Enantioselective Synthesis of cis-3-Fluoropiperidin-4-ol, a Building Block for Medicinal Chemistry

Abstract

The first enantioselective route to both enantiomers of cis-1-Boc-3-fluoropiperidin-4-ol, a highly prized building block for medicinal chemistry, is reported. An enantioselective fluorination is employed, taking advantage of the methodology reported by MacMillan, which uses a modified cinchona alkaloid catalyst. In studying the fluorination reaction, we have shown that the catalyst can be replaced by commercially available primary amines, including α-methylbenzylamine, with similar levels of enantioselectivity. The piperidinols are readily crystallized to obtain enantiopure material.

How Cinchona Alkaloid-Derived Primary Amines Control Asymmetric Electrophilic Fluorination of Cyclic Ketones

“…The fluorine transfer is predicted to be more difficult: the free energy of activation is 2.0 kcal/mol higher than in the case of TS-6a . This is qualitatively in line with the observation 7 that a pseudoenantiomer of IV gives poor conversion in the fluorination of the piperidinone ring.…”

New Advances in the Synthetic Application of Enantiomeric 1-Phenylethylamine (α-PEA): Privileged Chiral Inducer and Auxiliary

“…In the last decade, three organocatalytic reactions of this type have been reported. Specifically, the intramolecular tandem Michael-Henry reaction [80], α-fluorination of ketones [81], and Wittig rearrangement of ketones [82] were effectively carried out with α-PEA as an organocatalyst.…”

“…The piperidinols readily crystallized to the enantiopure material (Scheme 57). The products are important building blocks for the synthesis of pharmacologically active compounds [81]. The second example refers to the enantioselective synthesis of both enantiomers of cis-1-Boc-3-fluoropiperidin-4-ol by fluorination catalyzed through chiral primary amines.…”

“…The piperidinols readily crystallized to the enantiopure material (Scheme 57). The products are important building blocks for the synthesis of pharmacologically active compounds [81].…”

“…The piperidinols readily crystallized to the enantiopure material (Scheme 57). The products are important building blocks for the synthesis of pharmacologically active compounds [81]. The third case involves the organocatalytic effect of α-PEA in sigmatropic [2,3]-Wittig rearrangement of allyloxyketones described in 2019 by the Šebesta group.…”