DNA has a structural basis to array functionalized building blocks. Here we report the synthesis of a series of artificial oligonucleotides, d(5'-GH(n)C-3') (n = 1 to 5), with hydroxypyridone nucleobases (H) as flat bidentate ligands. Right-handed double helices of the oligonucleotides, nCu2+.d(5'-GH(n)C-3')2 (n = 1 to 5), were quantitatively formed through copper ion (Cu2+)-mediated alternative base pairing (H-Cu2+-H), where the Cu2+ ions incorporated into each complex were aligned along the helix axes inside the duplexes with the Cu2+-Cu2+ distance of 3.7 +/- 0.1 angstroms. The Cu2+ ions were coupled ferromagnetically with one another through unpaired d electrons to form magnetic chains.

Recently, we reported the first artificial nucleoside for alternative DNA base pairing through metal complexation (J. Org. Chem. 1999, 64, 5002-5003). In this regard, we report here the synthesis of a hydroxypyridone-bearing nucleoside and the incorporation of a neutral Cu(2+)-mediated base pair of hydroxypyridone nucleobases (H-Cu-H) in a DNA duplex. When the hydroxypyridone bases are incorporated into the middle of a 15 nucleotide duplex, the duplex displays high thermal stabilization in the presence of equimolar Cu(2+) ions in comparison with a duplex containing an A-T pair in place of the H-H pair. Monitoring temperature dependence of UV-absorption changes verified that a Cu(2+)-mediated base pair is stoichiometrically formed inside the duplex and dissociates upon thermal denaturation at elevated temperature. In addition, EPR and CD studies suggested that the radical site of a Cu(2+) center is formed within the right-handed double-strand structure of the oligonucleotide. The present strategy could be developed for controlled and periodic spacing of neutral metallobase pairs along the helix axis of DNA.

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Five nonnatural beta-C-nucleoside 5'-triphosphates bearing a 3,4-dihydroxyphenyl (1TP), a 2-hydroxyphenyl (2TP), a 3-hydroxyphenyl (3TP), a 4-hydroxyphenyl (4TP), or a phenyl (5TP) group were synthesized, and their structure-activity relationships were examined for a series of DNA polymerase reactions in vitro under typical polymerase chain reaction conditions. We found that the 5'-triphosphates (1TP-5TP) are not incorporated into DNA strands but inhibit the DNA polymerase reactions in the presence of natural nucleoside 5'-triphosphates (dNTPs). 1TP having two phenolic hydroxy groups at the nucleobase moiety showed the most potent inhibitory effect against DNA synthesis by Ex Taq polymerase (IC(50) = 30 microM). The competition assay indicated that 1TP and dNTPs are most likely to affect DNA polymerase reactions competitively. This finding may raise the appealing possibility that artificial nucleoside 5'-triphosphates having phenolic hydroxy groups could exhibit potent inhibitory activity against DNA-directed enzymatic reactions.

We report an effective dynamic kinetic resolution (DKR) system of racemic 2-(1H-pyrrol-1-yl)alkanoic acids, which consists of a rapid racemization step via an activating substrate and an enantio-discriminating step via catalytic esterification. The combination of pivalic anhydride as an activating agent, bis(α-naphthyl)methanol as an achiral alcohol, (R)-BTM as a chiral acyl-transfer catalyst, and Hünig's base converted racemic 2-(1H-pyrrol-1-yl)alkanoic acids to the corresponding chiral carboxylates, which can be transformed into chiral α-amino acid derivatives with maintained high enantiopurity.α-Amino acids have long been considered fundamental moieties in organic chemistry, and the enantio-controlled and catalytic construction of the chiral α-position of α-amino acids has been targeted as an attractive synthetic goal. 16In order to provide large amounts of chiral α-amino acids from racemic α-amino acids, dynamic kinetic resolution (DKR) 7,8 has been anticipated to be an ideal method. While a wide range of enzymatic DKRs 911 for α-amino acid derivatives has been disclosed as reliable methodologies, non-enzymatic DKRs have also emerged as promising approaches during the last decade. However, major examples of the successful nonenzymatic DKR of chiral α-amino acids have involved the catalytic ring-opening alcoholysis of cyclic precursors, such as racemic urethane-protected α-amino acid N-carboxyanhydrides (Deng 12 ) and racemic 2-phenylazlactones (Seebach, 13 Fu,14 Berkessel, 1517 Connon,18,19 Birman,20,21 etc.). Note that the DKR systems for racemic 2-phenylazlactones principally allowed production of N-benzoyl amino acids with high enantiopurities.As illustrated in Figure 1, we have reported the effective kinetic resolution (KR) of racemic α-arylpropanoic acids 22 using carboxylic anhydride as the coupling agent, bis(α-naphthyl)-methanol as the achiral alcohol, and benzotetramisole (BTM) 23 as the chiral acyl-transfer catalyst. In this procedure, a racemic mixture of α-arylpropanoic acids was separated into the corresponding chiral carboxylates and the recovered chiral carboxylic acids with high selectivity. A mechanistic study 24 revealed that this enantioselective esterification proceeds through a mixed anhydride (MA), a reactive intermediate formed from the substrate and the coupling reagent, followed by formation of a transition state (TS) with the achiral alcohol and chiral BTM. Furthermore, acceleration of the racemization process in a polar reaction media such as DMF led to the development of the corresponding DKR system for α-arylpropanoic acids. 25Despite the growing number of DKR systems reported to date, there has yet been no example of a catalytic DKR system for protected α-amino acids via direct esterification using acyclic precursors. Moreover, to the best of our knowledge, there are no examples of catalytic DKR systems for any racemic α-nitrogencontaining carboxylic acids. In the present study, we report the first DKR of racemic 2-(1H-pyrrol-1-yl)alkanoic acids, which can then be converted to α...

We report a new method for the preparation of chiral 2-aryl-2-fluoropropanoic acids, including 2-fluoroibuprofen, a fluorinated analogue of non-steroidal anti-inflammatory drugs (NSAIDs), by the kinetic resolution of racemic 2-aryl-2-fluoropropanoic acids using enantioselective esterification. By applying pivalic anhydride (Piv2O) as a coupling agent, bis(α-naphthyl)methanol [(α-Np)2CHOH] as an achiral alcohol, and (+)-benzotetramisole (BTM) as a chiral acyl-transfer catalyst, a series of racemic 2-aryl-2-fluoropropanoic acids were kinetically separated to afford the optically active carboxylic acids and the corresponding esters with good to high enantiomeric excesses. This technology can provide a convenient approach to furnish the chiral α-fluorinated drugs containing quaternary carbons at the α-positions in the 2-aryl-2-fluoropropanoic acid structure.

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