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Amy R. Howell
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(b.
1955)
Visiting Assistant Professor, University of Kentucky,
1993
Research Chemist, Glaxo Group Research, 1989-1993
Postdoctoral Research Fellow, Nottingham University,
1989
Postdoctoral Research Fellow, Northwestern University,
1988
Ph.D., University of Kentucky, 1987
B.S., Wheaton College, 1977
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| Our group is interested
in the exploitation of unusual strained heterocycles
to prepare compounds targeting specific biological questions.
In particular, we have developed the first general approaches
to 2-methyleneoxetanes 1 , 2,3-dimethyleneoxetanes
2 , 2-methyleneazetidines
3 , 1,5-dioxaspiro[3.2]hexanes 4
and 4-oxaspiro[2.3]hexanes 5 .
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We have examined in some detail the diverse reactivity
of 2-methyleneoxetanes 1 . Treatment
of 1 with a strong base provides
homopropargylic alcohols 6 . On the
other hand, reaction with less basic nucleophiles affords
beta -substituted ketones 7 .
An alternative route to functionalized ketones is via
arene-catalyzed, reductive ring opening of 2-methyleneoxetanes,
providing 8 . We also have reported
the first synthesis of [2.2.0] fused ketals
9 , and the first general syntheses of 1,5-dioxaspiro[3.2]hexanes
4 and 4-oxaspiro[2.3]hexanes 5 .
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An illustration of the utility and
importance of these unusual, strained heterocycles is
highlighted in two programs centered around the 1,5-dioxaspiro[3.2]hexanes
4 . From this one class we can access
glycosphingolipids 10 and novel oxetane
nucleosides 11 . Both 10
and 11 have important biological
targets. alpha -Glycosyl ceramides
10 have recently been shown to modulate the
immune system via the CD1d family of antigen presenting
proteins. An understanding of the molecular basis of
the interaction between the glycosyl ceramide antigen,
the CD1d antigen presenting protein and the T cell receptor
and the role of this ternary complex in regulating immune
response may have implications for the treatment of
autoimmune and cancer pathologies. The glycosphingolipids
we are synthesizing are being used by our collaborators
to examine how changes in glycolipid structure modulate
immune response and as potential chemotherapeutic agents
in autoimmune conditions. Nucleosides have long played
a prominent role as antiviral and anticancer chemotherapeutic
agents. Oxetane nucleoside analogs 11
represent novel nucleoside structures that may provide
new therapeutic agents.
In addition we are using small-ring heterocyclic templates
to construct marine natural products of biological interest.
Further details can be found at the Howell
Group Home Page.
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