Kenneth Gregory Hull

SYNTHESIS OF RO 25-8210 VIA AN ENANTIOSELECTIVE OXAZABOROLIDINE-CATALYZED REDUCTION

Abstract Prochiral ketones which contain nitrogen atoms have been reduced enantioselectively with chiral oxazaborolidines in the presence of excess borane. However, the pyridine system has been shown to be a poor substrate for this asymmetric reduction. For example, catalytic reduction of 2-acetylpyridine with a chiral oxazaborolidine provided the product alcohol in only 28% ee. We wish to report the enantioselective reduction of 2-(bromoacetyl)-pyridine 1 with chiral oxazaborolidines. Good enantiomeric excess was obtained in the reductions (80% ee) and could be improved to ≥95% ee upon recrystallization. Subsequently, bromohydrin 6 was used to prepare Ro 25-8210.

N-Cycloalkanoyl-L-phenylalanine derivatives as VCAM/VLA-4 antagonists.

A systematic structure-activity relationship investigation of the lead compound 1 resulted the identification of several N-[(substituted alkyl)cycloalkanoyl]-4-[((2,6-dichlorophenyl)carbonyl)amino]-L-phenylalanine derivatives as potent VCAM/VLA-4 antagonists. The data are consistent with a model of these compounds in which these alkanoylphenylalanines reside in a compact gauche (-) bioactive conformation.