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A toolbox for divergolide and hygrocin ansamycin assembly: total synthesis of divergolide I
A toolbox for divergolide and hygrocin ansamycin assembly: total synthesis of divergolide I
The results described in this thesis detail the efforts towards the chemical synthesis of members of the divergolide and hygrocin class of ansamycins. These related macrocyclic polyketides comprise a continually growing class of structurally diverse compounds that exhibit broad antibacterial activity. Their thoroughly researched biosynthesis hinges on different modes of ring-contraction of a macrocyclic progenitor, giving rise to many structurally distinct natural products. In the course of our campaign, we pursued diverse tactics to construct a precursor molecule that would allow us to study aforementioned ring-contractions. After evaluation of several unsuccessful strategies we eventually devised a pathway that allowed for atroposelective construction of a macrocycle that underwent a surprisingly selective biomimetic cyclization, culminating in the enantioselective total synthesis of the azepinone divergolide I. Our synthetic material could secure the absolute and relative configurations of the ansamycin families and revealed interesting stereochemical properties of the macrocyclic progenitor molecule. The established convergent route could then also be adopted for the synthesis of an epi-hygrocin, highlighting the power of our fragment-based approach.
Ansamycin, Divergolide, Hygrocin, Total Synthesis
Terwilliger, Daniel William
2018
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Terwilliger, Daniel William (2018): A toolbox for divergolide and hygrocin ansamycin assembly: total synthesis of divergolide I. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

The results described in this thesis detail the efforts towards the chemical synthesis of members of the divergolide and hygrocin class of ansamycins. These related macrocyclic polyketides comprise a continually growing class of structurally diverse compounds that exhibit broad antibacterial activity. Their thoroughly researched biosynthesis hinges on different modes of ring-contraction of a macrocyclic progenitor, giving rise to many structurally distinct natural products. In the course of our campaign, we pursued diverse tactics to construct a precursor molecule that would allow us to study aforementioned ring-contractions. After evaluation of several unsuccessful strategies we eventually devised a pathway that allowed for atroposelective construction of a macrocycle that underwent a surprisingly selective biomimetic cyclization, culminating in the enantioselective total synthesis of the azepinone divergolide I. Our synthetic material could secure the absolute and relative configurations of the ansamycin families and revealed interesting stereochemical properties of the macrocyclic progenitor molecule. The established convergent route could then also be adopted for the synthesis of an epi-hygrocin, highlighting the power of our fragment-based approach.