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Updated: Oct 2, 2026
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Solid-phase Synthesis of [4.4] Spirocyclic Oximes
Published on: February 6, 2019
Stereocontrolled preparation of a nonpeptidal (-)-spirobicyclic NK-1 receptor antagonist
Peter E Maligres1, Marjorie M Waters, Jaemoon Lee
1Department of Process Research, Merck Sharp & Dohme Research Laboratories, Merck & Co., Inc., Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU, UK. peter_maligres@merck.com
Abstract:
The synthesis of a spirobicyclic NK-1 receptor (Substance-P) antagonist 1 antipode is described. Retrosynthetic analysis reveals an allylic halide A bearing the cyclopropoxy-substituted aryl group and a 2-phenyl-3-piperidone B. The stereochemistry in the spirobicyclic system bearing three chiral centers is initially set via a highly diastereoselective zinc-mediated coupling of the allylic bromide 23 to the optically active ketopiperidine 3. The remaining benzylic asymmetric center is set by a diastereoselective hydroboration followed by cyclization to the spirobicyclic system.
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