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Abstract:
This work describes the development of new transformations of keteniminium salts generated via electrophilic activation of amides for the preparation of lactones. Drawing from an unexpected observation, the [2+2] cycloaddition chemistry of keteniminium salts was totally diverted towards a selective Claisen-like skeletal reorganization of δ-alkoxyamides. Allyl, propargyl and benzyl ethers smoothly rearranged to the corresponding α-allyl, allenyl and aryl lactones bearing challenging substitution patterns, in good to excellent yields. Mechanistic studies enabled the elucidation of the reaction intermediates, providing clear evidence in support of a [3,3]-sigmatropic rearrangement that likely proceeds through the formation of keteniminium ions. Stemming from serendipitous observations, we also developed rare and powerful O-C shifts, which document the possibility to steer the reaction pathway away from pericyclic manifolds simply by substrate design. The last part of this thesis describes another serendipitous finding. Our attempts to rationalize the formation of a byproduct common to several prior reactions led to the development of a novel lactonization strategy in which an alcohol or ether directly cyclizes onto an activated amide. This methodology proved to be efficient for the formation of variously substituted lactones of different ring sizes. The synthetic utility of this protocol was established by its application as key step in the short total synthesis of a natural product.
