THESIS
2015
xi, 104, [42] pages : illustrations ; 30 cm
Abstract
Total synthesis of natural products is a flagship and pivot of organic synthetic chemistry.
Not only does it serve for structural identification and elucidation, but also as an enabling
endeavor for the inspiration of novel methodology and strategy in chemistry and their
potential societal impact to chemical biology and other disciplines.
Lactone moiety is a common structural subunit present in many natural products,
including those isolated from insects, fungi, marine organisms, and plants. Natural products
containing the δ-lactone framework have been shown to exhibit a wide range of biological
activity. In recent years, multi-substituted lactones are of particular synthetic significance due
to their capacity as synthetic intermediates toward complex molecules. The structure of...[
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Total synthesis of natural products is a flagship and pivot of organic synthetic chemistry.
Not only does it serve for structural identification and elucidation, but also as an enabling
endeavor for the inspiration of novel methodology and strategy in chemistry and their
potential societal impact to chemical biology and other disciplines.
Lactone moiety is a common structural subunit present in many natural products,
including those isolated from insects, fungi, marine organisms, and plants. Natural products
containing the δ-lactone framework have been shown to exhibit a wide range of biological
activity. In recent years, multi-substituted lactones are of particular synthetic significance due
to their capacity as synthetic intermediates toward complex molecules. The structure of
spiro-δ-lactones and their derivatives have gained much attention.
Aogacillins A and B were isolated by Shiomi and co-workers in 2013 from a culture
broth of Simplicillium sp. FKI-5985 and have been found to be capable of overcoming
arbekacin resistance in methicillin-resistant Straphylococcus aureus (MRSA). Structurally,
Aogacillins represent an unusual δ-lactone with spiro-fused 2-ethyl-6-methylcyclohexane and
their highly dense functionalities on the δ-lactone pose a major challenge for their chemical synthesis.
A brief introduction of the structures of lactones and spiro-lactones, and the reported
natural products including lactones and spiro-lactones are given in chapter 1. It is followed by
an overview of construction method of spiro-lactones ring and its application in total synthesis. These serve as the background information for the proposed research in this thesis work.
Chapter 2 discusses the background of aogacillins A and B, including their isolation,
structural features and biological activity against methicillin-resistant Straphylococcus aureus
(MRSA). And there is also a plausible biosynthetic pathways for aogacillins A and B.
Chapter 3 summarizes our results on total synthesis towards aogacillins A and B. The
first total syntheses of (±)-aogacillin B have been achieved in 16 steps from
cis-2-methylcyclohexanone and simple furan compound. The key features of our synthesis
include Achmatowicz rearrangement to install the highly functionalized dihydropyranone
acetal. However, in aspect of aogacillin A synthesis, the late stage dehydration posed
synthetic challenges and could not afford target natural product. Moreover, in terms of
enantionselective synthesis, the furan coupling resulted in partial epimerization for achieving
fully enantiopure substance eventually.
The main experimental procedures, the characterization data of major compounds, and
the cited references are found at the end of the thesis. Copies of original
1H and
13C NMR
spectra of key compounds in the total synthesis towards Aogacillin A and B.
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