Condensations and Cyclizations to Bioactive Heterocycles

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DESCRIPTION: (Applicant's Descripiton) The isolation of biologically interesting natural products from sensitive sources continues to be one of the best ways of finding medicinally relevant lead compounds. Unfortunately, we are usually unable to isolate sufficient quantitites of many of these bioactive compounds for their full evaluation. Outlined herein are our plans to improve this situation through the synthesis of the bioactive natural products spirotryprostatin A spirotryprostatin B, and voachalotine. Also included are the description of new and improved (more efficient) synthetic techniques. The synthesis of the agents described in this proposal will not only provide quantities of materials that are not currently available but it is only through these efforts that we can begin to understand their important biological activity. The spirotryprostatins are members of the spiro-oxindole family of natural products isolated from Aspergillus fumigatus. They have demonstrated the ability to inhibit the mammalian cell cycle at the G2/M phase at the micromolar level and are therefore potential antineoplastic leads. Voachalotine is a spiro-fused oxindole alkaloid isolated from Voacanga chalotiana. Related compounds have demonstrated short term inhibitory activity of ganglionic transmission. In addition to synthesis efforts toward the agents mentioned above, we intend to answer several important questions related to organic chemistry methodology during the time period of this proposal. First, can we expand on our isonitrile-alkyne free-radical coupling chemistry to generate substituted indoles? Second, can we utilize thioamide-alkyne free-radical couplings to substituted indoles? Third, can we develop novel approaches to the asymmetric synthesis of substituted indoles?