Oligonucleotides Containing Pyrazolo[3,4-d]pyrimidines: The Influence of 7-Substituted 8-Aza-7-deaza-2′-deoxyguanosines on the Duplex Structure and Stability

Oligonucleotides containing 7-substituted 8-aza-7-deazaguanines (=6-amino-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-ones) were prepared by automated solid-phase synthesis. A series of 7-alkynylated 8-aza-7-deaza-2′-deoxyguanosines (see 4a – d ) were synthesized with the 7-iodonucleoside 3c as starting material and by the Pd⁰/Cu^I-catalyzed cross-coupling reaction with various alkynes. Phosphoramidites were prepared from the 7-substituted 8-aza-7-deaza-2′-deoxyguanosine derivatives carrying halogeno, cyano, and hexynyl substituents. From the melting profiles of oligonucleotide duplexes, the T_m values as well as the thermodynamic data were determined. A significant duplex stabilization by the 7-substituents was observed for the DNA⋅DNA duplexes, but not in the case of DNA⋅RNA hybrids.     

Synthesis and Complexation Properties of a New Class of Receptors based on a cone-configurated tetra-p-(tert-butyl)calix[4]arene and bipyridyl subunits

0The bipyridyl-armed tetra-p-(tert-butyl)calix[4]arenes 1 – 5 were synthesized from tetra-p-(tert-butyl)-calix[4]arene A and 6-(bromomethyl)-6′-methyl-2,2′-bipyridine ( B ) by direct base-strength-driven regioselective O-alkylation or by stepwise procedures. Preliminary complexation studies of the ligands 1 – 3 with Cu^I affording the complexes 6 – 8 are described.     

Asymmetric Total Synthesis of Hasubanan Alkaloids: Periglaucines A–C,N,O-Dimethyloxostephine and Oxostephabenine

We report herein the asymmetric total synthesis of periglaucines A–C, N,O-dimethyloxostephine and oxostephabenine. The key strategies used include: 1) a Rh^I-catalyzed regio- and diastereoselective Hayashi-Miyaura reaction to connect two necessary fragments; 2) an intramolecular photoenolization/Diels–Alder (PEDA) reaction to construct the highly functionalized tricyclic core skeleton bearing a quaternary center; 3) a bio-inspired intramolecular Michael addition and transannular acetalization to generate the aza[4.4.3]propellane and the tetrahydrofuran ring.     

Direct Synthesis of Chiral 3‐Arylsuccinimides by Rhodium‐Catalyzed Enantioselective Conjugate Addition of Arylboronic Acids to Maleimides

Chiral rhodium catalysts comprising 2,5‐diaryl‐ substituted bicyclo[2.2.1]diene ligands L1 – L10 were utilized in the enantioselective 1,4‐addition reaction of arylboronic acids to N‐substituted maleimides. In the presence of 2.5 mol % of Rh^I/ L2 , enantioenriched conjugate addition adducts were isolated in 72–99 % yields with 86–98 % ee. This protocol offers a convenient method to access a variety of 3‐arylsuccinimides in a highly enantioselective manner. Maleimides with readily cleavable N‐protecting groups were tolerated enabling the synthesis of useful synthetic intermediates. Pyrrolidine 4 , a biologically active compound, and pyrrolidine 5 , an ent‐precursor to an HSD‐1 inhibitor, were synthesized to demonstrate the utility of this method.     

Asymmetric Total Synthesis of Hasubanan Alkaloids: Periglaucines A–C,N,O-Dimethyloxostephine and Oxostephabenine

We report herein the asymmetric total synthesis of periglaucines A–C, N,O-dimethyloxostephine and oxostephabenine. The key strategies used include: 1) a Rh^I-catalyzed regio- and diastereoselective Hayashi-Miyaura reaction to connect two necessary fragments; 2) an intramolecular photoenolization/Diels–Alder (PEDA) reaction to construct the highly functionalized tricyclic core skeleton bearing a quaternary center; 3) a bio-inspired intramolecular Michael addition and transannular acetalization to generate the aza[4.4.3]propellane and the tetrahydrofuran ring.     

