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Towards The Total Synthesis Of The Xiamycin Family Of Indolosesquiterpenes: Synthesis Of Oridamycins A And B
Author
Trotta, Adam
Abstract
The xiamycin family of indolosesquiterpenes comprises bioactive compounds isolated from several strains of Streptomyces. Several dimeric family members have shown strong activity against several strains of bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin resistant Enterococcus (VRE). These promising initial results, coupled with the limited production of these compounds from their natural sources, prompted the design of a unified synthetic strategy capable of producing several family members from a common synthetic intermediate. Structurally, the xiamycin family members consist of a carbazole fused to a trans-decalin ring system. The difference between xiamycin A and oridamycin A is a single epimeric stereocenter at C16. It was envisioned that a key oxidative radical cyclization could produce both stereochemical patterns—with free-radical conditions generating the stereochemistry associated with oridamycin A, and chelated radical conditions producing the stereochemistry corresponding to xiamycin A. The total synthesis of oridamycins A and B was completed, utilizing a free-radical cyclization that correctly set three contiguous stereocenters, including two quaternary carbons. The fused carbazole was produced using a 6?-electrocyclization/aromatization sequence. Finally, oridamycin B was accessed through a palladium-catalyzed, oxime-directed C-H oxidation.
Date Issued
2018Subject
antibiotic; Oridamycin; radical cyclization; total synthesis; trans-decalin; Xiamycin
Degree Discipline
Chemical Biology
Degree Level
Doctor of Philosophy
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Type
dissertation or thesis
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International