Hilbert-Johnson reaction

What is Hilbert-Johnson reaction?

In 1929, Johnson and Hilbert reported a reaction that has come to be known as the Hilbert-Johnson reaction. This reaction involves the synthesis of pyrimidine nucleosides through the glycosylation of protected glycosyl halides with 2,4-dialkoxypyrimidines. Variations of this reaction have been given different names, such as the Hilbert-Johnson synthesis or the Hilbert-Johnson pyrimidine nucleoside synthesis.

Hilbert-Johnson reaction - general reaction scheme - Hilbert-Johnson synthesis - Hilbert-Johnson pyrimidine nucleoside synthesis
Hilbert-Johnson reaction

A more versatile and successful reaction for the preparation of pyrimidine nucleosides is the Lewis acid-promoted glycosylation using labile trimethylsilyl-protected pyrimidine and glycosyl acetate, which is referred to as the silyl-Hilbert-Johnson reaction. This reaction has been used to synthesize a variety of 2-oxo-pyridimine nucleosides, including uracil, cytosine, and thymine nucleosides.

Silyl Hilbert-Johnson reaction - Hilbert-Johnson reaction - general reaction scheme
Silyl Hilbert-Johnson reaction

The reaction with 2-methylthio protected pyrimidine stops at the quaternization step, producing an intermediate of glycosylpyrimidinium salt that can be converted into 2-oxo, 2-thio, and 2-aminopyrimidine nucleosides with high efficiency and regioselectivity. The β-anomer predominates in the products, regardless of whether they are condensed from α-glycosyl halide or β-glycosyl halide, except for the case of condensation with 3,5-di-O-p-toluyl-2-deoxy-D-ribofuranosyl chloride into 2-deoxyribofuranosylpyrimidines, which resulted in 66% of α-anomeric product.

The Hilbert-Johnson reaction has been used to synthesize a variety of 2-oxo-pyridimine nucleosides, including uracil, cytosine, and thymine nucleosides, as well as non-aromatic aglycons like 6-oxadihydrouracil. Suitably blocked pyranose derivatives can also undergo glycosylation, but under more stringent conditions and at slower rates than their corresponding furanose isomers. The protection by acetyl rather than benzoyl group leads to an improved yield.

Additionally, the reaction in nitrobenzene is significantly faster than in acetonitrile, which is the typical solvent used for this reaction. The Hilbert-Johnson reaction has also been extended to the preparation of purine nucleosides.

References

Shares