Rhodium(I)-catalyzed enantioselective 1,4-addition of nucleophilic silicon

A rhodium(I)-catalyzed activation of a silicon-boron linkage, that is, the transmetalation of silicon from boron to rhodium(I) by means of an Rh^I-OH complex, enables the conjugate transfer of nucleophilic silicon onto α,β-unsaturated acceptors. Pre- or in situ formed cationic rhodium(I)-binap complexes catalyze this novel carbon-silicon bond formation with exceptional enantiocontrol, 92 to >99% ee for cyclic carbonyl and carboxyl compounds as well as >99% ee for acyclic carboxyl compounds.     

First Stabilization of 14‐Electron Rhodium(I) Complexes by Hemichelation

Hemichelation is emerging as a new mode of coordination where non‐covalent interactions crucially contribute to the cohesion of electron‐unsaturated organometallic complexes. This study discloses an unprecedented demonstration of this concept to a Group 9 metal, that is, Rh^I. The syntheses of new 14‐electron Rh^I complexes were achieved by choosing the anti‐[(η⁶:η⁶‐fluorenyl){Cr(CO)₃}₂] anion as the ambiphilic hemichelating ligand, which was treated with [{Rh(nbd)Cl}₂] (nbd=norbornadiene) and [{Rh(CO)₂Cl}₂]. The new T‐shaped Rh^I hemichelates were characterized by analytical and structural methods. Investigations using the methods of the DFT and electron‐density topology analysis (NCI region analysis, QTAIM theory) confirmed the closed‐shell, non‐covalent and attractive characters of the interaction between the Rh^I center and the proximal Cr(CO)₃ moiety. This study shows that, by appropriate tuning of the electronic properties of the ambiphilic ligand, truly coordination‐unsaturated Rh^I complexes can be synthesized in a manageable form.     

Catalytic Enantioselective Hydrosilylation of Aromatic Ketones Using Rhodium Complexes of TADDOL-Derived Cyclic Phosphonites and Phosphites

Cyclic phosphonites and phosphites 2–4 are readily available from Cl₂PR and (R,R)- or (S,S)-α,α,α′,α′-tetraaryl-1,3-dioxolane-4,5-dimethanols (= TADDOLs 1 , which, in turn, are only two steps away from tartrate); the X-ray crystal structure of one representative, the phenyl phosphonite 2b , was determined. Five previously described and six new ones of the chiral P derivatives were tested as ligands for Rh^I- and Pd^O-catalyzed reactions such as hydrocarbonylations, hydroborations, and hydrosilylations of C?C bonds; while the resulting catalysts were highly active and regioselective, they did not lead to useful enantiomer enrichment in the products (Scheme 1). In contrast, hydrosilylation of phenyl and 2-naphthyl methyl or ethyl ketone by Ph₂SiH₂ (1.2 equiv.) gave, after desilylation, the corresponding secondary alcohols of (R)-configuration with up to 87% ee in the presence of 0.1 equiv. of the penta(2-naphthyl)-substituted phosphonite 3d and 0.02 mol-equiv. of Rh (Table 1).     

Electrochemical activity of rhodium complexes supported on fibrous-carbon material

The redox properties of heterogenized Rh^I, Rh^II, and Rh^III complexes with different, particularly organophosphorus, ligands were studied by cyclic voltammetry (CVA). The support is a carbon-paste electrode based on a fibrous-carbon material and activated carbon. The electrochemical reduction of Rh^III produces Rh metal, which further catalyzes hydrogen evolution. After the reduction of water-soluble binuclear Rh^II complexes, the CVA curves exhibit peaks of electrocatalytic hydrogen evolution and irreversible Rh^I→Rh^II oxidation. The Rh^II complexes with organophosphorus ligands are characterized only by the peak of Rh^I→Rh^II oxidation. After reduction, the Rh^I complexes behave as a pseudo-reverse Rh⁰/Rh^I pair. The electron-donating properties of the ligand determine the reversibility of the system. The degree of structurization of the carbon matrix and the presence of phosphorus(v) atoms in it affect the electrochemical activity of the Rh^II and Rh^I complexes. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 908–914, May, 1999.     

