Phosphodiester Approach - The first significant success was achieved by this approach; Khorana and coworkers synthesized the gene for alanine (suppressor) tRNA of yeast in 1970, while Brown and coworkers synthesized the gene for tyrosine (suppressor) tRNA of E. coli.

This approach has now been almost completely replaced by the more convenient approaches since it presents a variety of solubility problems.