5 research outputs found
Peroxide-Initiated Hydrophosphinylation of <i>gem</i>-Difluoroalkenes
The installation of fluorine and fluorinated functional
groups
into drug-like scaffolds can perturb the physicochemical, pharmacokinetic,
and pharmacodynamic properties of compounds. However, some potentially
useful fluorinated substructures reside predominantly outside the
realm of the current synthetic methodologies. One such substructure,
the α,α-difluorophosphine oxide, might be convergently
prepared by the reaction of a gem-difluorinated alkene
with a PâH bond, though such nucleophilic reactions instead
proceed through a CâF substitution pathway that delivers monofluorovinyl
products. In contrast, we report a peroxide-initiated hydrophosphinylation
reaction of gem-difluoroalkenes that avoids CâF
substitution and produces a wide range of α,α-difluorophosphine
oxides and functions using readily available reagents and green solvents
Ligand-Controlled Regioselective Copper-Catalyzed Trifluoromethylation To Generate (Trifluoromethyl)allenes
âCuâCF<sub>3</sub>â species have been used
historically for a broad spectrum of nucleophilic trifluoromethylation
reactions. Although recent advancements have employed ligands to stabilize
and harness the reactivity of this key organometallic intermediate,
the ability of a ligand to differentiate a regiochemical outcome of
a CuâCF<sub>3</sub>-mediated or -catalyzed reaction has not
been previously reported. Herein, we report the first example of a
Cu-catalyzed trifluoromethylation reaction in which a ligand controls
the regiochemical outcome. More specifically, we demonstrate the ability
of bipyridyl-derived ligands to control the regioselectivity of the
Cu-catalyzed nucleophilic trifluoromethylation reactions of propargyl
electrophiles to generate (trifluoromethyl)Âallenes. This method provides
a variety of di-, tri-, and tetrasubstituted (trifluoromethyl)Âallenes,
which can be further modified to generate complex fluorinated substructures
Copper-Catalyzed Synthesis of Trifluoroethylarenes from Benzylic Bromodifluoroacetates
Trifluoroethylarenes
are found in a variety of biologically active
molecules, and strategies for accessing this substructure are important
for developing therapeutic candidates and biological probes. Trifluoroethylarenes
can be directly accessed via nucleophilic trifluoromethylation of
benzylic electrophiles; however, current catalytic methods do not
effectively transform electron-deficient substrates and heterocycles.
To address this gap, we report a Cu-catalyzed decarboxylative trifluoromethylation
of benzylic bromodifluoroacetates. To account for the tolerance of
sensitive functional groups, we propose an inner-sphere mechanism
of decarboxylation
Base Catalysis Enables Access to α,α-DifluoroÂalkylÂthioethers
A nucleophilic addition
reaction of aryl thiols to readily available
ÎČ,ÎČ-difluorostyrenes provides α,α-difluoroÂalkylÂthioethers.
The reaction proceeds through an unstable anionic intermediate, prone
to eliminate fluoride and generate α-fluorovinylthioethers.
However, the use of base catalysis overcomes the facile ÎČ-fluoride
elimination, generating α,α-difluoroalkylÂthioethers
in excellent yields and selectivities
Tyr<sup>1</sup>âÏ[(<i>Z</i>)CFî»CH]-Gly<sup>2</sup> Fluorinated Peptidomimetic Improves Distribution and Metabolism Properties of Leu-Enkephalin
Opioid peptides are key regulators
in cellular and intercellular
physiological responses, and could be therapeutically useful for modulating
several pathological conditions. Unfortunately, the use of peptide-based
agonists to target centrally located opioid receptors is limited by
poor physicochemical (PC), distribution, metabolic, and pharmacokinetic
(DMPK) properties that restrict penetration across the blood-brain
barrier via passive diffusion. To address these problems, the present
paper exploits fluorinated peptidomimetics to simultaneously modify
PC and DMPK properties, thus facilitating entry into the central nervous
system. As an initial example, the present paper exploited the Tyr<sup>1</sup>-ÏÂ[(<i>Z</i>)ÂCFî»CH]-Gly<sup>2</sup> peptidomimetic to improve PC druglike characteristics (computational),
plasma and microsomal degradation, and systemic and CNS distribution
of Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu). Thus, the fluoroalkene replacement
transformed an instable in vitro tool compound into a stable and centrally
distributed in vivo probe. In contrast, the Tyr<sup>1</sup>-ÏÂ[CF<sub>3</sub>CH<sub>2</sub>âNH]-Gly<sup>2</sup> peptidomimetic decreased
stability by accelerating proteolysis at the Gly<sup>3</sup>âPhe<sup>4</sup> position