welwitindolinone-a and fischerindole

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.

Topics: Alkaloids; Biomimetic Materials; Indole Alkaloids; Indoles; Nitriles; Oxidation-Reduction; Stereoisomerism

The field of organic synthesis has made phenomenal advances in the past fifty years, yet chemists still struggle to design synthetic routes that will enable them to obtain sufficient quantities of complex molecules for biological and medical studies. Total synthesis is therefore increasingly focused on preparing natural products in the most efficient manner possible. Here we describe the preparative-scale, enantioselective, total syntheses of members of the hapalindole, fischerindole, welwitindolinone and ambiguine families, each constructed without the need for protecting groups--the use of such groups adds considerably to the cost and complexity of syntheses. As a consequence, molecules that have previously required twenty or more steps to synthesize racemically in milligram amounts can now be obtained as single enantiomers in significant quantities in ten steps or less. Through the extension of the general principles demonstrated here, it should be possible to access other complex molecular architectures without using protecting groups.

Topics: Alkaloids; Biological Products; Chemistry, Organic; Cyanobacteria; Indole Alkaloids; Indoles; Nitriles; Seawater

The first total syntheses of welwitindolinone A and the most complex members of the fischerindole family, fischerindoles I and G, are reported. Highlights of these short, protecting-group-free syntheses include the application of the recently developed direct indole-carbonyl coupling, a simple approach for installing the quaternary center with neighboring chlorine atom, a regioselective dehydrogenation/dehydration cascade to access fischerindole I, and a remarkably facile oxidative ring contraction to construct welwitindolinone A. An alternative biogenetic hypothesis, whose accuracy is suggested by the success of the current syntheses, is also put forth for this alkaloid family.

Topics: Alkaloids; Cyanobacteria; Indole Alkaloids; Indoles; Molecular Structure; Nitriles; Stereoisomerism