Nucleotides. Part XXXV. Synthesis of 3′-deoxyadenylyl-(2′–5′)-3′-deoxyadenyIyl-(2′–ω)-9-(ω-hydroxyalkyl)adenines

Via the phosphotriester approach, new structural analogs of (2′–5′)oligoadenyiates, namely 3′-deoxyadenylyl-(2′–5′)-3′-dcoxyadenylyl-(2′–ω)-9-(ω-hydroxyalkyl)adenines 18 – 21 , have been synthesized (see Scheme) which should preserve biological activity and show higher stability towards phosphodiesterases. The newly synthesized oligonucleotides 18 – 21 have been characterized by ¹H-NMR spectra, TLC, and HPLC analysis.     

Facile Synthesis and Versatile Reactivity of an Unusual Cyclometalated Rhodium(I) Pincer Complex

The synthesis of the reactive PN(C^H) ligand 2‐di(tert‐butylphosphanomethyl)‐6‐phenylpyridine ( 1^H ) and its versatile coordination to a Rh^I center is described. Facile C?H activation occurs in the presence of a (internal) base, thus resulting in the new cyclometalated complex [Rh^I(CO)(κ³‐P,N,C‐ 1 )] ( 3 ), which has been structurally characterized. The resulting tridentate ligand framework was experimentally and computationally shown to display dual‐site proton‐responsive reactivity, including reversible cyclometalation. This feature was probed by selective H/D exchange with [D₁]formic acid. The addition of HBF₄ to 3 leads to rapid net protonolysis of the Rh?C bond to produce [Rh^I(CO)(κ³‐P,N,(C?H)‐ 1 )] ( 4 ). This species features a rare aryl C?H agostic interaction in the solid state, as shown by X‐ray diffraction studies. The nature of this interaction was also studied computationally. Reaction of 3 with methyl iodide results in rapid and selective ortho‐methylation of the phenyl ring, thus generating [Rh^I(CO)(κ²‐P,N‐ 1^Me )] ( 5 ). Variable‐temperature NMR spectroscopy indicates the involvement of a Rh^III intermediate through formal oxidative addition to give trans‐[Rh^III(CH₃)(CO)(I)(κ³‐P,N,C‐ 1 )] prior to C?C reductive elimination. The Rh^III–trans‐diiodide complex [Rh^I(CO)(I)₂(κ³‐P,N,C‐ 1 )] ( 6 ) has been structurally characterized as a model compound for this elusive intermediate.     

Enantioselective Cleavage of Cyclobutanols Through Ir-Catalyzed C−C Bond Activation: Mechanistic and Synthetic Aspects

The Ir-catalyzed conversion of prochiral tert-cyclobutanols to β-methyl-substituted ketones proceeds under comparably mild conditions in toluene (45–110 °C) and is particularly suited for the enantioselective desymmetrization of β-oxy-substituted substrates to give products with a quaternary chirality center with up to 95 % ee using DTBM-SegPhos as a chiral ligand. Deuteration experiments and kinetic isotope effect measurements revealed major mechanistic differences to related Rh^I-catalyzed transformations. Supported by DFT calculations we propose the initial formation of an Ir^III hydride intermediate, which then undergoes a β-C elimination (C−C bond activation) prior to reductive C−H elimination. The computational model also allows the prediction of the stereochemical outcome. The Ir-catalyzed cyclobutanol cleavage is broadly applicable but fails for substrates bearing strongly coordinating groups. The method is of particular value for the stereo-controlled synthesis of substituted chromanes related to the tocopherols and other natural products.     

