Biomimetic Total Syntheses of Amorfrutins A, B, (S)‐D and (R)‐D and Formal Synthesis of Amorfrutin C

Abstract

Bibenzyl natural products, such as the amorfrutins, contain a heavily substituted aromatic core and display a diverse range of biological activities (anti‐tumor, anti‐diabetic, antimicrobial, and antibiotic). In this study, we report unified syntheses of amorfrutin A to D either through total or formal synthesis by employing a dual biomimetic strategy of polyketide aromatization followed by remote terpene functionalization. The key core structures were synthesized from β‐keto dioxinone esters through a magnesium(II) mediated regioselective C‐acylation, palladium catalyzed decarboxylative allylic rearrangement, and dehydrative cyclization.

Concise Total Syntheses of Amorfrutin A and B

“…(c) Generated from substituted keto‐ester precursors by cycloaromatization (Figure 2). [10b,c,k] However, all these methods′ elegance is diminished by such as the available length of the synthesis that generally more than seven steps are required, sometimes only moderate yields and scaling up difficult. Hence, we became interested in developing an efficient, facile and unified strategy to synthesize amorfrutin A and B from inexpensive and readily accessible starting material.…”

“…Due to these extraordinary biological properties and the predictable application prospects, amorfrutin A and B have attracted the concern of medicinal and synthetic chemists. To date, about thirteen total syntheses of 1 [7,9–10] and seven total syntheses of 2 [8a,9,10i–k,11] have already been reported. Based on the methods of generating the core structure these methods can be categorized into three types including: (a) Using benzoic acid derivatives as raw materials and employing HWE reaction, [10a,h] Sonogashira coupling, [7] Julia olefination [10d] or transition metal‐catalyzed olefination [10e] as a key step for the fabrication.…”