Towards the total synthesis of lactonamycin
Author(s)
Jacques, Sylvain Michel Matthieu Arthur
Type
Thesis
Abstract
The natural product lactonamycin (1) was isolated in Japan by Matsomoto et al.. Biological evaluation
of lactonamycin (1) against Gram-positive bacteria such as Staphylococcus aureus showed significant
levels of antimicrobial activity and it was especially active against clinically isolated-MRSA and -
VRE. In addition to interesting biological properties, lactonamycin (1) possesses an intriguing
molecular architecture (Figure 1). The novel, highly functionalized hexacyclic aglycone core, known
as lactonamycinone (2) contains, in the western half, a highly-oxygenated fused perhydrofuranfuranone
bicycle connected to a labile tertiary methoxy group, and in the eastern half, a
naphtha[e]isoindole ring system. Adding to the structural complexity of lactonamycin (1), a 2,3,6-
trideoxy sugar unit is connected to the core via a highly hindered tertiary glycosidic linkage. [Molecular structure diagrams appear here. To view, please open pdf attachment] Figure 1 - Structures of lactonamycin (1) and lactonamycinone (2). A key step in the current strategy is an electrodecarboxylation reaction to introduce the angular
methoxy group. Various experiments towards this electrodecarboxylation reaction are described using
simple model substrates. In particular, the synthesis of model system (3) and investigations towards
ABCD tetracycle model system (4) are described alongside our efforts towards the synthesis of
lactonamycin (1) (Figure 2). Finally, a new synthesis of known boronic ester 5 was investigated using
the biomimetic resorcylate methodology developed in the group. [Molecular structure diagrams appear here. To view, please open pdf attachment] Figure 2 – Structures of carboxylic model system 3, ABCD tetracycle model system 4
and boronic ester 5.
of lactonamycin (1) against Gram-positive bacteria such as Staphylococcus aureus showed significant
levels of antimicrobial activity and it was especially active against clinically isolated-MRSA and -
VRE. In addition to interesting biological properties, lactonamycin (1) possesses an intriguing
molecular architecture (Figure 1). The novel, highly functionalized hexacyclic aglycone core, known
as lactonamycinone (2) contains, in the western half, a highly-oxygenated fused perhydrofuranfuranone
bicycle connected to a labile tertiary methoxy group, and in the eastern half, a
naphtha[e]isoindole ring system. Adding to the structural complexity of lactonamycin (1), a 2,3,6-
trideoxy sugar unit is connected to the core via a highly hindered tertiary glycosidic linkage. [Molecular structure diagrams appear here. To view, please open pdf attachment] Figure 1 - Structures of lactonamycin (1) and lactonamycinone (2). A key step in the current strategy is an electrodecarboxylation reaction to introduce the angular
methoxy group. Various experiments towards this electrodecarboxylation reaction are described using
simple model substrates. In particular, the synthesis of model system (3) and investigations towards
ABCD tetracycle model system (4) are described alongside our efforts towards the synthesis of
lactonamycin (1) (Figure 2). Finally, a new synthesis of known boronic ester 5 was investigated using
the biomimetic resorcylate methodology developed in the group. [Molecular structure diagrams appear here. To view, please open pdf attachment] Figure 2 – Structures of carboxylic model system 3, ABCD tetracycle model system 4
and boronic ester 5.
Date Issued
2011
Date Awarded
2011-11
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Barrett, Anthony
Sponsor
Engineering and Physical Sciences Research Council
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)