Chemoenzymatic Total Syntheses of Some Biologically Relevant Scaffolds in Homochiral Form
Date
2017
Authors
Yang, Shuxin
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Abstract
Since time immemorial certain plants and/or extracts thereof have
been used for the treatment of various diseases. The utility of
such materials is normally attributed to the specific chemical
components within the source plants. For this reason, chemists
have sought to isolate the active principals for evaluation and
the more efficacious ones have been the subject of synthetic
studies. Since biological activity is normally embodied in one
but not the other enantiomeric form of homochiral natural
products, the selective synthesis of such species has become an
important aspect of such endeavours. The use of chirons for such
purposes has often provided a very effective means of obtaining a
given enantiomeric form of the target compound. Since various
enantiomerically pure cis-1,2-dihydrocatechols (such as compounds
3c and 3d) have become available in large quantity via the
whole-cell biotransformation of certain halogenated arenes they
have become particularly important starting materials in natural
product synthesis. This is all the more so with the recognition
that the “hidden symmetry elements” embodied within such
chirons can allow for the generation of either enantiomeric form
of a target compound from a single enantiomeric form of such
starting materials, a process sometimes termed enantiodivergent
synthesis. In this thesis, approaches to the syntheses of the
biologically significant systems such as ent-kirkamide,
(+)-lycorine, and (+)-narseronine are described by using
enzymatically generated cis-1,2-dihydrocatechols.Specifically,
the first chapter of this thesis analyses the current
state-of-play with respect to the generation of
cis-1,2-dihydrocatechols of the general form 3 and their
application in chemical synthesis, especially as this applies to
the assembly of biologically active natural products and related
systems. The approaches employed in establishing a
near-to-complete total synthesis of ent-kirkamide from
(1S,2S)-3-bromocyclohexa-3,5-diene-1,2-diol (3c) and its
iodo-counterpart 3d are described in Chapter Two. This is
preceded by a commentary on the origins, structural elucidation
and biological properties of the natural product (viz. kirkamide)
along with a description of the only total synthesis of this
compound reported to date.
A chemoenzymatic approach to the total synthesis of (+)-lycorine
using (1S,2S)-3-bromocyclohexa-3,5-diene-1,2-diol (3c) as
starting material is discussed in the third chapter. This is
preceded by a description of the synthetic approaches (reported
by others) to either the (+)- or (–)-form of lycorine.
The work reported in the fourth chapter on the successful
synthesis of (+)-narseronine from the bromobenzene-derived
metabolite 3c serves to emphasize the utility of
cis-1,2-dihydrocatechols as chiral building blocks. Since earlier
work within the Banwell Group had resulted in the development of
a synthesis of (–)-narseronine from the same starting material,
the present work serves to emphasize the capacity for undertaking
enantiodivergent syntheses using the “pseudo-symmetric”
cis-1,2-dihydrocatechol 3c as starting material.
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cis-1,2-Dihydrocatechols, Chemoenzymatic total synthesis, Natural product, Bioactivity, Enantiomerically pure
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