Diastereoselectivity in Lewis-Acid-Catalyzed Mukaiyama Aldol Reactions: A DFT Study

The basis for diastereoselectivity in Lewis-acid-catalyzed Mukaiyama aldol reactions was studied using density functional theory. By exploring the conformations of the transition structures for the diastereodifferentiating step of seven different reactions, simple models were generated. The effects of varying the substituents on the enol carbon and the α-carbon of the silyl enol ether from methyl to <i>tert</i>-butyl groups and the substituent on the aldehyde from methyl to phenyl groups were investigated by comparison of the transition structures for different reactions. Expanding on the previous qualitative models by Heathcock and Denmark, we found that while the pro-<i>anti</i> pathways take place via antiperiplanar transition structures, the pro-<i>syn</i> pathways prefer synclinal transition structures. The relative steric effects of the Lewis acid and trimethyl silyl groups and the influence of <i>E</i>/<i>Z</i> isomerism on the aldol transition state were investigated. By calculating 36 transition structures at the M06/6-311G*//B3LYP/6-31G* level of theory and employing the IEFPCM polarizable continuum model for solvation effects, this study expands the mechanistic knowledge and provides a model for understanding the diastereoselectivity in Lewis-acid-catalyzed Mukaiyama aldol reactions

Requirement of Watson-Crick Hydrogen Bonding for DNA Synthesis by Yeast DNA Polymerase η

Classical high-fidelity DNA polymerases discriminate between the correct and incorrect nucleotides by using geometric constraints imposed by the tight fit of the active site with the incipient base pair. Consequently, Watson-Crick (W-C) hydrogen bonding between the bases is not required for the efficiency and accuracy of DNA synthesis by these polymerases. DNA polymerase η (Polη) is a low-fidelity enzyme able to replicate through DNA lesions. Using difluorotoluene, a nonpolar isosteric analog of thymine unable to form W-C hydrogen bonds with adenine, we found that the efficiency and accuracy of nucleotide incorporation by Polη are severely impaired. From these observations, we suggest that W-C hydrogen bonding is required for DNA synthesis by Polη; in this regard, Polη differs strikingly from classical high-fidelity DNA polymerases

Stereoselectivity in (Acyloxy)borane-Catalyzed Mukaiyama Aldol Reactions

The origin of diastereo- and enantioselectivity in a Lewis acid-catalyzed Mukaiyama aldol reaction is investigated using a combination of dispersion corrected DFT calculations and transition state force fields (TSFF) developed using the quantum guided molecular mechanics (Q2MM) method. The reaction proceeds via a closed transition structure involving a nontraditional hydrogen bond that is 3.3 kJ/mol lower in energy than the corresponding open transition structure. The correct prediction of the diastereoselectivity of a Mukaiyama aldol reaction catalyzed by the conformationally flexible Yamamoto chiral (acyloxy) borane (CAB) requires extensive conformational sampling at the transition structure, which is achieved using a Q2MM-derived TSFF, followed by DFT calculations of the low energy conformational clusters. Finally, a conceptual model for the rationalization of the observed diastereo- and enantioselectivity of the reaction using a closed transition state model is proposed

Evidence for a Watson-Crick Hydrogen Bonding Requirement in DNA Synthesis by Human DNA Polymerase κ

The efficiency and fidelity of nucleotide incorporation by high-fidelity replicative DNA polymerases (Pols) are governed by the geometric constraints imposed upon the nascent base pair by the active site. Consequently, these polymerases can efficiently and accurately replicate through the template bases which are isosteric to natural DNA bases but which lack the ability to engage in Watson-Crick (W-C) hydrogen bonding. DNA synthesis by Polη, a low-fidelity polymerase able to replicate through DNA lesions, however, is inhibited in the presence of such an analog, suggesting a dependence of this polymerase upon W-C hydrogen bonding. Here we examine whether human Polκ, which differs from Polη in having a higher fidelity and which, unlike Polη, is inhibited at inserting nucleotides opposite DNA lesions, shows less of a dependence upon W-C hydrogen bonding than does Polη. We find that an isosteric thymidine analog is replicated with low efficiency by Polκ, whereas a nucleobase analog lacking minor-groove H bonding potential is replicated with high efficiency. These observations suggest that both Polη and Polκ rely on W-C hydrogen bonding for localizing the nascent base pair in the active site for the polymerization reaction to occur, thus overcoming these enzymes' low geometric selectivity