gem‐Difluoro‐3‐azabicycloalkanes and Their Derivatives – Bicyclic Fluorinated Piperidine Isosteres for Drug Discovery

An approach to gem‐difluoro‐3‐azabicyclo[3.n.1]alkane‐ derived building blocks through double‐Mannich addition– deoxofluorination sequence is described. The scope of the method was demonstrated for a series of saturated (hetero)cyclic ketones or ketoesters (including five‐ to seven‐membered cycloalk...

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Bibliographic Details
Published in:European journal of organic chemistry 2024-01, Vol.27 (2)
Main Authors: Kihakh, Serhii, Melnykov, Kostiantyn P, Bilenko, Vitalii, Trofymchuk, Serhii, Liashuk, Oleksandr S, Grygorenko, Oleksandr O
Format: Article
Language:English
Subjects:
Alkanes
Diamines
Functional groups
Ketones
Piperidine
Online Access:Get full text
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Summary:An approach to gem‐difluoro‐3‐azabicyclo[3.n.1]alkane‐ derived building blocks through double‐Mannich addition– deoxofluorination sequence is described. The scope of the method was demonstrated for a series of saturated (hetero)cyclic ketones or ketoesters (including five‐ to seven‐membered cycloalkane derivatives and N‐, O‐, S‐containing saturated heterocycles). Further transformations of functional groups produced various bifunctionalized difluorinated building blocks, namely, N‐protected aminoacids, mono‐N‐Boc‐protected diamines, and unprotected aminoalcohols in good to excellent overall yields. For the azabicyclo[3.3.1]alkane series, a potential for isosteric replacements is demonstrated by evaluation of the key physicochemical properties (i. e., pKa(H) and LogP).Dedicated to the people of Ukraine
ISSN:1434-193X
1099-0690
DOI:10.1002/ejoc.202300937