The following dissertation describes a collection of results that led to a successful formal total synthesis of a naturally-occurring antitumour antibiotic, (-)..echinosporin. To achieve that, various synthetic strategies were developed and examined, all of which relied on a cycloadditive event as a key step to prepare the [3.4.0J-bicyclic framework of (-)-echinosporin. The synthesis was eventually accomplished using the Padwa [3+2] cycloaddition-elimination of allenylphenylsulphone to a chiral sugar enone 6 as a key transformation. it provided the first recorded example of this reaction used in complex natural product total synthesis. Following a series of functional group interconversions on this cycloadduct, a mild new method for the C-carboxyalkylation of bromomagnesium ketone enolates was applied to install the C(11)~carboxylic group of (-)- echinosporin. The quaternary OH-bearing stereocentre was introduced via a substrate~directed osmylative dihydroxylation on a i3-keto ester enol 71 . The resulting ketone 77 was advanced into 70 via Barton deoxygenation. Following that, the crucial C(8)-C(9) unsaturation was introduced starting from the ketone 70 through a three-step sequence based on the Barton vinyl iodide synthesis and Pd(O)-mediated dehalogenation. Next, a TEMPO-based oxidation was used to bring the C(10)- position to a correct oxidation state. Following protection as the allyl ester, an E1cb silyloxy elimination installed the remaining C(4)-C(5) unsaturation. The allyl ester 90 was finally transformed into a primary amide and the C-2 ethyl glycoside was chemoselectively hydrolysed using aqueous HBF4 to reveal Smith's intermediate 1.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:601477 |
| Date | January 2013 |
| Creators | Flasz, Jakub Tadeusz |
| Publisher | Queen's University Belfast |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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