+2]/[3+2] cycloaddition of a highly functionalized, enantiomerically enriched nitroalkene to generate a pentacyclic nitroso acetal. The cycloaddition establishes six contiguous stereogenic centers including the critical CD ring junction that bears two quaternary stereogenic centers. Hydrogenolysis of the nitroso acetal followed by amide reduction and cyclization provided the AB rings. The methyl substituent on the A ring was installed in the correct configuration via hydrogenation of an exocyclic olefin in the final step.

Comparative Crystallographic and Hydrogen-bonding Analysis of Pregnane Derivatives

A crystallographic comparison comprised of some geometrical and structural features of a steroids series (pregnane derivatives) is made in the present paper. Some selected bond distances and bond angles of interest are discussed in detail. Conformations of individual ring systems in a series of 46 pregnane derivatives have been calculated and discussed. Correlation of ring conformations especially the rarer ones, vis-a-vis the multiple bonds and ring junctions has been discussed. Graphical presentations of ring conformations are made for all the five- and six-membered rings to show the relative frequency of their occurrence. 17β-side chain conformation is discussed in some pregn-20-one structures. X–H···A intra- and intermolecular interactions in the identified derivatives have been discussed with the standard distance and angle cut-off criteria. Distance-angle scatter plots for both kinds of interactions are presented for a better understanding of the packing interactions which exist in pregnane molecules.

Synthesis and Seed Germination Stimulating Activity of Some Imino Analogs of Strigolactones

Strigolactones are germination stimulants for seeds of the root parasitic weeds, Striga and Orobanche spp. The imino analog of GR24 showed moderate germination stimulating activity against the seeds of S. hermonthica. The seed germination stimulating activity of some phenyliminoacetates and phenyliminoacetonitriles was also examined. The degree of activity of the phenyliminoacetate was less than that of the phenylacrylates. On the other hand, the degree of activity of the phenyliminoacetonitrile was comparable to that of the phenylacrylonitriles. Among the tested compounds, the 3-pyridyliminoacetonitrile showed higher activity against the seeds of O. crenata than GR24. These findings demonstrate that it is not always essential to have the Michael acceptor of the C-D ring junction moiety which has been proposed to react with nucleophilic species presented at the target site to enhance the activity.

Structural Examination of Ring-Closing Metathesis-Derived 15-Member Macrocycles as Grb2 SH2 Domain-Binding Tetrapeptide Mimetics

Ring-closing metathesis (RCM) was employed to join carboxy-terminal alkenyl glycine side chains together with vinyl- and allyl-functionality appended to the beta-methylene of amino-terminal phosphotyrosyl (pTyr) mimetics. This required the synthesis of a variety of new pTyr mimetics, including a novel aza-containing analogue. Many of the resulting 15-member macrocyclic tetrapeptide mimetics exhibited low nanomolar Grb2 SH2 domain-binding affinities in spite of the fact that differing ring junction stereochemistries and geometries of the RCM-derived double bond were employed. The finding that significant latitude exists in the structural requirements for ring closure may facilitate the development of therapeutically relevant macrocyle-based Grb2 SH2 domain-binding antagonists. The synthetic approaches used in this study may also find application to peptide mimetics directed at other biological targets.

Conessine isolated from Holarrhena floribunda

The title compound, C24H40N2, has been isolated from Holarrhena floribunda G. Don. (Apocynaceae). The compound has a pentacyclic steroidal nucleus; the ring junctions share the same stereochemistry reported for this class of compounds. Of the three six-membered rings, rings A and C adopt a chair-like and ring B forms a half-chair-like conformation. The cyclopentane ring D shows a half-chair conformation and the methylpyrrolidine ring E adopts an envelope conformation. The dimethylamino substituent in ring A is equatorially oriented.

Structure–chiroptical properties relationship in clavams: An experimental and theoretical study

It is well known that the biological activity of clavams depends strongly on the absolute configuration at the ring junction carbon atom. Therefore, development of the efficient stereo-controlled synthetic methods for the new oxygen analogs of penams, and the structure-activity relationship studies call for a reliable determination of the absolute stereochemistry of newly synthesized compounds. Recently, we proposed an empirical helicity rule relating the configuration of the bridgehead carbon atom to the sign of the 240 nm band observed in the electronic circular dichroism (ECD) spectrum of clavams. In the present work, we investigate the validity of this structure-property relationship for several enantiomeric pairs of model compounds possessing an additional, interfering chromophore in the molecule. For this purpose a combination of the ECD spectroscopy and the time-dependent density functional theory (TD-DFT) is used. A comparison of the ECD spectra with the theoretical ones obtained by the TD-DFT calculations gives a reasonable interpretation of the Cotton effects observed in the 250-220 nm spectral range. Moreover, the calculations confirm validity of the helicity rule for systems studied here and demonstrate that ECD spectroscopy may be used as a highly sensitive probe of the three-dimensional molecular structure of clavams.

