Luminescence spectroscopy coupled with capillary electrophoresis (CE) provides insight into the nature and
stereoselectivity of Cr(diimine)3
3+ interactions with polynucleotides. Photoluminescence measurements on Cr(phen)3
3+ and Cr(bpy)3
3+ in air or N2-saturated solution demonstrate strong B-DNA quenching of Cr(diimine)3
3+
emission intensities and lifetimes. Both dynamic and static quenching are observed, the latter being attributed to
DNA bound Cr(diimine)3
3+. Very rapid quenching is also observed with deoxyguanosine monophosphate (dGMP),
while no bimolecular quenching is observed with other mononucleotides. Likewise, poly(dG-dC)·poly(dG-dC)
causes rapid quenching, while only minor quenching is observed for poly(dA-dT)·poly(dA-dT). These emission
results are consistent with a DNA quenching mechanism involving guanine base oxidation. The electropherogram
resulting from the co-injection of rac-Cr(phen)3
3+ and rac-Ru(phen)3
2+ into a capillary containing B-DNA indicates
a similar binding constant for the two complexes, while the enantiomeric stereoselectivities are reversed. CE
studies for Ru(phen)3
2+ with distamycin A (an AT selective minor groove binder) reveal a significant reduction
in complex migration times and a complete loss of enantiomeric discrimination. These results are consistent with
a literature model where nonelectrostatic binding for both isomers occurs in the minor groove. Analogous distamycin
studies with Cr(phen)3
3+ are also in accord with minor groove binding.
Stereogenic 2-(N-carbamoyl)pyrrolidinylcuprates prepared from scalemic (i.e., enantioenriched) N-Boc-2-lithiopyrrolidine and THF soluble CuCN.2LiCl react with vinyl iodides, vinyl triflates, beta-iodo-alpha,beta-enoates, propargyl mesylates, and allyl bromide to afford the substitution products with excellent enantioselectivity. Excellent enantiomeric ratios are obtained in the conjugate addition reactions with methyl vinyl ketone while low enantiomeric ratios can be achieved with acrylate esters using HMPA/TMSCl activation. Enantiomeric ratios vary with substrate substitution patterns and the observed enantioselectivities appear to be more a function of cuprate-electrophile reactivities than of the reaction type (e.g., substitution, conjugate addition). Low enantiomeric ratios are obtained with the alpha-(N-carbamoyl)benzylcuprates. The lithium-copper transmetalation and cuprate vinylation reactions proceed with retention of configuration.
The asymmetric synthesis of (-)-(R)-pyrrolam A was achieved in three operations from N-Boc pyrrolidine via an alpha-(N-carbamoyl)alkylcuprate vinylation reaction followed by N-Boc deprotection and cyclization. One-pot deprotection-cyclization procedures led to mixtures of pyrrolam A and its double bond isomers. These isomerization events could be circumvented by use of a two-step procedure. To guide aspects of the experiments, a series of computational energy evaluations and chemical shift predictions were performed with molecular mechanics, semiempirical, ab initio, and density functional methods. The relative stabilities of the double bond isomers, as estimated by experiment, challenged a number of computational methods, and only the MP2 model with its moderate degree of electron correlation came close to matching the experimental data. The MP2 method was further applied to an unusual aspect of the double bond migration between pyrrolam A and its isomer 9. The reaction (1 to 9) on neat samples is irreversible without racemization, and the alumina-mediated equilibration is accompanied by complete loss of enantiomeric excess. The source of the irreversibility was traced to asymmetric charge distribution in the intermediate dienolate anion. The analysis ultimately led to a semiquantitative sketch of the pyrrolam energy surface.
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