Rational Catalyst Design for an Optimized Aza-Michael Addition

Significance

3,3-Difluoropiperidines feature as prominent motifs in drug discovery programs with the most common method to access such compounds being the deoxyfluorination of the corresponding 3-piperidinones using DAST or similar reagents. While effective, these reagents present challenges with regard to toxicity and safety, particularly when used on scale. The current report describes the development of a gram-scale synthesis of a 3,3-difluorinated pyrazolo-piperidine (GSK3901383A, an intermediate required for the preparation of LRRK2 inhibitors) by exploiting an enantioselective, organolcatalytic aza-Michael addition of 4-nitro-pyrazole to ethyl (E)-2,2-difluoro-5-oxopent-3-enoate as the key step.

Comment

High-throughput experimentation was initially employed to examine the key proposed aza-Michael addition with 14 organocatalysts, 3 solvents and 7 acid additives evaluated in a matrix, with a control reaction demonstrating that no product was observed in the absence of an organocatalyst. The observed impact of the steric bulk of substituents, on both the aromatic and the silyl groups of the catalyst, led to a stereoselectivity model for the reaction being developed, enabling the rational design of a new organocatalyst for the process. Synthesis of the desired piperidine was completed by reductive amination under standard conditions followed by reduction of the intermediate lactam using NaBH₄ followed by treatment with formic acid.

Publication History

Article published online:
20 December 2024

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