Synthesis via Rearrangement Reactions

Certain substituted pyridines can be obtained via rearrangement of pyridine iV-oxides (Boekelheide reaction) or via rearrangement of an alternative heterocycle system, i.e., pyrrole (Ciamician—Dennstedt reaction). 

The Boekelheide reaction was applied by the Nicolaou groups in the synthesis of a model system of the thiopeptide antibiotic thiostrepton (302). The tetrahydroquinoline 303 was converted into the A -oxide by /w-CPBA oxidation followed by treatment with TFAA and then hydrolysis to afford key intermediate alcohol 304 as a diastereomeric mixture. 

A Fe(II)-binding agent pyrimidine 307 was synthesized starting from the bis-homophenylalanine 305 via the Boekelheide reaction with TFAA and hydrolysis to yield the advanced intermediate 306. 

Ticolubant (310) is a leukotriene receptor antagonist that exhibits anti-inflammatory activities. The Wittig reaction with 3-hydroxy-6-methylpicolinaldehyde followed by a Mitsunobu reaction with 2-phenylethanol gave phenyl ether 308. Oxidation with wCPBA converted the pyridine ring into the corresponding A-oxide, which then underwent the Boekelheide reaction with TFAA to afford the methyl alcohol 309. Reaction with thionyl chloride and then 2,5-dichlorothiophenol followed by saponification gave 310. °  

When the iV-alkoxypyridinyl compound is subjected to cyanide, it imdergoes the Reissert-Henze reaction to afford the 2-cyano-derivative with loss of the alkoxy group. Ethylation of W-oxide 311 with diethylsulfate afforded intermediate 312, which was treated with cyanide to afford the corresponding cyano-pyridine 313, an intermediate used in the synthesis of 5-adenosylmethionine decarboxylase inhibitor 314.  

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