4 research outputs found
Stereodivergent Resolution of Oxabicyclic Ketones: Preparation of Key Intermediates for Platensimycin and Other Natural Products
An
improved methodology for the preparation of enantiopure oxabicyclo[3.2.1]Âoctadienes
via a stereodivergent resolution is reported. High catalyst control
proximal to the oxabridged stereocenter produces readily separable
diastereomers in high yield (>92%) and with excellent optical purity
(>95% ee). This resolution strategy is amenable to large-scale
preparations,
and the utility of the resolution was further demonstrated in the
asymmetric preparation of a key intermediate used in the synthesis
of the antibiotic (−)-platensimycin
Oxy-Allyl Cation Catalysis: An Enantioselective Electrophilic Activation Mode
A generic
activation mode for asymmetric LUMO-lowering catalysis
has been developed using the long-established principles of oxy-allyl
cation chemistry. Here, the enantioselective conversion of racemic
α-tosyloxy ketones to optically enriched α-indolic carbonyls
has been accomplished using a new amino alcohol catalyst in the presence
of electron-rich indole nucleophiles. Kinetic studies reveal that
the rate-determining step in this S<sub>N</sub>1 pathway is the catalyst-mediated
α-tosyloxy ketone deprotonation step to form an enantiodiscriminant
oxy-allyl cation prior to the stereodefining nucleophilic addition
event
Oxy-Allyl Cation Catalysis: An Enantioselective Electrophilic Activation Mode
A generic
activation mode for asymmetric LUMO-lowering catalysis
has been developed using the long-established principles of oxy-allyl
cation chemistry. Here, the enantioselective conversion of racemic
α-tosyloxy ketones to optically enriched α-indolic carbonyls
has been accomplished using a new amino alcohol catalyst in the presence
of electron-rich indole nucleophiles. Kinetic studies reveal that
the rate-determining step in this S<sub>N</sub>1 pathway is the catalyst-mediated
α-tosyloxy ketone deprotonation step to form an enantiodiscriminant
oxy-allyl cation prior to the stereodefining nucleophilic addition
event
Tropolones As Lead-Like Natural Products: The Development of Potent and Selective Histone Deacetylase Inhibitors
Natural
products have long been recognized as a rich source of potent therapeutics
but further development is often limited by high structural complexity
and high molecular weight. In contrast, at the core of the thujaplicins
is a lead-like tropolone scaffold characterized by relatively low
molecular weight, ample sites for diversification, and metal-binding
functionality poised for targeting a range of metalloenzyme drug targets.
Here, we describe the development of this underutilized scaffold for
the discovery of tropolone derivatives that function as isozyme-selective
inhibitors of the validated anticancer drug target, histone deacetylase
(HDAC). Several monosubstituted tropolones display remarkable levels
of selectivity for HDAC2 and potently inhibit the growth of T-cell
lymphocyte cell lines. The tropolones represent a new chemotype of
isozyme-selective HDAC inhibitors