Aliphatic amines, oxygenated at remote positions within the molecule, represent an important class of synthetic building blocks to which there are currently no direct means of access. Reported herein ...is an efficient and scalable solution that relies upon decatungstate photocatalysis under acidic conditions using either H2O2 or O2 as the terminal oxidant. By using these reaction conditions a series of simple and unbiased aliphatic amine starting materials can be oxidized to value‐added ketone products. Lastly, NMR spectroscopy using in situ LED‐irradiated samples was utilized to monitor the kinetics of the reaction, thus enabling direct translation of the reaction into flow.
Going with the floW: Decatungstate anion, a UV absorbing photocatalyst, was utilized in the conversion of unprotected aliphatic amines, into products containing a ketone functionality at a remote position, by using either H2O2 or O2 as the terminal oxidant. NMR studies employing LED‐irradiated samples aided in the identification of a key reaction intermediate, and ultimately allowed the transformation to be translated into flow.
Prochiral hydrazones undergo efficient and highly selective hydrogenation in the presence of a chiral diphosphine ruthenium catalyst, yielding enantioenriched hydrazine products (up to 99% ee). The ...mild reaction conditions and broad functional group tolerance of this method allow access to versatile chiral hydrazine building blocks containing aryl bromide, heteroaryl, alkyl, cycloalkyl, and ester substituents. This method was also demonstrated on >150 g scale, providing a valuable hydrazine intermediate en route to an active pharmaceutical ingredient.
Major new advances in synthetic chemistry methods are typically reported using simple, non-standardized reaction substrates, and reaction failures are rarely documented. This makes the evaluation and ...choice of a synthetic method difficult. We report a standardized complex molecule diagnostic approach using collections of relevant drug-like molecules which we call chemistry informer libraries. With this approach, all chemistry results, successes and failures, can be documented to compare and evolve synthetic methods. To aid in the visualization of chemistry results in drug-like physicochemical space we have used an informatics methodology termed principal component analysis. We have validated this method using palladium- and copper-catalyzed reactions, including Suzuki-Miyaura, cyanation and Buchwald-Hartwig amination.
5′-Adenosine monophosphate-activated protein kinase (AMPK) is a key regulator of mammalian energy homeostasis and has been implicated in mediating many of the beneficial effects of exercise and ...weight loss including lipid and glucose trafficking. As such, the enzyme has long been of interest as a target for the treatment of Type 2 Diabetes Mellitus. We describe the optimization of β1-selective, liver-targeted AMPK activators and their evolution into systemic pan-activators capable of acutely lowering glucose in mouse models. Identifying surrogates for the key acid moiety in early generation compounds proved essential in improving β2-activation and in balancing improvements in plasma unbound fraction while avoiding liver sequestration.
Semi-synthetic water-soluble analogs were synthesized from nocathiacin I through the formation of a versatile intermediate nocathiacin amine 5, and subsequent transformation via reductive amination, ...acylation or urea formation.
Semi-synthetic water-soluble analogs were synthesized from nocathiacin I through the formation of a versatile intermediate nocathiacin amine 5, and subsequent transformation via reductive amination, acylation or urea formation. Several of the novel analogs displayed much improved aqueous solubility over 1, while retained antibacterial activity. Compound 15 and 16 from the amide series, demonstrated excellent in vitro and in vivo antibacterial activity.
The design and synthesis of a novel class of 2,3-dihydrobenzofuran-2-carboxylic acids as highly potent and subtype-selective PPARα agonists are reported. Systematic study of structure−activity ...relationships has identified several key structural elements within this class for maintaining the potency and subtype selectivity. Select compounds were evaluated in animal models of dyslipidemia using Syrian hamsters and male Beagle dogs, and all these compounds displayed excellent cholesterol- and triglyceride-lowering activity at dose levels that were much lower than the marketed weak PPARα agonist fenofibrate.
The synthesis and structure−activity relationships of novel series of α-aryloxyphenylacetic acids as PPARα/γ dual agonists are reported. The initial search for surrogates of the ester group in the ...screen lead led first to the optimization of a subseries with a ketone moiety. Further efforts to modify the ketone subseries led to the design and synthesis of two new subseries containing fused heterocyclic ring systems. All these analogues were characterized by their “super” PPARα agonist activity and weak or partial agonist activity on PPARγ in PPAR-GAL4 transactivation assays despite their similar binding affinities for both receptors. The cocrystal structures of compounds 7 and rosiglitazone with PPARγ-LBD were compared, and significant differences were found in their interactions with the receptor. Select analogues in each subseries were further evaluated for in vivo efficacy. They all showed excellent anti-hyperglycemic efficacy in a d b/d b mouse model and hypolipidemic activity in hamster and dog models without provoking the typical PPARγ-associated side effects in the rat tolerability assay.
A series of novel aryl indole-2-carboxylic acids has been identified as potent selective PPARγ modulators. Their chemical synthesis and in vitro activities are discussed. An optimized compound was ...efficacious in the
db/
db mouse model of type 2 diabetes.
A series of novel aryl indole-2-carboxylic acids has been identified as potent selective PPARγ modulators. Their chemical synthesis and in vitro activities are discussed. Compound
5 was selected for in vivo testing in the
db/
db mouse model of type 2 diabetes and resulted in reduction of hyperglycemia at comparable plasma exposure when compared to rosiglitazone.
Synthesis and SAR of novel water-soluble amide analogs of nocathiacin
1 are reported. Compound
19 was selected for further evaluation.
Novel water-soluble amide analogs were synthesized from ...nocathiacin I (
1) through the formation of the carboxylic acid intermediate followed by coupling to primary or secondary amines. Several compounds with potent antibacterial activity and adequate water solubility were identified. Of these, compound
19 was selected for more extensive evaluation because of its excellent in vitro antibacterial activity and in vivo efficacy, as well as clean off-target screening.
Aliphatic amines, oxygenated at remote positions within the molecule, represent an important class of synthetic building blocks to which there are currently no direct means of access. Reported herein ...is an efficient and scalable solution that relies upon decatungstate photocatalysis under acidic conditions using either H2O2 or O2 as the terminal oxidant. By using these reaction conditions a series of simple and unbiased aliphatic amine starting materials can be oxidized to value‐added ketone products. Lastly, NMR spectroscopy using in situ LED‐irradiated samples was utilized to monitor the kinetics of the reaction, thus enabling direct translation of the reaction into flow.
Das Decawolframat‐Anion, ein UV‐absorbierender Photokatalysator, wurde zur Umsetzung von ungeschützten aliphatischen Aminen in Produkte mit einer entfernt positionierten Ketonfunktionalität eingesetzt, wobei H2O2 oder O2 als Oxidationsmittel diente. NMR‐Studien an LED‐bestrahlten Proben führten zur Identifizierung eines Schlüsselintermediats und ermöglichten letztlich die Übertragung der Reaktion in einen Durchflussreaktor.
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