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Title: A new total synthesis of the antitumour macrolide, (+)-Brefeldin A, a new mild procedure for alkyne hydroxymethylation, and comparison studies on Bu3SnH vs Ph3SnH in O-directed alkylacetylene hydrostannation
Author: Xiong, Ziyue
ISNI:       0000 0004 6496 7149
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2017
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We developed a new mild alkyne hydroxymethylation method that is based upon the Carreira reaction of acetylenes with Zn(OTf)£/(-)-N-methylephedrine/Et§J\l and solid paraformaldehyde in PhMe. Various base-sensitive substrates were synthesized and tested under the newly developed Carreira conditions; the results of these studies are reported in Chapter 1. This Chapter also reports the outcome of studies into whether a deleterious 1,5-H-atom abstraction might potentially compromise the Ph^SnH/cat. Et^B O-directed free radical hydrostannation of several of those resulting alkynols (the pentynol O-glycosides 7, 8, and 37). Comparison studies of Bu3SnH vs Ph3SnH in the O-directed alkylacetylene hydrostannation are also described in Chapter 1. In Chapter 2 of this thesis, a new enantioselective total synthesis of (+)-brefeldin A is reported that proceeds in 33 steps. The new pathway that we have developed employs a Padwa anionic allenylsulfone [3+2]-cycloadditive-elimination as a key step in construction of the chiral cyclopentane found in the target. Subsequent Mitsunobu inversion and pyrrolidine-mediated aldehyde epimerisation tactics also played a substantive role in establishing the cyclopentane ring stereochemistry of the target. Successive Wittig and Julia/Kocienski olefination reactions simply and powerfully controlled the (E)-alkene geometries present at C(2)-C(3) and C(10)-C(11), and a high yielding Yamaguchi macrolactonisation very cleanly and efficiently forged the 13-membered ring of the macrolide. Significantly, this is only the second time that the Padwa allenylsulfone [3 +2]-cycloadditive-elimination has been deployed in complex natural product total synthesis and, as a consequence, we have now demonstrated that it is possible not only to access complex chiral cyclopentane ring-annulated target molecules that have a cis-ring junction (e.g. (-)-echinosporin), but also ones that have a trans ring-junction such as (+)-brefeldin A.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available