Enantiospecific Total Synthesis of the Hapalindoles, Fischerindoles, and Welwitindolinonesviaa Redox Economic Approach

Abstract

Full details are provided for the total synthesis of several members of the hapalindole family of natural products, including hapalindole Q, 12-epihapalindole 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, scaleable, 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.

Chemoselectivity and the Curious Reactivity Preferences of Functional Groups

“…[137] The core structure of a family of natural products including hapalindole, fischerindole, and ambiguine consists of an indole unit coupled to a carvone unit. [138] The core could, in theory, be accessed directly through an oxidative enolate heterocoupling, although the practical challenges associated with the simultaneous oxidation of different enolates and the avoidance of a statistical distribution of homo-and heterocoupled products would be challenging. Exposure of the carvone enolate and indole anion generated upon deprotonation of 158 and 159 with lithium hexamethyldisilazide (LiHMDS) to the copper(II) 2-ethylhexanoate oxidant successfully generated the desired product 160 in 53 % yield (Scheme 71).…”

Total Synthesis of Indotertine A and Drimentines A, F, and G

“…Acidic activation of the germinal diamine moiety of 3 may generate an iminium species 6, which could undergo an iminium-olefin cyclization [8,9] followed by a proton elimination of the cationic intermediate 7. Herein, we report the first total synthesis of drimentines A, G, and F (1-3), exploiting a photocatalyzed radical conjugate addition to address the problem of the C10b-C12 bond formation; a synthesis of indotertine A (5), guided by the above biosynthetic hypothesis, is also described.…”

Iron Catalysis in Synthetic Chemistry

“…It was found that with the indole type of moiety copper was best suited, where as for indinone the Fe based Fe(tBuCOCHCOMe) 3 was found to give the highest yield (105). 12 Examples (up to 67% isolated yields) Scheme 87. Another case of oxidative cross-coupling of β-naphthols to give C1-symmetric 1,1´-bi-2-naphthols (BINOLs) was reported by Katsuki and co-workers (106) using the [Fe(salen)] complex (39) as an active catalyst (Scheme 89).…”