ABSTRACT
A practical asymmetric synthesis of a highly substituted N-acylpyrrolidine on multi-kilogram scale is described. The key step in the construction of the three stereocenters is a [3+2] cycloaddition of methyl acrylate and an imino ester prepared from l-leucine t-butyl ester hydrochloride and 2-thiazolecarboxaldehyde. The cycloaddition features novel asymmetric catalysis via a complex of silver acetate and a cinchona alkaloid, particularly hydroquinine, with complete diastereomeric control and up to 87% enantiomeric control. The alkaloid serves as a ligand as well as a base for the formation of the azomethine ylide or 1,3-dipole. Experiments have shown that the hydroxyl group of hydroquinine is a critical element for the enantioselectivities observed. The cycloaddition methodology is also applicable to methylvinyl ketone, providing access to either alpha- or beta-epimers of 4-acetylpyrrolidine depending on the reaction conditions utilized. The synthesis also highlights an efficient N-acylation, selective O- versus N-methylation, and a unique ester reduction with NaBH4-MeOH catalyzed by NaB(OAc)3H that not only achieves excellent chemoselectivity but also avoids formation of the undesired but thermodynamically favored epimer. The highly functionalized target is synthesized in seven linear steps from l-leucine t-butyl ester hydrochloride with all three isolated intermediates being highly crystalline.
Subject(s)
DNA-Directed RNA Polymerases/antagonists & inhibitors , Hepacivirus/enzymology , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Acrylates/chemistry , Acylation , Alkaloids/chemistry , Crystallography, X-Ray , DNA-Directed RNA Polymerases/metabolism , Imines/chemistry , Models, Molecular , Molecular Structure , Pyrrolidines/chemistry , Silver/chemistry , Solvents , StereoisomerismABSTRACT
A short, high-yielding synthesis of differentially substituted resorcinol derivatives has been developed that utilizes 1,3-difluorobenzene as the starting material and employs sequential nucleophilic aromatic substitution (S(N)Ar) reactions to generate desymmetrized products. The scope and limitations of the second S(N)Ar reaction on the deactivated 1-alkoxy-3-fluorobenzene intermediates have been investigated. This methodology has also been employed in the synthesis of desymmetrized catechol derivatives from 1,2-difluorobenzene.
Subject(s)
Resorcinols/chemical synthesis , Catechols/chemical synthesis , Fluorides/chemistry , Fluorobenzenes/chemistry , Resorcinols/chemistryABSTRACT
A direct comparison between Weinreb amides and morpholine amides was made with regard to their reactions with alkynyllithium reagents to form ynones. While treatment with stoichiometric alkynyllithium generally effects complete reaction in the case of Weinreb amides, incomplete reactions are obtained from the corresponding morpholine amides. This difference is attributed to an unexpected equilibrium process in the latter case, and it is shown that the use of excess alkynyllithium reagent with morpholine amides provides a synthetically useful synthesis of ynones at 0 degrees C.
