Asymmetric synthesis of an N-acylpyrrolidine for inhibition of HCV polymerase.

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.

Efficient synthesis of (3R,3aS,6aR)- hexahydrofuro[2,3-b]furan-3-ol from glycolaldehyde.

A one-step diastereoselective (up to 98:2) synthesis of the bis-furan alcohol of Darunavir and other HIV drug candidates has been achieved utilizing the novel cyclization of glycolaldehyde and 2,3-dihydrofuran. The cycloaddition was catalyzed by a variety of catalysts including those formed from tin(II) triflate and common chiral ligands such as BINAP and Evans's box ligands. An efficient and unique enzymatic process enhanced the enantiomeric purity to provide the target in optically pure form.

Efficient synthesis of an adenosine A2a agonist: glycosylation of 2-haloadenines and an N2-alkyl-6-chloroguanine.

A convergent synthesis of adenosine A2a agonist 1 in the form of its maleate salt 2 was achieved. The key step in this approach was the highly selective 9beta-glycosylation reaction between 2-haloadenines or an N(2)-alkyl-6-chloroguanine and a D-ribose derivative containing a 2-ethyltetrazolyl moiety. Glycosylations of other purine derivatives were also examined, and the methods developed provide efficient access to a variety of adenosine analogues such as 2-alkylaminoadenosines, an attractive class of compounds with antiinflammatory activity.