The selective deoxygenation of polyols is a frontier in our ability to harness the stereochemical and structural complexity of natural and synthetic feedstocks. Herein, we describe a highly active and selective boron-based catalytic system for the selective deoxygenation of terminal 1,2-diols at the primary position, a process that is enabled by the transient formation of a cyclic siloxane. The method provides an ideal complement to well-known catalytic asymmetric reactions to prepare synthetically challenging chiral 2-alkanols in nearly perfect enantiomeric excess, as illustrated in a short synthesis of the anti-inflammatory drug (R)-lisofylline.
Bromodomains (BRDs)
are epigenetic interaction domains currently
recognized as emerging drug targets for development of anticancer
or anti-inflammatory agents. In this study, development of a selective
ligand of the fifth BRD of polybromo protein-1 (PB1(5)) related to
switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes
is presented. A compound collection was evaluated by consensus virtual
screening and a hit was identified. The biophysical study of protein–ligand
interactions was performed using X-ray crystallography and isothermal
titration calorimetry. Collective data supported the hypothesis that
affinity improvement could be achieved by enhancing interactions of
the complex with the solvent. The derived SAR along with free energy
calculations and a consensus hydration analysis using WaterMap and
SZmap algorithms guided rational design of a set of novel analogues.
The most potent analogue demonstrated high affinity of 3.3 μM
and an excellent selectivity profile, thus comprising a promising
lead for the development of chemical probes targeting PB1(5).
A catalytic pinacol-type reductive rearrangement reaction of internal 1,2-diols is reported herein. Several scaffolds not usually amenable to pinacol-type reactions, such as aliphatic secondary-secondary diols, undergo the transformation well without the need for prefunctionalization. The reaction uses a simple boron catalyst and two silanes and proceeds through a concerted, stereoinvertive mechanism that enables the preparation of highly enantiomerically enriched products. Computational studies have been used to rationalize the preference for migration over direct deoxygenation.
The
selective deoxygenation of polyols has emerged as an attractive
approach to transform biomass-derived polyols into valuable building
blocks. Herein, we present a theoretical study on the boron-catalyzed
selective deoxygenation of terminal 1,2-diols. The computational results
explain the different product distributions obtained with different
silanes and unveil the critical role of the cyclic siloxane intermediate.
Compared to noncyclic pathways, the cyclic pathway facilitates the
initial deoxygenation process because the cyclic structure minimizes
the steric repulsions between the reagents. It avoids overreduction
because the generated bulky disiloxane moiety hinders the second deoxygenation.
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