The basic objectives of this application are the development and application of the tandem (4+2)/(3+2) cycloaddition reaction of the nitroalkene functional group. The program is divided into two major sections with specific aims but unified in the common theme of new reaction chemistry for the preparation of biologically active alkaloids carbocylces and carbohydrates. The methodological objective is subdivided into two parts. The first will involve the expansion of the established modes of tandem cycloaddition, the intermolecular/intermolecular and, most importantly, all four subclasses of the intermolecular/intramolecular (4+2)/(3+2) modes. This investigation will encompass a survey a new reaction components: (1)nitroalkene heteroatom substitution, (2) dienophile variation, (3) the use of (chiral) Lewis acid catalysis for both (4+2) and (3+2) components, (4) studies on the transformations of the product nitroso acetals and (5) a thorough mechanistic examination of the (4+2) cycloaddition. New reaction chemistry will be developed to allow the introduction of heteroatom functions in the products. The second part of the methodological study is the exploration and development of the new family of intramolecular/intramolecular (4+2)/(3+2) tandem cycloadditions. If successful, this family of transformations will allow for the rapid and selective construction of complex polycyclic ring systems from simple acyclic precursors. A major activity will be the assessment of scope, viability and stereocontrol elements in the many permutations of this new class. The synthesis targets to be tackled belong to a wide range of natural product families. For example alkaloids in the pyrrolizidine, indolizidine, melodinus and cephalotaxus families. In addition a major effort will be directed to the synthesis of such important classes of biologically active compounds as the sialic acids (N-acetylneuraminic acid) amino carbasugars, amino sugars, and carbocyclic nucleoside analogs. In the more exploratory section of tandem double intramolecular (4+2)/(3+2) cycloaddition, medium size rings (seven- and eight membered carbo and oxacycles) are targeted. Feasibility studies are planned for new modes of cycloaddition that will allow the syntheses of morphinane alkaloids and the extraordinarily complex aconitine family of norditerpenoids.
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