ABSTRACT
Two new, reliable syntheses of a pyrido[2,3-d]-pyrimidine inhibitor of the CXCR3 receptor are described. A nine-step synthesis of the CXCR3 inhibitor (1) from 2-aminonicotinic acid was demonstrated on a multikilogram scale and incorporates a classic resolution to deliver the enantioenriched active pharmaceutical ingredient (API). A second synthesis of the CXCR3 inhibitor starts from (+)-(D)-Boc alanine and 2-chloronicotinic acid and utilizes a Goldberg coupling. This second synthesis, performed on a gram scale, intersects the former route at a common intermediate thereby completing a formal synthesis of the enantioenriched API in higher overall yield without the need for a resolution.
Subject(s)
Acetamides/chemical synthesis , Acetamides/pharmacology , Hydrocarbons, Fluorinated/chemical synthesis , Hydrocarbons, Fluorinated/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptors, CXCR3/antagonists & inhibitors , Acetamides/chemistry , Alanine/chemistry , Aldehydes/chemistry , Amines/chemistry , Stereoisomerism , Tartrates/chemistryABSTRACT
We describe in full the first synthesis of the potent insect antifeedant azadirachtin through a highly convergent approach. An O-alkylation reaction is used to unite decalin ketone and propargylic mesylate fragments, after which a Claisen rearrangement constructs the central C8-C14 bond in a stereoselective fashion. The allene which results from this sequence then enables a second critical carbon-carbon bond forming event whereby the [3.2.1] bicyclic system, present in the natural product, is generated via a 5-exo-radical cyclisation process. Finally, using knowledge gained through our early studies into the reactivity of the natural product, a series of carefully designed steps completes the synthesis of this challenging molecule.
Subject(s)
Insecticides/chemical synthesis , Limonins/chemical synthesis , Insecticides/chemistry , Limonins/chemistry , Molecular Conformation , StereoisomerismABSTRACT
Five enantiopure palladacycles containing palladium bonded to a stereogenic carbon and an N-coordinated oxindole were synthesized by the reaction of alkenyl aryl triflates 2 and 9 with Pd(0) bisphosphine complexes. Two palladacyclic complexes, 3beta and 10alpha, were characterized by single-crystal X-ray crystallography. The reactivity of neutral palladacycles 3beta and 10beta was studied in detail. These unusual palladium alkyls, which have three accessible beta-hydrogens, are thermally stable at temperatures as high as 120 degrees C. At higher temperature, or at room temperature in the presence of weak acids, these complexes epimerize at the stereogenic carbon bonded to palladium. The mechanism of the acid-promoted epimerization was studied in detail. During this epimerization, cationic palladium alkyls 13/14 and 33 and cationic palladium hydride alkene complexes 31 and 32 are in rapid equilibrium.
