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Title: Studies towards the total synthesis of the chivosazoles
Author: Jin, Jialu
ISNI:       0000 0004 7226 9869
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2018
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First isolated from the myxobacterium Sorangium cellulosm So Ce12 in 1994, the chivosazoles have been reported to possess antiproliferative activity against human cancer cell lines, as well as antifungal activity. This thesis focuses on studies towards the total synthesis of chivosazole F. Some developments towards the total synthesis of chivosazole A are also discussed. Chapter 1 discusses the isolation, characterisation and biological activity of the chivosazoles, as well as the first total synthesis of chivosazole F reported by the Kalesse group and the previous work towards synthesising chivosazole F in our group. Chapter 2 describes the synthesis of the three key fragments A, B and C, their coupling reactions and subsequent modifications for assembling the backbone of chivosazole F. Paterson boron aldol methodology and Evans-Tishchenko reduction were utilised to construct the 1,4-syn and 1,3-anti stereochemical relationships within both fragment A and fragment B. Di-tert-butyl silyl group was used for the efficient and precise protection of the terminal diol of B. The key stereochemistry of fragment C was defined with a vinylogous Mukaiyama aldol reaction. Site-selective Stille cross-coupling reactions of the three fragments, via a one-pot process, rapidly installed the requisite stereodefined polyene motifs within chivosazole F. Optimised Still-Gennari-type HWE olefination conditions were applied to install the (2Z,4E)-dienoate in D. MnO2-mediated double oxidation of D turned the terminal alcohol into an aldehyde and the oxazoline into an oxazole, followed by a Stork-Zhao olefination transforming the aldehyde to a Z-vinyl iodide for a macro-Stille coupling reaction, which achieved the ring closure to afford macrocycle E. Chapter 3 discusses the developments towards the synthesis of the southern fragment F of chivosazole A. Sugar I was prepared first and conditions were screened for the glycosylation of H and I to afford G. Chapter 4 outlines the achievements of this research and points out some future issues that need to be tackled.
Supervisor: Paterson, Ian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Total synthesis ; Chivosazoles ; Natural product ; Anticancer drugs