Stereochemical Aspects in the Interrupted Nazarov Reaction of Allenyl Vinyl Ketones: A Computational Study

Abstract

Transition state models are often invoked to explain stereochemical outcomes in chemical reactions. The relevance of these models to correctly predict these outcomes can be further validated by studying reactions where multiple stereocenters are formed sequentially. Through the use of computational methods, insight is provided on some sterochemical aspects of a two-step cascade reaction, i.e., a Nazarov/homologous Mukaiyama reaction sequence. The torquoselectivity in the thermal, Lewis acid-mediated Nazarov reaction of a series of terminally substituted allenyl vinyl ketones has been subjected to a computational investigation using density functional methods. In this conrotatory electrocyclization reaction, the preferred mode of rotation of the termini was found to be by outward rotation of the allenyl substituent. This leads to products that are not the lower-energy isomers because there are large steric interactions present in the kinetic products. However, the torquoselectivity is shown to be decided at the transition state more by steric interactions between the termini of the allenyl and the vinyl moieties than by the competing steric interactions between between substituents on the allene of the substrate. These steric interactions cause the transition state for the inward rotation of allenyl substituent to be more distorted than that for outward rotation, resulting in high levels of torquoselectivity (>20:1) in favor of outward rotation of the allenyl terminus. The diastereoselectivity in the trapping of an oxyallyl cation by a series silyloxy enol ethers and their corresponding enols through open-type transition states has also been assessed computationally. Perhaps as a consequence of the high reactivity of oxyallyl cations for addition by such electron-rich alkenes, multiple, nearly iso-energetic, reaction pathways were found. This should lead to low levels of diastereoselectivity. The results allowed some discussion with respect to how these transition states are ordered in terms of energy. However, the complexity of these open-type transition states, as opposed to the well-known cyclic aldol transition states, limits the interpretation of the results to a simplistic level. However, some published experimental results indicated that the diastereoselectivity could be quite high. Therefore, it is postulated that the observed diastereoselectivity must be due to equilibration of the products after the carbon-carbon forming event of the homologous Mukaiyama aldol addition. Overall, the results presented in this thesis show that the conventional use of steric and/or electronic arguments based on generally accepted models may not provide correct predictions in terms of the developing stereochemistry in a complex organic reaction, and that the use of computational methods is demonstrated herein to be crucial for attaining a better understanding of reaction mechanisms.