ABSTRACT
A potent reversible inhibitor of the cysteine protease cathepsin-S was prepared on large scale using a convergent synthetic route, free of chromatography and cryogenics. Late-stage peptide coupling of a chiral urea acid fragment with a functionalized aminonitrile was employed to prepare the target, using 2-hydroxypyridine as a robust, nonexplosive replacement for HOBT. The two key intermediates were prepared using a modified Strecker reaction for the aminonitrile and a phosphonation-olefination-rhodium-catalyzed asymmetric hydrogenation sequence for the urea. A palladium-catalyzed vinyl transfer coupled with a Claisen reaction was used to produce the aldehyde required for the side chain. Key scale up issues, safety calorimetry, and optimization of all steps for multikilogram production are discussed.
Subject(s)
Alkenes/chemical synthesis , Cathepsins/antagonists & inhibitors , Cathepsins/chemistry , Enzyme Inhibitors/chemical synthesis , Urea/chemical synthesis , Vinyl Compounds/chemical synthesis , Alkenes/chemistry , Calorimetry/methods , Catalysis , Cyclization , Enzyme Inhibitors/pharmacology , Indicators and Reagents/chemistry , Models, Molecular , Molecular Structure , Palladium/chemistry , Rhodium/chemistry , Stereoisomerism , Urea/chemistry , Vinyl Compounds/chemistryABSTRACT
Asymmetric hydrogenation of unsaturated urea esters with the BIPI Ligands has been examined. Optimization of the P-N ligand structure has led to the development of chiral rhodium catalysts capable of producing the targets with >99% ee. The critical phosphine borane SNAr reaction needed for ligand synthesis has been optimized to give the adducts in high yield at ambient temperature with no racemization. An extremely concise, economical, and scalable sequence to these important new ligands for catalysis of asymmetric hydrogenation has been developed.
