Ketone enolate C-acylation is certainly one of the fundamental transformations in organic chemistry, providing access to a wide range of building blocks and natural products. However, there are limitations to the currently existing methods which occasionally prove inadequate for sterically demanding or chemically sensitive systems. Such was the case of the antitumour natural product (-)-echinosporin, which led to the development of a new mild protocol for the C-acylation of ketone enolates. The use of MgBr2·Et2O/Pr2NEt/DMAP in the presence of a suitable pentafluorophenyl electrophile not only provided a desired advanced intermediate necessary for the synthesis of mentioned natural product, but also gave access to a wide range of -ketoesters, including· -keto thioesters and· - thionoesters which often are hard to obtain using previously developed protocols. Herein, we report the development and scope of the aforementioned protocol in simple aromatic as well as highly complex aliphatic systems. Total synthesis is unquestionably a crucial part of the organic synthesis field, providing access to a wide range of natural products which are often no longer accessible by other means, and providing a platform for further development of the organic synthesis protocols. As a contribution to the ever developing organic synthesis scene, our group has in recent years embarked on a quest to further expand the scope and capabilities of the Ph3SnH/Et3B O-directed free radical alkyne hydrostannation method developed in Hale's laboratories in 2005. The antitumour natural product (-)-inthomycin C attracted our attention in this respect because it provided an ideal test vehicle for studying whether unfavourable syn or gauche-gauche pentane repulsive interactions could thwart the O-directed hydrostannation or palladium cross-coupling steps. Therefore, the work described within provides a detailed discussion of the newest total synthesis of (-)-(3R)inthomycin C in 17 steps. The critical point of the project arose from the 3C-stereocentre controversy existing in the literature, yet not remarked on elsewhere. Consequently, a careful analysis of the absolute configuration of(-)-inthomycin C, and its significant relation to the optical rotation of the product, has been performed and widely discussed in the present work
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:676474 |
| Date | January 2014 |
| Creators | Grabski, Milosz Kamil |
| Publisher | Queen's University Belfast |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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