The total synthesis of dragmacidins D and F

Citation

Garg, Neil Kamal (2005) The total synthesis of dragmacidins D and F. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechETD:etd-03222005-133937

Abstract

The dragmacidins are an emerging class of bis(indole) natural products isolated from deep-water marine organisms. Although there has been a substantial effort to prepare the simple piperazine dragmacidins, little synthetic work has been done in the area of the pyrazinone-containing family members, dragmacidins D, E, and F. These compounds are particularly interesting due to their complex structures and broad range of biological activity. A highly convergent strategy to access dragmacidin D has been developed. In this approach, sequential halogen-selective Suzuki couplings were used to assemble the carbon scaffold of the natural product. After executing a highly optimized sequence of final events, the first completed total synthesis of dragmacidin D was achieved. An enantiodivergent strategy for the total chemical synthesis of both (+)- and (-)-dragmacidin F from a single enantiomer of quinic acid has been developed and successfully implemented. Although unique, the synthetic routes to these antipodes share a number of key features, including novel reductive isomerization reactions, Pd(II)-mediated oxidative carbocyclization reactions, halogen-selective Suzuki couplings, and high-yielding late-stage Neber rearrangements. The formal total syntheses of dragmacidin B, trans-dragmacidin C, and dihydrohamacanthin A are described. In addition, preliminary studies involving a novel approach for the preparation of dragmacidin E are reported.

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