Synthesis and Glycosidase Inhibitory Studies of Pentahydroxyindolizidines: D‐Glucose‐Derived Aziridine‐2‐carboxylate Approach

AbstractD‐Glucose‐derived aziridine‐2‐carboxylate 1 was converted into α‐amino aldehyde 7, which, after Wittig olefination, asymmetric dihydroxylation, hydrogenation followed byLiAlH4 reduction, and N‐Cbz protection, afforded two diastereomeric pyrrolidines 11a and 11b with sugar appendages. Removal of the 1,2‐acetonide functionality in 11a/11b and reductive amination gave the pentahydroxyindolizidine alkaloids 6g and 6h, respectively, with (S) absolute configurations at the ring junctions. The glycosidase inhibitory activities of these compounds were studied. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Multicomponent Domino [4+2]/[3+2] Cycloadditions of Nitroheteroaromatics: An Efficient Synthesis of Fused Nitrogenated Polycycles

Activation by high pressure allows 3-nitroindole and 3-nitropyrrole derivatives to behave as electron-poor heterodienes in multicomponent domino [4+2]/[3+2] cycloaddition processes. The primary [4+2] inverse demand cycloaddition appears to be completely endo selective, while the subsequent [3+2] process shows a total facial selectivity, setting the stereochemistry at ring junction, and an endo/exo selectivity depending on the nature of the heterocycle. In two operations, a polycyclic diamine featuring a quaternary center at ring junction is efficiently generated.

2,19-Dihydroxy-3-oxo-(2α,4α,19α)-24-nor-olean-12-en-28-oic acid monohydrate

The title triterpenoid compound, C29H44O5·H2O, was isolated from Terminalia triptera. The mol­ecule contains five fused six-membered rings, with three rings in chair, one in an envelope and one in half-chair conformations. The D and E rings are cis-fused, while the other ring junctions are trans-fused. An intra­molecular O—H⋯O hydrogen bond generates an S(5) ring motif. In the crystal structure, the mol­ecules are linked into a three-dimensional network by O—H⋯O hydrogen bonds and a weak C—H⋯O inter­molecular inter­action. The crystal structure is stabilized by intra- and inter­molecular O—H⋯O hydrogen bonds and weak C—H⋯O inter­actions.

(2RS,4aRS,8aRS)-6-Oxoperhydronaphthalene-2-acetic acid: catemeric hydrogen bonding in a bicyclic keto acid

The title racemate, C12H18O3, aggregates in the solid as translational acid-to-ketone hydrogen-bonding catemers [O⋯O = 2.6816 (17) Å and O—H⋯O = 169°]. The stereochemistry obtained for the side chain arises spontaneously during the synthesis, prior to the hydrogenation that produces the cis ring juncture. Three inter­molecular C—H⋯O close contacts were found.

2,2-Di-C-methoxy-1,4:3,6-dianhydromannitol

The title compound, C8H14O5, is a 1,4:3,6-dianhydro-d-fructose derivative. Its structure consists of two fused tetra­hydro­furan rings with a cis ring junction, giving a V-shaped mol­ecule with an angle between the two rings of 129.9°. Inter­molecular O—H⋯O hydrogen bonds help stabilize the crystal structure.

(2SR,8aSR)-1,2,3,4,6,7,8,8a-Octahydro-6-oxonaphthalene-2-acetic acid: hydrogen bonding in an unsaturated bicyclic keto acid

The title racemate, C12H16O3, aggregates in the solid state as translational acid-to-ketone hydrogen-bonded catemers. The stereochemistry of the side chain relative to the ring junction arises spontaneously during the synthesis. The four hydrogen-bonding chains passing through the unit cell are of alternating handedness, and are aligned along the [101] direction. Starting at the origin, the order of the directional alignment of these four chains with respect to the a axis is ++−−. One inter­molecular C—H⋯O=C close contact exists to the carboxyl O atom.

