The total synthesis of (−)-nitidasin, synthetic studies toward astellatol and retigeranic acid B, and development of novel photochromic ligands for L-type voltage-gated calcium channels

Huber, Florian Mauritius Erasmus (2014): The total synthesis of (−)-nitidasin, synthetic studies toward astellatol and retigeranic acid B, and development of novel photochromic ligands for L-type voltage-gated calcium channels: and development of novel photochromatic ligands for L-type coltage calcium channels. Dissertation, LMU München: Fakultät für Chemie und Pharmazie

Abstract

The first part of present doctoral thesis is dedicated to sesterterpenoid natural products, which constitute a relatively small subclass of the family of terpenoid compounds. In particular, a small number of biosynthetically closely related iso-propyl-substituted trans-hydrindane- based congeners were chosen as targets for a synthetic program that envisioned their chemical construction via a unified approach. In this context, the first total synthesis of the complex tetracarbocyclic sesterterpenoid (−)-nitidasin was disclosed. To this end, a highly convergent installation of its western cyclopentane moiety was demonstrated by use of an unprecedented Li-alkenyl addition to a versatile trans-hydrindanone building block. An efficient closure of the central 8-membered carbocycle was achieved by means of ring-closing metathesis that benefitted from finely tuned conformational parameters of the employed substrate. In summary, the developed protocol provides a scalable and continuously high yielding route for the assembly of the rare carbon skeleton of (−)-nitidasin. Furthermore, advanced synthetic studies toward the pentacyclic natural products retigeranic acid B and astellatol are described. Notably, the latter involved a biomimetic retrosynthetic proposal for the elaboration of its unique fused ring system. Two different strategies were followed in order to access viable precursors for the suggested cationic cascade, of which the latter allowed for the investigation of the mentioned key step experimentally and via computational methods. In the second section of this manuscript, the design and synthesis of the first known photochromic antagonist for L-type voltage-gated calcium channels is presented. The ultimate goal of this project lies in the establishment of a photopharmacological tool that supports the further elucidation of Ca2+-dependent cellular events, especially in neurons. The central pharmacophore of the prepared compounds was derived from the benzothiazepine drug cis-(+)-diltiazem. This parent substance also served as the starting point for the developed short and convergent semisynthetic strategy. Thirteen analogues were synthesized in total and a preliminary lead structure was identified using electrophysiolocigal methods. Based on these findings, two compounds of increased solubility and desirable photochemical properties were prepared. A possible explanation for their photodependent mode of action was proposed, which is currently subject of our ongoing investigations.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: natural product synthesis, sesterterpenoids, ring-closing metathesis, benzothiazepines, photochromic CaV antagonists
• 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: 12. November 2014
• 1. Bericht­erstatter:in: Trauner, Dirk