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Enantiospecific Total Synthesis of the Hapalindoles, Fischerindoles, and Welwitindolinones via a Redox Economic Approach

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posted on 2008-12-31, 00:00 authored by Jeremy M. Richter, Yoshihiro Ishihara, Takeshi Masuda, Brandon W. Whitefield, Tomás Llamas, Antti Pohjakallio, Phil S. Baran
Full details are provided for the total synthesis of several members of the hapalindole family of natural products, including hapalindole Q, 12-epi-hapalindole D, 12-epi-fischerindole U, 12-epi-fischerindole G, 12-epi-fischerindole I, and welwitindolinone A. Use of the recently developed direct indole coupling enabled an efficient, practical, scalable, and protecting-group-free synthesis of each of these natural products. The original biosynthetic proposal is reviewed, and a revised biosynthetic hypothesis is suggested, validated by the above syntheses. The syntheses are also characterized by an adherence to the concept of “redox economy”. Analogous to “atom economy” or “step economy”, “redox economy” minimizes the superfluous redox manipulations within a synthesis; rather, the oxidation state of intermediates linearly and steadily increases throughout the course of the synthesis.