3 research outputs found
Development of Synthetic Routes, via a Tropinone Intermediate, to a Long-Acting Muscarinic Antagonist for the Treatment of Respiratory Disease
This
contribution describes the development of two synthetic routes to
an investigational muscarinic antagonist for the treatment of chronic
obstructive pulmonary disease. The first route used a starting material
which was in plentiful supply within the GSK network and was used
to make material for early clinical trials and safety assessment studies.
Further investigations identified a second, potential long-term manufacturing
route from commercially available building blocks, using substrate
control to install the two stereocentres with excellent selectivity.
A key step was a substrate-directed epoxide reduction which also gave
rise to a minor byproduct through a skeletal rearrangement of the
tropane ring. A deuterium-labeling experiment was carried out, which
shed light on the origin of the byproduct, and also guided the improvement
of reaction conditions
Development of a Selective Friedel–Crafts Alkylation Surrogate: Safe Operating Conditions through Mechanistic Understanding
This article describes a selective one-pot, Friedel–Crafts
acylation/ketone reduction protocol, effectively a surrogate for the
Friedel–Crafts alkylation reaction with a primary alkyl halide.
A potentially dangerous failure mode was identified, resulting in
the uncontrolled evolution of hydrogen. A series of mechanistic experiments,
including analysis by <sup>27</sup>Al NMR, was undertaken, and the
reaction mechanism elucidated. Finally, the use of React IR to ensure
real-time reaction safety was demonstrated
Design and Application of a DNA-Encoded Macrocyclic Peptide Library
A DNA-encoded
macrocyclic peptide library was designed and synthesized
with 2.4 × 10<sup>12</sup> members composed of 4–20 natural
and non-natural amino acids. Affinity-based selection was performed
against two therapeutic targets, VHL and RSV N protein. On the basis
of selection data, some peptides were selected for resynthesis without
a DNA tag, and their activity was confirmed