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Updated: Sep 13, 2025
![Solid-phase Synthesis of [4.4] Spirocyclic Oximes](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F58508.jpg&w=3840&q=50)
Solid-phase Synthesis of [4.4] Spirocyclic Oximes
Published on: February 6, 2019
A Modular Approach to Trisubstituted Chiral Piperidines
Hojoon Park1, Kara Greene1, Samantha A Burgess2
1Department of Process Research and Development, Merck & Co., Inc., Boston, Massachusetts 02115, United States.
Abstract:
We report a modular strategy for the synthesis of trisubstituted chiral piperidines. First, a scalable, chiral-pool synthesis of an orthogonally protected piperidine tricarboxylic acid diester was developed. This synthesis involves a formal 4 + 2 cyclization between choro-homoserine and acetylene dicarboxylate, followed by a diastereoselective reduction, cyclic anhydride formation, and regioselective ring-opening process to give the final product as a single enantio- and diastereomer at >50 g scale. Next, we demonstrated that the piperidine tricarboxylate intermediate can undergo sequential decarboxylative functionalizations using modern transition metal-catalyzed or photocatalytic methodologies. As the result, highly elaborated chiral piperidines and pipecolic esters were prepared in a chemo- and stereoselective manner.
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