Development and Synthetic Application of Iodine(III)- and Chromium(VI)-Mediated Alkene Oxamidation

Earlier studies have shown that unsaturated O-alkyl hydroxamates undergo oxidative cyclization in the presence of phenyliodine(III) bis(trifluoroacetate) (PIFA) to form the lactam products. The mechanism of this transformation is thought to proceed via formation of an N-acylnitrenium ion, which undergoes alkene cycloaddition to form an N-acyl-N-alkoxy-aziridinium ion. Stereospecific and regioselective ion-pair collapse of this reactive intermediate then gives rise to the products of intramolecular amidotrifluoroacetoxylation. This previously reported methodology was extended to include [hydroxy(organosulfonyloxy)iodo]arenes, [hydroxy(diphenylphosphoryloxy)iodo]arenes and chromium(VI) oxidants, thereby providing access to a wide range of nitrogen-containing, saturated heterocycles, including pyrrolidines, piperidines, morpholines and piperazines. The broad functionalization scope of these simple methods allow for the efficient generation of sulfonates, phosphates, amino ketones, as well as spirolactams. The formal synthesis of kainic acid, an agonist of kainate ionotropic glutamate receptors, was achieved highlighted by a HMIB-mediated intramolecular alkene oxamidation. Utilizing the I(III)- or Cr(VI)-mediated oxamidation of alkenes, a wide-ranging strategy for the stereoselective construction of the morphan ring system, which is found in over 300 natural products, was developed. The preparation of an advanced bicyclic intermediate for the synthesis of the madangamine alkaloids was discussed. In addition, our oxamidation methodology was successfully applied to the preparation of advanced tetracyclic intermediates for the synthesis of the anti-inflammatory natural products E- and Z-alstoscholarine.