Studies toward the total synthesis of mitrephorone A

Weisheit, Lara (2019): Studies toward the total synthesis of mitrephorone A. Dissertation, LMU München: Fakultät für Chemie und Pharmazie

Abstract

This Ph.D. thesis describes progress toward the total syntheses of the ent-trachylobane diterpenoid mitrephorone A. Mitrephorone A was isolated from the bark of Mitrephora glabra, an Indonesian custard apple tree. The natural product possesses an interesting molecular scaffold, comprising a hexacyclic ring system with eight stereocenters, an adjacent ketone moiety and an oxetane ring. Mitrephorone A shows moderate cytotoxic activities against tumour cell lines, which makes it a potential chemotherapeutic agent. The first part of this thesis describes our efforts to develop an enantioselective and convergent synthetic route to the core structure of mitrephorone A. The elaborated route commences with the preparation of enone I via an enantioselective Diels–Alder reaction. Conversion to alkyne II is realized in a six-step sequence involving an intramolecular Diels–Alder reaction to build up the caged structure found in the natural product. Next, the two building blocks II and III are joined via a Sonogashira cross coupling. An asymmetric dearomative cyclization of V closes the last carbon ring of mitrephorone A and sets the right quaternary stereochemistry at C10. Moreover, studies to advance precursor VI to the natural product are presented. In the second part of this thesis, we present an alternative enantioselective synthesis of the complete mitrephorone A carbon skeleton. This robust synthetic sequence starts with literature-known building block VII. A Sharpless dihydroxylation and a Robinson annulation sequence gave enone VIII, which is further converted to IX by α-vinylation and a late stage intramolecular Diels–Alder reaction. The challenging final deprotection of carbonate IX afforded triol X. In summary, a versatile synthetic strategy which yields a decorated scaffold of the ent-trachylobanes under comparably mild conditions is presented.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: organic chemistry, natural product synthesis, total synthesis, diterpenoid
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 540 Chemie
• Fakultäten: Fakultät für Chemie und Pharmazie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 22. März 2019
• 1. Bericht­erstatter:in: Magauer, Thomas