Nucleotides. Part LIV. Synthesis of condensed N1-(2′-deoxy-β-D-ribofuranosyl)lumazines,New fluorescent building blocks in oligonucleotide synthesis

Various condensed areno[g]lumazine derivatives 2 , 3 , and 5 – 7 were synthesized as new fluorescent aglycones for glycosylation reactions with 2-deoxy-3, 5-di-O-(p-toluoyl)-α/β-D -erythro-pentofuranosyl chloride ( 10 ) to form, in a Hilbert-Johnson-Birkofer reaction, the corresponding N¹-(2′-deoxyribonucleosides) 15 – 21 . The β-D -anomers 15 , 17 , 19 , and 21 were deblocked to 24 – 27 and, together with N¹-(2′-deoxy-β-D -ribofuranosyl)lumazine ( 22 ) and its 6, 7-diphenyl derivative 23 , dimethoxytritylated in 5′-position to 28–33. These intermediates were then converted into the 3′-(2-cyanoethyI diisopropylphosphoramidites) 34 – 39 which function as monomeric building block in oligonucleotide syntheses as well as into the 3′-(hydrogen succinates) 40 – 45 which can be used for coupling with the solid-support material. A series of lumazine-modified oligonucleotides were synthesized and the influence of the new nucleobases on the stability of duplex formation studied by measuring the T_m values in comparison to model sequences. A substantial increase in the T_m is observed on introduction of areno[g]lumazine moieties in the oligonucleotide chain stabilizing obviously the helical structures by improved stacking effects. Stabilization is strongly dependent on the site of the modified nucleobase in the chain.     

Diminished electron density in the Vaska‐type rhodium(I) complex trans‐[Rh(NCBH3)(CO)(PPh3)2]

Vaska‐type complexes, i.e. trans‐[RhX(CO)(PPh₃)₂] (X is a halogen or pseudohalogen), undergo a range of reactions and exhibit considerable catalytic activity. The electron density on the Rh^I atom in these complexes plays an important role in their reactivity. Many cyanotrihydridoborate (BH₃CN⁻) complexes of Group 6–8 transition metals have been synthesized and structurally characterized, an exception being the rhodium(I) complex. Carbonyl(cyanotrihydridoborato‐κN)bis(triphenylphosphine‐κP)rhodium(I), [Rh(NCBH₃)(CO)(C₁₈H₁₅P)₂], was prepared by the metathesis reaction of sodium cyanotrihydridoborate with trans‐[RhCl(CO)(PPh₃)₂], and was characterized by single‐crystal X‐ray diffraction analysis and IR, ¹H, ¹³C and ¹¹B NMR spectroscopy. The X‐ray diffraction data indicate that the cyanotrihydridoborate ligand coordinates to the Rh^I atom through the N atom in a trans position with respect to the carbonyl ligand; this was also confirmed by the IR and NMR data. The carbonyl stretching frequency ν(CO) and the carbonyl carbon ¹J_C–Rh and ¹J_C–P coupling constants of the C_ipso atoms of the triphenylphosphine groups reflect the diminished electron density on the central Rh^I atom compared to the parent trans‐[RhCl(CO)(PPh₃)₂] complex.     

Oligonucleotides Containing 7‐Deaza‐2′‐deoxyinosine as Universal Nucleoside: Synthesis of 7‐Halogenated and 7‐Alkynylated Derivatives,Ambiguous Base Pairing,and Dye Functionalization by the Alkyne–Azide ‘Click’ Reaction

Oligonucleotides containing 7‐deaza‐2′‐deoxyinosine derivatives bearing 7‐halogen substituents or 7‐alkynyl groups were prepared. For this, the phosphoramidites 2b – 2g containing 7‐substituted 7‐deaza‐2′‐deoxyinosine analogues 1b – 1g were synthesized (Scheme 2). Hybridization experiments with modified oligonucleotides demonstrate that all 2′‐deoxyinosine derivatives show ambiguous base pairing, as 2′‐deoxyinosine does. The duplex stability decreases in the order C_d>A_d>T_d>G_d when 2b – 2g pair with these canonical nucleosides (Table 6). The self‐complementary duplexes 5′‐d(F⁷c⁷I‐C)₆, d(Br⁷c⁷I‐C)₆, and d(I⁷c⁷I‐C)₆ are more stable than the parent duplex d(c⁷I‐C)₆ (Table 7). An oligonucleotide containing the octa‐1,7‐diyn‐1‐yl derivative 1g , i.e., 27 , was functionalized with the nonfluorescent 3‐azido‐7‐hydroxycoumarin ( 28 ) by the Huisgen–Sharpless–Meldal cycloaddition ‘click’ reaction to afford the highly fluorescent oligonucleotide conjugate 29 (Scheme 3). Consequently, oligonucleotides incorporating the derivative 1g bearing a terminal C?C bond show a number of favorable properties: i) it is possible to activate them by labeling with reporter molecules employing the ‘click’ chemistry. ii) Space demanding residues introduced in the 7‐position of the 7‐deazapurine base does not interfere with duplex structure and stability (Table 8). iii) The ambiguous pairing character of the nucleobase makes them universal probes for numerous applications in oligonucleotide chemistry, molecular biology, and nanobiotechnology.     

