Studies in stereoelectronic effects at oxygen

Abstract

The thesis entitled “STUDIES IN STEREOELECTRONIC EFFECTS AT OXYGEN” is divided into five chapters.

Chapter I Chapter I describes a novel strategy for studying stereoelectronic effects in the breakdown of the Criegee acylperoxide intermediate of the Baeyer–Villiger reaction. A conformationally defined bicyclic Criegee intermediate was generated by intramolecular attack of peracid on ketone in 2?oxocyclohexaneperacetic acid. Different products are expected depending on whether this intermediate breaks down with stereoelectronic control or not. Results of the experiment are consistent with the sequence of events shown below, with the bicyclic peroxide intermediate breaking down such that cleavage of the O–O bond is concerted with cleavage of the anti?periplanar C–C bond (Scheme I). An extension of this strategy to 2?oxocyclopentaneperacetic acid showed that stereoelectronic control was not total—probably because of incursion of an intermolecular pathway, due to ring strain in the bicyclic peroxide intermediate.

Chapter II Chapter II describes solvent deuterium isotope effects on the hydrolysis of 2,4,10?trioxatricyclo[3.3.1.1³’?]decane, which was studied to understand its extraordinary stability. The ratio k(D?O) / k(H?O) was 0.76, suggesting general base?catalysed, A–1 rate?determining hydration of the intermediate dioxocarbonium ion, followed by much faster reclosure of this ion to the starting compound due to proximity of the reacting groups. Although this seemed to account for the hydrolytic stability of the tricyclic orthoformate, careful studies at constant ionic strength and varying general?base strengths in phosphate buffers showed an absence of external general?base catalysis. This apparent absence of catalysis is explained by intramolecular general?base catalysis by the alkoxide oxygen atom of the dioxocarbonium ion (consistent with the solvent isotope effect results) (Scheme II).

Chapter III Chapter III reports the preparation of 3?methoxy?2,4,10?trioxatricyclo[3.3.1.1³’?]decane, a novel orthocarbonate in which the exocyclic C–O bond possesses no anomeric stabilisation, as only endocyclic C–O bonds lie antiperiplanar to it (Scheme III). Also described are unsuccessful attempts to prepare 3?bromo?2,4,10?trioxatricyclo[3.3.1.1³’?]decane, expected to be an unusually stable bromo?orthoformate because no electron lone pair is antiperiplanar to the C–Br bond.

Chapter IV Chapter IV describes a novel synthetic application of the mechanistic results of Chapter II. Based on the discovery that reclosure of cleavage products to trioxatricyclodecane is very fast, it was expected that the corresponding trioxatricyclodecanemethyllithium derivative would be stable to ??elimination, a reaction normally expected in 2?lithio?orthoacetates. Experiments supported this expectation. The lithium compound reacted smoothly with non?enolisable aldehydes to give the expected alcohols, which were then oxidised to carboxyl?protected ??ketoacids. The keto?carbonyl groups of these ketoacids were converted to oximes, which on reduction yielded carboxyl?protected ??amino acids. These were hydrolysed to the ??amino acids, important precursors for the synthesis of ??lactams (Scheme IV).

Chapter V Chapter V describes an attempt to determine the specific rate of hydrolysis of equatorial?2?(4?nitrophenoxy)tetrahydropyran, from a knowledge of its concentration relative to the axial isomer (obtained using NMR spectroscopy), the reported specific rates for hydrolysis of 2?(4?nitrophenoxy)tetrahydropyran and axial?2?(4?nitrophenoxy)?1?oxadecalin, and the assumption that the axial isomers of the tetrahydropyran and oxadecalin derivatives have identical specific rates. Application of the Winstein–Holness equation was used to evaluate the result. The goal was to determine how greater conformational flexibility in the equatorial?tetrahydropyran affected reactivity relative to the equatorial?oxadecalin. Surprisingly, the former compound was retarded by a factor of about 0.64, in 30% dioxane–water at 39°C. Mechanistic explanations based on the Curtin–Hammett principle are offered.