5 research outputs found
Discovery of a Phosphine-Mediated Cycloisomerization of Alkynyl Hemiketals: Access to Spiroketals and Dihydropyrazoles via Tandem Reactions
Reported here are details on the discovery of a phosphine-catalyzed
isomerization of hemiketals and subsequent reactions of the cyclic
keto enol ether products. The new cycloisomerization complements a
previously reported amine-catalyzed process that gave oxepinones from
the same hemiketal starting materials. In the absence of functionality
(R<sup>2</sup>) on the cyclic keto enol ether, a rapid and facile
dimerization occurs, giving spiroketal products. When the enone is
substituted (i.e., R<sup>2</sup> = Ph), the cyclic keto enol ether
is sufficiently stable so that it can be isolated; it can then be
further reacted in the same pot to provide the corresponding dihydropyrazoles.
Both the spiroketal and dihydropyrazole products arise by a tandem
reaction that begins with the novel cycloisomerization. The method
allows for the rapid introduction of complexity in the products from
relatively simple starting materials. It should find application in
the synthesis of natural product-like molecules
Discovery of a Phosphine-Mediated Cycloisomerization of Alkynyl Hemiketals: Access to Spiroketals and Dihydropyrazoles via Tandem Reactions
Reported here are details on the discovery of a phosphine-catalyzed
isomerization of hemiketals and subsequent reactions of the cyclic
keto enol ether products. The new cycloisomerization complements a
previously reported amine-catalyzed process that gave oxepinones from
the same hemiketal starting materials. In the absence of functionality
(R<sup>2</sup>) on the cyclic keto enol ether, a rapid and facile
dimerization occurs, giving spiroketal products. When the enone is
substituted (i.e., R<sup>2</sup> = Ph), the cyclic keto enol ether
is sufficiently stable so that it can be isolated; it can then be
further reacted in the same pot to provide the corresponding dihydropyrazoles.
Both the spiroketal and dihydropyrazole products arise by a tandem
reaction that begins with the novel cycloisomerization. The method
allows for the rapid introduction of complexity in the products from
relatively simple starting materials. It should find application in
the synthesis of natural product-like molecules
Hypoxia-Activated Small Molecule-Induced Gene Expression
<div><div><div><p>Hypoxia, conditions of reduced oxygen, occur in a wide variety of biological contexts, including solid tumours and bacterial biofilms, which are relevant to human health. Consequently, the development of chemical tools to study hypoxia is vital. Here we report a hypoxia-activated small molecule-mediated gene expression system using a bioreductive prodrug of the inducer isopropyl 1-thio-β-D-galactopyranoside (IPTG). As a proof-of-concept we have placed the production of a green fluorescent protein under the control of hypoxia. Our system has the potential to be extended to regulate the production any given protein of choice.</p></div></div></div
An Uncharged Oxetanyl Sulfoxide as a Covalent Modifier for Improving Aqueous Solubility
Low
aqueous solubility is a common challenge in drug discovery
and development and can lead to inconclusive biological assay results.
Attaching small, polar groups that do not interfere with the bioactivity
of the pharmacophore often improves solubility, but there is a dearth
of viable neutral moieties available for this purpose. We have modified
several poorly soluble drugs or drug candidates with the oxetanyl
sulfoxide moiety of the DMSO analog MMS-350 and noted in most cases
a moderate to large improvement of aqueous solubility. Furthermore,
the membrane permeability of a test sample was enhanced compared to
the parent compound
Copper-Catalyst-Controlled Site-Selective Allenylation of Ketones and Aldehydes with Propargyl Boronates
A practical and highly site-selective copper-PhBPE-catalyst-controlled allenylation with propargyl boronates has been developed. The methodology has shown to be tolerant of diverse ketones and aldehydes providing the allenyl adducts in high selectivity. The BPE ligand and boronate substituents were shown to direct the site selectivity for which either propargyl or allenyl adducts can be acquired in high selectivity. A model is proposed that explains the origin of the site selectivity