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Kim YR, Hall DG. Optimization and multigram scalability of a catalytic enantioselective borylative migration for the synthesis of functionalized chiral piperidines. Org Biomol Chem. 2016;14(20):4739-48doi: 10.1039/c6ob00685j.
Kim, Y. R., & Hall, D. G. (2016). Optimization and multigram scalability of a catalytic enantioselective borylative migration for the synthesis of functionalized chiral piperidines. Organic & biomolecular chemistry, 14(20), 4739-48. https://doi.org/10.1039/c6ob00685j
Kim, You-Ri, and Hall, Dennis G. "Optimization and multigram scalability of a catalytic enantioselective borylative migration for the synthesis of functionalized chiral piperidines." Organic & biomolecular chemistry vol. 14,20 (2016): 4739-48. doi: https://doi.org/10.1039/c6ob00685j
Kim YR, Hall DG. Optimization and multigram scalability of a catalytic enantioselective borylative migration for the synthesis of functionalized chiral piperidines. Org Biomol Chem. 2016 May 18;14(20):4739-48. doi: 10.1039/c6ob00685j. PMID: 27143333.
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Org Biomol Chem. 2016 May 18;14(20):4739-48. doi: 10.1039/c6ob00685j.

Optimization and multigram scalability of a catalytic enantioselective borylative migration for the synthesis of functionalized chiral piperidines.

Organic & biomolecular chemistry

You-Ri Kim, Dennis G Hall

Affiliations

  1. Department of Chemistry, 4-010 Centennial Centre for Interdisciplinary Science, University of Alberta, Edmonton, Alberta, CanadaT6G 2G2. [email protected].

PMID: 27143333 DOI: 10.1039/c6ob00685j

Abstract

The development of new, efficient and economical methods for the preparation of functionalized, optically enriched piperidines is important in the field of drug discovery where this class of heterocycles is often deemed a privileged structure. We have optimized a Pd-catalyzed enantioselective borylative migration of an alkenyl nonaflate derivative of the simple precursor, N-Boc-4-piperidone. This anomalous borylation reaction lends access to a chiral optically enriched piperidinyl allylic boronate that can be employed in carbonyl allylboration and stereoselective cross-coupling to produce substituted dehydropiperidines related to numerous pharmaceutical agents. A systematic fine-tuning of reaction conditions revealed that diethyl ether and the green solvent cyclopentyl methyl ether are suitable reaction solvents providing the highest enantioselectivity (up to 92% ee) under a low catalyst loading of 3 mol%. Optimization of the aldehyde allylboration step led to higher yields with further solvent economy. The multigram-scalability of the entire process was demonstrated under the reaction conditions that provide optimal atom-economy and efficiency.

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