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A modular synthesis of tetracyclic meroterpenoid antibiotics. towards the total synthesis of cornexistin
A modular synthesis of tetracyclic meroterpenoid antibiotics. towards the total synthesis of cornexistin
Part I: A synthetic platform for the total synthesis of the structurally related tetracyclic meroterpenoids stachyflin, aureol, smenoqualone, strongylin A, and cyclosmenospongine was developed. Our synthetic strategy employed an auxiliary-controlled Diels–Alder reaction between V and VI to enable the enantioselective construction of the decalin subunit, which is connected to variously substituted arenes (IV) by either carbonyl addition chemistry or sterically demanding sp2–sp3 cross-coupling reactions. The selective installation of either the cis- or trans-decalin I or II stereochemistry was accomplished by an acid-mediated cyclization/isomerization reaction. This highly modular synthetic platform enabled the synthesis of each of these natural products and 15 non-natural derivatives. Biological profiling reveals that strongylin A and a simplified derivative had potent antibiotic activity against methicillin-resistant Staphylococcus aureus. Part II: In the second part of this thesis, the development of a synthetic route towards the total synthesis of cornexistin is described. Retrosynthetically, the complex nine-membered ring can be dissected into three building blocks VII, VIII and IX. Starting with the construction of the eastern part of cornexistin, VIII and IX were reacted in a syn-Evans-aldol reaction and X was further transformed into aldehyde XI. At this stage, the third building block VII was introduced via an intermolecular NHK reaction giving two diastereoisomers α-XII and β-XII. The cyclization precursor α-XIII was synthesized seven in seven linear steps. An exhaustive screen of reactions conditions revealed the formation of the nine-membered carbocycle α-XIV by treatment with DBU in acetonitrile. Upon treatment of α-XIV with triflic chloride, chloride α-XV was formed instead of the desired enoltriflate. The former is envisioned to undergo should undergo palladium catalyzed carbonylation reaction to form the anhydride moiety of the natural product. Global deprotection and oxidation state adjustment at C-1 would lead to the first total synthesis of cornexistin., UNSPECIFIED
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Wildermuth, Raphael
2018
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Wildermuth, Raphael (2018): A modular synthesis of tetracyclic meroterpenoid antibiotics: towards the total synthesis of cornexistin. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

Part I: A synthetic platform for the total synthesis of the structurally related tetracyclic meroterpenoids stachyflin, aureol, smenoqualone, strongylin A, and cyclosmenospongine was developed. Our synthetic strategy employed an auxiliary-controlled Diels–Alder reaction between V and VI to enable the enantioselective construction of the decalin subunit, which is connected to variously substituted arenes (IV) by either carbonyl addition chemistry or sterically demanding sp2–sp3 cross-coupling reactions. The selective installation of either the cis- or trans-decalin I or II stereochemistry was accomplished by an acid-mediated cyclization/isomerization reaction. This highly modular synthetic platform enabled the synthesis of each of these natural products and 15 non-natural derivatives. Biological profiling reveals that strongylin A and a simplified derivative had potent antibiotic activity against methicillin-resistant Staphylococcus aureus. Part II: In the second part of this thesis, the development of a synthetic route towards the total synthesis of cornexistin is described. Retrosynthetically, the complex nine-membered ring can be dissected into three building blocks VII, VIII and IX. Starting with the construction of the eastern part of cornexistin, VIII and IX were reacted in a syn-Evans-aldol reaction and X was further transformed into aldehyde XI. At this stage, the third building block VII was introduced via an intermolecular NHK reaction giving two diastereoisomers α-XII and β-XII. The cyclization precursor α-XIII was synthesized seven in seven linear steps. An exhaustive screen of reactions conditions revealed the formation of the nine-membered carbocycle α-XIV by treatment with DBU in acetonitrile. Upon treatment of α-XIV with triflic chloride, chloride α-XV was formed instead of the desired enoltriflate. The former is envisioned to undergo should undergo palladium catalyzed carbonylation reaction to form the anhydride moiety of the natural product. Global deprotection and oxidation state adjustment at C-1 would lead to the first total synthesis of cornexistin.

Abstract