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The synthesis of chiral nucleoside analogues with a unique structural feature is reported. The strategy is based on a reductive-oxidative process to complete the transposition of the leaving group in chiral oxathiolanes with known configuration.

Two series of optically pure 2,4-disubstituted 1,3-dioxolanes and −1,3-oxathiolane nucleosides containing (E)-5-(2-bromovinyl)uracil were synthesized and assayed for activity against HSV-1, HSV-2 and HCMV replication in vitro. The β-L (2S,4S) dioxolane nucleoside 10 displayed significant activity against HSV-1, whereas the β-D (2R,4) oxathiolane 14 demonstrated potent activity against HSV-2. The α-L (2S,4R) dioxolane 11 and oxathiolane 17 were moderately active against HSV-1 and HSV-2, respectively.

2-Phosphonomethyl-1,3-dioxolane nucleosides containing appropriately linked pyrimidine and purine bases at C-4 position were prepared as biomimetic analogues of antiviral 2′,3′-dideoxynucleoside monophosphates. The key coupling intermediate 10 was prepared by a cyclocondensation of diethylacetal 6 and diol 7 followed by hydrolysis and lead tetra-acetate oxidative decarboxylation.

Expeditious and diastereoselective total syntheses of the antiviral agents, β-L-ddC, β-L-5FddC and β-D-5FddC have been achieved in four steps from commercially available R-(-)-5-oxo-2-tetrahydrofurancarboxylic and its 2S isomer respectively.

The in vitro antihepatitis B virus (HBV) activities of eleven novel imidazo[1,2-c]pyrimidin-5(6H)-one dideoxynucleoside analogues in which the sugar ring is 1,3-dioxolane or 1,3-oxathiolane were compared in the chronically HBV-producing human cell line 2.2.15. Seven nucleoside analogues 4, 9, 10, 15, 16, 18, and 24, of which 16 possesses the trans relative stereochemistry, displayed good potency and selectivity towards HBV. The order of decreasing potency at the 90% extracellular DNA inhibition level was 15>16>24≈9>10>18 . None of the tested imidazo[1,2-c]pyrimidines inhibited the replication of HIV-1 in MT-4 cells.

The synthesis of 2′-phosphonomethyl(3′,4′-dihydroxylbutyl) nucleotides of cytosine and guanine 13 and 15 possessing the 2′S,3′S absolute configuration was readily accomplished in eleven and ten steps respectively from L-ascorbic acid via the protected tetrols 9 and 8. Alcohol 8 undergoes efficiently a regiospecific Mitsunobu coupling with 6-chloro-2-aminopurine to furnish the N-9 isomer which was further transformed to 15.

The synthesis of a novel series of 3,4-disubstituted tetrahydrofuran derived nucleosides and nucleotides analogues was achieved by a linear approach starting from azido intermediates 9 and 13 . The trans cytosine nucleoside 19 emerged with good activity (IC 50 = 3 μg/mL) against HCMV in vitro with a selectivity index of 33.

Mechanism based inhibitors of HCMV protease have been designed based on the monocyclic beta-lactam nucleus, which have been shown to acylate the viral enzyme in a time dependent manner. SAR in a series of monocyclic beta-lactam N-ureas, has defined the size and relative stereochemistry of the C-3 substituent producing a low micromolar inhibitor 17b with good aqueous stability and selectivity over the mammalian serine proteases.

Six new sesquiterpene lactone esters, daucoguaianolactones A–F (1–6), and one new sesquiterpene lactone, daucoeudesmanolactone A (7) were isolated from the leaves and stems of Daucus glaber (Forssk.) Thell., along with the known sesquiterpene lactones talasins A and B and badkhysin. The structures of 1–6 were established on the basis of extensive 1D- and 2D-NMR spectroscopic studies and that of 7 by X-ray crystallography. Compounds 4, 7, and talasins A and B showed moderate cytotoxicity against P-388 leukemia cells.

The oxidative palladium-catalyzed cross-coupling of pyrimidines containing pyridotriazol-1-yloxy (OPt) as either a urea or an amide functional group with arylboronic acids in the presence of Cs2CO3 in DME containing 0.6−1.0% H2O is described for the preparation of heteroaryl ethers. The bromo substitution in the case of 3-(5-bromo-pyrimidin-2-yloxy)-3H-[1,2,3]triazolo[4,5-b]pyridine 1 could serve as a handle for further elaborations such as Suzuki coupling for attaching varied aryl groups.

The palladium-catalyzed oxidative coupling of pyrido- and benzotriazol-1-yloxyquinazolines and -thienopyrimidines with aryl boronic acids in the presence of Pd(PPh3)4 and Cs2CO3 under oxygen in DME...

The development of HKI-272 and EKB-569 for the treatment of cancer is described. These compounds function as irreversible inhibitors of some members of the ErbB family of receptor tyrosine kinases. In particular, they target epidermal growth factor receptor (EGFR, also known as ErbB-1) and human epidermal growth factor receptor-2 (HER2, also known as ErbB-2). Both, HKI-272 and EKB-569 are 4-anilino-3-cyano quinoline derivatives that contain a 4-(dimethylamino)crotonamide Michael-acceptor group at the 6-position. These compounds inhibit the function of the target enzymes by forming a covalent interaction with a conserved cysteine residue located in the kinase domains of these proteins. The potential advantages of using irreversible inhibitors for this purpose are discussed. We summarize the recent findings concerning some somatic mutations in EGFR and their relevance with respect to the irreversible inhibitors. In particular, we highlight the findings that these irreversible inhibitors retain activity against tumors that have acquired a resistance to the reversible binding inhibitors gefitinib and erlotinib. The promising interim clinical trial results for HKI-272 and EKB-569 in treating colon, lung, and breast cancers are summarized.

[reaction: see text] An efficient one-step amination of cyclic amides and ureas has been developed. Treatment of cyclic amides and cyclic ureas with BOP in the presence of DBU in various solvents led to the formation of cyclic amidines and cyclic guanidines in good to excellent yields. Concise syntheses of biologically intriguing kinetin and potent kinase inhibitor olomoucin were thus achieved in just one and two steps, respectively.

A procedure for the 3,3‐dimethylation of 4‐chromanones under basic conditions was improved; the by‐product from chromanone ring opening was isolated and its structure was determined.

A previously reported route to (±)‐capreomycidine was improved via a key step of NO+ addition/retro‐Claisen reaction.

The conversion of dihalomethylarenes to the corresponding aldehydes is accomplished conveniently by using sulfoxides as the oxygen donor under neutral conditions.

[reaction: see text] Aldol reactions using bis-(chiral alpha-methylbenzyl)glycine esters with aldehydes gave excellent diastereoselectivity. Thus, an enantiopure ribosylglycine was prepared for the synthesis of analogues of the natural antibiotics muraymycin. This method was extended for formation of beta-hydroxyamino esters.

Various N-protected aminoacylimidazolides undergo decarboxylative carbon acylation with sodium or potassium nonomethylmalonate in THE in the presence of MgCl2, CoCl2 or MnCl2 to give dipeptide analogues (3) in 45–82% isolated yield. Amino Ketoester (3e) undergoes intramolecular cyclization induced by diisopropylethylamine and anhydrous magnesium chloride to trisubstituted tetramic acid (4).

The cyanoacetamides (III), prepared from cyanoacetic acid (I) and the anilines (II), react with methyl formate (IV) in the presence of sodium to produce the α-hydroxymethylene derivatives (V) after acidic work-up.