Macrocyclizations for Medicinal Chemistry: Synthesis of Druglike Macrocycles by High-Concentration Ullmann Coupling

Conditions have been identified for the efficient Ullmann macrocyclization of phenol and imidazole nucleophiles with aryl iodides at high reaction concentrations of up to 100 mM and using 5–10 mol % loading of an inexpensive copper catalyst. A range of substitution patterns and ring sizes are tolera...

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Bibliographic Details
Published in:Journal of organic chemistry 2012-12, Vol.77 (24), p.11079-11090
Main Authors: Collins, James C, Farley, Kathleen A, Limberakis, Chris, Liras, Spiros, Price, David, James, Keith
Format: Article
Language:English
Subjects:
Catalysis
Catalysts: preparations and properties
Chemistry
Chemistry Techniques, Synthetic
Chemistry, Pharmaceutical
Cyclization
Drug Design
Exact sciences and technology
General and physical chemistry
Heterocyclic compounds
Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings
Histidine - chemistry
Imidazoles - chemistry
Macrocyclic Compounds - chemical synthesis
Macrocyclic Compounds - chemistry
Noncondensed benzenic compounds
Organic chemistry
Phenols - chemistry
Preparations and properties
Theory of reactions, general kinetics. Catalysis. Nomenclature, chemical documentation, computer chemistry
Tyrosine - chemistry
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Summary:Conditions have been identified for the efficient Ullmann macrocyclization of phenol and imidazole nucleophiles with aryl iodides at high reaction concentrations of up to 100 mM and using 5–10 mol % loading of an inexpensive copper catalyst. A range of substitution patterns and ring sizes are tolerated, and the method has been exemplified by the synthesis of a set of druglike macrocycles.
ISSN:0022-3263
1520-6904
DOI:10.1021/jo302089f