Cationic (Azulene)(diene)rhodium(I) Complexes: Spectroscopic,Dynamic, and Catalytic Properties

New [Rh^I(η⁵‐azulene)(η⁴‐diene)][BF₄] complex salts 3 – 5 (diene=8,9,10‐trinorborna‐2,5‐diene (nbd) and (1Z,5Z)‐cycloocta‐1,5‐diene (cod)) were synthesized according to a known procedure (Scheme 1). All of these complexes show dynamic behavior of the diene ligand at room temperature. In the case of the [Rh^I(η⁵‐azulene)(cod)]⁺ complex salts 3 and [Rh^I(η⁵‐guaiazulene)(nbd)]⁺ complex salt 4a (guaiazulene=7‐isopropyl‐1,4‐dimethylazulene), the coalescence temperature of the ¹H‐NMR signals of the olefinic H‐atoms was determined. The free energy of activation (ΔG; Table 1) for the intramolecular movement of the diene ligands exhibits a distinct dependency on the HOMO/LUMO properties of the coordinated azulene ligand. The DFT (density‐functional theory) calculated ΔG values for the internal diene rotation are in good to excellent agreement with the observed ones in CD₂Cl₂ as solvent (Table 2). Moreover, the ΔG values can also be estimated in good approximation from the position of the longest‐wavelength, azulene‐centered UV/VIS absorption band of the complex salts (Table 2). These cationic Rh^I complexes are stable and air‐resistant and can be used, e.g., as precursor complexes in situ in the presence of (M)‐6,7‐bis[(diphenylphosphino)methyl]‐8,12‐diphenylbenzo[a]heptalene for asymmetric hydrogenation of (Z)‐α‐(acetamido)cinnamic acid with ee values of up to 68% (Table 4).     

Synthesis of a Stable N‐Hetero‐RhI‐Metallacyclic Silanone

A novel N‐hetero‐Rh^I‐metallacyclic silanone 2 has been synthesized. The silanone 2 , showing an extremely large dimerization energy (ΔG=+86.2 kcal mol^?1), displays considerable stability and persists in solution up to 60 °C. Above 120 °C, an intramolecular C_sp3?H insertion occurs slowly over a period of two weeks leading to the bicyclic silanol 5 . The exceptional stability of 2 , related to the unusual electronic and steric effects of Rh^I‐substituent, should allow for a more profound study and understanding of these new species. Furthermore, the metallacyclic silanone 2 presents two reactive centers (Si=O and Rh), which can be involved depending upon the nature of reagents. Of particular interest, the reaction with H₂ starts with the hydrogenation of Rh^I center leading to the corresponding Rh^III‐dihydride complex 7 and it undergoes a cis/trans‐isomerization via a particular mechanism, demonstrating that addition‐elimination processes can also happen for silanones just like for their carbon analogues!     

Reactions of Diazo Compounds with Imines. Preliminary communication

The [Rh₂(OAc)₄]-catalyzed addition of methyl diazoacetate to N-benzylideneaniline ( 1a ) afforded the imine cis- 2 in 35% yield. Under catalysis by chiral Rh^II catalysts, however, only racemic 1a was produced, and the yield was low. In the presence of dimethyl maleate, aziridine formation was suppressed, and an intermediate ylide 6 was trapped as cycloadduct 7 . No aziridines were obtained, however, from 1b, 1c , and 3 . The iminium salt 8 reacted with (trimethylsilyl)diazomethane in the absence of [Rh₂(OAc)₄] via dipolar cycloaddition followed by extrusion of N₂ to 10 .