An efficient enantiopure synthesis of a pivotal precursor to substance P antagonists

Many substance P antagonists have a core structure based on the quinuclidine skeleton. Manufacture of these drug antagonists proceeds through the advanced intermediate (2S,3S)-cis-2-benzhydryl-3-aminoquinuclidine 1, and all previous syntheses of 2S,3S-1 proceed through quinuclidinone 2. The synthesis described herein provides a 40% improved synthetic yield of (2S,3S)-l from quinuclidinone 2, when compared to all previously reported syntheses. The key process improvements originate from: (1) dynamic kinetic resolution of ketone rac-4, producing ketone (2S)-4 and (2) the subsequent reductive amination of ketone (2S)-4 without epimerization. The former dynamic kinetic resolution, the first demonstrated for this ketone (quinuclidinone) architecture, uses inexpensive (natural) L-tartaric acid to provide ketone (2S)-4 in high yield (90%) and enantiopurity (95% ee). The latter demonstrates the first use of Ti((OPr)-Pr-i)(4)/Pt-C/H-2 for reductive amination and is especially noteworthy for its ability to preserve the alpha-labile C2 stereo-center of ketone (2S)-4. The new reductive amination method is general in nature and should find broad applicability.