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Title: Total synthesis of (+)-belactosin A
Author: Scutt, James Nicholas
ISNI:       0000 0001 3391 7825
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2005
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(+)-Belactosin A is a novel peptide, first isolated in Japan in 1997, that has recently been shown to be a potent proteasome inhibitor. It contains a novel aminocyclopropyl alanine amino acid core, and a novel carboxamido β-lactone. Chapter 1 presents the isolation, structure and biological properties of (+)-belactosin A, then proceeds to review all relevant synthetic work prior to the start of our research programme, and also work published since we began investigations into this area. Chapter 2 begins with our synthetic plan aimed towards the total synthesis of (+)-belactosin A and analogues, then discusses execution of this strategy. All four stereosiomers of the central amino acid were successfully synthesised using an unusual epoxide cyclopropanation, and an organocatalytic amino acid synthesis as the two key steps. Efforts were also made to synthesise the β-lactone moiety using organocatalysis, but this was eventually accessed by a one-pot diastereoselective chlorination/lactonisation strategy. Finally, the first total synthesis of (+)-belactosin A was achieved using a new amino acid coupling procedure. Chapter 3 summarises the findings discussed in Chapter 2, and Chapter 4 gives full experimental details and spectroscopic and physical data for all new compounds prepared.
Supervisor: Armstrong, Alan Sponsor: EPSRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral