Total Synthesis of (+)-Belactosin A
File(s)
Scutt-JN-2005-PhD-Thesis
Author(s)
Scutt, James Nicholas
Type
Thesis
Abstract
(+)-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 (3-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 [3-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.
been shown to be a potent proteasome inhibitor. It contains a novel aminocyclopropyl
alanine amino acid core, and a novel carboxamido (3-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 [3-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.
Version
Open Access
Date Issued
2005-01
Date Awarded
2005-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
Advisor
Armstrong, Alan
Sponsor
EPSRC
Publisher Department
Department of Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)