A biocatalytic/reductive etherification approach to substituted piperidinyl ethers

Jeffrey T. Kuethe; Jacob M. Janey; Matthew Truppo; Juan Arredondo; Tao Li; Kelvin Yong; Shuwen He

doi:10.1016/j.tet.2014.04.064

A biocatalytic/reductive etherification approach to substituted piperidinyl ethers

Jeffrey T. Kuethe, Jacob M. Janey, Matthew Truppo, Juan Arredondo, Tao Li, Kelvin Yong, Shuwen He

Research output: Contribution to journal › Article › peer-review

Abstract

A synthetically useful protocol has been developed for the preparation of highly functionalized piperidinyl ethers. Biocatalytic reduction of cyclhexanones 7, 10, and 14 allows for the preparation of both cis- and trans diastereomers with an extremely high degree of stereochemical control. Reductive etherification of the corresponding trimethylsilylethers with 1-(benzyloxycarbonyl)-4-piperidinone 17 in the presence of triethylsilane and catalytic TMSO-Tf provides the desired piperidinyl ethers in good to excellent yields. Finally hygrogenolysis of the nitrogen protecting group leads to piperidinyl ethers in near quantitative yields. Application of the methodology to a range of piperidinyl ethers, including the core scaffolds of diphenylpyraline and ebastine, is also described.

Original language	American English
Pages (from-to)	4563-4570
Number of pages	8
Journal	Tetrahedron
Volume	70
Issue number	30
DOIs	https://doi.org/10.1016/j.tet.2014.04.064
State	Published - Jul 29 2014
Externally published	Yes

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

Keywords

Biocatalysis
Piperidinyl ether
Reductive etherification

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10.1016/j.tet.2014.04.064

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title = "A biocatalytic/reductive etherification approach to substituted piperidinyl ethers",

abstract = "A synthetically useful protocol has been developed for the preparation of highly functionalized piperidinyl ethers. Biocatalytic reduction of cyclhexanones 7, 10, and 14 allows for the preparation of both cis- and trans diastereomers with an extremely high degree of stereochemical control. Reductive etherification of the corresponding trimethylsilylethers with 1-(benzyloxycarbonyl)-4-piperidinone 17 in the presence of triethylsilane and catalytic TMSO-Tf provides the desired piperidinyl ethers in good to excellent yields. Finally hygrogenolysis of the nitrogen protecting group leads to piperidinyl ethers in near quantitative yields. Application of the methodology to a range of piperidinyl ethers, including the core scaffolds of diphenylpyraline and ebastine, is also described.",

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AU - Kuethe, Jeffrey T.

AU - Janey, Jacob M.

AU - Truppo, Matthew

AU - Arredondo, Juan

AU - Li, Tao

AU - Yong, Kelvin

AU - He, Shuwen

PY - 2014/7/29

Y1 - 2014/7/29

N2 - A synthetically useful protocol has been developed for the preparation of highly functionalized piperidinyl ethers. Biocatalytic reduction of cyclhexanones 7, 10, and 14 allows for the preparation of both cis- and trans diastereomers with an extremely high degree of stereochemical control. Reductive etherification of the corresponding trimethylsilylethers with 1-(benzyloxycarbonyl)-4-piperidinone 17 in the presence of triethylsilane and catalytic TMSO-Tf provides the desired piperidinyl ethers in good to excellent yields. Finally hygrogenolysis of the nitrogen protecting group leads to piperidinyl ethers in near quantitative yields. Application of the methodology to a range of piperidinyl ethers, including the core scaffolds of diphenylpyraline and ebastine, is also described.

AB - A synthetically useful protocol has been developed for the preparation of highly functionalized piperidinyl ethers. Biocatalytic reduction of cyclhexanones 7, 10, and 14 allows for the preparation of both cis- and trans diastereomers with an extremely high degree of stereochemical control. Reductive etherification of the corresponding trimethylsilylethers with 1-(benzyloxycarbonyl)-4-piperidinone 17 in the presence of triethylsilane and catalytic TMSO-Tf provides the desired piperidinyl ethers in good to excellent yields. Finally hygrogenolysis of the nitrogen protecting group leads to piperidinyl ethers in near quantitative yields. Application of the methodology to a range of piperidinyl ethers, including the core scaffolds of diphenylpyraline and ebastine, is also described.

KW - Biocatalysis

KW - Piperidinyl ether

KW - Reductive etherification

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A biocatalytic/reductive etherification approach to substituted piperidinyl ethers

Abstract

ASJC Scopus subject areas

Keywords

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