Combining computational modelling, NMR spectroscopy and assembly-line synthesis for studying molecular conformations

• Main Author: Zhong, Siying
• Format: Dissertation
• Language: English
• Published: University of Bristol 2019

This thesis reports the application of computational modelling, NMR spectroscopy and stereospecific iterative homologation of boronic esters to the three-dimensional structural elucidation of flexible organic small molecules, and the design and synthesis of flexible molecules with tailored conformations. Firstly, the configuration of a recently isolated polyketide baulamycin A, which exhibits potent antibacterial activity, was reassigned using a combination of Density Functional theory (DFT) calculations, NMR spectroscopy and synthesis. In this work, DFT calculations were employed to predict the complex dynamic conformations of eight possible diastereomers of baulamycins and to compute the ensemble-averaged chemical shifts, 1H-1H scalar coupling constants and 1H-1H distances. Comparison between the computed NMR parameters of each diastereomer with the experimentally determined values eliminated 112 out of the possible 128 diastereomeric candidates. Finally, synthesis allowed the relative and absolute configuration of baulamycin A to be positively identified. Secondly, inspired by the conformational control exerted by quaternary centres, a range of conformationally defined unnatural amino esters were designed with the aid of computational modelling. Two of the amino esters were synthesised and their solution state conformations were elucidated by a combination of DFT calculations and quantitative analysis of 1H-1H and 1H-13C scalar coupling constants. Their side chains are shown to take on defined orientations (syn-periplanar or turn a 120° corner) with controllable distances and could find application in areas such as drug design. Finally, factors controlling the helical screw-sense of hydrocarbons with all-syn contiguous methyl substituents was investigated. The solution-state conformational behaviour of hydrocarbons with different numbers of methyl substituents (from six to 11) was studied using a combination of DFT calculations and quantitative analysis of 1H-1H scalar coupling constants and 1H-1H distances. It was discovered that only hydrocarbons with even numbers of methyl substituents adopt regular helical conformation, whereas hydrocarbons with odd number of methyl substituents do not have a strong preference for a particular conformation. The preference of screw sense (if any) in each case was rationalised by the minimisation of gauche interactions.