Intramolecular Tricarbonyl-Ene Reactions and α-Hydroxy-ß-Diketone Rearrangements Inspired by the Biosynthesis of Polycyclic Polyprenylated Acylphloroglucinols.

Structurally unique natural products pose biosynthetic puzzles whose solution can inspire new chemical reactions. Herein, we propose a unified biosynthetic pathway towards some complex meroterpenoids-the hyperireflexolides, biyoulactones, hybeanones and hypermonones. This hypothesis led to the discovery of uncatalyzed, intramolecular carbonyl-ene reactions that are spontaneous at room temperature. We also developed an anionic cascade reaction featuring an α-hydroxy-ß-diketone rearrangement and an intramolecular aldol reaction to access four distinct natural product scaffolds from a common intermediate.

Bioinspired Total Synthesis of Hyperireflexolides A and B.

Hyperireflexolides A and B were synthesized in six steps via the dearomatization and fragmentation of a simple acylphloroglucinol starting material. The dearomatized acylphloroglucinol undergoes a sequence of oxidative radical cyclization, retro-Dieckmann fragmentation, stereodivergent intramolecular carbonyl-ene reactions, and final α-hydroxy-ß-diketone rearrangements to give the target natural products. This sequence is based on a biosynthetic proposal that claims the hyperireflexolides as highly rearranged polycyclic polyprenylated acylphloroglucinols (PPAPs), which is supported by the structural revision of hyperireflexolide B.

Total Synthesis and Biosynthesis of Cyclodepsipeptide Cochinmicin I.

Phenylglycines are building blocks of many non-ribosomally synthesized peptides. The dihydroxyphenylglycine-containing cyclodepsipeptide cochinmicin I exhibits endothelin receptor antagonist activity. Therefore, it represents an interesting and synthetically challenging molecule because of the racemization-prone nature of dihydroxyphenylglycine. We present the total synthesis of cochinmicin I and the non-natural derivative cochinmicin VI and describe the identification and assignment of the cochinmicin (cmn) biosynthesis gene cluster, encoding a five-module non-ribosomal peptide synthetase for cochinmicin assembly.