The use of push-pull dipoles for the construction of indole alkaloids: A total synthesis of aspidophytine

Push-pull dipoles generated from the Rh(II)-catalyzed reaction of diazo imides undergo successful intramolecular 1,3-dipolar cycloaddition across both alkenyl and heteroaromatic pi-bonds to provide novel pentacyclic compounds, in good yield and in a stereocontrolled fashion. The facility of the cycloaddition was found to be critically dependent on conformational factors in the transition state. Ligand substitution in the rhodium(II) catalyst markedly altered the product ratio between [3+2]-cycloaddition and intramolecular C-H insertion. The variation in reactivity reflects the difference in electrophilicity between the various rhodium carbenoid intermediates. Intramolecular C-H insertion is enhanced with the more electrophilic carbene generated using Rh(II) perfiuorobutyrate.; A search was, initiated to find efficient methods for the preparation of several synthetically promising diazo lactams with orthogonal chemical handles alpha to the diazo moiety and at a quaternary carbon stereocenter. A method was developed which allowed for their rapid construction using cheap and easily available reagents. The utility of this methodology was demonstrated by the synthesis of several complex natural product targets.; A new strategy for the synthesis of (+/-)-aspidophytine was developed and is based on a Rh(II)-catalyzed cyclization/dipolar-cycloaddition sequence. The resulting [3+2]-cycloadduct underwent an efficient Lewis acid mediated cascade that rapidly provided the complete skeleton of aspidophytine. The synthesis also featured an unusually gentle decarbomethoxylation reaction and a mild procedure to reduce thioamides in the presence of sensitive functionalities. A related tandem cyclization-cycloaddition cascade sequence was explored as a possible approach to the Kopsia alkaloids.