Mahesh K. Lakshman

Direct Arylation of 6-Phenylpurine and 6-Arylpurine Nucleosides by Ruthenium-Catalyzed CH Bond Activation†

C H bond activation represents an efficient approach to molecular functionalization. 2] In directed C H bond activation, Lewis basic sites are exploited to draw the catalyst proximal to the reactive center. We have been interested in the C H bond activation and arylation of nucleobases and nucleosides using the nitrogen atoms of the purine itself as the Lewis basic sites. In this context, 6-arylpurine has embedded 2-phenylpyridine and 4-phenylpyrimidine motifs. 2-Arylpyridines, and benzo[h]quinoline, which can be considered as containing a rigidified 2-phenylpyridine structure, have been the subject of C H bond activation/arylation strategies using Pd, Ru, Rh, and Fe. However, any metal-catalyzed conversion of purines and purine nucleosides is a challenging proposition owing to the presence of four nitrogen atoms in the nucleobases, plus additional oxygen atoms in the sugar unit; all of these heteroatoms could participate in metal sequestration and deactivation of catalytic processes. As shown in Scheme 1, the N1 nitrogen atom of purine is well positioned to direct C H bond activation. Alternatively, N7 can also function in a similar capacity. To gain preliminary insight, energy minimization was performed, using DFTat the B3LYP/6-311 ++ G(2d,2p) level of theory, on 2-phenylpyridine as well as 9-benzyl-6-phenyl-9H-purine. The distances between the metal-directing nitrogen atom and the orthohydrogen atom on the phenyl ring were calculated from the energy-minimized structures, and are shown in Figure 1.

Palladium-catalyzed C–N and C–C cross-couplings as versatile, new avenues for modifications of purine 2′-deoxynucleosides

Abstract Methods involving palladium-catalysis can be efficiently applied to the relatively labile purine 2′-deoxynucleosidic systems. The net result is the remarkably ready access to new and unusual 2′-deoxyribonucleoside analogs bearing subsitutents on the purine moiety. C–N cross-coupling reactions are particularly attractive for the synthesis of N6 and N2 substituted 2′-deoxyadenosines and 2′-deoxyguanosines, respectively, as well as C-8 modified 2′-deoxyguanosines. CC bond-formation on the other hand, provides access to nucleosides containing hydrophobic hydrocarbon entities. Although the common theme for C–N and C–C cross-coupling is catalysis by Pd, there are substantial differences between the two classes of reactions. Furthermore, there are pronounced differences in reactivity trends at the C-6 position compared to those at the C-2. Optimized reaction conditions for both varieties of transformations can be found whereby novel purine 2′-deoxynucleosides can be readily obtained.

Epoxide and diol epoxide adducts of polycyclic aromatic hydrocarbons at the exocyclic amino group of deoxyguanosine

Abstract Synthesis and separation of the diastereomeric trans N 2 -2′-deoxyguanosine adducts of tetrahydrophenanthrene 3,4-epoxide and benzo[a]pyrene 7,8-diol 9,10-epoxide (benzylic hydroxyl group and epoxide oxygen trans), as well as the incorporation of the former into the pentanucleotide TpApG * pApT, are described.

Simple Synthesis of Amides and Weinreb Amides Using PPh3 or Polymer-Supported PPh3 and Iodine

The combination of PPh3/I2 has been shown to be effective for conversion of a range of carboxylic acids to 2°, 3°, and Weinreb amides. Simplification of the procedure was possible with the use of polymer-supported PPh3/I2. Weinreb amides produced via the use of polymer-supported PPh3 could be filtered through a short silica gel plug and used in further transformations. Thus, use of polymer-supported PPh3 offers potential applicability to diversity-oriented reactions. Formal total syntheses of apocynin and pratosine, as well as syntheses of anhydrolychorinone and hippadine, have been achieved via the use of this amide-forming method. An attempt has been made to gain insight into this reaction.

Synthesis of Deuterated 1,2,3-Triazoles

The copper-catalyzed azide-alkyne cycloaddition (CuAAC) is a highly effective method for the selective incorporation of deuterium atom into the C-5 position of the 1,2,3-triazole structure. Reactions of alkynes and azides can be conveniently carried out in a biphasic medium of CH(2)Cl(2)/D(2)O, using the CuSO(4)/Na ascorbate system. The mildness of the method renders it applicable to substrates of relatively high complexity, such as nucleosides. Good yields and high levels of deuterium incorporation were observed. A reaction conducted in equimolar H(2)O and D(2)O showed 2.7 times greater incorporation of hydrogen atom as compared to deuterium. This is consistent with the H(+) and D(+) ion concentrations in H(2)O and D(2)O, respectively. With appropriately deuterated precursors, partially to fully deuterated triazoles were assembled where the final deuterium atom was incorporated in the triazole-forming step.

A Novel Polymer Supported Approach to Nucleoside Modification

Polymer-supported O(6)-(benzotriazol-1-yl)inosine derivatives (Pol-I and Pol-dI) have been synthesized reasonably effectively via reaction of nucleoside phosphonium salts with polymer-linked HOBt (Pol-HOBt). In constast to solution chemistry, use of polymer-supported BOP (Pol-BOP) did not lead to efficient nucleoside loading. Presence of the nucleosides on the support could be readily detected by MAS NMR. Exposure of the polymer-supported nucleosides, Pol-I and Pol-dI, to alcohol, phenol, thiol and amine nucleophiles caused cleavage from the support leading directly to the C-6 modified nucleoside analogues. To our knowledge, these are the first examples of the application of such technology for nucleoside modification. Where possible, results of reactions with the polymer-supported nucleosides are compared to those from solution chemistry, providing insight into the differences between the two techniques. These new polymer-supported nucleosides can be conveniently utilized for diversity-oriented synthesis.

