Total synthesis of variecolortides A–C

Kuttruff, Christian Andreas (2012): Total synthesis of variecolortides A–C: towards the total synthesis of naphthomycin K and divergolides C and D; synthesis of photochromic open-channel blockers. Dissertation, LMU München: Fakultät für Chemie und Pharmazie

Abstract

Part I: Total Synthesis of Variecolortides A–C The variecolortides are structurally intriguing, fungal natural products that present a unique merger of three major streams of biosynthesis. They can be traced back to other known natural products, namely the viocristins and echinulins, and we wanted to prove if they could somehow come together to form the variecolortides. Thus, these natural products were prepared in short sequences and their critical linkage was subsequently investigated. It was found that an unprecedented hetero-Diels-Alder reaction effected this linkage and furnished the central spirocyclic core of the variecolortides. Ultimately, a highly convergent route to all three variecolortides (A–C) was developed. The natural products were each efficiently synthesized as racemates in seven steps or less (longest linear sequence), largely avoiding protecting group chemistry. Part II: Towards the Total Synthesis of Naphthomycin K and Divergolides C and D Ansamycins are an important class of natural products that often show potent antibacterial and antiviral activities. We have engaged in the total syntheses of several new aminonaphthoquinone ansamycins, including naphthomycin K and divergolides C and D. A unified approach to their naphthoquinone core was targeted and led to the development of a novel, cyano-substituted Danishefsky-type diene. The latter was used in the synthesis of cyano-substituted naphthoquinones, naphthalenes and other highly functionalized small molecules. Since the cyano-substituted naphthoquinones could not be further elaborated into the desired natural products, alternatively substituted bromonaphthalenes were instead synthesized over short sequences. In addition, several strategies towards the synthesis of an ansa chain fragment of divergolides C and D were developed. Part III: Synthesis of Photochromic Open-Channel Blockers Optical control of transmembrane ion channel function with high temporal and spatial precision opens the door for a better understanding of neuronal circuits and pharmacological associated questions. Several red-shifted derivatives of QAQ (quaternary ammonium- azobenzene-quaternary ammonium), a powerful doubly charged photochromic blocker, have been synthesized. They allow for remote control of Kv and Nav channel conductance with light and offer the opportunity to reversibly silence neuronal activity.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Total Synthesis, Natural Products, Biomimetic Synthesis, Cycloaddition, Cascade reactions, Diels-Alder reaction
• 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: 16. Juli 2012
• 1. Bericht­erstatter:in: Trauner, Dirk