The first highly enantioselective catalytic protocol for the reductive coupling of ketones and hydrazones is reported. These reactions proceed through neutral ketyl radical intermediates generated via a concerted proton-coupled electron transfer (PCET) event jointly mediated by a chiral phosphoric acid catalyst and the photoredox catalyst Ir(ppy)2(dtbpy)PF6. Remarkably, these neutral ketyl radicals appear to remain H-bonded to the chiral conjugate base of the Brønsted acid during the course of a subsequent C-C bond-forming step, furnishing syn 1,2-amino alcohol derivatives with excellent levels of diastereo- and enantioselectivity. This work provides the first demonstration of the feasibility and potential benefits of concerted PCET activation in asymmetric catalysis.
We report a new photocatalytic protocol for the redox-neutral isomerization of cyclic alcohols to linear ketones via C-C bond scission. Mechanistic studies demonstrate that key alkoxy radical intermediates in this reaction are generated via the direct homolytic activation of alcohol O-H bonds in an unusual intramolecular PCET process, wherein the electron travels to a proximal radical cation in concert with proton transfer to a weak Brønsted base. Effective bond strength considerations are shown to accurately forecast the feasibility of alkoxy radical generation with a given oxidant/base pair.
Sickle cell disease (SCD) is a genetic
disorder caused by a single
point mutation (β6 Glu → Val) on the β-chain of
adult hemoglobin (HbA) that results in sickled hemoglobin (HbS). In
the deoxygenated state, polymerization of HbS leads to sickling of
red blood cells (RBC). Several downstream consequences of polymerization
and RBC sickling include vaso-occlusion, hemolytic anemia, and stroke.
We report the design of a noncovalent modulator of HbS, clinical candidate
PF-07059013 (23). The seminal hit molecule was discovered
by virtual screening and confirmed through a series of biochemical
and biophysical studies. After a significant optimization effort,
we arrived at 23, a compound that specifically binds
to Hb with nanomolar affinity and displays strong partitioning into
RBCs. In a 2-week multiple dose study using Townes SCD mice, 23 showed a 37.8% (±9.0%) reduction in sickling compared
to vehicle treated mice. 23 (PF-07059013) has advanced
to phase 1 clinical trials.
C–F functionalization of arenes with a range of alcohol and pyrazole nucleophiles has been achieved without the need for metal catalysts or highly electron‐poor substrates. Treatment of fluoroarenes with alcohols or pyrazoles and DDQ under irradiation by blue LED light provides the corresponding substituted products. The procedure is complementary to classical SNAr chemistry which generally requires basic reaction conditions and high temperatures, and provides products under non‐basic conditions at ≈ 40 °C.
Lufotrelvir was designed as a first in class 3CL protease
inhibitor
to treat COVID-19. Development of lufotrelvir was challenged by its
relatively poor stability due to its propensity to epimerize and degrade.
Key elements of process development included improvement of the supply
routes to the indole and lactam fragments, a Claisen addition to homologate
the lactam, and a subsequent phosphorylation reaction to prepare the
prodrug as well as identification of a DMSO solvated form of lufotrelvir
to enable long-term storage. As a new approach to preparing the indole
fragment, a Cu-catalyzed C–O coupling using oxalamide ligands
was demonstrated. The control of process-related impurities was essential
to accommodate the parenteral formulation. Isolation of an MEK solvate
followed by the DMSO solvate ensured that all impurities were controlled
appropriately.
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