Stereoselective Syntheses of the Octahydropyrano[2,3‐b]pyridine DE Core of 'Upenamide via a Stannous Chloride‐Induced Deacetalisation–Cyclisation Procedure

AbstractTwo stereoselective syntheses of the octahydropyrano[2,3‐b]pyridine DE hemiaminal core of the macrocyclic alkaloid 'upenamide are described. The syntheses proceeded through an efficient stannous chloride‐induced deacetalisation–cyclisation procedure. The aza‐annulation was stereoselective affording a single stereoisomer having the same relative configuration as in the natural product. The cis ring junction and the cis relationship between 2‐H and 8a‐H were established by NMR spectroscopy and confirmed by X‐ray crystallography. An asymmetric synthesis of the octahydropyrano[2,3‐b]pyridine ring system is also disclosed.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Brassinolide activities of 2α,3α-diols versus 3α,4α-diols in the bean second internode bioassay: Explanation by molecular modeling methods

In general, the structural requirements postulated for a high brassinolide activity are: 2α,3α-diol, 6-ketone or better 7-oxalactone in B-ring, A/B trans fused ring junction, a cis C-22,C-23-diol preferentially with RR configurations, and a C-24 methyl or ethyl substituent [Takatsuto S, Yazawa N, Ikekawa N, Takematsu T, Takeuchi Y, Koguchi M. Structure–activity relationship of brassinosteroids. Phytochemistry 1983;22:2437–41; Thompson MJ, Meudt WJ, Mandava NB, Dutky SR, Lusby WR, Spaulding DW. Synthesis of brassinosteroids and relationship of structure to plant growth-promoting effects. Steroids 1982;39:89–105]. We found that the 3α,4α-diols 4, 6 and 8 are more active than the 2α,3α-diols 3, 5 and 7 [Šíša M, Buděšínský M, Kohout L. Synthesis of 7a-homo and 7a,7b-dihomo-5α-cholestane analogues of brassinolide. Collect Czech Chem Commun 2003;68:2171–89]. This fact is in strong contrast with the structure requirements mentioned above. Our hypothesis suggests that the lower activity of 2α,3α-diols and/or the higher activity of 3α,4α-diols could be explained by twisting and distortion of the molecule due to the seven- or eight-membered B-ring and also by the position of a carbonyl group relative to the A-ring diol. 3D-SAR computer methodologies as alignments and overlaps of GRID maps and 3D-QSAR analysis GRID-GOLPE (CoMFA-like) were used as an effort to explain the higher bioactivity of 3α,4α-diols 4, 6 and 8 in comparison with the 2α,3α-diols 3, 5 and 7 of B-ring enlarged brassinosteroids.

Nonequilibrium Green’s function method for thermal transport in junctions

We present a detailed treatment of the nonequilibrium Green's function method for thermal transport due to atomic vibrations in nanostructures. Some of the key equations, such as self-energy and conductance with nonlinear effect, are derived. A self-consistent mean-field theory is proposed. Computational procedures are discussed. The method is applied to a number of systems including one-dimensional chains, a benzene ring junction, and carbon nanotubes. Mean-field calculations of the Fermi-Pasta-Ulam model are compared with classical molecular dynamics simulations using a generalized Langevin heat bath. We find that nonlinearity suppresses thermal transport even at moderately high temperatures.

Expedited Approach to the Vitamin D trans-Hydrindane Building Block from the Hajos Dione. Comparative Study on Various Methods for the Selective Deoxygenation of One of the Hydroxy Groups in a Diol

1 alpha,25-Dihydroxyvitamin D3 (calcitriol, 1) is a bioregulator important for the treatment of various human metabolic diseases and biomedical research. Herein, we report an efficient diastereoselective approach to the key trans-hydrindane building block for calcitriol synthesis (2a) starting from the readily accessible optically active tetrahydroindenedione derivative (Hajos dione, 3). It was found that epoxide ring opening in a related hydroxy epoxide (7) with sodium cyanoborohydride-BF3 x Et2O occurs by hydride anion addition at the ring juncture position to produce a vicinal diol with the trans-hydrindane ring system (6a). Four methods for selective deoxygenation of the sterically less shielded hydroxy group in diol 6a were examined with an approach based on a cyclic sulfate of the diol as the most efficient and operationally convenient method.