An Efficient Enantiopure Synthesis of a Pivotal Precursor to Substance P Antagonists1

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Abstract

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)-1 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(OiPr)4/Pt-C/H2 for reductive amination and is especially noteworthy for its ability to preserve the α-labile C2 stereocenter of ketone (2S)-4. The new reductive amination method is general in nature and should find broad applicability.

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