9 research outputs found
Ligand-Enabled CâH Hydroxylation with Aqueous H<sub>2</sub>O<sub>2</sub> at Room Temperature
With the large number of Pd(II)-catalyzed
CâH
activation
reactions of native substrates developed in the past decade, the development
of catalysts to enable the use of green oxidants under safe and practical
conditions has become an increasingly important challenge. Notably,
the compatibility of Pd(II) catalysts with sustainable aqueous H2O2 has been a long-standing challenge in catalysis
including Wacker-type oxidations. We report herein a bifunctional
bidentate carboxyl-pyridone (CarboxPyridone) ligand that enables room-temperature
Pd-catalyzed CâH hydroxylation of a broad range of benzoic
and phenylacetic acids with an industry-compatible oxidant, aqueous
hydrogen peroxide (35% H2O2). The scalability
of this methodology is demonstrated by a 1000 mmol scale reaction
of ibuprofen (206 g) using only a 1 mol % Pd catalyst loading. The
utility of this protocol is further illustrated through derivatization
of the products and synthesis of polyfluorinated natural product coumestan
and pterocarpene from phenol intermediates prepared using this methodology
Synthesis of Fmoc-Protected Arylphenylalanines (Bip Derivatives) via Nonaqueous Suzuki-Miyaura Cross-Coupling Reactions
A one-step synthesis
of Fmoc-protected aryl/heteroaryl-substituted
phenylalanines (Bip derivatives) using the nonaqueous palladium-catalyzed
SuzukiâMiyaura cross-coupling (SMC) reaction of Fmoc-protected
bromo- or iodophenylalanines is reported. This protocol allows for
the direct formation of a variety of unnatural biaryl-containing amino
acids in good to excellent yield, which can be readily used in subsequent
Fmoc solid-phase peptide synthesis. The synthetic utility of this
method is also demonstrated by the SMC reaction of bromophenylalanine-containing
tripeptides
Leveraging a âCatchâReleaseâ Logic Gate Process for the Synthesis and Nonchromatographic Purification of Thioether- or Amine-Bridged Macrocyclic Peptides
Macrocyclic peptides containing N-alkylated
amino acids have emerged
as a promising therapeutic modality, capable of modulating proteinâprotein
interactions and an intracellular delivery of hydrophilic payloads.
While multichannel automated solid-phase peptide synthesis (SPPS)
is a practical approach for peptide synthesis, the requirement for
slow and inefficient chromatographic purification of the product peptides
is a significant limitation to exploring these novel compounds. Herein,
we invent a âcatchâreleaseâ strategy for the
nonchromatographic purification of macrocyclic peptides. A traceless
catch process is enabled by the invention of a dual-functionalized
N-terminal acetate analogue, which serves as a handle for capture
onto a purification resin and as a leaving group for macrocyclization.
Displacement by a C-terminal nucleophilic side chain thus releases
the desired macrocycle from the purification resin. By design, this
catch/release process is a logic test for the presence of the key
components required for cyclization, thus removing impurities which
lack the required functionality, such as common classes of peptide impurities, including
hydrolysis fragments and truncated sequences. The method was shown
to be highly effective with three libraries of macrocyclic peptides,
containing macrocycles of 5â20 amino acids, with either thioether-
or amine-based macrocyclic linkages; in this latter class, the reported
method represents an enabling technology. In all cases, the catchârelease
protocol afforded significant enrichment of the target peptides purity,
in many cases completely obviating the need for chromatography. Importantly,
we have adapted this process for automation on a standard multichannel
peptide synthesizer, achieving an efficient and completely integrated
synthesis and purification platform for the preparation of these important
molecules
Ligand-Enabled βâC(sp<sup>3</sup>)âH Olefination of Free Carboxylic Acids
An acetyl-protected
aminoethyl phenyl thioether has been developed
to promote CÂ(sp<sup>3</sup>)âH activation. Significant ligand
enhancement is demonstrated by the realization of the first PdÂ(II)-catalyzed
olefination of CÂ(sp<sup>3</sup>)âH bonds of free carboxylic
acids without using an auxiliary. Subsequent lactonization of the
olefinated product via 1,4 addition provided exclusively monoselectivity
in the presence of multiple β-CâH bonds. The product
Îł-lactone can be readily opened to give either the highly valuable
β-olefinated or γ-hydroxylated aliphatic acids. Considering
the challenges in developing Heck couplings using alkyl halides, this
reaction offers a useful alternative
CITU: A Peptide and Decarboxylative Coupling Reagent
Tetra<b>c</b>hloro-<i>N</i>-hydroxyphthal<b>i</b>mide <b>t</b>etramethyl<b>u</b>ronium hexafluorophosphate
(CITU) is disclosed as a convenient and economical reagent for both
acylation and decarboxylative cross-coupling chemistries. Within the
former set of reactions, CITU displays reactivity similar to that
of common coupling reagents, but with increased safety and reduced
cost. Within the latter, increased yields, more rapid conversion,
and a simplified procedure are possible across a range of reported
decarboxylative transformations
Conformationally Constrained <i>ortho-</i>Anilino Diaryl Ureas: Discovery of 1â(2-(1â˛-Neopentylspiro[indoline-3,4â˛-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea, a Potent, Selective, and Bioavailable P2Y<sub>1</sub> Antagonist
Preclinical
antithrombotic efficacy and bleeding models have demonstrated
that P2Y<sub>1</sub> antagonists are efficacious as antiplatelet agents
and may offer a safety advantage over P2Y<sub>12</sub> antagonists
in terms of reduced bleeding liabilities. In this article, we describe
the structural modification of the <i>tert</i>-butyl phenoxy
portion of lead compound <b>1</b> and the subsequent discovery
of a novel series of conformationally constrained <i>ortho</i>-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted
diaryl ureas are described as potent, orally bioavailable small-molecule
P2Y<sub>1</sub> antagonists with improved activity in functional assays
and improved oral bioavailability in rats. Homology modeling and rat
PK/PD studies on benchmark compound <b>3l</b> will also be presented.
