As part of Merck's continued research effort on inflammation and pain, a safe synthesis of an orally bioavailable and CNS penetrant bradykinin 1 antagonist was developed and demonstrated on kilogram scale. The key step included a novel regioselective metal-halogen exchange reaction on 1,2-dibromo-5-chloro-3fluorobenzene using isopropyl magnesium chloride to install the 1,2,4-oxadiazole ring structure. Suzuki cross-coupling reaction between a highly functionalized and sterically hindered electrophile and boronic ester generated the biaryl ring system, which was converted to the target molecule (1) using standard chemistry. The safe installation of a 1,2,4-oxadiazole ring proved to be challenging since the original synthetic route relied on the preparation of a highly functionalized benzonitrile using potassium cyanide and resulted in low yields and large amounts of potentially hazardous waste. Overall, a safe and robust synthesis was developed, which occurred in eight linear steps with an overall yield of 28%.

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A general method for the enantioselective hydrogenation of protected allylic amine derivatives is described. This procedure relies on the generation of a cationic ruthenium complex with the axially chiral ligand (-)-TMBTP. The utility is highlighted by the highly enantioselective hydrogenation of a diene substrate that can then be elaborated to prepare Telcagepant, a compound currently in Phase III clinical trials. The scope of the hydrogenation reaction was studied, and a variety of substituted allylic amine derivatives could be hydrogenated with enantiomeric ratios of 92:8 or higher.

An efficient synthesis of 1R,5S-bicyclo[3.1.0]hexan-2-one from (R)-1,2-epoxyhex-5-ene is described. Development of a catalytic intramolecular cyclopropanation of (R)-1,2-epoxyhex-5-ene gives the key homochiral bicycle[3.1.0]hexan-1-ol, which is then oxidized to the desired ketone. This process has been successfully demonstrated on a multi-kilogram scale.

The development and execution of a practical asymmetric synthesis of the estrogen receptor beta selective agonist (8R,10aS)-6-(trifluoromethyl)-8,9,10,11-tetrahydro-8,10a-methanocyclohepta­[1,2]­indeno­[4,5-d]­[1,2,3]­triazol-7­(3H)-one is described. The optimized route features a key chiral auxiliary-mediated dialkylation approach to set the all-carbon quaternary center with exceptional stereocontrol. Overall, the chemistry has been used to prepare >30 kg of drug candidate in 21% overall yield through 13 longest linear steps and with >99% ee.