A chiral phosphoric acid catalyzed enantioselective bromocyclization of olefins is described. Various cis-, trans-, or trisubstituted γ-hydroxy-alkenes and γ-amino-alkenes can cyclize under the reaction conditions to give optically active 2-substituted tetrahydrofurans and tetrahydropyrroles in up to 91% ee.
Pure antiestrogens,
or selective estrogen receptor degraders (SERDs),
have proven to be effective in treating breast cancer that has progressed
on tamoxifen and/or aromatase inhibitors. However, the only FDA-approved
pure antiestrogen, fulvestrant, is limited in efficacy by its low
bioavailability. The search for orally bioavailable SERDs has continued
for nearly as long as the clinical history of the injection-only fulvestrant.
Oral SERDs that have been developed and tested in patients ranged
from nonsteroidal ER binders containing an acrylic acid or amino side
chain to bifunctional proteolysis-targeting chimera (PROTAC) pure
ER degraders. Structural evolution in the development of oral SERD
molecules has been closely associated with quantifiable ER-degrading
potency, as seen in the structural comparison analysis of acrylic
acid and basic amino side-chain-bearing SERDs. Failure to improve
on fulvestrant in the clinical trials by numerous acidic SERDs and
early basic SERDs is blamed on tolerability and/or insufficient efficacy,
which will likely be overcome by the new-generation basic SERD molecules
and PROTAC ER degraders with improved oral bioavailability, low toxicity,
and superior efficacy of receptor degradation.
The synthesis of optically pure (+)-ambrisentan has been achieved from 3,3-diphenylacrylate in four steps with 53% overall yield and >99% ee at the >100 g scale without column purification. The chiral epoxide intermediate was prepared via asymmetric epoxidation with a fructose-derived diacetate ketone as catalyst.
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