7 research outputs found
Control of Transient Aluminum–Aminals for Masking and Unmasking Reactive Carbonyl Groups
A new reagent, the dimethylaluminum <i>N</i>,<i>O</i>-dimethylhydroxylamine complex, is effective at masking reactive carbonyl groups in situ from nucleophilic addition. This reagent allows chemoselective addition of reducing reagents, Grignard reagents, organolithiums, Wittig reagents, and enolates into substrates with multiple carbonyl groups. Moreover, the trapped carbonyl group, a stable aminal, can be unmasked in situ for additional synthetic manipulations
Magnesium-Promoted Additions of Difluoroenolates to Unactivated Imines
Although there are many synthetic
methods to produce fluorinated
and trifluoromethylated organic structures, the construction of difluoromethylated
compounds remains a synthetic challenge. We have discovered that unactivated
imines will react with difluoroenolates under exceedingly mild conditions
when using magnesium salts and organic bases. We have applied this
approach to the iminoaldol reaction to produce difluoromethylene groups
as α,α-difluoro-β-amino-carbonyl groups. This method
provides synthetically useful quantities of difficult to access α,α-difluoro-β-aminoketones
without the need of protecting groups or the use of activated imines.
Moreover, we have applied this strategy to create analogues of the
dual orexin receptor antagonist, almorexant, in only two synthetic
steps
Magnesium-Promoted Additions of Difluoroenolates to Unactivated Imines
Although there are many synthetic
methods to produce fluorinated
and trifluoromethylated organic structures, the construction of difluoromethylated
compounds remains a synthetic challenge. We have discovered that unactivated
imines will react with difluoroenolates under exceedingly mild conditions
when using magnesium salts and organic bases. We have applied this
approach to the iminoaldol reaction to produce difluoromethylene groups
as α,α-difluoro-β-amino-carbonyl groups. This method
provides synthetically useful quantities of difficult to access α,α-difluoro-β-aminoketones
without the need of protecting groups or the use of activated imines.
Moreover, we have applied this strategy to create analogues of the
dual orexin receptor antagonist, almorexant, in only two synthetic
steps
Magnesium-Promoted Additions of Difluoroenolates to Unactivated Imines
Although there are many synthetic
methods to produce fluorinated
and trifluoromethylated organic structures, the construction of difluoromethylated
compounds remains a synthetic challenge. We have discovered that unactivated
imines will react with difluoroenolates under exceedingly mild conditions
when using magnesium salts and organic bases. We have applied this
approach to the iminoaldol reaction to produce difluoromethylene groups
as α,α-difluoro-β-amino-carbonyl groups. This method
provides synthetically useful quantities of difficult to access α,α-difluoro-β-aminoketones
without the need of protecting groups or the use of activated imines.
Moreover, we have applied this strategy to create analogues of the
dual orexin receptor antagonist, almorexant, in only two synthetic
steps
Magnesium-Promoted Additions of Difluoroenolates to Unactivated Imines
Although there are many synthetic
methods to produce fluorinated
and trifluoromethylated organic structures, the construction of difluoromethylated
compounds remains a synthetic challenge. We have discovered that unactivated
imines will react with difluoroenolates under exceedingly mild conditions
when using magnesium salts and organic bases. We have applied this
approach to the iminoaldol reaction to produce difluoromethylene groups
as α,α-difluoro-β-amino-carbonyl groups. This method
provides synthetically useful quantities of difficult to access α,α-difluoro-β-aminoketones
without the need of protecting groups or the use of activated imines.
Moreover, we have applied this strategy to create analogues of the
dual orexin receptor antagonist, almorexant, in only two synthetic
steps
Evaluation of Difluoromethyl Ketones as Agonists of the γ‑Aminobutyric Acid Type B (GABA<sub>B</sub>) Receptor
The design, synthesis, biological
evaluation, and in vivo studies
of difluoromethyl ketones as GABA<sub>B</sub> agonists that are not
structurally analogous to known GABA<sub>B</sub> agonists, such as
baclofen or 3-aminopropyl phosphinic acid, are presented. The difluoromethyl
ketones were assembled in three synthetic steps using a trifluoroacetate-release
aldol reaction. Following evaluation at clinically relevant GABA receptors,
we have identified a difluoromethyl ketone that is a potent GABA<sub>B</sub> agonist, obtained its X-ray structure, and presented preliminary
in vivo data in alcohol-preferring mice. The behavioral studies in
mice demonstrated that this compound tended to reduce the acoustic
startle response, which is consistent with an anxiolytic profile.
Structure–activity investigations determined that replacing
the fluorines of the difluoromethyl ketone with hydrogens resulted
in an inactive analogue. Resolution of the individual enantiomers
of the difluoromethyl ketone provided a compound with full biological
activity at concentrations less than an order of magnitude greater
than the pharmaceutical, baclofen
Evaluation of Difluoromethyl Ketones as Agonists of the γ‑Aminobutyric Acid Type B (GABA<sub>B</sub>) Receptor
The design, synthesis, biological
evaluation, and in vivo studies
of difluoromethyl ketones as GABA<sub>B</sub> agonists that are not
structurally analogous to known GABA<sub>B</sub> agonists, such as
baclofen or 3-aminopropyl phosphinic acid, are presented. The difluoromethyl
ketones were assembled in three synthetic steps using a trifluoroacetate-release
aldol reaction. Following evaluation at clinically relevant GABA receptors,
we have identified a difluoromethyl ketone that is a potent GABA<sub>B</sub> agonist, obtained its X-ray structure, and presented preliminary
in vivo data in alcohol-preferring mice. The behavioral studies in
mice demonstrated that this compound tended to reduce the acoustic
startle response, which is consistent with an anxiolytic profile.
Structure–activity investigations determined that replacing
the fluorines of the difluoromethyl ketone with hydrogens resulted
in an inactive analogue. Resolution of the individual enantiomers
of the difluoromethyl ketone provided a compound with full biological
activity at concentrations less than an order of magnitude greater
than the pharmaceutical, baclofen