A more general method for the synthesis of nucleosides is called Hilbert-Johnson
Nucleosidation1. Instead of the heavy metal salts the O-alkylated bases were be used2. In
these species the nucleophilicity of the lone pairs is exploited for the reaction (Fig
2.5.11).
Fig 2.5.11 Hilbert-Johnson nucleosidation..
The more nucleophilic nitrogen attacks the C1’ center leading to a quaternary ammonium
salt. This is then cleaved by the bromide nucleophile, which attacks the ether carbon
leading to elimination of ethyl bromide. The remaining imidol ether group could now be
cleaved either by ammonia ( to give an amine product) or water (to give an amide) (Fig
2.5.12).
1
T.B. Johnson, G. E. Hilbert, Science 69, 579 (1929)
G. E. Hilbert, T. B. Johnson, J. Am. Chem. soc. 52, 2001, 4489 (1930).
Advances in Heterocyclic Chemistry 8, 115-142 (1967)
2
These are alkylated derivatives of the metal salts used above. An ambident anion is thus avoided.
Fig 2.5.12 Hilbert Johnson nucleosidation leading to different nucleobases.
Wittenburg reported a mild two-step method for the synthesis of nucleosides in 19643. In
presence of a Lewis acid, this reaction proceeds stereoselectively in good yields (Fig
2.5.13). This procedure has several advantages. The silyl derivatives of bases are easily
synthesised in good yields. In the final hydrolysis step, the procedure offers a simple
cleavage of silyl ether group by aqueous ethanol, which symplifies the process
3
Wittenburg, E. A new synthesis of nucleosides. Z. Chem. 1964, 4, 303-304.