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Totally Synthetic by Paul H. Docherty, 1 June 2006

Total Synthesis of Nigellamin A


J. Bian, M. Van Wingerden, J. M. Ready, J. Am. Chem. Soc. 2006, 128, 7428-7429.

DOI: 10.1021/ja061559n

Using some interesting organometallic transformations, Ready et al. have completed a smart total synthesis of Nigellamine A. Containing the known dolabellane 5,11-trans-fused bicyclic ring system, the compound offers potent lipid metabolism-promoting activity. Starting with the construction of a 5,5-fused lactone, built via a Pd-mediated process, using an impressively low catalyst loading:

Iodocyclisation onto the free terminal alkene then allowed completion of the lactone, an left a terminal iodide which allowed displacement with a Fuchs radical alkynylation. They then planned to use a Negishi methyliodination to add across the acetylene, creating a vinyl iodide, but instead addition to the lactol occured. However, a modification developed by Wipf with the use of water allowed them to proceed.

Performing a Negishi coupling with a TMS-protected acetylene then presented another opportunity to use the methyliodination after deprotection, delivering a second vinyl iodide. Oxidation of both the terminal alcohol and lactol to the corresponding carbonyl species then allowed regioselective and diastereoselective Nozaki-Hiyama-Kishi (NHK) cyclisation.

Opening of the lactone, and functionalisation of the free terminal alcohols then led to the carbocyclic skeleton of nigellamine, which was transformed to the natural product in only a few more steps.