Total synthesis of all (−)-agelastatin alkaloids

Abstract

The pyrrole-imidazole family of marine alkaloids, derived from linear clathrodin-like precursors, constitutes a diverse array of structurally complex natural products. The bioactive agelastatins are members of this family that possess a tetracyclic molecular framework incorporating C4–C8 and C7–N12 bond connectivities. We provide a hypothesis for the formation of the unique agelastatin architecture that maximally exploits the intrinsic chemistry of plausible biosynthetic precursors. We report the concise enantioselective total syntheses of all known agelastatin alkaloids including the first total syntheses of agelastatins C, D, E, and F. Our gram-scale chemical synthesis of agelastatin A was inspired by our hypothesis for the biogenesis of the cyclopentane C-ring and required the development of new transformations including an imidazolone-forming annulation reaction and a carbohydroxylative trapping of imidazolones.

Biosynthesis, asymmetric synthesis, and pharmacology, including cellular targets, of the pyrrole-2-aminoimidazole marine alkaloids

“…However, mention must be made of the elegant and efficient biomimetic strategy leading to all congeners of agelastatin that was recently described by Movassaghi (Scheme 26). 157 Importantly, this synthesis follows one possible biosynthetic route premised on the isolation of the related P-2-AI, cyclooroidin ( 32 ).…”

Concise Total Synthesis of (+)-Asperazine, (+)-Pestalazine A, and (+)-iso-Pestalazine A. Structure Revision of (+)-Pestalazine A

“…Guided by our core ethos of retrobio-synthetic 2c,40 analysis, we developed a mild, regio– and stereocontrolled, ortho -directed Friedel–Crafts reaction for the formation of the critical C3–C8′ dimeric linkage in these molecules. Our late-stage C3–C8′ heterodimerization approach to structures (+)- 1 , (+)- 2 and (+)- 3 benefits from its use of advanced diketopiperazine tetracycles as easily interconvertible Friedel–Crafts components.…”

Recent advances in the total synthesis of agelastatins

“…Agelastatin E is formally O-methylagelastatin A; while agelastatin F is 14-bromoagelastatin D. The question whether agelastatin E is a natural product has not yet been addressed [4]. As indicated in Pietra's initial semi-synthesis work [6] (later confirmed by Movassaghi's seminal total synthesis [10]), treatment of 1 in the presence of Amberlyst 15 and MeOH results in methanol exchange at C(8), giving O-methylagelastatin A, the 1 H NMR spectrum of which is identical to that of agelastatin E (eq. 1).…”