Total synthesis of gomisin O; asymmetric total syntheses of eupomatilones 1, 2 and 5; and studies towards total synthesis of mayolide A
Abstract (Summary)Gomisins are oriental medicinal plant lignans characterized by a highly electron-rich dibenzocyclooctadiene core structure with a stereogenic axis about the biaryl bond, exhibiting atropisomerism. The cyclooctane ring is additionally substituted with several stereogenic methyl and hydroxyl groups. Most members of this family possess anti-HIV, anti-hepatitis, analgesic, anti-tussive and central nervous system depressant activities. A convergent, highly efficient total syntheses of gomisins O and E are discussed in this thesis with complete control of absolute and relative stereochemistry. The key steps involved in the total synthesis are a novel indium-mediated methylcrotylation, a diastereoselective B-alkyl Suzuki-Miyaura alkylborane coupling and an intramolecular oxidative biaryl cuprate cross-coupling with total atropdiastereocontrol. Eupomatilones are structurally novel fluxional plant lignans with varying degree of oxygenation on the biphenyl system. The ?-methylene-?-lactone moiety attached to the biphenyl, as found in eupomatilones 1, 2 and 5, readily forms covalent bonds to cellular proteins and is a cause of chronic actinic dermatitis (CAD). This moiety also forms photo adducts with DNA base thymine in sunlight and has been also shown to target the I?? kinase addition to the transcription factor regulator nuclear factor (NF-??), signifying their potential role in cellular signaling processes. Herein, we discuss a successful asymmetric strategy for the synthesis of a few members of this unique family of lignans. The key to the synthesis depends on an optimized Suzuki-Miyaura biaryl cross-coupling reaction with heavily electron-rich coupling partners. In addition to this, the synthesis is novel in demonstrating the first example of an asymmetric carbomethoxycrotylboration approach to the synthesis of the ?-methylene-?-lactone moiety, involving application of Miyaura’s boryl-copper chemistry. A novel route to the synthesis of the carbomethoxycrotylboronate reagent in enantiomerically pure form is described herein. Mayolides are cembrane diterpenes found in the lipids of marine soft corals exhibiting potent anti-cancer properties. Mayolide A is an ?-methylene-?-lactone derivative and also the first secocembrane diterpenoid to be isolated. In this thesis, we would discuss the synthetic strategy developed and the progress made towards the total synthesis of this structurally novel molecule, utilizing the carbomethoxycrotylation strategy developed during the total synthesis of eupomatilones as one of the key steps.
School:The Ohio State University
School Location:USA - Ohio
Source Type:Master's Thesis
Date of Publication:01/01/2007