Compound <b>3l</b> was our first P2Y<sub>1</sub> antagonist
to demonstrate a robust oral antithrombotic effect with mild bleeding
liability in the rat thrombosis and hemostasis models
Diphenylpyridylethanamine (DPPE) Derivatives as Cholesteryl Ester Transfer Protein (CETP) Inhibitors
A series of diphenylpyridylethanamine (DPPE) derivatives
was identified exhibiting potent CETP inhibition. Replacing the labile
ester functionality in the initial lead <b>7</b> generated a
series of amides and ureas. Further optimization of the DPPE series
for potency resulted in the discovery of cyclopentylurea <b>15d</b>, which demonstrated a reduction in cholesterol ester transfer activity
(48% of predose level) in hCETP/apoB-100 dual transgenic mice. The
PK profile of <b>15d</b> was suboptimal, and further optimization
of the N-terminus resulted in the discovery of amide <b>20</b> with an improved PK profile and robust efficacy in transgenic hCETP/apoB-100
mice and in hamsters. Compound <b>20</b> demonstrated no significant
changes in either mean arterial blood pressure or heart rate in telemeterized
rats despite sustained high exposures
Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of <i>N</i>â[(1<i>R</i>)â1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)Âphenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)Âbenzamide (BMS-795311)
Cholesteryl ester transfer protein
(CETP) inhibitors raise HDL-C
in animals and humans and may be antiatherosclerotic by enhancing
reverse cholesterol transport (RCT). In this article, we describe
the lead optimization efforts resulting in the discovery of a series
of triphenylethanamine (TPE) ureas and amides as potent and orally
available CETP inhibitors. Compound <b>10g</b> is a potent CETP
inhibitor that maximally inhibited cholesteryl ester (CE) transfer
activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic
mice and increased HDL cholesterol content and size comparable to
torcetrapib (<b>1</b>) in moderately-fat fed hamsters. In contrast
to the off-target liabilities with <b>1</b>, no blood pressure
increase was observed with <b>10g</b> in rat telemetry studies
and no increase of aldosterone synthase (CYP11B2) was detected in
H295R cells. On the basis of its preclinical profile, compound <b>10g</b> was advanced into preclinical safety studies
Triphenylethanamine Derivatives as Cholesteryl Ester Transfer Protein Inhibitors: Discovery of <i>N</i>â[(1<i>R</i>)â1-(3-Cyclopropoxy-4-fluorophenyl)-1-[3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)Âphenyl]-2-phenylethyl]-4-fluoro-3-(trifluoromethyl)Âbenzamide (BMS-795311)
Cholesteryl ester transfer protein
(CETP) inhibitors raise HDL-C
in animals and humans and may be antiatherosclerotic by enhancing
reverse cholesterol transport (RCT). In this article, we describe
the lead optimization efforts resulting in the discovery of a series
of triphenylethanamine (TPE) ureas and amides as potent and orally
available CETP inhibitors. Compound <b>10g</b> is a potent CETP
inhibitor that maximally inhibited cholesteryl ester (CE) transfer
activity at an oral dose of 1 mg/kg in human CETP/apoB-100 dual transgenic
mice and increased HDL cholesterol content and size comparable to
torcetrapib (<b>1</b>) in moderately-fat fed hamsters. In contrast
to the off-target liabilities with <b>1</b>, no blood pressure
increase was observed with <b>10g</b> in rat telemetry studies
and no increase of aldosterone synthase (CYP11B2) was detected in
H295R cells. On the basis of its preclinical profile, compound <b>10g</b> was advanced into preclinical safety studies