Switching the Stereochemical Outcome of 6-Endo-Trig Cyclizations; Synthesis of 2,6-Cis-6-Substituted 4‑Oxopipecolic Acids

A base-mediated 6-endo-trig cyclization of readily accessible enone-derived α-amino acids has been developed for the direct synthesis of novel 2,6-cis-6-substituted-4-oxo-l-pipecolic acids. A range of aliphatic and aryl side chains were tolerated by this mild procedure to give the target compounds i...

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Bibliographic Details
Published in:Journal of organic chemistry 2012-11, Vol.77 (22), p.10001-10009
Main Authors: Daly, Mark, Cant, Alastair A, Fowler, Lindsay S, Simpson, Graham L, Senn, Hans Martin, Sutherland, Andrew
Format: Article
Language:English
Subjects:
Aliphatic compounds
Chemistry
Cyclization
Exact sciences and technology
Heterocyclic compounds
Heterocyclic compounds with only one n hetero atom and condensed derivatives
Molecular Structure
Organic chemistry
Pipecolic Acids - chemical synthesis
Pipecolic Acids - chemistry
Preparations and properties
Stereoisomerism
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Summary:A base-mediated 6-endo-trig cyclization of readily accessible enone-derived α-amino acids has been developed for the direct synthesis of novel 2,6-cis-6-substituted-4-oxo-l-pipecolic acids. A range of aliphatic and aryl side chains were tolerated by this mild procedure to give the target compounds in good overall yields. Molecular modeling of the 6-endo-trig cyclization allowed some insight as to how these compounds were formed, with the enolate intermediate generated via an equilibrium process, followed by irreversible tautomerization/neutralization providing the driving force for product formation. Stereoselective reduction and deprotection of the resulting 2,6-cis-6-substituted 4-oxo-l-pipecolic acids to the corresponding 4-hydroxy-l-pipecolic acids was also performed.
ISSN:0022-3263
1520-6904
DOI:10.1021/jo3022583