Evaluation of the protective role of vitamin C in imidacloprid-induced hepatotoxicity in male Albino rats

In the present study, the effects of oral administration of imidacloprid for 4 weeks on serum biochemical, oxidative stress, histopathological and ultrastructural alterations were assessed in the liver of male rats. This study also aimed to investigate whether vitamin C could protect against the imidacloprid-induced oxidative stress. Forty-eight male Sprague dawley rats were divided into four groups of 12 animals each. Group 1 served as the control, while groups 2 and 4 were administered with imidacloprid (80 mg/kg body weight) daily by oral gavage for 28 days. In addition to imidacloprid, group 4 also received vitamin C at 10 mg/kg daily by oral gavage for 28 days. Group 3 was maintained as the vitamin C control (dose as above). The serum biochemical assays revealed a significant (P < 0.05) increase in alanine transaminase and aspartate transaminase and decrease in total protein in group 2. The tissue biochemical profile revealed a significant (P < 0.05) reduction in reduced glutathione concentration in the liver of group 2 animals. Histologically, the liver showed marked dilation, congestion of central vein, portal vein and sinusoidal spaces, vacuolation/fatty change and degenerated hepatocytes. Ultra thin sections of the liver revealed swollen nuclei, varied size and shape of mitochondria, disrupted chromatin and rough endoplasmic reticulum. Co-treatment with vitamin C significantly (P < 0.05) reversed the imidacloprid-induced changes.

Modular, Metal-Catalyzed Cycloisomerization Approach to Angularly Fused Polycyclic Aromatic Hydrocarbons and Their Oxidized Derivatives.

Palladium-catalyzed cross-coupling reactions of 2-bromobenzaldehyde and 6-bromo-2,3-dimethoxybenzaldehyde with 4-methyl-1-naphthaleneboronic acid and acenaphthene-5-boronic acid gave corresponding o-naphthyl benzaldehydes. Corey-Fuchs olefination followed by reaction with n-BuLi led to various 1-(2-ethynylphenyl)naphthalenes. Cycloisomerization of individual 1-(2-ethynylphenyl)naphthalenes to various benzo[c]phenanthrene (BcPh) analogues was accomplished smoothly with catalytic PtCl2 in PhMe. In the case of 4,5-dihydrobenzo[l]acephenanthrylene, oxidation with DDQ gave benzo[l]acephenanthrylene. The dimethoxy-substituted benzo[c]phenanthrenes were demethylated with BBr3 and oxidized to the o-quinones with PDC. Reduction of these quinones with NaBH4 in THF/EtOH in an oxygen atmosphere gave the respective dihydrodiols. Exposure of the dihydrodiols to N-bromoacetamide in THF-H2O led to bromohydrins that were cyclized with Amberlite IRA 400 HO(-) to yield the series 1 diol epoxides. Epoxidation of the dihydrodiols with mCPBA gave the isomeric series 2 diol epoxides. All of the hydrocarbons as well as the methoxy-substituted ones were crystallized and analyzed by X-ray crystallography, and these data are compared to other previously studied BcPh derivatives. The methodology described is highly modular and can be utilized for the synthesis of a wide variety of angularly fused polycyclic aromatic hydrocarbons and their putative metabolites and/or other derivatives.

Regio and stereocontrolled synthesis of aryl cis aminoalcohols from cis glycols

Reaction of aryl substituted cis diols with α-acetoxyisobutyryl chloride results in the formation of trans vicinal chlorohydrin acetates where the halide is benzylic. Displacement of chloride with azide ion, deprotection of the ester and reduction of the azide furnishes the requisite cis aminoalcohols. This facile four-step procedure results in the exclusive replacement of a benzylic hydroxyl with an amino group, with a net retention of stereochemistry. This set of transformations is generally applicable to a wide variety of cis diols, and the overall yields are excellent.

Palladium-Catalyzed Aryl Amination Reactions of 6-Bromo- and 6-Chloropurine Nucleosides

Abstract Palladium‐catalyzed C—N bond forming reactions of 6‐bromo‐ as well as 6‐chloropurine ribonucleosides and the 2′‐deoxy analogues with arylamines are described. Efficient conversions were observed with palladium(II) acetate/Xantphos/cesium carbonate, in toluene at 100 °C. Reactions of the bromonucleoside derivatives could be conducted at a lowered catalytic loading [5 mol% Pd(OAc)2/7.5 mol% Xantphos], whereas good product yields were obtained with a higher catalyst load [10 mol% Pd(OAc)2/15 mol% Xantphos] when the chloro analogue was employed. Among the examples evaluated, silyl protection for the hydroxy groups appears better as compared to acetyl. The methodology has been evaluated via reactions with a variety of arylamines and by synthesis of biologically relevant deoxyadenosine and adenosine dimers. This is the first detailed analysis of aryl amination reactions of 6‐chloropurine nucleosides, and comparison of the two halogenated nucleoside substrates.