Tactical design: The first total synthesis of (+)‐hypercalin C was achieved through a key C –C Suzuki–Miyaura coupling and a highly regioselective allylic oxidation. Several designed derivatives were targeted in the course of the synthesis to address the hypothesis that hypercalin C and congeners are cytotoxic, due to their potential as protonophores. An unexpected insertion into an ether C−H bond during Pd‐mediated coupling of an α‐bromo, methyl enol ether was discovered.
Abstract
The hypercalins are dearomatized acylphloroglucinols with a pendant complex cyclopentane ring that exhibit activity against several cancer cell lines. We report the first total synthesis of (+)‐hypercalin C employing a convergent strategy that enabled the dissection of the essential structural features required for the observed anticancer activity. A strategic disconnection involving an unusual C –C Suzuki–Miyaura coupling with an α‐bromo enolether also revealed an unexpected C−H activation. This strategy targeted designed analogues along the synthetic route to address particular biological questions. These results support the hypothesis that hypercalin C may act as a proton shuttle with the dearomatized acylphloroglucinol moiety being essential for this activity.
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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,